Testosterone Restoration Using Enclomiphene Citrate in Men with Secondary Hypogonadism: A Pharmacodynamic and Pharmacokinetic Study:
Goals: To determine the pharmacodynamic profile of serum total testosterone and luteinizing hormone levels in men with secondary hypogonadism after initial single dose and long-term oral administration of enclomiphene citrate compared with transdermal testosterone.
To determine the effect of enclomiphene citrate versus transdermal testosterone on other hormones and markers in men with secondary hypogonadism.
Patients and Methods: This study was a randomized, single-blind, two-center, phase 2 study to evaluate the effect of three different doses of enclomiphene citrate (6.25, 12.5, and 25 mg) versus transdermal testosterone on 24-hour LH and total testosterone levels in patients. with secondary hypogonadism without comorbidities.
Forty-eight men were included in the study, with 4 men having basal testosterone levels greater than 350 ng/dl. Forty-four patients completed the study in accordance with the protocol. All subjects included in this study demonstrated low testosterone levels (<350 ng/dL) and low to normal LH levels (<12 IU/L) on at least two measurements.
Total testosterone and LH levels were measured at 1 hour intervals over 24 hours to evaluate the effect of each of the three treatment doses of enclomiphene citrate compared to a standard dose (5 g) of transdermal testosterone. To assess the effect of the initial single dose, total testosterone and LH were determined in the control population after a single oral or transdermal dose (day 1). These data were contrasted with those obtained after 6 weeks of continuous oral or transdermal therapy (day 42).
The pharmacokinetics of enclomiphene citrate have been evaluated in a selected group of patients.
Restoring testosterone levels in men – Results
After 6 weeks of regular dosing, mean (standard deviation, SD) total testosterone by day 42 was 604 (160) ng/dL for men taking the highest dose of enclomiphene citrate (enclomiphene citrate, 25 mg once daily) and 500 (278) ng/dl in men treated with transdermal testosterone. These values were greater than day 1 values but were not statistically different from each other (p=0.23, t-test).
All three doses of enclomiphene citrate increased testosterone concentration to time point 0 of each 24-hour study interval, mean, maximum, minimum and range of testosterone concentrations over the 24-hour period. Transdermal testosterone also caused an increase in total testosterone levels, although with great variability and LH suppression.
The patterns of change in total testosterone over a 24-hour period after 6 weeks of use can be described by a non-linear function with a morning rise, daytime troughs, and nighttime rises.
Enclomiphene citrate and transdermal testosterone increased total testosterone levels for 2 weeks, while having opposite effects on FSH and LH.
Treatment with enclomiphene citrate had no significant effect on levels of TSH, ACTH, cortisol, lipids, and bone markers. Both transdermal testosterone and enclomiphene citrate reduced insulin-like growth factor-1 levels (p < 0.05), but the suppression was more pronounced in the enclomiphene citrate group.
Enclomiphene citrate increases LH and total serum testosterone levels; however, no temporal relationship was noted between peak levels of the drug and these hormones.
Enclomiphene citrate consistently increased serum total testosterone levels within normal limits and increased LH and FSH levels above normal limits. The effects of LH and total testosterone were present for at least 1 week after treatment was stopped.