The Role of Environmental Factors from Fetal Life to Adulthood in PCOS
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1 The Roe of Environmenta Factors from Feta Life to Aduthood in PCOS Richard S. Legro, M.D. Dept Ob/Gyn Penn State Coege of Medicine M.S. Hershey Medica Center Hershey, PA
2 Nature or Nurture Genes Environment u Compex genetic disease u Famiia custering u Disease aees identified Candidate Genes Genome Wide Association Study (GWAS) u Obesity u Birth environment u Medications Vaproate u Environmenta disrupters??? BPA Air poution
3 Environmenta Exposure Windows In Utero u Birthweight Low Birthweight (SGA) u Prenata Androgenization Exposure During Infancy/Adoescence u Vaproic Acid u Bispheno A (BPA) u Poycycic Aromatic Hydrocarbons or Ozone (Air Poution)
4 Large Fetus Nurture Insuin Sensitive Time Homeostasis Surpus Favorabe Intrauterine Miieu The Barker Hypothesis: Thrifty Phenotype Harsh Obesity Sma, Thrifty Fetus Nurture Insuin Resistant Time Diabetes Heart Disease Surpus
5 Birthweight as a Prenata Marker for Premature Pubarche, Ovarian Hyperandrogenism, and Hyperinsuinemia Birthweight SD Scores 1 P<0.01 P< P< Contros Premature Pubarche Premature pubarche Ovarian hyperandrogenism + + Insuin resistance + N Ibanez L et a. J Endocrino Invest 21:558, 1998
6 Ibanez et a, JCEM, 2002 Decreased Ovuation in Sma for Gestationa Age Girs
7 Norma Birthweights in PCOS famiies compared to contros and U.S. Popuation Norms Copyright 2010 The Endocrine Society Legro, R. S. et a. J Cin Endocrino Metab2010;95:
8 No Association between Birthweight and Major Reproductive or Metaboic Abnormaiities in PCOS famiies Copyright 2010 The Endocrine Society Legro, R. S. et a. J Cin Endocrino Metab2010;95:
9 The prevaence of SGA, appropriate for gestationa age (AGA), and LGA infants in PCOS (back bars) compared with contro (open bars) offspring by Endocrine Society Anderson H et a. JCEM 2010;95:
10 Does Prenata Androgenization Infuence the Deveopment of PCOS?
11 Effects of Prenata Androgenization in Femae Rhesus Monkeys Increased circuating androgens Dumesic et a, Ferti Steri, 2002 Abnorma gonadotropin eves Dumesic et a, Ferti Steri, 1997 Increased abdomina fat Eisner et a, Obes Res, 2003 Impaired insuin action Eisner, JCEM, 2000 Impaired oocyte deveopment Dumesic et a, JCEM, 2002
12 Decreased Insuin Action in Eary Androgen Exposed Rhesus Monkeys Contro Eary Intrauterine Late Intrauterine Eisner et a, JCEM, 2000
13 Eevated Androgens in PCOS During Human Pregnancy Sir-Petermann et a, Hum Reprod 2002
14
15 Serum Free Androgen Index Leves Normaize During Pregnancy PCOS Contro 0 6 wks 16 wks 26 wks 36 wks Dmitrovic et a, Obstet Gyneco, 2011
16 Persistent Hypergycemia During Eary Pregnancy in PCOS Dmitrovic et a, Obstet Gyneco, 2011
17 Summary-Prenata Androgenisation Unikey with endogenous androgens u They do not reach appreciabe eves u The pacenta is the most effective aromatizing (conversion of androgens to estrogens) organ Endocrine disruptor u Is there an environmenta androgen agonist?
18 PCOS: Endocrine Disruptors as the Cause Rukowska et a, Ferti Steri, 2016
19 Bispheno-A High-production voume chemica used in the synthesis of poycarbonate pastics and epoxy resins Used to ine cans containing food and beverages Seective Estrogen Receptor Moduator (SERM)
20 BPA and PCOS Rukowska et a, Ferti Steri, 2016
21 Air Poution and Reproduction Air poution is associated with udecreased feta weight upreterm birth uincreased Neonata morbidity and mortaity Smoking associated with infertiity, pregnancy oss, and pregnancy compications u PCOS women with increased rates of smoking
22 Dose Response Deficit in Birth Weight with Increasing Ozone in the Air Saam et a, Environ Hth Pers, 2005
23 Issues with Environmenta Disruptors and PCOS They are associations u Not cause and effect There is no statistica correction for mutipe testing u More Environmenta Disruptors than Genes!
24 Epiepsy/Bipoar Disease And PCOS Baseine Disorder and/or? PCOS Treatment of Disorder? Environmenta Caus
25 Epiepsy/Bipoar and VPA Vaproic Acid (VPA) is used to treat convusions/mood disorders and appears to exacerbate PCOS stigmata suggesting an environmenta modifier u Vaproic Acid (VPA) u Mechanisms of Action (?): enhanced neurotransmission of GABA Bocks votage gated sodium and cacium channes Inhibits histone deacetyase
26 Menstrua Disturbances, % Correation Between Anti-Epieptic Drugs and Menstrua Disturbances N=238 Vaproate Carbamazepine Carbamazepine + Other AEDs Vaproate AEDs=Antiepieptic drugs Isojärvi JI, et a. N Eng J Med. 1993;329:
27 Serum Insuin, mu/l Serum Testosterone, ng/dl Improved Reproductive/Metaboic Abnormaities After Switch From Vaproate to Lamotrigine * * VPA=Vaproate LTG=Lamotrigine VPA LTG 2 mo LTG 6 mo LTG Contro 12 mo VPA LTG 2 mo LTG 6 mo LTG Contro 12 mo *P<.05 compared with contro subjects. P<.01 compared with vaproate. P<.05 compared with vaproate. P<.001 compared with vaproate. Isojärvi JI, et a. Ann Neuro. 1998;43:
28 Vaproate Stimuates Human Theca Ce Androgen Biosynthesis Neson et a, Endocrinoogy, 2004
29 Testosterone Concentrations in Women With Epiepsy Treated With Vaproate or Lamotrigine Testosterone Leve, ng/dl Cinicay Significant Eevation (>70 ng/dl) Lamotrigine * Vaproate *P < 0.05
30 Summary Abnormaities in Feta Growth may ead to reproductive and metaboic abnormaities found in PCOS u Both sma and arge infant size may be a consequence and risk for these abnormaities
31 Summary: State of Evidence Environmenta disruptors that are ovariotoxic are unikey to cause PCOS- a condition of ovarian hyperfunction SERMs are both treatments and potentiay inducers of poycystic ovary syndrome BPA remains a strong candidate for inducing PCOS ike symptoms when given eary in deveopment u But primariy in anima modes
32 Acknowedgments: Penn State REI Research Team u Bi Dodson, M.D. u Caro Gnatuk, M.D. u Stephanie Estes, M.D. u Barb Scheetz u Jamie Ober u Sandy Eyer u Patsy Rawa Department of Pathoogy u Jan McAister, Ph.D. u Larry Demers, Ph.D. Department of Pubic Heath Sciences u u Duanping Liao Ph.D. Aen Kunseman Northwestern University u Andrea Dunaif, M.D. u Margrit Urbanek, Ph.D. University of Pennsyvania u Anuja Dokras M.D, Ph.D. u Christos Coutifaris, M.D., Ph.D Virginia Commonweath University u Jerry Strauss M.D. Ph.D. u John Nester, M.D. Supported NIH/NICHD: RO1, K24, U10, and U54
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