Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Polycystic Ovary Syndrome (PCOS): An Overview and Our Experience .


Affiliations
1 Department of Reproductive Biology, AIIMS, New Delhi - 110029, India ., India
2 Department of Reproductive Biology, AIIMS, New Delhi - 110029 ., India
     

   Subscribe/Renew Journal


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

Keywords

Advanced Glycation End products, Androgens, Anti-Mullerian Hormone, Bisphenol A, Epigenetic Associations, Genetic Associations, Polycystic Ovary Syndrome .
User
Subscription Login to verify subscription
Notifications
Font Size

  • 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. https://doi.org/10.4103/jhrs.JHRS_95_18 PMid:33627974 PMCid:PMC7879843
  • 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.
  • Bozdag G, Mumusoglu S, Zengin D, et al. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod 2016; 31:2841-55. https://doi.org/10.1093/humrep/dew218 PMid:27664216
  • Stein IF, Leventhal ML. Amenorrhoea associated with bilateral poly-cystic ovaries. Am J Obstet Gynecol. 1935; 29:181-91. https:// doi.org/10.1016/S0002-9378(15)30642-6
  • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19-25. https://doi.org/10.1016/j.fertnstert.2003.10.004
  • Azziz R, Carmina E, Dewailly D, 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. https://doi.org/10.1210/jc.2006-0178 PMid:16940456
  • National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome; 2012 Dec 3-5. Executive Summary. Available at: https://prevention.nih.gov/docs/programs/pcos/FinalReport.pdf.
  • Halder A and Kumar H. Polycystic Ovary Syndrome (PCOS): The Pros and Cons of Various Diagnostic Criteria. EC Gynaecology. 2020; 9(12): 39-41.
  • Neven ACH, Laven J, Teede HJ, Boyle JA. A summary on polycystic ovary syndrome: diagnostic criteria, prevalence, clinical manifestations, and management according to the latest international guidelines. Semin Reprod Med. 2018; 36:5-12. https://doi. org/10.1055/s-0038-1668085 PMid:30189445
  • Teede HJ, Misso ML, Costello MF, et al. International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018; 110(3):364-379. https://doi. org/10.1016/j.fertnstert.2018.05.004 PMid:30033227 PMCid:PMC6939856
  • Ramanand SJ, Ghongane BB, Ramanand JB, et al. Clinical characteristics of polycystic ovary syndrome in Indian women. Ind J Endocrin Metab. 2013; 17:138-45. https://doi.org/10.4103/2230-8210.107858 PMid:23776867 PMCid:PMC3659881
  • Zhang HY, Guo CX, Zhu FF, Qu et al. 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. https://doi.org/10.1007/s00404-0122568-z PMid:23108387
  • Allahbadia GN, Merchant R. Polycystic Ovary Syndrome and impact on health. Middle East Fertil Soc J. 2011; 16:19-37. https:// doi.org/10.1016/j.mefs.2010.10.002
  • Toosy S, Sodi R, Pappachan JM. Lean Polycystic Ovary Syndrome (PCOS): an evidence based practical approach. J Diabetes Metab Disord. 2018; 17:277-85. https://doi.org/10.1007/s40200-018-0371-5PMid:30918863 PMCid:PMC6405408 15.
  • Goodarzi, MO, Dumesic DA, Chazenbalk G, Azziz R. (2011). Polycystic Ovary Syndrome: etiology, pathogenesis, and diagnosis. Nat Rev Endocrinol. 2011; 7:219-31. https://doi.org/10.1038/nrendo.2010.217 PMid:21263450
  • Vallisneri A, 1721. Cited in Insler V, Lunesfeld B. Polycystic ovarian disease: A challenge and controversy. Gynecol Endocrinol. 1990; 4:51-69. https://doi.org/10.3109/09513599009030691 PMid:2186596
  • Chereau Achilles. Memoires pour Servir a l’Etude des Maladies des Ovaries. Paris: Fortin, Masson and Cie; 1844.
  • Rokitansky C. A Manual of Pathological Anatomy-Vol II. Philadelphia: Blanchard and Lea; 1855. p. 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. https://doi.org/10.1210/jcem-30-4-435 PMid:5435284
  • Davis CD, Ashe JR, Austin J. Sclerotic polycystic ovary syndrome. South Med J. 1956; 49:856-61. https://doi.org/10.1097/00007611- 195608000-00012 PMid:13351891
  • Keettel WC, Bradbury JT, Stoddard FJ. Observations on the polycystic ovary syndrome. Am J Obstet Gynecol. 1957; 73:954-62; discussion, 962-5. https://doi.org/10.1016/S0002-9378(16)37166-6
  • 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.
  • 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, et al. Task force on the phenotype of the polycystic ovary syndrome of the androgen excess and PCOS Ssociety. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: The complete task force report. Fertil Steril. 2009; 91:456-88. https://doi.org/10.1016/j.fertnstert.2008.06.035 PMid:18950759 30.
  • 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. https://doi.org/10.4103/2230-8210.131162 PMid:24944925 PMCid:PMC4056129
  • Wiweko B, Maidarti M, Priangga MD, et al. Anti-mullerian hormone as a diagnostic and prognostic tool for PCOS patients. J Assist Reprod Genet. 2014; 31:1311-6. https://doi.org/10.1007/s10815-014-0300-6 PMid:25119192 PMCid:PMC4171421
  • Goodman NF, Cobin RH, Futterweit W, et al. 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. https://doi.org/10.4158/ EP15748.DSC PMid:26509855
  • 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: Gguide to the best practices in the evaluation and treatment of polycystic ovary syndrome-part 2. Endocr Pract. 2015b; 21:141526. https://doi.org/10.4158/EP15748.DSCPT2 PMid:26642102
  • Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocr Metab 1961; 21:1440-7. https://doi. org/10.1210/jcem-21-11-1440 PMid:13892577
  • 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. https://doi.org/10.1016/S0015-0282(16)60070-5
  • 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. https://doi.org/10.1016/S0190-9622(88)70241-8
  • Slayden SM, Moran C, Sams WM Jr, Boots LR, Azziz R. Hyperandrogenaemia in patients presenting with acne. Fertil Steril 2001; 75:889-92. https://doi.org/10.1016/S0015-0282(01)01701-0
  • 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. https://doi.org/10.1210/jc.2003-032046https://doi.org/10.1210/ jcem.89.9.9990 PMid:15181052 .
  • 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. https://doi.org/10.1016/S0015-0282(97)00464-0
  • Rosner W. Errors in the measurement of plasma free testosterone. J Clin Endocrinol Metab 1997; 82:2014-5. https://doi. org/10.1210/jcem.82.6.9999 PMid:9177424
  • 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. https://doi.org/10.1530/ eje.0.1450749 PMid:11720900
  • 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. https://doi.org/10.1016/S0015-0282(98)00536-6
  • 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. https://doi.org/10.1530/eje.0.1430405 PMid:11022184
  • Pinola P, Piltonen TT, Puurunen J, , 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. https://doi.org/10.1210/jc.2015-2123 PMid:26192874
  • Bui HN, Sluss PM, Hayes FJ, 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. https://doi.org/10.1016/j. cca.2015.08.019 PMid:26327459
  • Eden JA, Place J, Carter GD, Jones J, et al. Elevated free androgen index as an indicator of polycystic ovaries in oligomenorrhoea without obesity or hirsute. Ann Clin Biochem. 1988; 25:346-9. https://doi.org/10.1177/000456328802500403 PMid:2975154
  • 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. https://doi.org/10.1155/2012/530121 PMid:22235201 PMCid:PMC3253436
  • Marti N, Galván, JA, Pandey AV, 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.https://doi.org/10.1016/j.mce.2016.07.029 PMid:27471004
  • Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. Endcr Rev. 2000; 21:347-62. https://doi.org/10.1210/er.21.4.347 https://doi. org/10.1210/edrv.21.4.0401 PMid:10950156
  • Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med. 2005; 353:2578-88. https://doi.org/10.1056/NEJMcp033496 PMid:16354894
  • 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.
  • Halder A, Kumar H, Kalsi AK, Jain M. Dihydrotestosterone (DHT): a potential biomarker of hyperandrogenaemia in polycystic ovary syndrome. Ind J End Metab. 2018; 22 (suppl 1):S72.
  • Weenen C, Laven JS, Von Bergh AR, 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. https://doi.org/10.1093/molehr/gah015 PMid:14742691
  • Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction. 2006; 131:1-9. https://doi.org/10.1530/rep.1.00529 PMid:16388003
  • Streuli I, Fraisse T, Pillet C, et al. 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. https://doi.org/10.1016/j.fertnstert.2007.06.023 PMid:17919608
  • Dewailly D, Gronier H, Poncelet E, 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. https:// doi.org/10.1093/humrep/der297 PMid:21926054
  • Teede H, Misso M, Tassone EC, et al. Anti-Müllerian Hormone in PCOS: A Review Informing International Guidelines. Trends Endocrinol Metab.2019; 30:467-78. https://doi.org/10.1016/j.tem.2019.04.006 PMid:31160167
  • 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. https://doi.org/10.1210/jc.2005-2076 PMid:16368745
  • Casadei L, Madrigale A, Puca F, et al. The role of serum Anti-Müllerian Hormone (AMH) in the hormonal diagnosis of polycystic ovary syndrome. Gynecol Endocrinol. 2013; 29:545-50. https://doi.org/10.3109/09513590.2013.777415 PMid:23506275
  • 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. https://doi.org/10.1210/jc.2013-1393 PMid:23775353 .
  • 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. https://doi.org/10.3904/kjim.2016.038 PMid:27899014 PMCid:PMC5511935
  • 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. https://doi.org/10.1507/endocrj.EJ160501 PMid:28381699
  • 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; accepted, in press).
  • Kumar Hemant, Kalsi APK, Jain M, Halder A. Serum Anti-Müllerian hormone (AMH) as a biomarker of PCOS diagnosis. Ind J Endocr Metabol. 2020; 24(5):460.
  • Pigny P, Gorisse E, Ghulam A, et al. Comparative assessment of five serum antimullerian hormone assays for the diagnosis of polycystic ovary syndrome. Fertil Steril. 2016; 105:1063-9. https://doi.org/10.1016/j.fertnstert.2015.12.023 PMid:26769302
  • Lin YH, Chiu WC, Wu CH, et al. Anti-mullerian hormone and polycystic ovary syndrome. Fertil Steril. 2011; 96:230-5.https://doi. org/10.1016/j.fertnstert.2011.04.003m PMid:21549367
  • Fauser BC, Pache TD, Lamberts SW, et al. 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. https://doi.org/10.1210/jcem-73-4-811 PMid:1909705
  • Taylor AE, McCourt B, Martin KA, et al. Determinants of abnormal gonadotropin secretion in clinically defined women with Polycystic Ovary Syndrome. J Clin Endocrinol Metab.1997; 82:2248-56. https://doi.org/10.1210/jcem.82.7.4105 https://doi. org/10.1210/jc.82.7.2248 PMid:9215302
  • 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. https://doi.org/10.1016/S0015-0282(97)80068-4
  • Cho LW, Jayagopal V, Kilpatrick ES, et al. The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome. Ann Clin Biochem.2006; 43:217-9. https://doi.org/10.1258/000456306776865188 PMid:16704758
  • Escobar-Morreale HF, Asunción M, Calvo RM, et al. 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. https://doi.org/10.1530/eje.0.1450619 PMid:11720881
  • Maffei M, Halaas J, Ravussin E, 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. https://doi.org/10.1038/nm1195-1155 PMid:7584987
  • Frederich RC, Hamann A, Anderson S, et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med.1995; 1:1311-4.https://doi.org/10.1038/nm1295-1311 PMid:7489415
  • Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. The N Engl J Med. 1996; 334:292-5.https://doi.org/10.1056/NEJM199602013340503 PMid:8532024
  • 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. https://doi.org/10.1038/ng0396-318 PMid:8589726
  • Barash IA. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996; 137:3144-7. https://doi.org/10.1210/ endo.137.7.8770941 PMid:8770941
  • Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996; 382:250-2. https://doi.org/10.1038/382250a0 PMid:8717038
  • 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. https://doi.org/10.1172/JCI119172 PMid:9022071 PMCid:PMC507811
  • Brzechffa PR, Jakimiuk AJ, Agarwal SK, et al. Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1996; 81:4166-9. https://doi.org/10.1210/jc.81.11.4166 https://doi.org/10.1210/ jcem .81.11.8923878 PMid:8923878
  • Halder A, Kumar H, Kalsi APK, Jain M. Polycystic Ovary Syndrome: The pros and cons of various diagnostic criteria and investigation to find out associations of various factors implicated with PCOS. Ind J Endocr Metabol 2017; 21: S68.
  • Welt CK, Smith ZA, Pauler DK, Hall JE. Differential regulation of inhibin A and inhibin B by luteinizing hormone, folliclestimulating hormone, and stage of follicle development. J Clin Endocrinol Metab. 2001; 86:2531-7. https://doi.org/10.1210/ jcem.86.6.7597 https://doi.org/10.1210/jc.86.6.2531 https://doi.org/10.1210/jcem.86.1.7107 https://doi.org/10.1210/jc.86.1.330 PMid:11397851 .
  • 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. https://doi.org/10.1016/B978-0-12-801028-0.00187-2 PMid:26559357
  • Kretser DM, Hedger MP, Loveland KL, Phillips DJ. Inhibins, activins, and follistatin in reproduction. Hum Reprod Update. 2002; 8:529-41. https://doi.org/10.1093/humupd/8.6.529 PMid:12498423
  • Segal S, Elmadjian M, Takeshige T, et al. 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. https://doi.org/10.1016/j. rbmo.2010.02.006 PMid:20231113
  • Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989; 38:1165-74.https://doi.org/10.2337/diab.38.9.1165 PMid:2670645
  • 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. https://doi.org/10.1210/jcem-57-2-356 PMid:6223044
  • 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. https://doi.org/10.2337/diacare.22.1.141 PMid:10333916
  • 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. https://doi.org/10.1210/jcem.84.1.5393 PMid:9920077
  • 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.https://doi.org/10.1093/humupd/ dmq001 PMid:20159883
  • Gambineri A, Patton L, Altieri P, et al. Polycystic Ovary Syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes. 2012; 61:2369-74. https://doi.org/10.2337/db11-1360 PMid:22698921 PMCid:PMC3425413
  • 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. New York, NY: Springer New York; 1996. p. 117-125. https://doi.org/10.1007/978-1-4613-8483-0_8
  • 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. https://doi.org/10.1172/JCI118126 PMid:7635975 PMCid:PMC185266
  • Mannerås-Holm L, Leonhardt H, Kullberg J, 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. https://doi.org/10.1210/jc.2010-1290 PMid:21084397
  • Stepto NK, Cassar S, Joham AE, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on the euglycaemichyperinsulinaemic clamp. Hum Reprod. 2013; 28:777-84. https://doi.org/10.1093/humrep/des463 PMid:23315061
  • Gennarelli G, Rovei V, Novi RF, , 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. https://doi.org/10.1210/ jc.2004-1973 PMid:15755857
  • 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. https://doi.org/10.1210/jcem.86.5.7518 PMid:11344202
  • Trout KK, Homko C, Tkacs NC. Methods of measuring insulin sensitivity. Biol Res Nurs. 2007; 8:305-18. https://doi. org/10.1177/1099800406298775 PMid:17456592
  • Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997; 18:774-800. https://doi.org/10.1210/edrv.18.6.0318 PMid:9408743
  • Nestler JE, Jakubowicz DJ, Vargas AF, et al. 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. https://doi.org/10.1210/jcem.83.6.4886 PMid:9626131
  • Nestler JE, Powers LP, Matt DW, 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. https://doi.org/10.1210/jcem-72-1-83 PMid:1898744
  • Baillargeon JP, Nestler JE. Commentary: polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin? J Clin Endocrinol Metab. 2006; 91:22-4. https://doi.org/10.1210/jc.2005-1804 PMid:16263814 PMCid:PMC3846532
  • Yildiz BO, Bozdag G, Yapici Z, et al. Prevalence, phenotype, and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod. 2012; 27:3067-73. https://doi.org/10.1093/humrep/des232 PMid:22777527 .
  • 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. https://doi.org/10.1111/j.1365-2265.2007.02764.x PMid:17371468
  • 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. https://doi.org/10.1111/j.1365-2265.2007.02954.x PMid:17760884
  • Diamanti-Kandarakis E, Argyrakopoulou G, Economou F, et al. 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. https://doi.org/10.1016/j. jsbmb.2008.03.014 PMid:18440223
  • Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999; 20:535-82. https://doi.org/10.1210/edrv.20.4.0374 PMid:10453357
  • 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. https://doi.org/10.1016/0026-0495(92)90175-A
  • Duleba AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian thecainterstitial cells. Fertil Steril. 1998; 69:335-40. https://doi.org/10.1016/S0015-0282(97)00473-1
  • Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular, inflammatory syndrome. Endocr Rev. 2003; 24:278301. https://doi.org/10.1210/er.2002-0010 PMid:12788800
  • Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in polycystic ovary syndrome. Mol Cell Endocrinol. 2011; 335:30-41. https://doi.org/10.1016/j.mce.2010.08.002 PMid:20708064
  • Shorakae S, Teede H, Courten B, et al. The emerging role of chronic low-grade inflammation in the pathophysiology of Polycystic Ovary Syndrome. Semin Reprod Med. 2015; 33:257-69. https://doi.org/10.1055/s-0035-1556568 PMid:26132930
  • González F. Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012; 77:300-5.https://doi.org/10.1016/j.steroids.2011.12.003 PMid:22178787 PMCid:PMC3309040
  • Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. 1999; 79:1-71. https://doi.org/10.1152/physrev.1999.79.1.1 PMid:9922367
  • Lansdown A, Rees DA. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clin Endocrinol (Oxf). 2012; 77:791-801. https://doi.org/10.1111/cen.12003 PMid:22882204
  • John WG, Lamb EJ. The Maillard or browning reaction in diabetes. Eye (Lond). 1993; 7:230-7. https://doi.org/10.1038/eye.1993.55 PMid:7607341
  • Garg D, Merhi Z. Relationship between advanced glycation end products and steroidogenesis in PCOS. Reprod Biol Endocrinol. 2016;14:71. https://doi.org/10.1186/s12958-016-0205-6 PMid:27769286 PMCid:PMC5073880
  • Garg D, Merhi Z. Advanced Glycation End Products: Link between Diet and Ovulatory Dysfunction in PCOS? Nutrients. 2015; 7:10129-44. https://doi.org/10.3390/nu7125524 PMid:26690206 PMCid:PMC4690076
  • 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.https://doi.org/10.1016/S0015-0282(01)01805-2
  • Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014; 29:135-45. https://doi. org/10.1093/humrep/det383 PMid:24173721
  • 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. https://doi.org/10.1016/j.bbamcr.2005.03.010 PMid:15890418
  • 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. https://doi.org/10.1002/dmrr.1188 PMid:21337488
  • 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. https://doi.org/10.2337/diabetes.50.12.2792 PMid:11723063
  • Inagi R. Inhibitors of advanced glycation and endoplasmic reticulum stress. Methods Enzymol. 2011; 491:361-80. https://doi. org/10.1016/B978-0-12-385928-0.00020-1 PMid:21329810
  • Piperi C, Adamopoulos C, Dalagiorgou G, et al. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol Metab. 2012; 97:2231-42. https://doi.org/10.1210/jc.2011-3408 PMid:22508704 .
  • 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. https://doi.org/10.1111/j.1365-2265.2004.02170.x PMid:15638868
  • 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. https://doi.org/10.1074/jbc.274.28.19919 PMid:10391939
  • Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. 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. https://doi.org/10.1111/j.13652265.2008.03247.x PMid:18363886
  • Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. 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. https://doi.org/10.1111/j.13652265.2006.02693.x PMid:17201808
  • Diamanti-Kandarakis E, Piperi C, Patsouris E, 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. https://doi. org/10.1007/s00418-006-0265-3 PMid:17205306
  • Biles JE, McNeal TP, Begley TH, Hollifield HC. Determination of Bisphenol-A in reusable polycarbonate food-contact plastics and migration to food-simulating liquids. J Agric Food Chem. 1997; 45:3541-4. https://doi.org/10.1021/jf970072i
  • Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev. 2009; 30:293-342. https://doi.org/10.1210/er.2009-0002 PMid:19502515 PMCid:PMC2726844
  • 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. https://doi.org/10.1016/j.reprotox.2007.07.006 PMid:17804194 PMCid:PMC2043380
  • 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. https://doi. org/10.1046/j.1525-142X.2003.03011.x PMid:12492412
  • Schönfelder G, Flick B, Mayr E, et al. In Utero Exposure to low doses of Bisphenol A lead to long-term deleterious effects in the vagina. Neoplasia. 2002; 4:98-102. https://doi.org/10.1038/sj.neo.7900212 PMid:11896564 PMCid:PMC1550317
  • Takeuchi T, Tsutsumi O, Ikezuki Y, et al. Positive relationship between androgen and the endocrine disruptor, Bisphenol A, in normal women and women with ovarian dysfunction. Endocr J. 2004; 51:165-9. https://doi.org/10.1507/endocrj.51.165 PMid:15118266
  • Vandenberg LN, Maffini MV, Sonnenschein C, et al. Bisphenol-A and the great divide: A review of controversies in the field of endocrine disruption. Endocr Rev. 2009; 30:75-95. https://doi.org/10.1210/er.2008-0021 PMid:19074586 PMCid:PMC2647705
  • Borrell B. Toxicology: The big test for bisphenol A. Nature. 2010 22; 464:1122-4. https://doi.org/10.1038/4641122a PMid:20414285
  • Zhou W, Liu J, Liao L, et al. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol. 2008 13; 283:12-8. https://doi.org/10.1016/j.mce.2007.10.010 PMid:18191889
  • 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. https://doi.org/10.1289/ehp.0800045 PMid:19590677 PMCid:PMC2702400
  • 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. https://doi. org/10.1289/ehp.0901257 PMid:20413367 PMCid:PMC2944080
  • Alonso-Magdalena P, Morimoto S, Ripoll C, et al. The estrogenic effect of bisphenol a disrupts pancreatic β-Cell function in vivo and induces insulin resistance. Environ Health Perspect. 2006; 114:106-12. https://doi.org/10.1289/ehp.8451 PMid:16393666 PMCid:PMC1332664
  • 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. https://doi.org/10.1007/s002040050518 PMid:9708877
  • Takeuchi T, Tsutsumi O, Ikezuki Y, et al. Elevated serum Bisphenol A-levels under hyperandrogenic conditions may be caused by decreased UDP-glucuronosyl transferase activity. Endocr J. 2006; 53:485-91. https://doi.org/10.1507/endocrj.K06-032 PMid:16829708
  • Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis suppressor gene. J Natl Cancer Inst. 1996; 88:1731-7. https://doi.org/10.1093/jnci/88.23.1731 PMid:8944003
  • Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001; 411:613-7. https://doi.org/10.1038/35079135 PMid:11385580
  • 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. https://doi.org/10.1007/s11154-007-9028-2 PMid:17340172
  • Silveira LG, Noel SD, Silveira-Neto AP, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010; 95:2276-80. https://doi.org/10.1210/jc.2009-2421 PMid:20237166 PMCid:PMC2869552
  • Araújo BS, Baracat MCP, Dos Santos Simões R, et al. Kisspeptin influence on polycystic ovary syndrome- A mini review. Reprod Sci. 2020; 27:455-460. https://doi.org/10.1007/s43032-019-00085-6 PMid:31919796
  • Yilmaz SA, Kerimoglu OS, Pekin AT, 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. https://doi.org/10.1016/j.ejogrb.2014.06.004 PMid:25020276
  • Owens LA, Abbara A, Lerner A, et al. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod. 2018; 33:292-302. https://doi.org/10.1093/humrep/dex357 PMid:29206944
  • Asghari MH, Moloudizargari M, Ghobadi E, et al. Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer. Life Sci. 2017; 185:38-45.https://doi.org/10.1016/j.lfs.2017.07.020 PMid:28739305
  • Reiter RJ, Tan DX, Tamura H, et al. Clinical relevance of melatonin in ovarian and placental physiology: a review. Gynecol Endocrinol. 2014; 30:83-9. https://doi.org/10.3109/09513590.2013.849238 PMid:24319996
  • Goradel NH, Asghari MH, Moloudizargari M, et al. Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence. Toxicol Appl Pharmacol. 2017 Nov 15; 335:56-63.https://doi.org/10.1016/j.taap.2017.09.022 PMid:28974455
  • Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002; 295:10703. https://doi.org/10.1126/science.1067262 PMid:11834835
  • Kohsaka A, Bass J. A sense of time: how molecular clocks organize metabolism. Trends Endocrinol Metab. 2007; 18:4-11. https:// doi.org/10.1016/j.tem.2006.11.005 PMid:17140805
  • Tamura H, Nakamura Y, Korkmaz A, et al. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009; 92:328-43.https://doi.org/10.1016/j.fertnstert.2008.05.016 PMid:18804205
  • Andreeva E, Absatarova Y, Sheremetyeva E, et al. Analysis of the informativeness of melatonin evaluation in polycystic ovary syndrome. Obesity Metab. 2016; 13:15-20. https://doi.org/10.14341/omet2016415-20
  • Jain P, Jain M, Haldar C, et al. Melatonin and its correlation with testosterone in polycystic ovarian syndrome. J Hum Reprod Sci. 2013; 6:253-8. https://doi.org/10.4103/0974-1208.126295 PMid:24672165 PMCid:PMC3963309
  • Li C, Shi Y, You L, et al. Melatonin receptor 1A gene polymorphism associated with polycystic ovary syndrome. Gynecol Obstet Invest. 2011; 72:130-4. https://doi.org/10.1159/000323542 PMid:21474908
  • Li C, Shi Y, You L, et al. 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. https://doi.org/10.1093/molehr/gaq087 PMid:20959387
  • Song X, Sun X, Ma G, 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. https://doi.org/10.1016/j.ejogrb.2015.09.043 PMid:26519818
  • Hague WM, Adams J, Reeders ST,. Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf). 1988; 29:593-605. https:// doi.org/10.1111/j.1365-2265.1988.tb03707.x PMid:3076848
  • 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.m https://doi.org/10.1210/jc.2005-1494 PMid:16219714
  • Kahsar-Miller MD, Nixon C, Boots LR, et al. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril. 2001; 75:53-8. https://doi.org/10.1016/S0015-0282(00)01662-9
  • Abbott DH, Bacha F. Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood. Fertil Steril. 2013; 100:2-11.m https://doi.org/10.1016/j.fertnstert.2013.05.023 PMid:23809624 PMCid:PMC3732450
  • Dunaif A. Perspectives in Polycystic Ovary Syndrome: From hair to eternity. J Clin Endocrinol Metab. 2016; 101:759-68 https:// doi.org/10.1210/jc.2015-3780 PMid:26908109 PMCid:PMC4803161
  • 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. https://doi.org/10.1210/jcem.86.5.7518 PMid:11344202 .
  • Demirci T, Cengiz H, Varım 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. https://doi.org/10.3906/ sag-2004-263 PMid:32892549 PMCid:PMC7775709
  • 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. https://doi.org/10.1097/OGX.0b013e318193301b PMid:19228439
  • Admoni O, Israel S, Lavi I, et al. Hyperandrogenism in carriers of CYP21 mutations: The role of genotype. Clin Endocrinol (Oxf). 2006; 64:645-51. https://doi.org/10.1111/j.1365-2265.2006.02521.xPMid:16712666
  • Reddy KR, Deepika ML, Supriya K, et al. CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. J Assist Reprod Genet. 2014; 31:857-63. https://doi.org/10.1007/s10815-014-0236-x PMid:24793009 PMCid:PMC4096885
  • Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010; 2010:625105. https://doi org/10.1186/1687-9856-2010-625105
  • 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. https://doi.org/10.1507/endocrj.51.31 PMid:15004406
  • Blanché H, Vexiau P, Clauin S, et al. Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women. Hum Genet. 1997; 101:56-60. https://doi.org/10.1007/s004390050586 PMid:9385370
  • 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. https://doi.org/10.1016/j. fertnstert.2009.06.025 PMid:19726039
  • Trakakis E, Rizos D, Loghis C, 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. https://doi.org/10.1507/ endocrj.K07-053 PMid:18187875
  • 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, et al. Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. J Clin Endocrinol Metab. 2009; 94:4992-5000. https://doi.org/10.1210/jc.2009-1460 PMid:19837910 PMCid:PMC2795645
  • Metherell LA, Naville D, Halaby G, et al. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009; 94:3865-71. https://doi.org/10.1210/jc.2009-0467 PMid:19773404 PMCid:PMC2860769
  • Jones MR, Mathur R, Cui J, et al. 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. https://doi.org/10.1210/jc.2009-0931 PMid:19837928 PMCid:PMC2795666
  • 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. https://doi.org/10.1186/1471-2350-11-12 PMid:20092643 PMCid:PMC2824654
  • 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. https://doi.org/10.1210/jc.2007-0761 PMid:17785364
  • Ewens KG, Stewart DR, Ankener W, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010; 95:2306-15. https://doi.org/10.1210/jc.2009-2703 PMid:20200332 PMCid:PMC2869537
  • Hayes MG, Urbanek M, Ehrmann DA, et al. Genome-wide association of Polycystic Ovary Syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015; 6:7502. https://doi.org/10.1038/ncomms8502 PMid:26284813 PMCid:PMC4557132
  • Chen ZJ, Zhao H, He L, 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. https://doi.org/10.1038/ng.732 PMid:21151128
  • Shi Y, Zhao H, Shi Y, et al. Genome-wide association study identifies eight new risk loci for Polycystic Ovary Syndrome. Nat Genet. 2012; 44:1020-5. https://doi.org/10.1038/ng.2384 PMid:22885925
  • Goodarzi MO, Jones MR, Li X, et al. Replication of association of DENND1A and THADA variants with Polycystic Ovary Syndrome in European cohorts. J Med Genet. 2012; 49:90-5. https://doi.org/10.1136/jmedgenet-2011-100427 PMid:22180642 PMCid:PMC3536488
  • Welt CK, Styrkarsdottir U, Ehrmann DA, et al. Variants in DENND1A are associated with Polycystic Ovary Syndrome in women of European ancestry. J Clin Endocrinol Metab. 2012; 97:E1342-7. https://doi.org/10.1210/jc.2011-3478 PMid:22547425 PMCid:PMC3387396
  • Day FR, Hinds DA, Tung JY, et al. Causal mechanisms and balancing selection inferred from genetic associations with Polycystic Ovary Syndrome. Nat Commun. 2015; 6:8464. https://doi.org/10.1038/ncomms9464 PMid:26416764 PMCid:PMC4598835
  • Azziz R. PCOS in 2015: New insights into the genetics of Polycystic Ovary Syndrome. Nat Rev Endocrinol. 2016; 12:74-5. https:// doi.org/10.1038/nrendo.2015.230 PMid:26729036
  • Chen MJ, Yang WS, Yang JH, et al. 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. https://doi.org/10.1093/humrep/del175 PMid:16757555
  • Lambertini L, Saul SR, Copperman AB, 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. https://doi.org/10.3389/ fendo.2017.00352 PMid:29326659 PMCid:PMC5741701
  • Tata B, Mimouni NEH, Barbotin AL, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018; 24:834-846. https://doi.org/10.1038/s41591-018-0035-5 PMid:29760445 PMCid:PMC6098696
  • 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. https://doi.org/10.1186/s12958-015-0134-9 PMid:26691645 PMCid:PMC4687350
  • Alebić MŠ, Stojanović 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. https://doi.org/10.1093/humrep/dev131 PMid:26048913
  • 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. https://doi.org/10.1186/s12958-020-00687-9 PMid:33446212 PMCid:PMC7807442
  • 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. https://doi.org/10.1007/s43032-021-00515-4 PMid:33709373
  • Day F, Karaderi T, Jones MR, 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. 200. Zhang Y, Ho K, Keaton JM, 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. https://doi.org/10.1016/j.ajog.2020.04.004 PMid:32289280
  • Zhang Y, Ho K, Keaton JM, 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. Indian J Endocrinol Metab. 2022 (under review).
  • Sharma P, Jain M, Halder A*. An investigation of steroid biosynthesis pathway genes in PCOS patients from North India. J Hum Reprod Sci. 2022; 15:240-9. https://doi.org/10.4103/jhrs.jhrs_86_22
  • 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. https://doi.org/10.1210/mend.13.6.0311 PMid:10379893
  • Wood JR, Nelson VL, Ho C, 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. https://doi.org/10.1074/jbc.M300688200 PMid:12734205
  • Wood JR, Ho CK, Nelson-DeGrave VL,. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol. 2004; 63:51-60. https://doi.org/10.1016/j.jri.2004.01.010 PMid:15284005
  • Diao FY, Xu M, Hu Y, et al. The molecular characteristics of Polycystic Ovary Syndrome (PCOS) ovary defined by human ovary cDNA microarray. J Mol Endocrinol. 2004; 33:59-72. https://doi.org/10.1677/jme.0.0330059 PMid:15291743
  • Jansen E, Laven JS, Dommerholt HB, et al. Abnormal gene expression profiles in human ovaries from Polycystic Ovary Syndrome patients. Mol Endocrinol. 2004; 18:3050-63. https://doi.org/10.1210/me.2004-0074 PMid:15308691
  • 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. https://doi.org/10.1210/jc.2006-2123 PMid:17148555
  • Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009; 23:781-3. https:// doi.org/10.1101/gad.1787609 PMid:19339683 PMCid:PMC3959995 .
  • Rivera CM, Ren B. Mapping human epigenomes. Cell. 2013 Sep 26; 155(1):39-55. https://doi.org/10.1016/j.cell.2013.09.011 PMid:24074860 PMCid:PMC3838898
  • Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006; 114:A160-7. https://doi.org/10.1289/ehp.114-a160
  • Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Front Cell Dev Biol. 2014; 2:49.https://doi. org/10.3389/fcell.2014.00049 PMid:25364756 PMCid:PMC4207041
  • Phillips T. The role of methylation in gene expression. Nat Educ. 2008; 1:116.
  • Bird A. Perceptions of epigenetics. Nature. 2007; 447:396-8. https://doi.org/10.1038/nature05913 PMid:17522671
  • 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. https://doi.org/10.1210/jc.2005-2757 PMid:16522691
  • Li Z, Huang H. Epigenetic abnormality: a possible mechanism underlying the fetal origin of Polycystic Ovary Syndrome. Med Hypotheses. 2008; 70:638-42. https://doi.org/10.1016/j.mehy.2006.09.076PMid:17764855
  • Hickey M, Sloboda DM, Atkinson HC, 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. https://doi.org/10.1210/ jc.2009-0544 PMid:19567524
  • 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. https://doi.org/10.1210/jc.2008-0038 PMid:18303071 PMCid:PMC2386276
  • 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. https://doi.org/10.1080/09513590.2016.1203409 PMid:27425146
  • 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. https://doi.org/10.1093/humupd/dmi013 PMid:15941725
  • 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. https:// doi.org/10.1016/j.reprotox.2012.08.010 PMid:22975477 PMCid:PMC3513590
  • 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. https://doi.org/10.1002/ajp.20679 PMid:19367587 PMCid:PMC2916860
  • Harries LW, Pilling LC, Hernandez LD, et al. CCAAT-enhancer-bindingprotein-beta expression in vivo is associated with muscle strength. Aging Cell. 2012; 11:262-8. https://doi.org/10.1111/j.1474-9726.2011.00782.x PMid:22152057 PMCid:PMC3486692
  • Shen HR, Qiu LH, Zhang ZQ, et al. Genome-wide methylated DNA immunoprecipitation analysis of patients with Polycystic Ovary Syndrome. PLoS One. 2013; 8:e64801. https://doi.org/10.1371/journal.pone.0064801 PMid:23705014 PMCid:PMC3660316
  • Qu F, Wang FF, Yin R, Ding 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. https://doi.org/10.1007/ s00109-012-0881-4 PMid:22349439
  • Jones MR, Chazenbalk G, Xu N, 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. https:// doi.org/10.1210/jc.2011-2153 PMid:22723319 PMCid:PMC3431575
  • Dumesic DA, Abbott DH, Padmanabhan V. Polycystic Ovary Syndrome and its developmental origins. Rev Endocr Metab Disord. 2007; 8:127-41. https://doi.org/10.1007/s11154-007-9046-0 PMid:17659447 PMCid:PMC2935197
  • Puttabyatappa M, Padmanabhan V. Developmental Programming of Ovarian Functions and Dysfunctions. Vitam Horm. 2018; 107:377-422. https://doi.org/10.1016/bs.vh.2018.01.017 PMid:29544638 PMCid:PMC6119353
  • Xu N, Kwon S, Abbott DH, 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. https://doi.org/10.1371/journal. pone.0027286 PMid:22076147 PMCid:PMC3208630
  • Rosenfield RL. Identifying Children at Risk for Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2007; 92:787-96. https://doi. org/10.1210/jc.2006-2012 PMid:17179197
  • 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. https://doi.org/10.1152/ajpregu.00310.2010 PMid:20631295 PMCid:PMC2944425 .
  • 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. https://doi.org/10.1056/NEJMra0708473 PMid:18596274 PMCid:PMC3923653
  • 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. https://doi.org/10.1007/s43032-021-00515-4 PMid:33709373
  • Wang XX, Wei JZ, Jiao J, et al. Genome-wide DNA methylation and gene expression patterns provide insight into Polycystic Ovary Syndrome development. Oncotarget. 2014 Aug 30; 5(16):6603-10. https://doi.org/10.18632/oncotarget.2224 PMid:25051372 PMCid:PMC4196149
  • Yu YY, Sun CX, Liu YK, et al. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertil Steril. 2015 Jul; 104(1):145-53.e6. https://doi.org/10.1016/j.fertnstert.2015.04.005 PMid:25956362
  • Xu J, Bao X, Peng Z, et al. Comprehensive analysis of genome-wide DNA methylation across human Polycystic Ovary Syndrome ovary granulosa cell. Oncotarget. 2016 May 10; 7(19):27899-909. https://doi.org/10.18632/oncotarget.8544 PMid:27056885 PMCid:PMC5053696
  • Jacobsen VM, Li S, Wang A, et al. Epigenetic association analysis of clinical sub-phenotypes in patients with Polycystic Ovary Syndrome (PCOS). Gynecol Endocrinol. 2019 Aug; 35(8):691-694.https://doi.org/10.1080/09513590.2019.1576617 PMid:30782033
  • Makrinou E, Drong AW, Christopoulos G, et al. Genome-wide methylation profiling in granulosa lutein cells of women with Polycystic Ovary Syndrome (PCOS). Mol Cell Endocrinol. 2020 Jan 15; 500:110611. https://doi.org/10.1016/j.mce.2019.110611 PMid:31600550 PMCid:PMC7116598
  • Li S, Zhu D, Duan H, et al Differential DNA methylation patterns of Polycystic Ovarian Syndrome in whole blood of Chinese women. Oncotarget. 2017 Mar 28; 8(13):20656-20666. https://doi.org/10.18632/oncotarget.9327 PMid:27192117 PMCid:PMC5400534
  • Jiang LL, Xie JK, Cui JQ, et al. Promoter methylation of yes-associated protein (YAP1) gene in Polycystic Ovary Syndrome. Medicine (Baltimore). 2017 Jan; 96(2):e5768. https://doi.org/10.1097/MD.0000000000005768 PMid:28079802 PMCid:PMC5266164
  • Brassard M, AinMelk Y, Baillargeon JP. Basic infertility including Polycystic Ovary Syndrome. Med Clin North Am 2008; 92(05): 1163-1192.https://doi.org/10.1016/j.mcna.2008.04.008 PMid:18721657
  • de Wilde MA, Lamain-de Ruiter M, Veltman-Verhulst SM, et al. Increased rates of complications in singleton pregnancies of women previously diagnosed with Polycystic Ovary Syndrome predominantly in the hyperandrogenic phenotype. Fertil Steril 2017; 108(02):333-340. https://doi.org/10.1016/j.fertnstert.2017.06.015 PMid:28778282
  • Sun B, Ma Y, Li L, et al. Factors Associated with Ovarian Hyperstimulation Syndrome (OHSS) severity in women with Polycystic Ovary Syndrome undergoing IVF/ICSI. Front Endocrinol (Lausanne). 2021; 11:615957. https://doi.org/10.3389/ fendo.2020.615957 PMid:33542709 PMCid:PMC7851086
  • Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with Polycystic Ovary Syndrome: A systematic review and meta-analysis. Hum Reprod Update 2014; 20(05):748-758. https://doi.org/10.1093/humupd/dmu012 PMid:24688118 PMCid:PMC4326303
  • Panidis D, Tziomalos K, Misichronis G, et al. Insulin resistance and endocrine characteristics of the different phenotypes of Polycystic Ovary Syndrome: A prospective study. Hum Reprod 2012; 27(02):541-549. https://doi.org/10.1093/humrep/der418 PMid:22144419
  • Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of Polycystic Ovary Syndrome. Endocr Rev 2015; 36(05):487-525. https://doi.org/10.1210/er.2015-1018 PMid:26426951 PMCid:PMC4591526
  • 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(01):165-169.https://doi.org/10.1210/jcem.84.1.5393 PMid:9920077
  • Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic Ovary Syndrome is associated with endothelial dysfunction. Circulation 2001; 103(10):1410-1415. https://doi.org/10.1161/01.CIR.103.10.1410 PMid:11245645
  • Talbott EO, Zborowski JV, Rager JR, et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2004; 89(11):5454-5461. https:// doi.org/10.1210/jc.2003-032237 PMid:15531497
  • Meun C, Franco OH, Dhana K, et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab 2018; 103(04):1622-1630. https://doi.org/10.1210/jc.201702421 PMid:29408955
  • Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on Polycystic Ovary Syndrome: A systematic review and metaanalysis. Obes Rev 2013; 14(02):95-109. https://doi.org/10.1111/j.1467-789X.2012.01053.x PMid:23114091
  • Helvaci N, Yildiz BO. Oral contraceptives in Polycystic Ovary Syndrome. Minerva Endocrinol 2014; 39(03):175-187.
  • van Zuuren EJ, Fedorowicz Z, Carter B, Pandis N. Interventions for hirsutism (excluding laser and photoepilation therapy alone). Cochrane Database Syst Rev 2015; 28(04):CD010334. https://doi.org/10.1002/14651858.CD010334.pub2
  • Skubleny D, Switzer NJ, Gill RS, et al. The impact of bariatric surgery on Polycystic Ovary Syndrome: a systematic review and meta-analysis. Obes Surg 2016; 26(01):169-176. https://doi.org/10.1007/s11695-015-1902-5 PMid:26431698 .

Abstract Views: 213

PDF Views: 1




  • Polycystic Ovary Syndrome (PCOS): An Overview and Our Experience .

Abstract Views: 213  |  PDF Views: 1

Authors

Ashutosh Halder
Department of Reproductive Biology, AIIMS, New Delhi - 110029, India ., India
Hemant Kumar
Department of Reproductive Biology, AIIMS, New Delhi - 110029, India ., India
Priyal Sharma
Department of Reproductive Biology, AIIMS, New Delhi - 110029 ., India
Manish Jain
Department of Reproductive Biology, AIIMS, New Delhi - 110029, India ., India
Mona Sharma
Department of Reproductive Biology, AIIMS, New Delhi - 110029, India ., India

Abstract


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

Keywords


Advanced Glycation End products, Androgens, Anti-Mullerian Hormone, Bisphenol A, Epigenetic Associations, Genetic Associations, Polycystic Ovary Syndrome .

References