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Polikistik Over Sendromu - PCOS - www.jinekolojivegebelik.com

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Polikistik Over Sendromu - PCOS - www.jinekolojivegebelik.com

Polikistik Over Sendromu - PCOS - www.jinekolojivegebelik.com

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  • Transcript

    • 1. Polycystic Ovarian Syndrome Sonia Ralli, M.D. January 18, 2007
    • 2. Case
      • A 40 yo female presents to you in clinic for a “physical exam”.
      • -PMH significant for HTN, on no meds
      • -had one child at age 30, required clomiphene induction
      • -on further asking, has had to wax her upper lip and chin for many years for “stubborn hair”
    • 3. Case (cont’d)
      • -PE significant for being mildly overweight (BMI~27), BP 140/80, HR 70.
      • -random accucheck in office: 150
      • Management options?
      • Screening options?
    • 4. History
      • Originally described by Stein and Leventhal in 1935, first known as the “ Stein-Leventhal syndrome ”
      • 7 women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance to their ovaries.
    • 5. What is PCOS?
      • Disorder characterized by 2 of the following:
        • Hyperandrogenism
        • Oligoovulation or chronic anovulation
        • Polycystic ovaries
        • In the absence of pituitary or adrenal disease
      • It is a syndrome, ie., no single test can establish the diagnosis.
    • 6. Why is PCOS important?
      • Affects 4-12% of women of reproductive age
      • Significant association between obesity, insulin resistance, and PCOS.
      • Huge impact on the reproductive, metabolic, and cardiovascular health of affected women.
    • 7. Pathogenesis
      • 1. Hyperandrogenism
      • 2 . Insulin resistance
    • 8. Ehrmann NEJM 2005
    • 9. Pathogenesis: Hyperandrogenism
      • Symptoms of androgen excess
      • Reduced sex-hormone-binding globulin (SHBG)  more free testosterone
      • Insulin insensitivity
      • Lipid abnormalities
      • Abdominal obesity
    • 10. Pathogenesis: Insulin resistance
      • Favors anovulation, androgen excess, reduced SHBG
      • Metabolic syndrome
      • Abdominal obesity
    • 11. Insulin resistance in PCOS: it’s not just a theory
      • Insulin resistance in PCOS is independent of obesity
        • Obese women with PCOS tend to be more insulin resistant than nml-wt counterparts.
        • Obesity is an independent risk factor for glucose intolerance or DM in PCOS
      • 3-fold increased incidence of metabolic syndrome in PCOS, vs general population, independent of obesity.
      • Insulin resistance ≠ glucose intolerance
        • Many insulin resistant PCOS pts have normal glucose tolerance
        • 30-40% prevalence of glucose intolerance in PCOS women
        • 7-10% prevalence of type 2 DM in PCOS women
        • Insulin resistance worsens over time
        • Increased risk for impaired glucose tolerance and type 2 DM
    • 12.  
    • 13. Diagnosis
      • Disorder characterized by 2 of the following:
        • Hyperandrogenism
        • Oligoovulation or chronic anovulation
        • Polycystic ovaries
      • And the absence of pituitary or adrenal disease
    • 14. Diagnosis
      • Hyperandrogenism
        • Clinical features
            • Hirsutism (growth of coarse hair on a woman in a male pattern– upper lip, chin, chest, upper abdomen, back, etc)
            • Acne
            • Male pattern alopecia
            • NOT virilization (clitoromegaly, deep voice, increased musculature, rapidly progressive hirsutism)
    • 15.  
    • 16. Not hirsutism!
    • 17. Hirsutism
    • 18. Diagnosis
      • Hyperandrogenism (cont’d)
        • Laboratory features
          • Elevated total testosterone
            • Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or adrenal tumor)
            • Free testosterone assays not reliable yet
          • DHEA-S
            • Most normal or slightly high in PCOS
            • If >800 mcg/dl, consider adrenal tumor
          • LH/FSH ratio
            • Levels vary over menstrual cycle, released in pulsatile fashion, affected by OCPs
            • LH/FSH ratio >2 has little diagnostic sensitivity and need not be documented
    • 19. Diagnosis
      • 2. Oligoovulation or anovulation
          • Oligomenorrhea or amenorrhea
          • Dysfunctional uterine bleeding
          • Infertility
            • 30-50% 1 st trimester miscarriage rate
          • 3-fold increased risk endometrial carcinoma
    • 20. Diagnosis
      • Polycystic Ovaries
          • Criteria by ultrasound
            • Increased ovarian area (>5.5 cm2) or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter
          • Polycystic ovaries not specific for PCOS
          • > 20% normal women have incidental polycystic ovaries
    • 21. Polycystic ovaries, by ultrasound
    • 22. Diagnosis
      • 4. Absence of other disorders to account for these symptoms.
        • Pregnancy  pregnancy test
        • Hypothyroidism  TSH
        • Hyperprolactinemia  prolactin
        • Late onset congenital adrenal hyperplasia  17-hydroxyprogesterone (r/o if <200 ng/dl)
        • Ovarian tumor  total testosterone (esp if >200 ng/dl)
        • Adrenal tumor  DHEA-S (esp if > 800 mcg/dl)
        • Cushing’s syndrome  salivary cortisol, 24 hr urine cortisol
    • 23. Diagnosis
      • 5. Supportive of insulin resistance
        • “ Syndrome XX”: 3 or more of the following criteria:
          • Waist circumference > 88 cm
          • Triglycerides > 150 mg/dl
          • HDL <50 mg/dl
          • BP > 130/85
          • Fasting glucose >110 mg/dl
        • ACOG and ADA suggest screening all women w/ PCOS for glucose intolerance, type 2 DM.
        • Oral glucose tolerance test more sensitive than fasting glucose.
        • Personal or family history of DM
        • Acanthosis nigricans
    • 24. Management
        • Immediate/Acute issues
            • Hirsutism
            • Regulation of menses
            • Fertility issues
        • Long-term issues
            • Insulin resistance
            • Cardiovascular risk
            • Obstructive sleep apnea
            • Malignancy risk
    • 25. Management: Immediate/Acute Issues
        • Control of hirsutism
          • Medical (need a trial of 6-12 mos before deemed ineffective)
            • Decrease testosterone production (predominantly from ovary)
              • OCPs (improvement scores 33%)
              • -Increase SHBG
              • Lifestyle modification/weight loss
              • Metformin (improvement scores 10-13%)
              • Glucocorticoids?
              • -Theory: ACTH stimulates adrenal androgen synthesis. So, suppress ACTH via glucocorticoids.
              • -Study by Vanky, et al- dexamethasone 0.25 mg/day vs placebo—reduction in testosterone, androstenedione, DHEA-S by 25-50%. No significant change in BMI, glucose, insulin, lipids
              • -problematic
    • 26. Management: Immediate/Acute Issues
        • Control of hirsutism (cont’d)
          • Decrease testosterone action
            • Antiandrogens
              • Spironolactone (start 50 mg bid  100 mg bid)
              • -Reduction in hirsutism 45%
              • -Preferred use w/ OCPs, 75% response
              • Drospirenone (analogue of spironolactone, approved in Yasmin)
              • 5α-reductase inhibitors (ex. Finasteride)
            • Lifestyle modification/weight loss
            • Metformin
    • 27. Management: Immediate/Acute Issues
        • Control of hirsutism (cont’d)
          • Mechanical
            • Plucking/shaving/electrolysis/laser
            • Vaniqa cream (eflornithine hydrochloride 13.9%)
              • Mechanism: slows growth of hair by inhibiting L-ornithine decarboxylase (enzyme involved in hair growth)
              • 58% demonstrated some improvement in hair growth vs 32% with placebo
              • Hair growth rates return to nml 8 wks off therapy
              • Not covered by most insurance policies
    • 28. Management: Immediate/Acute Issues
      • Regulation of menses
          • Oral contraceptives
          • Periodic progesterone withdrawal
            • Medroxyprogesterone 10 mg/day x 7-10 days, every 3 months (approx 4 menses annually)
          • Lifestyle modification/weight loss
          • Metformin- ie., hitting the “root cause”
            • 500-1000 mg bid, 6 month trial reasonable for improvement of menses
    • 29. Management: Immediate/Acute Issues
      • Fertility issues
        • Lifestyle modification/weight loss
          • Loss of >5% body wt, calorie-restricted diet, and exercise associated with improvement in spontaneous pregnancy rates (7.5-15% improvement)
        • Clomiphene citrate
            • Most women with PCOS do not respond to normal dose—20% ovulation rate!
    • 30. Management: Immediate/Acute Issues
      • Fertility issues (cont’d)
        • Metformin
            • OR 3.88 in achieving fertility (compared to placebo), 4.4 (for metformin+clomiphene compared to clomiphene alone)
            • Improved outcomes with in vitro fertilization (reduced risk of ovarian hyperstimulation when treated with FSH)
            • Reduction in 1st trimester spontaneous abortions
        • Thiazolidinediones
          • Early studies w/ rosiglitazone prior to conception  30% improvement in fertility rates.
    • 31. Management: Long-Term Issues
      • Insulin resistance
          • Lifestyle modification/weight loss
    • 32. Management: Long-Term Issues
      • Insulin resistance
        • Metformin
          • Function
            • Lowers hepatic glucose production by reducing gluconeogenesis
            • Increases peripheral glucose uptake by skeletal muscle and adipose tissue
            • Reduces intestinal glucose absorption
          • Outcomes
            • Estimated 31% reduction in development of type II DM over mean period 3 years
            • Taken during pregnancy, reduction in gestational diabetes and major fetal complications
    • 33. Management: Long-Term Issues
      • Insulin resistance
        • Thiazolidinediones
          • Function
            • Selective ligands of the nuclear transcription PPARγ, expressed in adipose tissue, pancreatic beta cells, vascular endothelium, macrophages, HPO axis.
            • “ fatty acid steal” hypothesis
              • 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)
            • Increased expression of adiponectin (adipocytokine with an insulin sensitivity effect)
            • Decreased expression of 11β-hydroxysteroid dehydrogenase type 1 (enzyme converts inactive cortisone to active cortisol)
          • Outcomes
    • 34. Management: Long-Term Issues
      • Cardiovascular Risk
        • Increased prevalence of HTN
        • Dyslipidemia ( ↑ TG, ↓ HDL, ↑ LDL)
        • Predisposition to macrovascular disease and thrombosis
          • Nurses’ health study: 20-60% increased risk of CAD events
          • Studies of pts undergoing coronary angiography: women with significant h/o hirsutism or polycystic ovaries more likely to have CAD, and if they had it, more extensive CAD, compared to female controls.
        • Aggressive management…”CHAMP”?
    • 35. Management: Long-Term Issues
      • Obstructive Sleep Apnea
        • 30-fold increased risk of OSA, not explained by obesity alone.
        • Insulin resistance strongest predictor of OSA (not BMI, age, testosterone)
        • Consider polysomnography if at risk
    • 36. Management: Long-Term Issues
      • Risk for malignancy
        • 3X increased risk endometrial carcinoma in PCOS
        • Increased risk of ovarian and breast cancer
        • Warrants regular screening, low threshold for endometrial biopsy
    • 37.  
    • 38. Other issues Role of epilepsy?
        • Increased incidence of reproductive disorders in patients with epilepsy
        • Pts on valproic acid may have higher levels of insulin, testosterone, and TG
    • 39. New things on the horizon…
      • Somatostatin analogs
        • Function
          • Blunts LH response to GnRH
          • Decreases GH secretion by pituitary
          • Inhibits pancreatic insulin release
        • Outcomes: limited studies
          • 7 d administration octreotide in PCOS women  decreased fasting and glucose-stimulated insulin levels
          • Reduced LH, androgen, IGF-1 levels
          • Short half-life (80-110 min) requiring multiple injections
          • Extended release octreotide (octreotide-LAR)- inject IM Q28 days- results in improvement in GH, insulin, IGF-1, hirsutism
          • Not approved yet
    • 40. References
      • American College of Obstetricians and Gynecologists (ACOG) practice bulletin. Polycystic ovary syndrome. 2002.
      • Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale H, Futterweit W, Janssen O, Legro RS, Norman RJ, Taylor AE, Witchel SF. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. Journal of Clinical Endocrinology & Metabolism 2006;91:4237-45.
      • Barber TM, McCarthy MI, Wass JA, Franks S. Obesity and polycystic ovary syndrome. Clin Endocrinol 2006;65:137-45.
      • Ehrmann DA. Polycystic Ovary Syndrome. NEJM 2005;352:1223-36.
      • Froment P, Gizard F, Defever D, Staels B, Dupont J, Monget P. Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition. Journal of Endocrinology 2006;189:199-209.
      • Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang P. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Human Reproduction 2003;18:1618-25.
      • Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165-9.
      • Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. NEJM 1998;338:1876-80.
      • Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251-7.
      • Pasquali R, Gambineri A. Insulin-sensitizing agents in polycystic ovary syndrome. European Journal of Endocrinology 2006;154:763-75.
      • Schneider JG, Tompkins C, Blumenthal RS, Mora S. The metabolic syndrome in women. Cardiol Rev 2006;14:286-91.
      • Shapiro J, Lui H. Treatments for unwanted facial hair. Skin Therapy Lett 2006;10:1-4.
      • Sheehan, MT. Polycystic ovarian syndrome: diagnosis and management. Clinical Medicine and Research 2004;2:13-27.
      • Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril 2006;86:1432-7.
      • Srikanthan P, Korenman S, Davis S. Polycystic ovarian syndrome: the next cardiovascular dilemma in women? Endocrinol Clin North Am 2006;35:611-31.