Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics

Abstract

Objectives: To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism.

Patients and methods: This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids.

Results: After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 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 increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups.

Conclusions: Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.

Keywords: LH; Serum testosterone; Testosterone Restoration; secondary hypogonadism; transdermal testosterone.

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Figures

Fig. 1

Effect of enclomiphene citrate on the pharmacodynamics of serum total testosterone compared with transdermal testosterone. The effects of various treatments are seen over 24-h period and compared between an initial dose and a dose given following 6 weeks of continuous treatment. Men with AIHH were treated with (A) transdermal testosterone according to label instructions initially (open triangles and dashed line) and after daily dosing (filled triangles and solid line); (B) enclomiphene citrate 6.25 mg initially (open diamonds and dashed line) and after daily oral dosing (filled diamond and solid line); (C) enclomiphene citrate 12.5 mg initially (open circles and dashed line) and after daily oral dosing (filled circles and solid line); and (D) enclomiphene citrate 25 mg initially (open squares and dashed line) and after daily oral dosing (filled squares and solid line). A second order polynomial is fitted to the data points and the R2 value is given next to the line. TT, total testosterone.

Fig. 2

Outlier values of serum total testosterone found during the 24-h pharmacodynamic studies' PP population. The distribution of morning TT values determined during the two pharmacodynamic studies which were conducted before and after 6 weeks of continuous treatment. Subjects randomized to the transdermal testosterone (Gel) group are shown by solid bars; lightly stippled bars represent the enclomiphene citrate 6.25 mg group, darkly stippled bars represent the enclomiphene citrate 12.5 mg group and the vertical lined bars represent the enclomiphene citrate 25 mg group. TT, total testosterone.

Fig. 3

Effect of enclomiphene citrate on the pharmacodynamics of serum LH compared with transdermal testosterone. The effects of various treatments are seen over 24 h and compared between an initial dose and a dose given after 6 weeks of continuous treatment. Men with AIHH were treated with (A) transdermal testosterone according to label instructions initially (open triangles and dashed line) and after daily dosing (filled triangles and solid line); (B) enclomiphene citrate 6.25 mg initially (open diamonds and dashed line) and after daily oral dosing (filled diamond and solid line); (C) enclomiphene citrate 12.5 mg initially (open circles and dashed line) and after daily oral dosing (filled circles and solid line); and (D) enclomiphene citrate 25 mg initially (open squares and dashed line) and after daily oral dosing (filled squares and solid line.) A second order polynomial is fitted to the data points and the R2 value is given next to the line.

Fig. 4

Pharmacokinetics of serum enclomiphene citrate. After 6 weeks of continuous oral dosing at various dosages of enclomiphene citrate, serum samples were obtained at various time points for the assessment of serum drug levels. The levels of serum enclomiphene citrate are given for subjects taking 6.25 mg (filled diamonds), 12.5 mg (filled circles), and 25 mg (filled squares) of study drug.

Fig. 5

Relationship in morning total testosterone concentration to average total testosterone concentration for the enclomiphene citrate 25 mg group. An example of the relationship between a morning total testosterone value and the average total testosterone value over a 24-h period is given. Subjects were all men with AIHH who had been treated for 6 weeks with enclomiphene citrate and the pharmacodynamics of their total testosterone was determined (pharmacodynamic study part 2); thus, they were assessed for total testosterone every hour for 24 h and the mean hourly total testosterone was determined. TT, total testosterone.

Fig. 6

Time course of effects on serum total testosterone. Figure shows the levels of serum total testosterone found before and after treatment with daily doses of enclomiphene citrate 6.25 mg (open squares), enclomiphene citrate 12.5 mg (green squares), enclomiphene citrate 25 mg (red squares) or transdermal testosterone (orange triangles). TT, total testosterone.

Fig. 7

Time course of effects on LH. The levels of serum LH are shown before and after daily treatment with enclomiphene citrate 6.25 mg (open squares), enclomiphene citrate 12.5 mg (green squares), enclomiphene citrate 25 mg (red squares) or transdermal testosterone (orange triangles).

Fig. 8

Time course of effects on FSH. The levels of serum FSH are shown before and after treatment with 6.25 mg enclomiphene citrate (open squares), 12.5 mg enclomiphene citrate (grey squares), enclomiphene citrate 25 mg (black squares) or transdermal testosterone (grey triangles).

Fig. 9

Effect of 6 weeks of treatment on serum IGF-1. Red bars represent pretreatment values, and green bars indicate levels after 6 weeks of treatment.