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Metabolic syndrome, characterized by a group of risk factors that include abdominal obesity, dyslipidemia, hypertension, and insulin resistance, is a growing health concern. What is the relationship between metabolic syndrome and hypogonadism, and why is it imperative to screen for and treat both conditions?

Response by Andre T. Guay, MD
Metabolic syndrome is defined as a cluster of medical conditions associated with the risk of developing insulin resistance, type 2 diabetes,1 and cardiovascular disease1,2 (CVD) and higher risk of incident CVD and mortality.3

Although several definitions of metabolic syndrome exist (eg, National Cholesterol Education Program-Adult Treatment Panel III [NCEP-ATP III], World Health Organization [WHO], American College of Endocrinology [ACE], and International Diabetes Federation [IDF]), criteria overlap, including abnormalities in glucose metabolism (or frank diabetes), blood pressure, and obesity (body mass index [BMI]) or waist circumference, and dyslipidemia (elevated triglycerides and/or low high-density lipoprotein).4-7 Generally, if 3 of the 5 abnormalities are present, then metabolic syndrome is said to exist. Metabolic syndrome guides the clinician to assess cardiovascular risk, because each component of metabolic syndrome has been independently associated with cardiovascular risk through the common thread of endothelial dysfunction.8,9 The implications of this are very important, because the age-adjusted prevalence of metabolic syndrome in our population is 23.7%, approximately 47 million people.10

Hypogonadism, defined as comprising symptoms of androgen deficiency along with a low or borderline testosterone level, has shown a clear association with metabolic syndrome. Kupelian et al showed in the longitudinal Massachusetts Male Aging Study that metabolic syndrome was several times more likely to develop in men with low testosterone levels.11 This was recently confirmed by Haring et al, who further showed that low testosterone predicted the development of metabolic syndrome in a population-based study of >1000 men.12 Even more interesting is the fact that low testosterone was a strong predictor in young men aged 20 to 39 years.12 Laaksonen et al’s results agreed with the above data but also showed that this relationship is bidirectional, ie, that men with metabolic syndrome had a higher chance of having hypogonadism.13 They also found that low testosterone predicted metabolic syndrome in men who were not obese,14 a fact confirmed by Kupelian et al.11 Having said this, the current obesity epidemic does play a large part in the high prevalence of metabolic syndrome and its consequences.

In a thorough, current review by Zitzmann, the relationship between hypogonadism, insulin resistance, and metabolic syndrome has been solidified.15 The relationship between hypogonadism and metabolic syndrome can also be predicted because its components—especially diabetes, hypertension, hyperlipidemia, and obesity—have been shown to be independently associated with hypogonadism, for example, when studied by clinicians in the primary care setting for the Hypogonadism in Males (HIM) study.16 Of late, more attention has been given to the relationship between low testosterone and the development of insulin resistance, a critical component at the core of metabolic syndrome, and an inverse relationship between testosterone levels and insulin resistance has been shown.17 An even stronger relationship was shown by Yeap et al, who found in a cross-sectional analysis that low testosterone levels were independently associated with insulin resistance in men without diabetes (n=2470).18 Of special note is the apparent independence of this association with BMI.18 This is reinforced by the observation that insulin resistance develops rather quickly after withdrawal of testosterone treatment in young idiopathic hypogonadotropic hypogonadal men receiving treatment for hypogonadism.19 More dramatic is the observation that insulin resistance decreased in only 48 hours after testosterone therapy was initiated in men previously rendered hypogonadal.20 Testosterone, and especially the lack of it, appears to have a strong relationship to insulin resistance and therefore to metabolic syndrome and the subsequent development of diabetes and CVD.

There is compelling evidence that early serum testosterone assessment may have prognostic benefit, helping to identify men in whom metabolic syndrome and CVD will likely develop.9 Furthermore, in light of these data supporting a bidirectional relationship between hypogonadism and metabolic syndrome,13 clinicians should consider regular periodic screening of men with hypogonadism for cardiovascular risk factors (which are really metabolic syndrome components), and conversely, patients with metabolic syndrome or its components should be screened for hypogonadism.

Response by Abdulmaged M. Traish, MBA, PhD
If hypogonadism is a fundamental component of metabolic syndrome, as the evidence suggests, then testosterone therapy for hypogonadal men who have metabolic syndrome should improve some of the components of metabolic syndrome. A growing body of evidence indicates that testosterone therapy does indeed improve body composition, lipid profiles, insulin sensitivity, and the endothelial cell function that underlies CVD.8,21,22

Recent evidence suggests that the response to testosterone therapy is dose-dependent.21 A dose-response study of two formulations of testosterone in elderly men with late-onset hypogonadism and symptoms of metabolic syndrome, for example, found that the higher plasma levels achieved with parenteral testosterone undecanoate (n=28) were associated with greater improvement in symptoms (eg, reductions in waist circumference and beneficial changes in cholesterol levels) compared with the testosterone gel formulation (n=27).23 In addition, in 60 nonobese men who had low-normal serum testosterone levels and symptoms of androgen deficiency, testosterone patches prevented gain of visceral adiposity.24

A recently published study of parenteral testosterone undecanoate in 117 elderly hypogonadal men improved body composition (ie, weight, BMI, and waist circumference) and lipid profiles, decreasing from 74 to 42 the number of men who met NCEP criteria for metabolic syndrome.25

Some evidence suggests that testosterone therapy also reduces insulin resistance.15,22 Recent data show that adding testosterone gel to a supervised regimen of medical nutrition therapy (MNT) and exercise for 32 hypogonadal men with newly diagnosed type 2 diabetes produced greater increases in insulin sensitivity and improved glycemic control in addition to reductions in visceral adiposity, waist circumference, and high-density lipoprotein (HDL) and triglycerides compared with MNT and exercise alone.26 After 52 weeks, 100% and 87.5% of the testosterone group attained a glycosylated hemoglobin (A1C) level of <7.0% and <6.5%, respectively, compared with 40% and 0%, respectively, of the MNT-and-exercise-only group. Importantly, 81.3% of the testosterone group no longer matched NCEP-ATP III criteria for metabolic syndrome, compared with 31.3% of the MNT-and-exercise-only group. Changes in serum testosterone correlated significantly with improvements in components of metabolic syndrome.

After 6 months of therapy with intramuscular testosterone, 24 young men (mean age, 21 y) with idiopathic hypogonadotropic hypogonadism had significant increases in insulin sensitivity and reductions in body fat mass (26.55% to 11.13%).27

The influence of testosterone on endothelial function is the cornerstone of treatment: In a cross-sectional survey of 187 men who underwent flow-mediated vasodilation of the brachial artery using ultrasonography, Akishita et al demonstrated that low plasma testosterone levels in men are associated with endothelial dysfunction independent of other risk factors, indicating endogenous testosterone’s protective effect on the endothelium.28 Furthermore, results of a placebo-controlled, 12-week study of 35 men with coronary artery disease showed that testosterone treatment had positive effects on endothelial function as measured by brachial-arterial vasoreactivity.29

Discussions at the 6th World Congress on Men’s Health, held in Vienna October 9-11, 2009, highlighted the importance of testosterone to men’s health, some challenges in diagnosis and treatment of hypogonadism, and the need for and benefits of treatment.30,31

A recent epidemiologic study of nearly 1000 men in the Boston, Massachusetts, area showed a high prevalence of hypogonadism (36%) that was strongly correlated with hypertension, sleep apnea, and life and work stresses.31 We presented results of an extensive review of the literature that substantiate the negative effects of hypogonadism on men’s health and the potential benefits of timely treatment.8,21,22,30 Saad et al presented previously unpublished data detailing the timetable for improvements in sexual function and mood with testosterone therapy, which may provide useful guidance and reassurance for physicians and their patients receiving testosterone therapy.32 These data are now published in Aging Male by Jockenhövel et al.33

Based on worldwide demographic treatment data showing that hypogonadism remains highly undertreated, particularly in men older than 50 years of age receiving testosterone therapy—<2% in Europe and <8% in the United States receive treatment34,35—it seems of paramount importance to raise awareness about hypogonadism and understand the potential implications of its treatment. The emerging evidence suggesting that hypogonadism is a risk factor for metabolic syndrome, type 2 diabetes, insulin resistance, and CVD further reinforces the critical importance of understanding the extent to which the risk of these pathologies may be reduced with testosterone therapy.8,21,22,30


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  2. Anand SS, Yi Q, Gerstein H, et al; Study of Health Assessment and Risk in Ethnic Groups (SHARE), Study of Health Assessment and Risk Evaluation in Aboriginal Peoples (SHARE-AP) Investigators. Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease. Circulation. 2003;108(4):420-425.
  3. Franco OH, Massaro JM, Civil J, Cobain MR, O’Malley B, D’Agostino RB Sr. Trajectories of entering the metabolic syndrome: the Framingham Heart Study. Circulation. 2009;120(20):1943-1950.
  4. National Heart, Lung, and Blood Institute, National Institutes of Health. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): executive summary. Bethesda, MD: National Institutes of Health; May 2001. NIH publication 01-3670.
  5. 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. World Health Organization website. 1999. http://whqlibdoc.who.int/hq/1999/
    WHO_NCD_NCS_99.2.pdf. Accessed November 22, 2009.
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  9. Spark RF. Testosterone, diabetes mellitus, and the metabolic syndrome [review]. Curr Urol Rep. 2007;8(6):467-471.
  10. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359.
  11. 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. 2006;91(3):843-850.
  12. Haring R, Völzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the Study of Health in Pomerania. Diabetes. 2009;58(9):2027-2031.
  13. Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab. 2005;90(2):712-719.
  14. 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 Care. 2004;27(5):1036-1041.
  15. Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome [review]. Nat Rev Endocrinol. 2009;5(12):673-681.
  16. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769.
  17. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care. 2004;27(4):861-868.
  18. Yeap BB, Chubb SA, Hyde Z, et al. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health in Men study. Eur J Endocrinol. 2009;161(4):591-598.
  19. Yialamis 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. 2007;92(11):4254-4259.
  20. 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. 2005;90(5):2636-2641.
  21. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction [review]. J Androl. 2009;30(1):10-22.
  22. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance [review]. J Androl. 2009;30(1):23-32.
  23. Saad F, Gooren LJ, Haider A, Yassin A.  A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl. 2008;29(1):102-105.
  24. Allan CA, Strauss BJG, 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. 2008;93(1):139-146.
  25. Haider A, Gooren LJG, Padungtod P, Saad F. Improvement of the metabolic syndrome and of
    non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate. Exp Clin Endocrinol Diabetes. 2009 May 26 [E-pub ahead of print].
  26. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two–week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl.  2009;30(6):726-733.
  27. Naharci MI, Pinar M, Bolu E, Olgun A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocr Pract. 2007;13(6):629-635.
  28. Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30(11):1029-1034.
  29. Kang SM, Jang Y, Kim JY, et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am J Cardiol. 2002;89(7):862-864.
  30. Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: diabetes, metabolic syndrome, cardiovascular disease and erectile dysfunction [abstract]. J Mens Health. 2009;6(3):236. Abstract 30.
  31. Guay AT, Traish AM. Psychological as well as medical conditions are associated with a high prevalence of hypogonadism [abstract]. J Mens Health. 2009;6(3):237. Abstract 33.
  32. Saad F, Jockenhoevel F, Minnemann T, et al. Time table of effects of testosterone administration to hypogonadal men on variables of sex and mood [abstract]. J Mens Health. 2009;6(3):238. Abstract 40.
  33. Jockenhövel F, Minnemann T, Schubert M, et al. Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood. Aging Male. 2009;12(4):113-118.
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  35. Carruthers M. Time for international action on treating testosterone deficiency syndrome [abstract]. J Mens Health. 2009;6(3):235. Abstract 28.

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