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To determine the pharmacodynamic profile of serum total testosterone and luteinizing hormone (LH) levels in men with secondary hypogonadism after initial and chronic daily oral doses of enclomiphene citrate vs transdermal testosterone.To determine the effects of daily oral doses of enclomiphene citrate in comparison with transdermal testosterone on other hormones and markers in men with secondary hypogonadism.This was a randomized, single-blind, two-centre, phase II study to evaluate the effects of three different doses of enclomiphene citrate (6.25, 12.5 and 25 mg) vs transdermal testosterone on 24-h LH and total testosterone in otherwise normal healthy men with secondary hypogonadism.Forty-eight men were enrolled in the trial (the intent-to-treat population), but four men had testosterone levels >350 ng/dL at baseline. Forty-four men completed the study per protocol. All subjects enrolled in this trial had serum total testosterone in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions.Total testosterone and LH levels were assessed each hour for 24 h to examine the effects at each of three treatment doses of enclomiphene citrate vs a standard dose (5 g) of transdermal testosterone. In the initial profile, total testosterone and LH were determined in a naïve population after a single initial oral or transdermal treatment (day 1). This was contrasted to that seen after 6 weeks of continuous daily oral or transdermal treatment (day 42).The pharmacokinetics of enclomiphene citrate were assessed in a select subpopulation.Serum samples were obtained over the course of the study to determine the levels of various hormones and lipids.After 6 weeks of continuous use, the mean (SD) concentration of total testosterone at day 42 was 604 (160) ng/dL for men taking the highest dose of enclomiphene citrate (enclomiphene citrate, 25 mg daily) and 500 (278) ng in those men treated with transdermal testosterone. These values were higher than day 1 values but not different from each other (P = 0.23, t-test).All three doses of enclomiphene citrate increased the testosterone concentration at time 0 of each 24-h sampling period, and the mean, maximum, minimum and range of testosterone concentrations over the 24-h sampling period. Transdermal testosterone also raised total testosterone, albeit with more variability, and with suppressed LH levels.The patterns of total testosterone over the 24-h period after 6 weeks of dosing could be fit to a nonlinear function with morning elevations, mid-day troughs, and rising night-time levels.Enclomiphene citrate and transdermal testosterone increased levels of total testosterone within 2 weeks, but they had opposite effects on FSH and LH.Treatment with enclomiphene citrate did not significantly affect levels of thyroid-stimulating hormone, adenocorticotropic hormone, cortisol, lipids or bone markers. Both transdermal testosterone and enclomiphene citrate decreased insulin-like growth factor-1 levels (P < 0.05) but suppression was greater in the enclomiphene citrate groups.Enclomiphene citrate increased serum LH and total testosterone; however, there was not a temporal association between the peak drug levels and the maximum concentration levels of LH or total testosterone.Enclomiphene citrate consistently increased serum total testosterone into the normal range and increased LH and FSH above the normal range. The effects on LH and total testosterone persisted for at least 1 week after stopping treatment.