POLYCYSTIC OVARY SYNDROME (PCOS): The Latest in PCOS Research

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1 POLYCYSTIC OVARY SYNDROME (PCOS): The Latest in PCOS Research Ricardo Azziz, M.D., M.P.H., M.B.A. Chief Officer of Academic Health & Hospital Affairs State University of New York (SUNY) System Administration Research Professor, Health Policy, Management & Behavior School of Public Health, Univ. at Albany, SUNY

2 COI Consulting for Bayer Pharma, Fractyl, Longitude Capital, and Ansh Labs; and on the advisory board for GlobalPET Imaging

3 DIAGNOSIS

4 ROTTERDAM 2003 AND AE-PCOS 2006 ARE EXPANSIONS OF NIH 1990 Rotterdam, 2003 AE-PCOS Soc., 2006 NIH 1990

5 COMPARING THE PHENOTYPES OF PCOS BY NIH 1990, ROTTERDAM 2003, AND AE-PCOS 2006 Phenotypes Characteristics A B C D Hirsutism/HA Ö Ö Ö Ovulatory Dysfunction Ö Ö Ö Polycystic ovaries Ö Ö Ö NIH 1990 Ö Ö Rotterdam 2003 Ö Ö Ö Ö AE-PCOS 2006 Ö Ö Ö

6 HYPERANDROGENISM IN PCOS IS ASSOCIATED WITH RISK OF METABOLIC SYNDROME A B C D Phenotypes Age-adjusted prevalence of MS is higher in all hyperandrogenic phenotypes of PCOS, compared to the nonhyperandrogenic PCOS phenotype and to controls Shroff et al, Fertil Steril 88: , 2007

7 % Non-Hispanic Whites THE IMPACT OF REFERRAL BIAS ON THE PHENOTYPE OF PCOS Prevalence of Hirsutism (%) Prevalence of Hyperandrogenemia (%) Ezeh et al. J Clin Endocrinol Metab. 2013; 98:E

PHENOTYPES IN WOMEN WITH PCOS IDENTIFIED IN REFERRAL VS. UNSELECTED POPULATIONS: SYSTEMATIC REVIEW AND META-ANALYSIS Phenotype A: 50% in referral vs.

8 PHENOTYPES IN WOMEN WITH PCOS IDENTIFIED IN REFERRAL VS. UNSELECTED POPULATIONS: SYSTEMATIC REVIEW AND META-ANALYSIS Phenotype A: 50% in referral vs. 19% in unselected* Phenotype B: 13% in referral vs. 25% in unselected* Phenotype C: 14% in referral vs. 34% in unselected* Phenotype D: 17% in referral vs. 19% in unselected *Significant difference Lizneva et al, F&S 106: , 2016

10 DIAGNOSING PCOS IN ADOLESCENCE There are no established criteria for the diagnosis of PCOS in adolescents The diagnosis of PCOS has life-long implications and the features of PCOS may be less well established in adolescents Thus, the diagnosis of PCOS in adolescents should be made with great caution If the diagnosis is unclear then the most prudent course may be: Expectant management with regular, but not overzealous, follow-up Reassurance and patient (and family) education Lifestyle modification Treatment of individual symptoms/complaints, if needed/desired

11 EPIDEMIOLOGY

12 PREVALENCE STUDIES OF PCOS AROUND THE GLOBE-2015

13 PCOS PREVALENCE ACCORDING TO NIH 1990 CRITERIA: A META- ANALYSIS Bolzag et al, Hum Reprod 31: , 2016

14 PCOS PREVALENCE ACCORDING TO ROTTERDAM 2003 CRITERIA: A META- ANALYSIS Bolzag et al, Hum Reprod 31: , 2016

15 PCOS PREVALENCE ACCORDING TO AE-PCOS SOCIETY 2006 CRITERIA: A META- ANALYSIS Bolzag et al, Hum Reprod 31: , 2016

16 PATHOPHYSIOLOGY

17 SNPS AND GENES ASSOCIATED WITH PCOS IN GWAS STUDIES AS OF 2016 # Locus SNP* Gene Description Population Chromosome 2 1 2p16.3 rs LHCGR Luteinizing hormone/choriogonadotropin receptor Chinese, Surinamese, European, Egyptian, Indian, Arabic 2 rs FSHR Follicle-stimulating hormone receptor - possible association with European, Arabic, Chinese 3 rs erectile dysfunction European, Arabic, Chinese 4 2p21 rs THADA Thyroid adenoma associated protein increase of luteinizing European, Chinese hormone and testosterone. 5 2q34 rs ERBB4 Receptor tyrosine-protein kinase erbb-4 European Chromosome 5 6 5q31.1 rs RAD50 DNA repair protein RAD50 European Chromosome 8 7 8p32.1 rs GATA4 Transcription factor GATA-4 protein European Chromosome 9 8 9q33.3 rs * DENND1A DENN domain-containing protein 1A protein mediation of endocytosis 9 9q22.32 rs C9orf3 Chromosome 9 open reading frame 3/aminopeptidase O cleavage of N-terminal amino acid; possible association with erectile dysfunction Chinese, European Chinese, European Chromosome p14.1 rs FSHB Follitropin subunit beta/follicle-stimulating hormone beta subunit Chinese, European 11 11q22.1 rs YAP1 Yes-associated protein 1 activates transcription Chinese, European 12 rs Chinese, European Chromosome q13.2 rs705702* RAB5B/SUOX RAS oncogene protein/ sulfite oxidase associated with insulin and Chinese, European glucose level 14 12q14.3 rs HMGA2 High-mobility group AT-hook 2 protein possibly transcriptional Chinese, European regulating factor 15 12q21.2 rs KRR1 Small subunit processome component homolog European Chromosome q12.1 rs TOX3 TOX high mobility group box family member 3 transcription factor Chinese, European Chromosome p13.3 rs INSR Insulin receptor gene Chinese, European Chromosome q13.2 rs SUMO1P1 Pseudogene 1 Chinese * Reported significance p<2x10 Adapted from Mykhalchenko K, Lizneva DL, Trofimova T, Walker W, Suturina L, Diamond MP, Azziz R. Genetics of the Polycystic Ovary Syndrome. Expert Rev Mol Diagn. 2017;17:

18 BMI IN WOMEN WITH PCOS IDENTIFIED IN REFERRAL VS. UNSELECTED POPULATIONS: SYSTEMATIC REVIEW AND META-ANALYSIS Overall, in this small analysis, referral PCOS subjects had a greater BMI as compared with local controls, which was not immediately apparent or was less severe in women with PCOS detected in unselected populations Lizneva et al, F&S 106: , 2016

19 NO OBVIOUS DEFECT IN PI3-K/AKT INSULIN-SIGNALING PATHWAY IN ADIPOSE OF PCOS Chen et al. Diabetes 62: , 2013

20 DYSREGULATION OF ADIPOKINE SECRETION BY ADIPOCYTES OF PCOS WOMEN Chazenbalk et al. JCEM 2010; 95:935-42, and unpublished

21 mir-93 IS OVEREXPRESSED AND IS NEGATIVELY ASSOCIATED WITH GLUT-4 EXPRESSION IN ADIPOSE TISSUE OF PCOS Chen et al. Diabetes 62: , 2013

22 MOLECULAR MECHANISMS OF INSULIN RESISTANCE IDENTIFIED IN ADIPOSE TISSUE OF WOMEN WITH PCOS Azziz et al, Nat Rev Dis Primers. 2016;2:16057

23 MOLECULAR MECHANISMS OF INSULIN RESISTANCE IDENTIFIED IN MYOCYTES AND FIBROBLASTS OF WOMEN WITH PCOS Azziz et al, Nat Rev Dis Primers. 2016;2:16057

24 ROLE OF AMH IN PCOS Azziz et al, Nat Rev Dis Primers. 2016;2:16057

25 SEVERITY OF MENSTRUAL DYSFUNCTION PREDICTS DEGREE OF IR IN 494 PCOS Modified from Brower et al, J Clin Endocrinol Metab 98: E1967 E1971, 2013

26 TREATMENT

27 TREATMENT OF PCOS Goals include treatment & prevention of: Dermatologic disorders (hirsutism, acne, alopecia) Ovulatory & menstrual dysfunction (DUB, endometrial hyperplasia or Ca) Metabolic abnormalities, incl. dyslipidemia, glucose intolerance & obesity Infertility Optimum treatment is generally combination therapy

28 PCOS: CREATING A TREATMENT PLAN Good treatment plans are based on sound and complete evaluations History of the disorder Evaluation history Treatment history Past medical/surgical history Family history Physical exam TV U/S Laboratory

29 PCOS: CREATING A TREATMENT PLAN Rx includes: OCs or progestins, for endometrial protection/ha Antiandrogens, for hirsutism, alopecia Metformin for metabolic dysfunction Ovulation induction for infertility Life-style modification Cosmetic care PCOS treatment generally requires combination Rx, and life-long care and counseling

30 PPCOS I TRIAL: CC VS. CC+MET VS. MET FOR PREGNANCY Rate of Live Births Legro et al. N Engl J Med 2007;356:551-66

31 CC VS. LETROZOLE AS FIRST-LINE OVULATION INDUCTION IN INFERTILE PCOS WOMEN: A PROSPECTIVE RCT Kar. J Hum Reprod Sci. 2012;5:262-5

32 PPCOS II TRIAL: CC VS. LETROZOLE FOR PREGNANCY Legro et al. N Engl J Med. 2014;371:119-29

33 EMERGING THERAPIES IN PCOS 1) Neurokinin B (kisspepetin-neurokinin B or NKB) receptor antagonists a) To reduce LH and LH-stimulated T levels i) AZD4901 (Astra-Zeneca, now Millendo) ii) ESN364 (EuroScreen) 2) 17b-hydroxysteroid dehydrogenase, Type 5 (AKR1C3) inhibitors a) To suppress androgen biosynthesis i) KDT501 (KinDex Therapeutics) 3) Nitric Oxide (NO) synthesis stimulation a) To improve endothelial function i) N-acetyl cysteine (NAC), alone or with CC and/or metformin ii) L-Arginine, alone or with OCPs, CC or metformin iii) Soluble guanylate cyclase (sgc) stimulators

34 EMERGING THERAPIES IN PCOS 4) DENND1A (aka connecdenn 1) inhibition a) To decrease CYP17 and androgen biosynthesis i) Anti DNEEN1A.V2 IgG 5) Increasing FSH a) Modified longer-acting FSH i) Follitropin Delta (Ferring) 6) Increasing SHBG levels a) Recombinant SHBG a)serono 7) Antiandrogens a) AR antagonist i) BAY (Bayer) ii) Others?

35 EMERGING THERAPIES IN PCOS 8) Insulin sensitizers a) Glucagon-like peptide (GLP)-1 agonists/stimulators i) Long-acting glucagon-like peptide (GLP)-1 receptor agonist (Liraglutide) ii) Enhancement of GLP-1 action via inhibition of phosphodiesterase enzyme (PDE)-4 b)inositols i) D-chiro-inositol or myo-inositol alone ii) D-chiro-inositol + myo-inositol (Ovasitol from Theralogix) c) Novel TZDs? 9) Aromatase inhibitors a) Letrozole b)others? 10) Micro-RNA modulation a) mir-93 inhibition b)others?

36 EMERGING THERAPIES IN PCOS 11) Acupuncture a) A systematic review & meta-analysis including 27 RCTs noted (Jo et al, 2017): i) A low level of evidence that acupuncture improves ovulation & menstruation rate ii) A low/very low level of evidence that acupuncture as an adjunct to medication improves LH, LH/FSH ratio, TT, fasting insulin, and pregnancy rates 12) Elemental Supplementation a) Chromium i) JDS Therapeutics 13) Fenugreek Seed Extract (Furocyst)

37 HERBAL MEDICINES IN PCOS Berberine Resveratrol Cryptotanshinone Paeniflorin Ginsenosides Ong et al, Am J Chin Med 2017; 45:405-22

38 HERBAL MEDICINES IN PCOS Bushen Huatan Wen Jing Tang Tian Gui Caps. Ong et al, Am J Chin Med 2017; 45:405-22

39 THANK YOU

CREATING A PCOS TREATMENT PLAN. Ricardo Azziz, M.D., M.P.H., M.B.A. Georgia Regents University

CREATING A PCOS TREATMENT PLAN Ricardo Azziz, M.D., M.P.H., M.B.A. Georgia Regents University PCOS: CREATING A TREATMENT PLAN Good treatment plans are based on sound and complete evaluations History of