Polikistik Over Sendromu - PCOS - www.jinekolojivegebelik.com


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Polikistik Over Sendromu - PCOS - www.jinekolojivegebelik.com

  1. 1. Polycystic Ovary Syndrome Camille Andy, MD Cone Family Practice June 9, 2006
  2. 2. Case Study <ul><li>26 yo Latina female presents with primary complaint of infertility </li></ul><ul><li>Married and sexually active with partner, but never has been pregnant </li></ul><ul><li>Never has used birth control </li></ul>
  3. 3. You Notice… <ul><li>Central obesity; Her BMI is 29 </li></ul><ul><li>Acne on her face and upper back </li></ul><ul><li>Increased facial hair </li></ul>
  4. 4. She Says… <ul><li>Menstrual cycles have always been irregular, usually once every 3-8 months </li></ul><ul><li>She has been overweight since teenager; she eats the typical high carb mexican diet </li></ul><ul><li>Little exercise </li></ul><ul><li>She feels depressed and worried about not being able to conceive </li></ul><ul><li>Family history + for DMII, CAD in mother </li></ul>
  5. 5. Does She Have PCOS? Is It Important to Know?
  6. 6. Case 2 <ul><li>34 yo with abrupt onset (<1 year) of hirsutism and pustular acne </li></ul><ul><li>History of normal menses and 2 healthy children, but now amenorrhea </li></ul><ul><li>Husband has noticed deepening of voice </li></ul><ul><li>Labs? Diagnosis? </li></ul>
  7. 7. Case 3 <ul><li>24 year old presents with c/o “no menses for one year” </li></ul><ul><li>Occasional galactorrhea </li></ul><ul><li>PE is significant for normal body hair patterns and clear skin, normal BMI, no striae </li></ul><ul><li>Labs? Diagnosis? </li></ul>
  8. 8. Objectives <ul><li>Learn to make the diagnosis of PCOS </li></ul><ul><li>Understand importance of this syndrome </li></ul><ul><li>Clarify the distinguishing hormonal patterns of PCOS </li></ul><ul><li>Discuss management goals </li></ul>
  9. 9. PCOS <ul><li>Most common endocrinopathy among women of reproductive age </li></ul><ul><li>Affects up to 10% of US women </li></ul><ul><li>Approx 5 million women </li></ul>
  10. 10. Stein-Leventhal Syndrome <ul><li>Masculinized women with amenorrhea, sterility, and enlarged ovaries with multiple cysts </li></ul><ul><li>A “gynecologic” disorder </li></ul><ul><li>Management focused on bleeding abnormalities and infertility </li></ul>
  11. 11. New Information <ul><li>By early 1980’s, syndrome linked to hyperinsulinemia and impaired glucose tolerance </li></ul><ul><li>1990’s, found a defect in an insulin receptor </li></ul><ul><li>Now, much broader long-term health implications for women with PCOS </li></ul>
  12. 12. Clinical Course <ul><li>Young women seek medical attention </li></ul><ul><ul><li>Irregular menses </li></ul></ul><ul><ul><li>Hirsutism </li></ul></ul><ul><ul><li>Infertility </li></ul></ul><ul><ul><li>Obesity </li></ul></ul><ul><li>Peripubertal onset </li></ul><ul><li>Hormonal imbalance leads to symptoms throughout reproductive years </li></ul>
  13. 13. Long-term Consequences <ul><li>Infertility </li></ul><ul><li>Recurrent SAB </li></ul><ul><li>Depression/anxiety </li></ul><ul><li>Dyslipidemias </li></ul><ul><ul><li>Elevated cholesterol, LDL, and triglycerides </li></ul></ul><ul><ul><li>Decreased HDL </li></ul></ul><ul><li>Hypertension </li></ul><ul><li>Type 2 Diabetes </li></ul><ul><li>CAD </li></ul><ul><li>CVA </li></ul><ul><li>Endometrial Carcinoma </li></ul>
  14. 14. Diagnostic Criteria <ul><li>2003 Consensus Meeting (European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine) </li></ul><ul><li>Need 2 of 3: </li></ul><ul><ul><li>Oligo- and/or anovulation </li></ul></ul><ul><ul><li>Clinical and/or biochemical signs of hyperandrogenism </li></ul></ul><ul><ul><li>Polycystic ovaries (by ultrasound) </li></ul></ul><ul><li>And must exclude other endocrinopathies </li></ul>
  15. 15. Menstrual Cycle
  16. 16. Chronic Anovulation <ul><li>Due to hormonal imbalance of gonadotropins and ovarian dysfunction </li></ul><ul><li>Reduction in ovulatory events lead to deficient progesterone secretion </li></ul><ul><li>Chronic unopposed estrogen stimulation of endometrium </li></ul><ul><ul><li>Hyperplasia </li></ul></ul><ul><ul><li>Intermittent breakthrough bleeding </li></ul></ul><ul><ul><li>Dysfunctional uterine bleeding </li></ul></ul>
  17. 17. Oligo- or amenorrhea <ul><li>Occurs in 70% </li></ul><ul><li>Typically a peripubertal onset </li></ul><ul><ul><li>Normal or slightly delayed menarche, then irregular cycles </li></ul></ul><ul><ul><li>Can have normal cycles at first, then irregular after weight gain </li></ul></ul><ul><ul><li>Some with prolonged amenorrhea due to high androgens affecting endometrium </li></ul></ul><ul><li>Many patients won’t think this is abnormal </li></ul>
  18. 18. Hyperandrogenism <ul><li>Clinical </li></ul><ul><ul><li>Hirsutism - excess terminal (thick, pigmented) body hair in a male distribution </li></ul></ul><ul><ul><li>Acne </li></ul></ul><ul><ul><li>Android body habitus </li></ul></ul><ul><li>Biochemical </li></ul><ul><ul><li>50% – 90% have elevated serum androgen levels </li></ul></ul><ul><ul><li>Produced by ovaries and adrenals </li></ul></ul>
  19. 19. Hirsutism - the Best Clinical Marker of Hyperandrogenism
  20. 20. Acne – a More Variable Marker
  21. 21. Other Symptoms <ul><li>Obesity </li></ul><ul><ul><li>> 65% have elevated BMI </li></ul></ul><ul><ul><li>Usually fat is abdominal/visceral </li></ul></ul><ul><ul><li>Strongly associated with metabolic disturbances </li></ul></ul><ul><li>Acanthosis nigricans </li></ul><ul><ul><li>Due to insulin stimulation of epidermis </li></ul></ul><ul><li>Polycystic ovaries </li></ul><ul><ul><li>80% w/ PCOS </li></ul></ul>
  22. 22. Polycystic Ovaries <ul><li>>10 follicles 2-8mm in diameter, peripheral, increased stroma </li></ul><ul><li>80% w/ hyper-androgenism (PCOS) </li></ul><ul><li>87% w/ oligo-menorrhea </li></ul><ul><li>82% premenopausal w/ DM2 </li></ul><ul><li>26% amenorrhea </li></ul><ul><li>16-23% NORMALS </li></ul>
  23. 23. Let’s Talk Hormones <ul><li>Too much androgen </li></ul><ul><li>Too much estrogen </li></ul><ul><li>Too much insulin </li></ul><ul><li>What about </li></ul><ul><ul><li>LH/FSH? </li></ul></ul><ul><ul><li>SHBG? </li></ul></ul><ul><ul><li>Prolactin? </li></ul></ul>
  24. 24. Androgen Metabolism <ul><li>Produced by adrenals and ovaries, and peripheral conversion </li></ul><ul><li>Testosterone most potent </li></ul><ul><ul><li>Free form is biologically active </li></ul></ul><ul><ul><li>Determined by Serum Hormone Binding Globulin (SHBG) </li></ul></ul><ul><ul><li>Free levels tend to be elevated due to decreased SHBG (due to estrogen, androgens, and insulin) </li></ul></ul>
  25. 25. Androstenedione <ul><li>Androstenedione is the immediate precursor to testosterone, produced in ovaries, stimulated by LH </li></ul><ul><li>In ovaries, it gets converted by aromatase to estrone and estradiol </li></ul><ul><li>But in PCOS, decreased activity of enzyme result in large amounts of androgen to be sent into circulation </li></ul>
  26. 26. DHEA-S <ul><li>Majority from adrenal glands with little peripheral conversion from DHEA </li></ul><ul><li>Therefore, good marker for adrenal androgen production </li></ul><ul><ul><li>ie, can rule out adrenal secreting tumor if OK </li></ul></ul><ul><li>Little intrinsic androgenic activity </li></ul>
  27. 27. Estrogen Metabolism <ul><li>PCOS is a slightly hyperestrogenic state due to normal to slightly elevated estradiol and estrone concentrations </li></ul><ul><ul><li>Due to increased estrogen production from polycystic ovaries and increased peripheral conversion from fat cells </li></ul></ul><ul><li>Therefore, at increased risk of endometrial hyperplasia, even if amenorrheic </li></ul>
  28. 28. Control of Hormone Production <ul><li>COMPLEX!! </li></ul><ul><li>Incompletely understood </li></ul><ul><ul><li>Genetic predisposition </li></ul></ul><ul><ul><li>Hypothal-pituitary-ovarian axis dysfunction </li></ul></ul><ul><ul><li>Increased theca cells in ovary with increased hormonal response </li></ul></ul><ul><ul><li>Changes in important enzymatic pathways </li></ul></ul>
  29. 29. Insulin Resistance <ul><li>Both insulin resistance and hyperinsulinemia appear to be almost universal in PCOS </li></ul><ul><li>> 50% of obese women with PCOS </li></ul><ul><li>But non-obese women with PCOS also associated with IR </li></ul><ul><li>25-30% show impaired glucose tolerance by age 30, and 8% develop frank DM2 annually </li></ul>
  30. 30. Role of Insulin <ul><li>Insulin receptors are found in the ovary </li></ul><ul><li>Insulin stimulates androgen production by the ovarian theca cells </li></ul><ul><li>Plasma insulin correlates with androgen levels </li></ul><ul><li>Hyperinsulinemia induces higher androgen production by both ovary and adrenals </li></ul>
  31. 31. Endless Cycle <ul><li>This elevation of insulin stimulates ovarian androgen production and suppresses serum SHBG, further increasing hyperandrogenism </li></ul><ul><li>So, even though insulin resistant in adipose, muscle and liver, the ovaries are insulin sensitive </li></ul>
  32. 32. How To Make The Diagnosis <ul><li>Criteria suggest it is a clinical diagnosis </li></ul><ul><ul><li>But, “must exclude other endocrinopathies” </li></ul></ul><ul><li>Congenital adrenal hyperplasia </li></ul><ul><li>Androgen secreting tumors </li></ul><ul><li>Pituitary adenoma </li></ul><ul><li>Thyroid abnormalities </li></ul><ul><li>Cushing’s syndrome </li></ul><ul><li>Drugs </li></ul>
  33. 33. Which Labs? <ul><li>Check for hormonal changes that will either rule out other significant disorders that can impact the patient AND/OR those hormonal patterns that confirm an unclear clinical picture </li></ul><ul><li>Once the diagnosis is made, monitor important markers of insulin resistance or CAD </li></ul>
  34. 34. Diagnostic Labs <ul><li>BetaHcG </li></ul><ul><li>TSH </li></ul><ul><li>Prolactin </li></ul><ul><li>Testosterone (free or total) </li></ul><ul><li>DHEA-S </li></ul><ul><li>Androstenedione </li></ul><ul><li>17-OHP </li></ul><ul><li>Fasting insulin </li></ul><ul><li>Fasting glucose </li></ul><ul><li>Oral glucose tolerance test </li></ul><ul><li>LH </li></ul><ul><li>FSH </li></ul><ul><li>Lipids </li></ul><ul><li>Pelvic ultrasound </li></ul>
  35. 35. Testosterone Levels and DHEA-S <ul><li>Can be misleading </li></ul><ul><li>Can be normal to slightly elevated </li></ul><ul><li>Free testosterone most accurate (but more expensive) </li></ul><ul><li>Order to exclude androgen-secreting neoplasm and/or to monitor therapy </li></ul>
  36. 36. 17-hydroxyprogesterone <ul><li>In steroid synthesis pathway, 21-hydroxylase deficiency causes nonclassical congenital adrenal hyperplasia </li></ul><ul><li>If elevated 17OHP found, order ACTH stimulation test to clarify disorder </li></ul><ul><li>RARE </li></ul>
  37. 37. LH/FSH <ul><li>Ratio > 2.5 (or 3) is strongly associated with PCOS </li></ul><ul><li>Dependent upon timing of sample, so not helpful if negative </li></ul>
  38. 38. Glucose Testing <ul><li>Oral glucose tolerance testing with insulin levels </li></ul><ul><ul><li>Reserve for family history, morbid obesity, or symptoms </li></ul></ul><ul><li>Ratio of fasting glucose levels to insulin </li></ul><ul><ul><li><4.5 correlates with insulin resistance </li></ul></ul><ul><ul><li>PPV 97% in obese pts with PCOS </li></ul></ul>
  39. 39. Summary of Diagnostic Approach to Hirsutism <ul><li>If long-standing mild hirsutism, like family members, and normal menses, NO LABS needed </li></ul><ul><li>If mild-mod hirsutism and irregular cycles, check testosterone, prolactin, and TSH </li></ul><ul><li>If moderate-severe or rapidly progressive hirsutism or other virilizing signs, check androgens including DHEA-S </li></ul>
  40. 40. Management Goals <ul><li>Primary goal for all is to suppress insulin-facilitated, LH-driven androgen production </li></ul><ul><li>Must consider individual patient’s goals regarding reproductive goals and long-term risks of CAD and endometrial cancer </li></ul>
  41. 41. First! <ul><li>Lifestyle modification should be first-line therapy </li></ul><ul><li>7-10% weight loss is associated with a return to normal menstrual cycles and decreased insulin resistance </li></ul>
  42. 42. Insulin Sensitizers <ul><li>Metformin </li></ul><ul><li>Thioglitazones </li></ul>
  43. 43. Exercise <ul><li>Approximately 80% of the body’s insulin mediated glucose uptake takes place in muscles, making physical activity essential for reducing insulin resistance </li></ul><ul><li>Multiple studies support benefits of exercise </li></ul>
  44. 44. Infertility <ul><li>Weight loss can initiate ovulation </li></ul><ul><li>Clomid (clomiphene citrate) </li></ul><ul><ul><li>Will induce ovulation in 80% </li></ul></ul><ul><ul><li>Only 50% with successful fertilization </li></ul></ul><ul><ul><li>50mg qd x 5d, days 5-9 after onset of spontaneous or progesterone-induced menses </li></ul></ul><ul><ul><li>Can add metformin 500mg tid </li></ul></ul>
  45. 45. Amenorrhea <ul><li>Must protect the endometrium </li></ul><ul><ul><li>Combined oral contraceptives with low androgenic progesterone </li></ul></ul><ul><ul><li>Yasmin, spironalactone analog </li></ul></ul><ul><li>If OCPs contraindicated, should use cyclic provera, q 3 months, to withdraw endometrium </li></ul><ul><li>Can try metformin to induce ovulatory cycles </li></ul>
  46. 46. Hirsutism/acne <ul><li>Shaving is safe and effective </li></ul><ul><li>Bleaching, depliatory, laser, and electrolysis </li></ul><ul><li>Vaniqua cream </li></ul><ul><li>OCPs </li></ul><ul><li>Spironolactone – need to have contraception as well </li></ul><ul><li>Therapies take time to work </li></ul>
  47. 47. Case 1 <ul><li>Latina w/ irregular menses and clinical hyperandrogenism, infertility </li></ul><ul><ul><li>PCOS </li></ul></ul><ul><ul><li>weight loss, metformin and/or clomid </li></ul></ul><ul><ul><li>look at lipids, BP </li></ul></ul><ul><ul><li>discuss diagnosis/prognosis </li></ul></ul><ul><ul><li>address depression </li></ul></ul>
  48. 48. Case 2 <ul><li>34 yo with abrupt onset (<1 year) of hirsutism and pustular acne </li></ul><ul><li>History of normal menses and 2 healthy children, but now amenorrhea </li></ul><ul><li>Husband has noticed deepening of voice </li></ul><ul><li>Labs? Diagnosis? </li></ul>
  49. 49. Case 2 <ul><li>What’s different? </li></ul><ul><li>Labs </li></ul><ul><ul><li>Extremely elevated DHEA-S and testosterone levels indicating an adrenal tumor </li></ul></ul>
  50. 50. Case 3 <ul><li>24 year old presents with c/o “no menses for one year” </li></ul><ul><li>Occasional galactorrhea </li></ul><ul><li>PE is significant for normal body hair patterns and clear skin, normal BMI, no striae </li></ul><ul><li>Labs? Diagnosis? </li></ul>
  51. 51. Case 3 <ul><li>Why not PCOS? </li></ul><ul><li>Labs </li></ul><ul><ul><li>Normal LH/FSH, normal androgens, normal TSH </li></ul></ul><ul><ul><li>Moderately elevated prolactin </li></ul></ul><ul><ul><li>MRI reveals a pituitary macroadenoma </li></ul></ul>
  52. 52. Take Home <ul><li>Remember brief menstrual history </li></ul><ul><li>If you notice hirsutism, think of PCOS </li></ul><ul><li>Don’t go crazy with labs, and understand which test tells you what </li></ul><ul><li>Think insulin resistance and long-term consequences </li></ul>