Enclomifene

Identity, and the isomer it was separated from

Clomifene citrate, the ovulation-induction agent, is a mixture of two geometric isomers: zuclomifene, the cis or (Z) form, and enclomifene, the trans or (E) form. PubChem holds the free base as CID 1548953, formula C26H28ClNO, molecular weight 406.0, CAS 15690-57-0, UNII R6D2UI4FLS. The citrate salt is CID 6420009, C32H36ClNO8, 598.1 g/mol, CAS 7599-79-3, UNII J303A6U9Y6. The FDA Global Substance Registration System gives the free base a calculated mass of 405.9605, records the INN enclomifene under INN code 2334, and carries the old research designation ICI-46476. It is a triphenylethylene small molecule, not a peptide. Enclomifene is one half of a marketed medicine rather than a compound of its own.

PubChem's synonym list for CID 1548953, the record whose IUPAC name specifies the (E) configuration, carries the bare name clomifene, the label clomiphene trans-form, and, contradicting both, cisclomiphene. Its ChEMBL cross-reference, CHEMBL954, is assigned to the (E) isomer by two independent registries: the FDA Global Substance Registration System record for UNII R6D2UI4FLS carries codeSystem ChEMBL, code CHEMBL954, while PubChem's stereo-unspecified mixture record, CID 2800, carries CHEMBL2355051 instead. The ChEMBL API could not be reached this session to confirm what the CHEMBL954 record itself contains. A name-based search still returns entries describing three different things: the pure trans isomer, the isomeric mixture dispensed as clomifene citrate, and on one line the cis isomer that makes up the rest of it. The two views of the same record diverge.

Two official statements of the trans proportion exist, and neither reduces to a single number. The FDA-approved clomifene citrate tablet label describes a mixture of the two geometric isomers "containing between 30% and 50% of the cis-isomer", a range rather than a figure, and gives no trans percentage at all. FDA's 2022 evaluation memorandum states the other side of it directly, citing the United States Pharmacopeia monograph: the content of enclomifene citrate in clomifene citrate is in the range of about 50% to 70%. Two sources, one range, no fixed value. Secondary sources almost uniformly report a single precise pair of numbers instead, and that claim is recorded in the untraced list below with the search that failed to place it.

What the Repros trials measured

The phase 2b trial ZA-203 (NCT01270841) randomised men with morning total testosterone below 250 ng/dL to oral enclomifene citrate 12.5 mg, oral enclomifene citrate 25 mg, 1% topical testosterone gel, or placebo for three months, under the development code Androxal and the sponsorship of Repros Therapeutics. Posted results give mean change in morning total testosterone at three months of +258.5 ng/dL (SD 201.5) at 12.5 mg, +197.3 (162.6) at 25 mg, +253.7 (292.3) on the gel and −16.9 (47.5) on placebo. Luteinising hormone moved in opposite directions: +4.8 and +6.9 mIU/mL on the two oral arms, −2.4 on the gel.

Of 151 men randomised in ZA-301 (NCT01532414), the phase 3 trial with posted results, 78.8% of the pooled enclomifene subjects (95% CI 70.3 to 85.3) reached a 24-hour average testosterone inside 300 to 1040 ng/dL at twelve weeks. Arm sizes were 92, 21 and 38. The second co-primary endpoint ran the other way. A fall of 50% or more in sperm concentration at twelve weeks was recorded in 14.2% of the pooled enclomifene subjects against 2.6% of placebo subjects, a difference in the direction opposite to the way the compound is usually summarised.

ZA-302 has no ClinicalTrials.gov record at all and survives only in the European dossier, which describes its design as identical to ZA-301's. One hundred and thirty-four men were randomised to enclomifene and 47 to placebo for twelve weeks, with a six-month extension phase. One hundred and nine of the 134, or 81.3% (95% Wilson score interval 73.9 to 87.0), achieved a 24-hour average testosterone in the normal range (EMA/88321/2018, pp. 70 to 72). Nothing from this trial has been posted to a registry or published in a peer-reviewed journal.

Kim and colleagues published the two remaining registered phase 3 trials, ZA-304 and ZA-305, together in 2016. Across 256 overweight men aged 18 to 60 treated for sixteen weeks with enclomifene citrate in a fixed lower-dose arm (n=43), an up-titrated higher-dose arm (n=42), topical testosterone gel (n=85) or placebo (n=86), total testosterone rose in every active arm, LH and FSH rose on enclomifene and fell on the gel, and sperm concentration was maintained on enclomifene but not on the gel. The values the paper reports only as directions appear in the European assessment report: in ZA-304, 63.4% of enclomifene subjects reached the normal testosterone range against 44.2% on gel and 4.4% on placebo. Adverse events judged possibly, probably or definitely drug-related occurred in 53 of 256 men, and two deaths occurred, both in the fixed lower-dose arm.

Pharmacokinetics were characterised in a separate phase 2 study. Wiehle and colleagues randomised 48 men, 44 completing per protocol, to enclomifene citrate at 6.25, 12.5 or 25 mg or to transdermal testosterone, sampling testosterone and LH hourly for 24 hours at baseline and again at six weeks. Mean trough testosterone at day 42 was 604 ± 160 ng/dL on 25 mg against 500 ± 278 ng/dL on transdermal testosterone, a difference that was not significant (p = 0.23). Time to peak drug concentration was two to three hours. Effects on LH and testosterone persisted at least a week after treatment stopped.

The endpoint that stopped the programme

An advisory committee meeting scheduled for November 2015 to review NDA 207959 was cancelled over questions about bioanalytical method validation that arose late in the review. In December 2015 Repros announced a Complete Response Letter stating that the design of the phase 3 studies was no longer adequate to demonstrate clinical benefit and recommending an additional phase 3 study or studies. The letter also raised concerns about study entry criteria, titration and bioanalytical method validation across the phase 3 programme. FDA's own 2022 evaluation memorandum reproduces this sequence and cites the company's SEC filings for it.

A year later the Bone, Reproductive and Urologic Drugs Advisory Committee was convened on the general question rather than the product. Asked whether raising serum testosterone into the normal range and maintaining sperm concentration is sufficient to establish clinical benefit in men with hypogonadism attributed to obesity, a majority voted that it is not. The same committee voted that raising sperm concentration above a threshold would not establish benefit either, and that pregnancy outcomes would be required. FDA's May 2018 guidance made the position explicit: serum testosterone is not a validated surrogate endpoint in this population.

European review reached the same place on independent evidence. Renable Pharma applied in 2016 for authorisation of enclomifene under the name EnCyzix. The Committee for Medicinal Products for Human Use adopted a negative opinion on 25 January 2018 and the European Commission refused authorisation on 6 April 2018. The assessment report concluded that although testosterone rose, there was no evidence of clinically meaningful benefit on the recognised signs and symptoms of secondary hypogonadism, that validated patient-reported outcome measures were lacking from the pivotal programme supporting the proposed indication, and that participants had not been recruited on the basis of symptoms at all.

Validated symptom instruments were administered once in the development record, in a supportive study. ZA-003 enrolled 194 men aged 18 to 68 and used the International Index of Erectile Function, the Sexual Desire section of the Derogatis Interview for Sexual Function, and the Male Sexual Distress Scale IV-A. On the libido component of the IIEF only the testosterone gel arm improved significantly at every time point; on erectile function only the placebo group did; and on the Derogatis and Male Sexual Distress instruments every group including placebo improved significantly. CHMP recorded that the other instruments used in that study "were not able to show any benefit" for enclomifene against placebo (EMA/88321/2018, pp. 84 and 90). The compound was tested on this question and did not separate from placebo.

The isomer argument, and what carries it

Fontenot and colleagues gave male mice enclomifene citrate or zuclomifene citrate by oral gavage at 4 and 40 mg/kg/day against placebo across five groups. Effects on Leydig cells, epididymis, seminal vesicles and kidneys, and changes in serum testosterone, FSH and LH, were reported with zuclomifene only; the enclomifene arms showed no change in testicular histology. The authors read the result as justifying a monoisomeric preparation. Group sizes were not stated in the record retrieved for this page, so the sample behind that separation is not established here.

Helo and colleagues measured both isomers directly in men. Fifteen men taking clomifene citrate 25 mg daily for at least six weeks had median serum enclomifene of 2.2 ng/mL and median zuclomifene of 44.0 ng/mL, a ratio of roughly 20 to 1 in favour of the isomer with the longer residence time. Age, body mass index, duration of treatment and serum testosterone predicted neither concentration. Median total testosterone in the same men had risen from 205.0 to 488.0 ng/dL on treatment, and median oestradiol from 17.0 to 34.0 pg/mL.

Which isomer does the work was not always answered the same way. Mikkelson and colleagues, reporting single-dose pharmacokinetics of 50 mg clomifene citrate in 24 healthy adult female volunteers in 1986, described the Z isomer as the active one and the E isomer as inactive, the reverse of the modern framing. The only clinical comparison of the two in men is not a trial: Saffati and colleagues reviewed 66 patients at one academic centre prescribed clomifene and later enclomifene, using the clomifene period as the baseline for the second. Sequence was not randomised and assessment was not blinded.

Adverse events on the record

The largest safety dataset is an open-label study, ZA-300 (NCT01534208), which followed 499 men aged 18 to 65 for 26 weeks. Posted results record serious adverse events in 6 of 207 men on 12.5 mg and 9 of 283 on 25 mg. FDA's summary of those reports lists bradycardia, atrial flutter, chest pain, transient ischaemic attack, pulmonary embolism, two deep vein thromboses, seminoma, diverticulitis and hypotension. The three most frequent non-serious events across both arms were upper respiratory tract infection (53), headache (35) and muscle spasms (22); hot flush and daytime urinary frequency, the two of mechanistic interest, were recorded 11 times each, behind sinusitis (13) and influenza (12). Causality assessments are not published for these events, and FDA noted that no corresponding publication exists.

Thromboembolism is the signal both regulators singled out. The EMA assessment recorded four thromboembolic events across the programme, one of them fatal, with none in the testosterone or placebo arms despite a population already at elevated risk. Cardiac disorders, raised haematocrit, raised prostate-specific antigen, eye disorders and psychiatric disorders were reported more often on enclomifene than on placebo. EMA did not resolve whether the clots were attributable to the drug itself, to rising testosterone and erythropoiesis, to rising oestradiol, or to the comorbidity of an overweight middle-aged cohort. FDA's adverse event database held no reports for enclomifene citrate when searched through 13 October 2021.

In a 26-week oral rat study no no-adverse-effect level could be assigned: prostate, seminal vesicle and coagulating gland atrophy, Leydig cell atrophy and depletion, and renal tubular dilatation appeared at 0.5, 5 and 10 mg/kg/day, every dose tested. A nine-month oral dog study set a no-adverse-effect level of 2 mg/kg/day, with high-dose deaths attributed to hepatotoxicity and cataracts reported at mid and high dose. A peer review characterised the lens finding as minimal fibre swelling that did not progress between the thirteen-week and nine-month necropsies.

The trials that reported only to a regulator

ZA-303 (NCT01619683) was a single-blind, placebo-controlled phase 3 study of 52 weeks of enclomifene citrate in 300 overweight men, with bone mineral density as its primary outcome and no other registered trial asking that question. It completed in September 2014. The registry record has not been updated since 29 September 2014 and carries no posted results, and a PubMed search combining enclomifene with bone and with bone mineral density returns no records. The results are not absent from the public record, though: the European assessment report summarises the study and presents change from baseline in testosterone and in bone mineral density as Tables 58 and 59 (EMA/88321/2018, p. 82). Both tables are images in the published PDF, and no numeric values can be extracted from them.

ZA-304 and ZA-305 (NCT01993212 and NCT01993225) carry no posted results on ClinicalTrials.gov either, and their endpoint values reached the public record through the European dossier rather than through the registry (EMA/88321/2018, pp. 103 and 106). Registry figures do not always agree with one another. ZA-203's enrolment field reads 83, its posted baseline table counts 121, and its own participant-flow module counts 124 started and 73 completed, the same pair FDA's memorandum reports. Where those three disagree, this page reports each rather than choosing between them.

Four further enclomifene studies exist only in the European dossier. ZA-302, a pivotal phase 3, and ZA-202, an exploratory glycaemic-control study in men with type 2 diabetes, have no ClinicalTrials.gov record. ZA-003, 194 men aged 18 to 68, was initially planned as a phase 3 and later treated by the applicant as supportive; 63.8% and 64.0% of its two enclomifene arms reached the defined physiological testosterone range at three months against 22.4% on placebo. Three 12-month open-label extension studies followed ZA-003, ZA-203 and the ZA-301/302 pair. EMA recorded 1403 people exposed to enclomifene across phase 2 and phase 3, 482 of them for more than six months and 116 for a year or more.

Regulatory position

No FDA-approved drug product contains enclomifene citrate as an active ingredient. A compounding pharmacy nominated the substance in 2015 for the section 503A bulk drug substances list under docket FDA-2015-N-3534. FDA evaluated it and recommended against inclusion. The Pharmacy Compounding Advisory Committee voted on 8 June 2022: four in favour of adding it to the list, eight against, none abstaining. Members voting against cited a lack of clinical efficacy evidence. The member voting in favour argued from the existence of a United States Pharmacopeia monograph for clomifene citrate, the mixture that contains it. The only published clinical report of a compounded enclomifene preparation is a retrospective series of 15 men given a sublingual multi-ingredient product, uncontrolled, with neither LH nor FSH measured, whose author states that causality cannot be determined.

FDA's stated grounds were narrower than a safety veto. The substance was found to be well characterised and expected to be stable under ordinary storage when protected from light. The nonclinical profile was described as exaggerated pharmacology of the drug class rather than unexpected toxicity. Clinical safety concerns were listed as cardiac and thromboembolic events, elevated oestradiol, raised prostate-specific antigen and raised haematocrit, alongside limited pharmacokinetic data in renal and hepatic impairment. On effectiveness the memorandum concluded that the available information was insufficient, and stated its reasoning as uncertainty rather than as a settled negative: it is unclear whether increasing testosterone concentrations alone in men with secondary hypogonadism equates to clinical effectiveness or confers clinical benefit. The stronger claim belongs to the separate May 2018 guidance.

On the FDA list updated 14 May 2026, enclomifene citrate remains in 503A Category 1, substances under evaluation. It is not on the bulks list and it is not in Category 2, the group FDA has flagged for significant safety risks. FDA also recorded that outsourcing facility reporting from January 2017 to June 2021 contained no compounded products containing it, and that neither the European nor the Japanese pharmacopoeia carries a monograph. One registered trial of an isolated clomifene isomer outside the Repros programme has posted results, and it studied the other isomer: NCT03646162 lists its intervention as VERU-944, other name zuclomiphene citrate, with the derived MeSH term D064696 Zuclomiphene. Selective oestrogen receptor modulators are prohibited in sport; Miller and colleagues found zuclomifene detectable in urine from 121 to more than 261 days after a 30-day course of clomifene.

What is not known

The published record establishes what happens to three hormones and one semen parameter over sixteen weeks, and very little else. Validated symptom instruments were administered in exactly one study, ZA-003, where enclomifene did not separate from placebo on any of them and the comparator gel separated on one; no pivotal trial supporting the proposed indication used a validated patient-reported outcome at all, which is the specific gap both regulators cited when refusing it. No trial has measured pregnancy, live birth or time to conception. The longest exposure with any public result is 52 weeks, from ZA-303, whose bone mineral density table survives only as an unreadable image in the European assessment report; the longest with posted registry results is 26 weeks, from an open-label safety study with no control arm, and EMA recorded 116 people exposed for a year or more. Three of the five phase 3 registry records carry no posted results, and two further pivotal or supportive studies, ZA-302 and ZA-003, have no registry record at all. Pharmacokinetics are incomplete by the EMA's own assessment: exposure is higher in hepatic and renal impairment without characterised consequences, dose adjustment for poor CYP2D6 metabolisers is uncharacterised, and the possibility of a unique human metabolite of significance has not been excluded. The terminal half-life quoted everywhere traces to a paper not indexed in PubMed. Four thromboembolic events including one death were recorded across the programme with none on comparator or placebo, and no study has been powered to determine whether that is attributable to the compound. Trial populations were overweight men with functional rather than structural hypogonadism, with age ceilings of 60 in the pivotal 16-week trials, 65 in ZA-203 and ZA-300, and 68 to 69 in ZA-003 and its extension; nothing addresses men with classical hypogonadism. Enclomifene is not an approved medicine in any jurisdiction, and material obtained outside a registered trial has not been subject to the identity, purity or sterility controls that apply to investigational supply.

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