Effect of Testosterone Replacement on Insulin Sensitivity
Animal Models
The effects of androgens on insulin sensitivity have been studied in animal models and the Results of these concur with those observed in men. Castrated male rats
exposed to supraphysiological doses of testosterone have increased insulin resistance but, conversely, physiological testosterone replacement improves insulin sensitivity.[71] This implies that testosterone has a major role as a regulator of insulin sensitivity.
The effects of long-term administration of testosterone enanthate on glucose metabolism in rhesus monkeys were studied by Tyagi et al.[72] Nine adult male rhesus monkeys were given 50 mg of testosterone enanthate bimonthly for 32 months and glycaemic control was compared with placebo-treated animals. Significant changes in the glucose tolerance test were not observed in animals treated with testosterone throughout this period. However, serum insulin levels decreased significantly between 27 and 32 months in the testosterone-treated group and returned to baseline values within 3 months of stopping the treatment.
Centol et al.[73] compared serum androgen levels in streptozotocin-induced diabetic rats with controls. The diabetic state produced a marked reduction in serum androgen levels between 10 and 15 days after streptozotocin administration. Further studies with streptozotocin-induced diabetic rats have also shown a similar decrease in testosterone levels, which have been shown to occur as a combination of impaired gonadotrophin secretion at the pituitary level[74] and reduced function of the LH receptor in the testes.[75] Moreover, insulin administration in these diabetic rats partially restored the circulating androgen levels by stimulating testicular 3-beta-hydroxysteroid dehydrogenase activity,[74] thereby enhancing testosterone synthesis as well as receptor binding capacity.
Effect of Anabolic Steroids
Early literature revealed that anabolic steroids lowered fasting blood sugar and reduced glycosuria.[76] The cause for this effect was unknown, although methandienone was reported to enhance insulin secretion.[77] Subsequent research, however, has shown that anabolic steroids adversely affect glucose metabolism. Godsland et al.[78] found that when anabolic steroid methandrostenolone was given to underweight men, insulin action was impaired. Similar Results were also seen when oxymethalone led to impaired glucose intolerance and hyperinsulinaemia in children with idiopathic acquired aplastic anaemia or Fanconi's anaemia.[79] Cohen and Hickman[80] found that powerlifters who ingested anabolic steroids had insulin resistance compared to the nonsteroid-using powerlifters, obese men or nonobese sedentary men. Further evidence of impaired insulin action with high-dose testosterone comes from a study of a transsexual population that included women who chose to become men.[60] The women were treated with high doses of testosterone that resulted in impaired glucose uptake. Thus it would seem that excess androgen and anabolic steroid use reduces insulin sensitivity and impairs glucose tolerance. However, a study in healthy men has shown that nandrolone improved glucose metabolism by enhancing noninsulin-mediated glucose disposal.[81]
Effect of Testosterone Replacement in Hypogonadal Men
No adverse effects of testosterone therapy on insulin secretion or glucose tolerance have been demonstrated in normal men with pharmacologically-induced hypogonadism.[82] Sixty-one eugonadal men between 18 and 35 years of age were randomly assigned to receive monthly injections of long-acting GnRH agonist, to suppress endogenous testosterone secretion, and then given weekly doses of 25, 50, 125, 300 or 600 mg of testosterone enanthate for 20 weeks. In this study no significant effect of testosterone on insulin sensitivity was observed, even though the higher doses of testosterone produced an increase in fat free mass and muscle size. Friedl et al.[83] also demonstrated that pharmacological doses of testosterone and 19-nortestosterone given for 6 weeks to normal men did not impair glucose tolerance.
Testosterone replacement therapy in adult men with hypogonadism improves insulin sensitivity. Simon et al.[84] randomized 18 men to one of three treatment groups – testosterone, dihydrotestosterone and placebo, administered in the form of gel. At the end of 3 months, men receiving androgens had a significantly lower fasting plasma insulin, fasting plasma insulin/fasting plasma glucose ratio, HOMA index and leptin levels. However, in another study of 10 men with idiopathic hypogonadotrophic hypogonadism treated with testosterone, no decrease in insulin sensitivity was observed using the hyperglycaemic euglycaemic clamp method.[85]
A beneficial effect of testosterone treatment on insulin resistance has also been seen in a study in HIV-infected men.[86] Reduced circulating testosterone levels are commonly found in patients with HIV infection and these levels correlate with weight loss and generalized muscle wasting. Sattler et al.[86] compared the effects of nandrolone decanoate and resistance training in 30 HIV-infected men over a 3-month period. Those patients who received both treatments had significantly lower fasting insulin and glucose levels and HOMA index. However, these changes were transient, with the metabolic effects returning to baseline 2 months after treatment was withdrawn.
Effect of Testosterone Treatment in Obese Men
Intra-abdominal fat may be a part of the pathway through which lower testosterone level is related to insulin resistance. Marin et al.[70] examined the effects of testosterone administration in middle-aged obese men. Reduced glucose tolerance was observed 1 week following intramuscular injection of 500 mg testosterone (producing supraphysiological plasma levels of testosterone). However, following treatment with doses achieving plasma levels high in the physiological range, plasma levels of insulin were reduced and insulin sensitivity increased. The greatest effect was observed in menwith lower baseline testosterone levels. In another study by the same group, 23 middle-aged abdominally obese men were randomized to 8 months of treatment with testosterone and placebo.[87] Testosterone treatment led to reduced insulin resistance. These changes could be due either to the effects of testosterone on visceral fat or to a direct effect on muscle insulin sensitivity.
Effect of Testosterone Replacement in Diabetic Men
Men with type 2 diabetes have a higher prevalence of hypogonadism, as mentioned earlier. Testosterone is an important modulator of insulin sensitivity and the consequences of improved insulin sensitivity in diabetic subjects is better glycaemic control. There are, however, few interventional studies that have been performed in this group of patients. Boyanov et al.[88] assessed the effects of oral testosterone supplementation in 48 type 2 diabetic men with mild androgen deficiency. Twenty-four men received testosterone and the other 24 men were given placebo. Oral treatment with testosterone resulted in a significant reduction in body weight, body fat, blood glucose and mean glycated haemoglobin (from 10·4% to 8·6%). Even though this was a nonblinded study and oral testosterone was used, favourable effects of testosterone treatment on the metabolic parameters in type 2 diabetic men were observed. However, although Corrales et al.[89] also found a high prevalence of hypogonadism in type 2 diabetic men, a neutral effect on glycaemic control with intramuscular testosterone replacement therapy was observed in 10 type 2 diabetic men with partial androgen deficiency.
