Atenuated form of CAH(enzymatic deficinecies of adrenal cortex)

How informative is Late onset of CAH: Attenuated form CAH : Mild enzymatic disorder of adrenal steroids. There are three definite hormone producing layers of cortex. We, at present are referring to corticosteroid forming enzyme deficiencies,  Once a year:-CAH(Adrenal hyperplasia) : How best to diagnose??

Congenital adrenal hyperplasia is an inherited autosomal recessive enzyme defect that results in metabolic disorders and masculinization of newborn females. It is fortunately rare. A milder form, with onset at or following menarche, is variously labeled late-onset, adult-onset, acquired, partial, attenuated and non-classical adrenal hyperplasia. The most common form is due to 21-hydroxylase deficiency; other forms are due to 11β-hydroxylase deficiency and 3β-hydroxysteroid dehydrogenase deficiency. Clinical signs include mild hirsutism, increased skin sebum   causing mild acne, increased scalp sebum making daily hair washing necessary and mild hypertension. The diagnosis is confirmed by 17-hydroxyprogesterone (17OHP) levels ≥ 200 ng/dL or dehydroepiandrosterone sulfate (DHEAS) levels ≥ 180 μg/dL, which may also originate in the ovary. Elevated DHEAS is more common in mild cases and can be measured first. 17OHP should be measured first if there is virilization (hirsutism, male-pattern baldness or clitoral enlargement). Treatment for either defect is low-dose corticosteroid (0.5 mg dexamethasone or 5 mg prednisone) daily at bedtime. The addition of CC is often necessary or ovulation. Corticosteroids should be discontinued after ovulation, because of the risk of birth defects. Amenorrhea and excess androgen may be due to Cushing’s syndrome or acromegaly. Rapid development of virilization may be due to an androgen-producing tumor.

Hyperandrogenism may present clinically as hirsutism, acne, and/or male pattern alopecia. Hirsutism can be defined as the growth of coarse hair on a woman in a male pattern (upper lip, chin, chest, upper abdomen, back etc.). This is to be distinguished from hypertrichosis that involves a more uniform, whole body distribution of fine hair. Acne related to hyperandrogenism may be difficult to distinguish from normal pubertal acne in an adolescent with PCOS though pubertal acne in general is twice as prevalent in adolescent males versus females and males are more likely to have severe disease. Thus, an adolescent female with moderate to severe acne should be investigated for PCOS. Furthermore, the development or persistence of acne into adulthood is unusual and should raise attention. The severity of any of these manifestations is highly variable and may depend on genetic and ethnic differences in the sensitivity to the effects of androgens. The presence of virilization (clitoromegaly, deepening voice, increased musculature, or rapidly progressive hirsutism or alopecia), however, is not a feature of PCOS, but instead of more severe hyperandrogenism. Chronic anovulation often presents as oligomenorrhea, amenorrhea, dysfunctional uterine bleeding, and/or infertility. Interestingly, however, around 20% of patients with PCOS may describe normal menstrual cycles.8 often, but not always, menstrual abnormalities are long-standing, even since menarche. Other women may only develop menstrual problems later in life, perhaps after significant weight gain. Furthermore, primary amenorrhea is possible although not common

Congenital adrenal hyperplasia is an inherited autosomal recessive enzyme defect that results in metabolic disorders and masculinization of newborn females. It is fortunately rare. A milder form, with onset at or following menarche, is variously labeled late-onset, adult-onset, acquired, partial, attenuated and non-classical adrenal hyperplasia. The most common form is due to 21-hydroxylase deficiency; other forms are due to 11β-hydroxylase deficiency and 3β-hydroxysteroid dehydrogenase deficiency. Clinical signs include mild hirsutism, increased skin sebum   causing mild acne, increased scalp sebum making daily hair washing necessary and mild hypertension. The diagnosis is confirmed by 17-hydroxyprogesterone (17OHP) levels ≥ 200 ng/dL or dehydroepiandrosterone sulfate (DHEAS) levels ≥ 180 μg/dL, which may also originate in the ovary. Elevated DHEAS is more common in mild cases and can be measured first. 17OHP should be measured first if there is virilization (hirsutism, male-pattern baldness or clitoral enlargement). Treatment for either defect is low-dose corticosteroid (0.5 mg dexamethasone or 5 mg prednisone) daily at bedtime. The addition of CC is often necessary or ovulation. Corticosteroids should be discontinued after ovulation, because of the risk of birth defects. Amenorrhea and excess androgen may be due to Cushing’s syndrome or DHEASO4.

Hormonal evaluations -When?? – When to ask for such costly investigations? Risk factor based Screening protocols or Universal Screening in following situations? What is your practice pattern, dear members?

Why many of us hesitate on “hormonal evaluations”? What is in our back of mind?? I feel it is because of the following facts that hormonal evaluations are lastly considered after routine blood tets, USG etc:  Limitations of hormone tests are because of the fact that these are - 1) costly 2) cumbersome and 3) units of expressions 4) day of m cycle 5) delay of estimation due to transportation to other lab and 6) most importantly sometimes difficult to interpret due to phenotypic variations. Acknolwdgening this limitations  most of us insist on costly endocrine evaluations  in following conditions more so if associated with subfertility or menstrual disorders more so secondary amenorrhoea, Such syndromes are  following diseases 1) PCOS, 2) Non-PCOS secondary amenorrhoea,3)  anovulatory n women, 4) Galactorrhoea, 5) acne,6)  alopecia,7)  hirsutism, 8)  Acanthosis nigricans , 9) all obese women-warrant detailed endocrine evaluation to arrive at a definitive diagnosis. These nine groups of women and women heading for induction of ovulation and unexplained infertility mandate detailed but selective endocrine evaluation-though most cannot afford. That is not done: Complimenting the endocrine evaluation at later date. Initial step will be a tentative diag with  USG  :-The fact someone has enough money that does not mean that we will be asking A-Z hormones evaluations(say LH, FSH, E2,Prog, DHEAS04, TSH, Insulin,  , 17OH Prog, androstenedione,  Free testosterone, FAI,  hPL ,hCG . Growth Hormone, Cortisol, parathormone, Leptin, adiponectin in all cases...An experienced astute clinician can select which hormone to test – (selective screening) from symp, signs & USG findings (reproducible) and other endocrine test at a later date.

Cause of PCO in a given case comes from the womb / Brain of scientists. Still as a clinician, what hormone/ to order in PCO??? Let us at the onset be acquanatied with PCOS first. PCO is a syndrome and many diseases can mimic/present as PCOS. Fertile or not fertile -it is not sufficient to simply stamp a woman as PCOS. All PCOS are endocrinologically alike. Our duty as a clinician (we are not researchers neither scientists) we have to find the exact endocrine abnormality in a given PCOS and select most suitable treatment for her. In fact adolescent PCOS also mandate diagnosis of exact endocrine disorder for the origin of PCOS and then select appropriate treatment protocol. In such adolescents- it is more due to cardio-metabolic aberration induced by “Adiponectin-Leptin-Gherkin-insulin disorder “backed up tyrosine kinase activity disorders. But unfortunately tyrosine kinase activity disorders, Aromatase dynamics and more importantly Adiponectin-Leptin-Gherkin-insulin disorder can’t be diagnosed in Lab. Cause of PCO comes It comes from the womb of scientists.

. Not all PCOS are alike: In PCO with or without subfertility.-Coming to the problem of subfertility with PCO (keeping in mind that not all PCO are anovulatory):- In fact we formulate the treatment plan to treat a PCOS on the bases of her hormonal aberration which are not alike in all PCOS. Some exhibit high insulin or high androgen levels, some exhibit Hyperprolactinaemia, high DHEASO4 or rarely cortisol. The clinician cannot ask for testing all the six hormones. Phenotypic analysis helps us to select which hormones to test- test by exclusion.

What endocrine tests in a case of oligomenorrhea?? Like PCO or say abnormal hair growth in women, in cases of oligomenorrhoic too, there are many causes of sec ameno. However,  The causes are mostly endocrine disorder, though few may be due to target organ damage (synechaie, genital Koch’s) or stress (WHO class I anovulation).In Nonlactating women , or in case  of Post pill ameno sec ameno and PCO avail the same endocrine pathway in many cases if no  autoimmune disorder or DOR. If she does not want fertility is not an issue, diagnosis by exclusion of subfertile women may be due to following clinical conditions as well. And each disease mandate different treatment protocol for their primary disease and also for treatment of subfertility.PRL (pooled-fractional bioactive, LH, Fish, T4, E2 ) will be enough as an initial investigating. Other tests like adrenal functions, other Pit or gonadal functions and autoimmune disorders will follow at second/ third visits.

What endocrine evalutiion in cases of abnormal haor growth particularly in androgen dependent  ares of female body. (earlier called Hirsutism):=: Initial comments :: How serious is the symptom?? Firstly I must say this  For this syndrome there are some set endocrine markers that can’t be missed, should not be omitted because this symp is a societal problem, She , sadly can’t go to play, colleges, private caching, travel by public transport can’t go to gossip at college canteen. Even she avoids family get together or dislikes going to holiday trips for so many acne and visible hair growths. So put in such a situation we should not limit endocrine evaluation as a phase wise or stepwise manner. Instead we should ask for endocrine venality as a war footings (beg your pardon to use this word) and refer to an endocrinologist at an early date if such a specialist is available at your town. Though many respond well by 6 months to monotherapy of low dose OCP, but many will warrant Aldactone (with 3 monthly  K⁺  estimations) or many other anti-androgens. So far Cosmetics, (discussed so much in menopausal congress held at Kolkata in Feb 2019) there were not much  discussion on facial  cosmetic of acne & abnormal hair growth . Be that as it may,  sadly such cosmetic skin tr(cheek in particular) facilities don’t reach up to small town,

. Cause findings by exclusion:-Hirsutism can be caused by:

·         1) Polycystic ovary syndrome. This most common cause of hirsutism is caused by an imbalance of sex hormones that can result in irregular periods, obesity, infertility and sometimes multiple cysts on your ovaries.

·         2) rarely-Cushing's syndrome. This occurs when your body is exposed to high levels of the hormone cortisol. It can develop from your adrenal glands making too much cortisol or from taking medications such as prednisone over a long period.

·         3) Very rarely-Congenital adrenal hyperplasia. This inherited condition is characterized by abnormal production of steroid hormones, including cortisol and androgen, by your adrenal glands.

·         5) As rare as CAH are androgen secreting tumours Tumors. Rarely, an androgen-secreting tumor in the ovaries or adrenal glands can cause hirsutism.

·         6) Medications. Some medications can cause hirsutism. These include danazol, which is used to treat women with endometriosis; systemic corticosteroids and fluoxetine (Prozac) for depression.

Sometimes, hirsutism can occur with no identifiable cause. This happens more frequently in certain populations, such as in women of Mediterranean, Middle Eastern and South Asian ancestry. Most women with hirsutism do not have a major underlying disease causing their problem, few blood tests are necessary.

• Money doesn’t fall from sky!!! Which group of teens do not need any investigations?? .
• Are at investigations essential for this symptom??  Ask yourself :-Are detailed investigations are so essential more so at OPD settings of a Govt hospital . My ans:- No. In absence of virilization , obesity or menst disorders women with abnormal  hair  growth at androgen dependent sites of a teen or even in third to 4^th decade of life  with a) mild to moderate excess hair growth b) which has developed gradually and c) who have regular periods do not need any investigations.

• Then which women with ab hair growth  badly warrant detailed investigations ?? A) Women with more extensive hair growth (severe hirsutism) and regular periods should have their blood androgen levels measured.
• B) Women with increased hair growth and irregular periods need to have more extensive blood hormone tests done.

What tests then?? Women with moderate to severe hirsutism may be advised to have an ultrasound of the ovaries, especially if they have irregular menstrual cycles. The need for other specialised tests is determined by the results of the initial investigations.

What are the Risk factors for so called ab hair growth?? Several factors can influence your likelihood of developing hirsutism, including:

·         Family history. Several conditions that cause hirsutism, including congenital adrenal hyperplasia and polycystic ovary syndrome, run in families.

·         Ancestry. Women of Mediterranean, Middle Eastern and South Asian ancestry are more likely to develop hirsutism with no identifiable cause than are other women.

·         Obesity. Being obese causes increased androgen production, which can worsen hirsutism.

Complications

Hirsutism can be emotionally distressing. Some women feel self-conscious about having unwanted body hair. Some develop depression. Also, although hirsutism doesn't cause physical complications, the underlying cause of a hormonal imbalance can.

If you have hirsutism and irregular periods, you might have polycystic ovary syndrome, which can inhibit fertility. Women who take certain medications to treat hirsutism should avoid pregnancy because of the risk of birth defects.

Most women with hirsutism do not have a major underlying disease causing their problem, few blood tests are necessary.

• Women with mild to moderate excess hair growth which has developed gradually and who have regular periods do not need any investigations.
• Women with more extensive hair growth (severe hirsutism) and regular periods should have their blood androgen levels measured.
• Women with increased hair growth and irregular periods need to have more extensive blood hormone tests done.

Women with moderate to severe hirsutism may be advised to have an ultrasound of the ovaries, especially if they have irregular menstrual cycles. The need for other specialised tests is determined by the results of the initial investigations.

Management of Hirsutism Normal body hair growth is determined genetically and differs both within and between different racial groups. The number of hair follicles one has is established before birth. Hair follicles are found all over the body except for the palms, lips and soles of the feet. Most body hair is fine and unpigmented. Body hair growth is governed by the action of sex hormones on the hair follicles. Not only are the absolute levels of sex hormones in the blood important but also the sensitivity of the hair follicles to the hormones. Thus two women with the same blood hormone levels will have different body hair growth patterns according to the number of hair follicles over their bodies and how sensitive their hair follicles are to the growth stimulating effects of the hormones.

The main hormones stimulating hair growth are called ‘androgens’. Androgens are commonly called ‘male hormones’ but this is somewhat misleading, as androgens are normally produced by both the adrenal glands and ovaries in women and have important actions in normal healthy women.

The adrenal glands sit above the kidneys and as well as producing androgens, produce the important ‘stress’ hormones cortisol and adrenaline. The most well known androgen is testosterone. Testosterone is converted to oestrogen in the ovaries and body fat. Women cannot make oestrogen unless they can first make testosterone or adrenal androgens.

The other important hormones that are converted in cells into androgens are dehydroepiandrosterone (DHEA) and androstenedione (A). The skin and hair follicles convert DHEA and A to testosterone therefore high levels of these weak androgens can cause acne and excess hair growth.

Hair follicles in certain parts of the body are more sensitive to the influence of androgens and are called the hormone or androgen sensitive areas of the body. These areas include the upper lip, sides of the face, chin, central chest and around the nipples, lower abdomen, back, upper arms, pubic region and inner thighs. In contrast, the arms and lower legs are less sensitive to the effects of hormones. Androgens not only stimulate hair growth in the hormone sensitive areas by increasing the speed of hair growth but also increase the pigmentation (darkening) of hair and the thickness of the hairs. Thus androgens convert fine unpigmented hair into coarser dark more rapidly growing hair.

Puberty begins with the development of underarm and pubic hair. This sexual hair starts to appear when the adrenal glands ‘switch on’ and produce increasing amounts of androgens at the onset of puberty. We do not know what triggers this initial phase of maturation. By the end of puberty there is considerable variation in the amount of body hair between individuals. As women age, their overall amount of coarse body hair tends to gradually increase, again with a wide range of individual variation.

Determining excess hair growth

Hair removal treatments are often used for cosmetic reasons by people with normal hair pattern. Race and ethnicity play a major role in how much body hair is considered normal. Most Asian women, for example, have little body hair whilst Mediterranean women have relatively heavy body hair. An important consideration, irrespective of background is a change in pattern of hair growth or rate of growth.

When a woman considers she has excessive facial or body hair she should seek medical assessment and advice. An underlying hormonal disorder is more likely in women who have a recent change in the amount of rate of growth of body hair, and in those who have irregular periods or acne. Other specific signs of abnormal hormone levels include deepening of the voice, loss of scalp hair in a pattern similar to balding in men and an increase in libido. Hirsutism may also be linked to obesity and diabetes in some women.

Body hair can be assessed using a scoring system devised many years ago by the researchers Ferriman and Gallway. The system is quite simple. The body is considered as nine separate regions and the extent of hair in each region is given a value ranging from zero (no hair) to 4 (complete coverage of hair equivalent to male pattern growth). A total score over 8 is said to indicate hair growth in excess of that expected for a woman, whereas the problem is described as severe when a woman is given a total body score greater than 19.

Most women with the problem of hirsutism do not have a specific hormonal abnormality and are said to have idiopathic hirsutism. Blood tests may reveal slightly increased levels of adrenal and ovarian androgenic hormones but usually the levels are normal. Many women with hirsutism have normal blood hormone levels and have increased androgen turnover and/or enhanced sensitivity to normal levels of circulating hormones.

Polycystic Ovarian Syndrome (PCOS) is the most commonly identified condition causing excess hair growth in women and affects up to 10-15% of women in some communities. PCOS classically develops after puberty when girls experience irregular, infrequent periods. The progressive increase in body hair is usually associated with weight gain. Acne is also a common feature. The name of this condition ‘PCOS’ is misleading. The ovaries are not actually full of cysts but contain excess numbers of follicles which are best described as minicysts which develop as a result of failed ovulation.

In simple terms, certain cells in the ovaries of women with PCOS overproduce androgens especially testosterone. These high levels of androgens in the ovaries interfere with the development of a normal egg and instead of normal ovulation proceeding the nest of cells or the follicle containing the developing egg turns into a ‘mini cyst’. These mini cysts are clearly identified by an ultrasound examination. It is essential that the diagnosis of PCOS is made by someone experienced in ultrasound of the ovaries. PCO can easily be confused with multicystic ovaries which is a biological variation of normal and does not appear to be related to hormonal imbalance. Whereas a normal ovary contains up to three small follicles; the ovaries of women with PCO contain ten or more follicles. This condition appears to affect up to twenty percent of women with varying degrees of severity.

Women who have both PCO and a problem with weight are more likely to have higher androgen levels, excess body hair and problems with infertility. Women with PCO and obesity usually have high blood insulin levels and are at significant risk of developing diabetes.

The next most common medical condition causing excessive body hair growth is Congenital Adrenal Hyperplasia (CAH). This is an inherited condition usually diagnosed in childhood. However more subtle forms of this condition may not appear until after puberty as increased body hair in women. When this occurs it is called late–onset CAH. This condition is more common in certain ethnic groups and can be diagnosed with specific blood tests.

It is rare for excess body hair growth to be caused by over production of one of the pituitary hormones, growth hormone, prolactin or the adrenal stimulating hormone. Usually other identifying abnormal symptoms and signs are present and specialised blood tests lead to the correct diagnosis.

Tumours which produce abnormal quantities of androgens are fortunately extremely rare. They are usually associated with a sudden and significant increase in hair growth and other signs of masculinisation.

Some medications can cause an increase in body hair, the most commonly prescribed one being phenytoin (Dilantin) which is used in the treatment of epilepsy.

Should hormone levels be measured?

As most women with hirsutism do not have a major underlying disease causing their problem, few blood tests are necessary.

• Women with mild to moderate excess hair growth which has developed gradually and who have regular periods do not need any investigations.
• Women with more extensive hair growth (severe hirsutism) and regular periods should have their blood androgen levels measured.
• Women with increased hair growth and irregular periods need to have more extensive blood hormone tests done.

Women with moderate to severe hirsutism may be advised to have an ultrasound of the ovaries, especially if they have irregular menstrual cycles. The need for other specialised tests is determined by the results of the initial investigations.

Management of Hirsutism

There is no instant or permanent cure for hirsutism. Initial management is exclusion of any serious underlying pathology. For the majority of women the primary aim of treatment is to achieve a body image that is acceptable. This is generally accomplished with either cosmetic or pharmacological measures, or both.

Cosmetic Measures
Excess hair in regions that are non-androgen dependent, such as the arms and lower legs, may have an ethnic basis and cosmetic treatments are usually effective. Common cosmetic approaches include bleaching with peroxide, heavy makeup, shaving, plucking, waxing and depilatory creams. These methods are time consuming and expensive. They are effective for mild forms of hirsutism, but for patients with moderate to severe hirsutism their effects are only temporary. Problems with such treatments include skin irritation from bleaches and depilatory creams, folliculitis with plucking, burns from waxing and the development of stubble after shaving. Skin irritation or plucking rapidly induces the anagen (growth) stage and hair follicle growth, and shaving tends to reinforce a masculinised self-image. Both electrolysis and photothermolysis (eg laser) require trained personnel to provide treatment, are repetitious and expensive and practical for treating limited areas only, although electrolysis may be rapid and cost effective where the hair density is sparse. Laser therapy allows larger areas to be treated over a short time period.

Electrolysis
Electrolysis produces permanent destruction of the dermal papilla. The two basic methods of electrolysis are galvanic and thermolytic with galvanic being more common. In the galvanic method the hair follicle is destroyed using a direct current. The most effective form, the blend technique, combines thermolysis with electrolysis. Thermolysis creates heat within the follicle causing its destruction by use of an alternating current.

A benefit compared to laser treatment is that it can be used on both dark and light skinned patients and those with fair hair. It is painful. Other side effects of redness and swelling are generally temporary. Acne and ingrown hairs as well as postinflammatory pigment changes may occur, as well as scarring and keloid formation in susceptible patients. Success depends on the skill of the operator.

People with pacemakers should not undergo electrolysis.

Photo thermolysis – Lasers and Intense Pulsed Light (IPL) treatment 
Laser and light source treatment targets melanin (pigmentation) in the hair bulb which absorbs the light emitted by the laser or light source. This light energy changes into heat causing destruction of the hair bulb. If adjacent skin is also pigmented, however, the laser energy is absorbed into the surrounding epidermis causing damage or interference with absorption so that hair destruction is less effective. Therefore dark haired and fair skinned individuals, with relatively higher concentration of melanin in the hair compared to the epidermis, allow more selective absorption of light within the bulb. White or gray hair conversely is a poor target for laser treatment.

There is evidence to suggest that some lasers produce short-term effect of approximately 50% hair reduction up to 6 months after treatment (alexandrite and diode).

The most common side effects are redness and swelling which usually resolve within 24 hours after treatment. It can be slightly painful because of the heat energy created. Other side effects include hypopigmentaion and hyperpigmentation.

There have been instances of an increase in hair density, colour, coarseness or a combination of these (hypertrichosis) following laser therapy. However this is a rare event currently without explanation and definite cause and effect relationship with laser therapy has not been proven.

Intense Pulsed Light generates specific wavelengths of light with the addition of filters to tailor treatment to skin type and hair colour of the patient.

Most trials examined short- term effect of six months following treatment. Evidence is lacking for long-term hair removal. High quality research is required.

 Coming back to indications of endocrine evacuation in subfertility with or without menst diosrders:_Whta other evaluation ??

Ans To conclude the issue of association of oligo with or without subfertility problem  :-the following endocrine evaluations  are warranted in situations like : Such , I must say  mimic like PCOS (oligomenorrhoic/ eumenorrheic) and with without hirsutism mandate endocrine evaluation to arrive at a definitive clinical diagnosis. Such condition are 1) NC-CAH (Nonclassical adrenal hyperplasia), 2) Cushing syndrome, 3) Virilising ovarian tumour-all presenting with evidence of hyperandrogenism. The other four conditions which usually present as PCOS 4) hypothyroid, 5) Hyperprolactinaemia, 6) acromegaly, and 7) premature ovarian failure (Oligomenorrhea, weight gain, ovarian enlargement) are. Sometimes 8) drug-related hyperandrogenism may report to us. Elicit detailed drug history before much money is spent on hormone testing with an erroneous diagnosis of PCOS of endocrine disorders and in cases of thyroid disorders  we have to insist on both TSH and T4 measurements,.

Premature Ovarian Failure: - One should insist on endocrine confirmation.

An appaeal : To refrain from Unnecessary hormone testing  It is true that selections of endocrine tests is guided by the personal and then present history. We often miss this and do unnecessary hormone testing like androgen levels and PRL, Cortisol, DHEASO4 in all cases of PCOS who do not need it. But it is equally true that the Continuum of symptoms mandate  

 Endocrine evaluations including imaging modalities Heart of the hormones in many cases is insulin and Androgens-but sadly the reports of such reports are fraught with much fallacy so not commonly done in clinical practice.

 Rule of thumb is  broken due to circumstance in PCO:-

To whom to consider that it is classical PCO? The problem is that all the four features of PCO are not present in all cases of PCOS and even if present do not express in equal severity. The problem is that symptoms appear as spectrum of symptoms and signs the occurrence which is dissimilar. It is a continuum and we have to add more endocrine tests as clinical signs appear. The usual sequence is Acne/slight hair growthàslight aberrations in M. cyclesàWt gainà

Problem and Solutions: But if a girl was born in mother who had PCOS, hyperandrogenism, dyslipidaemia, & now that mother are diabetic then there is a resin to believe that this adolescent girl is suffering from adolescent Classical PCOS.A low birth weight, premature puberache (appearance of pubic hairs before the age of 8 years.)-need much vigilance for onward development of PCOS. Puberache is an expression of premature activation of Hypothalamo-Pituitary-Adrenal axis.

Although the generalizability the issue of Hyperprolactinaemia.

If two fold raise that will speak of hyperprolactinaemia. In 20-40% of clinically diagnosed PCOS PRL will be slightly raised but to diagnose that PRL is the primary cause of PCOS (no other endocrine disorder) - then there should be at least two fold rise of PRL. This is due to hyperoestrinism à activation of Lactotrophsà more release of PRLà mastodynia, tenderness of breasts and bloating. If less than double level-do not treat by dopamine agonist. Better treat by Insulin sensitizers if unmarried and by OCP if married and does not seek for restoration of fertility Role of estimating 17 hydroxyl progesterone.

This is a screening test for CAH (adult onset type) which is also called as NCAH-non classic Adrenal Hyperplasia.

 The sample should be drawn in early follicular phase and the result should be normally

Rule of thumb was broken due to circumstance

Stress and Female Subfertility...

Causes of elevated DHEASO4 1) attenuated adrenal enzyme deficiency- proved by ACTH stimulation test; 2) Cushing syndrome & Adrenal Tumours are uncommon causes of raised DHEASO4,

In cases of documented NC-CAH & also in cases where there has been repeated anovulation inspite of CC- then administration of dexamethasone will increase the adrenal pool of androgens.

In some cases it will improve the ovulation rate. 

But after one month of initiation of dexamethasone - morning cortisol should be done to assess the degree of suppression of endogenous cortisol by exogenous Dexamethasone. If cortisol is< 3 mcg. /mlàthen the dose of Dexamethasone should be decreased. It is not used in pregnancy,

B) A total testosterone is likely to be more reliable than a free testosterone given the difficulties seen with many of the assays used for the latter.Testosterone values may be normal in PCOS. Oral contraceptives will lower total testosterone, and interpretation in this setting is difficult (3 months off oral contraceptives is best to get a “true” testosterone value).Most testosterone values in PCOS will be ≤150 ng/dL (≤5.2 nmol/L).

Differential diagnoses and screening tests. Of PCO

A careful history and physical examination, looking for other signs of those disorders that may not be a part of PCOS, must be performed. Symptoms of cold intolerance, dry skin, and increased fatigue (among others) may signify hypothyroidism, as would the presence of a goiter. Galactorrhea may or may not be present in women with hyperprolactinemia. Signs of virilization signify more significantly elevated androgen levels than those seen in PCOS (see below) and may indicate an ovarian or adrenal tumor. Patients with Cushing's syndrome may be more apt to have hypertension, purple abdominal striae, prominent dorsal cervical fat pads, and a rounded, plethoric face.

Late-onset congenital adrenal hyperplasia, even though relatively rare, deserves mention as it can mimic PCOS in all regards clinically. Congenital adrenal hyperplasia is due to one of a variety of enzymatic defects in adrenal steroidogenesis (which leads to increased levels of precursor hormones that have androgenic properties). The classic forms of these disorders involve complete enzymatic defects and present in newborn girls as ambiguous genitalia

.

CAH:-In such cases-What investigations?? Ans:-17-hydroxyprogesterone.A morning, fasting, unstimulated level of <200 ng/dL (<6 nmol/L) in the follicular phase reliably excludes late-onset 21-hydroxylase deficiency.

Further evaluation of levels ≥200 ng/dL involves adrenocorticotropic hormone (ACTH)-stimulation with an intravenous 250 µg dose and a 30 minute value (stimulated values ≥1,000 ng/dL (≥30 nmol/L) confirm the diagnosis).

Oral contraceptives and glucocorticoids can affect values.

24-hour urine free cortisol. Mild elevations can be seen in PCOS with values ≥2 times the upper limit of normal more consistent with Cushing's syndrome.

For mild elevations a dexamethasone-suppression, corticotropin-releasing hormone stimulation test is needed to distinguish mild Cushing's syndrome from pseudo-Cushing's..

Interpretation of serum (but not urine) cortisol levels in patients on oral contraceptives is problematic as cortisol-binding globulin may be increased falsely elevating the values (it is especially important that oral contraceptives be discontinued before dynamic testing is performed).Luteinizing hormone/follicle stimulating hormone (LS/FSH) ratio.

A ratio ≥2.0 is suggestive of PCOS but is not highly sensitive or specific.Gonadotropin levels are affected by oral contraceptives CAH:-In such cases-What investigations?? Ans:-17-hydroxyprogesterone.A morning, fasting, unstimulated level of <200 ng/dL (<6 nmol/L) in the follicular phase reliably excludes late-onset 21-hydroxylase deficiency.

Further evaluation of levels ≥200 ng/dL involves adrenocorticotropic hormone (ACTH)-stimulation with an intravenous 250 µg dose and a 30 minute value (stimulated values ≥1,000 ng/dL (≥30 nmol/L) confirm the diagnosis).

Oral contraceptives and glucocorticoids can affect values.

24-hour urine free cortisol. Mild elevations can be seen in PCOS with values ≥2 times the upper limit of normal more consistent with Cushing's syndrome.

For mild elevations a dexamethasone-suppression, corticotropin-releasing hormone stimulation test is needed to distinguish mild Cushing's syndrome from pseudo-Cushing's..

Interpretation of serum (but not urine) cortisol levels in patients on oral contraceptives is problematic as cortisol-binding globulin may be increased falsely elevating the values (it is especially important that oral contraceptives be discontinued before dynamic testing is performed).Luteinizing hormone/follicle stimulating hormone (LS/FSH) ratio.

A ratio ≥2.0 is suggestive of PCOS but is not highly sensitive or specific.  Gonadotropin levels are affected by oral contraceptives

·         serum FSH level of >40 IU/ml, and a serum estradiol level of less than 40 pg/ml to document postmenopausal status.