Introduction: Clomiphene citrate has been used off-label to increase luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men with secondary hypogonadism. A newer agent, enclomiphene citrate, is the transisomer of clomiphene citrate and is being investigated for use in hypogonadal men. While clomiphene citrate consists of a mixture of isomers, enclomiphene citrate is a single isomer with pure estrogen antagonism.
Methods: This randomized phase IIB study enrolled 124 men with a morning serum T level of <250 ng/dL on 2 occasions. The subjects were randomized to one of two doses of enclomiphene citrate (12.5-mg or 25-mg), 1% topical testosterone, or placebo. Hormone levels of LH, FSH, and T and semen level were measured before, during and after 3 months of treatment.
The primary end point was the change in morning total testosterone level from baseline to the end of the 3-month dosing period.
Results: A total of 113 men received 3 months of treatment, and 73 completed the study and provided both baseline and at least 1 semen sample at the end of the study. All 3 active treatment groups showed significantly increases in total testosterone level from baseline compared with placebo, with no statistically significant difference in testosterone levels found between the active treatment groups compared with placebo (Table).
Levels of LH and FSH increased in the 12.5-mg and 25-mg enclomiphene citrate groups (by 5.1 and 7.4 mIU/mL and by 4.8 and 6.9 mIU/mL, respectively), decreased in the topical T group (by –4.4 mIU/mL and –2.4 mIU/mL, respectively), and showed little change in the placebo group.
Sperm concentration was significantly lower in the topical testosterone group compared with the 12.5-mg and 25-mg enclomiphene citrate groups after 3 months of treatment (P=0.008 and P=0.0007, respectively). In contrast, sperm concentration was not significantly different between the 2 enclomiphene citrate groups, or between these 2 groups and placebo.
More than half (54%) of men in the topical T group became oligospermic during treatment compared with 14.6% of the enclomiphene citrate groups (P=0.001). No significant difference was found in the proportion of men who became oligospermic with enclomiphene citrate versus placebo.
Only 4 patients withdrew from the study, 3 of whom received 25-mg enclomiphene citrate and 1 of whom received topical testosterone. Two of the withdrawals in the 25-mg enclomiphene citrate group were considered possibly related to the study drug: inability to climax and loss of sensation during intercourse in 1 patient, and mild nausea and mild dry heaving in 1 patient.
Conclusion: Use of 12.5-mg and 25-mg enclomiphene citrate significantly increased total T levels in hypogonadal men, with an efficacy that was comparable to topical testosterone. Increases in LH and FSH levels also were found with enclomiphene citrate treatment. In contrast to topical T, enclomiphene citrate did not adversely affect sperm concentration.
Wiehle RD, Fontenot GK, Wike J, et al. ZA-203 Clinical Study Group. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-727.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
A 2012 survey of urologists found that 25% of 387 respondents used testosterone as treatment for infertility in men actively seeking fertility, a concerning statistic given that exogenous testosterone hampers fertility by suppressing FSH (negative feedback) and thus spermatogenesis. Clomiphene citrate (CC) was the most common prescription for infertile men among the respondents.1 CC—clomid—has itself been used to increase testosterone and gonadotropin levels in men,2 and in at least one retrospective analysis led to similar satisfaction scores as did exogenous testosterone,3 but is not approved for that indication by the FDA. Wiehle and colleagues studied the impact of enclomiphene citrate (EC), the trans-stereoisomer of CC, comparing its effect on testosterone and gonadotropin levels and on sperm parameters to the effect of testosterone gel.
Wiehle and colleagues studied a cohort of men with secondary hypogonadism (appropriately measured). The men were randomized to one of 4 groups: EC 12.5-mg, EC 25-mg, topical T gel 1%, (T) and placebo. Treatment period was 3 months.
All treatment groups showed an increase in testosterone, vs the placebo group that had a decrease in testosterone over the time period of the study. A dose response was not observed—in fact, the higher-dose EC group had less of a T increase than the lower-dose EC group though this did not meet significance—suggesting there might be a threshold effect. However, LH and FSH values were higher with 25-mg vs 12.5-mg of EC.
Measuring total sperm count, the post-study difference between placebo group and low-dose EC group did reach significance, with the 12.5-mg EC group having a higher sperm count (P=0.036). While there was no significant difference in sperm concentration between EC groups and placebo group, the numbers analyzed were not large, and a change in sperm concentration by 3 months might be detectable in larger groups. There was no significant difference in other measured sperm parameters between EC and placebo groups. The testosterone group, unsurprisingly, had lower sperm parameters than all other groups.
It would be interesting to measure sperm concentration after a longer period of treatment to see if there were improvement, and whether certain characteristics (BMI, etiology of hypogonadism) predict response. The cohort in this study by Wiehle and colleagues had secondary hypogonadism, but further information on likely etiology was not specified. If the cohort included men with a dearth of functioning GnRH, LH, or FSH cells, the results may be correspondingly less than what might be observed in a more tightly defined population.
The authors note that, of the men with baseline oligospermia, there was no significant improvement on EC. While EC may not be helpful in restoring fertility, there are several alternate explanations. EC may not be helpful in all cases or over the time period studies. Etiology of hypogonadism may be important, as noted above, though testosterone levels did increase significantly. The authors do not note what the testosterone increases were in the men with baseline oligospermia—numbers were small, but a subanalysis may be enlightening, and larger and longer studies might show different results.
Testosterone and clomiphene's different mechanisms of action may explain the differing impact on pituitary hormones LH and FSH.
The Hypothalamic-Pituitary-Gonadal Axis
In a healthy male in hormonal equilibrium, both testosterone and sperm are made in the testes (Figure 1). LH is secreted from the pituitary and stimulates testicular production of testosterone. FSH is secreted from the pituitary and stimulates spermatogenesis (for which testosterone is also necessary). When sufficient testosterone is produced, the testosterone serves as a negative feedback signal to inhibit further pituitary LH and FSH secretion. If exogenous testosterone is given, it will suppress both LH and FSH production. Thus, exogenous testosterone can treat testosterone deficiency but inhibits fertility.
Clomiphene citrate works at the level of the hypothalamus to block estradiol's negative feedback on GnRH production—thus leading to an increase in secretion of GnRH and subsequently LH and FSH. The hypothalamic-pituitary-testicular axis function must be preserved for CC or EC to be effective. A male must have functioning GnRH, LH, and FSH-secreting cells, and Leydig cells in order for either medication to improve testosterone levels. That is, if there are not sufficient functional GnRH-producing cells (such as in Kallmann's syndrome) or pituitary LH and FSH cells (such as in some patients with large sellar tumors or a history of sellar radiation), one would not expect to see an effect. Indeed, there is some evidence that CC does not increase testosterone levels in men with hypogonadism from pituitary tumors.4
Thus, one would expect testosterone replacement to result in suppression of LH and FSH, and thus a decrease in sperm production. This is an important point to share with patients who are interested in fertility. EC is of interest as an alternative to testosterone in men with hypogonadism seeking fertility. In this study, no difference was seen in sperm concentration or development of oligospermia in the EC vs placebo group. This may be related to the number of subjects who completed the study and provided semen samples, but bears further study. While the authors report that EC does not adversely affect sperm, one might predict that it would improve semen parameters. The lack of this response may be due to sample size, to heterogeneity of hypogonadism etiology as noted above, or to baseline semen parameters (was the baseline testosterone low enough to impact semen analysis?)—or might be an indication that EC may not improve sperm concentration.
Overall, this study confirmed that EC led to increased T levels (regardless of dose) as well as consistently applied topical T, and did not result in the same decrease in gonadotropins or sperm concentration. However, there was no significant increase in sperm concentration vs placebo over the time period studied. Longer study with larger cohort may provide additional information. In addition, it would be instructive to specify likely etiology, as there is theoretical and some clinical evidence that CC does not increase T levels in patients with pituitary disease.
1. Ko EY, Siddiqi K, Brannigan RE, Sabanegh ES Jr. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187:973–978.
2. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int. 2012;110(4):573-578.
3. Ramasamy R, Scovell JM, Kovac JR, et al. Testosterone supplementation versus clompiphene citrate for hypogonadism: an age matched comparison of satisfaction and efficacy. J Urol. 2014;192-(3):875-870.
4. Ribeiro RS, Abucham J. Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas. Arq Bras Endocrinol Metabol. 2011;55(4):266-271.