Hypogonadotropic Hypogonadism in Men With Diabesity

Abstract

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA_1c in men with diabetes. The effect of testosterone replacement on cardiovascular events or mortality in men with diabesity is not known and remains to be studied in prospective trials.

Figure 1

Prevalence of subnormal free testosterone concentrations in lean, overweight, and obese men (based on BMI) with and without diabetes. Mean age 60 years; range 45–96 years. A total of 44% of men with diabetes and 33% of age-matched men without diabetes had subnormal free testosterone concentrations, respectively. Sample size: 275 lean, 687 overweight, and 489 obese men without diabetes; 36 lean, 135 overweight, and 227 obese men with diabetes. *P < 0.05 vs. obese men in the same group (with diabetes or without diabetes); #P < 0.05 vs. men without diabetes. Adapted from data published in Dhindsa et al. (3).

Figure 2

Men with HH have lower free estradiol concentrations than eugonadal men. Estradiol concentrations in men with and without HH were 0.47 (0.35, 0.68) and 0.63 (0.46, 0.77) pg/mL, respectively. Adapted from Dhindsa et al. (21).

Figure 3

Interplay of different factors in obesity associated HH. The thickness of arrows is proportional to the strength of available evidence supporting the mechanism.

Figure 4

A: Insulin sensitivity measured by hyperinsulinemic-euglycemic insulin clamps in 94 men with type 2 diabetes (44 men had HH, and 50 were eugonadal). Men with HH had greater BMI (40 vs. 34 kg/m²; P < 0.001) but similar age (55 vs. 52 years; P = 0.08) and HbA_1c (7.0 vs. 7.1%; P = 0.7) as compared with eugonadal men. The glucose infusion rate during hyperinsulinemic-euglycemic insulin clamps was 36% lower in men with HH as compared with eugonadal men. The glucose infusion rate between men with and without HH was, however, not different once adjusted for BMI difference in the two groups. This suggests that obesity is the predominant determinant of insulin resistance in men with HH. B: A total of 44 men with HH were randomized to intramuscular testosterone or placebo injections every 2 weeks for 6 months. Insulin sensitivity (glucose uptake during clamps) increased by 32% after 6 months. Data adapted from Dhindsa et al. (44).