Environmental determinants of polycystic ovary syndrome

In this review, we summarize existing research on a variety of environmental factors potentially involved in the etiology, prevalence, and modulation of polycystic ovary syndrome (PCOS), and we suggest avenues for future research. The main environmental factors we consider include environmental toxins, diet and nutrition, socioeconomic status, and geography. There is some evidence that environmental toxins play a role in disrupting reproductive health, but there is limited research as to how these toxins may affect the development of PCOS. Although research has also shown that PCOS symptoms are reduced with certain dietary supplements and with weight loss among obese women, additional research is needed to compare various approaches to weight loss, as well as nutritional factors that may play a role in preventing or mitigating the development of PCOS. Limited studies indicate some association of low socioeconomic status with certain PCOS phenotypes, and future research should consider socioeconomic conditions during childhood or adolescence that may be more relevant to the developmental onset of PCOS. Finally, the limited scope of comparable international studies on PCOS needs to be addressed, because global patterns of PCOS are potentially valuable indicators of cultural, environmental, and genetic factors that may contribute to excess risk in certain regions of the world. In this review, we summarize existing research on a variety of environmental factors potentially involved in the etiology, prevalence, and modulation of polycystic ovary syndrome (PCOS), and we suggest avenues for future research. The main environmental factors we consider include environmental toxins, diet and nutrition, socioeconomic status, and geography. There is some evidence that environmental toxins play a role in disrupting reproductive health, but there is limited research as to how these toxins may affect the development of PCOS. Although research has also shown that PCOS symptoms are reduced with certain dietary supplements and with weight loss among obese women, additional research is needed to compare various approaches to weight loss, as well as nutritional factors that may play a role in preventing or mitigating the development of PCOS. Limited studies indicate some association of low socioeconomic status with certain PCOS phenotypes, and future research should consider socioeconomic conditions during childhood or adolescence that may be more relevant to the developmental onset of PCOS. Finally, the limited scope of comparable international studies on PCOS needs to be addressed, because global patterns of PCOS are potentially valuable indicators of cultural, environmental, and genetic factors that may contribute to excess risk in certain regions of the world. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/merkins-environmental-determinants-pcos/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/merkins-environmental-determinants-pcos/ Recent reviews of polycystic ovary syndrome (PCOS) research have found that genetic susceptibility has been associated with PCOS, and that the environment is likely to play an important role in the expression of those genetic traits (1Diamanti-Kandarakis E. Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications.Endocr Rev. 2012; 33: 981-1030Crossref PubMed Scopus (1047) Google Scholar, 2de Melo A.S. Dias S.V. Cavalli Rde C. Cardoso V.C. Bettiol H. Barbieri M.A. et al.Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause.Reproduction. 2015; 150: R11-R24Crossref PubMed Scopus (62) Google Scholar). Environmental risk factors may include exposure to harmful conditions throughout life that trigger or exacerbate the pathology of PCOS (3Escobar-Morreale H.F. Luque-Ramírez M. San Millán J.L. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.Endocr Rev. 2005; 26: 251-282Crossref PubMed Scopus (325) Google Scholar). In this report, we discuss specific environmental factors potentially involved in the etiology, prevalence, and modulation of the PCOS phenotype, including environmental toxins, diet and nutrition, socioeconomic status (SES), and geography. There is a growing interest in considering PCOS pathology across the life course (2de Melo A.S. Dias S.V. Cavalli Rde C. Cardoso V.C. Bettiol H. Barbieri M.A. et al.Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause.Reproduction. 2015; 150: R11-R24Crossref PubMed Scopus (62) Google Scholar, 4Sanchez N. A life course perspective on polycystic ovary syndrome.Int J Womens Health. 2014; 6: 115-122Crossref PubMed Scopus (15) Google Scholar, 5Teede H. Deeks A. Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan.BMC Med. 2010; 8: 41Crossref PubMed Scopus (785) Google Scholar, 6Pasquali R. Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age.Ann N Y Acad Sci. 2006; 1092: 158-174Crossref PubMed Scopus (112) Google Scholar, 7Welt C.K. Carmina E. Lifecycle of polycystic ovary syndrome (PCOS): From in utero to menopause.J Clin Endocrinol Metab. 2013; 98: 4629-4638Crossref PubMed Scopus (101) Google Scholar). That is, although PCOS symptoms are often recognized in adolescence, the physiologic ramifications of the condition influence a woman throughout her life, with metabolic and hyperandrogenic signs and symptoms appearing early in life, reproductive dysfunction becoming more obvious in adulthood, and metabolic and cardiovascular risk increasing in middle and later life (5Teede H. Deeks A. Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan.BMC Med. 2010; 8: 41Crossref PubMed Scopus (785) Google Scholar, 6Pasquali R. Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age.Ann N Y Acad Sci. 2006; 1092: 158-174Crossref PubMed Scopus (112) Google Scholar, 7Welt C.K. Carmina E. Lifecycle of polycystic ovary syndrome (PCOS): From in utero to menopause.J Clin Endocrinol Metab. 2013; 98: 4629-4638Crossref PubMed Scopus (101) Google Scholar). To consider those environmental factors related to PCOS, it is therefore crucial to consider the timing of when these environmental insults may occur and how exposure at various stages may affect the natural progression of this disease. Considering the early presentation of PCOS, generally during adolescence, researchers have considered potential environmental risk during the prenatal and postnatal periods. Evidence from experimental studies suggest that intrauterine exposure to excess androgens or glucocorticoids during certain critical periods of fetal development may lead to the development of PCOS symptoms as well as determine the phenotypic expression of PCOS during adulthood (2de Melo A.S. Dias S.V. Cavalli Rde C. Cardoso V.C. Bettiol H. Barbieri M.A. et al.Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause.Reproduction. 2015; 150: R11-R24Crossref PubMed Scopus (62) Google Scholar). One hypothesis is that intrauterine growth restriction (IUGR) can lead to increased prenatal exposure of androgens/glucocorticoids, which in turn may induce the fetal programming of PCOS (2de Melo A.S. Dias S.V. Cavalli Rde C. Cardoso V.C. Bettiol H. Barbieri M.A. et al.Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause.Reproduction. 2015; 150: R11-R24Crossref PubMed Scopus (62) Google Scholar, 8Melo A.S. Vieira C.S. Barbieri M.A. Rosa-E-Silva A.C. Silva A.A. Cardoso V.C. et al.High prevalence of polycystic ovary syndrome in women born small for gestational age.Hum Reprod. 2010; 25: 2124-2131Crossref PubMed Scopus (81) Google Scholar). The research on this potential pathway is mixed, with some data supporting an association between those born small for gestational age (SGA; a condition indicative of IUGR) and PCOS (8Melo A.S. Vieira C.S. Barbieri M.A. Rosa-E-Silva A.C. Silva A.A. Cardoso V.C. et al.High prevalence of polycystic ovary syndrome in women born small for gestational age.Hum Reprod. 2010; 25: 2124-2131Crossref PubMed Scopus (81) Google Scholar) and other data indicating no such association (9Laitinen J. Taponen S. Martikainen H. Pouta A. Millwood I. Hartikainen A.L. et al.Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms.Int J Obes Relat Metab Disord. 2003; 27: 710-715Crossref PubMed Scopus (119) Google Scholar, 10Ibáñez L. López-Bermejo A. Callejo J. Torres A. Cabré S. Dunger D. et al.Polycystic ovaries in nonobese adolescents and young women with ovarian androgen excess: relation to prenatal growth.J Clin Endocrinol Metab. 2008; 93: 196-199Crossref PubMed Scopus (40) Google Scholar). Although evidence from human studies is lacking regarding potential prenatal environmental factors, there is more evidence that postnatal exposure to environmental risk factors are linked to PCOS. Harmful lifestyle factors, including obesity and lack of exercise have been suggested as potential environmental risk factors associated with the metabolic conditions related to PCOS (2de Melo A.S. Dias S.V. Cavalli Rde C. Cardoso V.C. Bettiol H. Barbieri M.A. et al.Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause.Reproduction. 2015; 150: R11-R24Crossref PubMed Scopus (62) Google Scholar). Obesity has been found to be related to exacerbated metabolic and ovulatory dysfunction related to PCOS (11Moran L.J. Pasquali R. Teede H.J. Hoeger K.M. Norman R.J. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society.Fertil Steril. 2009; 92: 1966-1982Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 12Lim S.S. Norman R.J. Davies M.J. Moran L.J. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis.Obes Rev. 2013; 14: 95-109Crossref PubMed Scopus (311) Google Scholar), and weight loss has been found to restore ovulation and improve hyperandrogenism (13Moran L.J. Hutchison S.K. Norman R.J. Teede H.J. Lifestyle changes in women with polycystic ovary syndrome.Cochrane Database Syst Rev. 2011; : CD007506Google Scholar, 14Thessaloniki ESHRE/ASRM–Sponsored PCOS Consensus Workshop GroupConsensus on infertility treatment related to polycystic ovary syndrome.Fertil Steril. 2008; 89: 505-522Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). In addition, racial/ethnic variation in phenotypes further suggests that lifestyle and cultural factors are likely to play a role in these metabolic consequences of PCOS (3Escobar-Morreale H.F. Luque-Ramírez M. San Millán J.L. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.Endocr Rev. 2005; 26: 251-282Crossref PubMed Scopus (325) Google Scholar). In the present report we therefore aim to outline the current research on environmental risk factors of PCOS and potential avenues for future research. There is a growing body of evidence that environmental toxins have a significant impact on human health and reproduction (15American College of Obstetricians and Gynecologists. Committee opinion: exposure to toxic environmental agents. No. 575, October 2013:1–5.Google Scholar, 16di Renzo G.C. Conray J.A. Blake J. DeFrancesco M.A. DeNicola N. Martin Jr., J.N. et al.International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.Int J Gynecol Obstetrics. 2015; 131: 219-225Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). Environmental toxins are defined as chemical pollutants in the environment that have adverse effects on biologic organisms. These pollutants may be inhaled, absorbed through skin and mucous membranes, or ingested. Scientific evidence has emerged showing significant and lasting effects of environmental toxins on human reproductive health (17Diamanti-Kandarakis E. Bourguignon J.P. Giudice L.C. Hauser R. Prins G.S. Soto A.M. et al.Endocrine-disrupting chemicals: an Endocrine Society scientific statement.Endocr Rev. 2009; 30: 293-342Crossref PubMed Scopus (2997) Google Scholar, 18Woodruff T.J. Janssen S. Guillette Jr., L.J. Giudice L.C. Environmental impacts on reproductive health and fertility. Cambridge University Press, New York2010Crossref Scopus (31) Google Scholar, 19Boekelheide K. Blumberg B. Chapin R.E. Cote I. Graziano J.H. Janesick A. et al.Predicting later-life outcomes of early-life exposures.Environ Health Perspect. 2012; 120: 1353-1361Crossref PubMed Scopus (134) Google Scholar). Although pollutants such as tobacco smoke, lead, pesticides, and mercury are harmful to the general population, endocrine-disrupting chemicals (EDCs) are of particular interest to reproductive health, including PCOS and its related symptoms. In 1996, the United States Environmental Protection Agency (EPA) was given a mandate under the Food Quality Protection Act and Safe Drinking Water Act to develop testing to screen for specific endocrine effects related to environmental EDCs after evidence demonstrated an association between EDCs, including environmental estrogens, antiandrogens, and chemicals such as phthalates, and decline in sperm count and cryptorchid testes among men (20Colborn T. The wildlife/human connection: modernizing risk decisions.Environ Health Perspect. 1994; 102: 55-59Crossref PubMed Scopus (48) Google Scholar, 21Food Quality Protection Act of 1996. Pub. L, No. 104–70, § 301, 110 Stat 1489 (1996).Google Scholar). Subsequent research as a result of the EPA mandate, demonstrated EDCs present in organic wastewater, primarily in the form of human byproducts, including potent pharmaceutical products, phytosterols such as estrogens, β-blockers, antiepileptic drugs, and lipid-regulating agents (22Hotchkiss A. Rider C. Blystone C. Wilson V. Hartig P. Anklley G. et al.Fifteen years after “Wingspread”—environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go.Toxicol Sci. 2008; 105: 235-259Crossref PubMed Scopus (393) Google Scholar). These organic contaminants were identified in United States streams, with the potential of contaminating the water supply (23Kolpin D.W. Thurman E.M. Linhart S.M. The environmental occurrence of herbicides: the importance of degradates in ground water.Arch Environ Contam Toxicol. 1998; 35: 385-390Crossref PubMed Scopus (171) Google Scholar, 24Kolpin D.W. Furlon E.T. Meyer M.T. et al.Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams 1999–2000: a national reconnaissance.Environ Sci Technol. 2002; 36: 1202-1211Crossref PubMed Scopus (6732) Google Scholar, 25Kolpin D.W. Skopec M. Meyer M.T. Furlong E.T. Zaugg S.D. Urban contribution of pharmaceuticals and other organic wastewater contaminants to streams during differing flow conditions.Sci Total Environ. 2004; 328: 119-130Crossref PubMed Scopus (441) Google Scholar). Two recent case-control studies investigated the association between concentrations of specific EDCs and PCOS (26Vagi S.J. Azziz-Baumgartner E. Sjödin A. Calafat A.M. Dumesic D. Gonzalez L. et al.Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.BMC Endocr Disord. 2014; 14: 86Crossref PubMed Scopus (88) Google Scholar, 27Yang Q. Zhao Y. Qiu X. Zhang C. Li R. Qiao J. Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case-control study.Hum Rep. 2015; 30: 1964-1973Crossref PubMed Scopus (55) Google Scholar). These studies found significantly higher serum levels of perfluorinated compounds (specifically perfluorooctanoate and perfluorooctaone sulfonate), polychlorinated biphenyls (PCBs), pesticides, and polycyclic aromatic hydrocarbons among women with PCOS compared with control subjects, although a causative relationship could not be determined (26Vagi S.J. Azziz-Baumgartner E. Sjödin A. Calafat A.M. Dumesic D. Gonzalez L. et al.Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.BMC Endocr Disord. 2014; 14: 86Crossref PubMed Scopus (88) Google Scholar, 27Yang Q. Zhao Y. Qiu X. Zhang C. Li R. Qiao J. Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case-control study.Hum Rep. 2015; 30: 1964-1973Crossref PubMed Scopus (55) Google Scholar). There is also evidence indicating higher serum levels of bisphenol A (BPA), a synthetic compound with mild estrogenic activity found in many common plastic consumer products, among women with PCOS compared with control subjects (28Kandaraki E. Chatzigeorgiou A. Lividas S. Palioura E. Economou F. Koutsilieris M. et al.Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS.J Clin Endocrinol Metab. 2011; 96: E480-E484Crossref PubMed Scopus (253) Google Scholar); some evidence from animal studies suggests an association between neonatal exposure to BPA and subsequent development of PCOS-like symptoms (29Fernandez M. Bourguignon N. Lux-Lantos V. Libertun C. Neonatal exposure to bisphenol A and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats.Environ Health Perspect. 2010; 118: 1217-1222Crossref PubMed Scopus (189) Google Scholar). Higher levels of BPA exposure can lead to elevated androgen levels, which can then lead to impaired metabolism of BPA (28Kandaraki E. Chatzigeorgiou A. Lividas S. Palioura E. Economou F. Koutsilieris M. et al.Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS.J Clin Endocrinol Metab. 2011; 96: E480-E484Crossref PubMed Scopus (253) Google Scholar, 30Palioura E. Kandaraki E. Diamanti-Kandarakis E. Endocrine disruptors and polycystic ovary syndrome: a focus on bisphenol A and its potential pathophysiological aspects.Horm Mol Biol Clin Investig. 2014; 17: 137-144PubMed Google Scholar). Considering the confirmed presence of these environmental contaminants in groundwater, food, air, and common household products (31Centers for Disease Control and Prevention. Fourth national report on human exposure to environmental chemicals, updated tables Available at.http://www.cdc.gov/exposurereport/pdf/fourthreport.pdfDate: 2012Google Scholar), and the evidence of association with PCOS (26Vagi S.J. Azziz-Baumgartner E. Sjödin A. Calafat A.M. Dumesic D. Gonzalez L. et al.Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.BMC Endocr Disord. 2014; 14: 86Crossref PubMed Scopus (88) Google Scholar, 27Yang Q. Zhao Y. Qiu X. Zhang C. Li R. Qiao J. Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case-control study.Hum Rep. 2015; 30: 1964-1973Crossref PubMed Scopus (55) Google Scholar, 28Kandaraki E. Chatzigeorgiou A. Lividas S. Palioura E. Economou F. Koutsilieris M. et al.Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS.J Clin Endocrinol Metab. 2011; 96: E480-E484Crossref PubMed Scopus (253) Google Scholar, 30Palioura E. Kandaraki E. Diamanti-Kandarakis E. Endocrine disruptors and polycystic ovary syndrome: a focus on bisphenol A and its potential pathophysiological aspects.Horm Mol Biol Clin Investig. 2014; 17: 137-144PubMed Google Scholar), future research is needed to assess the role that these EDCs may play in disrupting reproductive health among women and possibly triggering or exacerbating PCOS and its related symptoms. Although a limited number of EDCs have been linked to reproductive health in general and to PCOS in particular, many other EDCs have yet to be considered regarding their possible role in the development of PCOS. Potential suspect EDCs that future research should consider, include additional PCBs, polychlorinated dibenzofurans, chlordecone, and dibromochloropropane, which have been found to alter pubertal development and fecundity (32Klaasen C.D. Casarett and Doull’s toxicology: the basic science of poisons. McGraw-Hill Education, New York2013Google Scholar, 33Jacobson J.L. Jacobson S.W. Evidence for PCBs as neurodevelopmental toxicants in humans.Neurotoxicology. 1997; 18: 415-424PubMed Google Scholar, 34Hammond B. Katzenellenbogen B.S. Krauthammer N. McConnell J. Estrogenic activity of the insecticide chlordecone (Kepone) and interaction with uterine estrogen receptors.Proc Natl Acad Sci U S A. 1979; 76: 6641-6645Crossref PubMed Scopus (156) Google Scholar, 35Boekelheide K. Darney S.P. Daston G.P. et al.NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of 2-bromopropane.Reprod Toxicol. 2004; 18: 189-217Crossref PubMed Scopus (19) Google Scholar). 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Prolactin may be increased in newly diagnosed celiac children and adolescents and decreases after 6 months of gluten-free diet.Horm Res Paediatr. 2014; 81: 309-313Crossref PubMed Scopus (16) Google Scholar). The mechanism by which grains alter the endocrine system may be through their inherent phytoestrogen production (39Tolman J. Nature’s hormone factory: endocrine disruptors in the natural environment. 1996. Competitive Enterprise Institute.Google Scholar) or from agricultural pesticides found to interact with thyroid, androgen, and estrogen pathways (40United States Environmental Protection Agency. EPA releases screening results of endocrine disruptor screening for 52 pesticide chemical. June 30, 2015.Google Scholar). Dairy products from lactating cows may affect estrogen and testosterone levels as well as insulin resistance from the milk itself or potentially from hormones administered to animals (41Tucker L.A. Erickson A. LeCheminant J.D. Bailey B.W. Dairy consumption and insulin resistance: the role of body fat, physical activity, and energy intake.J Diabetes Res. 2015; : 206959PubMed Google Scholar). In general, milk proteins have insulinotropic properties, but the whey component is the predominant influence on insulin secretion (42Nilsson M. Stenberg M. Frid A.H. Holst J.J. Björck I.M. Glycemia and insulinemia in healthy subjects after lactose equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins.Am J Clin Nutr. 2004; 80: 1246-1253PubMed Scopus (357) Google Scholar, 43Frid A. Milsson M. Holst J. Bjork M. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects.Am J Clin Nutr. 2005; 82: 69-75Crossref PubMed Scopus (314) Google Scholar). Whey protein is an estrogenic endocrine disruptor present in many sports nutritional supplements (44Plotan M. Elliott C.T. Frizzell C. Connolly L. 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Further research is needed to determine the causes of metabolic inflexibility in women with PCOS, and environmental toxins and EDCs could play an important role in this process. Although there is some evidence of environmental toxins that play a role in disrupting reproductive health, there is limited research as to how these toxins may affect the development of PCOS. Known EDCs, as described above, and other similar toxins should be primary targets for future research on the role of environmental factors that may trigger or contribute to the development and severity of PCOS. High carbohydrate intake is often identified as an exacerbating factor for PCOS (49Legro R.S. Kunselman A.R. Dodson W.E. Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.J Clin Endocrinol Metab. 1999; 84: 165-169Crossref PubMed Scopus (1537) Google Scholar), although diet itself is not likely a cause of PCOS. Sjaarda et al. evaluated the association between dietary macronutrient intake and carbohydrate consumption on androgens and insulin in 259 eumenorrheic women without a history of PCOS or infertility (50Sjaarda L.A. Schisterman E.F. Schliep K.C. Plowden T. Zarek S.M. Yeung E. et al.Dietary carbohydrate intake does not impact insulin resistance or androgens in healthy, eumenorrheic women.J Clin Endocrinol Metab. 2015; 11: 2979-2986Crossref Scopus (17) Google Scholar). No significant relationships were identified between carbohydrate or any macronutrient intake and hormones such as insulin, antimüllerian hormone, and total and free testosterone, suggesting that no particular macronutrient is responsible for producing a PCOS phenotype in regularly menstruating women. Similarly, dietary composition is not associated with greater indices of insulin resistance in women who have the diagnosis of PCOS compared with control subjects (51Douglas C.C. Norris L.E. Oster R.A. Darnell B.E. Azziz R. Gower B.A. Difference in dietary intake between women with polycystic ovary syndrome and healthy controls.Fertil Steril. 2006; 86: 411-417Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). A variety of dietary supplements have been proposed to improve the PCOS in obese women. Inositols are 6-carbon compounds classified as insulin-sensitizing agents found in many foods, including fruits and beans (52Dinicola S. Chiu T.T. Unfer V. Carlomagno G. 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