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  • Clinical Features of PCOS. Hyperandrogenism.
    Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair.1
    1. Lobo RA, et al. Ann Intern Med. 2000;132:989-993.
  • Heritability. Due to the observable trends within families concerning insulin resistance, the question remains whether PCOS has a genetic connection. For instance, first degree relatives inherit B-cell dysfunction (secretory deficits). Franks and colleagues offered the following hypothesis: Linage analysis-syndrome inherited in autosomal recessive fashion; heterogeneous disorder-need to focus on hyperandrogenism to assign phenotype.
  • Infertility Treatments. Another complicating feature of PCOS is the effects it has on ovulation and fertility. Since there are so many facets to PCOS, there are also multiple options for treating infertility based upon the patient’s characteristics. First line of treatment in overweight patients is weight loss through lifestyle modification. Another cautious approach is administering CC as first line then insulin sensitizer if REGNANCY desired outcome. However, only short-term treatment with sensitizer and although CC has demonstrated benefit it should be limited to three cycles (Gysler et al. Fert Ster 37:161; 1982). The infertility industry has developed multiple treatment protocols to offer women with PCOS. The following slides review two studies demonstrating the published success.
  • Transcript

    • 1. INTRODUCTION  Classic syndrome originally described by Stein and Levanthal in 1935  Hyperandrogenism  Menstrual irregularity  Polycystic ovaries  The most common endocrine disorder in women of reproductive age (~ 5%-10%)  Syndrome (association of several clinically recognizable features), not a disease— multiple potential etiologies with variable clinical expression Stein IF, Leventhal ML. 1935. Dunaif A, et al. 2001
    • 2.  NIH Criteria (1990) (To include all of the following)  Menstrual irregularity due to anovulation or oligo- ovulation  Evidence of clinical or biochemical hyperandrogenism  Hirsutism, acne, male pattern baldness  High serum androgen levels  Exclusion of other related disorders Azziz 2007
    • 4. FEATURES OF PCOS  Ovulatory and menstrual dysfunction  Hyperandrogenemia  Polycystic ovaries  Gonadotropin abnormalities (LH/FSH)  Insulin Resistance and Hyperinsulinemia  Dyslipidemia  Obesity  Type 2 diabetes  Cardiovascular diseases Mark O. et al 2011
    • 5. OVULATORY AND MENSTRUAL DYSFUNCTION  75-85% PCOS patients diagnosed with oligo-amenorrhea or abnormal uterine bleeding  40% PCOS patients with normal menses have chronic anovulation  20-50% hyperandrogenic women with apparent eumenorrhea have chronic anovulation, may be considered to be affected by PCOS. Azziz et al 2009
    • 6. HYPERANDROGENEMIA Refers to supranormal levels of circulating endogenous androgens such as:  Total, unbound, or free testosterone (T)  Androstenedione (A4)  Dehydroepiandrosterone (DHEA)  DHEA metabolite DHEA sulphate (DHEAS) Azziz R, Carmina E, Dewailly D, et al. 2009
    • 7. … HYPERANDROGENEMIA  T circulates bound to SHBG and albumin and only free fraction enters into target tissue. Assessment of free T levels much more sensitive for diagnosis of hyperandrogenemia. Elevated in ~70% PCOS patients  Only few studies of prospective value available for using A4 levels as a diagnostic criterion. However, ~10% patients have elevated A4 levels  ~20-30% PCOS patients have elevated DHEAS levels, but also increased in other hyperandrogenic disorders and DHEAS levels also decrease with age  Therefore, serum androgen level cannot be used as sole diagnostic criterion of PCOS Azziz R, Carmina E, Dewailly D, et al. 2009
    • 8. MANIFESTATION OF HYPERANDROGENISM Clinically hyperandrogenism can manifest itself in the form of:  Hirsutism  Acne  Androgenic Alopecia
    • 9. MANIFESTATION OF HYPERANDROGENISM Symptoms may include hirsutism, acne, male pattern balding, and/or male distribution of body hair Hirsutism Acne Alopecia Lobo RA, et al. 2000
    • 10. HIRSUTISM  Is the presence of terminal hair in a female body in a male-type pattern, includes hair on 9 body areas: upper lip, chin, chest, upper back, lower back, upper and lower abdomen, upper arm and thigh  Method to determine presence of hirsutism uses a visual score, most common is modified FerrimanGallwey score  0 score represents absence of terminal hair and score of 4 represents extensive terminal hair growth. Hirsutism is defined by an mGF score of ≥ 6  However, prevalence of hirsutism varies according to race and ethnicity of population DeUgarte et al 2006
    • 11. ACNE AND ANDROGENIC ALOPECIA  Acne affects 15-25% PCOS patients but unclear whether its prevalence is significantly increased in these patients over general population. No single scoring system used, also varies with ethnicity  Androgenic alopecia or scalp hair loss may affect 5 – 50% PCOS patients but further studies are needed to better define this prevalence Azziz R, Carmina E, Dewailly D, et al. 2009
    • 12. POLYCYSTIC OVARIES  3 features used to define PCO:  Ovarian size and volume  Stromal volume  Follicle size and number  Rotterdam criteria defines PCO solely on total follicle no. : presence of ≥ 12 follicles measuring 2-9 mm in diameter and/or increased ovarian volume >10 mL in at least one ovary  Rotterdam definition of PCO cannot be applied to women taking oral contraceptives as the have modified ovarian morphology Azziz R, Carmina E, Dewailly D, et al. 2009
    • 13. OVARIAN ABNORMALITIES • Multiple follicles in peripheral location • 80% of women with PCOS have classic cysts ULTRASOUND IMAGE OF POLYCYSTIC OVARIES Smith R. 2006
    • 14. GONADOTROPIC ABNORMALITIES  Accelarated GnRH/LH pulse amplitude leads to increased secretion of LH whereas FSH levels are normal or even decreased  >75% PCOS patients have a dysregulated gonadotropin function  Conceptually, increased surge of LH and increased LH:FSH ratio during the follicular phase of menstrual cycle has been considered as a marker of PCOS. However, normal ratio may be found in obese patients Goodarzi, Dumesic et al 2011
    • 15. Abnormal Pituitary Function Altered Negative Feedback Loop  Increased GnRH from hypothalamus  Excessive LH secretion relative to FSH by pituitary gland  LH stimulates ovarian thecal cells - androgen production  Ineffective suppression of the LH pulse frequency by estradiol and progesterone  Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone Allahbadia, Merchant, 2010
    • 16. GnRH LH hypothalamus pituitary X Androgens block inhibitory effect of progesterone ovary androgens Abnormal Pituitary Function— Altered Negative Feedback
    • 17. Abnormal steroidogenenesis  Intraovarian androgen excess results in excessive growth of small ovarian follicles  Follicular maturation is inhibited  Excess androgen causes thecal and stromal hyperplasia
    • 18. INSULIN RESISTANCE AND HYPERINSULINEMIA  50-70% women with PCOS have insulin resistance  Defined as a subnormal target tissue response to a given amount of insulin  Results in Hyperinsulinemia, by the pancreatic islet cells to maintain normal glucose homeostasis  IR can lead to elevated circulating levels of glucose, impaired glucose tolerance and eventually diabetes  IR may not always be accompanied by elevated circulating levels of insulin Franks S. 1995. Hopkinson 1998.
    • 20. RELATIONSHIP B/W HYPERINSULINEMA & HYPERANDROGENISM  If hyperandrogenism caused insulin-resistance, amelioration of hyperandrogenism would be expected to improve insulin sensitivity  But antiandrogen therapy has failed to produce significant improvements in insulin resistance  More support in literature that hyperinsulinemia causes hyperandrogenism. Recent data suggest that physiologic insulin levels enhance androgen production from the granulosa cells of polycystic ovaries and may act synergistically with LH. Legro
    • 21. Calculation of HOMA-IR Glucose in Molar Units mmol/L Glucose in mass units mg/dL Matthews, 1935
    • 22. DYSLIPIDEMIA AND OBESITY Decreased levels of HDL-C Increased levels of LDL-C Increased levels of triyglycerides A great reduction of (HDL) with higher increase of both triglycerides & total cholesterol, may make them prone to hypertension as well.  Risk of atherosclerosis & premature cardiovascular events increases  About 50% PCOS women are obese, it appears that risk of PCOS increases with obesity     Goodarzi, Dumesic, Azziz, 2011
    • 24.  Binding of insulin to its receptor results in autophosphorylation and tyrosine kinase activation of the receptor which furthers phosphorylates other downstream mediators [insulin receptor substrate (IRS) and Src homology domain containing transforming protein 2 (Shc)].  These mediators then differentially activate various downstream signaling proteins. Phosphatidylinositol 3-Kinase (PI3K) plays a major role in glucose transport, glycogenesis and protein synthesis.  On the other hand, Grb2/SOS (growth factor receptor-bound receptor 2/ Son of sevenless) complex activates mitogenactivated protein kinase pathway (MAPK) playing a crucial role in mitogenic response.  Another pathway via inositolglycan generation has been suggested which may play a vital role in steroidogenesis.
    • 25. OVARIAN STEROID BIOSYNTHETIC PATHWAY Wickenheisser, McAllister, 2007
    • 26. ABNORMALITIES OF PCOS OVARY  Increase in CYP17 leads to increased p450c17 enzyme and hence increased androgen synthesis  Decrease in CYP19 decreases aromatase enzyme activity and conversion of androgens to E2 (Estradiol) is reduced  Increased 5α-Reductase activity leads to increased metabolism of ∆4-Androstenedione to 5αAndrostenedione, a competetive inhibitor of aromatase activity  This loss of aromatase and E2 biosynthesis has been proposed to involve dysregulation of autocrine and paracrine signaling within the follicle leading to follicular arrest Wickenheisser, McAllister, 2007
    • 27. OVARIAN STEROID BIOSYNTHETIC PATHWAY Wickenheisser, McAllister, 2007
    • 28. GENETIC LINK Familial clustering of PCOS common  1st degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance  Mothers and sisters of PCOS patients have higher androgen levels than control subjects
    • 29. INFERTILITY  Intermittent ovulation or anovulation  Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid
    • 30. Treatment  The first step is to help the patient understand that this chronic disease process can be controlled by changes in lifestyle.  Lifestyle modification must be emphasized to include appropriate diets & exercise program is essential. Azziz R, Carmina E, Dewailly D, et al. 2009
    • 31. …Treatment  Metformin may complement the effects of lifestyle modification, it causes marked improvement in menstrual pattern & may improve the response to ovulatory agents.  Clomifene-citrate (competitive inhibitor of estrogen receptor) is the standard method of medical ovulation induction in anovulatory women. Azziz R, Carmina E, Dewailly D, et al. 2009
    • 32. …Treatment  Anti-androgens: cyproterone acetate  Spironolactone: alternative anti-androgen.  Low dose of oral contraceptives are effective in treating acne & hirsutism, minimum of 2 years & cosmetic measures are needed to achieve good results. Azziz R, Carmina E, Dewailly D, et al. 2009
    • 33.  Susceptibility of PCOS patients to cardiovascular diseases and diabetes  Women with PCOS at ages 20–32 were more likely to develop incident diabetes by the time they reached 38– 50 years of age  Altered signaling pathways and susceptibility genes  Marker genes for these diseases