Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study

Context Low testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate. Objective To evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET). Design Cross-over, randomized, double-blind, placebo-controlled study. Methods 24 obese men, aged 47.3 +/- 6.3 (range 35-55 years), with low T level (<= 3 ng/mL) and naive diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment. Results Of 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03 +/- 0.80 to 5.99 +/- 1.67 ng/mL P<0.001) but not after the Plac treatment (2.87 +/- 0.78 to 3.09 +/- 0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83 +/- 1.45 to 8.53 +/- 6.40 mU/mL; FSH 4.84 +/- 1.67 to 10.15 +/- 5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51 +/- 1.59 to 3.63 +/- 1.39 mU/mL) but a smooth increased for FSH (4.61 +/- 2.49 to 5.39 +/- 2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8 +/- 23.2 to 101.1 +/- 25.7 mg/dL; P = 0.004), insulin (19.3 +/- 12.1 to 15.6 +/- 10.1 mu U/mL; P = 0.010) and HOMA-IR (4.94 +/- 2.89 to 3.69 +/- 2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment. Conclusions A low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters.