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Adolescents, hyperandrogenism, insulin resistance, ovarian dysfunction, polycystic ovarian syndrome
Polycystic ovarian syndrome is a common endocrinologic condition diagnosed in women of childbearing age. It is primarily associated with androgen excess and ovarian dysfunction, which contribute to menstrual irregularity, oligo-anovulation, infertility, hirsutism and acne. It is associated with several systemic conditions, including type 2 diabetes mellitus, cardiovascular disease, obesity and neuropsychological disorders. The exact pathophysiology and clinical features are highly variable and, thus, there is still controversy in defining the diagnostic criteria. In this review, we outline the main diagnostic criteria, discuss the mechanisms involved in the complex pathogenesis, and present the associated clinical manifestations and therapeutic management of the syndrome in adolescents.
2. 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 Endocrinol Metab. 2004; 89:2745-9.
3. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106:6-15.
4. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature reviews Endocrinology. 2018;14:270-84.
5. Pena AS, Witchel SF, Hoeger KM, et al. Adolescent polycystic ovary syndrome according to the international evidence-based guideline. BMC Medicine. 2020;18(1):72. doi: 10.1186/s12916-020-01516-x.
6. Ibanez L, Oberfield SE, Witchel S, et al. An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence. Horm Res Paediatr. 2017; 88:371-95.
7. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7:219-31.
8. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obs Gynecol. 1935;29:181-91.
9. Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. JOGC.2008;30:671-9.
10. Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo JS. Polycystic ovary syndrome in adolescents. Best Pract Res Clin Obstet Gynaecol.2018;48:103-14.
11. Wang R, Mol BW. The Rotterdam criteria for polycystic ovary syndrome: evidence-based criteria? Hum Reprod. 2017;32:261-4.
12. Rotterdam EA-SPcwg. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41-7.
13. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91:456-88.
14. Azziz R, Carmina E, Dewailly D, et al. 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.
15. Rosenfield RL. The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics. 2015; 136:1154-65.
16. Kamboj MK, Bonny AE. Polycystic ovary syndrome in adolescence: diagnostic and therapeutic strategies. Translational Pediatr. 2017; 6:248-55.
17. Fruzzetti F, Campagna AM, Perini D, Carmina E. Ovarian volume in normal and hyperandrogenic adolescent women. Fertil Steril. 2015;104:196-9.
18. Bridges NA, Cooke A, Healy MJ, Hindmarsh PC, Brook CG. Standards for ovarian volume in childhood and puberty. Fertil Steril. 1993; 60:456-60.
19. Fitzgerald S, DiVasta A, Gooding H. An update on PCOS in adolescents. Curr Opin Pediatr. 2018;30:459-65.
20. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018; 33:1602-18.
21. Witchel SF, Oberfield SE, Pena AS. Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls. J Endocrine Soc.2019;3:1545-73.
22. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016;37:467-520.
23. Andersen CY, Ezcurra D. Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins. Reprod Biol Endocrinol.2014;12:128. doi: 10.1186/1477-7827-12-128.
24. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes.1992;4:1257-66.
25. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med. 1986;315:215-9.
26. Stepto NK, Cassar S, Joham AE, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod. 2013;28:777-84.
27. Franks S, Gilling-Smith C, Watson H, Willis D. Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am.1999;28:361-78.
28. 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.
29. Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology.1981;108:1441-9.
30. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Front Biosci (Elite Ed). 2014 Jan 1;6:104-19.
31. Motta AB. The role of obesity in the development of polycystic ovary syndrome. Curr Pharm Des.2012;18:2482-91.
32. Sam S. Obesity and Polycystic Ovary Syndrome. Obes Manag. 2007;3:69-73.
33. Lebbe M, Woodruff TK. Involvement of androgens in ovarian health and disease. Mol Hum Reprod. 2013;19:828-37.
34. Nelson VL, Legro RS, Strauss JF, 3rd, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999; 13:946-57.
35. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 2008;14:367-78.
36. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057. Published 2016 Aug 11. doi:10.1038/nrdp.2016.57.
37. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015;36:487-525.
38. 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.
39. Thompson IR, Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol.2014;385:28-35.
40. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009;30:713-43.
41. Herbison AE, Moenter SM. Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. J Neuroendocrinol. 2011;23:557-69.
42. Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci (U S A). 2015;112:596-601.
43. Dadachanji R, Shaikh N, Mukherjee S. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology. Genet Res Int. 2018 Feb 18;2018:7624932. doi: 10.1155/2018/7624932
44. Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. Eur J Obstet Gynecol Reprod Biol X. 2019 Jun 8;3:100060. doi: 10.1016/j.eurox.2019.100060..
45. Echiburu B, Perez-Bravo F, Maliqueo M, Sanchez F, Crisosto N, Sir-Petermann T. Polymorphism T --> C (-34 base pairs) of gene CYP17 promoter in women with polycystic ovary syndrome is associated with increased body weight and insulin resistance: a preliminary study. Metabolism.2008;57:1765-71.
46. Jin JL, Sun J, Ge HJ, et al. Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women. BMC Med Genet. 2009;10:139. doi:10.1186/1471-2350-10-139.
47. Urbanek M. The genetics of the polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab. 2007;3:103-11.
48. Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest.2002;109:973-81.
49. Dapas M, Lin FTJ, Nadkarni GN, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLoS Med.2020; 17(6):e1003132.doi: 10.1371/journal.pmed.1003132.
50. Kshetrimayum C, Sharma A, Mishra VV, Kumar S. Polycystic ovarian syndrome: Environmental/occupational, lifestyle factors; an overview. J Turk Ger Gynecol Assoc. 2019;20:255-63.
51. Ibanez L, Ong K, Dunger DB, de Zegher F. Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children. J Clin Endocrinol Metab.2006; 91:2153-8.
52. Ibanez L, Valls C, Potau N, Marcos MV, de Zegher F. Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect. Clin Endocrinol (Oxf). 2001;55:667-72.
53. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007;8:127-41.
54. Merkin SS, Phy JL, Sites CK, Yang D. Environmental determinants of polycystic ovary syndrome. Fertil Steril.2016;106:16-24.
55. Walker MD, Zylberberg HM, Green PHR, Katz MS. Endocrine complications of celiac disease: a case report and review of the literature. Endocrine Res.2019;44:27-45.
56. Tucker LA, Erickson A, LeCheminant JD, Bailey BW. Dairy consumption and insulin resistance: the role of body fat, physical activity, and energy intake. J Diabetes Res. 2015;2015:206959. doi:10.1155/2015/206959.
57. Phy JL, Pohlmeier AM, Cooper JA, et al. Low Starch/Low Dairy Diet Results in Successful Treatment of Obesity and Co-Morbidities Linked to Polycystic Ovary Syndrome (PCOS). J Obes Weight Loss Ther. 2015 Apr;5(2):259. doi: 10.4172/2165-7904.1000259
58. Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, et al. Fifteen years after “Wingspread”--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go. Toxicol Sci. 2008;105:235-59.
59. Fernandez 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.
60. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13.
61. Goodman NF, Cobin RH, Futterweit W, et al. 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. 2015;21:1415-26.
62. Lumezi BG, Berisha VL, Pupovci HL, Goci A, Hajrushi AB. Grading of hirsutism based on the Ferriman-Gallwey scoring system in Kosovar women. Postepy Dermatol Alergol. 2018;35:631-5.
63. Meier RK. Polycystic Ovary Syndrome. Nurs Clin North Am. 2018;53:407-20.
64. Sheehan MT. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res. 2004;2:13-27.
65. Lane DE. Polycystic ovary syndrome and its differential diagnosis. Obstet Gynecol Surv. 2006;61:125-35.
66. Neocleous V, Shammas C, Phedonos AA, Phylactou LA, Skordis N. Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations. Indian J Endocrinol Metab. 2014;18 (Suppl 1):S72-9.
67. Settas N, Dracopoulou-Vabouli M, Dastamani A, et al. CYP21A2 mutations in women with polycystic ovary syndrome (PCOS). Horm Metab Res.2013; 45:383-6.
68. Skordis N, Shammas C, Phedonos AA, et al. Genetic defects of the CYP21A2 gene in girls with premature adrenarche. J Endocrinol Invest. 2015;38:535-9.
69. Guarnotta V, Niceta M, Bono M, et al. Clinical and hormonal characteristics in heterozygote carriers of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2020;198:105554. doi:10.1016/j.jsbmb.2019.105554.
70. Cisternino M, Dondi E, Martinetti M, et al. Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty. Clin Endocrinol (Oxf).1998;48:555-60.
71. Neocleous V, Fanis P, Toumba M, et al. The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis. Horm Metab Res. 2019;51:586-94.
72. 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.
73. Khan MJ, Ullah A, Basit S. Genetic Basis of Polycystic Ovary Syndrome (PCOS): Current Perspectives. Appl Clin Genet. 2019;12:249-60.
74. Goss AM, Chandler-Laney PC, Ovalle F, et al. Effects of a eucaloric reduced-carbohydrate diet on body composition and fat distribution in women with PCOS. Metabolism.2014;63:1257-64.
75. Marsh KA, Steinbeck KS, Atkinson FS, Petocz P, Brand-Miller JC. Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am J Clin Nutr. 2010; 92:83-92.
76. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Dietary fatty acid intakes and the risk of ovulatory infertility. Am J Clin Nutr. 2007;85:231-7.
77. Vigorito C, Giallauria F, Palomba S, et al. Beneficial effects of a three-month structured exercise training program on cardiopulmonary functional capacity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92:1379-84.
78. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics (Sao Paulo).2015;70:765-9.
79. Seyedoshohadaei F, Zandvakily F, Shahgeibi S. Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation. Iran J Reprod Med. 2012;10:531-6.
80. Practice Committee of American Society for Reproductive M. Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril. 2008;90 (5 Suppl):S7-12.
81. Misso ML, Wong JL, Teede HJ, et al. Aromatase inhibitors for PCOS: a systematic review and meta-analysis. Hum Reprod Update.2012;18:301-12.
82. Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril.2009;92:858-9.
83. Saleh AM, Khalil HS. Review of nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of infertile women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2004;83:614-21.
84. Hueb CK, Dias Junior JA, Abrao MS, Filho EK. Drilling: medical indications and surgical technique. Rev Assoc Med Bras. 2015;61:530-5.
85. Practice Committee of the American Society for Reproductive Medicine. Electronic address Aao, Practice Committee of the American Society for Reproductive M. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017;108:426-41.
86. Legro RS, Barnhart HX, Schlaff WD, et al. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab.2008; 93:792-800.