Testosterone exerts various effects in different organs and it is involved in carbohydrate and fat metabolism. Testosterone concentrations decrease as men age, beginning at the fourth or the fifth decade of life 1,2. This decrease can be up to 2% per year in some cohorts 3,4. The actual prevalence of hypogonadism, defined as total testosterone less than 400 ng/dl, has been estimated to be 39% in men aged 45 years or older presenting to primary care offices in the USA 2.
With aging, glucose tolerance has also been shown to deteriorate 5,6 and, subsequently, the prevalence of type 2 diabetes mellitus (T2DM) increases as men grow older. The association of T2DM and low testosterone levels has long been described. T2DM has been proposed as a risk factor for hypogonadism in men because of a reduction in sex hormone-binding globulin levels induced by insulin resistance which, in turn, leads to a reduction in testosterone levels 7,8. It is estimated that 30–50% of men attending a diabetes clinic have low testosterone concentrations 4, being the highest among obese patients with T2DM 9. Furthermore, current guidelines published by the Endocrine Society in 2010 recommend measurement of morning total testosterone as an initial screening test for androgen deficiency in patients with T2DM 10.
Body composition is also affected by age. In the elderly, there is an increase in fat mass and BMI with redistribution of body fat and a decrease in bone mineral density, muscle mass, and muscle strength 11,12. Moreover, with age, an increase in the concentration of atherogenic LDL particles has been observed 13. These alterations have also been described in testosterone-deficient states 2. Various cross-sectional and prospective studies have reported that men with dyslipidemia have significantly lower levels of total testosterone and observed that testosterone is correlated positively with HDL and correlated negatively with total cholesterol, LDL, and triglycerides. 14–24. These observations of various investigators have led to speculations that the decrease in testosterone concentrations with age may cause or exacerbate abnormalities in lipid metabolism, contributing toward various metabolic and cardiovascular risks.
Testosterone replacement therapy (TRT) has, therefore, been proposed as a therapeutic approach to revert these metabolic disturbances.
Effects of testosterone replacement therapy on glucose metabolism
Testosterone and development of type 2 diabetes mellitus
Epidemiological and clinical studies have supported the association between testosterone concentrations, insulin resistance, and T2DM. Furthermore, low testosterone concentrations have been shown to predict future risk of developing T2DM. Whether the association between testosterone and development of diabetes is dependent or not on BMI, weight, and visceral fat is less clear 4.
Effects of testosterone replacement therapy on carbohydrate metabolism
In rats, testosterone replacement restores insulin action, increases islet insulin content, and enhances insulin secretion 25,26.
In humans, there is controversial evidence of the effects of testosterone on carbohydrate metabolism. Testosterone did not show any effect on insulin action in healthy young men 27. Centrally obese middle-aged men receiving testosterone showed an improvement in insulin sensitivity (by hyperinsulinemic/euglycemic clamp studies) and a lowering of serum insulin levels 28. Studies carried out by us and others, however, have shown that TRT, aiming at restoring physiological levels of testosterone in hypogonadal men, has no effect on glucose metabolism 29–31. Some of these differences may be partly explained by different study sample sizes, and different techniques and measurements as metabolic outcomes.
We conducted a 2-year placebo-controlled, randomized, double-blind trial in which men with relative testosterone deficiency underwent a mixed meal test and a frequently sampled intravenous glucose tolerance test before and after TRT or placebo. Fasting glucose, insulin, and C-peptide concentrations did not differ following 2 years of treatment with testosterone or placebo. Postprandial increments (i.e. area above basal) of glucose, insulin, and C-peptide concentrations also did not differ following treatment with testosterone or placebo. Fasting and postprandial glucose fluxes (endogenous glucose production, glucose disappearance, meal appearance) did not differ after treatment in either group (Fig. 1). Insulin action, glucose effectiveness, and hepatic insulin clearance measured with either the unlabeled oral or the unlabeled ‘oral’ or ‘intravenous’ glucose minimal models did not differ following 2 years of treatment with either testosterone or placebo. The change from basal in meal and intravenous glucose tolerance test insulin secretion indexes did not differ, which resulted in no difference in the change from baseline in either the meal or intravenous glucose disposition indexes in the testosterone and placebo groups 29.
Testosterone replacement therapy in type 2 diabetes mellitus
The effects of TRT in patients with T2DM are just as controversial. There is evidence that testosterone can improve glycemic control, as measured by glycated hemoglobin, but study designs did not allow for body composition changes to be excluded as confounders 32,33. A recent systematic review and meta-analysis of five randomized-controlled trials on the metabolic effects of TRT on hypogonadal men with T2DM found that glycemic control was improved with testosterone. The meta-analysis for HbA1c% included 124 patients and found a mean decrease of 0.87% (P=0.0001) 7. The longest duration of testosterone intervention in these trials was 12 months and, as described previously, body composition changes were not taken into account when analyzing HbA1c difference.
Effects of testosterone replacement therapy on body composition
Low levels of testosterone have long been associated with obesity 34–38. Testosterone affects body fat distribution. It has been shown that hypogonadal men store a greater proportion of both dietary fatty acids and free fatty acids (FFA) in lower body subcutaneous fat than eugonadal men 39. Moreover, weight reduction has been associated with increases in testosterone levels 37,40.
Some studies have proposed that TRT may reduce BMI and visceral fat in obese men 28,41–46. However, in a placebo-controlled, randomized, double-blind study carried out by our group, 2-year low-dose TRT in overweight men with low levels of bioavailable testosterone did not alter visceral or percentage body fat, although it resulted in a slight but statistically significant increase in fat-free mass 29,30. In contrast, a more recent double-blinded placebo-controlled study of men with metabolic syndrome and hypogonadism showed significant decreases in weight, BMI, and waist circumference following 30 weeks of testosterone replacement to the normal range 47.
Effects of testosterone replacement therapy on fat metabolism
Lipid panel changes
Most of the studies investigating TRT in hypogonadal and eugonadal men have shown some beneficial effects on serum lipids. Significant reductions in total cholesterol and LDL were observed following TRT in hypogonadal men 48,49, with either a decrease 50 or an increase 33,44, or no change 32,51–54 in HDL cholesterol. The differences in these observations may be because of the differences in doses, routes of administration, and duration of TRT in these studies.
Testosterone supplementation in men has shown an increase in lipolysis and decrease in lipoprotein lipase activity and triglyceride turnover in abdominal fat, with no effect on femoral fat metabolism. These findings suggest a site-specific regulation of lipolysis following TRT, causing an increase in FFA concentrations 41,43,55. Freidreiksen et al.53 reported significant changes in body composition following TRT as a gel preparation, but did not observe significant changes in FFA concentrations. Moreover, following a 2-year patch-administered TRT, Koutsari et al.56 observed no change in post absorptive or whole-body lipolysis in elderly men. These differences in observations suggest that the route of testosterone administration for replacement therapy may play a role in the metabolic effects of TRT.
Fat oxidation and storage
Studies have observed decreased fat oxidation in androgen-deprived elderly men with prostate cancer or post orchiectomy 48,57,58. Short-term TRT in men with testosterone deficiency because of hypopituitarism have shown stimulation of whole-body fat oxidation 59, which was also observed in healthy elderly men following TRT of 6 months. In contrast, Koutsari et al.56 observed no change in meal fat oxidation following 2 years of TRT, although they found a partially restored meal fat storage pattern without affecting regional adiposity in elderly men.
Implications of testosterone replacement therapy on cardiovascular disease
Patients with low testosterone levels are at an increased risk for cardiovascular disease. Epidemiological studies, androgen deprivation therapy studies, and TRT studies have shown that low testosterone is associated with higher cardiovascular risk factors and increased mortality 60. However, TRT has yielded controversial cardiovascular outcomes in men. Some studies have shown carotid intima media thickness reduction and improvement in blood pressure, whereas others have described an increase in cardiovascular adverse effects 2. Further studies are needed to clarify the cardiovascular effects of TRT, especially on patients who are at an already increased risk, such as those with T2DM and dyslipidemia.
TRT has been shown to exert beneficial metabolic effects. Testosterone increases fat-free mass and improves the lipid panel; however, there is no strong evidence of glucose tolerance improvement nor a decrease in the incidence of T2DM. Cardiovascular safety continues to be a concern. Current evidence supports screening for hypoandrogenism in certain populations at risk for developing low testosterone levels, such as in T2DM patients. We agree with the recommendations of the Endocrine Society 2010 that TRT be reserved for men with symptomatic androgen deficiency aiming to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. Until more evidence builds up, we do not support TRT as a treatment to improve carbohydrate or lipid metabolism.
This study was funded by NIH (DK29953 and AG14383).
Conflicts of interest
There are no conflicts of interest.
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