Polycystic Ovary Syndrome

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1 Polycystic Ovary Syndrome An Individualized Approach Alice Y. Chang, MD, MSc Assistant Professor Mayo Clinic Division of Endocrinology, Diabetes, Nutrition and Metabolism

2 Learning Objectives: To Individualize or Personalize the Evaluation and Treatment of PCOS Review the diagnostic criteria for PCOS Understand how the criteria can guide management Select among treatment options Based on patient characteristics and desires Select among options to screen and treat co-morbidities of PCOS

3 Who are these women in your practice? Affects 6 to 8 % of women in the US Women with hirsutism Unwanted hair or hair loss Acne Women with infertility Women with irregular periods or amenorrhea Worried women told they have PCOS Azziz, R et al. JCEM 2004 As many as 20% by Rotterdam criteria Chang, AY et al. Clin Endo 2011

4 Breast cancer affects 1 in 8 women PCOS affects 1 in 5 women 2012 MFMER

5 Learning Objectives: To Individualize or Personalize the Evaluation and Treatment of PCOS Review the diagnostic criteria for PCOS Select among treatment options for hirsutism Select among options to screen and treat co-morbidities of PCOS

6 Case 1: 25 yo with Oligomenorrhea Do I have PCOS? Menarche age 12 Contraceptives: Birth control pill use age NuvaRing age Discontinued contraceptives x 8 months: Irregular periods every days Bleeds for 5-10 days, minimal cramping

7 Case 1: 25 yo with Oligomenorrhea PE: BMI 28 kg/m 2, BP 116/81 No cushingoid features Minimal acne over back Dark hair growth upper lip, upper/lower abdomen, upper/lower back, inner thighs No acanthosis nigricans

8 Ferriman-Gallwey 8 mild, > 15 moderate/severe MFMER

9 Case 1: Evaluation Question 1 What diagnostic biochemical testing to obtain? Prolactin TSH Total Testosterone Free Testosterone DHEA-S Androstenedione 17-OH Progesterone 24 hour urinary free cortisol Anti-mullerian hormone Day 21 progesterone Pelvic ultrasound?

10 Case 1: Evaluation Question 1 Established hirsutism and oligomenorrhea Prolactin TSH Total Testosterone Free Testosterone DHEA-S Androstenedione 17-OH Progesterone 24 hour urinary free cortisol Anti-mullerian hormone Day 21 progesterone Pelvic ultrasound? In addition to: pregnancy test, +/- FSH/LH

11 Case 1: Evaluation Question 1 No hirsutism, + oligomenorrhea? Prolactin TSH Total Testosterone Free Testosterone DHEA-S Androstenedione 17-OH Progesterone 24 hour urinary free cortisol Anti-mullerian hormone Day 21 progesterone Pelvic ultrasound?

12 Case 1: Evaluation Question 1 Hirsutism and regular menses? Prolactin TSH Total Testosterone Free Testosterone Day 3 DHEA-S Androstenedione 17-OH Progesterone 24 hour urinary free cortisol Anti-mullerian hormone Day 21 progesterone Pelvic ultrasound

13 Myth I need a pelvic ultrasound to diagnose PCOS False Misconception #1 The diagnosis of PCOS does not require documentation of polycystic ovaries They are really follicles not cysts 2012 MFMER

14 Case 1: 25 yo with Hirsutism and Oligomenorrhea Prolactin 12 ng/ml (N, < 20) TSH 1.7 miu/l (N, ) Total Testosterone 58 ng/dl (N, 8 60) DHEA-S 132 mcg/dl (N, ) 17-OH Progesterone 127 ng/dl Follicular <80 ng/dl Luteal <285 ng/dl

15 Case 1: Question for Audience Does this woman have PCOS? 1. Yes 2. No 3. It s unclear. We shouldn t treat her as if she has PCOS. 4. It s unclear. We can be comfortable treating her as if she has PCOS.

16 What is PCOS? 1. Hyperandrogenism The NIH Definition, the more severe phenotype - clinically (hirsutism) - OR elevated total testosterone 2. Irregular Menses (< 9 periods/yr) - since puberty or 20s Alopecia Acne Terminal Hair

17 What else is PCOS? Polycystic Ovaries one ovary with > 12 follicles, 2 to 10mm ultrasound OR ovarian volume > 10cc no cyst > 1cm 2014 AE-PCOS: transducer frequency 8MHz. At least one ovary containing 25 follicles

18 What else is PCOS? Insulin Resistance Insulin Resistance ~ 50%, even in lean Obesity Dyslipidemia Hypertension Acanthosis nigricans Metabolic Syndrome Syndrome XX

19 What are the 3 myths about the PCOS name? The diagnosis does not require having polycystic ovaries They are really follicles not cysts The ovary is not the cause of the syndrome 19

PANEL RECOMMENDS CHANGING NAME the complex

20 "The name PCOS is a News distraction Releasethat impedes Wednesday, January 23, 2013 progress. It is time to assign a name that reflects PANEL RECOMMENDS CHANGING NAME the complex interactions OF COMMON DISORDER IN WOMEN that characterize the syndrome." 2012 MFMER

21 Metabolic Reproductive Syndrome MRS JCEM, November 2013 ADA 2016 It is time to assign a new name that actually reflects the complex features of the condition, Helena J. Teede, MBBS, FRACP, PhD, professor and head of the Women s Public Health Research Program 2012 MFMER

22 Insulin Resistance, Pituitary, Ovary gonadotrophin release ovarian steroidogenesis Nestler, J. E. et al. N Engl J Med 1996;335:

23 Androgens Insulin resistance 2012 MFMER

24 Learning Objectives: To Individualize or Personalize the Evaluation and Treatment of PCOS Review the diagnostic criteria for PCOS Select among treatment options Select among options to screen and treat co-morbidities of PCOS

25 Case 1: Patient Question What treatment is right for me? What are you trying to treat? Hirsutism, irregular cycles, fertility?

26 Case 1: Question for Audience What would be your first approach to treating her excess hair growth? 1.Oral contraceptive 2.Oral contraceptive & spironolactone 3.Oral contraceptive & flutamide or finasteride 4. Metformin 5.Spironolactone & metformin 6.Oral contraceptive & spironolactone & metformin 7.Weight loss first 8.Laser therapy

27 Hirsutism guideline Endocrine Society First line, oral contraceptives Ovarian suppression AND increases SHBG? transvaginal estrogen as effective Consider anti-androgen after 6 months if suboptimal. Recommend against anti-androgen without adequate contraception. Data does not support use of insulin-lowering drugs for hirsutism. JCEM Vol. 93, issue 4, pg , MFMER

28 Hirsutism Therapy Ovarian suppression Suppresses ovarian androgen production Increases SHBG, decreases bioavailable T Resume menses, endometrial protection contraception Less androgenic progestin (19-Nor-Ts) Desogestrel, Norgestimate, Gestodene Drospirenone = AR Antagonist (Yasmin, Apri) GnRH Agonist: Rarely needed

29 Hirsutism Therapy Androgen Blockade Spironolactone really works! Start mg bid, check K, up to 100 mg BID Can increase in 3 month intervals Always combine with OCP Yasmin, Yaz, Desogen less Androgenic Cyproterone Acetate is the best Diana, Dianette not in USA Flutamide, Bicalutamide: Costly, Toxic Finasteride: $$

30 Hirsutism Therapy What To Expect Terminal hairs never go away Thinner hair shaft = less visible Longer telogen = less hairs at any time BEFORE laser or electrolysis, institute anti-androgen therapy to prevent new terminal hair SAVE MONEY $$$$

31 Treatment of Hirsutism Topical and Mechanical Plucking & shaving: Painful, iterative Waxing: less painful, more expensive Eflornithine (DFMO, Vaniqua ) ODC inhibitor, polyamine biosynthesis Slows rate of anagen phase Electrolysis: Very effective, expensive Laser: Very effective, expensive

Therapy: Adrenal Suppression Reserved for clearly documented 21OHD Partial replacement, not suppression In reality, glucocorticoid side effects

32 Therapy: Adrenal Suppression Reserved for clearly documented 21OHD Partial replacement, not suppression In reality, glucocorticoid side effects occur before effect on hirsutism Anti-androgen, OCP Glucocorticoid treatment best reserved for infertility in Non-Classic Congenital Adrenal Hyperplasia

33 What is the best treatment for irregular menses in PCOS? 1.Oral contraceptive 2. Metformin 3.Weight loss

34 Myth or Reality In most cases, it s best to treat PCOS with oral contraceptives True False Misconception #2 OCP are not a treatment for PCOS per se Some women feel better off OCP OCP can worsen insulin sensitivity or increase blood pressure Alternatives exist for managing irregular menses 2012 MFMER

35 Case 1: Treatment of irregular cycles 1.Oral contraceptive 2. Metformin 3.Weight loss Fertility sooner and age close to 30 reproductive endocrine clomiphene, letrozole Fertility near future metformin NEJM, 2014 Fertility in more than a year oral contraceptives

36 Learning Objectives: To Individualize or Personalize the Evaluation and Treatment of PCOS Review the diagnostic criteria for PCOS Select among treatment options Select among options to screen and treat co-morbidities of PCOS

37 Case 2: 28 year-old with infertility Menarche age 11 with < 6 periods/year Age 16 diagnosed with PCOS Acne, progressive hirsutism (chin, upper lip, abdomen, arms (shaves, laser to face) On OCPs until one year ago Trying to conceive Has infrequent periods and gained 50 lbs Concerned about increased risk for diabetes Wants to get healthy before pregnancy

38 Case 2: 28 year-old with infertility Parents immigrated from Mexico. Mother and maternal grandmother with type 2 diabetes. Mother had a MI at age 45 Exam BMI 36 kg/m 2, BP125/77 Ferriman-Gallwey scale of hirsutism 12 Acne & mild acanthosis nigricans Laboratory data from primary MD Total testosterone 137 ng/dl Normal TSH & prolactin

39 Question for Audience How would you screen for insulin resistance in this woman? 1. 2 hour oral glucose tolerance test 2. Fasting glucose 3. Hemoglobin A1c 4. Fasting insulin 5. Fasting lipid panel

40 Misconception #3: I can test for insulin resistance Insulin resistance can only be defined when infusing insulin (i.e. clamp) Fasting insulin only helpful if high Hemoglobin A1c does not perform as well in PCOS For PCOS, recommendation is oral glucose tolerance test to detect impaired glucose tolerance MFMER

41 Diabetes Risk Assessment in PCOS Androgen Excess PCOS Society Recommendations: 2 hour 75 g oral glucose tolerance test BMI > 30 Lean PCOS over age 40 Gestational diabetes, family hx of type 2 diabetes NL: suggest every 2 yrs or new risk factors Wild et al. JCEM, 95(5): , 2010 Endocrine Society Recommendations: In all adolescents and women with PCOS HgbA1c if unable to complete OGTT Rescreen every 3 to 5 yrs or earlier if change Legro et al. JCEM, 98(12): , 2013

44 Conversion to Diabetes and Impaired Glucose Tolerance 71 women with PCOS, 23 regular controls Percent (%) conversion Year 5 years control PCOS High Risk Legro, R. S. et al. J Clin Endocrinol Metab, 2005 Kjus, SL, et al. Diabetes, MFMER

45 Doctor, What is My Risk for Developing Diabetes? Higher than someone without PCOS Not as bad as other risk groups Personal history of gestational diabetes Family history of diabetes Ethnicity BMI 2012 MFMER

46 Which PCOS is riskier? NIH PCOS Phenotypes PCOS Features Androgen Excess Society Rotterdam (ESHRE/ASRM) Hyperandrogenism Oligo- or anovulation Polycystic ovaries CV Risk Factors Insulin resistance /- Obesity /- Dyslipidemia /- Adapted from Norman, RJ et al. Lancet, MFMER

47 PCOS is NOT associated with premature CV events or death PCOS deaths due to diabetes, not CV disease. UK PCOS, SMR Diabetes 4.60 ( ) No increase in CV events before : 7-fold modeled risk for MI 2011: 21 yrs later no increase in actual events 2012: Rochester Epidemiology Project Wild, Pierpoint, et. Al. Clin Endo, 2000 Dahlgren et al., Acta Ob Gyn Scand, 1992 Schmidt et. al. JCEM, 2011 Iftikhar et. al. Neth J Med, 2012

48 Increased CV risk with post-menopausal surrogates of PCOS Nurses Health Study very irregular menses RR 1.34 ( ) diabetes RR 3.86 ( ) Solomon, C, et. al. JAMA, 2001 Solomon, C, et. al. JCEM, 2002 Rancho-Bernardo elevated androgens, central adiposity, insulin resistance, irregular menses, infertility OR 1.36 ( ) WISE elevated androgens, irregular menses HR 1.59 ( ) Krentz, Menopause, 2007 Shaw et. al. JCEM, 2008

49 Summary: Evidence for PCOS and CV Risk Little evidence for premature events Greatest mortality risk may be from diabetes After menopause, associated risk factors persistence of elevated androgens metabolic syndrome obesity

50 Question for Audience Which co-morbidity would you screen for in this woman with PCOS, fatigue and family history of diabetes and cardiovascular disease? 1. Hyperlipidemia 2. Mood disorders 3. Cardiovascular disease 4. Obstructive sleep apnea 5. Fatty liver disease

51 Case 2: Lab Results Fasting glucose 97 mg/dl (N, ) 2 hour OGTT 140 mg/dl HbA1c 5.7% (N, %) Chol 211 mg/dl, trigs 322 mg/dl, HDL 42 mg/dl, LDL 140 mg/dl AST 60 U/L (N, < 48) ALT 50 U/L (N, < 75) Normal bilirubin & Alk Phos Sleep study: diagnosis of obstructive sleep apnea

52 Question for Audience What treatment approach would you recommend first? 1. Metformin 2. Statin 3. Weight loss 4. Bariatric surgery consult 5. CPAP 6. GI consult for a liver biopsy

53 Myth or Reality? I need to document impaired fasting glucose or impaired glucose tolerance to start metformin? True False 2012 MFMER

54 Treatments that Prevent Diabetes: Would Lifestyle win in PCOS? Metformin 31% Lifestyle 58% Diabetes Prevention Program, NEJM, 2002 Meta-analysis with 600+ PCOS, 40% reduction diabetes Salpeter, Am Journal Medicine, 2008

55 Indications for Metformin in PCOS For type 2 DM and pre-diabetes who fail lifestyle modification For women with menstrual irregularity who cannot take oral contraceptives Evidence for effect on metabolic consequences May assist in weight loss goals Legro et al. JCEM, 98(12): , 2013 You do not have to have pre-diabetes to see an effect 2012 MFMER

56 CHALLENGE QUESTION: Text page this am call gyn #55555 regarding PCOS pt 22 year old female with new onset hirsutism significant acne, never during adolescence 2 months ago started on oral contraceptives How long should we stop the oral contraceptives to test her androgens, how long? Which androgens to test? When should we consider adding on other therapies? 2012 MFMER

57 Take Home Points about PCOS Diagnostic Criteria Use Rotterdam but do not need all tests depending on history and physical Classic NIH criteria and androgen excess: associated with greater risk factors Treatment goals can guide your diagnosis Hirsutism Irregular menses/anovulation Risk factor reduction

58 Take Home Points about PCOS Treatment for Hirsutism First line, estrogens Estrogens > spironolactone > metformin Do no harm Not recommended: flutamide, finasteride/dutasteride, corticosteroids Lower androgen effect before definitive electrolysis/laser therapy

59 Take Home Points about PCOS Anovulatory cycles Metformin may help restore ovulatory cycles Closer to the age of 30, if fertility desired, refer for clomiphene Oral contraceptives if fertility not desired in near future. Take advantage of a window of 3 to 6 months after stopping oral contraceptives to conceive

60 Take Home Points about PCOS Co-morbidities assessment Screen for impaired glucose tolerance with a 2 hour OGTT Negative tests do not exclude insulin resistance HbA1c misses IGT Use acanthosis nigricans, family history, gestational history to increase or decrease risk factor status Use history and treatment goals to screen for other comorbidities

with Polycystic Ovary Syndrome and/or Idiopathic

61 PCOS, astronauts and Mayo Clinic Astronaut Ophthalmic Issues and One Carbon Metabolism: Evaluation in Patients with Polycystic Ovary Syndrome and/or Idiopathic Intracranial Hypertension Contact ,

62 Suggested References Legro et al. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. JCEM 98 (12): Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. JCEM 93 (5): , 2008 Loriaux, DL. An Approach to the Patient with Hirsutism. JCEM 97 (9): , Tang T et al. Insulin-sensitising drugs for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev May 16 Wild et al. Assessment of Cardiovascular Risk and Prevention of Cardiovascular Disease in Women with the Polycystic Ovary Syndrome: A Consensus Statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. JCEM, 95(5): , MFMER

Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018

Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018 Learning Objectives At the conclusion of this lecture, learners should: 1) Know the various diagnostic