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The Role of Androgen Excess in Metabolic Dysfunction in Women

Androgen Excess and Female Metabolic Dysfunction
  • Héctor F. Escobar-Morreale
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)

Abstract

Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

Keywords

Hyperandrogenism Obesity Insulin resistance Metabolic dysfunction Bariatric surgery Fertility 

Notes

Acknowledgments

Supported by grants PI110357, PI11/00357, and PIE16/00050 and CIBER Diabetes y Enfermedades Metabólicas Asociadas CB07/08/0005, from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Spain. Supported in part by Fondo Europeo de Desarrollo Regional FEDER.

References

  1. Abbott, D. H., Dumesic, D. A., & Franks, S. (2002). Developmental origin of polycystic ovary syndrome – A hypothesis. Journal of Endocrinology, 174, 1–5.CrossRefPubMedGoogle Scholar
  2. Abbott, D. H., Bruns, C. M., Barnett, D. K., & Dumesic, D. A. (2007). Fetal programming of polycystic ovary syndrome. In G. Kovacs & R. Norman (Eds.), Polycystic ovary syndrome (2nd ed.). Cambridge, UK: Cambridge University Press.Google Scholar
  3. Alvarez-Blasco, F., Botella-Carretero, J. I., San Millan, J. L., & Escobar-Morreale, H. F. (2006). Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Archives of Internal Medicine, 166, 2081–2086.CrossRefPubMedGoogle Scholar
  4. Alvarez-Blasco, F., Luque-Ramirez, M., & Escobar-Morreale, H. F. (2010). Obesity impairs general health-related quality of life (HR-QoL) in premenopausal women to a greater extent than polycystic ovary syndrome (PCOS). Clinical Endocrinology, 73, 595–601.CrossRefPubMedGoogle Scholar
  5. Asuncion, M., Calvo, R. M., San Millan, J. L., Sancho, J., Avila, S., & Escobar-Morreale, H. F. (2000). A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. Journal of Clinical Endocrinology and Metabolism, 85, 2434–2438.PubMedGoogle Scholar
  6. Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., & Witchel, S. F. (2006). Position statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An Androgen Excess Society guideline. The Journal of Clinical Endocrinology and Metabolism, 91, 4237–4245.CrossRefPubMedGoogle Scholar
  7. Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., & Witchel, S. F. (2009). The androgen excess and PCOS society criteria for the polycystic ovary syndrome: The complete task force report. Fertility and Sterility, 91, 456–488.CrossRefPubMedGoogle Scholar
  8. Barry, J. A., Hardiman, P. J., Siddiqui, M. R., & Thomas, M. (2011). Meta-analysis of sex difference in testosterone levels in umbilical cord blood. Journal of Obstetrics and Gynaecology, 31, 697–702.CrossRefPubMedGoogle Scholar
  9. Borruel, S., Fernández-Durán, E., Alpañés, M., Martí, D., Álvarez-Blasco, F., Luque-Ramírez, M., & Escobar-Morreale, H. F. (2013). Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). The Journal of Clinical Endocrinology and Metabolism, 98, 1254-1263.Google Scholar
  10. Carmina, E., Orio, F., Palomba, S., Longo, R. A., Cascella, T., Colao, A., Lombardi, G., Rini, G. B., & Lobo, R. A. (2006). Endothelial dysfunction in PCOS: Role of obesity and adipose hormones. American Journal of Medicine, 119(356), e1–e6.Google Scholar
  11. Ciampelli, M., Fulghesu, A. M., Cucinelli, F., Pavone, V., Caruso, A., Mancuso, S., & Lanzone, A. (1997). Heterogeneity in beta cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. Human Reproduction, 12, 1897–1901.CrossRefPubMedGoogle Scholar
  12. Corton, M., Botella-Carretero, J. I., Benguria, A., Villuendas, G., Zaballos, A., San Millan, J. L., Escobar-Morreale, H. F., & Peral, B. (2007). Differential gene expression profile in omental adipose tissue in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism, 92, 328–337.CrossRefPubMedGoogle Scholar
  13. Corton, M., Botella-Carretero, J. I., Lopez, J. A., Camafeita, E., San Millan, J. L., Escobar-Morreale, H. F., & Peral, B. (2008). Proteomic analysis of human omental adipose tissue in the polycystic ovary syndrome using two-dimensional difference gel electrophoresis and mass spectrometry. Human Reproduction, 23, 651–661.CrossRefPubMedGoogle Scholar
  14. Costello, M., Shrestha, B., Eden, J., Sjoblom, P., & Johnson, N. (2007). Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews, (1) CD005552.Google Scholar
  15. Diamanti-Kandarakis, E., Baillargeon, J. P., Iuorno, M. J., Jakubowicz, D. J., & Nestler, J. E. (2003). A modern medical quandary: Polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. Journal of Clinical Endocrinology and Metabolism, 88, 1927–1932.CrossRefPubMedGoogle Scholar
  16. Duleba, A. J. (2012). Medical management of metabolic dysfunction in PCOS. Steroids, 77, 306–311.CrossRefPubMedGoogle Scholar
  17. Ehrmann, D., Barnes, R., Rosenfield, R., Cavaghan, M., & Imperial, J. (1999). Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care, 22, 141–146.CrossRefPubMedGoogle Scholar
  18. Elbers, J. M., Asscheman, H., Seidell, J. C., Megens, J. A., & Gooren, L. J. (1997). Long-term testosterone administration increases visceral fat in female to male transsexuals. The Journal of Clinical Endocrinology and Metabolism, 82, 2044–2047.PubMedGoogle Scholar
  19. Elbers, J. M., Giltay, E. J., Teerlink, T., Scheffer, P. G., Asscheman, H., Seidell, J. C., & Gooren, L. J. (2003). Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clinical Endocrinology, 58, 562–571.CrossRefPubMedGoogle Scholar
  20. Escobar-Morreale, H. F., & San Millan, J. L. (2007). Abdominal adiposity and the polycystic ovary syndrome. Trends in Endocrinology and Metabolism, 18, 266–272.CrossRefPubMedGoogle Scholar
  21. Escobar-Morreale, H. F., Botella-Carretero, J. I., Alvarez-Blasco, F., Sancho, J., & San Millan, J. L. (2005a). The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. The Journal of Clinical Endocrinology and Metabolism, 90, 6364–6369.CrossRefPubMedGoogle Scholar
  22. Escobar-Morreale, H. F., Luque-Ramirez, M., & San Millan, J. L. (2005b). The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocrine Reviews, 26, 251–282.CrossRefPubMedGoogle Scholar
  23. Escobar-Morreale, H. F., Samino, S., Insenser, M., Vinaixa, M., Luque-Ramirez, M., Lasuncion, M. A., & Correig, X. (2012). Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: Plasma metabolomic approach using GC-MS. Clinical Chemistry, 58, 999–1009.CrossRefPubMedGoogle Scholar
  24. Escobar-Morreale, H. F., Santacruz, E., Luque-Ramirez, M., & Botella Carretero, J. I. (2017). Prevalence of ‘obesity-associated gonadal dysfunction’ in severely obese men and women and its resolution after bariatric surgery: A systematic review and meta-analysis. Human Reproduction Update, 23, 390–408.CrossRefPubMedGoogle Scholar
  25. Fernandez-Real, J. M., & Ricart, W. (1999). Insulin resistance and inflammation in an evolutionary perspective: The contribution of cytokine genotype/phenotype to thriftiness. Diabetologia, 42, 1367–1374.CrossRefPubMedGoogle Scholar
  26. Gambineri, A., & Pasquali, R. (2006). Insulin resistance, obesity and metabolic syndrome in polycystic ovary syndrome. Endocrinología y Nutrición, 53(Suppl 1), 49–55.Google Scholar
  27. Gambineri, A., Pelusi, C., Genghini, S., Morselli-Labate, A. M., Cacciari, M., Pagotto, U., & Pasquali, R. (2004). Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clinical Endocrinology, 60, 241–249.CrossRefPubMedGoogle Scholar
  28. Gambineri, A., Patton, L., Vaccina, A., Cacciari, M., Morselli-Labate, A. M., Cavazza, C., Pagotto, U., & Pasquali, R. (2006). Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: A randomized, 12-month, placebo-controlled study. The Journal of Clinical Endocrinology and Metabolism, 91, 3970–3980.CrossRefPubMedGoogle Scholar
  29. Insenser, M., Montes-Nieto, R., Vilarrasa, N., Lecube, A., Simo, R., Vendrell, J., & Escobar-Morreale, H. F. (2012). A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Molecular and Cellular Endocrinology, 363, 10–19.CrossRefPubMedGoogle Scholar
  30. Legro, R. S., Kunselman, A. R., Dodson, W. C., & Dunaif, A. (1999). 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. The Journal of Clinical Endocrinology and Metabolism, 84, 165–169.PubMedGoogle Scholar
  31. Legro, R. S., Kunselman, A. R., & Dunaif, A. (2001). Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. The American Journal of Medicine, 111, 607–613.CrossRefPubMedGoogle Scholar
  32. Luque-Ramirez, M., & Escobar-Morreale, H. F. (2016). Adrenal hyperandrogenism and polycystic ovary syndrome. Current Pharmaceutical Design, 22, 5588–5602.CrossRefPubMedGoogle Scholar
  33. Luque-Ramirez, M., Alvarez-Blasco, F., Botella-Carretero, J. I., Martinez-Bermejo, E., Lasuncion, M. A., & Escobar-Morreale, H. F. (2007a). Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism, 92, 2453–2461.CrossRefPubMedGoogle Scholar
  34. Luque-Ramirez, M., Alvarez-Blasco, F., Mendieta-Azcona, C., Botella-Carretero, J. I., & Escobar-Morreale, H. F. (2007b). Obesity is the major determinant of the abnormalities in blood pressure found in young women with the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism, 92, 2141–2148.CrossRefPubMedGoogle Scholar
  35. Luque-Ramirez, M., Mendieta-Azcona, C., Alvarez-Blasco, F., & Escobar-Morreale, H. F. (2007c). Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Human Reproduction, 22, 3197–3203.CrossRefPubMedGoogle Scholar
  36. Luque-Ramirez, M., Alvarez-Blasco, F., Uriol Rivera, M. G., & Escobar-Morreale, H. F. (2008). Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: Effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin. Human Reproduction, 23, 1594–1601.CrossRefPubMedGoogle Scholar
  37. Moghetti, P., Tosi, F., Bonin, C., Di Sarra, D., Fiers, T., Kaufman, J. M., Giagulli, V. A., Signori, C., Zambotti, F., Dall’alda, M., Spiazzi, G., Zanolin, M. E., & Bonora, E. (2013). Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 98, E628–E637.CrossRefPubMedGoogle Scholar
  38. Moran, L. J., Hutchison, S. K., Norman, R. J., & Teede, H. J. (2011). Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews, CD007506.Google Scholar
  39. Norman, R. J., Davies, M. J., Lord, J., & Moran, L. J. (2002). The role of lifestyle modification in polycystic ovary syndrome. Trends in Endocrinology and Metabolism, 13, 251–257.CrossRefPubMedGoogle Scholar
  40. Polin, R. A., Abman, S. H., Rowitch, D., & Benitz, W. E. (2016). Fetal and neonatal physiology. Philadelphia, PA: Elsevier Health Sciences.Google Scholar
  41. Recabarren, S. E., Smith, R., Rios, R., Maliqueo, M., Echiburu, B., Codner, E., Cassorla, F., Rojas, P., & Sir-Petermann, T. (2008). Metabolic profile in sons of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 93, 1820–1826.CrossRefPubMedGoogle Scholar
  42. Salley, K. E., Wickham, E. P., Cheang, K. I., Essah, P. A., Karjane, N. W., & Nestler, J. E. (2007). Glucose intolerance in polycystic ovary syndrome – A position statement of the Androgen Excess Society. Journal of Clinical Endocrinology and Metabolism, 92, 4546–4556.CrossRefPubMedGoogle Scholar
  43. Sam, S., & Dunaif, A. (2003). Polycystic ovary syndrome: Syndrome XX? Trends in Endocrinology and Metabolism, 14, 365–370.CrossRefPubMedGoogle Scholar
  44. Sanchon, R., Gambineri, A., Alpanes, M., Martinez-Garcia, M. A., Pasquali, R., & Escobar-Morreale, H. F. (2012). Prevalence of functional disorders of androgen excess in unselected premenopausal women: A study in blood donors. Human Reproduction, 27, 1209–1216.CrossRefPubMedGoogle Scholar
  45. Semmelweis, I. P. (1861). Die ätiologie, der begriff und die prophylaxe des kindbettfiebers. Pest, Hungary/Wien, Austria/Leipzig, Germany: Hartleben, C. A.Google Scholar
  46. Seow, K.-M., Juan, C.-C., Ho, L.-T., Hsu, Y.-P., Lin, Y.-H., Huang, L.-W., & Hwang, J.-L. (2007a). Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome. Human Reproduction, 22, 1100–1106.CrossRefPubMedGoogle Scholar
  47. Seow, K.-M., Juan, C.-C., Hsu, Y.-P., Hwang, J.-L., Huang, L.-W., & Ho, L.-T. (2007b). Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Human Reproduction, 22, 1003–1010.CrossRefPubMedGoogle Scholar
  48. Sir-Petermann, T., Maliqueo, M., Angel, B., Lara, H. E., Perez-Bravo, F., & Recabarren, S. E. (2002). Maternal serum androgens in pregnant women with polycystic ovarian syndrome: Possible implications in prenatal androgenization. Human Reproduction, 17, 2573–2579.CrossRefPubMedGoogle Scholar
  49. Sir-Petermann, T., Codner, E., Perez, V., Echiburu, B., Maliqueo, M., Ladron De Guevara, A., Preisler, J., Crisosto, N., Sanchez, F., Cassorla, F., & Bhasin, S. (2009). Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 94, 1923–1930.CrossRefPubMedCentralPubMedGoogle Scholar
  50. Wells, J. C. (2007). Sexual dimorphism of body composition. Best Practice & Research Clinical Endocrinology & Metabolism, 21, 415–430.CrossRefGoogle Scholar
  51. Wickenheisser, J. K., Nelson-Degrave, V. L., & Mcallister, J. M. (2006). Human ovarian theca cells in culture. Trends in Endocrinology and Metabolism, 17, 65–71.CrossRefPubMedGoogle Scholar
  52. Wild, R. A., Carmina, E., Diamanti-Kandarakis, E., Dokras, A., Escobar-Morreale, H. F., Futterweit, W., Lobo, R., Norman, R. J., Talbott, E., & Dumesic, D. A. (2010). Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. Journal of Clinical Endocrinology and Metabolism, 95, 2038–2049.CrossRefPubMedGoogle Scholar
  53. Yanovski, S. Z., & Yanovski, J. A. (2002). Obesity. The New England Journal of Medicine, 346, 591–602.CrossRefPubMedGoogle Scholar
  54. Yildirim, B., Sabir, N., & Kaleli, B. (2003). Relation of intra-abdominal fat distribution to metabolic disorders in nonobese patients with polycystic ovary syndrome. Fertility and Sterility, 79, 1358–1364.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Diabetes Obesity and Human Reproduction Research Group, Department of Endocrinology & NutritionHospital Universitario Ramon y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEMMadridSpain

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