Polycystic Ovary Syndrome (PCOS): An Overview and Our Experience
Authors
-
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ,IN
Ashutosh Halder -
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ,INHemant Kumar
-
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ,INPriyal Sharma
-
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ,INManish Jain
-
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ,INMona Sharma
DOI:
https://doi.org/10.18311/jer/2022/30241Keywords:
Advanced Glycation End products, Androgens, Anti-Mullerian Hormone, Bisphenol A, Epigenetic Associations, Genetic Associations, Polycystic Ovary SyndromeAbstract
Polycystic Ovary Syndrome (PCOS) is the most common reproductive endocrine disorder in women of reproductive age. PCOS is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology. The PCOS is known for more than 100 years; however, many areas of PCOS such as diagnosis, etiology, clinical features, and treatment are still debatable. This review aims to provide an overview of the historical evolution, diagnosis, biomarkers, and etiologic associations of PCOS as of today. A brief review of publications on PCOS and our research experience on PCOS are combined. All available biomarkers/associations implicated with PCOS, like androgens (testosterone, free androgen index, DHEAS, androstenedione, dihydrotestosterone), LH, 17-OH Progesterone, anti-Mullerian Hormone (AMH), inhibin B, leptin, insulin, interleukins, advanced glycation end product (AGE), bisphenol A (BPA), kisspeptin, melatonin, etc., besides genetic and epigenetic factors, associated with PCOS are briefed, along-with our research experience. The most acceptable consensus in naming the syndrome is Polycystic Ovary Syndrome (PCOS) and consensus diagnostic criteria presently followed are Rotterdam 2003 criteria with phenotypic classification (NIH 2012 criteria). Ideal androgen, method of estimation and its cut-off value is still a subject of controversy. DHT, an androgen, seems promising. The best available biomarker associated with PCOS could be AMH. Environmental contaminants such as bisphenol A and AGEs, and endogenous factors such as kisspeptin and melatonin have strong association with PCOS. Epigenetic alterations affecting various pathways (metabolic, steroid biosynthesis, ovarian function, AGE/RAGE, AMPK, inflammatory, etc.) and pathogenic variants of various genes (INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc.) in some PCOS cases may be linked as underlying etiopathology. PCOS is a complex heterogeneous disorder, with genetic susceptibility besides environmental and epigenetic influences.
Downloads
Metrics
Downloads
Published
How to Cite
Issue
Section
References
References
Deswal R, Narwal V, Dang A, Pundir CS. The prevalence of polycystic ovary syndrome: a brief systematic review. J Hum Reprod Sci. 2020;13:261-71.
Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific, 1992: 377– 84.
Stein IF, Leventhal ML. Amenorrhoea associated with bilateral poly-cystic ovaries. Am J Obstet Gynecol. 1935;29:181-91.
The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised consensus on diagnostic criteria and long-term health risk related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91:4237-45.
National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome, December 3–5, 2012 Executive Summary. Available at: https://prevention.nih.gov /docs/programs/pcos/FinalReport.pdf.
Ramanand SJ, Ghongane BB, Ramanand JB, Patwardhan MH, Ghanghas RR, Jain SS. Clinical characteristics of polycystic ovary syndrome in Indian women. Ind J Endocrin Metab. 2013;17:138-45.
Zhang HY, Guo CX, Zhu FF, Qu PP, Lin WJ, Xiong J. Clinical characteristics, metabolic features, and phenotype of Chinese women with polycystic ovary syndrome: a large-scale case-control study. Arch Gynecol Obstet 2013;287:525-31.
Allahbadia GN, Merchant R. Polycystic ovary syndrome and impact on health. Middle East Fertility Society Journal 2011;16:19-37.
Toosy S, Sodi R, Pappachan JM. Lean polycystic ovary syndrome (PCOS): an evidence based practical approach. J Diabetes Metab Disord. 2018;17:277-85.
Goodarzi, M. O., Dumesic, D. A., Chazenbalk, G., & Azziz, R. (2011). Polycystic ovary syndrome: etiology, pathogenesis, and diagnosis. Nat Rev Endocrinol. 2011;7:219-31.
Vallisneri A, 1721. Cited in Insler V, Lunesfeld B. Polycystic ovarian disease: A challenge and controversy. Gynecol Endocrinol. 1990;4:51-69.
Chereau Achilles. Memoires pour Servir a l’Etude des Maladies des Ovaries. Paris: Fortin, Masson & Cie; 1844.
Rokitansky C. A Manual of Pathological Anatomy–Vol II. Philadelphia: Blanchard & Lea; 1855, 246.
Bulius G, Kretschmar C. Angiodystrophia. Stuttgart: Verlag von Fer-dinand Enke; 1897.
McGlinn JA. The end results of resection of the ovaries for microcystic disease. Am J Obstet Dis Women Child. 1916;73:435-9.
du Toit DAH. Polycystic ovaries, menstrual disturbances and hirsutism: Hyperthecosis. Ned Tijdschr Geneeskd. 1952;96:700.
Yen SSC, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian dis-ease. J Clin Endocrinol Metab. 1970;30:435-42.
Davis CD, Ashe JR, Austin J. Sclerotic polycystic ovary syndrome. South Med J. 1956;49:856-61.
Keettel WC, Bradbury JT, Stoddard FJ. Observations on the polycystic ovary syndrome. Am J Obstet Gynecol. 1957;73:954-62; discussion, 962-5.
Evans TN, Riley GM. Polycystic ovarian disease (Stein-Leventhal syndrome); etiology and rationale for surgical treatment. Obstet Gynecol. 1958;12:168-79.
Lambeth SS, Kintner EP. Polycystic ovary disease. J Tn State Med Assoc. 1959;52:475-9.
Cook WS. Polycystic Ovarian Syndrome. J Miss State Med Assoc. 1965;6:171-3.
Lavric MV. Galactorrhea and amenorrhea with polycystic ovaries. Del Castillo syndrome or polycystic ovarian syndrome. Am J Obstet Gynecol. 1969;104:814-7.
Vokaer R. Le syndrome des ovaires micro-polykystiques (O.M.P.K.) [The ovarian Micro-polycystic syndrome]. Bull Mem Acad R Med Belg. 1977;132:182-92.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91:456-88.
Joshi B, Mukherjee S, Patil A, Purandare A, Chauhan S, Vaidya R. A cross-sectional study of polycystic ovarian syndrome among adolescent and young girls in Mumbai, India. Indian J Endocrinol Metab. 2014;18:317-24.
Wiweko B, Maidarti M, Priangga MD, Shafira N, Fernando D, Sumapraja K, et al. Anti-mullerian hormone as a diagnostic and prognostic tool for PCOS patients. J Assist Reprod Genet. 2014;31:1311-6.
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E. American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American association of clinical endocrinologists, American college of endocrinology, and Androgen excess and PCOS society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome--part 1. Endocr Pract. 2015a;21:1291-1300.
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E. American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society. American association of clinical endocrinologists, American college of endocrinology, and Androgen excess and PCOS society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome--part 2. Endocr Pract. 2015b;21:1415-26.
Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocr Metab 1961;21:1440-7.
Ruutiainen K, Erkkola R, Gronroos MA, Irjala K. Influence of body mass index and age on the grade of hair growth in hirsute women of reproductive ages. Fertil Steril 1998;50:260-5.
Futterweit W, Dunaif A, Yeh C, Kingsley P. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Med Acad Dermatol 1988;19:831-6.
Slayden SM, Moran C, Sams WM Jr, Boots LR, Azziz R. Hyperandrogenaemia in patients presenting with acne. Fertil Steril 2001;75:889-92.
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocr Metab 2004;89:2745-9.
Boots LR, Potter S, Potter HD, Azziz R. Measurement of total serum testosterone levels using commercially available kits: high degree of between-kit variability. Fertil Steril 1998;69:286-92.
Rosner W. Errors in the measurement of plasma free testosterone. J Clin Endocrinol Metab 1997;82:2014-5.
Bili H, Laven J, Imani B, Eijkemans MJ, Fauser BC. Age related differences in features associated with PCOS in normogonadotrophic oligo-amenorrheic infertile women of reproductive years. Eur J Endocrinol 2001;145:749-55.
Moran C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril 1999;71:671-4.
Cibula D, Hill M, Starka L. The best correlation of the new index of hyperandrogenism with the grade of increased hair. Eur J Endocrinol 2000;143:405-8.
Pinola P, Piltonen TT, Puurunen J, Vanky E, Sundström-Poromaa I, Stener-Victorin E, et al. Androgen Profile Through Life in Women with Polycystic Ovary Syndrome: A Nordic Multicenter Collaboration Study. J Clin Endocrinol Metab 2015;100:3400-7.
Bui HN, Sluss PM, Hayes FJ, Blincko S, Knol DL, Blankenstein MA, et al. Testosterone, free testosterone, and free androgen index in women: Reference intervals, biological variation, and diagnostic value in polycystic ovary syndrome. Clin Chim Acta 2015;450:227-32.
Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson M. Elevated free androgen index as an indicator of polycystic ovaries in oligomenorrhoea without obesity or hirsute. Ann Clin Biochem. 1988;25:346-9.
Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol 2012;2012:530121.
Marti N, Galván, JA, Pandey AV, Trippel M, Tapia C, Müller M, et al. Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome. Mol Cell Endocrin. 2017;441:116-23.
Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. Endcr Rev. 2000;21:347-62.
Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med. 2005;353:2578-88.
Kumar H, Halder A, Sharma M, Kalsi AK, Jain M. Dihydrotestosterone: a potential biomarker of hyperandrogenaemia in PCOS. J Clin Diagn Res. 2022;16:QC09-QC14.
Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10:77-83.
Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction. 2006;131:1-9.
Streuli I, Fraisse T, Pillet C, Ibecheole V, Bischof P, de Ziegler D. Serum AMH levels remain stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids. Fertil Steril. 2008;90:395-400.
Dewailly D, Gronier H, Poncelet E, Robin G, Leroy M, Pigny P, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26:3123-9.
Teede H, Misso M, Tassone EC, Dewailly D, Ng EH, Azziz R, et al. Anti-Müllerian Hormone in PCOS: A Review Informing International Guidelines. Trends Endocrinol Metab. 2019;30:467-78.
Pigny P, Jonard S, Robert Y, Dewailly D. Serum anti-Mullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:941-5.
Casadei L, Madrigale A, Puca F, Manicuti C, Emidi E, Piccione E, et al. The role of serum anti-Müllerian hormone (AMH) in the hormonal diagnosis of polycystic ovary syndrome. Gynecol Endocrinol. 2013;29:545-50.
Iliodromiti S, Kelsey TW, Anderson RA, Nelson SM. Can anti-Mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data. J Clin Endocrinol Metab. 2013;98:3332-40.
Song DK, Oh JY, Lee H, Sung YA. Differentiation between polycystic ovary syndrome and polycystic ovarian morphology by means of an anti-Mullerian hormone cut off value. Korean J Intern Med. 2017;32:690-8.
Matsuzaki T, Munkhzaya M, Iwasa T, Tungalagsuvd A, Yano K, Mayila Y, et al. Relationship between serum anti-Mullerian hormone and clinical parameters in polycystic ovary syndrome. Endocr J. 2017;64:531-41.
Halder A, Kumar H, Sharma M, Jain M, Kalsi AK. Serum Anti-Müllerian hormone (AMH): most potential biomarker of PCOS from North India. Ind J Med Res. (IJMR_4608_20; R2) .
Pigny P, Gorisse E, Ghulam A, Robin G, Catteau-Jonard S, Duhamel A, et al. Comparative assessment of five serum antimullerian hormone assays for the diagnosis of polycystic ovary syndrome. Fertil Steril. 2016;105:1063-9.
Lin YH, Chiu WC, Wu CH, Tzeng CR, Sen Hsu C, Hsu MI. Anti-mullerian hormone and polycystic ovary syndrome. Fertil Steril. 2011;96:230-5.
Fauser BC, Pache TD, Lamberts SW, Hop WC, de Jong FH, Dahl KD. Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J Clin Endocrinol Metab. 1991;73:811-7.
Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, et al. Determinants of Abnormal Gonadotropin Secretion in Clinically Defined Women with Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 1997;82:2248-56.
Van Santbrink EJ, Hop WC, Fauser BC. Classification of normogonadotropin infertility: polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of PCOS. Fertil Steril. 1997;67:452-8.
Cho LW, Jayagopal V, Kilpatrick ES, Holding S, Atkin SL. The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome. Ann Clin Biochem. 2006;43:217-9.
Escobar-Morreale HF, Asunción M, Calvo RM, Sancho J, San Millán JL. Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies. Eur J Endocrinol. 2001;145:619-24.
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155-61.
Frederich RC, Hamann A, Anderson S, Löllmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311-4.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. The N Engl J Med. 1996;334:292-5.
Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996;12:318-20.
Barash IA. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996;137:3144-7.
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250-2.
Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest. 1997;99:391-5.
Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA. Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:4166-9.
Welt CK, Smith ZA, Pauler DK, Hall JE. Differential regulation of inhibin A and inhibin B by luteinizing hormone, follicle-stimulating hormone, and stage of follicle development. J Clin Endocrinol Metab. 2001;86:2531-7.
Kaneko H. Subchapter 33A - Inhibin. In Y Takei, H Ando, K Tsutsui. Handbook of hormones (First edition, pp.292-e33A-4). 2016 Oxford: Academic Press.
Kretser DM, Hedger MP, Loveland KL, Phillips DJ. Inhibins, activins, and follistatin in reproduction. Hum Reprod Update. 2002;8:529-41.
Segal S, Elmadjian M, Takeshige T, Karp S, Mercado R, Rivnay B. Serum inhibin A concentration in women with the polycystic ovarian syndrome and the correlation to ethnicity, androgens, and insulin resistance. Reprod Biomed Online. 2010;20:675-80.
Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-74.
Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with the polycystic ovarian disease. J Clin Endocrinol Metab. 1983;57:356-9.
Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-6.
Legro RS, Kunselman AR, Dodson WC, 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;84:165-9.
Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes, and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16:347-63.
Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, Pasquali R. Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes. 2012;61:2369-74.
Mantzoros CS, Flier JS. Insulin resistance: the clinical spectrum. Adv Endocrinol Metab. 1995;6:193-232.
Book CB, Dunaif A. Insulin Resistance in Polycystic Ovary Syndrome. In RJ Chang, Polycystic Ovary Syndrome 1996 (pp. 117–125). New York, NY: Springer New York.
Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96:801-10.
Mannerås-Holm L, Leonhardt H, Kullberg J, Jennische E, Odén A, Holm G, et al. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab. 2011;96:E304-11.
Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ. Women with polycystic ovary syndrome have intrinsic insulin resistance on the euglycaemic-hyperinsulinaemic clamp. Hum Reprod. 2013;28:777-84.
Gennarelli G, Rovei V, Novi RF, Holte J, Bongioanni F, Revelli A, et al. Preserved insulin sensitivity and beta-cell activity but decreased glucose effectiveness in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:3381-6.
Colilla S, Cox NJ, Ehrmann DA. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first-degree relatives. J Clin Endocrinol Metab. 2001;86:2027-31.
Trout KK, Homko C, Tkacs NC. Methods of measuring insulin sensitivity. Biol Res Nurs. 2007;8:305-18.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774-800.
Nestler JE, Jakubowicz DJ, Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositol glycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83:2001-5.
Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83-9.
Baillargeon JP, Nestler JE. Commentary: polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin? J Clin Endocrinol Metab. 2006;91:22-4.
Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence, phenotype, and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod. 2012;27:3067-73.
Barber TM, Wass JA, McCarthy MI, Franks S. Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2007;66:513-7.
Diamanti-Kandarakis E, Panidis D. Unraveling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS. Clin Endocrinol (Oxf). 2007;67:735-42.
Diamanti-Kandarakis E, Argyrakopoulou G, Economou F, Kandaraki E, Koutsilieris M. Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS). J Steroid Biochem Mol Biol. 2008;109:242-6.
Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999;20:535-82.
Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41:903-10.
Duleba AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells. Fertil Steril. 1998;69:335-40.
Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular, inflammatory syndrome. Endocr Rev. 2003;24:278-301.
Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in polycystic ovary syndrome. Mol Cell Endocrinol. 2011;335:30-41.
Shorakae S, Teede H, Courten B, Lambert G, Boyle J, Moran LJ.;33:257- The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome. Semin Reprod Med. 2015;33:257-69.
González F. Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012;77:300-5.
Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. 1999;79:1-71.
Lansdown A, Rees DA. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clin Endocrinol (Oxf). 2012;77:791-801.
John WG, Lamb EJ. The Maillard or browning reaction in diabetes. Eye (Lond). 1993;7:230-7.
Garg D, Merhi Z. Relationship between Advanced Glycation End Products and Steroidogenesis in PCOS. Reprod Biol Endocrinol. 2016;14:71.
Garg D, Merhi Z. Advanced Glycation End Products: Link between Diet and Ovulatory Dysfunction in PCOS? Nutrients. 2015;7:10129-44.
Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril. 2001;75:1141-7.
Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29:135-45.
Mukhopadhyay S, Mukherjee TK. Bridging advanced glycation end product, the receptor for the advanced glycation end product and nitric oxide with hormonal replacement/estrogen therapy in healthy versus diabetic postmenopausal women: a perspective. Biochim Biophys Acta. 2005;1745:145-55.
Tan KC, Shiu SW, Wong Y, Tam X. Serum advanced glycation end products (AGEs) are associated with insulin resistance. Diabetes Metab Res Rev. 2011;27:488-92.
Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes. 2001;50:2792-808.
Inagi R. Inhibitors of advanced glycation and endoplasmic reticulum stress. Methods Enzymol. 2011;491:361-80.
Piperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E, Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol Metab. 2012;97:2231-42.
Diamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G. Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2005;62:37-43.
Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999;274:19919-24.
Diamanti?Kandarakis E, Katsikis I, Piperi C, Kandaraki E, Piouka A, Papavassiliou AG, Panidis D. Increased serum advanced glycation end?products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2008;69:634-41.
Diamanti?Kandarakis E, Katsikis I, Piperi C, Alexandraki K, Panidis D. Effect of long?term orlistat treatment on serum levels of advanced glycation end?products in women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2007;66:103-9.
Diamanti-Kandarakis E, Piperi C, Patsouris E, Korkolopoulou P, Panidis D, Pawelczyk L, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol. 2007;127:581-9.
Biles JE, McNeal TP, Begley TH, Hollifield HC. Determination of Bisphenol-A in Reusable Polycarbonate Food-Contact Plastics and Migration to Food-Simulating Liquids. Journal of Agricultural and Food Chemistry 1997;45:3541-4.
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30:293-342.
Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol. 2007;24:253-8.
Markey CM, Coombs MA, Sonnenschein C, Soto AM. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev. 2003;5:67-75.
Schönfelder G, Flick B, Mayr E, Talsness C, Paul M, Chahoud I. In Utero Exposure to Low Doses of Bisphenol A Lead to Long-term Deleterious Effects in the Vagina. Neoplasia. 2002;4:98-102.
Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr J. 2004;51:165-9.
Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev. 2009;30:75-95.
Borrell B. Toxicology: The big test for bisphenol A. Nature. 2010 22;464:1122-4.
Zhou W, Liu J, Liao L, Han S, Liu J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol. 2008 13;283:12-8.
Newbold RR, Jefferson WN, Padilla-Banks E. Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life. Environ Health Perspect. 2009;117:879-85.
Fernández 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;118:1217-22.
Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. The Estrogenic Effect of Bisphenol A Disrupts Pancreatic β-Cell Function In Vivo and Induces Insulin Resistance. Environ Health Perspect. 2006;114:106-12.
Hanioka N, Jinno H, Nishimura T, Ando M. Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver. Arch Toxicol. 1998;72:387-94.
Takeuchi T, Tsutsumi O, Ikezuki Y, Kamei Y, Osuga Y, Fujiwara T, et al. Elevated Serum Bisphenol A-Levels under Hyperandrogenic Conditions may be Caused by Decreased UDP-glucuronosyltransferase Activity. Endocr J. 2006;53:485-91.
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. KiSS-1, a novel human malignant melanoma metastasis suppressor gene. J Natl Cancer Inst. 1996;88:1731-7.
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613-7.
Navarro VM, Castellano JM, García-Galiano D, Tena-Sempere M. Neuroendocrine factors in the initiation of puberty: the emergent role of kisspeptin. Rev Endocr Metab Disord. 2007;8:11-20.
Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95:2276-80.
Araújo BS, Baracat MCP, Dos Santos Simões R, de Oliveira Nuñes C, Maciel GAR, Lobo RA, et al. Kisspeptin Influence on Polycystic Ovary Syndrome-a Mini Review. Reprod Sci. 2020;27:455-460.
Yilmaz SA, Kerimoglu OS, Pekin AT, Incesu F, Dogan NU, Celik C, et al. Metastin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2014;180:56-60.
Owens LA, Abbara A, Lerner A, O’floinn S, Christopoulos G, Khanjani S, et al. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod. 2018;33:292-302.
Asghari MH, Moloudizargari M, Ghobadi E, Fallah M, Abdollahi M. Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer. Life Sci. 2017;185:38-45.
Reiter RJ, Tan DX, Tamura H, Cruz MH, Fuentes-Broto L. Clinical relevance of melatonin in ovarian and placental physiology: a review. Gynecol Endocrinol. 2014;30:83-9.
Goradel NH, Asghari MH, Moloudizargari M, Negahdari B, Haghi-Aminjan H, Abdollahi M. Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence. Toxicol Appl Pharmacol. 2017 Nov 15;335:56-63.
Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070-3.
Kohsaka A, Bass J. A sense of time: how molecular clocks organize metabolism. Trends Endocrinol Metab. 2007;18:4-11.
Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, et al. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009;92:328-43.
Andreeva E, Absatarova Y, Sheremetyeva E, Derkatch D, Ponomareva T, Tiulpakov A, et al. Analysis of the informativeness of melatonin evaluation in polycystic ovary syndrome. Obesity and Metabolism 2016;13:15-20.
Jain P, Jain M, Haldar C, Singh TB, Jain S. Melatonin and its correlation with testosterone in polycystic ovarian syndrome. J Hum Reprod Sci. 2013;6:253-8.
Li C, Shi Y, You L, Wang L, Chen ZJ. Melatonin receptor 1A gene polymorphism associated with polycystic ovary syndrome. Gynecol Obstet Invest. 2011;72:130-4.
Li C, Shi Y, You L, Wang L, Chen ZJ. Association of rs10830963 and rs10830962 SNPs in the melatonin receptor (MTNR1B) gene among Han Chinese women with polycystic ovary syndrome. Mol Hum Reprod. 2011;17:193-8.
Song X, Sun X, Ma G, Sun Y, Shi Y, Du Y, et al. Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese. Eur J Obstet Gynecol Reprod Biol. 2015;195:108-12.
Hague WM, Adams J, Reeders ST, Peto TE, Jacobs HS. Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf). 1988;29:593-605.
Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100-4.
Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril. 2001;75:53-8.
Abbott DH, Bacha F. Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood. Fertil Steril. 2013;100:2-11.
Dunaif A. Perspectives in Polycystic Ovary Syndrome: From Hair to Eternity. J Clin Endocrinol Metab. 2016;101:759-68.
Colilla S, Cox NJ, Ehrmann DA. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab. 2001;86:2027-31.
Demirci T, Cengiz H, Var?m C, Çetin S. The role and importance of auxiliary tests in differential diagnosis in patients with mildly high basal 17-OH-progesterone levels in the evaluation of hirsutism. Turk J Med Sci. 2020;50:1976-1982.
Trakakis E, Loghis C, Kassanos D. Congenital adrenal hyperplasia because of 21-hydroxylase deficiency. A genetic disorder of interest to obstetricians and gynecologists. Obstet Gynecol Surv. 2009;64:177-89.
Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol (Oxf). 2006;64:645-51.
Reddy KR, Deepika ML, Supriya K, Latha KP, Rao SS, Rani VU, Jahan P. CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. J Assist Reprod Genet. 2014;31:857-63.
Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010;2010:625105.
Yarman S, Dursun A, Oguz F, Alagol F. The prevalence, molecular analysis and HLA typing of late-onset 21-hydroxylase deficiency in Turkish woman with hirsutism and polycystic ovary. Endocr J. 2004;51:31-6.
Blanché H, Vexiau P, Clauin S, Le Gall I, Fiet J, Mornet E, et al. Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women. Hum Genet. 1997;101:56-60.
Pall M, Azziz R, Beires J, Pignatelli D. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril. 2010;94:684-9.
Trakakis E, Rizos D, Loghis C, Chryssikopoulos A, Spyropoulou M, Salamalekis E, et al. The prevalence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with hirsutism and polycystic ovary syndrome. Endocr J. 2008;55:33-9.
Khandekar S, Lata V, Dash RJ. Screening for late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Indian J Med Res. 1990;92:79-82.
Sahakitrungruang T, Huang N, Tee MK, Agrawal V, Russell WE, Crock P, et al. Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. J Clin Endocrinol Metab. 2009;94:4992-5000.
Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, et al. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009;94:3865-71.
Jones MR, Mathur R, Cui J, Guo X, Azziz R, Goodarzi MO. Independent confirmation of association between metabolic phenotypes of polycystic ovary syndrome and variation in the type 6 17beta-hydroxysteroid dehydrogenase gene. J Clin Endocrinol Metab. 2009;94:5034-8.
Tan S, Scherag A, Janssen OE, Hahn S, Lahner H, Dietz T, et al. Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC Med Genet. 2010;11:12.
Urbanek M, Sam S, Legro RS, Dunaif A. Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype. J Clin Endocrinol Metab. 2007;92:4191-8.
Ewens KG, Stewart DR, Ankener W, Urbanek M, McAllister JM, Chen C, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:2306-15.
Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6:7502.
Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011;43:55-9.
Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44:1020-5.
Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YD, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012;49:90-5.
Welt CK, Styrkarsdottir U, Ehrmann DA, Thorleifsson G, Arason G, Gudmundsson JA, et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab. 2012;97:E1342-7.
Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:8464.
Azziz R. PCOS in 2015: New insights into the genetics of polycystic ovary syndrome. Nat Rev Endocrinol. 2016;12:74-5.
Chen MJ, Yang WS, Yang JH, Hsiao CK, Yang YS, Ho HN. Low sex hormone-binding globulin is associated with low high-density lipoprotein cholesterol and metabolic syndrome in women with PCOS. Hum Reprod. 2006;21:2266-71.
Lambertini L, Saul SR, Copperman AB, Hammerstad SS, Yi Z, Zhang W, et al. Intrauterine Reprogramming of the Polycystic Ovary Syndrome: Evidence from a Pilot Study of Cord Blood Global Methylation Analysis. Front Endocrinol (Lausanne). 2017;8:352.
Tata B, Mimouni NEH, Barbotin AL, Malone SA, Loyens A, Pigny P, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24:834-846.
Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of antimüllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: a review. Reprod Biol Endocrinol. 2015;13:137.
Alebi? MŠ, Stojanovi? N, Duhamel A, Dewailly D. The phenotypic diversity in per follicle anti mullerian hormone production in polycystic ovary syndrome. Hum Reprod. 2015;30:1927-33.
Mu L, Sun X, Tu M, Zhang D. Non-coding RNAs in polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2021;19:10.
Bruni V, Capozzi A, Lello S. The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art. Reprod Sci. 2022;29:668-679.
Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14:e1007813.
Zhang Y, Ho K, Keaton JM, Hartzel DN, Day F, Justice AE, et al. A genome-wide association study of polycystic ovary syndrome identified from electronic health record. Am J Obstet Gynecol. 2020;223:559.e1-559.e21.
Sharma P, Jain M, Halder A. Whole Exome Sequencing identifies rare variants in obesity- and hyperinsulinemia-related genes in PCOS patients with high BMI and fasting insulin. Reproductive Sciences (EMID:43703f6e8f375326; submitted).
Nelson VL, Legro RS, Strauss JF, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999;13:946-57.
Wood JR, Nelson VL, Ho C, Jansen E, Wang CY, Urbanek M, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem. 2003;278:26380-90.
Wood JR, Ho CK, Nelson-DeGrave VL, McAllister JM, Strauss JF. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol. 2004;63:51-60.
Diao FY, Xu M, Hu Y, Li J, Xu Z, Lin M, et al. The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray. J Mol Endocrinol. 2004;33:59-72.
Jansen E, Laven JS, Dommerholt HB, Polman J, van Rijt C, van den Hurk C, et al. Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients. Mol Endocrinol. 2004;18:3050-63.
Wood JR, Dumesic DA, Abbott DH, Strauss JF. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92:705-13.
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781-3.
Rivera CM, Ren B. Mapping human epigenomes. Cell. 2013 Sep 26;155(1):39-55.
Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114:A160-7.
Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Front Cell Dev Biol. 2014;2:49.
Phillips T. The role of methylation in gene expression. Nat Educ 2008;1:116.
Bird A. Perceptions of epigenetics. Nature. 2007;447:396-8.
Xita N, Tsatsoulis A. Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab. 2006;91:1660-6.
Li Z, Huang H. Epigenetic abnormality: a possible mechanism underlying the fetal origin of polycystic ovary syndrome. Med Hypotheses. 2008;70:638-42.
Hickey M, Sloboda DM, Atkinson HC, Doherty DA, Franks S, Norman RJ, et al. The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study. J Clin Endocrinol Metab. 2009;94:3714-20.
Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:1939-45.
Li S, Zhu D, Duan H, Tan Q. The epigenomics of polycystic ovarian syndrome: from pathogenesis to clinical manifestations. Gynecol Endocrinol. 2016;32:942-946.
Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental etiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11:357-74.
Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations. Reprod Toxicol. 2012;34:708-19.
Abbott DH, Tarantal AF, Dumesic DA. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am J Primatol. 2009;71:776-84.
Harries LW, Pilling LC, Hernandez LD, Bradley-Smith R, Henley W, Singleton AB, et al. CCAAT-enhancer-bindingprotein-beta expression in vivo is associated with muscle strength. Aging Cell. 2012;11:262-8.
Shen HR, Qiu LH, Zhang ZQ, Qin YY, Cao C, Di W. Genome-wide methylated DNA immunoprecipitation analysis of patients with polycystic ovary syndrome. PLoS One. 2013;8:e64801.
Qu F, Wang FF, Yin R, Ding GL, El-Prince M, Gao Q, et al. A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med (Berl). 2012;90:911-23.
Jones MR, Chazenbalk G, Xu N, Chua AK, Eigler T, Mengesha E, et al. Steroidogenic regulatory factor FOS is under expressed in polycystic ovary syndrome (PCOS) adipose tissue and genetically associated with PCOS susceptibility. J Clin Endocrinol Metab. 2012;97:E1750-7.
Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007;8:127-41.
Puttabyatappa M, Padmanabhan V. Developmental Programming of Ovarian Functions and Dysfunctions. Vitam Horm. 2018;107:377-422.
Xu N, Kwon S, Abbott DH, Geller DH, Dumesic DA, Azziz R, et al. The epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys. PLoS One. 2011;6:e27286.
Rosenfield RL. Identifying Children at Risk for Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2007;92:787-96.
Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integr Comp Physiol. 2010;299:R711-22.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359:61-73.
Bruni V, Capozzi A, Lello S. The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art. Reprod Sci. 2022;29:668-679.
