Enclomiphene Citrate Appetite & Cravings Changes: What the Evidence Shows

Does enclomiphene change appetite or cravings?

Enclomiphene is an oral selective estrogen receptor modulator (SERM): it blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH, which tells the testes to make more testosterone [1].

FDA's May 2018 guidance, as described by FDA in 2022, says it is unclear whether raising testosterone in secondary hypogonadism produces clinical benefit, and that trials should show meaningful improvement in at least one symptom or sign [1]. EMA's committee, recommending refusal of EnCyzix in January 2018, noted that the studies showed higher testosterone but did not examine whether symptoms improved, across four main studies in 588 patients [2].

What the trials measured

ZA-302 was a randomized, double-blind, placebo-controlled phase 3 trial in 181 men (112 on 12.5 mg, 22 on 25 mg, 47 on placebo) over 12 weeks. Normal-range average 24-hour testosterone of 300 to 1,040 ng/dL was reached by 81.3% of men on enclomiphene (95% CI 73.9 to 87.0); sperm concentration fell by 50% or more in 14.2% on enclomiphene versus 4.3% on placebo [3].

ZA-304 and ZA-305 compared two enclomiphene doses with AndroGel 1.62% in overweight men aged 18 to 60 with secondary hypogonadism over 16 weeks. Total testosterone rose in all groups; LH and FSH rose with enclomiphene and fell with the gel; sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on the gel [4].

What the side-effect lists say

The most frequent side effects 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].

Clomiphene citrate, the two-isomer mixture, has a separate record. Its FDA label lists appetite increase among events reported in fewer than 1% of patients in clinical trials, alongside weight gain/loss [5]. That label covers clomiphene tablets, approved only for ovulatory dysfunction in women who want to become pregnant, and it states that no adequate or well-controlled studies show clomiphene works in male infertility [5].