A review of hyperandrogenism state in polycystic ovarian syndrome

Authors

  • Mohamed Shabi M. Department of Pharmacology, Faculty of Pharmacy, Ramaiah University of Applied Sciences, New BEL Road, MSR Nagar, Bangalore, Karnataka, India
  • Nivya P. S. Department of Pharmacology, Ikon Pharmacy College, Bengaluru, Karnataka, India
  • Devika C. S. Department of Pharmacology, Ikon Pharmacy College, Bengaluru, Karnataka, India
  • Malayanur Suhas Reddy Department of Pharmacology, Ikon Pharmacy College, Bengaluru, Karnataka, India
  • Poornima N. Department of Pharmacology, Faculty of Pharmacy, Ramaiah University of Applied Sciences, New BEL Road, MSR Nagar, Bangalore, Karnataka, India
  • Roopesh K. R. Department of Pharmacology, Ikon Pharmacy College, Bengaluru, Karnataka, India
  • Joel Joseph Department of Pharmacology, Ikon Pharmacy College, Bengaluru, Karnataka, India
  • Shivanand Kolageri Department of Pharmaceutical Chemistry, BLDEA’s SSM College of Pharmacy and Research Centre, Vijayapur, Karnataka, India

DOI:

https://doi.org/10.18203/2320-1770.ijrcog20233666

Keywords:

PCOS, Androgen, Hyperandrogenic state, CYP11A, CYP17, CYP19

Abstract

Polycystic ovary syndrome is one of the most prevalent endocrinopathy in premenopausal women. The pathophysiology of PCOS is not clear, however disturbance in the hypothalamic-pituitary-ovarian axis and abnormal steroidogenesis along with genetic and environmental factors act as main contributors to this disorder. The steroidogenic pathway is affected by the overexpression of the CYP11A, CYP17, and CYP19 genes in PCOS, which results in a hyperandrogenic condition. The initial effect of too much androgen in PCOS is impaired folliculogenesis. The most frequent clinical manifestations of hyperandrogenism in women with PCOS include hirsutism, acne, and androgenic alopecia. Women with PCOS may have an excess of androgen during foetal life due to the elevated expression of P450c17a during the whole pregnancy. PCOS is believed to be formed in utero by the influence of androgen excess on gene expression in adolescence and adulthood, which offers more solid evidence that real PCOS can be induced by prenatal androgenization. A prenatal androgen excess-induced epigenetic phenomena is suggested by the current theory of PCOS's developmental genesis. It is currently believed that the many tiny follicles seen in polycystic ovaries and the considerable irregularity in the very early stages of folliculogenesis are associated to the formation of anovulation in PCOS.

References

Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999;84(6):1897-9.

Jerome FIIIS. The synthesis and metabolism of steroid hormones. In: Yen & Jaffe’s Reproductive Endocrinology. USA: Elsevier; 2009:79-104.

Abbott DA, Dumesic DA. Fetal androgen excess provides a developmental origin for polycystic ovary syndrome. Expert Rev Obstet Gynecol. 2009;4(1):1-7.

Sasano H, Okamoto M, Mason JI, Simpson ER, Mendelson CR. Immunolocalization of aromatase, 17~-hydroxylase and side-chain cleavages cytochromes P450 in the human ovary. J Reprod Fert. 1989;85:163-9.

Richards JS, Hedin L. Molecular aspects of hormone action in ovarian follicular development, ovulation, and luteinization. Rev Physiol. 1988;50:441-63.

Reddy KR, Deepika MLN, Supriy K, Latha KP, Lakshmana SS. CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. J Assist Reprod Genet. 2014;31:857-63.

Nelson VL, Qin Kn KN, Rosenfield RL, Wood JR, Penning TM, Legro RS. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:5925-33.

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.

Franks S. Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin Endocrinol Metab. 2002;16:263-72.

Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988;9(3):295-318.

Prapas N, Karkanaki A, Prapas I, Kalogiannidis I, Katsikis I, Panidis D. G enetics of polycystic ovary syndrome. Hippokratia. 2009; 13(4):216-23.

Ehrmann DA, Rosenfield RL, Barnes RB, Brigell FD, Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med. 1992;327:157-62.

Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab. 1994;79:1158-65.

Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C. Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia:does idiopathic hirsutism exist?. Metab. 1997;46:902-7.

Erickson GF, Hsueh AJW, Quigley ME, Rebar RW, Yen SS. Functional studies of aromatase activity in human granulosa cells from normal and polycystic ovaries. J Clin Endocr Metab. 1979;49(4):514-9.

Jakimiuk J, Weitsman SR, Brzechffa PR, Magon DA. Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol Hum Reprod. 1998;4(1): 1-8.

ItoY, Fisher CR, Conte FA, Grumbach MM, Simpson ER. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci. 1993;90(24):11673-7.

Zhang XL, Zhang CW, Xu P, Liang FJ, Che YN, Xia YJ. SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patient. Mol Med Reports. 2012;5(1):245-9.

Nisenblat A, Norman RJ. Androgens and polycystic ovary syndrome Curr Opin Endocrinol Diabetes Obes. 2009;16(3):224- 31.

Fauser BC, Pache TD, Lamberts SW, Hop WC, de Jong FH, Dahl KD. Serum bioactive and immunoreactive luteinizing hormone and follicle- stimulating hormone levels in women with cycle abnormalities with or without polycystic ovarian disease. J Clin Endocrinol Metab. 1991;73(4):811-7.

Van Santbrink EJ, Hop WC, Fauser BC. Classification of normogonadotropic infertility:polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of polycystic ovary syndrome. Fertil Steril. 1997;67(3):452-8.

Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction:a developmental aetiology for polycystic ovary syndrome?. Hum Reprod Update. 2005;11:357-74.

Wu S, Divall S, Nwaopara A, Radovick S, Wondisford F. Obesity induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes. 2014;63(4):1270-82.

Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler, JE. Effects of metformin and rosiglitazone, alone and in combination in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril. 2004; 82(4):893-902.

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis, E, Escobar MHF, Futterweit W, 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.

Pasquali R, Gambineri A. Treating hirsutism in polycystic ovary syndrome. Europ J Endocrinol. 2014: 170 (2);R75-90.

Spritzer PM, Barone CR, Oliveira FB. Hirsutism in polycystic ovary syndrome:pathophysiology and management. Curr Pharma Design. 2016;22(36):5603-13.

Abid K, Shah IH, Sheikh G. Cutaneous manifestations of polycystic ovary syndrome:a cross sectional clinical study. Indian Dermatol. 2017;8:104-10.

Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-7.

Grover S, Ranyal RK, Bedi MK. A cross section of skin diseases in rural Allahabad. Indian J Dermatol. 2008; 53(4):179-81.

Jones GL, Benes K, Clark TL, Denham R, Holder MG, Haynes TJ. The polycystic ovary syndrome health related quality of life questionnaire (PCOSQ):a validation. Hum Reprod. 2004;19:371-7.

Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab. 2005;90:4650-8.

Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, et al. Androgen excess in women:experience with over 1000 consecutive patients. J Clin Endocrinol Metab. 2004;89(2):453-62.

Carmina E, Rosato F, Janni A, Rizzo, M, Longo RA. Extensive clinical experience:relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91(1):2-6.

Ozdemir S, Ozdemir M, Gorkemli H, Kiyici A, Bodur S. Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand. 2010; 89:199-204.

Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. Am J Clin Dermatol. 2007; 8:201-19.

Wickenheisser JK, Nelson-DeGrave VL, McAllister JM. Human ovarian theca cellsin culture. Trends Endocrinol Metab. 2006;17(2):65-71.

Cole B, Hensinger K, Maciel GA, Chang RJ, Erickson GF. Human fetal ovary development involved the spatiotemporal expression of p450c17. J Clin Endocrinol Metab. 2006;91:3654-61.

Calvo RM, Asuncion M, Telleria D, Sancho J, San Millan JL, Escobar- Morreale, HF. Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women. J Clin Endocrinol Metab. 2001;86(4):1746-9.

San Millan JL, Sancho J, Calvo RM, Escobar-Morreale HF. Role of the pentanucleotide (tttta)(n) polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism. Fertil Steril. 2001; 75(4):797-802.

Techatraisk K, Conway GS, Rumsby G. Frequency of a polymorphism in the regulatory region of the 17a-hydroxylase (CYP17) gene in hyperandrogenic states. Clin Endocrinol. 1997;46:131-4.

Diamanti-Kandarakis E, Bartzis MI, Zapanti ED. Polymorphism T–>C (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome. Fertil Steril, 1999;71(3):431-5.

Witchel SF, Lee PA, Suda-Hartman M, Smith R, Hoffman EP. 17 a- hydroxylase/17,20-lyase dysregulation is not caused by mutations in the coding regions of CYP17. J Pediatr Adolesc Gynecol. 1998; 11(3):133-7.

Walker EA, Schneider SB, Walker OJ, Edelstein M, Arlt W, Stewart PM. Hexose-6-phosphate dehydrogenase crucially regulates 11b- hydroxysteroid dehydrogenase Type 1 oxoreductase activity evidence from bacterial and yeast co-expression studies. In: The Endocrine Society’s 86th Annual Meeting. USA: 2004.

Lavery GG, Walker EA, Tiganescu A. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. J Clin Endocrinol Metab. 2008;93(10):3827-32.

Gambineri A, Vicennati V, Genghini S. Genetic variation in 11b- hydroxysteroid dehydrogenase Type 1 predicts adrenal hyperandrogenism amongst lean women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(6):2295-302.

San Millan JL, Botella-Carretero JI, Alvarez-Blasco F. A study of the hexose-6-phosphate dehydrogenase gene R453Q and 11b- hydroxysteroid dehydrogenase type 1 gene 83557insA polymorphisms in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(7):4157-62.

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.

Hines M, Golombok S, Rust J, Johnston KJ, Golding J. Testosterone during pregnancy and gender role behavior of preschool children:a longitudinal population study. Child Dev. 2002;73:1678-87.

Berenbaum SA, Hines M. Early androgens are related to childhood sex- typed toy preferences. Psychol Sci. 1992;3:203-6.

Grimshaw GM, Sitarenios G, Finegan JK. Mental rotation at 7 years:relations with prenatal testosterone levels and spatial play experiences. Brain Cogn. 1995; 29:85-100.

Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL, et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders:evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab. 1994;79:1328-33.

Phocas I, Chryssikopoulos A, Sarandakou A, Rizos D, Trakakis E. A contribution to the classification of cases of non-classic 21-hydroxylase- deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 1995;9(3): 229-38

Merke DP, Cutler GB. New ideas for medical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:121-35.

Stikkelbroeck NM, Hermus ER, Braat DD, Otten BJ. Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstet Gynecol Surv. 2003;58:275-84.

Abbott DH, Dumesic DA, Eisner JR, Kemnitz JW, Goy RW. The prenatally androgenized female rhesus monkey as a model for polycystic ovarian syndrome. In: Azziz R, Nestler JE, Dewailly D, eds. Androgen Excess Disorders in Women. USA: Lippencott- Raven Press; 1997:369-82.

Abbott DH, Dumesic DA, Eisner JR, Colman RJ, Kemnitz JW. Insights into the development of PCOS from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab. 1998;9:62-7.

Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndrome a hypothesis. J Endocrinol. 2002;174:1-5.

Dumesic DA, Schramm RD, Abbott DH. Early origins of polycystic ovary syndrome (PCOS). Reprod Fertil Dev. 2005;17:349-60.

Abbott DH, Barnett DK, Levine JE, Padmanabhan V, Dumesic DA, Jacoris S, et al. Endocrine antecedents of polycystic ovary syndrome in fetal and infant prenatally androgenized female rhesus monkeys. Biol Reprod. 2008;73:154-63.

Sarma HN, Manikkam M, Herkimer C, DellO´ J, Welch KB, Foster DL, et al. Programming: excess prenatal testosterone reduces postnatal luteinising hormone, but not follicle-stimulating hormone responsiveness, to estradiol negative feedback in the female. Endocrinology. 2005;146:4281-91.

Eisner JR, Dumesic DA, Kemnitz JW, Abbott DH. Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys. J Clin Endocrinol Metab, 2000;85:1206-10.

Padmanabhan V, Manikkam M, Recabarren S, Foster D. Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female. Mol Cell Endocrinol. 2006;246:165-74.

Jiang F, Wang Z. Identification of androgen-responsive genes in the rat ventral prostate by complementary deoxyribonucleic acid subtraction and microarray. Endocrinology. 2003;144:1257-65.

Laurich VM, Trbovich AM, O’Neil FH, Houk CP, Sluss PM, Payne AH, et al. Mullerian inhibiting substance blocks the protein kinase A-induced expression of cytochrome p450 17 alpha hydroxylase/c(17-20) lyase in RNA in a mouse Leydig cell line independent of camp responsive element binding protein phosphorylation. Endocrinology. 2002;143:3351-60.

Sir-Petermann T, Maliqueo M, Lura HE, Perez-Bravo F, Recabarren SE. Maternal serum androgen in pregnant women with polycystic ovary syndrome:possible implications in prenatal androgenisation. Hum Reprod. 2002;17:2573-9.

Gitau R, Adams D, Fisk NM, Glover V. Fetal plasma testosterone correlates positively with cortisol. Arch Dis Child Fetal Neonatal. 2005;90:F166-9.

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.

Zhou R, Bird IM, Dumesic DA, Abbott DH. Adrenal hyperandrogenism is induced by fetal androgen excess in a rhesus monkey model of polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:6630-7.

Gitau R, Adams D, Fisk NM, Glover V. Fetal plasma testosterone correlates positively with cortisol. Arch Dis Child Fetal Neonatal. 2005;Ed 90:F166-9.

Steckler T, Manikkam M, Inskeep EK, Padmanabhan V. Developmental programming:follicular persistence in prenatal testosterone-treated sheep is not programmed by androgenic actions of testosterone. Endocrinology. 2007;148:3532-40.

Hillier SG, Tetsukara M. Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol. 1997;11:249-60.

Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle- stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999;84:2951-6.

Webber LJ, Stubbs S, Stark J, Trew GH, Margara R, Hardy K, et al. Formation and early development of follicles in the polycystic ovary. Lancet. 2003;362: 1017-21.

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Published

2023-11-28

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