Enclomiphene vs Clomiphene for Low Testosterone: Do They Work the Same for Boosting Testosterone, LH, and FSH?

madman · 2026-04-27T21:13:05-0500

Abstract

INTRODUCTION AND OBJECTIVES:

Clomiphene citrate has been used off-label to treat male hypogonadism by stimulating endogenous gonadotropin secretion. Enclomiphene, the trans-isomer of clomiphene, is increasingly prescribed, but comparative data remain limited. We aimed to assess whether enclomiphene provides hormonal outcomes comparable to clomiphene in men with hypogonadism.

METHODS:

We performed a retrospective cohort study evaluating men treated with either enclomiphene or clomiphene for hypogonadism or testicular dysfunction. Patients with bilateral orchiectomy, Klinefelter syndrome, overlapping enclomiphene and clomiphene therapy, or concurrent testosterone therapy, anastrozole, or hCG were excluded. Hormone values (testosterone, estradiol, FSH, and LH) were collected at baseline and at 3, 6, 9, and 12 months of therapy. Longitudinal changes were analyzed using mixed-effects models with repeated measures. The primary outcome was the change in testosterone over time; secondary outcomes were estradiol, FSH, and LH trajectories.

RESULTS:

The enclomiphene cohort consisted of 72 patients, and the clomiphene cohort had 861 patients. Both therapies produced significant increases in testosterone from baseline through 3–12 months, with a mean rise of 210.40 ng/dL (95% CI 180.84–239.96, p<0.001). There was no significant difference in testosterone response between therapies (treatment × time interaction = −17.17 ng/dL, 95% CI −69.60–35.27, p = 0.521). Estradiol increased from baseline with a mean rise of 10.02 pg/mL (95% CI 7.02–13.03, p<0.001). The estradiol increase was not significantly different between therapies (treatment × time interaction = 1.01 pg/mL, 95% CI −3.28–5.31, p = 0.644). FSH rose modestly by 1.16 IU/L (95% CI 0.22–2.10, p = 0.015) without a between-group difference (interaction = 0.94 IU/L, 95% CI −0.32–2.21, p = 0.143). LH increased by 2.23 IU/L (95% CI 1.46–3.01, p<0.001), with no significant difference between therapies (treatment × time interaction = 0.11 IU/L, 95% CI −0.96–1.19, p = 0.835).

CONCLUSIONS:

Enclomiphene and clomiphene produced similar hormonal responses in men with hypogonadism, each significantly increasing testosterone, estradiol, FSH, and LH from baseline without differences in magnitude between therapies. These results suggest that enclomiphene is a viable alternative to clomiphene for men seeking selective estrogen receptor modulator based therapy for hypogonadism. Further prospective evaluation is warranted to confirm these findings.