Enclomiphene Citrate and Prednisone Interaction: What Patients and Clinicians Need to Know

Is there a documented interaction between enclomiphene citrate and prednisone?

We found no published study that tested enclomiphene citrate together with prednisone. Enclomiphene is not an FDA-approved drug, so there is no enclomiphene label with a drug interactions section [1]. The closest approved relative, clomiphene citrate, is a different product: a mixture of enclomiphene and zuclomiphene, approved only for ovulatory dysfunction in women who want to become pregnant, with no male indication [1][8]. Male use of clomiphene is off-label, and its label states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility [8]. A clomiphene label is not an enclomiphene label.

The pituitary axis: where prednisone and enclomiphene meet

According to a review of the mechanism, glucocorticoids act on reproduction at three levels: they decrease the synthesis and release of GnRH from the hypothalamus, they inhibit the synthesis and release of LH and FSH from the pituitary, and they act directly on the testis and ovary [2].

Enclomiphene blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH, which signal the testes to make testosterone and keep making sperm [1]. The two drugs therefore act on parts of the same hormone pathway, in opposite directions at the pituitary.

What enclomiphene does on its own is well described. In the ZA-301 trial, 151 overweight men with secondary hypogonadism took 12.5 mg or 25 mg daily or placebo for 12 weeks, and 78.8% of men on enclomiphene (95% CI 70.3 to 85.3) reached a normal 24-hour average testosterone [10]. ZA-302, 181 men with the same design, reported 81.3% (95% CI 73.9 to 87.0) [11]. In the two 16-week studies that compared enclomiphene with testosterone gel, LH and FSH rose on enclomiphene and fell on the gel [12].

Blood sugar: prednisone is the drug that moves it

A review of glucocorticoid-induced hyperglycemia calls it common in people with and without diabetes. It puts the odds ratio for new-onset diabetes at roughly 1.5 to 2.5, with total dose and duration the strongest predictors [4].

In a hospital review of 50 patients with glucose data who received at least 40 mg a day of prednisone or equivalent for two or more days, 32 (64%) had at least one glucose reading of 200 mg/dL or higher, and 19 of the 34 patients with no diabetes history (56%) had hyperglycemia at least once [13]. That was a small single-center review of high-dose inpatient use, not a study of outpatient courses.

The publicly posted enclomiphene phase 3 results describe hormone and sperm outcomes [10][11].

Blood clots: two separate signals

FDA's 2022 safety review of enclomiphene listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, among its concerns [1]. EMA's refusal of the European application cited a risk of venous thromboembolism and noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [6].

Short oral corticosteroid courses have their own signal. In a US claims study of 1,548,945 adults, the rate of venous thromboembolism during the 30 days after starting a short oral corticosteroid course was 3.33 times the rate during the comparison period for the same patients (95% CI 2.78 to 3.99), and the excess diminished over the following 31 to 90 days [3]. That was an observational, self-controlled design, so it shows an association rather than proof of cause.

Bone: what oral corticosteroids do, and what the guideline advises

Fracture risk with oral corticosteroids is dose dependent. In a UK general practice cohort of 244,235 oral corticosteroid users and matched controls, the relative rate of vertebral fracture was 1.55 below 2.5 mg a day of prednisolone, 2.59 at 2.5 to 7.5 mg, and 5.18 at 7.5 mg or more; hip fracture went from 0.99 to 1.77 to 2.27 across the same bands [5]. In the US claims study, fracture rates were 1.87 times higher in the 30 days after a short oral steroid course began [3].

The 2022 American College of Rheumatology guideline covers adults who will take at least 2.5 mg a day of glucocorticoids for more than 3 months. It strongly recommends assessing fracture risk as soon as steroids start, using a clinical fracture assessment, bone density with vertebral fracture assessment or spinal x-ray, and FRAX if the patient is 40 or older, plus drug treatment for those at medium, high or very high risk [14]. Enclomiphene's public trial reports describe hormone and sperm outcomes, not bone density [10][11].

Enclomiphene doses and side effects

A phase 2 dose-finding study tested 6.25, 12.5 and 25 mg once daily for 6 weeks [7]. The phase 3 protocols used 12.5 mg once daily, increased to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [10]. No FDA-approved dose exists [1].

Reported side effects included headache, hot flushes, nausea and muscle spasm; reported reasons for stopping included blurred vision, muscle spasm, headache and aggression [11]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo, and nausea by 4 of 112 and 3 of 47 [11].

Regulatory status

Enclomiphene is not approved by FDA or EMA [1][6]. In June 2022, FDA's advisory committee voted 4 yes and 8 no on adding enclomiphene citrate to the list of bulk substances that can be used in compounding, with members who voted no citing a lack of clinical efficacy evidence [15]. FDA's list places it in Category 1, bulk drug substances under evaluation, which means enforcement discretion under stated conditions rather than approval [16]. In January 2018, the CHMP refused marketing authorisation for EnCyzix in Europe, based on four main studies in 588 patients. The studies showed higher testosterone but did not look at whether symptoms improved, and there was a risk of venous thromboembolism [6]. A 2026 British Society of Sexual Medicine position statement advises use only by experienced clinicians in specialist or research settings, noting that long-term efficacy and safety data are lacking [17].