PATHOGENESIS OF THE DECREASED ANDROGEN LEVELS IN OBESE MEN

In obese men, sex hormone-binding globulin levels (SHBG) as well as total plasma testosterone (T) levels are decreased. Data concerning the levels of nonprotein-bound testosterone (FT) are discordant, with some researchers reporting normal levels, and others reporting decreased levels. The latter imply an impairment of the feedback regulation mechanism of FT levels. We investigated whether an eventual decrease in FT levels and, hence, functional impairment of the gonadostat might occur only at a more severe degree of obesity than that required for a decrease in SHBG and total T levels. We, therefore, determined androgen and precursor levels in three groups of male subjects: nonobese controls [body mass index (BMI), G (kg)/L(2) (m) < 26; n = 70]; moderately (BMI, 30-35; n = 18),and severely (BMI, >40; n = 22) obese men, respectively. In a subgroup of these controls, moderately and severely obese subjects, respectively we studied LH levels as well as LH pulsatility. Moreover, as a decrease in FT levels might affect the metabolic pattern of the androgens and, more specifically, Sor-reductase activity, we determined the plasma levels of the major 5 alpha-reduced metabolites, androstanediol glucuronide and androsterone glucuronide (AG), as well as the urinary excretion of the major 5 alpha (androsterone glucuronide) and the major 5 beta (etiocholanolone glucuronide) metabolite of the androgens. In moderately obese men, T levels were decreased, which was the consequence of the decreased SHBG-binding capacity. FT levels, however, were normal as were LH levels and both pulse amplitude and frequency of LH pulses, suggesting a normal hypothalamic control of LH secretion. In severely obese men (BMI, >40), total T, FT, and LH levels as well as LH pulse amplitude were decreased indicating a functional impairment of the gonadostat. Even in massively obese subjects with decreased FT levels, androgen metabolism and 5 alpha-reductase activity appeared to be normal, as suggested by similar androstanediol glucuronide and AG levels, determined by RIA or calculated from the conversion rates of precursors obtained in nonobese subjects. This was confirmed by the similar AG/etiocholanolone glucuronide ratios in obese and nonobese men. In conclusion, the decrease in T levels in obese subjects has a double origin: on the one hand, a decrease in SHBG levels, which is the major factor responsible for the decreased T levels in moderately obese men, and on the other, an impaired regulation of the gonadostat, characterized by decreased LH levels and LH pulse amplitude, observed only in the massively obese men and responsible for the decreased FT levels and hypoandrogenism. The metabolism of the androgens remains unchanged in obese subjects, and the eventual decrease in plasma levels of 5 alpha-reduced metabolites appears to be the consequence of decreased precursor levels only.