A 3-month randomized placebocontrolled trial I n men, an association between lower plasma total testosterone (PTT) and insulin resistance has been found in cross-sectional studies (1,2) and in one nested case-control study (3) without any possible conclusion in terms of causality or direction of the relationship. Indeed, to obtain such information, randomized controlled trials are needed. Until now, only one clinical trial has suggested that testosterone therapy improves insulin sensitivity in obese men (4). Crosssectional studies concerning leptin regulation by androgens have provided no definitive conclusions as to whether the negative association between androgens and leptin level is independent (5) or dependent (6). This randomized controlled trial was designed to assess the role of androgens on insulin sensitivity and leptin regulation in healthy adult men.This study was a randomized, double-blind, unicentric, controlled, clinical trial. Three treatments (testosterone, dihydrotestosterone [DHT], and placebo) were compared in parallel groups during a 3-month period. All of the examinations were performed by only two physicians, using a standardized protocol. Blood was drawn between 8:00 A.M. and 9:30 A.M. after an overnight fast to determine fasting plasma glucose, insulin, leptin, sex hormones, lipids, coagulation and fibrinolysis parameters, hepatic enzymes, and prostate-specific antigen (PSA) and blood cell count. Then, a standard 75-g oral glucose tolerance test and a digital rectal examination were performed. In addition, between days 10 and 20, all of the subjects were monitored to measure sex hormones in order to adapt the treatment dose. The study protocol was approved by the Henri Mondor Hospital Ethics Committee. All of the included subjects gave written informed consent.Men with low levels of PTT (confirmed by two measurements) were selected from a large occupation-based population. The inclusion criteria were as follows: 1) either PTT Յ3.4 ng/ml [5th percentile value of PTT distribution in the 1,718 men of the TELECOM Study (7)] from 1985 to 1987 and Ͻ4.0 ng/ml (13th percentile value) from 1992 to 1993 (3) or PTT Ͻ4.0 ng/ml from 1992 to 1993 and Ͻ4.0 ng/ml a few days before inclusion; 2) no history of vascular thrombosis or ischemic heart disease; 3) no treatment by androgens, anti-androgens, and antidiabetic or antithrombotic drugs; 4) normal values of plasma prolactin, estradiol, and thyroxin; 5) no current prostatic disease and a normal PSA value. A total of 18 healthy men with stable low plasma androgens (Table 1) and a range of PTT from 1.4 to 3.7 ng/ml at baseline were included.The 18 selected men were randomly assigned to one of three treatment groups: testosterone, DHT, or placebo. The randomization code was known only to the study manager. Treatment was a gel administered every morning by percutaneous route. The daily dose during the first weeks was 125 mg for the testosterone and 35 mg for the DHT treatment groups. The adaptation of treatment doses between days 10 and 20 aimed at obtain...