TESTOSTERONE SUBSTITUTION NORMALIZES ELEVATED SERUM LEPTIN LEVELS IN HYPOGONADAL MEN

The ob gene product leptin (OB is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels tha n women even after adjustment for percent body fat. We. therefore, inv estigated the influence of testosterone (T) substitution in hypogonada l men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assign ed to two treatment groups: testosterone enanthate (TE; 2.50 mg, im, e very 21 days; n = 10) or a single sc implantation of 1200 mg crystalli ne T (TPEL; n = 12). Blood samples for determination of T, 5 alpha-dih ydrotestosterone (DHT), sex hormone-binding globulin, and 17 beta-estr adiol were obtained before therapy and then every 21 days until day 18 9 and at follow-up visits on days 246 and 300. Serum OB levels were as sessed on days 0, 42, 84, 126, 168, and 300. OB levels were referred t o a normal range for men based on the analysis of OB levels in 393 adu lt men. Substitution with T led to a large rise in T and DHT in both g roups compared to baseline values (average T, days 21-189: TE, 14.33 /- 2.63 nmol/L; TPEL, 24.98 +/- 1.64; average DHT, days 21-189: TE, 4. 20 +/- 0.57 nmol/L: TPEL, 5.11 +/- 0.56: P less than or equal to 0.05) . Concomitantly, 17 beta-estradiol increased in both groups, and sex h ormone-binding globulin levels were significantly decreased. At baseli ne, serum OB levels in hypogonadal men were 3-fold elevated compared t o those in normal men (12.39 +/- 2.93 mu g/L vs. 4.28 +/- 0.52; P < 0. 01) and not different between groups (TE, 13.7 +/- 5.6; TPEL, 11.3 +/- 2.9 mu g/L). This elevation was retained after adjustment for body ma ss index in the normal control group [TE, 1.45 +/- 0.51 SD score (P < 0.0001); TPEL, 0.98 +/- 0.35 SD score (P < 0.0008)]. During T substitu tion serum OB was completely normalized (trough levels: TE, 4.6 +/- 1. 0 mu g/L; TPEL, 4.3 +/- 0.9 mu g/L). In multiple regression analysis, the androgen (T plus DHT/estrogen ratio was the only significant deter minant of OB levels (r = -0.32; P < 0.01). At baseline, OB levels did net correlate with body mass index, but during substitution, the corre lation was considerably improved. We conclude that hypogonadal men exh ibit elevated OB levels that are normalized by substitution with T. Th e only determinant of OB levels was the androgen/estrogen ratio, indic ating a major influence of sex steroids on OB production. The interact ion of T and OB might be part of a hypothalamic-pituitary-gonadal-adip ose tissue axis that is involved in body weight maintenance and reprod uctive function.