Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-586b7cd67f-dsjbd Total loading time: 0 Render date: 2024-11-24T10:57:54.083Z Has data issue: false hasContentIssue false

Chapter 8 - Adrenal and Polycystic Ovary Syndrome

Published online by Cambridge University Press:  13 May 2022

By
Ozlem Celik  and
Bülent Okan Yildiz
Edited by
Gabor T. Kovacs ,
Bart Fauser  and
Richard S. Legro
Gabor T. Kovacs
Affiliation:
Monash University, Melbourne, Australia
Bart Fauser
Affiliation:
University Medical Center, Utrecht, Netherlands
Richard S. Legro
Affiliation:
Penn State Medical Center, Hershey, PA, USA
Get access

Summary

Polycystic ovary syndrome (PCOS) is characterized by clinical or biochemical hyperandrogenism, oligo-anovulation and polycystic ovarian morphology on ultrasound. Although the ovaries are the primary source of hyperandrogenism in PCOS, between 20% and 30% of patients with PCOS demonstrate adrenal androgen (AA) excess, as reflected by the circulating dehydroepiandrosterone sulfate (DHEAS) levels. The contribution of AA excess to the development or phenotypic expression of PCOS is not fully understood. Women with PCOS, particularly those with hyperandrogenic subphenotypes, show generalized hypersecretion of adrenocortical products, basally and in response to adrenocorticotropic hormone (ACTH). Alterations in adrenocortical biosynthesis, an exaggeration in the responsivity to ACTH, defects in cortisol metabolism and extra-adrenal factors, including obesity, insulin and glucose levels, and ovarian secretions play a limited role in increased AA production observed in PCOS. Adrenal androgen (AA) levels and their response to ACTH stimulation are highly individualized and relatively constant over time, suggesting that AA hypersecretion may be an inherited trait. Familial aggregation of AA excess in both brothers and sisters of patients with PCOS also supports heritability. However, studies to date have failed to identify specific genetic defects in adrenocortical dysfunction of PCOS due to the genetic and phenotypic heterogeneity of the syndrome and the lack of insufficiently large cohorts.

Keywords

polycystic ovary syndrome (PCOS)hyperandrogenismadrenaladrenal androgendehydroepiandrosterone (DHEA)dehydroepiandrosterone sulfate (DHEAS)
Type
Chapter
Information
Polycystic Ovary Syndrome , pp. 67 - 79
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Yildiz, B. O., Bozdag, G., Yapici, Z., Esinler, I. and Yarali, H. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod 2012; 27(10): 3067–3073.CrossRefGoogle ScholarPubMed
Azziz, R., Carmina, E., Chen, Z. et al. Polycystic ovary syndrome. Nat Rev Dis Primers 2016; 11(2): 16057.CrossRefGoogle Scholar
Baskind, N. E. and Balen, A. H. Hypothalamic-pituitary, ovarian and adrenal contributions to polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2016; 37: 80–97.Google Scholar
Miller, W. L. and Auchus, R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32(1): 81–151.CrossRefGoogle ScholarPubMed
Yildiz, B. O. and Azziz, R. The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 2007; 8(4): 331–342.Google Scholar
Gallagher, T. F., Kappas, A., Hellman, L., Lipsett, M. B., Pearson, O. H. and West, C. D. Adrenocortical hyperfunction in idiopathic hirsutism and the Stein-Leventhal syndrome. J Clin Invest 1958; 37(6): 794–799.Google Scholar
Wild, R. A., Umstot, E. S., Andersen, R. N., Ranney, G. B. and Givens, J. R. Androgen parameters and their correlation with body weight in one hundred thirty-eight women thought to have hyperandrogenism. Am J Obstet Gynecol 1983; 146(6): 602–606.Google Scholar
Hoffman, D. I., Klove, K. and Lobo, R. A. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984; 42(1): 76–81.Google Scholar
Kumar, A., Woods, K. S., Bartolucci, A. and Azziz, R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2005; 62(6): 644–649.Google Scholar
Carmina, E., Koyama, T., Chang, L., Stanczyk, F. Z. and Lobo, R. A. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992; 167(6): 1807–1812.Google Scholar
Ezeh, U., Ida Chen, Y. D. and Azziz, R. Racial and ethnic differences in the metabolic response of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2020; 93(2): 163–172.CrossRefGoogle ScholarPubMed
Azziz, R. and Koulianos, G. Adrenal androgens and reproductive aging in females. Semin Reprod Endocrinol 1991; 9: 249–260.CrossRefGoogle Scholar
Puurunen, J., Piltonen, T., Jaakkola, P., Ruokonen, A., Morin-Papunen, L. and Tapanainen, J. S. Adrenal androgen production capacity remains high up to menopause in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94(6): 1973–1978.Google Scholar
Azziz, R., Gay, F. L., Potter, S. R., Bradley, E., Jr. and Boots, L. R. The effects of prolonged hypertestosteronemia on adrenocortical biosynthesis in oophorectomized women. J Clin Endocrinol Metab 1991; 72(5): 1025–1030.CrossRefGoogle ScholarPubMed
Azziz, R., Rittmaster, R. S. and Fox, L. M. Role of the ovary in the adrenal androgen excess of hyperandrogenic women. Fertil Steril 1998; 69(5): 851–859.CrossRefGoogle ScholarPubMed
Hines, G. A., Smith, E. R. and Azziz, R. Influence of insulin and testosterone on adrenocortical steroidogenesis in vitro: Preliminary studies. Fertil Steril 2001; 76(4): 730–735.CrossRefGoogle ScholarPubMed
Huerta, R., Dewailly, D., Decanter, C., Knochenhauer, E. S., Boots, L. R. and Azziz, R. 11beta-hydroxyandrostenedione and delta 5-androstenediol as markers of adrenal androgen production in patients with 21-hydroxylase deficient nonclassic adrenal hyperplasia. Fertil. Steril 1999; 72(6): 996–1000.Google Scholar
O’Reilly, M. W., Kempegowda, P., Jenkinson, C. et al11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome. J Clin Endocrinol Metab 2017; 102(3): 840–848.CrossRefGoogle ScholarPubMed
Swart, A. C., du Toit, T., Gourgari, E. et al. Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS. Pediatr Res 2021; 89(1): 118–126.CrossRefGoogle Scholar
Azziz, R., Bradley, E., Jr., Huth, J., Boots, L. R., Parker, C. R., Jr. and Zacur, H. A. Acute adrenocorticotropin-(1–24) (ACTH) adrenal stimulation in eumenorrheic women: Reproducibility and effect of ACTH dose, subject weight, and sampling time. J Clin Endocrinol Metab 1990; 70(5): 1273–1279.Google Scholar
Azziz, R., Black, V., Hines, G. A., Fox, L. M. and Boots, L. R. Adrenal androgen excess in the polycystic ovary syndrome: Sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998; 83(7): 2317–2323.Google ScholarPubMed
Goodarzi, M. O., Carmina, E. and Azziz, R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol 2015; 145: 213–225.Google Scholar
Carbunaru, G., Prasad, P., Scoccia, B. et al.The hormonal phenotype of Nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 2004; 89(2): 783–794.CrossRefGoogle Scholar
Moran, C., Azziz, R., Carmina, E. et al. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: A multicenter study. Am J Obstet Gynecol 2000; 183(6): 1468–1474.CrossRefGoogle ScholarPubMed
Yildiz, B. O., Goodarzi, M. O., Guo, X., Rotter, J. I. and Azziz, R. Heritability of dehydroepiandrosterone sulfate in women with polycystic ovary syndrome and their sisters. Fertil Steril 2006; 86(6): 1688–1693.Google Scholar
Cinar, N., Harmanci, A., Aksoy, D. Y., Aydin, K. and Yildiz, B. O. Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome. J Ovarian Res 2012; 5(1): 42.CrossRefGoogle ScholarPubMed
Stewart, P. M., Shackleton, C. H., Beastall, G. H. and Edwards, C. R. 5 alpha-reductase activity in polycystic ovary syndrome. Lancet 1990 335(8687): 431–433.Google Scholar
Vassiliadi, D. A., Barber, T. M., Hughes, B. A. et alIncreased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94(9): 3558–3566.CrossRefGoogle ScholarPubMed
Tsilchorozidou, T., Honour, J. W. and Conway, G. S. Altered cortisol metabolism in polycystic ovary syndrome: Insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 2003; 88(12): 5907–5913.Google Scholar
Rodin, A., Thakkar, H., Taylor, N. and Clayton, R. Hyperandrogenism in polycystic ovary syndrome: Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase. N Engl J Med 1994; 330(7): 460–465.CrossRefGoogle Scholar
Stewart, P. M. and Edwards, C. R. Hyperandrogenism in polycystic ovary syndrome. N Engl J Med 1994; 331(2): 131–132.Google Scholar
Gonzalez, F., Hatala, D. A. and Speroff, L. Adrenal and ovarian steroid hormone responses to gonadotropin-releasing hormone agonist treatment in polycystic ovary syndrome. Am J Obstet Gynecol 1991; 165(3): 535–545.Google Scholar
Ditkoff, E. C., Fruzzetti, F., Chang, L., Stancyzk, F. Z. and Lobo, R. A. The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. J Clin Endocrinol Metab 1995; 80(2): 603–607.Google Scholar
Azziz, R., Chang, W. Y., Stanczyk, F .Z. and Woods, K. Effect of bilateral oophorectomy on adrenocortical function in women with polycystic ovary syndrome. Fertil Steril 2013; 99(2): 599–604.Google Scholar
Legro, R. S., Kunselman, A. R., Dodson, W. C. and 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(1): 165–169.Google Scholar
Nestler, J. E., Usiskin, K. S., Barlascini, C. O., Welty, D. F., Clore, J. N. and Blackard, W. G. Suppression of serum dehydroepiandrosterone sulfate levels by insulin: An evaluation of possible mechanisms. J Clin Endocrinol Metab 1989; 69(5): 1040–1046.Google Scholar
Azziz, R. and Owerbach, D. Molecular abnormalities of the 21-hydroxylase gene in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to shortterm adrenal stimulation. Am J Obstet Gynecol 1995; 172(3): 914–918.Google Scholar
Falcone, T., Finegood, D. T., Fantus, I. G. and Morris, D. Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women. J Clin. Endocrinol Metab 1990; 71(6): 1653–1657.Google Scholar
Farah-Eways, L., Reyna, R., Knochenhauer, E. S., Bartolucci, A. A. and Azziz, R. Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome. Fertil Steril 2004; 81(1): 120–125.Google Scholar
Brennan, K., Huang, A. and Azziz, R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril 2009; 91(5): 1848–1852.Google Scholar
Carmina, E., Gonzalez, F., Chang, L. and Lobo, R A. Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome. Obstet Gynecol 1995; 85(6): 971–976.Google Scholar
Chen, M. J., Chen, C. D., Yang, J. H et al. High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity in women with polycystic ovary syndrome. Hum Reprod 2011; 26(1): 227–234.Google Scholar
Lerchbaum, E., Schwetz, V., Giuliani, A., Pieber, T. R. and Obermayer-Pietsch, B. Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. Fertil Steril 2012; 98(5): 1318–1325.Google Scholar
Paschou, S. A., Palioura, E., Ioannidis, D. et al. Adrenal hyperandrogenism does not deteriorate insulin resistance and lipid profile in women with PCOS. Endocr Connect 2017; 6(8): 601–606.CrossRefGoogle Scholar
Alpañés, M., Luque-Ramírez, M., Martínez-García, M. Á., Fernández-Durán, E. and Álvarez-Blasco, F. Escobar-Morreale HF Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome. Fertil Steril 2015; 103(3): 795–801.CrossRefGoogle ScholarPubMed
Azziz, R., Ehrmann, D. A., Legro, R. S., Fereshetian, A. G., O’Keefe, M. and Ghazzi, M. N. PCOS/Troglitazone Study Group: Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome. Fertil Steril 2003; 79(4): 932–937.CrossRefGoogle Scholar
Arlt, W., Auchus, R. J. and Miller, W. L. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3beta-hydroxysteroid dehydrogenase. J Biol Chem 2001; 276(20): 16767–16771.CrossRefGoogle ScholarPubMed
Li, X. J., Yu, Y. X., Liu, C. Q. et al.Metformin vs thiazolidinediones for treatment of clinical, hormonal and metabolic characteristics of polycystic ovary syndrome: A meta-analysis. Clin Endocrinol (Oxf) 2011; 74(3): 332–339.CrossRefGoogle ScholarPubMed
Azziz, R., Zacur, H. A., Parker, C. R., Jr., Bradley, E. L., Jr., Boots, L. R. Effect of obesity on the response to acute adrenocorticotropin stimulation in eumenorrheic women. Fertil Steril 1991; 56(3): 427–433.CrossRefGoogle ScholarPubMed
Vicennati, V., Calzoni, F., Gambineri, A. et al. Secretion of major adrenal androgens following ACTH administration in obese women with different body fat distribution. Horm Metab Res 1998; 30(3): 133–136.Google Scholar
Moran, C., Arriaga, M., Arechavaleta-Velasco, F. and Moran, S. Adrenal androgen excess and body mass index in polycystic ovary syndrome. J Clin Endocrinol Metab 2015; 100(3): 942–950.CrossRefGoogle ScholarPubMed
Deng, Y., Zhang, Y., Li, S. et al. Steroid hormone profiling in obese and nonobese women with polycystic ovary syndrome. Sci Rep 2017;7(1):14156.Google Scholar
Yildiz, B. O., Woods, K. S., Stanczyk, F., Bartolucci, A. and Azziz, R. Stability of adrenocortical steroidogenesis over time in healthy women and women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004, 89(11): 5558–5562.Google Scholar
Legro, R. S., Kunselman, A. R., Demers, L., Wang, S. C., Bentley-Lewis, R. and Dunaif, A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87(5): 2134–2138.Google Scholar
Goodarzi, M. O., Antoine, H. J. and 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(7): 2659–2664.Google Scholar
Louwers, Y. V., de Jong, F. H., van Herwaarden, N. A. et al. Variants in SULT2A1 affect the DHEA sulphate to DHEA ratio in patients with polycystic ovary syndrome but not the hyperandrogenic phenotype. J Clin Endocrinol Metab 2013; 98(9): 3848–3855.Google Scholar
Dumesic, D. A., Oberfield, S. E., Stener-Victorin, E., Marshall, J. C., Laven, J. S. and Legro, R. S. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 2015; 36(5): 487–525.Google Scholar
Zhai, G., Teumer, A., Stolk, L. et al. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS Genet 2011; 7(4): e1002025.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×