Enclomiphene Citrate Non-Responder Profile: Who Does Not Respond and Why

What does non-response mean in the enclomiphene trials?

The two 12-week phase 3 trials, ZA-301 and ZA-302, enrolled overweight men aged 18 to 60 with acquired hypogonadotropic hypogonadism, morning testosterone under 300 ng/dL and normal sperm concentration [2][3]. Men took enclomiphene 12.5 mg or 25 mg once daily, or placebo [2][3]. The trials' success measure was an average 24-hour testosterone in the normal range of 300 to 1040 ng/dL, not a symptom score [2].

In ZA-301, 78.8% of men on enclomiphene reached that target (95% CI 70.3 to 85.3, n=113) [2]. In ZA-302, 81.3% did (95% CI 73.9 to 87.0, n=134) [3]. The remaining men did not meet the trial definition. These percentages apply only to the men who received enclomiphene, 113 in ZA-301 and 134 in ZA-302. The full trials also included placebo groups, so the figures are not a response rate for everyone enrolled and not a general non-response rate for every man who takes enclomiphene [2][3].

A hormone target is also not the same as feeling better. FDA's 2015 complete response said the phase 3 design was not adequate to demonstrate clinical benefit and raised concerns about entry criteria, titration and bioanalytical method validation [1]. EMA's 2018 refusal said the studies showed higher testosterone but did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved [4]. FDA's 2018 guidance on secondary hypogonadism says it is unclear whether raising testosterone in this population gives clinical benefit, and that semen changes alone are not enough to establish efficacy [1].

Who is the clearest non-responder?

Men with primary hypogonadism, meaning testicular failure. Enclomiphene is an oral SERM that blocks estrogen receptors in the pituitary. Estrogen normally suppresses the pituitary-testis axis, so the pituitary releases more LH and FSH, which tells the testes to make more testosterone and keep making sperm [1]. This treats secondary (hypogonadotropic) hypogonadism, where the testes are healthy but under-stimulated. It would not be expected to work in primary hypogonadism [1]. The phase 3 trials enrolled men with secondary hypogonadism, so they did not test this group [2][3].

Are there other confirmed predictors?

The trials did not establish whether age, BMI or baseline hormone levels predict who will miss the testosterone target [2][3]. The group percentages are the only guide they give. Both trials enrolled overweight men aged 18 to 60 with morning testosterone under 300 ng/dL, so the results describe that group rather than every man who takes enclomiphene [2][3].

Does the dose explain non-response?

Enclomiphene has no FDA-approved dose [1]. The phase 2 dose-finding trial tested 6.25, 12.5 and 25 mg once daily for 6 weeks [5]. The phase 3 protocols used 12.5 mg once daily, with up-titration to 25 mg daily at week 6 if morning testosterone stayed below 300 ng/dL [2]. The trials do not establish whether dose or titration explains why some men miss the testosterone target.

What about sperm count?

Enclomiphene preserved sperm concentration in the phase 3 comparison with testosterone gel, while testosterone gel caused a marked reduction in spermatogenesis [6]. In the placebo-controlled trials, sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo in ZA-301, and 14.2% versus 4.3% in ZA-302 [2][3]. So sperm concentration did fall substantially in some men on enclomiphene.

If clomiphene did not work, does enclomiphene?

Clomiphene citrate is a mixture of enclomiphene and zuclomiphene; the two are related but not the same drug [1]. Clomiphene is FDA-approved only for ovulatory dysfunction in women, and its label states that there are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility [7].

A retrospective study of 66 men who took clomiphene and later enclomiphene found a median testosterone rise of 166 ng/dL on enclomiphene versus 98 ng/dL on clomiphene (P=0.20), an estradiol change of -5.92 versus +17.50 pg/mL (P=0.001), and fewer side effects on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44) [8]. It was not randomized, so it does not show that a man who did not respond to clomiphene will respond to enclomiphene.

What safety issues are known?

The most frequent side effects in phase 3 and EMA data were headache, hot flushes, nausea and muscle spasm; reasons for stopping included blurred vision, muscle spasm, headache and aggression [3]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg versus 1 of 47 on placebo, and nausea by 4 of 112 versus 3 of 47 [3].

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA, raised hematocrit and no long-term safety data [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone; cataracts were seen in nonclinical studies and were not conclusively linked in people, and EMA wanted ocular monitoring [1]. The 2026 British Society of Sexual Medicine position statement says long-term efficacy and safety data are lacking and advises use only by experienced clinicians in specialist or research settings [9].

Where the drug stands

FDA's advisory-committee presentation says no FDA-approved drugs contain enclomiphene as an active ingredient [1]. The sponsor's new drug application for Androxal received a complete response letter in 2015, and no FDA approval has followed [1]. EMA's committee adopted a negative opinion on EnCyzix in January 2018 [4]. The British Society of Sexual Medicine statement says the manufacturer discontinued development in 2021 [9].

At the FDA Pharmacy Compounding Advisory Committee in June 2022, FDA proposed that enclomiphene citrate not be added to the list of allowed bulk substances; the committee voted 4 yes, 8 no [10]. FDA lists enclomiphene citrate in Category 1, bulk drug substances under evaluation [11]. Compounded enclomiphene products have not been reviewed by FDA for safety, effectiveness or quality [12].