We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Open Drawer MenuClose Drawer Menu
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Review

Low testosterone levels and the risk of metabolic syndrome in men

    Micol S Rothman

    Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.

    Search for more papers by this author

    Email the corresponding author at micol.rothman@ucdenver.edu

    &
    Margaret E Wierman

    † Author for correspondence

    Departments of Medicine, Physiology & Biophysics, University of Colorado School of Medicine, Aurora, CO 80045, USA and, Veterans Affairs Medical Center, Denver, CO 80220, USA.

    Search for more papers by this author

    Email the corresponding author at margaret.wierman@ucdenver.edu

    Published Online:18 Mar 2009https://doi.org/10.2217/ahe.09.2

    Abstract

    The implications of low testosterone levels in aging men is an area of active investigation. Epidemiologic studies initially outlined the association between low testosterone and components of the metabolic syndrome in cross-sectional analyses. Prospective and mechanistic studies have been conducted in an attempt to improve the understanding of the role of sex steroids in insulin resistance, obesity, lipoprotein abnormalities and cardiovascular risk. The data are difficult to interpret because of problems with total testosterone measurement since most testosterone circulates are bound to sex hormone-binding globulin. Many factors regulate sex hormone-binding globulin and, thus, indirectly testosterone. Studies of normal aging, models of hypogonadism including Klinefelter’s syndrome and men undergoing surgical or medical castration after prostate cancer provide new insights into the role of both testosterone and estradiol in the development or maintenance of the metabolic syndrome.

    Papers of special note have been highlighted as: • of interest •• of considerable interest

    Bibliography

    • 1  Gruenewald DA, Matsumoto AM: Testosterone supplementation therapy for older men: potential benefits and risks. J. Am. Geriatr. Soc.51,101–115; discussion 115 (2003).
      MedlineGoogle Scholar
    • 2  Despres JP, Lemieux I, Bergeron J et al.: Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler. Thromb. Vasc. Biol.28,1039–1049 (2008).
      Medline CASGoogle Scholar
    • 3  Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet365,1415–1428 (2005).
      Medline CASGoogle Scholar
    • 4  Gami AS, Witt BJ, Howard DE et al.: Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J. Am. Coll. Cardiol.49,403–414 (2007).
      Medline CASGoogle Scholar
    • 5  Sattar N, McConnachie A, Shaper AG et al.: Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet371,1927–1935 (2008).
      MedlineGoogle Scholar
    • 6  Nilsson PM: Cardiovascular risk in the metabolic syndrome: fact or fiction? Curr. Cardiol. Rep.9,479–485 (2007).
      MedlineGoogle Scholar
    • 7  Mozaffarian D, Kamineni A, Prineas RJ, Siscovick DS: Metabolic syndrome and mortality in older adults: the Cardiovascular Health Study. Arch. Intern. Med.168,969–978 (2008).
      MedlineGoogle Scholar
    • 8  Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M: Metabolic syndrome in men with Klinefelter’s syndrome. Urology71,1109–1113 (2008).
      MedlineGoogle Scholar
    • 9  Laaksonen DE, Niskanen L, Punnonen K et al.: Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care27,1036–1041 (2004).•• One of the studies that demonstrated the key role of sex hormone-binding globulin related to the connection of testosterone and the metabolic syndrome (MetS).
      Medline CASGoogle Scholar
    • 10  Khosla S: Editorial: Sex hormone binding globulin: inhibitor or facilitator (or both) of sex steroid action? J. Clin. Endocrinol. Metab.91,4764–4766 (2006).
      Medline CASGoogle Scholar
    • 11  Matsumoto AM, Bremner WJ: Serum testosterone assays – accuracy matters. J. Clin. Endocrinol. Metab.89,520–524 (2004).
      Medline CASGoogle Scholar
    • 12  Vermeulen A, Verdonck L, Kaufman JM: A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab.84,3666–3672 (1999).
      Medline CASGoogle Scholar
    • 13  Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H: Utility, limitations and pitfalls in measuring testosterone: an Endocrine Society position statement. J. Clin. Endocrinol. Metab.92(2),405–413 (2007).
      Medline CASGoogle Scholar
    • 14  Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT: Endogenous sex hormones and metabolic syndrome in aging men. J. Clin. Endocrinol. Metab.90,2618–2623 (2005).
      Medline CASGoogle Scholar
    • 15  Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB: Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J. Clin. Endocrinol. Metab.91,843–850 (2006).
      Medline CASGoogle Scholar
    • 16  Rodriguez A, Muller DC, Metter EJ et al.: Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J. Clin. Endocrinol. Metab.92,3568–3572 (2007).
      Medline CASGoogle Scholar
    • 17  Kupelian V, Hayes FJ, Link CL, Rosen R, McKinlay JB: Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. J. Clin. Endocrinol. Metab.93(9),3403–3410 (2008).
      Medline CASGoogle Scholar
    • 18  Shahani S, Braga-Basaria M, Basaria S: Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J. Clin. Endocrinol. Metab.93,2042–2049 (2008).
      Medline CASGoogle Scholar
    • 19  Braga-Basaria M, Dobs AS, Muller DC et al.: Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J. Clin. Oncol.24,3979–3983 (2006).
      MedlineGoogle Scholar
    • 20  Rothman MS, Wierman ME: The role of gonadotropin releasing hormone in normal and pathologic endocrine processes. Curr. Opin. Endocrinol. Diabetes Obes.14,306–310 (2007).
      Medline CASGoogle Scholar
    • 21  Keating NL, AJ O’Malley, Smith MR: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol.24,4448–4456 (2006).
      Medline CASGoogle Scholar
    • 22  Grumbach MM, Auchus RJ: Estrogen: consequences and implications of human mutations in synthesis and action. J. Clin. Endocrinol. Metab.84,4677–4694 (1999).
      Medline CASGoogle Scholar
    • 23  Jones ME, McInnes KJ, Boon WC, Simpson ER: Estrogen and adiposity – utilizing models of aromatase deficiency to explore the relationship. J. Steroid Biochem. Mol. Biol.106,3–7 (2007).• Discusses models of aromatase deficiency.
      Medline CASGoogle Scholar
    • 24  Smith MR, Lee H, Fallon MA, Nathan DM: Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology71,318–322 (2008).
      MedlineGoogle Scholar
    • 25  Smith MR, Lee H, McGovern F et al.: Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer112,2188–2194 (2008).• Describes the difference in MetS among men with androgen-deprivation therapy use for prostate cancer.
      Medline CASGoogle Scholar
    • 26  Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS: Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer110,1493–1500 (2007).
      Medline CASGoogle Scholar
    • 27  Kalyani R, Dobs A: Androgen deficiency, diabetes and the metabolic syndrome in men. Curr. Opin. Endocrinol. Diabetes Obes.14,226–234 (2007).
      Medline CASGoogle Scholar
    • 28  Chubb SA, Hyde Z, Almeida OP et al.: Lower sex hormone-binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the Health in Men Study. Eur. J. Endocrinol.158,785–792 (2008).
      Medline CASGoogle Scholar
    • 29  Tomar R, Dhindsa S, Chaudhuri A, Mohanty P, Garg R, Dandona P: Contrasting testosterone concentrations in Type 1 and Type 2 diabetes. Diabetes Care29,1120–1122 (2006).
      Medline CASGoogle Scholar
    • 30  Smith MR, Lee H, Nathan DM: Insulin sensitivity during combined androgen blockade for prostate cancer. J. Clin. Endocrinol. Metab.91,1305–1308 (2006).
      Medline CASGoogle Scholar
    • 31  Lage MJ, Barber BL, Markus RA: Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer. Urology70,1104–1108 (2007).
      Medline CASGoogle Scholar
    • 32  Shabsigh R, Arver S, Channer KS et al.: The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int. J. Clin. Pract.62,791–798 (2008).
      Medline CASGoogle Scholar
    • 33  Lima N, Cavaliere H, Knobel M, Halpern A, Medeiros-Neto G: Decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat. Int. J. Obes. Relat. Metab. Disord.24,1433–1437 (2000).
      Medline CASGoogle Scholar
    • 34  Pitteloud N, Hardin M, Dwyer AA et al.: Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J. Clin. Endocrinol. Metab.90,2636–2641 (2005).
      Medline CASGoogle Scholar
    • 35  Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ: Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab.92,4254–4259 (2007).•• Androgens may have an effect on insulin sensitivity independent of bodyweight.
      Medline CASGoogle Scholar
    • 36  Cohen JC, Hickman R: Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J. Clin. Endocrinol. Metab.64,960–963 (1987).
      Medline CASGoogle Scholar
    • 37  Lobo RA: Metabolic syndrome after menopause and the role of hormones. Maturitas60,10–18 (2008).
      Medline CASGoogle Scholar
    • 38  Kaplan SA, Meehan AG, Shah A: The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men? J. Urol.176,1524–1527; discussion 1527–1528 (2006).
      Medline CASGoogle Scholar
    • 39  Blouin K, Boivin A, Tchernof A: Androgens and body fat distribution. J. Steroid Biochem. Mol. Biol.108,272–280 (2008).
      Medline CASGoogle Scholar
    • 40  Basaria S, Lieb J 2nd, Tang AM et al.: Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin. Endocrinol. (Oxf.)56,779–786 (2002).
      Medline CASGoogle Scholar
    • 41  Smith MR, Finkelstein JS, McGovern FJ et al.: Changes in body composition during androgen deprivation therapy for prostate cancer. J. Clin. Endocrinol. Metab.87,599–603 (2002).
      Medline CASGoogle Scholar
    • 42  Yanase T, Fan W, Kyoya K et al.: Androgens and metabolic syndrome: lessons from androgen receptor knock out (ARKO) mice. J. Steroid Biochem. Mol. Biol.109,254–257 (2008).
      Medline CASGoogle Scholar
    • 43  Yeh S, Tsai MY, Xu Q et al.: Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc. Natl Acad. Sci. USA99,13498–13503 (2002).
      Medline CASGoogle Scholar
    • 44  Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH: Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am. J. Epidemiol.146,609–617 (1997).
      Medline CASGoogle Scholar
    • 45  Makinen JI, Perheentupa A, Irjala K et al.: Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis197,688–693 (2008).
      Medline CASGoogle Scholar
    • 46  Isidori AM, Giannetta E, Greco EA et al.: Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin. Endocrinol. (Oxf.)63,280–293 (2005).
      Medline CASGoogle Scholar
    • 47  Gyllenborg J, Rasmussen SL, Borch-Johnsen K, Heitmann BL, Skakkebaek NE, Juul A: Cardiovascular risk factors in men: the role of gonadal steroids and sex hormone-binding globulin. Metabolism50,882–888 (2001).
      Medline CASGoogle Scholar
    • 48  Smith MR: Androgen deprivation therapy for prostate cancer: new concepts and concerns. Curr. Opin. Endocrinol. Diabetes Obes.14,247–254 (2007).
      MedlineGoogle Scholar
    • 49  Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C: Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin. Sci. (Lond.)104,195–201 (2003).
      Medline CASGoogle Scholar
    • 50  Rosano GM, Leonardo F, Pagnotta P et al.: Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation99,1666–1670 (1999).
      Medline CASGoogle Scholar
    • 51  Malkin CJ, Pugh PJ, Morris PD et al.: Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart90,871–876 (2004).
      Medline CASGoogle Scholar
    • 52  English KM, Steeds RP, Jones TH, DiverMJ, Channer KS: Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation102,1906–1911 (2000).
      Medline CASGoogle Scholar
    • 53  Kienitz T, Quinkler M: Testosterone and blood pressure regulation. Kidney Blood Press. Res.31,71–79 (2008).
      Medline CASGoogle Scholar
    • 54  Rolf C, von Eckardstein S, Koken U, Nieschlag E: Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study. Eur. J. Endocrinol.146,505–511 (2002).
      Medline CASGoogle Scholar
    • 55  Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH: The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with Type 2 diabetes. Eur. J. Endocrinol.156,595–602 (2007).
      Medline CASGoogle Scholar
    • 56  Kapoor D, Goodwin E, Channer KS, Jones TH: Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur. J. Endocrinol.154,899–906 (2006).
      Medline CASGoogle Scholar
    • 57  Nishizawa H, Shimomura I, Kishida K et al.: Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes51,2734–2741 (2002).
      Medline CASGoogle Scholar
    • 58  Page ST, Herbst KL, Amory JK et al.: Testosterone administration suppresses adiponectin levels in men. J. Androl.26,85–92 (2005).
      Medline CASGoogle Scholar
    • 59  Saad F, Gooren L, Haider A, Yassin A: An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch. Androl.53,353–357 (2007).
      Medline CASGoogle Scholar
    • 60  Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI: Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J. Clin. Endocrinol. Metab.93,139–146 (2008).• Placebo-controlled study investigating testosterone on some components of MetS.
      Medline CASGoogle Scholar
    • 61  Bhasin S, Cunningham GR, Hayes FJ et al.: Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab.91,1995–2010 (2006).
      Medline CASGoogle Scholar
    • 62  Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Rissanen A: Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes. Metab.6,208–215 (2004).• Effect of weight loss on sex hormones.
      Medline CASGoogle Scholar
    • 63  Allan GF, Tannenbaum P, Sbriscia T et al.: A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats. Endocrine32,41–51 (2007).
      Medline CASGoogle Scholar