Steroid hormone metabolism in polycystic ovary syndrome
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Polycystic ovary syndrome (PCOS) is characterized clinically by menstrual dysfunction, including oligo- or anovulation and signs of hyperandrogenism . This review will describe the abnormalities in steroid hormones that are present in this disorder, including the factors responsible for the increase in androgen production. The clinical manifestations of PCOS are discussed separately. (See "Clinical manifestations of polycystic ovary syndrome in adults".)
As a group, women with PCOS have serum concentrations of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS) that are significantly elevated compared with ovulatory, nonhirsute women (figure 1) [1,2]. There is, however, significant individual variation, and some women with PCOS may have normal androgen levels when assayed in a single blood specimen .
In women, androgens are produced by the adrenal glands and the ovaries, as well as by conversion of less potent to more potent androgens in the periphery. The source of the major androgens in PCOS is shown in the table (table 1). In PCOS, androstenedione and testosterone are secreted primarily by the ovaries and to a lesser degree the adrenals. This pattern differs from that in normal premenopausal women who have approximately equal androstenedione and testosterone production from the ovaries and the adrenals .
Testosterone — Testosterone is the most potent circulating androgen. Its biologic activity is determined by the amount of binding to sex hormone-binding globulin (SHBG), as only the free fraction is active, and by the rate of conversion of testosterone to the potent intracellular androgen, dihydrotestosterone (DHT) (see 'Dihydrotestosterone' below). Serum SHBG concentrations are controlled by androgens (decrease), estrogens (increase), and insulin (decrease) . Thus, hyperandrogenic women with PCOS tend to have low serum SHBG concentrations. This decrease tends to mask the degree of testosterone excess if only serum total testosterone concentration is measured. Thus, a higher proportion of women with PCOS have elevated serum free testosterone concentrations than have elevated serum total testosterone concentrations.
Body mass index (BMI) is positively correlated with serum total testosterone and inversely correlated with SHBG concentrations in women of all reproductive ages.
Subscribers log in hereLiterature review current through: Jul 2017. | This topic last updated: Apr 13, 2017.References
- Zawadzki JK, Dunaif A. Diagnostic criteria for PCOS: towards a rational approach. In: PCOS: current issues in endocrinology and metabolism, Dunaif A, Givens JR, Hazeltine FP, Merriam GR (Eds), Blackwell Scientific, Boston 1992. Vol 4, p.235.
- DeVane GW, Czekala NM, Judd HL, Yen SS. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 1975; 121:496.
- Longcope C. Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab 1986; 15:213.
- 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.
- Taponen S, Martikainen H, Järvelin MR, et al. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland birth cohort 1966 study. J Clin Endocrinol Metab 2003; 88:141.
- Randolph JF Jr, Sowers M, Gold EB, et al. Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab 2003; 88:1516.
- Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95:1218.
- Sowers MF, Beebe JL, McConnell D, et al. Testosterone concentrations in women aged 25-50 years: associations with lifestyle, body composition, and ovarian status. Am J Epidemiol 2001; 153:256.
- Rosencrantz MA, Coffler MS, Haggan A, et al. Clinical evidence for predominance of delta-5 steroid production in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2011; 96:1106.
- Vassiliadi DA, Barber TM, Hughes BA, et al. Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94:3558.
- Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 2009; 94:103.
- Erickson GF, Magoffin DA, Dyer CA, Hofeditz C. The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 1985; 6:371.
- Risma KA, Clay CM, Nett TM, et al. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A 1995; 92:1322.
- Tapanainen JS, Koivunen R, Fauser BC, et al. A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone. J Clin Endocrinol Metab 1999; 84:1711.
- Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab 2001; 86:1318.
- Nelson VL, Qin KN, Rosenfield RL, et al. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2001; 86:5925.
- Barbieri RL, Makris A, Ryan KJ. Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstet Gynecol 1984; 64:73S.
- Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335:617.
- Nestler JE, Barlascini CO, Matt DW, et al. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1989; 68:1027.
- Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995; 80:3788.
- Garg D, Tal R. The role of AMH in the pathophysiology of polycystic ovarian syndrome. Reprod Biomed Online 2016; 33:15.
- Pellatt L, Rice S, Dilaver N, et al. Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells. Fertil Steril 2011; 96:1246.
- Chang HM, Klausen C, Leung PC. Antimüllerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. Fertil Steril 2013; 100:585.
- Mason HD, Willis DS, Beard RW, et al. Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J Clin Endocrinol Metab 1994; 79:1355.
- Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 1989; 320:559.
- Gilling-Smith C, Story H, Rogers V, Franks S. Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1997; 47:93.
- Wickenheisser JK, Nelson-Degrave VL, McAllister JM. Dysregulation of cytochrome P450 17alpha-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90:1720.
- Nelson-Degrave VL, Wickenheisser JK, Hendricks KL, et al. Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol 2005; 19:379.
- Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci U S A 1995; 92:10619.
- Ho CK, Wood JR, Stewart DR, et al. Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 2005; 90:6596.
- Azziz R, Black V, Hines GA, et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998; 83:2317.
- Glintborg D, Hermann AP, Brusgaard K, et al. Significantly higher adrenocorticotropin-stimulated cortisol and 17-hydroxyprogesterone levels in 337 consecutive, premenopausal, caucasian, hirsute patients compared with healthy controls. J Clin Endocrinol Metab 2005; 90:1347.
- Puurunen J, Piltonen T, Jaakkola P, et al. Adrenal androgen production capacity remains high up to menopause in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94:1973.
- Hague WM, Adams J, Reeders ST, et al. Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf) 1988; 29:593.
- Givens JR. Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 1988; 17:771.
- Lucky AW, Rosenfield RL, McGuire J, et al. Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche. J Clin Endocrinol Metab 1986; 62:840.
- Toscano V, Balducci R, Bianchi P, et al. Ovarian 17-ketosteroid reductase deficiency as a possible cause of polycystic ovarian disease. J Clin Endocrinol Metab 1990; 71:288.
- Vermesh M, Silva PD, Rosen GF, et al. Effect of androgen on adrenal steroidogenesis in normal women. J Clin Endocrinol Metab 1988; 66:128.
- Ehrmann DA, Rosenfield RL, Barnes RB, et al. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 1992; 327:157.
- Goodarzi MO, Antoine HJ, Azziz R. Genes for enzymes regulating dehydroepiandrosterone sulfonation are associated with levels of dehydroepiandrosterone sulfate in polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:2659.
- Goodarzi MO, Xu N, Azziz R. Association of CYP3A7*1C and serum dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93:2909.
- 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.
- ANDROGEN METABOLISM
- Dehydroepiandrosterone sulfate
- ESTROGEN METABOLISM
- CONTROL OF ANDROGEN PRODUCTION
- Ovarian androgen secretion
- - Role of insulin
- - Role of anti-müllerian hormone (AMH)
- - Other factors
- Adrenal androgen secretion