Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz IN SUMMARY HST 071 Polycystic Ovarian Syndrome POLYCYSTIC OVARIAN SYNDROME Presence of oligo-or anovulation in combination with hyperandrogenism. • Chronic anovulation may present as irregular menstrual periods or amenorrhea. • It is not essential to document anovulation by ultrasonography or progesterone measurements in the presence of a clear clinical history • PCOS occurs in 85 to 90% of women with oligomenorrhea and in 30-40% of women with amenorrhea • Diagnosed either by clinical (hirsutism) or laboratory (elevated testosterone or androstenedione) • Should not be diagnosed if evidence of other causes of oligo-ovulation and hyperandrogenism(ovarian androgen secreting tumor or nonclassical adrenal hyperplasia) • Prevalence of PCOS is approximately 5–7% of women of reproductive age • 50% of PCOS women are obese and tend to have an android pattern of obesity Elevated levels of serum LH -increased LH pulse amplitude and LH pulse frequency • Steady-state levels of gonadotropins and ovarian steroids o “chronic estrous state” o Proliferation and hyperplasia of the endometrium o Can lead to unpredictable bleeding episodes o Unopposed estrogen exposure -confirmed by progesterone withdrawal test • Women with PCOS have higher mean concentrations of LH o Increased bioactivity of LH o Low to low-normal levels of follicle stimulating hormone • Obese PCOS women do not have elevated LH levels o normal LH level or normal LH/FSH ratio does not rule out PCOS o LH/FSH ratio is now not included in the diagnostic criteria of PCOS • In research studies almost all women with PCOS have elevated LH secretion. • In clinical practice -difficult to use a single measurement of LH to diagnose PCOS,  LH is secreted in a pulsatile manner  Normal range of serum LH concentration decreases with increasing body mass index (BMI)IN SUMMARY HST 071 Polycystic Ovarian Syndrome Association between hyperinsulinemia and PCOS • First noted by 1980 • Significant positive correlation between insulin, androstenedione and testosterone levels among PCOS women • It is estimated that 20-40% of PCOS women have impaired glucose tolerance o Seven-fold higher than the rates in age and weight-matched women o Prevalence of type 2 diabetes mellitus is also increased in PCOS women (15% versus 2.3% in normal women) o Lean PCOS women have lower rates of carbohydrate intolerance o Lean PCOS women still have higher rates than age and weight-matched controls. PCOS is associated with insulin resistance independent of total or fat-free body mass o Obese PCOS women are more insulin resistant than obese non-PCOS or non-obese PCOS women • Pancreatic beta cell secretory dysfunction in a subset of PCOS women o Probably has the highest risk of developing carbohydrate intolerance o Type 2 diabetes. o Oral glucose tolerance tests recommended for obese PCOS patients • PCOS in 8 out 30 premenopausal women with type 2 diabetes o Insulin resistance is characterized by post-receptor defect in the action of insulin o Cause of this defect is still being elucidated Action of insulin o Binds to the cell-surface receptor o Receptor undergoes auto-phosphorylation on specific tyrosine residues o Accomplished by activation of insulin receptor tyrosine kinase o Activated receptor then activates insulin receptor substrates (IRS-1,2 and 3) o Binds to signaling molecules such as PI3 kinase o Activates downstream signaling o Leads to insulin-mediated glucose transportIN SUMMARY HST 071 Polycystic Ovarian Syndrome PCO insulin resistance o Abnormalities in both insulin receptor tyrosine kinase o Mediators distal to the receptor are present in insulin resistance states o Adipocytes from women with PCOS o Adipocyte insensitivity to inhibition of lipolysis by insulin o Decrease in maximal rates of adipocyte glucose uptake o Occur in PCOS in the absence of obesity o Decreased insulin receptor auto-phosphorylation in 50% of fibroblasts removed from PCOS women o Due to increased receptor serine phosphorylation o Serine phosphorylation -associated with decreased insulin receptor tyrosine auto-phosphorylation • In vitro human theca cell studies o Insulin has direct stimulatory effects on ovarian steroidogenesis o Insulin produced a greater increase in androgen production by theca cells in PCOS than in cells obtained without PCOS o Effect is mediated specifically through insulin receptor o Insulin enhances the effect of LH on preovulatory ovarian follicles o Premature activation and subsequent follicle arrest o hyperinsulinemia (due to insulin resistance) drives the LH effect on ovarian theca cells  Causes androgen excess which are intrinsically programmed to produce more androgen  Excess androgens are known to interfere with the process of follicular maturation  Inhibiting ovulation  Producing more arrested follicles • 1983 it was proposed that severe hyperinsulinemia caused by insulin resistance results in ovarian hyperandrogenism (Barbieri & Ryan) • PCOS is associated with insulin resistance independent of total or fat free body mass o Hyperandrogenism, insulin resistance and acanthosis nigricans syndrome • Cause of the insulin resistance – germ line mutation in the insulin receptor gene o Prevents normal function of the insulin receptor. • Puberty: LH secretion rises o Severe insulin resistance o LH stimulation  hypersecretion of testosterone by the ovary o Often present with severe insulin resistance and hyperandrogenism including virilization and amenorrheaIN SUMMARY HST 071 Polycystic Ovarian Syndrome • Acanthosis nigricans o Dermatologic manifestation of the hyperinsulinemia o Hyperandrogenism • Clinical criteria suggestive of insulin resistance o BMI greater than 27 kg/m2 o Waist-to-hip ratio greater than 0.85 o Presence of acanthosis nigricans • Laboratory criteria o Elevated fasting insulin concentration o Elevated glucose-to-insulin ratio • Must have 2 of the following 3 manifestations o Irregular or absent ovulation o Elevated levels of androgenic hormones o Enlarged ovaries containing at least 12 follicles each • Polycystic ovaries are defined -on ultrasound o To contain 12 or more follicles o Measuring 2 to 9 mm in diameter o Increased volume of 10 mL or