DOI: http://dx.doi.org/10.18203/2320-1770.ijrcog20210350

Polycystic ovarian syndrome: pathogenesis and management

Coumba Aicha Thiam, Malyn M. L. K. Antoine, Chrystal D. Antoine-Frank

Abstract


Polycystic ovarian syndrome (PCOS) is an endocrine disorder that commonly affects women of reproductive age. Its prevalence varies quite significantly and its clinical presentation includes: reproductive, metabolic and psychological issues.  PCOS develops due to a variety of factors some of which are not yet fully understood. Due to the complexity in the development and presentation of this condition, the management of PCOS in most instances is complicated and involves the combination of pharmacological, non-pharmacological and surgical interventions. This review discusses the pathogenesis and management of PCOS as means of providing information that would enhance understanding and control of this disease.


Keywords


Hyperandrogenemia, Insulin resistance, Polycystic ovarian syndrome, Type-2 diabetes mellitus

Full Text:

PDF

References


Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016;22(6):687-708.

Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602-18.

March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-51.

Trikudanathan S. Polycystic ovarian syndrome. Med Clin North Am. 2015;99:221-35.

Vgontzas AN, Legro RS, Bixler EO, Grayev A, Kales A, Chrousos GP. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab. 2001;86(2):517-20.

Venkatesan AM, Dunaif A, Corbould A. Insulin resistance in polycystic ovary syndrome: progress and paradoxes. Recent Prog Horm Res. 2001;56:295-308.

Spritzer PM. Polycystic ovary syndrome: reviewing diagnosis and management of metabolic disturbances. Arq Bras Endocrinol Metab. 2014;58:182-7.

Nelson VL, Legro RS, Strauss III JF, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Molecular endocrinology. 1999 Jun 1;13(6):946-57.

Takai I, Taii S, Takakura K, Mori T. Three types of polycystic ovarian syndrome in relation to androgenic function. Fertil Steril. 1991;56(5):856-62.

Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Prime. 2016;2(1):1-8.

Asunción M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85(7):2434-8.

Azziz, R. Diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab. 2006;91:781-5.

Hsu MI, Liou TH, Chou SY, Chang CY, Hsu CS. Diagnostic criteria for polycystic ovary syndrome in Taiwanese Chinese women: comparison between Rotterdam 2003 and NIH 1990. Fertil Steril. 2007;88:727-9.

Mohammad MB, Seghinsara AM. Polycystic ovary syndrome (PCOS), diagnostic criteria, and AMH. Asian Pac J Cancer Prev. 2017;18:17-21.

Durlinger A, Visser J, Themmen A. Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction. 2002.

Durlinger AL, Gruijters MJ, Kramer P, Karels B, Ingraham HA, Nachtigal MW, et al. Anti-Mullerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology. 2002;143(3):1076-84.

Durlinger AL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, et al. Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse ovary. Endocrinology. 1999;140(12):5789-96.

Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic ovary syndrome. Diabetes Res Clin Pract. 2017;130:163-70.

Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981-1030.

Maqbool M, Dar MA, Gani I, Geer MI. Insulin resistance and polycystic ovary syndrome: a review. J Drug Deliv Ther. 2019;9:433-6.

Nestler JE, Jakubowicz DJ, Falcon de Vargas A, 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 inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83(6):2001-5.

Weiss JM, Polack S, Diedrich K, Ortmann, O. Effects of insulin on luteinizing hormone and prolactin secretion and calcium signaling in female rat pituitary cells. Arch Gynecol Obstet. 2003;269:45-50.

Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-Mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metabolism. 2004;89(1):318-23.

Cook CL, Siow Y, Brenner AG, Fallat ME. Relationship between serum müllerian-inhibiting substance and other reproductive hormones in untreated women with polycystic ovary syndrome and normal women. Fertil Steril. 2002;77:141-6.

Cimino I, Casoni F, Liu X, Messina A, Parkash J, Jamin SP, et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat Commun. 2016;7(1):1-2.

Wang F, Niu W, Kong H, Guo YH, Sun Y. The role of AMH and its receptor SNP in the pathogenesis of PCOS. Mol Cell Endocrinol. 2017;439:363-8.

Legro RS, Driscoll D, Strauss JF, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Nat Acad Sci. 1998;95:14956-60.

Vink JM, Sadrzadeh S, Lambalk CB, Boomsma D. I. Heritability of polycystic ovary syndrome in a dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100-4.

Kashar-Miller M, Azziz R. Heritability and the risk of developing androgen excess. J Steroid Biochem Mol Biol. 1999;69:261-8.

Franks S, Gharani N, Waterworth D, Batty S, White D, Williamson R, et al. The genetic basis of polycystic ovary syndrome. Hum Reprod. 1997;12(12):2641-8.

Ehrman DA, Barnes RB, Rosenfield RL. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 1995;16:322-53.

Clayton D. A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet. 1999;65:1170-7.

Tucci S, Futterweit W, Concepcion ES, Greenberg DA, Villanueva R, Davies TF, et al. Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab. 2001;86(1):446-9.

Villuendas G, Tosi F, Sancho J, Moghetti P, San Millán JL. Association between the D19S884 marker at the insulin receptor gene locus and polycystic ovary syndrome. Fertil Steril. 2003;79(1):219-20.

Prodoehl MJ, Hatzirodos N, Irving-Rodgers HF, Zhao ZZ, Painter JN, Hickey TE, et al. Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries. Mol Hum Reprod. 2009;15(12):829-41.

Jordan CD, Bohling SD, Charbonneau NL, Sakai LY. Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS? J Histochem Cytochem. 2010;58:903-15.

Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007;8:127-41.

Dumesic DA, Abbott DH, Eisner JR, Goy RW. Prenatal exposure of female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood. Fertil Steril. 1997;67:155-63.

Eisner JR, Dumesic DA, Kemnitz JW, Colman R, Abbott DH. Increased adiposity in female rhesus monkeys exposed to androgen excess during early gestation. Obes Res. 2003;11:279-86.

Franks S, Mccarthy MI, Hardy K. Development of polycystic ovary syndrome: involvement of genetic and environmental factors. Int J Androl. 2006;29:278-85.

Cole B, Hensinger K, Maciel GAR, Chang RJ, Erickson GF. Human fetal ovary development involves the spatiotemporal expression of P450c17 protein. J Clin Endocrinol Metab. 2006;91:3654-61.

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(10):3714-20.

Cresswell JL, Barker DJ, Osmond C, Egger P, Phillips DI, Fraser RB. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet. 1997;350(9085):1131-5.

Ibáñez L, de Zegher F, Potau N. Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: from a complex constellation to a simple sequence of prenatal onset. J Endocrinol Invest. 1998;21:558-66 .

Laitinen J, Taponen S, Martikainen H, Pouta A, Millwood I, Hartikainen AL, et al. Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms. Int J Obes. 2003;27(6):710-5.

Sadrzadeh S, Painter RC, Lambalk CB. Developmental origins of polycystic ovary syndrome (PCOS), a case control study comparing birth weight in women with PCOS and control group. Gynecol Endocrinol. 2016;32:856-9.

Tabassum R, Imtiaz F, Sharafat S, Shukar-ud-din S, Nusrat U. Prevalence and clinical profile of insulin resistance in young women of poly cystic ovary syndrome: a study from Pakistan. Pak J Med Sci. 2013;29:593-6.

McCall B. Long-term metformin in PCOS benefits women of all weights. Madescape Medical News. 2018. Available from: https://www.medscape.com/viewarticle/891653. Accessed on 23 September 2020.

Marshall JC, Dunaif A. All women with PCOS should be treated for insulin resistance. Fertil Steril. 2012;97:18-22.

Almenning I, Rieber-Mohn A, Lundgren KM, Løvvik TS, Garnæs KK, Moholdt T. Effects of high intensity interval training and strength training on metabolic, cardiovascular and hormonal outcomes in women with polycystic ovary syndrome: a pilot study. PLoS One. 2015;10(9):e0138793.

Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937.

Hamilton KP, Zelig R, Parker AR, Haggag A. Insulin resistance and serum magnesium concentrations among women with polycystic ovary syndrome. Curr Dev Nutr. 2019;3.

Conte F, Banting L, Teede HJ, Stepto NK. Mental health and physical activity in women with polycystic ovary syndrome: a brief review. Sports Med Auckl Nz. 2015;45:497-504.

Hutchison SK, Stepto NK, Harrison CL, Moran LJ, Strauss BJ, Teede HJ. Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metab. 2011;96(1):E48-56.

Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J Translat Med. 2020;18(1):1-1.

Zhang X, Zheng Y, Guo Y, Lai Z. The effect of low carbohydrate diet on polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2019;2019:4386401.

Günalan E, Yaba A, Yılmaz B. The effect of nutrient supplementation in the management of polycystic ovary syndrome-associated metabolic dysfunctions: A critical review. J Turk Ger Gynecol Assoc. 2018;19:220-32.

Chiofalo B, Laganà AS, Palmara V, Granese R, Corrado G, Mancini E, et al. Fasting as possible complementary approach for polycystic ovary syndrome: Hope or hype? Med Hypothes. 2017;105:1-3.

Pasquali R. Contemporary approaches to the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2018;9:123-34.

Porchia LM, Hernandez-Garcia SC, Gonzalez-Mejia ME, López-Bayghen E. Diets with lower carbohydrate concentrations improve insulin sensitivity in women with polycystic ovary syndrome: A meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020;248:110-7.

Pasquali R, Gambineri A. Therapy in endocrine disease: treatment of hirsutism in the polycystic ovary syndrome. Eur J Endocrinol. 2014;170:R75-90.

Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010;122:42-52.

Gadalla MA, Norman RJ, Tay CT, Hiam DS, Melder A, Pundir J, et al. Medical and surgical treatment of reproductive outcomes in polycystic ovary syndrome: an overview of systematic reviews. Int J Fertil Steril. 2020;13(4):257.

Orbetzova MM. Clinical Impact of Insulin Resistance in Women with Polycystic Ovary Syndrome. In: Polycystic Ovarian Syndrome. IntechOpen. 2020.

Nestler JE. Metformin in the treatment of infertility in PCOS: an alternative perspective. Fertil Steril. 2008;90:14-6.

Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E. 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. 2015;21(11):1291-300.

Stout DL, Fugate SE. Thiazolidinediones for treatment of polycystic ovary syndrome. Pharmacotherapy. 2005;25:244-52.

Costello M, Garad R, Hart R, Homer H, Johnson L, Jordan C, et al. A review of first line infertility treatments and supporting evidence in women with polycystic ovary syndrome. Med Sci. 2019;7(9):95.

Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015;70:765-9.

Takasaki A, Tamura I, Okada‐Hayashi M, Orita T, Tanabe M, Maruyama S, et al. Usefulness of intermittent clomiphene citrate treatment for women with polycystic ovarian syndrome that is resistant to standard clomiphene citrate treatment. Reprod Med Biol. 2018;17(4):454-8.

Xi W, Liu S, Mao H, Yang Y, Xue X, Lu X. Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene-resistant infertile women with polycystic ovary syndrome: a prospective study. Drug Design Develop Therap. 2015;9:6001.

Sinha P, Chitra T, Papa D, Nandeesha H. Laparoscopic ovarian drilling reduces testosterone and luteinizing hormone/follicle-stimulating hormone ratio and improves clinical outcome in women with polycystic ovary syndrome. J Hum Reprod Sci. 2019;12:224-8.

Hashim HA, Foda O, El Rakhawy M. Unilateral or bilateral laparoscopic ovarian drilling in polycystic ovary syndrome: a meta-analysis of randomized trials. Arch Gynecol Obstet. 2018;297(4):859-70.

Costello MF, Misso ML, Balen A, Boyle J, Devoto L, Garad RM, et al. A brief update on the evidence supporting the treatment of infertility in polycystic ovary syndrome. ANZ J Obstet Gynaecol. 2019;59(6):867-73.