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Lect 2-polycystic ovarian syndrome


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Lect 2-polycystic ovarian syndrome

  1. 1. Polycystic Ovarian Syndrome
  2. 2. Polycystic Ovarian Syndrome (PCOS) Overview <ul><li>Polycystic ovarian syndrome (Stein-Leventhal syndrome) is a complex endocrine disorder affecting women in their reproductive years. </li></ul><ul><li>It is characterized by increased androgen production and disordered gonadotropin secretion, which results in chronic anovulation. </li></ul><ul><li>It is the leading cause of anovulatory infertility and hirsutism. </li></ul><ul><li>PCOS is also associated with disorders of reproduction, metabolism, and general health, including increased risk of miscarriage, insulin resistance, hyperlipidemia, cardiovascular disease, and endometrial cancer. </li></ul><ul><li>Obesity is common but not universal in women with PCOS. </li></ul><ul><li>Women with PCOS have high rate of type 2 diabetes; these women have hyperlipidemia and a greatly increased risk of cardiovascular disease. </li></ul>
  3. 3. INTRODUCTION <ul><li>Most common cause of infertility in women </li></ul><ul><li>Classic syndrome originally described by Stein and Levanthal </li></ul><ul><ul><ul><li>Hyperandrogenism </li></ul></ul></ul><ul><ul><ul><li>Menstrual irregularity </li></ul></ul></ul><ul><ul><ul><li>Polycystic ovaries </li></ul></ul></ul><ul><ul><ul><li>Central adiposity </li></ul></ul></ul><ul><li>Syndrome, not a disease—multiple potential etiologies with variable clinical expression </li></ul>
  4. 4. Why is PCOS important? <ul><li>Affects 4-12% of women of reproductive age </li></ul><ul><li>Significant association between obesity, insulin resistance, and PCOS. </li></ul><ul><li>Huge impact on the reproductive, metabolic, and cardiovascular health of affected women. </li></ul>
  5. 5. Clinical Features of PCOS Menstrual Irregularity <ul><ul><li>May appear at puberty with a delayed menarche followed by the onset of irregular periods or as the breakdown of a previously regular cycle </li></ul></ul><ul><ul><li>Anovulation is usually chronic and presents as oligomenorrhea or amenorrhea </li></ul></ul>
  6. 6. Clinical Features of PCOS Hyperandrogenism <ul><li>Symptoms may include hirsutism, acne, male pattern balding, and/or male distribution of body hair </li></ul>Hirsutism Acne
  7. 7. Pathogenesis <ul><li>1. Hyperandrogenism </li></ul><ul><li>2. Insulin resistance </li></ul>
  8. 8. Common Endocrine Abnormalities in PCOS <ul><ul><li>Elevated luteinizing hormone (LH) </li></ul></ul><ul><ul><li>Increased LH/follicle-stimulating hormone (FSH) ratio </li></ul></ul><ul><ul><li>Elevated androgen levels </li></ul></ul><ul><ul><li>Decreased sex hormone binding globulin levels </li></ul></ul>
  9. 10. <ul><li>In PCOS, discovered increased pulse frequency of GnRH (2/2 abnml pulse generator), resulting in relatively increased pulse frequency of LH, over FSH. </li></ul><ul><li>Increased frequency of LH pulses in PCOS. Progesterone administration can restrain rapid pulse frequency. Increased LH results in increased production of androgens by ovarian theca cells. </li></ul><ul><li>INSULIN acts synergistically with LH to enhance androgen production. INSULIN suppresses SHBG (the key protein that binds testosterone), resulting in increased free testosterone. </li></ul><ul><li>TESTOSTERONE inhibits and estrogen stimulates hepatic synthesis of Sex hormone-binding globulin (SHBG). </li></ul>
  10. 11. Pathogenesis: Hyperandrogenism <ul><li>Symptoms of androgen excess </li></ul><ul><li>Reduced sex-hormone-binding globulin (SHBG)  more free testosterone  conversion of androstenedione in adipose tissue </li></ul><ul><li>Insulin insensitivity </li></ul><ul><li>Lipid abnormalities </li></ul><ul><li>Abdominal obesity </li></ul>
  11. 12. Metabolic Abnormalities in PCOS <ul><ul><li>Hyperinsulinemia and insulin resistance </li></ul></ul><ul><ul><li>Insulin resistance may be independent of the effect of obesity </li></ul></ul><ul><ul><li>Decreased peripheral insulin sensitivity and consequent hyperinsulinemia may play an important role in the pathogenesis of PCOS </li></ul></ul>
  12. 13. Lipid and Lipoprotein Abnormalities in PCOS <ul><ul><li>Elevated LDL cholesterol </li></ul></ul><ul><ul><li>Elevated triglycerides </li></ul></ul><ul><ul><li>Decreased HDL cholesterol </li></ul></ul><ul><ul><li>Decreased apolipoprotein A-I </li></ul></ul><ul><ul><li>Impaired fibrinolytic activity </li></ul></ul>
  13. 14. Pathogenesis: Insulin resistance <ul><li>Favors anovulation, androgen excess, reduced SHBG </li></ul><ul><li>Metabolic syndrome </li></ul><ul><li>Abdominal obesity </li></ul>
  14. 16. Abnormal Pituitary Function—Altered Negative Feedback Loop <ul><li>Increased GnRH from hypothalamus </li></ul><ul><li>Excessive LH secretion relative to FSH by pituitary gland </li></ul><ul><li>LH stimulates ovarian thecal cells-- androgen production </li></ul><ul><li>Ineffective suppression of the LH pulse frequency by estradiol and progesterone </li></ul><ul><li>Androgen(such as testosterone or androsterone) excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone </li></ul>
  15. 17. hypothalamus pituitary ovary GnRH LH androgens Androgens block inhibitory effect of progesterone X
  16. 18. Abnormal steroidogenenesis <ul><li>Intraovarian androgen excess results in excessive growth of small ovarian follicles </li></ul><ul><li>Follicular maturation is inhibited </li></ul><ul><li>Excess androgen causes thecal and stromal hyperplasia </li></ul>
  17. 19. HYPERINSULINEMIA <ul><li>Excess insulin production and insulin resistance </li></ul><ul><li>Genetic link </li></ul><ul><li>Hyperandrogenism vs. hyperinsulinemia </li></ul><ul><ul><li>Which came first? </li></ul></ul>
  19. 21. <ul><ul><li>Menstrual irregularity due to anovulation or oligo-ovulation </li></ul></ul><ul><ul><li>Evidence of clinical or biochemical hyperandrogenism </li></ul></ul><ul><ul><ul><li>Hirsutism, acne, male pattern baldness </li></ul></ul></ul><ul><ul><ul><li>High serum androgen levels </li></ul></ul></ul><ul><ul><li>Exclusion of other causes (CAH, tumors, hyperprolactinemia) </li></ul></ul>DIAGNOSTIC CRITERIA
  20. 22. MENSTRUAL DYSFUNCTION <ul><li>Oligo or amenorrhea </li></ul><ul><ul><li>Menstrual irregularity typically begins in the peripubertal period </li></ul></ul><ul><ul><li>Delayed menarche </li></ul></ul><ul><li>Reduction in ovulatory events leads to deficient progesterone secretion </li></ul><ul><li>Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding </li></ul><ul><li>Increased risk for endometrial hyperplasia and/or endometrial CA </li></ul>
  21. 24. HYPERANDROGENISM <ul><li>Hirsutism, acne, male pattern balding, alopecia </li></ul><ul><li>50-90% patients have elevated serum androgen levels </li></ul><ul><li>Free testosterone levels most sensitive </li></ul><ul><li>Rare : increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm) </li></ul>
  22. 25. Diagnosis <ul><li>Hyperandrogenism (cont’d) </li></ul><ul><ul><li>Laboratory features </li></ul></ul><ul><ul><ul><li>Elevated total testosterone </li></ul></ul></ul><ul><ul><ul><ul><li>Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or adrenal tumor) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Free testosterone assays not reliable yet </li></ul></ul></ul></ul><ul><ul><ul><li>DHEA-S </li></ul></ul></ul><ul><ul><ul><ul><li>Most normal or slightly high in PCOS </li></ul></ul></ul></ul><ul><ul><ul><ul><li>If >800 mcg/dl, consider adrenal tumor </li></ul></ul></ul></ul><ul><ul><ul><li>LH/FSH ratio </li></ul></ul></ul><ul><ul><ul><ul><li>Levels vary over menstrual cycle, released in pulsatile fashion, affected by OCPs ( contraceptives) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>LH/FSH ratio >2 has little diagnostic sensitivity </li></ul></ul></ul></ul>
  23. 26. Diagnosis <ul><li>2. Oligoovulation or anovulation </li></ul><ul><ul><ul><li>Oligomenorrhea or amenorrhea </li></ul></ul></ul><ul><ul><ul><li>Dysfunctional uterine bleeding </li></ul></ul></ul><ul><ul><ul><li>Infertility </li></ul></ul></ul><ul><ul><ul><ul><li>30-50% 1 st trimester miscarriage rate </li></ul></ul></ul></ul><ul><ul><ul><li>3-fold increased risk endometrial carcinoma </li></ul></ul></ul>
  24. 27. Diagnosis <ul><li>Polycystic Ovaries </li></ul><ul><ul><ul><li>Criteria by ultrasound </li></ul></ul></ul><ul><ul><ul><ul><li>Increased ovarian area (>5.5 cm2) or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter </li></ul></ul></ul></ul><ul><ul><ul><li>Polycystic ovaries not specific for PCOS </li></ul></ul></ul><ul><ul><ul><li>> 20% normal women have incidental polycystic ovaries </li></ul></ul></ul>
  25. 28. OVARIAN ABNORMALITIES <ul><li>Thickened sclerotic cortex </li></ul><ul><li>Multiple follicles in peripheral location </li></ul><ul><li>80% of women with PCOS have classic cysts </li></ul>
  26. 32. INFERTILITY <ul><li>Intermittent ovulation or anovulation </li></ul><ul><li>Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid </li></ul>
  27. 33. Diagnosis <ul><li>4. Absence of other disorders to account for these symptoms. </li></ul><ul><ul><li>Pregnancy  pregnancy test </li></ul></ul><ul><ul><li>Hypothyroidism  TSH </li></ul></ul><ul><ul><li>Hyperprolactinemia  prolactin </li></ul></ul><ul><ul><li>Late onset congenital adrenal hyperplasia  17-hydroxyprogesterone (r/o if <200 ng/dl) </li></ul></ul><ul><ul><li>Ovarian tumor  total testosterone (esp if >200 ng/dl) </li></ul></ul><ul><ul><li>Adrenal tumor  DHEA-S (esp if > 800 mcg/dl) </li></ul></ul><ul><ul><li>Cushing’s syndrome  salivary cortisol, 24 hr urine cortisol </li></ul></ul>
  28. 34. Diagnosis <ul><li>5. Supportive of insulin resistance </li></ul><ul><ul><li>“ Syndrome XX”: 3 or more of the following criteria: </li></ul></ul><ul><ul><ul><li>Waist circumference > 88 cm </li></ul></ul></ul><ul><ul><ul><li>Triglycerides > 150 mg/dl </li></ul></ul></ul><ul><ul><ul><li>HDL <50 mg/dl </li></ul></ul></ul><ul><ul><ul><li>BP > 130/85 </li></ul></ul></ul><ul><ul><ul><li>Fasting glucose >110 mg/dl </li></ul></ul></ul><ul><ul><li>ACOG and ADA suggest screening all women w/ PCOS for glucose intolerance, type 2 DM. </li></ul></ul><ul><ul><li>Oral glucose tolerance test more sensitive than fasting glucose. </li></ul></ul><ul><ul><li>Personal or family history of DM </li></ul></ul><ul><ul><li>Acanthosis nigricans </li></ul></ul>
  29. 35. OBESITY AND INSULIN RESISTANCE <ul><li>½ patients with PCOS are obese </li></ul><ul><li>> 80% are hyperinsulinemic and have insulin resistance (independent of obesity) </li></ul><ul><li>Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver </li></ul>
  30. 36. ASSOCIATED MEDICAL CONDITIONS <ul><li>Increased risk of developing Type 2 Diabetes and Gestational diabetes </li></ul><ul><li>Low HDL and high triglycerides </li></ul><ul><li>Sleep apnea </li></ul><ul><li>Nonalcoholic steatohepatitis </li></ul><ul><li>Metabolic syndrome—43% of PCOS patients (2 fold higher than age-matched population) </li></ul><ul><li>Elevated CRP and heart disease </li></ul><ul><li>Advanced atherosclerosis </li></ul>
  31. 37. DIFFERENTIAL DIAGNOSIS <ul><li>Hyperprolactinemia </li></ul><ul><ul><li>Prominent menstrual dysfunction </li></ul></ul><ul><ul><li>Little hyperandrogenism </li></ul></ul><ul><li>2. Congenital Adrenal Hyperplasia </li></ul><ul><ul><li>morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis </li></ul></ul><ul><ul><li>confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL </li></ul></ul>
  32. 38. <ul><li>3. Ovarian and adrenal tumors </li></ul><ul><ul><li>serum testosterone concentrations are always higher than 150 ng/dL </li></ul></ul><ul><ul><li>adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL </li></ul></ul><ul><ul><li>LOW serum LH concentrations </li></ul></ul><ul><li>4. Cushing’s syndrome </li></ul><ul><li>5. Drugs: danazol; OCPs with high androgenicity </li></ul>
  33. 39. TESTING <ul><li>Serum HCG </li></ul><ul><li>Serum prolactin </li></ul><ul><li>Thyroid panel </li></ul><ul><li>FSH: r/o ovarian failure </li></ul><ul><li>Serum luteinizing hormone (LH)—elevated </li></ul><ul><li>Serum estradiol—normal </li></ul><ul><li>Serum estrone—elevated </li></ul>
  34. 40. TESTING <ul><li>Fasting glucose: elevated </li></ul><ul><li>2 hour OGTT: elevated </li></ul><ul><li>Fasting insulin: elevated </li></ul><ul><li>Free testosterone: elevated </li></ul><ul><li>DHEA-S: normal </li></ul><ul><li>17-hydroxyprogesterone: normal </li></ul><ul><li>Pelvic US </li></ul><ul><li>Lipids </li></ul>
  35. 41. TREATMENT Management <ul><ul><li>Immediate/Acute issues </li></ul></ul><ul><ul><ul><ul><li>Hirsutism </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Regulation of menses </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Fertility issues </li></ul></ul></ul></ul><ul><ul><li>Long-term issues </li></ul></ul><ul><ul><ul><ul><li>Insulin resistance </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cardiovascular risk </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Malignancy risk </li></ul></ul></ul></ul>
  36. 42. WEIGHT LOSS <ul><li>Weight loss </li></ul><ul><li>Weight loss </li></ul><ul><li>Weight loss </li></ul>
  37. 43. Management: Immediate/Acute Issues <ul><li>Regulation of menses </li></ul><ul><ul><ul><li>Oral contraceptives </li></ul></ul></ul><ul><ul><ul><li>Periodic progesterone withdrawal </li></ul></ul></ul><ul><ul><ul><ul><li>Medroxyprogesterone 10 mg/day x 7-10 days, every 3 months (approx 4 menses annually) </li></ul></ul></ul></ul><ul><ul><ul><li>Lifestyle modification/weight loss </li></ul></ul></ul><ul><ul><ul><li>Metformin- ie., hitting the “root cause” </li></ul></ul></ul><ul><ul><ul><ul><li>500-1000 mg bid, 6 month trial reasonable for improvement of menses </li></ul></ul></ul></ul>
  38. 44. Oligomenorrhea <ul><li>Combination estrogen-progestin pill first line when fertility is not desired </li></ul><ul><ul><li>Decrease in LH secretion and decrease in androgen production </li></ul></ul><ul><ul><li>Increase in hepatic production of sex-hormone binding globulin </li></ul></ul><ul><ul><li>Decreased bioavailablity of testosterone </li></ul></ul><ul><ul><li>Decreased adrenal androgen secretion </li></ul></ul><ul><ul><li>Regular withdrawal bleeds </li></ul></ul><ul><ul><li>Prevention of endometrial hyperplasia </li></ul></ul>
  39. 45. Management: Immediate/Acute Issues <ul><ul><li>no fertility desired </li></ul></ul><ul><li>Monophasic antiandrogenic OCP </li></ul><ul><ul><li>ON 1/35 (norethindrone) </li></ul></ul><ul><ul><li>Orthocyclen (norgestimate) </li></ul></ul><ul><ul><li>Desogen or Orthocept (desogestrel) </li></ul></ul><ul><ul><li>Yasmin </li></ul></ul><ul><li>Fertility issues </li></ul><ul><ul><li>Metformin </li></ul></ul><ul><ul><li>Thiazolidinediones </li></ul></ul>
  40. 46. INFERTILITY TREATMEN T <ul><li>Metformin </li></ul><ul><ul><li>500 mg daily </li></ul></ul><ul><ul><li>Increase by 500 mg each week until: </li></ul></ul><ul><ul><ul><li>Normal menses </li></ul></ul></ul><ul><ul><ul><li>Reached max dose </li></ul></ul></ul><ul><ul><ul><li>Side-effects </li></ul></ul></ul><ul><li>Clomid </li></ul><ul><ul><li>50 mg days 3-7 for 3 months </li></ul></ul><ul><ul><li>100 mg days 3-7 for 3 months </li></ul></ul>
  41. 47. METFORMIN <ul><li>Decreases hepatic glucose production </li></ul><ul><li>Reduces need for insulin secretion </li></ul><ul><li>Improves insulin sensitivity (increases peripheral glucose uptake and utilization) </li></ul><ul><li>Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis </li></ul>
  42. 48. Infertility <ul><li>Weight loss—reduction in serum testosterone concentration and resumption of ovulation </li></ul><ul><li>Clomid: 80% will ovulate, 50% will conceive </li></ul><ul><li>Metformin: when added to clomid, improves ovulatory rates </li></ul><ul><li>FSH injections </li></ul><ul><li>Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery </li></ul><ul><li>IVF= Vitro Fertilization </li></ul>
  43. 49. Management: Long-Term Issues <ul><li>Insulin resistance </li></ul><ul><ul><li>Metformin </li></ul></ul><ul><ul><ul><li>Function </li></ul></ul></ul><ul><ul><ul><ul><li>Lowers hepatic glucose production by reducing gluconeogenesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increases peripheral glucose uptake by skeletal muscle and adipose tissue </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Reduces intestinal glucose absorption </li></ul></ul></ul></ul><ul><ul><ul><li>Outcomes </li></ul></ul></ul><ul><ul><ul><ul><li>Estimated 31% reduction in development of type II DM over mean period 3 years </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Taken during pregnancy, reduction in gestational diabetes and major fetal complications </li></ul></ul></ul></ul>
  44. 50. Management: Long-Term Issues <ul><li>Insulin resistance </li></ul><ul><ul><li>Thiazolidinediones </li></ul></ul><ul><ul><ul><li>Function </li></ul></ul></ul><ul><ul><ul><ul><li>Selective ligands of the nuclear transcription PPARγ, expressed in adipose tissue, pancreatic beta cells, vascular endothelium, macrophages, HPO axis. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>“ fatty acid steal” hypothesis </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Promote fatty acid uptake and storage in adipose tissue, sparing other tissues (muscle, liver) from harmful metabolic effects of free fatty acids (high levels in PCOS) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Increased expression of adiponectin (adipocytokine with an insulin sensitivity effect) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decreased expression of 11β-hydroxysteroid dehydrogenase type 1 (enzyme converts inactive cortisone to active cortisol) </li></ul></ul></ul></ul>
  45. 51. Management: Long-Term Issues <ul><li>Cardiovascular Risk </li></ul><ul><ul><li>Increased prevalence of HTN </li></ul></ul><ul><ul><li>Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL) </li></ul></ul><ul><ul><li>Predisposition to macrovascular disease and thrombosis </li></ul></ul><ul><ul><li>Aggressive management…”CHAMP”? </li></ul></ul>
  46. 52. Management: Long-Term Issues <ul><li>Risk for malignancy </li></ul><ul><ul><li>3X increased risk endometrial carcinoma in PCOS </li></ul></ul><ul><ul><li>Increased risk of ovarian and breast cancer </li></ul></ul><ul><ul><li>Warrants regular screening, low threshold for endometrial biopsy </li></ul></ul>
  47. 54. Diet and Exercise <ul><li>In patients with PCOS who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. </li></ul><ul><li>Their SHBG levels rise and free testosterone levels fall by 2-fold. </li></ul><ul><li>Serum insulin and IGF-1 levels also decrease. </li></ul><ul><li>Weight loss in patients with PCOS who are obese is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women. </li></ul>
  48. 55. Diet and Exercise <ul><li>A moderate amount of daily exercise increases of levels of IGF-1 binding protein and decreases IGF-1 levels by 20%. </li></ul><ul><li>Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. </li></ul><ul><li>A daily 500-1000 calorie deficit with 150 minutes of exercise per week can cause ovulation. </li></ul><ul><li>The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications. </li></ul>