PCO is it a metabolic diseases ??

What are the grey areas in the syndrome of adolescent PCOS?

The ever growing knowledge on different aspects of adult PCOS has already perplexed many clinicians so as   how best to suspect or diagnose the PCOS at an early stage of life. But sadly as yet there is no well-defined, uniform set criteria for diagnosis of ‘probable cases of PCOS’ in adolescenc.. As of now various definitions that are in vogue are in fact outcomes of consensus statements, namely the committee opinions, and not the robust and solid findings of clinical trial evidenc. For instance, whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided. Additionally which of the usual four symptoms and signs, namely persistent menstrual disorders, obesity, clinical  or laboratory evidences of 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 as yet no universally accepted set laboratory workup for this syndrome not to speak of a single test. To add to the problem this syndrome is now considered as primarily an androgen excess disorder. But paradoxically there is no universally accepted cut off value of serum androgens for this syndrome neither the methodology of estimation of serum testosterone have been simplified till date

Further, to what percent adolescent PCOS suffering from one phenotype changes to another as a girl   grows up and how does this transition affect her long-lasting health status has not been evaluated in any country. Neither, the magnitude of the societal obstacles in screening all adolescents for PCOS (universal screening) and cost of such screening have been evaluated.

While acknowledging 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 labeled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.   The authors also like to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out

  we already  know that “Transient but exaggerated functional hyperandrogenism of adolescence” is a syndrome that warrants a diligent follow up . This is not to be confused with adolescent PCOS but they need follow up.

 The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called “mini-PCOS or nascent PCOS” have drawn the attention of many researchers in this field.  Scientists, however now believe that most, but not all healthy adolescents reveal some degree of demonstrable hyperandrgenaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group though Fauser et al vouched that hyperandrogenemia is the most important finding in diagnosing adolescent PCOS even if no clinical features of hyperandrgenaemia are present .

 Researchers now believe that supraphysiological production of androgens or exaggerated response of androgen sensitive tissues in some adolescents is the core defect of evolution of future PCOS. They believe that  and augmented androgen levels is primarily produced in ovaries due to persistent  altered sensitivity of ovaries to amplified LH secretion which was initiated at pubertal period. In fact puberty is the first test of ovarian handling of insulin and LH stimuli and therefore offers an opportunity for early diagnosis of PCOS  

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms. Why regressions fail to occur in some girls?

Fortunately in most girls’ clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia of puberty 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 in whom such symptoms will aggravate giving rise to full- fledged PCOS in later life. The authors feels that the task of researchers now bestow to find out some special and specific biomarkers to identify such at- risk girls who are destined to develop from ‘mini PCOS; to ‘full-fledged PCOS’ in adult life^.

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

The problem is that the transition from normal pubertal changes either to normal healthy adult or to a full-blown PCOS is a slow process and therefore need long follow up for at least 5-7 years .Though in majority adolescents’ trivial symptoms like oligomenorrhea, obesity, acne, hyperseborrhoea and occasionally hirsutism will disappear within 1-2 years but in some adolescents symptoms will worsen giving rise to full- blown PCOS by couple of years. It is difficult for clinicians to forecast which girls are going finally to develop PCOS in later life and also difficult to predict the magnitude of systemic or reproductive ill effects based on degree of associated hyperinsulinaemia and or hyperandrgenaemia of puberty. Many scientists however now believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS.

What factors matter most in persistence of ‘nascent PCOS of adolescence’ up to adult life?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years which were ignored both by the family members and family physicians. It is now theorized that early symptom of PCOS may vary and with what symptom a girl will present that depend primarily upon the phenotypic presentation destined for that concerned adolescent, therefore perplexing the family physicians to whom they report first . There are several phenotypes of adolescent PCOS and the role of genetic versus environmental factors in the causation of each phenotype has long been debated. Researchers believe that three factors like quality of diet, degree of physical exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible in some adolescents to move from one phenotype to another as she 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 even 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 the differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for treatment of subfertility  _{Obesity seems to amplify the degree of t}

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

Many research workers are of opinion that girls even with isolated symptom of acne, hirsutism, and irregular menstrual cycles should be offered targeted screening. The present authors also concur the same view and firmly believe that expenses borne in this screening programme are cost effective in the long run²². 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 having only one symptom say oligomenorrhoea or only obesity. Burks et al firmly recommended that all girls with isolated symptoms of acne, hirsutism, and or irregular menstrual cycles should be offered targeted screening ^.Benefits of targeted screening have also been vouched by many more research workers.

 In this context authors are aware that   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 Indian adolescents those who are asymptomatic for the disease PCOS is not recommended by any national organization neither there is any Government policy to make this into effect. But the fact remains that the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reduction of cardio vascular risks is significant, if such at risk adolescents (probable PCOS) are picked up early. Even implementing targeted screening at school level   remains a challenge to policy makers.

how far we learnt from half century long PCO ?? Are we aware of  the task ahead. Metabolic syndrome is rampant in our country. Is community based study of PCOS possible by field staff, without the physical presence of physicians in the rural areas?

The symptoms of oligomenorrhoea, excessive weight gain and acne 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 too. 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%. In India, PCOS is reported among 9% of adolescents If any single commonly seen clinical abnormality of PCOS was evident in adolescent age group in the field study like persistent menstrual disorders two years after onset of  menarche , persistent acne or gain in weight or more than normal waist circumference then such adolescents were   initially   labeled as ‘probable case of PCOS’ and such  clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of adolescent PCOS and were counseled for follow up for a period of five years.  That was the theme of study at Sri Lanka.

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 designates .  It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community, parents in particular need to be educated on this issue including other conventional lifestyle management  right at standard XI class level onwards and such counseling may also be done during the process of school health visits by government staff and selective

? Take home meassage on PCO  : In spite 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 workers. The main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS and then educating them about the lifestyle management at an early date. Respective parents may be approached to report to school for group discussion and counseling by public health workers.

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 adolescence is essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if community screening is implemented in our country then early diagnosis of most PCOS may become feasible. If such universal screening programme is operational 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 authors also firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important topic. Authors are of opinion that adolescent girls with history of persistent oligomenorrhoea and or those who exhibit BMI > 25 with cutaneous evidence of androgen excess should preferably be given choice to undergo a   few basic endocrine tests and tests for metabolic parameters.

What are the grey areas in the syndrome of adolescent PCOS?

The ever growing knowledge on different aspects of adult PCOS has already perplexed many clinicians so as   how best to suspect or diagnose the PCOS at an early stage of life. But sadly as yet there is no well-defined, uniform set criteria for diagnosis of ‘probable cases of PCOS’ in adolescence . As of now various definitions that are in vogue are in fact outcomes of consensus statements, namely the committee opinions, and not the robust and solid findings of clinical trial evidence. For instance, whether androgen excess should be a sine qua non in PCOS diagnosis is still undecided. Additionally which of the usual four symptoms and signs, namely persistent menstrual disorders, obesity, clinical  or laboratory evidences of 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 as yet no universally accepted set laboratory workup for this syndrome not to speak of a single test. To add to the problem this syndrome is now considered as primarily an androgen excess disorder. But paradoxically there is no universally accepted cut off value of serum androgens for this syndrome neither the methodology of estimation of serum testosterone have been simplified till date .Further, to what percent adolescent PCOS suffering from one phenotype changes to another as a girl   grows up and how does this transition affect her long-lasting health status has not been evaluated in any country. Neither, the magnitude of the societal obstacles in screening all adolescents for PCOS (universal screening) and cost of such screening have been evaluated. While acknowledging 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 labeled as PCOS keeping in mind that the definition of this syndrome will evolve over time to incorporate new research findings.   The authors also like to highlight that the association of this syndrome with morphological appearance and ultrasonographic features of ovaries are fading out .

Transient but exaggerated functional hyperandrogenism of adolescence. This is not to be confused with adolescent PCOS but they need follow up.

 The issue of ‘physiological hyperandrogenism’ and/ or ‘physiological hyperinsulinaemia’ of puberty in the causation of so called “mini-PCOS or nascent PCOS” have drawn the attention of many researchers in this field.  Scientists, however now believe that most, but not all healthy adolescents reveal some degree of demonstrable hyperandrgenaemia and or features of hyperandrogenism which is quite physiological and transitory in nature at this age group though Fauser et al vouched that hyperandrogenemia is the most important finding in diagnosing adolescent PCOS even if no clinical features of hyperandrgenaemia are present.

 Researchers now believe that supraphysiological production of androgens or exaggerated response of androgen sensitive tissues in some adolescents is the core defect of evolution of future PCOS. They believe that  and augmented androgen levels is primarily produced in ovaries due to persistent  altered sensitivity of ovaries to amplified LH secretion which was initiated at pubertal period. In fact puberty is the first test of ovarian handling of insulin and LH stimuli and therefore offers an opportunity for early diagnosis of PCOS.

The issue of regression or progression of   mini-PCOS / nascent PCOS/ hyperpubertal symptoms. Why regressions fail to occur in some girls?

Fortunately in most girls’ clinical and hormonal parameters induced by   such temporary hyperandrogenemia and or hyperinsulinaemia of puberty 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 in whom such symptoms will aggravate giving rise to full- fledged PCOS in later life. The authors feels that the task of researchers now bestow to find out some special and specific biomarkers to identify such at- risk girls who are destined to develop from ‘mini PCOS; to ‘full-fledged PCOS’ in adult life^.

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

The problem is that the transition from normal pubertal changes either to normal healthy adult or to a full-blown PCOS is a slow process and therefore need long follow up for at least 5-7 years .Though in majority adolescents’ trivial symptoms like oligomenorrhea, obesity, acne, hyperseborrhoea and occasionally hirsutism will disappear within 1-2 years but in some adolescents symptoms will worsen giving rise to full- blown PCOS by couple of years. It is difficult for clinicians to forecast which girls are going finally to develop PCOS in later life and also difficult to predict the magnitude of systemic or reproductive ill effects based on degree of associated hyperinsulinaemia and or hyperandrgenaemia of puberty. Many scientists however now believe that obesity, and or laboratory evidence of frank insulin resistance predispose to development of full- blown PCOS.

What factors matter most in persistence of ‘nascent PCOS of adolescence’ up to adult life?

As a matter of fact, quite often PCOS women seen at late twenty can trace their symptoms to peripubertal years which were ignored both by the family members and family physicians. It is now theorized that early symptom of PCOS may vary and with what symptom a girl will present that depend primarily upon the phenotypic presentation destined for that concerned adolescent, therefore perplexing the family physicians to whom they report first^{18, 19}. There are several phenotypes of adolescent PCOS and the role of genetic versus environmental factors in the causation of each phenotype has long been debated. Researchers believe that three factors like quality of diet, degree of physical exercise and environment modify the particular genetic alterations differently therefore culminating into different phenotypes. What is more important is that it may be possible in some adolescents to move from one phenotype to another as she 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 even 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 the differential diagnosis. In fact most adult women with PCOS are not diagnosed until after seeking help for treatment of subfertility. _{Obesity seems to amplify the degree of t}

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

Many research workers are of opinion that girls even with isolated symptom of acne, hirsutism, and irregular menstrual cycles should be offered targeted screening. The present authors also concur the same view and firmly believe that expenses borne in this screening programme are cost effective in the long run²². 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 having only one symptom say oligomenorrhoea or only obesity. Burks et al firmly recommended that all girls with isolated symptoms of acne, hirsutism, and or irregular menstrual cycles should be offered targeted screening . Benefits of targeted screening have also been touched by many more research worker. this context authors are aware that   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 Indian adolescents those who are asymptomatic for the disease PCOS is not recommended by any national organization neither there is any Government policy to make this into effect. But the fact remains that the long term benefit of ameliorating the hormonal and metabolic profile, quality of life and reduction of cardio vascular risks is significant, if such at risk adolescents (probable PCOS) are picked up early. Even implementing targeted screening at school level   remains a challenge to policy makers

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

The symptoms of oligomenorrhoea, excessive weight gain and acne 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 too. 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%²⁸. In India, PCOS is reported among 9% of adolescents^{29, 30}. If any single commonly seen clinical abnormality of PCOS was evident in adolescent age group in the field study like persistent menstrual disorders two years after onset of  menarche , persistent acne or gain in weight or more than normal waist circumference then such adolescents were   initially   labeled as ‘probable case of PCOS’ and such  clinically suspected girls were referred to level II care centre for detailed endocrine assessment, ovarian ultrasound to confirm or refute the diagnosis of adolescent PCOS and were counseled for follow up for a period of five years.  That was the theme of study at Sri Lanka.

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 designates ¹³ .  It has been noticed that serum level of AGE is high in adolescents suffering from PCOS. Indian community, parents in particular need to be educated on this issue including other conventional lifestyle management  right at standard XI class level onwards and such counseling may also be done during the process of school health visits by government staff and selective screening may be stressed

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 workers. The main concern for the people involved in public health programme is to stratify girls supposed to be suffering from PCOS and then educating them about the lifestyle management at an early date. Respective parents may be approached to report to school for group discussion and counseling by public health workers.

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 adolescence is essential in ensuring good adulthood health and restoring self-esteem. It is hoped that if community screening is implemented in our country then early diagnosis of most PCOS may become feasible. If such universal screening programme is operational 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 authors also firmly believe that this current review will sensitize the healthcare providers to pave the way for further research on this important topic. Authors are of opinion that adolescent girls with history of persistent oligomenorrhoea and or those who exhibit BMI > 25 with cutaneous evidence of androgen excess should preferably be given choice to undergo a   few basic endocrine tests and tests for metabolic parameters.