Polycystic Ovary SyndromeSimplifiedJan Shepherd, MD, FACOG
ObjectivesDiscuss the current understanding of the pathophysiology of PCOSIdentify management options for the gynecologic consequences of PCOS: oligo-ovulation, hirsutism, and infertilityIdentify management options for the metabolic effects of PCOS
Polycystic Ovary Syndrome (PCOS)Most common endocrine abnormality in reproductive-aged women Affects 6-10% 35% of adult-onset anovulationMost common cause of hyperandrogenism
Genetic SusceptibilityApparent autosomal dominant pattern70% concordance in identical twins, 5-7X increased risk in siblings BUT Many genes and environment interact20-40% penetranceVariable presentation in femalesMales hyperandrogenic and insulin resistantEntire family needs increased surveillance*Speroff. Clinical Gynecologic Endocrinology and Infertility
Proposed Pathophysiology Genetic susceptibility Abnormal setting of hypothalamus Abnormal pulsatility of GnRH LH (and FSH) production ovarian androgens*Speroff. Clinical Gynecologic Endocrinology and Infertility
Excess in ovarian androgens Excess terminal hair production, also acne and sometimes alopecia AND Increased peripheral conversion off androstenedione to estrone
Further inhibits FSH production, which arrests follicle development and maturation ANDProliferates the endometrium unopposed, which increases the risk of endometrial hyperplasia/cancer
In AdditionVarious diabetes susceptibility genes appear to be linked to genes affecting GnRH sensitivity 50-75% of PCOS patients are insulin-resistant, which can lead to:Impaired glucose tolerance (30-40%) Frank diabetes mellitus (7.5-10%)Acanthosis nigricansCentral obesity (~60%)Metabolic syndrome (43-46%)
Associated Clinical FeaturesHyperlipidemia (70%)total cholesterolTG, LDL, HDLHypertension (40% by perimenopause)Atherosclerosis intimal thicknesscoronary artery calcification7X normal risk of MI
AndBoth the ovary and adrenal gland contain insulin receptors LH is augmented by insulin Further increase in androgen synthesis
Summary of PCOS
Criteria for Diagnosis
Stein-Leventhal (1935)1990 NIH Conference2003 Rotterdam Consensus WorkshopAmenorrheaOligo-ovulation2 out of 3 Oligo-ovulationHirsutismClinical or biochemical hyperandrogenismClinical or biochemical hyperandrogenismPolycystic ovariesExclusion of other endocrinopathiesPolycystic ovaries (>12 follicles, 2-9mm)Incidental finding: ~ 60% obesePlusExclusion of other endocrinopathies
How Important Are Cysts?Ovaries in women with PCOS are usually 2-5 times larger than normal Usually have a thickened cortex with multiple cysts BUT Only 50-75% of women with clinical PCOS have polycystic ovaries 75% of anovulatory women from any cause have polycystic-appearing ovaries 8-25% of endocrinologically normal women have polycystic-appearing ovaries
Newest Criteria(Androgen Excess Society 2009)Hyperandrogenism hirsutism and/or hyperandrogenemia andOvarian Dysfunction oligo-ovulation and/or polycystic ovaries andExclusion of other endocrinopathiesFertil Steril 2009;91:456-88.
Fertil Steril 2009;91:456-88.
PCOS: A Practical EvaluationHistoryAge at onset of oligomenorrhea, hyperandrogenismRate of progressionSymptoms of related endocrinopathiesGalactorrheaHyper/HypothyroidismCushings syndromePhysical ExamSigns of hyperandrogenismAcanthosis nigricansSigns of related endocrinopathies
CaseA 22-year-old Caucasian female g0 presents with irregular (q 3-4 months) heavy menses. She states her periods have never been regular and shes had a long-standing problem with facial hair. On PE, you note evidence that she has shaved her chin and upper lip and a male escutcheon on her lower abdomen. What tests are needed to make your diagnosis?
PCOS: A Clinical DiagnosisGuzick D. Obstet Gynecol 2004;103:181-93.
17-OH Progesterone Rules Out Atypical Congenital Adrenal HyperplasiaPrimarily seen in Ashkenazi Jews, Hispanics, Italians, Yugoslavs, and Inuits
CaseA 23-year-old Chinese-American g0 presents with irregular (q 3-4 months) heavy menses since menarche at age 11. She denies hirsutism and you see no evidence of it on PE. She denies galactorrhea and any symptoms of thyroid dysfunction. What tests are needed to make your diagnosis?
CaseA 30-year-old AA female g2p2 presents with increasingly irregular and heavy menses for the past year. She has also begun to notice facial hair during this time and states the problem is getting worse. On exam you notice a male escutcheon and mild clitoromegaly. What tests are needed to make your diagnosis?
Additional Optional TestsLH, FSHLH/FSH > 2 is consistent with PCOSDHEAS> 700 = adrenal pathology24-hour urine free cortisolPelvic ultrasound
Polycystic Ovary on Ultrasound> 12 small (2-9mm) subcapsular cystsString of pearls effectHyperechogenic stromaConsider measurement of endometrial thickness
Essential Medical EvaluationWeight BMIBlood pressureFasting lipid profile2-hour GTTInsulin Resistance: FBS > 110, 2 hr. > 140Type II Diabetes: FBS > 126, 2 hr. > 200
Management of PCOS: A Practical ApproachControl weight with diet and exercise to reduce health risks and improve ovulation Utilize hormones, antiandrogens, and local treatments to reduce hirsutism Assure adequate progestin to reduce risk of endometrial hyperplasiaIndividualize endocrine treatment based on presentation and time in life cycleNeed for contraceptionInfertilityManagement will span all of a womans reproductive years
CaseA 22-year-old Caucasian female g0 presents with irregular (q 3-4 months) heavy menses. She states her periods have never been regular and shes had a long-standing problem with facial hair. On PE, you note evidence that she has shaved her chin and upper lip and a male escutcheon on her lower abdomen. How will you manage her PCOS?
Management of HirsutismWeight controlLocal treatmentsOral contraceptivesAnti-androgens Insulin-lowering agents
Local TreatmentsTemporaryPermanentElectrolysisPhotoepilation (laser) quicker and less painful, but more expensiveEflornithineBlocks enzyme required for hair growthWorks in 6-8 weeksCan be combined with laser therapy
Oral ContraceptivesHighly effective LH ovarian androgen production estrogen SHBG free testosterone (dose-related)BUTEthinyl estradiol can insulin sensitivity (dose-related)Some progestins are androgenic and these can also insulin sensitivityLow androgenic OCPs LDL, HDL, but triglyceridesOCPs risk of VTE, especially with obesity
Recommendations for OCPs25-30 g pill with minimally androgenic or anti-androgenic progestin often idealIf OCP contraindicated, cyclic MPA acetate or progestin-only contraception will LH and help alleviate hirsutism Add metformin if insulin resistantAdd statin if abnormal lipid profileIndividualize!
Anti-AndrogensHighly effectiveAndrogen receptor blockersSpironolactoneFlutemide (can be hepatotoxic)5 -reductase blocker FinasterideBUTCan feminize a male fetus!Use only if not sexually active or in combination with contraception (OCPs)
Recommendation for Hirsutism:
OCPs (if not contraindicated) and local treatments x 6 months; if unsatisfactory results, add anti-androgen at that time.Endocrine Society Practice Guidelines. J Clin Endocrinol Metab 2008;93:1105-20.
Endocrine Society Practice Guidelines. J Clin Endocrinol Metab 2008;93:1105-20.
Prevention of Endometrial HyperplasiaWith regulation of menstrual cycleOral contraceptives, if not contraindicatedCyclic progestins
Endometrial protection onlyProgestin-only contraceptives
InfertilityClomiphene leads to increased FSH enhanced follicular development70-80% of PCO patients ovulate1Metformin corrects insulin, androgen, and LH imbalances70-80% of PCO patients ovulate2
1. J Clin Endocrinol Metab 1998;83:2361-65. 2. J Clin Endocrinol Metab 2000;85:139-146.
1. J Clin Endocrinol Metab 1998;83:2361-65. 2. J Clin Endocrinol Metab 2000;85:139-146.
- Metformin +/- Clomiphene (CC)Reproductive Medicine NetworkN Engl J Med 2007;551-566.*p
Clomiphene Resistant?Add metformin, especially if obeseIf obeseMay require metformin + thiazolidinedioneBUT weight loss alone effective 10-15% reduction enough to resume ovulation
Weight LossLow-carbohydrate diet may be superior to low-fat diet in obese women with metabolic syndromeRelapse rate is highN Engl J Med 2003;348:2074-81.
N Engl J Med 2003;348:2074-81.
Medical Management Routine assessmentWeightBlood pressure2-hour glucose tolerance (~q 2 yrs.)If known insulin insensitivity, can monitor HgA1CLipid profile (every year after age 40)Routine guidance re weight controlInsulin-sensitizing agents (2-hr. glucose 140-199)Metformin? Thiazolidinediones (rosiglitazone, pioglitazone)
Benefits of MetforminImproves insulin sensitivity Insulin levels Testosterone levelsCan restore menses, ovulation total cholesterol, LDL, triglycerides Lp(a), homocysteine, small HDLSmall blood pressureSmall weight reductionPregnancy Category BMay risk of gestational diabetesMay risk of progression