How to scren adolescent girls for PCO & how to curtail the future metabolic burden

Screening of PCO in adolescent girls:: Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynaecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

   

BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 Diag dilemma on diagnosing adolescent PCOS still exists:-However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

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BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

?

Adolescent PCOS :Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

 Screening of PCO in adolescent girls:: Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynaecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

   

BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 Diag dilemma on diagnosing adolescent PCOS still exists:-However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

?

Adolescent PCOS :Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

 With references; Not for Publications but Stock.

Screening of PCO in adolescent girls:: Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynaecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

   

BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 Diag dilemma on diagnosing adolescent PCOS still exists:-However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

? Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

.

BOOK No. -1

Investigation of Female subfertility, CC cycles, Basics of male infertility.

Azoo-266, AFC-24; 7, 37: AMH-349.Anta-151/206, 310, Aged Couple-111.	CM of Ut-149.
Anovulation causes-p.23/107: AGONIST-200/205: Adjuncts-153/162; Agent selection-25.	CC: - Adding E2-89/229/256/228/99. How to avoid multiple preg  and OHSS (201).				Ovum Nutrients-153/257/ OHSS:- 192.		Mae Antioxidanrs-261-265/269.
Androgens-237. Basal Scan-23;	Chr. Low dose--119/ 174/ 180.				Ov Reserve-24/25/111 ::POF-339/343.		Myoma-140
Bormo-132,235,	Other protocol-167/ 168.				NAC-259/254.		MI-157/253.
Basal Evaluation-p41			Growth factors-331		What Protocol-143/151.Drug Selection-142/ 42.		NAC:-254.
BMI-361. ; Monitoring-80/91,	Ovulation Induction:-151/168.		Gonadotrophins-302/88/166.Hirsuitism-312.IUI-280, IVF-57.		PCOS-162/250/274,PRL:-128
CC-152: resistance-: 161, failure: 160: Causes of F subfertility-22; Cabergolin-133; Coastig-191, Cx Score-97, Cx Factos-248;CAH-258.	CC: day-of initiation-40/38/152,Contra-86,Monitor first cycle-82.84,160, Trigger-p,202, 137;Extended-54 CC & HMG-231/220/ Adding small LH:-238.		Hormones-Normal-5, 342/36/92/108, Investigations: 36/46/107/146. IR-157. Basal FSH-41/244: LH-45, BMI-361 Progesterone-230.CAH-258; Cortisol-318; Insulin-237: Thyroid-229.LH-89./344.		“Pretreatments” Dexa (53/ 236.); OCP-   (234, 53/153.) Agonists (205); Metformin   (218/357): Bomo-132/235.: Vitamin D (  ). ASA(236/ ): Growth hormone-235
Evaluation cycle-Normal-21;88,			Obesity-319.		Thin ET-98/99/ 100/14/147. Menopause-324,;
Growth of normal follicles-p. 17.		Endometriosis-1142, Ectopic-145,		Kochs-p.13. Luteal Support-Progesterone-307,230.=48/53/43/90.LH-88. LUF: 89		SERM-31.Tamoxifene-55/ 164/321/31. .Trigger-191.		Unexplained:-286.
Follicular cysts-p86.		Tests for FGR-340:: PCOS-339.RPL: 146.

JIMA.

Adolescent Polycystic Ovary Syndrome-An Enigma for Family Physicians.”

ABSTRACT:  (The prevalence and phenotypic presentations of adolescent girls suffering from Polycystic Ovary Syndrome (PCOS) have eluded many family physicians who are the key persons for maintaining health of our citizen. Ethnicity has a substantial impact on clinical expression and progression of this syndrome and therefore the symptoms and signs of PCOS diverge from country to country. This apparently benign syndrome mostly beginning soon after menarche has been aptly attributed as a forerunner of reproductive menace and metabolic malady appearing in third or fourth decade of life. On realizing this, endocrinologists are trying to devise ways and means to develop  diagnostic criteria not only for adolescents who are already suffering from established PCOS but devising screening  tests to identify adolescents who are prone to develop PCOS so that early measures can be initiated   in susceptible cases. Unfortunately the symptoms of PCOS in adolescent age group are varied and complex therefore demands much knowledge and skill both for correct diagnosis and management. The possibility of overdiagonosing and under diagnosing of this common syndrome still prevails as there are no unanimous set diagnostic criteria for adolescent PCOS by any internati What is already known about adolescent Polycystic Ovary Syndrome?

Hyperandrogenic ovulatory dysfunction commonly called as Polycystic Ovary Syndrome or simply PCOS is the most common reason for which an adolescent girl is referred to sonology unit of a radiology department. Quite often such girls are referred by a gynecologist colleague with the solo complaint of oligomenorrhea and on further appraisal some of them show symptoms and signs of hyperandrogenism e.g. acne, hyperseborrhoea, male-pattern hair growth and alopecia. Few such teenagers also exhibit central obesity (high waist circumference) but it is uncommon to come across such young girls with other evidences of metabolic syndrome e.g. hypertension, dyslipidemia and overt insulin resistance (IR though there is no unanimously accepted definition of the metabolic syndrome (MetS) in children and adolescents^2,3 .Hyperinsulinaemia and associated metabolic defects may even predate the PCOS since it is most likely that the syndrome is genetic in nature⁴and many scientists now believe that adolescent PCOS is primary an adrenal hyperandrogenism rather than ovarian disease⁵

What is not known about adolescent PCOS? What are the grey areas in the syndrome of adolescent PCOS?   

The ever growing knowledge on different aspects of adult PCOS has perplexed many clinicians how best to suspect or diagnose the PCOS at an early stage of life but sadly there is as yet no well-defined, uniform set criteria for diagnosis of PCOS in adolescence and the various definitions used today are outcomes of consensus statements, namely the majority opinion, and not the robust and solid findings of clinical trial evidence. Whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided ⁶ and  which of the usual four symptoms and signs (menstrual disorders, obesity,  androgen excess and altered ovarian morphology in sonography) is more relevant in the causation of cardiometabolic risks in later life is still unanswered. Likewise, there is no universally accepted set laboratory workup for this syndrome not to speak of a single test. Most importantly, though this syndrome is considered as an androgen excess disorder there is no universally accepted cut off value of for androgens for this syndrome. This has surprised the present author! Further, to what extent   adolescent PCOS  suffering from  one phenotype change to another as one  grow up and how does this transition affect their long-lasting health status has not been evaluated in any country  neither the magnitude of the societal obstacles in screening all adolescents for PCOS and cost of such screening has been assessed.

While acknowledging all these knowledge gaps, this review will critically analyze the opinions expressed by different international organizations and experts in this field so as to define which teenagers should be leveled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.    The author also likes to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out  ^8,9,    8)Duijkers IJ, Klipping C. - Polycystic Ovaries as defined by the 2003 Rotterdam consensus criteria are found to be very common in young healthy women.  Gynaecol Endocinol 2010; 26:152-160.

  9)  Jhonstone EB,RosenMP,Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-Andersen C, McConnell D, Pera RR , Cedars MI.  The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab 2010; 95:4965-4972

 Transient but exaggagerated functional hyperandrogenism of adolescence.  The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called mini-PCOS or nascent PCOS.

Scientists now believe that most, but not all healthy adolescents reveal demonstrable hyperandrogeniaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group, ^{6, 10},   Cortet-Rudelli C, Dewailly D. Hyperandrogenism in adolescent girls. In Sultan C(ed) Paediatric and Adolescent Gynaecology, Evidence-Based Clinical Practice. Endocrine Dev. Basel, Karger, 2004, vol 7, pp148-62.

 Supraphysiological production of androgens or exaggerated response of androgen sensitive tissues is now proposed as the core defect of PCOS and augmented androgen levels is primarily produced in ovaries due to altered  sensitivity of ovaries to amplified LH secretion as observed in this age group5( Roe, AH, Dokras A-The Diagnosis of polycystic Ovary Syndrome in Adolescents.5^. The dynamics of acquisition of maturity of hypothalamo-pituitary axis and quantum of response of ovaries to amplified LH pulse frequency show an incongruity in different girls leading to overproduction of androgens in some girls. This action of LH may be potentiated by associated hyperinsulinaemia and diminution of insulin like growth factor binding protein -1(IGFBP-1) in few cases ^10,11 Ibanez L, Potau N, Carrascosa A: Possible genesis of polycystic ovary syndrome in periadolescent girl. Curr. Opin Endocrinol Diab. 1998, 5:19-25.

 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237-4245.) Azziz R, Carmina E, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF-Criteria for defining Polycystic ovary Syndrome as a predominantly Hyperandrogenic Syndrome: An Androgen Excess Society Guideline” J Clinical Endocrinol Metab 2006;91:4237-4245.)

Researchers have also noticed that are is a subset of otherwise normal adolescents who  demonstrate physiological hyperinsulinaemia  initially unaccompanied by hyperandrogeniaemia  and such changes are believed to be due to altered growth hormone/ IGF1 axis, whose hyperactivity induces a selective insulin resistance Hannon TS, Jannosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Paediatr res .2006; 60:759-63-ref CR Dokras 10     Primary supraphysiological hyperinsulinaemia in turn is responsible for the increase in insulin plasma level and decrease in SHBG and IGFBP-1 hepatic production. Afterwards hyperinsulinaemia lead to hyperandrogeniaemia. It is also believed that ethnic differences play a major role in the clinical expression of features of hyperinsulinaemia¹².

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms.

Whether the pathogenesis is initiated by hyperandrogeniaemia or hyperinsulinaemia is still controversial but the clinical expressions of such changes were earlier used to be designated as nascent PCOS, hyperpubertal state or physiological mini-PCOS^13,14.  According to present author such a term or clinical note in the case sheet is appropriate as such a note will remind the treating physician to follow her up more scrupulously at a subsequent date. As stated earlier in some girls with such exaggerated physiological changes will not reverse with passage of time. (CR Rudely no 13,Nobles F, Dewailly D. Puberty and polycystic ovary syndrome: The insulin/insulin like growth factor1 hypothesis. Fertil Steril 1992; 58:655-66. which author feels is quite appropriate  12 (Venturoli S, Poreu E, Fabbri R, Magrini O, Paradrisi R, Pallotti G, Gammi I, Flamigni C. Postmenarcheal evolution of endocrine pattern and ovarian aspects in  adolescents with menstrual irregularities. Fertil Steril 1987; 48:78-85).  Fortunately in most girls clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia will normalize with passage of time but   it is difficult to distinguish biologically and ultrasonically those adolescent at the age group 12-17 years where such normal evolutionary changes will persist and aggravate giving rise to full- fledged PCOS. The author feels the task of researchers now bestow to find out some biological markers to identify such at- risk cases who are destined to develop from mini PCOS to full-fledged PCOS ¹⁴

What are the reasons for medical attention? What are, then the common symptoms of adolescent PCOS?

The phenotypic expression of this syndrome is heterogeneous but in most cases this syndrome commences with ordinary normal pubertal symptom like oligomenorrhea, obesity, persistent acne, hyperseborrhoea and occasionally with hirsutism. Rarely there may be only one finding like central adiposity, acanthosis nigricans, alopecia or even secondary amenorrhoea ¹⁵. The symptoms quoted above are often common accompaniment of normal adolescence and such trivial symptoms are becoming more common as nutritional status of our adolescents is improving in our country too¹⁶.Karla P,   Bansal B, Nag P, Singh JK, Gupta RK, Kumar S et al . Abdominal fat distribution and insulin resistance in Indian women with polycystic ovary syndrome. Steril 2009; 91:1437-40

.

Is it possible to predict occurrence of full-blown PCOS in early adolescence?

The problem is that the transition from normal pubertal changes to normal healthy adult or to a full-blown PCOS is an illdefined and slow process .Though in majority adolescents such trivial symptoms disappear within 1-2 years but in some symptoms will worsen giving rise to full- blown PCOS. It is difficult for clinicians to forecast which girls are going to finally develop PCOS by couple of years and also difficult to predict the magnitude of ill effects through associated hyperinsulinaemia and or hyperandrogeniaemia. Many scientists however believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS¹⁷.

 Criteria of adult PCOS are well defined but what are the diagnostic criteria of adolescent PCOS?

The etiology of otherwise normal metabolic-hormonal complexity of adolescent girls is partly understood. But why in some girls such physiological abnormality persists giving rise to full- blown PCOS is not known. As stated, till date there is no international consensus on definition of adolescent PCOS! Even there is lack of unanimously agreed standard screening protocol and tests to confirm PCOS in adolescent girls. Put in such a situation many clinicians wrongly apply diagnostic criteria designed for adult women to adolescent girls.  Adopting such a policy, author is afraid, that many otherwise healthy adolescent girls are being and will continue to be falsely leveled as PCOS.

 However on realizing this some experts and international academic bodies recently have come forward to settle the issue of diagnostic criteria of adolescent PCOS. For instance Prof. Dr. Charles Sultan of Montpellier¹⁸, France, who by profession is a pediatric endocrinologist and his colleague, suggested that to qualify for adolescent PCOS there should be presence of at least four of the following five criteria. These are 1) clinical hyperandrogenism 2) biological hyperandrogenemia, 2) insulin resistance and hyperinsulinaemia, 4) oligomenorrhea persisting for 2 years postmenarche and 5) polycystic ovaries on ultrasound. If we accept the definition proposed above then it is understandable that one has to rely heavily on estimation of different hormones to substantiate the diagnosis of adolescent PCOS which is not a very common practice in our country. Instead, till date more reliance is usually paid on sonography in diagnosing PCOS both in adolescent and adult population.

 Another group of investigators, Carmina et al ¹⁷ have defined adolescent PCOS in some other way. They are of opinion that any adolescent having all the three and not just two features of Rotterdam Criteria (2003) should be primarily leveled as adolescent PCO and thereafter followed up regularly.  Lifestyle modifications and dietary alterations should be instituted immediately because there is a growing bodies of evidence that metabolic syndrome which commonly associated with these conditions can be reversed. de Ferranti SD. Recovery from metabolic syndrome is both possible and beneficial .Clin Chem, 2010, 56(7)1053-55 ^19.

 Carmina et al¹⁷ have also proposed following classifications of PCOS in adolescents e.g. a) Diagnosis of PCOS is certain if all three criteria are fulfilled b) Diagnosis of PCOS is probable but not certain if there is hyperandrogenism and oligomenorrhoea unassociated with polycystic ovaries. c) They have also admitted there is a subset of teenagers in whom diagnosis of PCOS is not possible during adolescence if there is combination of features of hyperandrogenism and polycystic ovaries (unassociated with oligomenorrhoea) or oligomenorrhoea with polycystic ovaries unaccompanied by hyperandrogenism. Carmina et al have also warned that presence of any of three features appearing in isolation should not at all be considered as PCOS¹².

 Roe and Dokras⁵, however, recently (2011) framed still another guideline for diagnosing PCOS during adolescence. They have proposed that during adolescence, a positive diagnosis of PCOS should require all elements of the Rotterdam consensus meant for adult women and not just two out of three. Additionally they have also insisted on laboratory documentation of hyperandrogenemia i.e. elevated blood androgens as observed by using sensitive assay i.e. liquid chromatography with tandem mass spectrometry which they considered as a must for accurate diagnosis of hyperandrogenaemia.²⁰ () Rosner W, Auchus RJ ,Aziz R, Sluss PM, Raff H- Utility ,limitations, and pitfalls in measuring testosterone : An Endocrine Society position statement . J Clin Endocrinol Metab 2007; 92:405-413.

?

Adolescent PCOS :Where do we stand now?

The Third Consensus Workshop Group on Women’s Health aspects of polycystic ovary syndrome (PCOS) organized by ESHRE/ASRM in the year 2010 at Amsterdam²¹, though very rightly devoted one session on adolescent PCOS but disappointingly abortive to formulate any definite criteria for diagnosing or screening for adolescent PCOS!  . Similarly, the Board of Directors of one new society (Androgen Excess and PCOS society formed in 2000) failed to outline any ideal criteria of the above syndrome²². They however evaluated all girls and women suffering from androgen excess of any etiology. Surprisingly some members of the society were of opinion that there may be forms of PCOS without overt evidence of hyperandrogenism as well. They have documented as many as nine phenotypes of PCOS and according to present author the society has performed an admirable job by stratifying the probability of risk of metabolic malady according to each phenotype.

 At what age we should level an adolescent girl as PCOS? 

Diagnosing this disorder before or soon after onset of menarche is difficult because   girls with PCOS generally seek medical help   only when they suffer from irregular menses or skin changes for long time. This usually takes couple of years after the onset of menarche. To begin with PCOS may masquerade as simple obesity or idiopathic hirsutism and in most cases such symptoms disappear with time. Therefore very logically   Carmina et al (2010)⁷ have suggested avoiding making the diagnosis of PCOS until the age of 18 years. Unfortunately, this has made a sense of reluctance among many gynecologists to investigate an adolescent girl with persistent oligomenorrhoea at an early age of 15-17 years.

Are there any premonitory signs before the onset of full blown symptoms of PCOS? Can we identify children at risk of developing PCOS?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years²³. (Franks S. Adult polycystic ovary syndromes begin in childhood. Best Pract Res Clin Endocrinol Metab 2002; 16:263-72).   Occasionally PCOS may emerge as premature pubarche or premature adrenarche (PA), a condition secondary to early maturation of zona reticularis of the adrenal gland which leads to premature androgen secretion and appearance of pubic hairs before the age of eight years of age²⁴. Ibanez L, Potau N, de Zegher F: Precocious pubarche, dyslipidaemia and low IGF binding protein -1 in girls: Relation to reduced prenatal growth. Paediatr. Res, 1999; 46:320-2)Ref article 2,        Premature adrenarche, a mild form of adrenal hyperandrogenism, potentially poses increased risk for the development of PCOS, particularly in obese girls ²⁵( Ref;Ibanez L, Virdis R, Potau

 N . Natural history of premature puberache: An auxological study. J. Clin Endocrinol. Metab 1992;74:254-7 .But it is now known that before the classical well recognized symptoms of PCOS appear there can be some laboratory evidences which may exist well before the full- blown disease²⁶,. Turhan NO, Toppare MF, Seckin NC, Dilmen G: ‘The Predictive Power of Endocrine Tests for the Diagnosis of Polycystic Ovaries in Women with Oligomenorrhoea’ Gynaecol Obstet Invest 1999;48:183-186.-)   

Depending upon the phenotypic presentation destined for the concerned adolescent it is theorized that early symptom of PCOS may vary, perplexing the family physicians.

There are several phenotypes of adolescent PCOS the role of genetic versus environmental factors in the causation of each phenotype has long been debated. It is now believed that quality of diet, exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible to move from a phenotype to another as women ages.

Are we under-diagnosing or missing the diagnosis in some adolescent PCOS? Early and especially very early clinical features of PCOS are often ignored.

Though PCOS is a common disorder but the diagnosis is often overlooked during adolescence, as irregular menses with anovulatory cycles, obesity and acne are quite frequent in perfectly healthy adolescent girls. It is equally true that many adolescents’ even adult women suffer from oligomenorrhea but do not consult a physician and they take it granted that oligomenorrhoea is her usual menstrual pattern. Therefore the possibility of PCOS is not taken into account in differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for subfertility.

Parents are more worried about the symptom of oligomenorrhoea rather than obesity.

Increased body mass index and visceral obesity are associated with greater prevalence of IR as compared to general population though there are no long term studies on adolescent girls suffering from PCOS regarding the probability of developing cardiometabolic risks in later life. Author has noticed that most adolescents who are referred to sonology unit for ovarian morphology evaluation suffer from oligomenorrhoeaadolescents girls suffering from oligomenorrhoea are more often taken to a medical practitioner. By contrast girls suffering from overweight or frank obesity are seldom taken to a doctor by their parents not to speak of an endocrinologist or metabolic physician. This is because parents often correlate future fertility potential of their daughter more often with the symptom of oligomenorrhoea rather than body weight. Metabolic physicians however are of opinion that persistence of menstrual irregularity (oligomenorrhea) is more correlated with BMI rather than increased androgens, polycystic ovaries in ultrasound or increased serum LH level²⁷ (Van Hooff MH, Voorhorst FJ, KB, Hirasing RA, Koppenaal C, Schoemaker J. 1K-7) T. Predictive value of menstrual cycle pattern, body mass index, hormonal levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod.2004; 19:383-92

All such four factors can independently initiate oligomenorrhoea. In multivariate analysis only a normal to high BMI (>19.6 kg/m2) consistently contributed significantly to predict persistent oligomenorrhoea. Obesity potentially predisposes to the development of PCOS by causing premenarcheal LH excess that is mediated by peripubertal hyperandrogenemia ²⁸[11–13] Rosenfield RL,( Email- robros@peds.bsd.uchicago.edu regarding ‘ LH dynamics in Overweight

 _{Obesity seems to amplify the degree of t}

 As a result they experience considerable financial and emotional hardships in the later years that could have been avoided if PCOS had been detected at an early age. To make the matter worse the chronology of appearance of early symptoms varies largely depending upon the ethnicity and degree of expression of gene.

As of now, are we overdiagonosing   adolescent   PCOS?  Application of criteria of adult PCOS may erroneously include some perfectly normal adolescent girls as PCOS.

There is great variability in normal pubertal changes of healthy girls as well as who are destined to develop PCOS. This has eluded the parents and led much confusion amongst gynecologists, endocrinologists and family physician in particular. Prematurely assigning a diagnostic label of PCOS to an otherwise healthy adolescent may lead to incorrect diagnosis, may impose psychological distress and possibly inappropriate medication.   But the fact remains that the definitions proposed by Sultan 12and Carmina for adolescents PCOS are stricter than their adult counterparts, and if such criteria are implemented in routine practice used then this will limit inappropriate early diagnosis.

Can physicians convince parents for agreeing to bear expenses for screening tests of their daughters when the mother of the daughter had PCOS?

The present author firmly believes that expenses borne in this screening programme are cost effective in the long run⁶(.5 Livadas S, Diamanti-Kandaraki E-Polycystic Ovary Syndrome: Definitions, Phenotypes and Diagnostic Approach. In :Macut D, Pfeier M, Yildiz BO, Evanthia, Diamanti-Kandaraki(eds), Polycystic ovary syndrome –Novel Insights into Causes and therapy”,1^st. ed. ,New Delhi, Karger ,2013 ,13.)But it is a hard task on the part of Indian family physicians to convince the parents about benefits of screening of such girls particularly when their daughter is still asymptomatic. In this context author may also mention that routine screening for glucose intolerance and dyslipidemia in adolescents whose parent is diabetic is not the practice. Similarly, as of now, routine screening of all adolescents for PCOS is not recommended by any national organization in otherwise asymptomatic Indian adolescents neither  there is any Government policy to make this in effect though the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reducing  cardio vascular risks is significant. This however remains a challenge to policy makers.

    Lessons learnt and task ahead. Metabolic syndrome is rampant in our vast country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

According to one recent community based study in Sri Lanka the incidence of adolescent PCOS based solely on history and clinical examination by health workers was 7.5%³¹. If clinical abnormalities of PCOS were evident in the field study then such adolescents were   initially   labeled as ‘probable case of PCOS’ and those clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of PCOS.

The growing habit of consumption of heat-treated foods amongst urban Indian adolescents containing high level of AGEs (advanced glycated end products) is a matter of concern as such type of diet are potent source of endocrine disruptor designates³². It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community needs to be educated on this issue

 CONCLUSION:

Despite high prevalence, the diagnosis and differential diagnosis of adolescent PCOS remain perplexing. As such, protocols used for diagnosis by care givers are empiric and driven by expert opinions. There is a need for consensus on diagnostic criteria of adolescent PCOS which will provide an international framework for collaborative studies and research .

works., the main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS according to probability of developing comorbidities in later life.

This syndrome, many believe lasts from womb to tomb and the metabolic syndrome is a common accompaniment of PCOS. As such, early diagnosis and treatment of PCOS in adolescent are essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if early diagnosis of all PCOS become feasible in India then thousands of women’s life will not become miserable by third and fourth decade of life due to Type 2 diabetes and hypertension.  The author firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important  topic. Author also believes that basic endocrine tests and few tests for metabolic parameters should preferably precede ultrasonographic assessment in the evaluation of PCOS.

 

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