PCO with hyperandrogenism is really PCOS. PCOS without Hyperandrogenism is not PCOS. Disclosures-Richard S. Legro, M.D. Funding

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Hyperandrogenism is not PCOS Disclosures-Richard S. Legro, M.D. Funding Pennsylvania Department of Health Tobacco Settlement Funds U.

1 PCO with hyperandrogenism is really PCOS Richard S. Legro, M.D. Professor, Department of Obstetrics and Gynecology Penn State College of Medicine Hershey, PA PCOS without Hyperandrogenism is not PCOS Disclosures-Richard S. Legro, M.D. Funding Pennsylvania Department of Health Tobacco Settlement Funds U.S. National Institutes of Health Mention of U.S. FDA off label uses of drugs Metformin and TZDs do not have an indication for PCOS

2 Learning Objectives Identify the role of hyperandrogenism in the diagnosis of PCOS State the relationship between hyperandrogenism and metabolic abnormalities in PCOS Discuss the prognostic power of hyperandrogenism in the treatment of PCOS Review the utility of hyperandrogenism in clinical trials and genetic analyses in PCOS Polycystic Ovary Syndrome The most common endocrinopathy in the U.S. among reproductive aged women (prevalence rate ~ 8%) Associated with reproductive problems Anovulatory infertility Dysfunctional vaginal bleeding Hirsutism Also associated with metabolic issues Insulin resistance, increased Type 2 DM, and increased CVD risk profile The Importance of Diagnosing Hyperandrogenism in PCOS 2) Th f t th t i b t i t d ith t b li 2) The feature that is best associated with metabolic abnormalities 3) A prognostic factor for treatment success 4) An objective criteria that best allows for the conduct of multi-center trials

3 What is the PCOS Phenotype? Anovulation Polycystic Ovaries PCOS is an ovarian disorder Hyperandrogenism Required Diagnostic Criteria for PCOS (All Expert Based) NIH (1992) Rotterdam (ASRM/ESHR E 2004) 2 of 3 Androgen Excess Oligomenorrhea Yes Maybe Maybe Hyperandrogenism (Biochemical and/ or Clinical) Yes Maybe Yes Polycystic ovaries No Maybe Maybe Society (2006) HA + 1 All Criteria Agree: PCOS is a Diagnosis of Exclusion Congenital Adrenal Hyperplasia (CAH) Cushing's Syndrome Androgen producing tumor-ovary ovary or adrenal Exogenous sex steroids Simple Obesity Severely insulin resistant states Other menstrual disorders (hypothalamic amenorrhea, etc.)

Importance of Diagnosing Hyperandrogenism in Menstrual Dysfunction Hypothalamic Amenorrhea PCOS Low/Non-detectable Normal lto High Osteoporosis, No Diabetes, CVD, Less Hormonal Related CA Weight

4 Importance of Diagnosing Hyperandrogenism in Menstrual Dysfunction Hypothalamic Amenorrhea PCOS Low/Non-detectable Normal lto High Osteoporosis, No Diabetes, CVD, Less Hormonal Related CA Weight gain, reduced exercise, No Anti-Diabetic Drugs, Gonadotropins Increased BMD, Diabetes,?CVD, More Hormonal related CA- Endometrial Weight loss, exercise, Anti- Diabetic Drugs, Clomiphene Variability in Androgens during a Normal Menstrual Cycle Changes in testosterone, t t free testosterone, and androstenedione in 12 eumenorrhoic women during follicular and luteal menstrual phases. Massafra et al. JCEM 1999;84:971 Total T 90 ng/dl Baseline Follow-up PCOS (N = 75) Control (N = 24) Mean follow-up 2-3 yrs later 14 women with PCOS on confounding meds: (10 OCP, 4 Metformin)

5 Limitations of Testosterone Levels in PCOS Suppressed more rapidly by hormonal suppression than other clinical features, e.g. hirsutism Altered by age and BMI Affected by reproductive events: i.e. lowered by ovulation, increased by pregnancy, etc. Little normative data in adolescent and older women Normative values vary from lab to lab; and often are based on bias reference populations Inaccurate and variable methods of measurement The Importance of Diagnosing Hyperandrogenemia in PCOS 1) A diagnostic feature that allows for discrimination from other causes of the combination of oligomenorrhea and polycystic ovaries 3) A prognostic factor for treatment success 4) An objective criteria that best allows for the conduct of multi-center trials The Vicious Circle

6 Association Between Metabolic Syndrome and Free Testosterone in PCOS Lowest Quartile %MBS 2nd Quartile 3rd Quartile P =.056 (BMI adjusted) Highest Quartile Ehrmann et al. JCEM 2006 Hyperandrogenism Predicts Severity of PCOS Phenotype Severe PCOS (N =1212) Mild Parameter HA/CA/PCO HA/CA HA/PCO CA/PCO Controls ( N = 254) BMI Testosterone Androstenedione Fasting Insulin AUC Glucose Panidis et al, Hum Reprod, 2012 Hyperandrogenemia(HA) Identifies Insulin Resistance in PCOS Sisters * * * * PCOS HA UA Control 0 G:I Ratio Fasting I * P <.05 vs UA/Control Legro et al, JCEM, 2002

Mothers of women with PCOS with history of irregular menses have elevated T and Insulin Resistance Copyright 2006 by the National Academy of Sciences Sam, Susan et al.

USA 103, 7030-7035 Effects of Prenatal Androgenization in Female Rhesus Monkeys Increased circulating androgens Dumesic et al, Fertil Steril, 2002 Abnormal gonadotropin levels

7 Mothers of women with PCOS with history of irregular menses have elevated T and Insulin Resistance Copyright 2006 by the National Academy of Sciences Sam, Susan et al. (2006) Proc. Natl. Acad. Sci. USA 103, Effects of Prenatal Androgenization in Female Rhesus Monkeys Increased circulating androgens Dumesic et al, Fertil Steril, 2002 Abnormal gonadotropin levels Dumesic et al, Fertil Steril, 1997 Increased abdominal fat Eisner et al, Obes Res, 2003 Impaired insulin action Eisner, JCEM, 2000 Impaired oocyte development Dumesic et al, JCEM, 2002 Elevated Testosterone in PCOS Associated with Sleep Apnea Copyright 2001 The Endocrine Society Fogel, R. B. et al. J Clin Endocrinol Metab 2001;86:

8 Hyperandrogenism and CVD 102 Women undergoing cardiac catheterization Increased hirsutism among those with confirmed CAD Wild RA et al, Fertil Steril 1990 Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival Shaw et al, JCEM, 2008 The Importance of Diagnosing Hyperandrogenism in PCOS 1) A diagnostic feature that allows for discrimination from other causes of the combination of oligomenorrhea and polycystic ovaries 2) The feature that t is best associated with metabolic abnormalities 4) An objective criteria that best allows for the conduct of multi-center trials

9 What are the factors that predict live birth in PCOS Infertility therapy Younger Age Lower BMI Shorter Duration of Infertility therapy Less Severe Oligomenorrhea Lower androgen levels Less Hirsutism Nomogram to Predict Ovulation/Live Birth in WHO Type II Anovulation with Clomiphene Retrospective case series of 259 couples Imani et al, Fertil Steril 2002 Multivariable Logistic Regression Model to Predict Pregnancy with rfsh treatment in PCOS Odds Ratio 95% Confidence Intervals Oligomenorrhea vs to Amenorrhea P = 0.04 Duration of Infertility to 1.04 P = 0.13 Free Androgen Index to 0.98 P = pregnancies in 85 patients Van Wely et al, Hum Reprod, 2005

Predictors of Live Birth in PPCOS Effect Baseline Free Androgen Index > 10 (Reference) Odds Ratio [95% CI) 1.0 <10 16 1.6 [14-3 [1.4 3.1] Hirsutism Score 16 (Reference) 1.

2] Rausch et al, JCEM, 2009 Hirsutism Score Clinical Hyperandrogenism as a significant livebirth prognostic factor Hirsutism Score Rausch et al, JCEM, 2009 Predictive

10 Predictors of Live Birth in PPCOS Effect Baseline Free Androgen Index > 10 (Reference) Odds Ratio [95% CI) 1.0 < [14-3 [ ] Hirsutism Score 16 (Reference) [0.9-2.]) < [ ] Rausch et al, JCEM, 2009 Hirsutism Score Clinical Hyperandrogenism as a significant livebirth prognostic factor Hirsutism Score Rausch et al, JCEM, 2009 Predictive Variables of Metformin Clinical Efficacy in PCOS Variable Serum Androstenedion Basal menses frequency (cycles/yr) Fasting Plasma Insulin e Adjusted Odds ratio 0.65 ( ) 1.60 ( ) 1.15 ( ) P va lue Model Accounted for 55% of total variability Moghetti et al, JCEM, 2000

11 Improving Hyperandrogenism is the Goal/Result of all Effective Treatments for PCOS Oral Contraceptives Lifestyle Insulin Sensitizers Ovarian Surgery Ovulation Induction in PCOS Clomiphene, GnRH, Aromatase Inhibitor SHBG Insulin Sensitizing Agents, Weight loss, Exercise FSH, Ovarian Drilling Long Term Improvement in Androgen Levels After Ovarian Diathermy in PCOS Gjonnaess H. Fertil Steril 69: , 1998

Metformin Improves Adrenal Hyperfunction in Adolescent PCOS RN = reference normal females Arslanian et al, JCEM, 2003 Mean Change in Serum Free Testosterone with Troglitazone e (pg/ml) 0-1 PBO TGZ

12 Metformin Improves Adrenal Hyperfunction in Adolescent PCOS RN = reference normal females Arslanian et al, JCEM, 2003 Mean Change in Serum Free Testosterone with Troglitazone e (pg/ml) 0-1 PBO TGZ 150 TGZ 300 TGZ Adjusted Mean Chang * P = * P = * P = Azziz R et al, JCEM, 2001 Incidence Rate of Ovulation with Troglitazone Number of (observed/expected) ovulations averaged for each treatment group 0.8 Based on Pdg Peak > 5 days P = n Rate Adjusted Mean P = * 0.62* 0 PBO T 150 T 300 T 600 Azziz et al, JCEM, 2001

13 Effect on Total Testosterone and SHBG in PPCOS ng/dl * Total T CC Met Comb * 0 nmol/l * SHBG CC Met Comb * * Significant compared to baseline Legro et al, NEJM, 2007 Improvement in HA on OCP (EEE/CPA) in PCOS Nmol/L Morin Papunen et al, JCEM, 2000 Lifestyle Improves HA Moran et al, Cochrane Syst Rev, 2011

2) The feature that t is best associated with metabolic abnormalities 3) A prognostic factor for treatment success Predictor of live birth Correlation of PCOS Traits in Twins/Sisters Monzygotic

14 HA improves in morbidly obese women with PCOS after bariatric surgery Escobar-Morreale, H. F. et al. JCEM 2005 The Importance of Diagnosing Hyperandrogenism in PCOS 1) A diagnostic feature that allows for discrimination from other causes of the combination of oligomenorrhea and polycystic ovaries 2) The feature that t is best associated with metabolic abnormalities 3) A prognostic factor for treatment success Predictor of live birth Correlation of PCOS Traits in Twins/Sisters Monzygotic Twins N =1332 R (95% CI) Dizygotic Twins/Sisters N = 1873 R (95% CI) Oligomenorrhea (0.49 to 0.80) ( to 034) 0.34) Acne 0.78 (0.69 to 0.84) Hirsutism 0.86 (0.75 to 0.92) PCOS 0.71 (0.43 to 0.88) Vink et al, JCEM, (0.30 to 0.56) 0.28 (0.05 to 0.50) 0.38 (0.00 to 0.66)

15 T ng/dl Hyperandrogenemia is a Familial Trait: Elevated Testosterone Levels in Affected Sisters (and DHEAS levels) ut ng/dl Proband PCOS Sister HA Sister Unaffected Sister Control 0 Proband PCOS Sister HA Unaffected Sister Control Sister T measured by DPC RIA- Demers Legro et al, Proc Natl Acad Sci 95:14956, 1998 D19S884 Intron 55 Fibrillin 3 Gene ElavL1 CCL25 FBN3 25 kb FBN3 Fibrillin 3 FBN1=Marfan s Syndrome, major constituent of extracellular microfibrils, FBN2=congenital contractural arachnodactyly Fibrillins modify TGFβ signaling Urbanek et al J Clin Endocrinol Metab 90: , 6629, 2005 D19S884 Allele 8 Associated with PCOS by Transmission Disequilibrium Test Data Set Families T* Not - T* Total %T* χ 2 P-Value Set 1 Urbanek et al (1999) Set 2 Urbanek et al (2005) < Set 3 Stewart et al (2006) Total < *T, number of transmissions TDT Stewart et al J Clin Endocrinol Metab, 2006

January 2011 January 2011 SNP Chromosome Nearby Gene Symbol(s) Function rs13405728 2p16.3 FSHR, LHCGR Gonadotropin Receptors multiple 2p.

16 January 2011 January 2011 SNP Chromosome Nearby Gene Symbol(s) Function rs p16.3 FSHR, LHCGR Gonadotropin Receptors multiple 2p.21 THADA Disrupted in thyroid adenomas multiple 9q33.3 DENND1A domain differentially expressed in normal and neoplastic cells (DENN) binds to endoplasmic reticulum aminopeptidase 1 (ERAP1) as a negative regulator January 2011

J Med Genet. 2012 Feb;49(2):90-5. Epub 2011 Dec 17.

17 J Med Genet Feb;49(2):90-5. Epub 2011 Dec 17. Multi-center RCTs and Dx Criteria Azziz et al, 2001 JCEM Study N Treatments Diagnostic Criteria 410 Dose ranging study of troglitazone Elevated Free T in core lab and oligomenorrhea Moll et al, 225 Clomiphene citrate Oligomenorrhea and 2006, BMJ (CC) vs Metformin/CC for infertility polycystic ovaries Legro et al, 2007, NEJM 626 CC vs Metformin vs CC/ Metformin for infertility Homburg et al 302 CC vs Low Dose 2011, Hum FSH for infertility Reprod Elevated T (total, free, bioavailable) in local labs and oligomenorrhea Anovulatory Infertility + either Hyperandrogenism or PCO The Importance of Diagnosing Hyperandrogenism in PCOS 1) A diagnostic feature that allows for discrimination from other causes of the combination of oligomenorrhea and polycystic ovaries 2) The feature that t is best associated with metabolic abnormalities 3) A prognostic factor for treatment success The goal of treatment is to improve HA 4) An objective criteria that best allows for the conduct of multi-center trials

18 Acknowledgments Penn State REI Research Team Bill Dodson, M.D. Carol Gnatuk, M.D. Stephanie Estes, M.D. Barb Scheetz. Sandy Eyer Jamie Ober, Patsy Rawa Christy Slaughter Allen Kunselmen Larry Demers Penn State McAllister Team Jan McAllister, Ph.D. Indiana University and Penn State Peter Lee, M.D., Ph.D. Northwestern University Andrea Dunaif, M.D. Margrit Urbanek, Ph.D. University of Pennsylvania Rich Spielman, Ph.D. Doug Stewart, M.D. Kathy Ewen, Ph.D. Christos Coutifaris, M.D., Ph.D Anuja Dokras, M.D., Ph.D.. Virginia Commonwealth University Jerry Strauss M.D. Ph.D. John Nestler, M.D., Ph.D. The Reproductive Medicine Network Supported NIH/NICHD: RO1, RO3, K24, U10, and U54

Does PCOS Compromise the oocyte and embryo quality or the endometrium?

Does PCOS Compromise the oocyte and embryo quality or the endometrium? Richard S. Legro, M.D., Penn State College of Medicine, Dept of Ob/Gyn, Hershey, PA, USA Disclosures Consultant: Bayer, Ogeda (Euroscreen),