Top

Published in:

01-04-2014 | Diabetes and Cardiovascular Disease (S Malik, Section Editor)

Endogenous Sex Hormones, Metabolic Syndrome, and Diabetes in Men and Women

Authors: Catherine Kim, Jeffrey B. Halter

Published in: Current Cardiology Reports | Issue 4/2014

Abstract

Endogenous sex hormones predict impairments of glucose regulation. Cross-sectional studies suggest that lower levels of testosterone in men and higher levels in women increase risk of metabolic syndrome and diabetes, whereas lower levels of sex hormone binding globulin in both men and women increase risk of metabolic syndrome and diabetes. In a systematic review, we summarize existing longitudinal studies, which suggest similar patterns. However, these studies are often limited to a single sex steroid measure. Whether these associations are primarily a marker of adiposity, and whether these associations differ between younger eugonadal vs older hypogonadal adults is also uncertain. The impact of exogenous sex steroid therapy may not reflect relationships between sex hormones and impaired glucose regulation that occur without supplementation. Therefore, examination of endogenous sex steroid trajectories and obesity trajectories within individuals might aid our understanding of how sex steroids contribute to glucose regulation.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62–9.PubMedCentralCrossRef

Grundy S, Brewer Jr H, Cleeman J, Smith Jr S, Spertus J, Lenfant C, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433–8.PubMedCrossRef

Ford E. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care. 2005;28:1769.PubMedCrossRef

Kannel W, McGee D. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care. 1979;2:120.PubMedCrossRef

World Health Organization. World Health Expert Committee on Diabetes Mellitus: Second Report. Geneva: World Health Organization; 1980.

World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1. Diagnosis and classification of diabetes mellitus. Geneva: World Health Organization; 1999.

Alberti K, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059–62.PubMedCrossRef

8.••

Wildman R, McGinn A, Kim M, Muntner P, Wang D, Cohen H, et al. Empircal derivation to improve the definition of the metabolic syndrome in the evaluation of cardiovascular disease risk. Diabetes Care. 2011;34:746–8. This paper noted that for the purposes of predicting cardiovascular risk, definitions of MetS are essentially equivalent.PubMedCentralPubMedCrossRef

Muniyappa R, Lee S, Chen H, Quon M. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008;294:E15–26.PubMedCrossRef

10.

Chang A, Smith M, Bloem C, Galecki A, Halter J, Supiano M. Limitation of the homeostasis model assessment to predict insulin resistance and beta-cell dysfunction in older people. J Clin Endocrinol Metab. 2006;91:629–34.PubMedCrossRef

11.

Labrie F, Belanger A, Belanger P, Berube R, Martel C, Cusan L, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol. 2006;99:182–8.PubMedCrossRef

12.

Orentreich N, Brind J, Rizer R, Vogelman J. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984;59:551–5.PubMedCrossRef

13.

Laughlin G, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab. 2000;85:645–51.PubMed

14.

Davison S, Bell R, Donath S, Montalto J, Davis S. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90:3847.PubMedCrossRef

15.

Sowers M, Zheng H, McConnell D, Nan B, Karvonen-Gutierrez C, Randolph Jr J. Testosterone, sex hormone-binding globulin, and free-androgen index among adult women: chronological and ovarian aging. Hum Reprod. 2009;24:2276–85.PubMedCentralPubMedCrossRef

16.

Torrens J, Sutton-Tyrrell K, Zhao X, Matthews K, Brockwell S, Sowers M, et al. Relative androgen excess during the menopausal transition predicts incident metabolic syndrome in midlife women: Study of Women's Health Across the Nation. Menopause. 2009;16:257–64.PubMedCentralPubMedCrossRef

17.•

Rosner W, Hankinson S, Sluss P, Vesper H, Wierman M. Challenges to the measurement of estradiol: an endocrine society position statement. J Clin Endocrinol Metab. 2013;98:1376–87. This report summarizes existing methods of E2 measurement and the lack of consensus regarding optimal method and the variety of methods.PubMedCrossRef

18.

Rosner W, Auchus R, Azziz R, Sluss P, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:405–13.PubMedCrossRef

19.

Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72.PubMedCrossRef

20.

Sodergard R, Backstrom T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. 1982;16:801–10.PubMedCrossRef

21.

Espeland M, Hogan P, Fineberg S, Howard G, Schrott H, Waclawiw M, et al. Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investig Diabetes Care. 1998;21:1589–95.CrossRef

22.

Kanaya A, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. Ann Intern Med. 2003;138:1–9.PubMedCrossRef

23.

Sites C, L'Hommedieu G, Toh M, Brochu M, Cooper B, Fairhurst P. The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2005;90:2701–7.PubMedCrossRef

24.

Godsland I, Manassiev N, Felton C, Proudler A, Crook D, Whitehad M, et al. Effects of low and high-dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women. Clin Endocrinol (Oxf). 2004;60:541–9.CrossRef

25.

Kim C, Kong S, Laughlin G, Golden S, Mather K, Nan B, et al. Reductions in glucose among postmenopausal women who use and do not use estrogen therapy. Menopause. 2012;20:393–400.

26.••

Kim C, Nan B, Laughlin G, Golden S, Mather K, Kong S, et al. Endogenous sex hormone changes in postmenopausal women in the Diabetes Prevention Program. J Clin Endocrinol Metab. 2012;97:2853–61. Lifestyle-induced weight changes in overweight, glucose-intolerant postmenopausal women improved glucose but had less of an impact upon E2 levels, and E2 levels were associated with reduced glucose, suggesting that E2 was not a proxy for adiposity, could not be lowered by interventions aimed at weight, but might play a role in glucose; SHBG was more strongly associated with weight loss and independently associated with fasting and post-challenge glucose.PubMedCentralPubMedCrossRef

27.

Kim, C., Golden, S., Kong, S., Nan, B., Mather, K., Barrett-Connor, E., et al. Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program? Menopause. 2013;21(5):1–7.

28.

Golden S, Kim C, Barrett-Connor E, Nan B, Kong S, Goldberg R, et al. The association of elective hormone therapy with changes in lipids among glucose-intolerant postmenopausal women in the Diabetes Prevention Program. Metabolism. 2013;62:1313–22.PubMedCrossRef

29.

Troisi R, Cowie C, Harris M. Hormone replacement therapy and glucose metabolism. Obstet Gynecol. 2000;96:655–70.

30.

Zhang Y, Howard B, Cowan L, Yeh J, Schaefer C, Wild R, et al. The effect of estrogen use on levels of glucose and insulin and the risk of type 2 diabetes in American Indian postmenopausal women: the Strong Heart Study. Diabetes Care. 2002;25:500–4.PubMedCrossRef

31.

van Genugten R, Utzschneider K, Tong J, Gerchman F, Zraika S, Udayasankar J, et al. Effects of sex and hormone replacement therapy use on the prevalence of isolated impaired fasting glucose and isolated impaired glucose tolerance in subjects with a family history of type 2 diabetes. Diabetes. 2006;55:3529–35.PubMedCrossRef

32.

Davidson M, Maki H, Marx P, Maki A, Cyrowski M, Nanavati N, et al. Effects on continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women. Arch Intern Med. 2000;160:3315–25.PubMedCrossRef

33.

The Writing Group for the PEPI Trial, Miller V, LaRosa J, Barnabei V, Kessler C, Levin G, et al. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199–208.CrossRef

34.

Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96:2643–51.PubMedCentralPubMedCrossRef

35.

Vigen R, O'Donnell C, Baron A, Grunwald G, Maddox T, Bradley S, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829–36.PubMedCrossRef

36.

Basu R, Dalla Man C, Campioni M, Basu A, Nair K, Jensen M, et al. Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men. Diabetes Care. 2007;30:1972–8.PubMedCrossRef

37.

Hildreth K, Barry D, Moreau K, Vande Griend J, Meacham R, Nakamura T, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab. 2013;98:1891–900.PubMedCrossRef

38.

Rubinow K, Snyder C, Amory J, Hoofnagle A, Page S. Acute testosterone deprivation reduces insulin sensitivity in men. Clin Endocrinol (Oxf). 2012;76:281–8.CrossRef

39.

Jones T, Arver S, Behre H, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34:828–37.PubMedCentralPubMedCrossRef

40.

Nair K, Rizza R, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355:1647–59.PubMedCrossRef

41.

Dhatariya K, Bigelow M, Nair K. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes. 2005;54:765–9.PubMedCrossRef

42.

Brand J, van der Tweel I, Grobbee D, Emmelot-vonk M, van der Schouw Y. Testosterone, sex hormone binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011;40:189–207.PubMedCrossRef

43.

Ding E, Song Y, Malik V, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes. JAMA. 2006;295:1288–99.PubMedCrossRef

44.

Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl. 2010;34:528–40.PubMedCrossRef

45.

Ding E, Song Y, Manson J, Rifai N, Buring J, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia. 2007;50:2076–84.PubMedCrossRef

46.

Lakshman K, Bhasin S, Araujo A. Sex hormone-binding globulin as an independent predictor of incident type 2 diabetes mellitus in men. J Gerntol A Biol Sci Med Sci. 2010;65A:503–9.CrossRef

47.

Schipf S, Haring R, Friedrich N, Nauck M, Lau K, Alte D, et al. Low testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP). Aging Male. 2011;14:168–75.PubMedCrossRef

48.

Vikan T, Schirmer H, Njolstad I, Svartberg J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur J Endocrinol. 2010;162:747–54.PubMedCrossRef

49.

Haffner S, Shaten J, Sternh M, Smith G, Kuller L, MRFIT Research Group. Low levels of sex hormone binding globulin and testosterone predict the incidence of noninsulin dependent diabetes mellitus in men. Diabetes. 1996;143:889–97.

50.

Kalyani R, Franco M, Dobs A, Ouyang P, Vaidya D, Bertoni A, et al. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009;94:4127–35.PubMedCentralPubMedCrossRef

51.

Laaksonen D, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen T, Valkonen V, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27:1036–41.PubMedCrossRef

52.

Lindstedt G, Lundberg P, Lapidus L, Lundgren H, Bengtsson C, Bjorntorp P. Low sex hormone binding globulin concentration as independent risk factor for development of NIDDM: 12 year follow-up of population study of women in Gothenburg, Sweden. Diabetes. 1991;40:123–8.PubMedCrossRef

53.

Haffner S, Valdez R, Morales P, Hazuda H, Stern M. Decreased sex hormone binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. J Clin Endocrinol Metab. 1993;77:56–60.PubMed

54.

Kameda W, Daimon M, Oizumi T, Jimbu Y, Kimura M, Hirata A, et al. Association of decrease in serum dehydroepandrosterone sulfate levels with the progresstion to type 2 diabetes in men of a Japanese population: the Fungata Study. Metabolism. 2005;54:669–76.PubMedCrossRef

55.

Oh J, Barrett-Connor E, Wedick N, Wingard D. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo Study. Diabetes Care. 2002;25:55–60.PubMedCrossRef

56.

Okubo M, Tokui M, Egusa G, Yamakido M. Association of sex hormone binding globulin and insulin resistance among Japanese-American subjects. Diabetes Res Clin Pract. 2000;47:71–5.PubMedCrossRef

57.

Tibblin G, Adlerberth A, Lindstedt G, Bjorntorp P. The pituitary-gonadal axis and health in elderly men: a study of men born in 1913. Diabetes. 1996;45:1605–9.PubMedCrossRef

58.

Stellato R, Feldman H, Hamdy O, Horton E, McKinlay J. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men. Diabetes Care. 2000;23:490–4.PubMedCrossRef

59.

Soriguer F, Rubio-Martin E, Fernandez D, Valdes S, Garcia-Escobar E, Martin-Nunez G, et al. Testosterone, SHBG and risk of type 2 diabetes in the second evaluation of the Pizarra cohort study. Eur J Clin Invest. 2012;42:79–85.PubMedCrossRef

60.

Haring R, Volzke H, Spielhagen C, Nauck M, Wallaschofski H. The role of sex hormone-binding globulin and testosterone in the risk of incident metabolic syndrome. Eur J Prev Cardiol. 2013. 20(6):1061–8.

61.

Haring R, Volzke H, Felix S, Schipf S, Dorr M, Rosskopf D, et al. Prediction of metabolic syndrome by low serum testosterone levels in men. Diabetes. 2009;58:2027–31.PubMedCentralPubMedCrossRef

62.

Kupelian V, Page S, Araujo A, Travison T, Bremner W, McKinlay J. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with the development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91:843–50.PubMedCrossRef

63.

Rodriguez A, Muller D, Metter E, Maggio M, Harman S, Blackman M, et al. Aging, androgens and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab. 2007;92:3568–72.PubMedCrossRef

64.

Bhasin S, Jasjua G, Pencina M, D'Agostino Sr R, Coviello A, Vasan R, et al. Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men. Diabetes Care. 2011;34:2464–70.PubMedCentralPubMedCrossRef

65.

Janssen I, Powell L, Crawford S, Lasley B, Sutton-Tyrrell K. Menopause and the metabolic syndrome. Arch Intern Med. 2008;168:1568–75.PubMedCentralPubMedCrossRef

66.••

Wildman R, Tepper P, Crawford S, Finkelstein J, Sutton-Tyrrell K, Thurston R, et al. Do changes in sex steroid hormones precede or follow increases in body weight during the menopause transition? Results from the Study of Women's Health Across the Nation. J Clin Endocrinol Metab. 2012;97:1695–704. A provocative paper suggesting that the menopausal sex steroid changes over the menopause may be driven by changes in adiposity rather than sex steroids in the later part of the transition.CrossRef

67.

Laaksonen D, Niskanen L, Punnonen K. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab. 2005;90:712–9.PubMedCrossRef

68.

Peter A, Kantartzis K, Machann J, Shick F, Staiger H, Machicao F, et al. Relationship of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes. 2010;59:3167–73.PubMedCentralPubMedCrossRef

69.

Kim C, Barrett-Connor E, Randolph Jr J, Kong S, Nan B, Mather K, et al. Sex steroid levels and response to weight loss interventions among postmenopausal women in the Diabetes Prevention Program. Obesity (Silver Spring). 2013. doi:10.1002/oby.20527.PubMedCentral

70.

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale H, 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.PubMedCrossRef

71.

Kim C, Pi-Sunyer X, Barrett-Connor E, Stentz F, Murphy M, Kong S, et al. Sex hormone globulin and sex steroids among premenopausal women in the Diabetes Prevention Program. J Clin Endocrinol Metab. 2013;98:3049–57.PubMedCrossRef

72.

American Diabetes Association. Standards of medical care in diabetes: position statement. Diabetes Care. 2013;36(Suppl):S11–66.PubMedCentralCrossRef

73.

Alberti K, Eckel R, Grundy S, Zimmet P, JI C, Donato K, et al. Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation; International Atherosclerosis Society, and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.PubMedCrossRef

Title: Endogenous Sex Hormones, Metabolic Syndrome, and Diabetes in Men and Women
Authors: Catherine Kim
Jeffrey B. Halter
Publication date: 01-04-2014
Publisher: Springer US
Published in: Current Cardiology Reports / Issue 4/2014
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI: https://doi.org/10.1007/s11886-014-0467-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Endogenous Sex Hormones, Metabolic Syndrome, and Diabetes in Men and Women

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2014

Same Day Discharge After Elective Percutaneous Coronary Intervention

Making Sense of High Sensitivity Troponin Assays and their Role in Clinical Care

Choosing the Right Coronary Stent in the Modern Era

Assessing Clinical Impact of Myocardial Perfusion Studies: Ischemia or Other Prognostic Indicators?

The Practical Role of Echocardiography in Selection, Implantation, and Management of Patients Requiring LVAD Therapy

Assessing the Prognostic Implications of Myocardial Perfusion Studies: Identification of Patients at Risk vs Patients who May Benefit from Intervention?