updates in pcos research: facts & perspectives

UPDATES IN PCOS RESEARCH:FACTS & PERSPECTIVES

Daria Lizneva1Dept. of OB/GYN, Georgia Regent University Augusta, GA, United States2Dept. of Reproductive Health Protection, Scientific Center of Family Health and Human Reproduction, Irkutsk, Eastern Siberia, Russian Federation

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NEED TO UNDERSTAND INCREASING MORE COMPLEX BIOLOGICAL SYSTEMS

Brent Cell, 2000

MULTI- AND INTERDISCIPLINARY RESEARCH WILL BE REQUIRED TO SOLVE THE “PUZZLE” OF COMPLEX DISEASES AND CONDITIONS

• Genes• Behavior• Diet/Nutrition• Infectious agents• Environment • Society• ???

UPDATES IN PCOS: FACTS & PERSPECTIVES

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§Evolutionary

§Epidemiologic

§Genetic

DETERMINANTS OF POLYCYSTIC OVARY SYNDROME

EVOLUTIONARY DETERMINANTS OF PCOS

• Reduced fertility and fecundity

• However, it has persisted hundreds of thousands of years with a significant prevalence (5-15% of female population)

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PCOS: AN EVOLUTIONARY PUZZLE

PCOS: ADAPTIVE EVOLUTION

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Metabolic Advantages = “Thrifty Gene Hypothesis”

Fessler DM, Natterson-Horowitz B, Azziz R. Fertil Steril. 2016 Jul;106(1)42-7; Escobar-Morreale, H.F., Luque-Ramirez, M., and San Millan, J.L. Endocr Rev. 2005; 26: 251–282; Shaw, L.M. and Elton, S. Br J Obstet Gynecol. 2008; 115: 144–148; Corbett, S.J., McMichael, A.J., and Prentice, A.M. Am J Hum Biol. 2009;21: 587–598

• Past: food shortage → “thrifty” phenotype conserved energy

• Multigenerational facultative adjustment to food scarcity

• No negative selection in populations with a long history of successful agriculture

• Prevalence of PCOS is too low to reflect the past positive selection

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Immune Advantages = “Hygiene Hypothesis”

Fessler DM, Natterson-Horowitz B, Azziz R. Fertil Steril. 2016 Jul;106(1):42-7; Escobar-Morreale, H.F., Luque-Ramirez, M., and San Millan, J.L. Endocr Rev. 2005; 26: 251–282; Vasunilashorn, S., Crimmins, E.M., Kim, J.K., Winking, J., Gurven, M., Kaplan, H. et al. Am J Hum Biol. 2010; 22: 731–740

• Past: pathogen-rich ancestral environments → disease protection offered by ↑ inflammatory state

• Contemporary small societies with ↑ pathogens → no capacity for facultative adjustment of inflammation


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Reproductive Longevity Advantages

Fessler DM, Natterson-Horowitz B, Azziz R. Fertil Steril. 2016 Jul;106(1):42-7. Saxena, R., Bjonnes, A.C., Georgopoulos, N.A., Koika, V., Panidis, D., and Welt, C.K. Hum Reprod. 2015; 30: 1697–1703; Perry, J.R., Hsu, Y.H., Chasman, D.I., Johnson, A.D., Elks, C., Albrecht, E. et al. Hum Mol Genet. 2014; 23: 2490–2497; Schmidt, J., Brännström, M., Landin-Wilhelmsen, K., and Dahlgren, E. J Clin Endocrinol Metab. 2011; 96: 2178–2185; Wild, S., Pierpoint, T., Jacobs, H., and McKeigue, P. Hum Fertil (Camb). 2000; 3: 101–105

• PCOS ~ associated with enhanced reproductive longevity• PCOS locus near RAD50 - DNA double-strand break repair• ↑ AMH in PCOS - larger ovarian primordial follicle pool

• Studies do not confirm later age at menopause


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Musculoskeletal Advantages

Fessler DM, Natterson-Horowitz B, Azziz R. Fertil Steril. 2016 Jul;106(1):42-7.Escobar-Morreale, H.F., Luque-Ramirez, M., and San Millan, J.L. Endocr Rev. 2005; 26: 251–282Shaw, L.M. and Elton, S. Br J Obstet Gynecol. 2008; 115: 144–148Corbett, S.J., McMichael, A.J., and Prentice, A.M. Am J Hum Biol. 2009;21: 587–598

• Greater muscle mass, bone density, possible aggressiveness → favored survival in the past

• Difficult to understand how increased androgenization at the cost of reduced fertility enhanced overall ‘fitness’


10Kemper, K.E., Saxton, S.J., Bolormaa, S., Hayes, B.J., and Goddard, M.E. Selection for complex traits leaves little or no classic signatures of selection. BMC Genomics. 2014; 15: 246


However, LITTLE evidence for a strong positive selection of PCOS-

susceptibility alleles

(e.g. prevalence would be higher)

PCOS: NON-ADAPTIVE EVOLUTION

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Persistence theory

Fessler DM, Natterson-Horowitz B, Azziz R. Fertil Steril. 2016 Jul;106(1):42-7; Kemper, K.E., Saxton, S.J., Bolormaa, S., Hayes, B.J., and Goddard, M.E. BMC Genomics. 2014; 15: 246 Legro, R.S., Kunselman, A.R., Demers, L., Wang, S.C., Bentley-Lewis, R., and Dunaif, A. J Clin Endocrinol Metab. 2002; 87: 2134–2138; Casarini, L. and Brigante, G; J Clin Endocrinol Metab. 2014; 99: E2412–E2420; Casarini, L., Simoni, M., and Brigante, G. Reprod Biomed Online. 2016; 32: 350–361

• PCOS was Asymptomatic• or• PCOS traits were in Balance in the population:

• one group has a ‘fitness’ advantage / another has a ‘fitness’ disadvantage• e.g. “good for men / bad for women”, where several

genetic loci associated with the disorder differently modulate the reproductive parameters of men vs. those of women

• Little data is yet available

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Source population

UPDATES IN PCOS:EPIDEMIOLOGIC PERSPECTIVE

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PCOS in source population

TO STUDY• Disease Frequency• Measures of Association (Risks)• Causality


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PCOS seeking medical care



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TO STUDY• Diagnostic modalities• Treatment options

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Disease Frequency

Association with• Metabolic• Reproductive• Mood• Cardiovascular

EPIDEMIOLOGIC DETERMINANTS OF PCOS

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Are PCOS patients seeking medical care representative of the

disorder?

REFFERAL BIAS (?)

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3 original study – general and clinical PCOS • same region / same center / same tools

USA (NIH PCOS) Ezeh et al.• ↑ prevalence of the more severe PCOS phenotypes• greater BMI• more severe hirsutism• more pronounced hyperandrogenemia

China (Rott 2003 PCOS) Ma et al.• ↑ prevalence of PCOS phenotype A and• ↑ rate of menstrual dysfunction

Spain (Functional HA) Luque-Ramírez et al. • ↑ more hirsute, • ↑ % clinical and biochemical HA, • ↑ % obesity• ↑ % prevalence of PCOS

U. Ezeh, B.O. Yildiz, R. Azziz. J Clin Endocrinol Metab, 98 (2013), pp. E1088; M. Luque-Ramirez, M. Alpanes, R. Sanchon, E. Fernandez-Duran, A.E. Ortiz-Flores; H.F. Escobar-Morreale. Eur J Endocrinol, 173 (2015), pp. 603–610; Y.M. Ma, Chin Med J (Engl), 123 (2010), pp. 2185–2189

REFFERAL BIAS (?)

19Lizneva D, Kirubakaran R, Mykhalchenko K et al., Fertil Steril. 2016 Aug 13. pii: S0015-0282(16)62666-3.


Design• Systematic review and meta-analysis.

• 41 study• N=13796 Patient(s)• Extended 2003 Rotterdam criteria• PUBMED, EMBASE, Cochrane Library• 2003–2016• Observational studies

Main Outcome Measure(s)• PCOS phenotypes

• in general • clinical population

REFFERAL BIAS (?)



Design• Systematic review and meta-analysis.

• 41 study• N=13796 Patient(s)• Extended 2003 Rotterdam criteria• PUBMED, EMBASE, Cochrane Library• 2003–2016• Observational studies

Main Outcome Measure(s)• PCOS phenotypes

• in general • clinical population

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RELATION OF HYPERANDROGENISM TO METABOLIC COMPLICATIONS IN PCOS

Vs non-hyperandrogenic PCOS phenotypes and controls3 ,hyperandrogenic PCOS phenotypes have:• A six- to eightfold increased risk of MS vs control group1

• IR than non-hyperandrogenic PCOS in some studies2

• risk of hepatic steatosis

Non-hyperandrogenic PCOS phenotypes have• No significant difference in the prevalence of MS vs. controls1

• Similar mean TG and HDL levels vs. controls1

• Conflicting data on prevalence of IR

1Shroff, B.S. et al, Fertility and Sterility 2007; 2Goverde A et al. Hum. Reprod, 2009; Jones H et al. JCEM 2012;97:3709-3716

REFFERAL BIAS

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PREVALENCE OF PCOS PHENOTYPES (%, 95% CI)Phenotype AHA/OD/PCOM

Phenotype BHA/OD

Phenotype CHA/PCOM

Phenotype DOD/PCOM

GENERAL 19% (13%–27%) 25% (15%–37%) 34% (25%–46%) 19% (14%–25%)

CLINICAL 50% (46%–54%) 13% (11%–17%) 14% (12%–16%) 17% (13%–22%)

P P<0.001 P=0.026 P<0.001 NS

Lizneva D, Kirubakaran R, Mykhalchenko K et al., Fertil Steril. 2016 Aug 13. pii: S0015-0282(16)62666-3.




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PCOS in source population ≠ PCOS seeking medical care

50% 13% 14% 17%

19% 25% 34% 19%


GENERALPOPULATION:3studies CLINICALPOPULATION:2studies

REFFERAL BIAS: BMI

0.53 kg/m2, 95% CI, 0.39, 0.66 kg/m2, P<0.001

0.18 kg/m2,95% CI, 0.15, 0.51 kg/m2, P=0.30


PCOS PCOSCONTROL

CONTROL

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Does the current data confirm the “Persistence Hypothesis’ (i.e.

PCOS was essentially asymptomatic in prehistory)?

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Eastern Siberia Settings§ Scientific Center of Family

Health Protection and Human Reproduction

§ Two regions:Ø Irkutsk ØUlan-Ude

§ 4 cites

§ Collected at baseline

§ 2015 - 2017 years

ONGOING STUDIES: ES-PEP STUDY


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SITE N, total N, < 45 years old

N, ≥45 years old

Irkutsk Aviation Plant, Irkutsk 4875 2875 2000

Irkutsk State Technical University, Irkutsk 1998 935 1063

Water Distribution Company, Ulan-Ude 353 165 188

Buryat State University, Ulan-Ude 936 568 395

Total 8162 4543 3646

ES-PEP: Eastern Siberia PCOS Epidemiology and Phenotype Study• 5162 women are undergoing screening, ages 18-85 yrs.• Cross-sectional / longitudinal design / 10 years follow-up• Well defined exposures and outcomes for White and Asian

• PCOS / H/ HA/ PCOM • Validated liquid chromatography-tandem mass spectrometry for T

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Race

Caucasian (Russian)

Asian (Buryat ~ northern subgroup / Mongols)

vs


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ONGOING STUDIES: GHANA-PEP STUDY

Design: Cross-Sectional

Community - Based Study

Study aim: To determine the prevalence of PCOS and the PCOS subphenotypes in unselected women in Nsawam, Ghana

• 3,052 houses• 8,832 households

Population: 36,687 in 2014 with a population growth rate of 1.4% per annum

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GENETIC DETERMINANTS OF PCOS:GWAS

B.C. Fauser, B.C. Tarlatzis, R.W. Rebar et al. Fertil Steril, 97 (2012), pp. 28–38.e25. R.S. Legro, S.A. Arslanian, D.A. Ehrmann et al. J Clin Endocrinol Metab, 98 (2013), pp. 4565–4592

LOCUS NEAREST GENE SNP P DISCOVERY REPLICATION

1 2p16.3 LHCGR rs13405728 7.55 × 10−21 CHN SRD, EUR, EGY, IND, ARB, CHN2 2p16.3 FSHR rs2268361 9.89 × 10−13 CHN EUR, ARB, CHN

rs2349415 2.35 × 10−12 CHN3 2p21 THADA rs13429458 1.73 × 10−23 CHN EUR, CHN4 2q34 ERBB4 rs1351592 1.2 × 10−12 EUR5 5q31.1 RAD50 rs13164856 3.5 × 10−9 EUR6 8p32.1 GATA4 rs804279 8.0 × 10−10 EUR7 9q33.3 DENND1A rs2479106 8.12 × 10−9 CHN EUR

8 9q22.32 C9orf3 rs4385527 5.87 × 10−9 CHN CHN, EUR9 11p14.1 FSHB rs11031006 1.9 × 10−8 EUR EUR, CHN10 11q22.1 YAP1 rs1894116 1.08 × 10−22 CHN EUR, CHN

rs11225154 7.6 × 10−11 EUR CHN11 12q14.3 HMGA2 rs2272046 1.95 × 10−21 CHN EUR12 12q13.2 RAB5B/SUOX rs705702 8.64 × 10−26 CHN EUR13 12q21.2 KRR1 rs1275468 1.9 × 10−8 EUR14 16q12.1 TOX3 rs4784165 3.64 × 10−11 CHN EUR15 19p13.3 INSR rs2059807 1.09 × 10−8 CHN EUR16 20q13.2 SUMO1P1 rs6022786 1.83 × 10−9 CHN

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GENETIC DETERMINANTS OF PCOS:GWAS

B.C. Fauser, B.C. Tarlatzis, R.W. Rebar et al. Fertil Steril, 97 (2012), pp. 28–38.e25. R.S. Legro, S.A. Arslanian, D.A. Ehrmann et al. J Clin Endocrinol Metab, 98 (2013), pp. 4565–4592

The potential for gene discovery to improve diagnosis and treatment of PCOS is promising, though there is much to be

done in the field before the current findings can be translated to the clinic

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SUMMARY

• Persistence theory

• Need longitudinal data for PCOS in general

population to understand

• Causation

• Risks

• Further explore genetic/epigenetic factors1Shroff, B.S. et al, Fertility and Sterility 2007; 2Goverde A et al. Hum. Reprod, 2009; Jones H et al. JCEM 2012;97:3709-3716

ACKNOWLEDGMENTS

USA

RUSSIA

1Dept. of Obstetrics and Gynecology, Medical College of Georgia, Georgia Regents University, 2Dept. of Medicine, Medical College of Georgia, Georgia Regents University, Augusta 3Dept. of Reproductive Health Protection, Scientific Center of Family Health and Human Reproduction, 4Department of Population, Family and Reproductive Health, School of Public Health, University of Ghana, Legon, Accra,

Ghana.

Ricardo Azziz 1,2

Yen Hao Chen1

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Larisa Suturina3

Adanu RM4

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updates in pcos research: facts & perspectives

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