Enclomiphene Citrate Cancer Risk Signal Review

Does enclomiphene increase cancer risk?

The enclomiphene trials were built around hormones and sperm, so they do not show whether it affects cancer risk one way or the other. Two parallel phase 3 trials reported by Kim and colleagues in BJU International in 2016 compared enclomiphene with testosterone gel 1.62% in overweight men aged 18 to 60 with secondary hypogonadism for 16 weeks [1]. Total testosterone rose in all groups, LH and FSH rose with enclomiphene and fell with testosterone gel, and sperm concentration stayed in the normal range on enclomiphene while testosterone gel caused a marked reduction in spermatogenesis [1].

A smaller phase 2b study followed 12 men for six months. Sperm counts rose in 7 of 7 men on enclomiphene at three months, and testosterone fell back to pre-treatment values one month after stopping [2].

The phase 3 results posted for ZA-301 and ZA-302 cover 12 weeks. ZA-301 enrolled 151 men; 78.8% on enclomiphene reached a normal average 24-hour testosterone (95% CI 70.3 to 85.3; n=113), and sperm concentration fell by 50% or more in 14.2% on enclomiphene versus 2.6% on placebo [5]. ZA-302 enrolled 181 men; 81.3% reached normal testosterone (95% CI 73.9 to 87.0; n=134), and sperm fell by 50% or more in 14.2% versus 4.3% [6]. A separate open-label safety study, ZA-300, followed 499 men aged 18 to 65 for six months on 12.5 or 25 mg daily [18].

What the regulators found

FDA's 2022 advisory committee presentation lists the safety concerns from published trials, adverse event reports and EMA's review: 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 [3].

EMA's CHMP adopted a negative opinion on 25 January 2018, recommending refusal of marketing authorisation for EnCyzix. Its reasons were that the studies showed higher testosterone but did not test whether symptoms improved, and that there was a risk of venous thromboembolism. The review was based on four main studies in 588 patients [4].

FDA's 2015 complete response letter for Androxal, as FDA later summarised it, said the phase 3 design was not adequate to demonstrate clinical benefit and raised concerns about entry criteria, titration and bioanalytical method validation [3]. The reasons given concerned trial design, symptom benefit and venous thromboembolism [3][4]. FDA's May 2018 guidance on secondary hypogonadism, as described by FDA in 2022, also says semen-parameter changes alone are not enough to establish efficacy [3].

Why clomiphene data do not answer the question for enclomiphene

Clomiphene citrate is a mixture of two isomers, enclomiphene (trans) and zuclomiphene (cis). FDA's summary of the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [3]. They are related but not the same drug.

The Clomid label is approved only for ovulatory dysfunction in women desiring pregnancy. It has no male indication and states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility [7].

The label's postmarketing section lists neoplasms among reported adverse reactions, including liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma), breast (fibrocystic disease, breast carcinoma), endometrium (endometrial carcinoma) and ovary (ovarian carcinoma). These are voluntary reports from a population of uncertain size, and the label says it is not always possible to establish a causal relationship [7].

The same label says epidemiology data suggest prolonged clomiphene use may increase the risk of a borderline or invasive ovarian tumour [7]. A 2019 Cochrane review of ovarian stimulating drugs for subfertility, covering 13 case-control and 24 cohort studies and 4,684,724 women, reported that two cohort studies found increased invasive ovarian cancer in exposed subfertile women. One reported a hazard ratio of 1.93 (95% CI 1.18 to 3.18), with higher risk in women who remained nulligravid after clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) than in multiparous women (HR 1.52, 95% CI 0.67 to 3.42); this was very low-certainty evidence [8].

The pharmacokinetics differ. Enclomiphene has a half-life of about 10 hours [3]. The label states zuclomiphene has a longer half-life than enclomiphene and that detectable zuclomiphene persisted for longer than a month in single-dose studies [7].

Testosterone, PSA and the prostate

Enclomiphene raises endogenous testosterone, and because of its pituitary mechanism LH and FSH rise too [11]. In testosterone therapy trials, a 2005 meta-analysis of 19 randomised placebo-controlled trials (651 men on testosterone, 433 on placebo) found more prostate events with testosterone (OR 1.78, 95% CI 1.07 to 2.95). Rates of prostate cancer, PSA above 4 ng/mL and prostate biopsies were numerically higher but not individually statistically significant. Testosterone-treated men were nearly four times as likely to have a hematocrit above 50% (OR 3.69, 95% CI 1.82 to 7.51) [12]. That meta-analysis tested testosterone, not enclomiphene.

The Endocrine Society's 2018 guideline recommends against starting testosterone therapy in men with breast or prostate cancer [13]. That guideline covers testosterone therapy, not enclomiphene.

Side effects and label warnings

The most frequent side effects reported in the phase 3 programme were headache, hot flushes, nausea and muscle spasm; reasons for stopping included blurred vision, muscle spasm, headache and aggression. In ZA-302, headache occurred in 7 of 112 men on 12.5 mg versus 1 of 47 on placebo, and nausea in 4 of 112 versus 3 of 47 [6].

The Clomid label describes visual symptoms such as blurring, spots or flashes. It says these are usually reversible but reports that they can sometimes persist. That warning applies to clomiphene, a mixture, and has not been established for enclomiphene alone [7]. The label's contraindications for clomiphene include liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumour and pregnancy [7].

Compounded enclomiphene products have not been reviewed by FDA for safety, effectiveness or quality [14]. FDA lists enclomiphene citrate in Category 1, bulk drug substances under evaluation, and in 2022 its advisory committee voted 4 yes and 8 no on adding it to the allowed list [15][16].

Bottom line

Enclomiphene's documented safety issues are the ones regulators listed: cardiac and thromboembolic events, raised estradiol, raised PSA and raised hematocrit [3]. The 2026 BSSM position statement advises use only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [17].