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3 Objectives 1. Be able to describe the classic presentation and diagnostic criteria 2. Be able to explain long-term health concerns associated with the diagnosis 3. Understand what basic treatment options are available for presenting complaints

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5 Azziz 2011

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7 Presenting complaints Goldzieher

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9 PCOS Diagnosis NIH 1990 Rotterdam Androgen Excess Society Hyperandogenism R NR R Oligo/amenorrhe a R NR NR PCO NR NR

10 Signs & symptoms of Hirsutism androgen excess Htn Acne Tachycardia Oily skin Male body habitus Anovulation **Time/duration important Voice deepening Balding Clitoromegaly Increased libido Precocious puberty Acanthosis nigricans

11 The PCO PCO in one or both ovaries 12 or more follicles measuring 2-9mm Ovarian volume > 10cm3 Repeat scan if volume unable to be calculated due to cyst, single ovary can meet definition

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15 BP BMI, waist circumference (>35 abn) Hyperandrogenism stigmata Hyperinsulinemia stigmata

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18 Suggested by ACOG Hormonal T tot, SHBG or bioavailable & free T TSH Prolactin 17OHP (random <4, follicular morning fasting < 2ng/mL?Cushing s screen & acromegaly screen 2 h GTT Metabolic 2h GTT Fasting Lipids Ultrasound PCO Endometrial evaluation Optional consideration Gonadotropins to exclude alternate etiology of oligo or amenorrhea Fasting insulin Cushing s

19 17OHP? 21 hydroxylase or CYP21 Prevalence in USA Ashkenazi Jewish Hispanics Yugoslavs Native American Inuits Italians Specificity reduced in luteal phase Morning fasting follicular Elevated ACTH stim test

20 Diagnosis of Exclusion: also known as: So, did I miss

21 Ehrmann 2006

22 Fasting glucose or 2hGTT? Legro 1999

23 AES Suggest 2h GTT if: Obesity FH T2DM Hx GDM Age > 40 JCEM 2010; 95:

24 Insulin Hypothalamic Decr SHBG Direct trophic stimulation Abnormal appetite Incr GnRH pulse, LH downstream Incr Bio T Adrenals Ovaries

25 Quick Diabetes Review Normal glucose metabolism Hyperinsulinemia Impaired glucose tolerance Diabetes Type 2 Loss of pancreatic insulin secretion

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27 Reproductive Uterine health PCOS CVD DM

28 Reproductive Pregnancy Risks Infertility Risks GDM Hypertensive D/O Multifetal Risks Incr OHSS Incr Multiples

29 Uterine health Irregular menstrual bleeding Menorrhagia Ablation? - reconsider Endometrial hyperplasia Prevention? Correct P4 dosage?, Metformin?, Mirena? Progestin LARC Is this a better option than tubal ligation?

30 Diabetes Prospective cohort > 30yo 11.9% DM vs. 1.4% controls Up to 40% of PCOS women could be insulin resistant Conversion to impaired glucose tolerance up to 20% per year 3-10% undiagnosed DM rate

31 Dyslipidemia Borderline or high lipids 70% Suspect increased risk, no prospective studies Nurse s Health Study increased dose-response risk of CVD w/ increasing oligomenorrhea, PCOS sx Increased subclinical atherosclerosis

32 Additional considerations Depression Sleep Apnea Hirsutism Acne Alopecia NAFLD

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34 Weight loss Reduced androgens Menstrual frequency increases PR increases Hirsutism decreased Glucose utilization improves Lipid normalization As little as 5% weight loss may help (obvious limitations of this classically reported number)

35 Are combined HC ok? Do not appear to increase r/o DM Consider other risk factors Obesity, clotting history, smoking, htn

36 Anovulatory Infertility Hirsutism Alopecia Menstrual Disorders Obesity Lifestyle Intervention Obesity surgery Metformin* TZDs* Ovarian drilling GnRH analogues* Combination contraceptives* Steroids (Dex)* Progestins* Statins* +CC in obese women: NNT 4.6

37 Anovulatory Infertility Hirsutism Alopecia Menstrual Disorders Obesity Clomiphene Letrozole * Gonadotropins IUD Uterine surgery Eflornithine HCl crème Spironolactone* Androgen receptor antagonists* 5-alpha reductase inhibitor (Finasteride)* Mechanical hair removal Contraindicated with fertility Rx May create

38 References ACOG Practice Bulletin 108, 2009, reaffirmed 2011 Goldzieher JW, Axelrod LR1963 Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 14: Legro RS, Kunselman AR, Dodson WC, Dunaif A1999 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.. Journal of Clinical Endocrinology & Metabolism 84: Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN2006 Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 91:48-53 PCOS an ancient disorder? Azziz, Dumesic, Goodarzi. Fertil Steril 95:1544

39 SHBG 80% of T is bound to SHBG Liver Increased by E Decreased by androgens, progestins & insulin 19% bound to albumin 1% free & active ASD, DHEA, DHEAS not bound

40 DHT Testosterone 5α reductase 3α-keto-reductase DHT 3β-keto-reductase 3α androstanediol* 3β androstanediol

41 DHT Precursor in women ASD and DHEAS 1/10 th blood level of testosterone Tissue differences Male internal v. external genitalia Hair follicle/pilosebaceous unit 5α-reductase in skin Muscle, brain, liver, breast

42 Hair Growth

43 How many hairs? All follicles present by 22 wks gestation Concentration per unit facial skin Not differ between sexes Differs between racial groups Also 5α-reductase activity Asynchronous

44 Hair & puberty Vellus hair DHT Terminal hair Duration of exposure and intrinsic potential Eyebrow, eyelashes, scalp

45 Definitions Hirsutism Excessive body & facial hair in androgen dependent sites Defeminization Weakening or loss of feminine characteristics Virilization Acquisition of mature male somitic characteristics

46 PCOS and hyperandrogenism Hypothalamus & Pituitary Peripheral fat Adrenals Ovaries

47 Insulin resistance Archard and Thiers 1921 Acanthosis nigricans Several mechanisms Peripheral target tissue resistance Decreased hepatic clearance Increased pancreatic sensitivity

48 Peripheral resistance Decreased insulin receptor numbers Decreased insulin binding Postreceptor failure

49 IR & Co-morbidities Insulin directly related to HTN (late) triglycerides and HDL (early) CAD!!! Increased production of plasminogen inhibitor type-1 Impaired fibrinolysis vascular tissue changes

50 Hormone assays DHEAS, ASD Not significantly protein bound Routine immunoassay DHEAS Adrenal disease Total testosterone Bound and unbound No direct correlation with level of hirsutism Concentration SHBG

51 SHBG Produced in liver Increased by estrogens and thyroid hormone Excess androgen Decreases SHBG Percent free/active T elevated Increased metabolic clearance of T

52 DHT 3α androstanediol glucuronide Peripheral metabolite Excellent correlation 5 α reductase activity