Enclomiphene Citrate Autoimmune Disease Considerations

What is enclomiphene and what is it approved for?

Enclomiphene is an oral selective estrogen receptor modulator (SERM) that blocks estrogen receptors in the pituitary, raising LH and FSH and testosterone production [1]. It is not approved by the FDA or in the EU [1][2]. FDA's 2022 advisory-committee presentation says no FDA-approved drugs contain enclomiphene as an active ingredient; the EMA refused marketing authorisation for EnCyzix (enclomifene) in 2018 [1][2].

What did regulators flag?

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, PSA and hematocrit, and no long-term safety data; the EMA noted a slightly higher rate than with testosterone [1]. The EMA refusal was based on four main studies in 588 patients and cited a risk of venous thromboembolism [2].

What about autoimmune disease specifically?

The 2016 phase 3 report measured testosterone, LH, FSH and sperm concentration and does not report immune outcomes [5]. Two parallel phase 3 studies compared enclomiphene with AndroGel 1.62% over 16 weeks; testosterone rose in all groups, LH and FSH rose with enclomiphene and fell with testosterone gel, and sperm concentration stayed normal on enclomiphene while spermatogenesis fell markedly on the gel [5].

What does the clomiphene label add?

The FDA label is for Clomid (clomiphene citrate), which is approved only for ovulatory dysfunction in women desiring pregnancy [3]. Clomiphene citrate is a mixture of the two isomers, enclomiphene and zuclomiphene, which are related but are not the same drug [1]. The label has no male indication, states there are no adequate or well-controlled studies demonstrating effectiveness in male infertility, and reports testicular tumors and gynecomastia in men using clomiphene, with cause and effect not known [3]. Its contraindications include liver disease or a history of liver dysfunction, uncontrolled thyroid or adrenal dysfunction, and pituitary tumor [3]. These are statements about the mixture and have not been shown for enclomiphene alone.

Compounding status

FDA lists enclomiphene citrate in Category 1 as a bulk drug substance under evaluation, an enforcement-discretion position rather than approval or a finding of safety [4]. Compounded enclomiphene has not been FDA-reviewed for safety, effectiveness or quality [6].