Thoughts on PCOS Female Androgenization Syndrome FAS

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1 Thoughts on PCOS Female Androgenization Syndrome FAS Stan Korenman, M.D. Distinguished Professor of Medicine-Endocrinology and Associate Dean - Ethics David Geffen School of Medicine at UCLA

2 Conflicts of Interest None

3 Definition 1990 National Institute of Child Health and Human Development consensus conference Hyperandrogenism and/or hyperandrogenemia Oligo-ovulation Exclusion of other known disorders, such as Cushing s, hyperprolactinemia, CAH Rotterdam 2003 conference added Polycystic ovaries and 2 of 3 criteria for Dx particularly controversial.

5 Why Is This Condition So Prevalent? A set of beneficial genes until the middle of the 20 th century in developed countries. Some of these women had a few children when young and became anovulatory. This improved maternal and child survivability. Increased survival of grandmothers main providers to grandchildren in hard times. Legros speculated that in good times the women were anovulatory and when food became scarce they lost weight and became fertile preserving the tribe.

6 Features Elevated androgens, decreased SHBG Hirsutism, acne, seborrhea, alopecia Polycystic ovaries, diagnostic in 40% or so. Insulin resistance, Dyslipidemia, HDL, LDL, TG Central obesity, increased upper body muscle Reduced fertility and increased fetal wastage Wide ethnic variation in clinical manifestations

7 Complications Type 2 DM: at least 2 fold increased risk Hypertension: Endometrial hyperplasia & cancer Depression, social isolation Infertility Gestational diabetes, pregnancy loss Coronary Heart Disease increased risk

8 Prevalence of Elevated Androgen Measures in 858 Patients With Androgen Excess Abnormal androgen(s) Number Prevalence (%) None Total T only Free T only DHEAS only Total T and freet Total T and DHEAS Free T and DHEAS Total T, free T, and DHEAS Total Aziz et al; JCEM 89: 453, 2004

9 Insulin Resistance

10 Insulin Actions in PCOS Stimulates ovarian androgen production Inhibits hepatic SHBG production May stimulate LH secretion Mitogenic effect on epidermis: acanthosis nigricans Decreases IGFBP-1, increasing free IGF-1 which then stimulates ovarian/adrenal androgen production

11 Measurements of Insulin Criteria: Resistance Fasting, morning G/I < /20=4.5 HOMA IR = I x G x HOMA b-cell from same data gives b Cell secretory capacity for every level of blood sugar.

Relationship of HOMA-IR to Lipids Comparing PCOS to NHanes 2.8 NHANES NHANES Fitted PCOS 2.6 PCOS Fitted Cholesterol 2.5 NHANES NHANES Fitted PCOS PCOS Fitted 2 Hdl log10(total Cholesterol) 2.

12 Relationship of HOMA-IR to Lipids Comparing PCOS to NHanes 2.8 NHANES NHANES Fitted PCOS 2.6 PCOS Fitted Cholesterol 2.5 NHANES NHANES Fitted PCOS PCOS Fitted 2 Hdl log10(total Cholesterol) 2.4 log10(hdl Cholesterol) log10(homa IR) log10(homa IR) NHANES NHANES Fitted PCOS PCOS Fitted Triglycerides log10(triglycerid es) log10(homa IR)

13 Cardiovascular Issues

14 Cardiovascular Risk Factors Dyslipidemia: HDL, TG, LDL, small, dense LDL PAI-1, tpa Carotid intima-media thickness Endothelin-1 C-reactive protein Homocysteine levels These factors are correlated with hyperinsulinemia and improve with metformin therapy.

15 Impact of Surrogate CV Disease Markers How do the huge increases of cardiovascular risk factors play out in terms of increases of CAD and stroke?

16 Mortality of Women With PCOS at Long-term Follow-up, Pierpoint Et Al, J Clin Epid 51: cases of women Dxed with PCOS, UK Most Dxed by histology of wedge-resected ovaries Got almost all the old records for clinical manifestations Most had a definite Dx, but some were possible 786 women could be traced by the National Health Registry giving 59 deaths from all causes

17 Deaths by Underlying Cause, Compared With Expected Numbers Derived From National Rates Pierpoint et al,j Clin epid 51: Cause of death Observed Expected 95% CI All causes All circulatory Ischemic heart disease Other circulatory All neoplasms Breast Bronchus Ovary Other/unknown primary External Diabetes mellitus Other No death certificate 2

18 CV Disease in PCOS, a Retrospective Study: Wild et al Clin Endo 2000:52, 595 Follow up on Pierpoint Study. Data from PCOS and 3 controls. Questionnaires, GP records, bloods Mortality and morbidity data.

19 Prevalence of CHD and CHD Risk Factors in Control and PCOS, Wild PCOS% Control% P CHD Cerebrovascular Dis.* Diabetes* Diagnosed hypertension Current smoker High cholesterol* <.001 BMI > <.001 FH CHD FH Diabetes * persists after correction for BMI

20 Number of Deaths by ICD Codes Compared to Standardized Mortality Rates, Wild Underlying cause of death # All causes 70 Cardiovascular disease 17 Coronary heart disease 14 Cerebrovascular disease 2 Diabetes 4 None of these was significantly different from the standard mortality rates except DM as the main cause of death.

D and CV events in PCOS Mani et al Clin Endo 2013;78:926-34 20 year FU, average age 36.

21 D and CV events in PCOS Mani et al Clin Endo 2013;78: year FU, average age 36.3 with many Asian ethnicities. Increased incidence and age-group specific prevalence of T2DM, MI, and angina in PCOS esp over age of 65.

22 Implications of Diabetes High blood sugar is key- glycosylation Advanced glycosylation end products are toxic Microvascular» Main cause of kidney failure and transplantation» Main cause of blindness - retinopathy» Main cause of peripheral neuropathy Macrovascular» Main cause of amputation of extremities» Closely related to heart attacks, angina, strokes and congestive heart failure

Reach Study "We found, as has been shown in prior analyses, that diabetes raises the risk of MI, stroke, and CV death, but what I think was interesting and more novel from this analysis was that we

23 Reach Study "We found, as has been shown in prior analyses, that diabetes raises the risk of MI, stroke, and CV death, but what I think was interesting and more novel from this analysis was that we also showed just what a high risk patients with diabetes have for heart failure. And this is something that I feel is quite underappreciated by cardiologists and certainly by primary-care physicians and endocrinologists, so the important message to physicians is, yes, of course, worry about the things that everybody knows about the risk of MI, protecting the feet, checking the eyes but now physicians need to be more vigilant and look for evidence of heart failure on their history and physical as well. Deepak L Bhatt (Brigham and Women's Hospital Heart & Vascular Center, Boston. MA.

26 Cipala-Griffin et al, Am J Wom Health Depression, anxiety, satisfaction Mainly whites, mean age 35, mostly married, not taking meds, working 161 cases and controls from CV study, 12 year follow-up. mild to mod depression (31vs17%) p<.016. Beck score predicts PCOS Within cases BMI parity education degree PCOS not assoc. with anger, hostility, cynicism, or decreased life satisfaction.

15 years 5 vs 2 admissions This study used hospital chart reviews

27 Potential Implications for Health with FAS 2566 hospitalized with FAS vs 25,660 others Western Australia- underpopulated, dry Over 15 years 5 vs 2 admissions This study used hospital chart reviews Mean age at first hosp was 27.9 yrs. Hart et al 2015, JCE100:911-19

28 Medical Implications Type 2 diabetes 12.5 vs 3.8% Obesity 16.0 vs 3.7 Hypertension 3.8 vs 0.7 Ischemic heart dis 0.8 vs 0.2 CVA 0.6 vs 0.2 Arterial dis 0.5 vs 0.2 Venous dis vs 5.6 Asthma 10.6 vs 4.5 All P <.001

29 More Implications Stress-anxiety 14.0 vs 5.9% Depression 9.8 vs 4.3 Drug-related 8.8 vs 4.5 Self-harm 7.2 vs 2.9 Land transport accidents 5.2 vs 3.8 Mortality 0.7 vs 0.4 Higher rates of gynecological conditions and fertility treatments All P <.001

30 Our Method of Evaluation and Rx We look for current and history of depression:- fatigue, sleep, concentration, panic, somatic Sx, substance abuse, irritability. Give a PHQ 9 test. We evaluate BT, DHEA, 17OHP, Glu, Ins, HgbA1c, TFTs, Lipids, chem panel if not already available. We treat each component, obesity, depression, social isolation, hirsutism, oligo-ovulaton, IR effects (lipids, hypertension, diabetes), thyroid dis.

Metformin Therapy for PCOS Activates AMP kinase System, decreases IR Increases ovulation rates and # cycles Increases fertility Decreases early fetal wastage Facilitates weight loss Decreases

31 Metformin Therapy for PCOS Activates AMP kinase System, decreases IR Increases ovulation rates and # cycles Increases fertility Decreases early fetal wastage Facilitates weight loss Decreases androgen levels LH, PAI-1, BP, SHBG In diabetics, metformin facilitates weight loss and also reduces triglycerides, LDL (10-15%), total cholesterol; and increases HDL slightly. In prediabetics it may substantially delay the development of diabetes.

32 Components of Metabolic Syndrome and Carotid IMT after 1 yr with successful weight loss Successful Weight Loss (BMI SDS reduction >0.2) Variable Baseline 1 yr later BMI (kg/m²) Waist Circumference (cm) Triglycerides (mg/dl) HDL-cholesterol (mg/dl) Insulin (mu/liter) HOMA h glucose in ogtt (mg/dl) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Metabolic syndrome (IDF definition) 35% 4% Intima-media thickness (cm) Lass, et al.; J Clin Endocrinol Metab. 96(11):3536, 2011

33 Clinical features of 254 patients at intake and during follow-up First Visit y y Mean Interval, y Clinical characteristics BMI, kg/m² Amenorrhea Oligomenorrhea Regular Cycle T, ng/ml Brown. The phenotype of PCOS ameliorates with aging. Fertil Steril 2011.

Diabetes and Cardiovascular Risks in the Polycystic Ovary Syndrome

Diabetes and Cardiovascular Risks in the Polycystic Ovary Syndrome John E. Nestler, M.D. William Branch Porter Professor of Medicine Chair, Department of Internal Medicine Virginia Commonwealth University