Polycystic Ovarian Syndrome (PCOS) Bill D Hampton, MS-4 Endocrinology Department 19 October 2000

PCOS - Overview Definition Statistics Onset Clinical History Signs & Symptoms Oligomenorrhea Androgen excess Infertility Obesity Insulin resistance Insulin Resistance Physiology Differential Diagnosis Ovarian hyperthecosis CAH Cushing’s Syndrome Androgen-producing Neoplasm Treatments Future Research

PCOS - Definition “a condition commonly characterized by hirsutism, obesity, menstrual irregularities, infertility, and enlarged ovaries; thought to reflect excessive androgen secretion of ovarian stroma.” “hyperandrogenism with chronic anovulation, with exclusion of such secondary causes as nonclassic CAH, Cushing’s syndrome, and hyperprolactinemia.”

PCOS - Statistics Most common endocrinopathy of women of the developed world Affects 1/20 reproductive-aged women Responsible for 9/10 of cases of oligomenorrhea 2/5 women show glucose intolerance

PCOS - Pathophysiology Although it is the most common endocrinopathy of women of the developed world, the fundamental pathophysiologic defect has not been determined.

PCOS - Onset Menarche - often followed by menstrual irregularity for 1.5 years If irregular bleeding persists beyond this time (and certainly after 3 years) then PCOS must be suspected

PCOS - Clinical History 1) Appearance of hirsutism is gradual. 2) Episodes of irregular bleeding are NOT typically preceded by premenstrual symptomatology (highly suggestive of anovulation) 3) The onset of symptoms tends to be recognized at or soon after puberty. 4) Despite similarities with other conditions, PCOS occurs far more frequently.

PCOS - Oligomenorrhea Lack of awareness before menses Varying degrees of bleeding 85% - 90% due to PCOS 30% - 40% of amenorrhea due to PCOS NOT all patients are anovulatory

PCOS - Androgen Excess 4/5 patients demonstrate excessive hair growth Involvement of face & chin, typically Male pattern of distribution: chest, perineum, back, extremities Hair growth should be gradual in PCOS Virilizing signs (clitoromegaly, male body habitus) are NOT usually seen in PCOS Acne is NOT specific to PCOS

PCOS - Infertility Most common presenting complaint Increasing evidence suggests women with PCOS have  incidence of miscarriage (unknown mechanism) NOT all patients are anovulatory

PCOS - Obesity 1/2 of PCOS women are obese “Android” pattern of obesity Distribution of obesity tends to be  waist-to-hip ratio

PCOS - Insulin Resistance > 50% adult women with PCOS exhibit insulin resistance and hyperinsulinemia 40% of patients with PCOS demonstrate glucose intolerance Hyperinsulinemia more prevalent in obese PCOS patients but is seen independent of obesity Molecular mechanism of insulin resistance in PCOS is unknown, however…

PCOS - Insulin Resistance Acanthosis Nigricans - an eruption of velvet warty benign growths and hyperpigmentation occurring in the skin of the axillae, neck, anogenital area, and groins; associated with internal malignancy, endocrine disorders, or obesity. Responsible factors remain unidentified Associated with insulin resistance Close association suggests that insulin may induce / contribute to its development NO correlation with severity of insulinemia

PCOS - Insulin Resistance Assessment of insulin resistance may be by oral / IV glucose tolerance test Because of long-term health risks, insulin secretion should be evaluated once diagnosis of PCOS is established However, determination of insulin resistance is NOT essential to diagnosis of PCOS

PCOS - Hyperinsulinemia Due to insulin resistance seen in PCOS Important mechanism in ovarian hyperandrogenism Rat theca cells in culture respond equally when exposed to LH or insulin, but have a synergistic greater response when given both LH and insulin Insulin and IGF-I can act as “co-gonadotropins”  enhanced LH secretion

PCOS - Hyperinsulinemia Potentiates ovarian hyperandrogenism by enhancing LH secretion from theca cells Potentiates 17-hydroxylase Suppresses SHBG capacity, which in turn, raises total level of unbound (free) testosterone

PCOS - Hormonal & Metabolic Profile Hyperandrogenism  Total testosterone  Androstenedione  Sex hormone-binding globulin (SHBG) Acyclic estrogen production  Insulin (with insulin resistance)

PCOS - Hormonal & Metabolic Profile Hyperandrogenism  insulin amplifies gonadotropin-induced androgen production by isolated ovarian tissue  insulin acts synergystically with LH to promote ovarian hyperandrogenism  insulin and IGF-I stimulate insulin receptors on ovarian thecal & granulosa cells as co-gonadotropins, thus amplifying androgen production

PCOS - Hormonal & Metabolic Profile  Total testosterone  insulin negatively regulates SHBG, which in turn allows for  levels of unbound testosterone  insulin also promotes ovarian and adrenal hyperandrogenism, which will also  total serum testosterone

PCOS - Hormonal & Metabolic Profile  Androstenedione  insulin promotes gonadotropin-induced androgen production by isolated ovarian tissue  insulin negatively regulates SHBG

PCOS - Hormonal & Metabolic Profile  Sex Hormone-Binding Globulin (SHBG)  insulin negatively regulates SHBG

PCOS - Hormonal & Metabolic Profile Acyclic estrogen production PCOS gonadotropin pattern is typically  LH and  FSH Urinary studies have shown an abormal, erratic pulses of LH secretion

PCOS - Hormonal & Metabolic Profile  Insulin (with insulin resistance) 1) After LOC (laparoscopic ovarian cautery), significant decreases in testosterone & andrestenedione were observed, but there was NO effect on insulin resistance or liproprotein abnormalities associated with PCOS

PCOS - Hormonal & Metabolic Profile  Insulin (with insulin resistance) 2) After amplifying the entire coding region of the insulin receptor gene, Talbot, et. al. (1995) found “that insulin resistance in subjects with PCOS is not commonly a consequence of missense mutations in the insulin receptor gene.”

Differential Diagnosis Ovarian hyperthecosis An unusual proliferative condition in which the ovary contains nests of lutenized theca cells scattered throughout the stroma The minimal form of ovarian hyperthecosis has been seen in PCOS, suggesting a continuous spectrum of disease

Differential Diagnosis Congenital Adrenal Hyperplasia (CAH) Made up of several enzymatic defects Autosomal recessive inheritance pattern Best approximation to PCOS is incomplete 21-hydroxylase deficiency  accumulation of 17-hydroxyprogesterone (androgen precursor)   production of androstenedione and testosterone  hyperandrogenism Unlike PCOS, CAH has severe hirsutism, clitoromegaly, regular menses, and short stature

Differential Diagnosis Cushing’s Syndrome Clinical features result from excessive cortisol production Signs/Symptoms include obesity, hirsutism, acne, and irregular menses Unlike PCOS, Cushing’s also has moonlike facies, buffalo hump, HTN, muscle wasting, abdominal striae, and osteoporosis

Differential Diagnosis Androgen-producing Neoplasm May arise from ovary or adrenals Signs/Symptoms include functional hyperandrogenism, severe hirsutism, male body habitus, virilization (clitoromegaly), acne, voice-lowering, irregular menses Unlike PCOS, these symptoms typically have a rapid onset, progressing over a matter of months

PCOS - Diagnosis Clinical diagnosis with laboratory exclusion of other causes Labs: serum total testosterone (androgen-producing tumor of ovary) Labs: DHEA sulfate (androgen-producing tumor of adrenal) Labs: 17-hydroxyprogesterone (CAH due to 21-hydroxylase deficiency) Labs: despite widespread practice, LH/FSH ratio is insensitive, with <50% of PCOS pts having an abnormal value, and <20% having a ratio of >3:1.

PCOS - Diagnosis Imaging: ovarian morphologic characteristics, as many as 1/5 women have PCOS features on US, while only a fraction also have hyperandrogenemia and menstrual irregularity Combinations: ovarian morphologic characteristics with elevated circulating androgen value

PCOS - Diagnosis Suggested Labs: level of unbound testosterone, provides best correlation with hirsutism, and because SHBG tends to be negatively regulated by insulin levels, an unbound / bioavailable testosterone level may reflect the combined effects of insulin resistance ( insulin and  SHBG) and ovarian and adrenal hyperandrogenism ( total circulating testosterone).

PCOS - Goals of Therapy Normalize the endometrium Antagonize androgen action at target tissues Reduce insulin resistance Correct anovulation, if necessary

PCOS - Treatment Dilemma Because the primary cause of PCOS is currently unknown, treatment options are at present symptom based.

PCOS - Treatment Options Gold Standard - weight loss, diet, and exercise (as little as 5% of initial weight) has resulted in lower circulating androgen levels, spontaneous resumption of menses, and decreased levels of circulating insulin.

PCOS - Treatment Options Infertility - clomiphene (Clomid) a partial agonist at estrogen receptors in the pituitary prevents feedback inhibition, which increases LH & FSH  ovulation - 4/5 women ovulate with Clomid alone - small studies have shown significant improvement in ovulatory response with addition of metformin (Glucophage) or INS-1, but population is 20% - 50% of PCOS pts who are Clomid nonresponders

PCOS - Treatment Options Hirsutism - antiandrogens are very effective, however, their use is precluded in fertility treatment because these agents suppress ovulation or have potential teratogenic effects - antiandrogens have been shown to significantly improve insulin sensitivity in PCOS by partially reversing the peripheral insulin resistance associated with hyperandrogenism (with greater effectiveness in lean subjects and no significant improvement in obese patients)

PCOS - Treatment Options Oligomenorrhea - oral contraceptives (OCs) are considered the first line of treatment for irregular menses, however, they also are clearly impossible as concordant infertility therapy - Furthermore, there has been some evidence that OCs may actually worsen insulin resistance in PCOS, and they may accelerate the progression of impaired glucose tolerance and type 2 Diabetes

PCOS - Treatment Options Antidiabetics - drugs that improve insulin action have consistently been found to improve reproductive abnormalities in PCOS - small studies have demonstrated conclusively that a reduction in serum insulin levels is associated with a reduction of ovarian androgen secretion in PCOS (because hyperinsulinemia   ovarian androgen secretion and  SHBG)

PCOS - Antidiabetic Agents metformin (Glucophage) - a biguanide whose major effect is seen in hepatic glucose output - improvement in testosterone and free testosterone levels in obese patients -  SHBG,  free testosterone, improve ovulation rates, and improve ovulation in response to clomiphene (Clomid) - also  free androgen levels in lean pts. - also demonstrated weight loss in pts.

PCOS - Antidiabetic Agents metformin (Glucophage) - has NOT been shown to  total androgens as a marker of ovarian androgen secretion (suggesting metformin’s MOA is through  SHBG) - in studies where metformin  serum insulin, same studies also show  serum testosterone; the converse is true, thus the two seem to be interdependent - 30% - 50% women shown to experience regular menses on metformin

PCOS - Antidiabetic Agents metformin (Glucophage) - some, but not all unsuccessful trials have involved extreme cases of obesity, suggesting metformin is less successful among the very obese - variability in dosing also does not clearly correlate with efficacy - metformin has no known teratogenic effects, but this reflects a lack of substantial body of evidence with women of reproductive age using the medication

PCOS - Antidiabetic Agents troglitazone (Rezulin) - a thiazolidinedione that directly reduces insulin resistance and circulating insulin levels - demonstrated a  in circulating androgen levels in women with PCOS - studies have shown a improvement in insulin sensitivity and reduced circulating androgen levels with higher doses (200 mg vs. 400 mg) -  in free testosterone levels also seen with concomitant  SHBG

PCOS - Antidiabetic Agents troglitazone (Rezulin) - some evidence exists that suggests that the thiazolidinediones can directly inhibit ovarian steroidogenesis - most promising, however, is a study of troglitazone that included women who were just as obese as women who failed to respond to metformin, suggesting that troglitazone might be more effective in the severely overweight (BMI > 35)

PCOS - Antidiabetic Agents pioglitazone (Actos) / rosiglitazone (Avandia) - as of the September 2000 publication of one of the cited articles, “no published reports are available of either drug in the treatment of PCOS. If the effects of troglitazone are applicable to all members of the same drug class, it would be anticipated that rosiglitazone and pioglitazone would be effective in the treatment of PCOS.”

PCOS - Antidiabetic Agents D-chiro-inositol - a naturally occurring substance that seems to imrpove insulin action by increasing insulin signal transduction at the postreceptor level - in 20 obese women with PCOS, d-chiro-inositol improved serum insulin levels and serum androgen levels to about the same degree as other agents

PCOS - Antidiabetic Agents A word of caution - none of the insulin-reducing medications can be adopted as first-line therapy for PCOS because not all women with PCOS are insulin resistant, and it is not clear that insulin resistance is the primary defect of the heterogenous disorder of PCOS. - more importantly, none of the drugs has been administered for long enough periods of time or to a sufficient number of subjects to allow an evaluation of any of the critical clinical endpoints or to prove superiority over other established therapies

PCOS - Antidiabetic Agents Duration - to date, the longest study of insulin-reducing agents for the treatment of PCOS has been 6 months Menstrual dysfunction - although the improvements are encouraging, careful evaluation of persistent ovulation rates must be performed before it can be concluded that insulin-lowering drugs are acceptable therapy for irregular menses Infertility - before insulin-lowering drugs can be used, their safety, their efficacy, and their cost relative to other potential therapies for infertility due to PCOS must be evaluated

PCOS - Antidiabetic Agents Combination therapies - because of the potential direct and unique beneficial effects of insulin-lowering drugs on metabolism, studies must be performed to evaluate their efficacy in combination with other therapies, especially oral contraceptives

References Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels. Lemieux S - J Clin Endocrinol Metab - 1999 Nov; 84(11): 4278-82 Polycystic ovary syndrome. Goudas VT - Endocrinol Metab Clin North Am - 1997 Dec; 26(4): 893-912 Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. Talbot JA - J Clin Endocrinol Metab - 1996 May; 81(5): 1979-83 Diagnosis of polycystic ovary syndrome. Chang RJ - Endocrinol Metab Clin North Am - 1999 Jun; 28(2): 397-408, vii The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. Moghetti P - J Clin Endocrinol Metab - 1996 Mar; 81(3): 952-60

References Polycystic ovary syndrome: current and future treatment paradigms. Legro RS - Am J Obstet Gynecol - 1998 Dec; 179(6 Pt 2): S101-S108 Insulin-lowering Medications in Polycystic Ovary Syndrome. Taylor AE - Obstet Gynecol Clin North Am - 2000 Sep; 27(3); 583-595 Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. Moghetti P - J Clin Endocrinol Metab - 2000 Jan; 85(1): 139-46