Enclomiphene: The Evidence Card. Every Study, Every Trial, and Why Regulators Said No

Enclomiphene is the (E)-isomer of clomiphene, isolated and developed by Repros Therapeutics as a drug for low testosterone in men under the names Androxal (United States) and EnCyzix (European Union). It is the only compound in this catalogue with a full Phase 3 programme behind it, and its programme ended without approval: the FDA issued a Complete Response Letter in November 2015 and the European Commission refused authorisation in April 2018. This dossier counts every PubMed article and every registered trial that names it, classifies them one by one, and reads the official refusal documents line by line.

Evidence Card version 1.0-rc. Data cut-off 17 October 2026. Prepared by Condor Research Editorial. Conflict of interest: Condor Research sells enclomiphene as a research-use-only compound; see the declaration at the end of the page.

What does the evidence base look like at a glance?

Table 1. The Condor Evidence Index row for enclomiphene before and after the hand recount (units in the first column).

Evidence level in one line: consistent hormonal-marker results in men from the sponsor’s randomised trials; no clinical outcome established; no completed randomised trial without a sponsor link located.

Which studies have given enclomiphene to people?

Three units are kept apart on this page: articles (PubMed records), trials (registered or reported studies; one article can report more than one) and participants (enrolment, which counts every arm). Eight PubMed articles report men who received enclomiphene: seven gave it alone and one (Warren 2026) as part of a multi-ingredient product. Four are randomised and report five trials, because Kim 2016 publishes ZA-304 and ZA-305 together. Reading the full texts closes the mapping to the registry: Wiehle 2014 is ZA-203 (NCT number in the article), Kim 2016 names ZA-304 and ZA-305, and the two articles that carry no identifier match ZA-204 (Wiehle 2013: same design and arm sizes 16, 14, 16 and 14; its July to October 2011 conduct is compatible with, not identical to, the registry’s June to October 2011) and ZA-201 (Kaminetsky 2013: arm sizes 7 and 5, identical to the registry’s groups A and B). The other four are uncontrolled; in Warren 2026 the result cannot be attributed to enclomiphene alone. A ninth article, from Edinburgh in 1989, gave each isomer separately to 19 women; it is listed for completeness as an isomer comparison and is not counted among the eight.¹

Table 2. PubMed articles in which men received enclomiphene: 8 articles (7 with enclomiphene alone, 1 with a multi-ingredient product) reporting 9 trials or case series, since Kim 2016 reports two trials, plus the one isomer-comparison study in women, listed separately. Doses and regimens are deliberately omitted. Enrolled = all arms.

The scope of the independence statement is precise: in PubMed and ClinicalTrials.gov at the cut-off, every published randomised trial of enclomiphene identified in men belongs to the sponsor’s programme, and the only randomised trial registered by anyone else (an infertility study at Baylor College of Medicine) was withdrawn before enrolment. Studies in other registries, conference abstracts or non-indexed journals were not searched. The independent human record located consists of two retrospective cohorts, one case series of a combination product and one case report.

Two meta-analyses pool enclomiphene with clomiphene. One pooled seven before-and-after studies in 292 obese men and reported a testosterone increase with both agents; its full text shows that the enclomiphene data are the four arms of Kim 2016 and Wiehle 2014, both sponsor trials;¹² the other restricted itself to randomised trials and reported higher testosterone, LH and FSH with selective estrogen receptor modulators than with placebo.¹³ Because no randomised enclomiphene trial without a sponsor link was located, the enclomiphene component of any pooled randomised estimate rests on sponsor data.

What the full texts add. Every one of the four randomised articles reports a size that differs from its registry record. Wiehle 2013 states 48 men enrolled while listing arms of 16, 14, 16 and 14 (60, the registry figure). Wiehle 2014 reports 124 enrolled, 120 randomised and 73 completing, against 83 on the registry. Kaminetsky 2013 reports 12 men, while the registry entry it matches lists 17, with a third arm of 5 that the article does not describe. Kim 2016 analyses 256 men (129 and 127 in the intention-to-treat populations, matching the EPAR) against registry enrolments of 120 and 120. Conflict-of-interest reporting is uneven: Kaminetsky 2013 declares two authors as Repros employees and stockholders; Wiehle 2013, with six of nine authors at Repros, prints “None declared”; in Wiehle 2014, four Repros-affiliated authors report “nothing to disclose”, one declares a patent on trans-clomiphene and the Baylor co-author declares Repros consultancy; in Kim 2016, two authors declare Repros consultancy and Repros staff assembled the data.²⁴³⁵

The randomised trials in men measured hormones and sperm. None of the published articles reports a symptom, body-composition or bone outcome.

What did the registered trials find, and where are their results?

ClinicalTrials.gov returns 285 records for “enclomiphene” because it silently adds clomiphene synonyms. Only 29 name the compound; four of those are clomiphene or zuclomiphene trials (zuclomiphene was later tested by Veru as VERU-944). That leaves 25 interventional enclomiphene trials: 24 sponsored by Repros between 2006 and 2017, all completed, with 2,171 enrolments in total (extension studies re-enrol the same men, so this is not a count of people), and one academic infertility trial at Baylor withdrawn before enrolling anyone.¹⁴ The tables below split them by purpose, as registered.

Table 3. Efficacy trials (10). Result column summarises the registry, the EMA assessment report or the article, whichever is most complete. Enrolment is the registry’s actual figure (all arms).

Table 4. Safety and long-term trials (7), including extensions. “est.” marks an estimated enrolment.

Table 5. Clinical pharmacology trials (8). None has a journal article.

Three patterns stand out. First, 5 of the 24 completed sponsor trials (20.8%) have a journal article: ZA-203 by NCT number, ZA-304 and ZA-305 by code, and ZA-201 and ZA-204 by design, dates and arm sizes read from the full texts. All five are Phase 2 or Phase 3 hormone-and-semen trials; none of the seven safety trials or eight pharmacology trials has an article. Second, 14 trials have no results on the registry 11.8 to 19.4 years after completion; for twelve of them the only public trace is a summary inside the EMA refusal report (including the ZA-203 and ZA-301 extensions, EPAR Tables 62 and 65). Results therefore exist in some public form for all 24 trials, but for half of them only in a regulatory report. Third, the two trials that measured what regulators later asked for are among those without a journal article. This page does not infer the direction of any publication bias; no pre-specified criterion for “favourable” was applied.

• ZA-003, the first Phase 3 study (194 men), included validated patient-reported questionnaires. In the EMA’s words, only the testosterone comparator improved the libido component at every time point, and the other questionnaires showed no benefit for enclomiphene over placebo.⁶
• ZA-205, started after the FDA decision, randomised 50 obese men for 48 weeks with lean body mass and strength as primary endpoints. The posted results show no difference from placebo (p-values 0.45 to 0.93) while testosterone rose (p < 0.01).¹⁴
• ZA-301 and ZA-302, the pivotal placebo-controlled trials, met their testosterone endpoint (78.8% and 81.3% of men in range), but 14.2% of enclomiphene-treated men had a fall in sperm concentration of 50% or more, against 2.6% and 4.3% on placebo. In both pivotal studies, non-inferiority on sperm held in the intention-to-treat population and failed in the per-protocol population.⁶

Note on ZA-305. Three figures circulate for the comparator arm. EPAR Table 39 prints 7 of 42 successes “(16.3%)”; 7 of 42 is actually 16.7%, and 7 plus the 36 failures printed in the same column makes 43, not 42, which matches the comparator column of ZA-304 exactly. The EPAR discussion gives 33.3%. Recomputing Table 39’s own p-values (0.0025 chi-square, 0.0047 Fisher, enclomiphene 29 of 44) reproduces them only with 14 of 42, that is 33.3%. The pooled article confirms it independently: Kim 2016 reports a pooled comparator success rate of 24.7%, which is exactly (7 + 14) / (43 + 42); with 7 of 42 it would be 16.5%. This page therefore uses 33.3%. The registry has no posted results for ZA-305.⁶⁵

Why did the FDA and the EMA not approve it?

United States. Repros agreed the design of its pivotal trials with the FDA under a Special Protocol Assessment in July 2012, submitted the New Drug Application on 2 February 2015 and received a goal date of 30 November 2015. An advisory committee planned for 3 November 2015 was cancelled because of questions about bioanalytical method validation that, according to the company, “could affect interpretability of certain pivotal study data”.¹⁵ The Complete Response Letter arrived on 30 November 2015. The company’s announcement says the FDA considered the Phase 3 design “no longer adequate to demonstrate clinical benefit” in light of recent scientific developments, recommended further Phase 3 work, and raised concerns about entry criteria, titration and bioanalytical validation.¹⁶ On 6 December 2016 an FDA advisory committee met to discuss acceptable endpoints for drugs intended for secondary hypogonadism that preserve spermatogenesis;¹⁷ the company reports that the panel voted 16 to 5 that raising testosterone while maintaining spermatogenesis was not sufficient on its own to show clinical benefit.¹⁵

European Union. The marketing authorisation application for EnCyzix, filed by the Repros subsidiary Renable Pharma, reached the EMA on 12 September 2016 for men with secondary hypogonadism and a BMI of at least 25.⁶ After two rounds of questions and an oral explanation, the CHMP adopted a negative opinion on 25 January 2018, by majority, and the European Commission refused the authorisation on 6 April 2018.¹⁸ The refusal documents give three grounds:

1. Surrogate endpoint only. The four pivotal studies (588 patients) showed normalised testosterone, but the CHMP ruled that, given the mechanism, “normalisation of testosterone alone” is not sufficient to demonstrate efficacy. No validated symptom questionnaires or physiological endpoints (body fat, muscle, bone density) were studied in the pivotal studies, and men had been selected on BMI and laboratory values rather than on symptoms. In the applicant’s own review, obesity was the dominant problem in about 70% of participants.⁶
2. Venous thromboembolism. Across the Phase 2 and 3 programme, four thromboembolic events, including one fatal ischaemic stroke, occurred in enclomiphene-treated men and none in the testosterone or placebo arms. All four had other risk factors, which the committee acknowledged while concluding that the risk could not be excluded.⁶
3. Incomplete long-term safety package. Of 1,403 people exposed in Phase 2 and 3, 482 were exposed for more than 6 months and 116 for more than 12 months; the committee also judged the characterisation of human metabolites in the mass-balance study insufficient to support chronic use.⁶

The decision was not unanimous. Five members (from Sweden, Belgium, Hungary, Iceland and the Commission) signed a divergent position arguing that serum testosterone is an accepted biomarker, that the effect was at least as large as an approved testosterone product, and that the thrombotic risk could be managed with product information and post-authorisation studies.⁶ The applicant told the CHMP that no clinical trials or compassionate-use programmes were ongoing.¹⁹ Repros announced the negative opinion on 26 January 2018 while a tender offer for the company by Allergan was under way.²⁰

The EMA did not say enclomiphene fails to raise testosterone. It said raising testosterone was the only thing the pivotal studies had shown.

What is its regulatory status by jurisdiction?

Table 6. Regulatory status by jurisdiction from primary documents, consulted 2026-10-17. Published anti-doping work reports that zuclomiphene remains detectable in urine for months after clomiphene exposure.²⁴

How much literature is there, and what kind?

The PubMed query uses every name that PubChem lists for the E-isomer and its citrate, after removing names that belong to the mixture (clomifene, Clomid, Serophene), a mislabelled synonym (“Cisclomiphene”), a meaningless one (“ISOMER B”) and vendor catalogue codes. It returns 107 articles. For scale, the same database holds 7,653 articles on clomiphene in general, so enclomiphene-specific work is 1.4% of the clomiphene literature.

Table 7. The 107 PubMed articles by model. “Human” means people were enrolled; experiments on human cells or tissue count as in vitro.

Two different literatures share the name. Before 2000, enclomiphene was a laboratory tool: an antiestrogen used to probe estrogen receptors in rat uterus, sheep pituitary or breast cancer cells, usually beside tamoxifen and zuclomiphene. 41 articles compare the two isomers and 33 study enclomiphene as an isolated agent. Since 2009 the profile inverts: 37 articles, of which 13 enrolled people, 10 are reviews and 7 are comments or letters. Where the record carries an affiliation (66 of 107), the first author is in the United States in 37 cases. The most recent animal article reports increased fusion of the interfrontal suture in zebrafish larvae exposed to clomiphene or to enclomiphene, a developmental finding with no human counterpart in the literature located.²⁵

What is enclomiphene, chemically?

Clomiphene is not one molecule. Clomiphene citrate is a mixture of two geometric isomers around a chloro-substituted carbon-carbon double bond, and US labelling specifies that it contains between 30% and 50% of the cis (Z) isomer, zuclomiphene.²⁶ The remaining 50% to 70% is the trans (E) isomer, enclomiphene. Both share formula C₂₆H₂₈ClNO and connectivity; they differ only in whether the chlorine sits on the same side of the double bond as the aminoethoxyphenyl ring (Z) or opposite it (E).²⁷

Table 8. Identity and comparative pharmacokinetics of the two isomers, as reported in the cited sources. PK rows come from different populations and designs and are not directly comparable.

The isomer distinction explains why an isolated enclomiphene was developed at all. Zuclomiphene is cleared so slowly that, in men with at least six weeks of clomiphene exposure, it dominated serum about 20 to 1;³² and in a chronic study in male mice by the developer’s scientists, the adverse effects on Leydig cells, epididymis and seminal vesicles tracked zuclomiphene, not enclomiphene.³⁴ The argument for a single-isomer preparation is older than that programme: it was set out for ovulation induction in 1993.²⁹ The EMA, however, concluded in 2018 that enclomiphene “is considered to not be a new active substance”, because it does not differ significantly from the clomiphene already authorised in the EU.⁶

Mechanistically, both isomers bind estrogen receptors. Enclomiphene behaves mainly as an antagonist at the hypothalamus and pituitary, which removes estradiol’s negative feedback on gonadotropin release; LH and FSH rise and the testes produce more testosterone.³⁵ In the developer’s Phase 3 trials, LH and FSH rose with enclomiphene and fell with the testosterone comparator, which is the pharmacological signature of the two approaches.⁵

A trap in the older literature. Before 1976 the antiestrogenic isomer (then called isomer B, today enclomiphene) was labelled cis and the estrogenic isomer A (today zuclomiphene) was labelled trans. X-ray crystallography by Ernst and colleagues showed that the correct structures “are the reverse of those previously assigned”.³⁶ A 1977 article accordingly describes zuclomiphene as “formerly called trans-clomiphene”,³⁷ and a 1993 review restates the relabelling.²⁹ Ten articles in this census use cis/trans labels from before the correction: in each, “trans” should be read as zuclomiphene and “cis” as enclomiphene. Nine compare both isomers, so the reversal changes which isomer produced which effect but not their inclusion; the tenth (PMID 61699), indexed as enclomiphene literature, studied only the then “trans” isomer and is therefore about zuclomiphene. Even after the correction, the field disagreed about which isomer mattered: a 1986 pharmacokinetic study called zuclomiphene the “active” isomer,²⁸ while the 1989 Edinburgh study and the 1993 review concluded that enclomiphene drives follicular development.¹²⁹ The confusion persists in databases: PubChem lists “trans-Clomiphene” as a synonym of enclomiphene and “Transclomiphene” as a synonym of zuclomiphene.²⁷ The E/Z descriptor is unambiguous and is the only one used in this dossier.

In analytical terms, the EMA assessment records that zuclomiphene is treated as an isomeric impurity of enclomiphene citrate and is “routinely controlled by HPLC”, and that the substance crystallises consistently as one polymorph (Form I).⁶ Separation of the two isomers has been described by capillary electrophoresis³⁸ and by LC-MS in patient plasma,³⁹ and their amorphous states differ measurably.⁴⁰

What does this literature allow us to say, and what not?

1. It allows: in men with low testosterone and low or normal LH, serum testosterone rose relative to placebo in every placebo-controlled trial with published or posted results (ZA-203, ZA-301, ZA-302, ZA-304, ZA-305), with LH and FSH rising where reported. The two randomised trials without placebo (ZA-201, ZA-204) compared enclomiphene with a testosterone product and with baseline: testosterone was similar to the comparator, while LH rose only with enclomiphene. Over 16 weeks, sperm concentration was better maintained than with the testosterone comparator (Tables 2 and 3).
2. It does not allow any claim about symptoms, sexual function, body composition, strength or bone. The only sponsor trial with validated questionnaires (ZA-003) and the only one with lean mass and strength as primary endpoints (ZA-205) did not separate from placebo, and neither has a journal article.
3. Independence is the weakest link. The published randomised trials identified in men (4 articles, 5 trials, all now matched to sponsor registry records) and 24 of the 25 registered trials come from one developer; the 25th was withdrawn. Their articles report conflicts unevenly and all four disagree with the registry on enrolment. The independent human record located is two retrospective cohorts, one case series of a combination product and one case report.
4. “Preserves sperm” is narrower than usually written. It holds against testosterone products in 16-week trials; against placebo, one in seven enclomiphene-treated men in the pivotal studies had a sperm drop of 50% or more, and non-inferiority failed per protocol in both.
5. The results exist, but mostly outside journals. 5 of 24 completed sponsor trials (20.8%; 3 of 24 by explicit identifier) have an article, all efficacy trials; 10 (41.7%) have registry results; 12 are visible only through the EMA refusal report. Every trial has some public result.
6. The thrombotic signal is open, not closed. Four events, all on enclomiphene, in a programme with 116 people exposed for more than a year. No published study located since 2018 has measured it.
7. Most of the 107 articles are not about enclomiphene as a drug. 62 are animal or in vitro work, mostly before 2000; 8 of the 17 articles that enrolled people concern clomiphene. Only 8 of 107 (7.5%) report men given enclomiphene, one of them in combination.
8. Synonym hygiene changes the numbers by an order of magnitude. An unfiltered synonym list doubled the PubMed count, and registry term expansion multiplied the trial count by ten.

What is still unknown?

• Whether enclomiphene changes any patient-relevant outcome in an adequately powered randomised trial without a sponsor link.
• The incidence of venous thromboembolism and erythrocytosis beyond 12 months of exposure.
• The full set of circulating human metabolites, which the EMA judged incompletely characterised.
• The full results of ZA-003, ZA-303 (52-week bone density, 300 men) and the extension studies, which exist only as EPAR summaries.
• Effects in men who are not overweight: every pivotal trial enrolled men with a BMI of 25 or more.
• Whether any developer will run the trial both regulators described: symptom-selected men, validated patient-reported outcomes and physiological endpoints. None was located on ClinicalTrials.gov at the cut-off.
• The legal reach of clomifene entries in national lists over the isolated E-isomer.

How was this dossier built?

Synonyms. PubChem CID 1548953 (98 synonyms) and the citrate CID 6420009 (75 synonyms) were downloaded on 2026-10-17. Accepted for PubMed: enclomiphene, enclomifene, trans-clomiphene, trans-clomifene, transclomiphene, (E)-clomiphene, E-clomiphene, en-clomiphene, clomiphene B, Androxal, Enclomid. Rejected: Clomifene, Clomifeno, Clomifenum, Clomid, Serophene (names of the mixture); Cisclomiphene (the Z-isomer, listed in error); ISOMER B (107 PubMed hits, none about clomiphene); RMI 16,289 and ICI 46476 (0 hits); vendor and screening codes.

PubMed query (E-utilities, 2026-10-17): enclomiphene[all] OR "trans-clomiphene"[tiab] OR transclomiphene[tiab] OR "trans-clomifene"[tiab] OR androxal[tiab] OR enclomid[tiab] OR "en-clomiphene"[tiab] OR "E-clomiphene"[tiab] OR "(E)-clomiphene"[tiab] OR "clomiphene B"[tiab] OR "trans-clomiphene citrate"[tiab], 107 records. Reference queries: clomiphene clomiphene[tiab] OR clomifene[tiab] OR "Clomiphene"[mh], 7,653; zuclomiphene zuclomiphene[all] OR "cis-clomiphene"[tiab] OR "cis-clomifene"[tiab], 58.

Classification and reliability. Each article was coded from title, abstract, MeSH, affiliations and conflict statements for model, role (isolated enclomiphene, combination, isomer comparison, clomiphene mixture, secondary literature, zuclomiphene mislabelled, tangential) and link to the developer (Repros authors, Repros trial data, none visible), following a written codebook published with the dataset. A random sample of 40 articles (37% of the census; seed 20261017) was coded a second time, blind to the first coding. Agreement was 100% for model (Cohen’s kappa 1.00), 97.5% for role (kappa 0.97) and 100% for link to the developer (kappa 1.00). The one disagreement (PMID 6781360) was adjudicated to “isolated enclomiphene”. Both codings were done by language-model instances working from the same codebook, the second in a separate session that saw only the codebook and the 40 records; this measures consistency of the coding rules, not agreement between two human experts.

Trials. ClinicalTrials.gov API v2, query.term and query.intr for enclomiphene, Androxal, trans-clomiphene, enclomiphene citrate, enclomifene, Enclomid and zuclomiphene; the union (285 records) was filtered to those whose protocol text names the compound (29). Publications were matched by NCT number or trial code in the article, or, where the article carries no identifier, by design, dates and arm sizes read from the full text.

Full texts. Eleven full texts were read: Ernst 1976, Mikkelson 1986, Adashi 1993, Young 1999, Kaminetsky 2013, Wiehle 2013, Wiehle 2014, Kim 2016, Rodriguez 2016, Helo 2017 and Tienforti 2023 (Rodriguez 2016 replaces Hill 2009, whose full text was not obtained). Every sentence citing them was rechecked against the text. All other articles were classified from title and abstract.

Sensitivity of the headline numbers. Excluding the article that is really about zuclomiphene leaves 105; excluding all pre-1977 cis/trans articles leaves 97. Men given enclomiphene: 7 articles if the combination product is excluded, 9 if the isomer comparison in women is added. Sponsor share of randomised articles in men: 4 of 4 as coded, 3 of 4 if Kim 2016 (sponsor trials, investigator authors) were counted as independent. Trials with a journal article: 3 of 24 (12.5%) if only explicit identifiers count, 5 of 24 (20.8%) with the two full-text matches. Trials with any public results, counting EPAR summaries: 24 of 24.

Regulatory documents. EMA medicine page, refusal Q&A and public assessment report EMA/88321/2018; Repros Therapeutics filings on SEC EDGAR (8-K of 1 December 2015 and 26 January 2018; 10-K filed 31 March 2017); Federal Register notice 2016-22925; FDA 503A list; WADA 2026 Prohibited List; Slov-Lex text of Act 397/2015.

Limitations. Classification is from abstracts, not full texts; 41 articles have no affiliation in PubMed, so country and authorship links are incomplete for older work. A link to the developer is coded only when visible in authorship or trial codes; undisclosed funding would be missed. Negative statements mean “not located in PubMed or ClinicalTrials.gov at 2026-10-17”; other registries, conference abstracts and grey literature were not searched. The FDA letter has not been published, so its content is known through the company’s summary; the panel vote is reported by the company. EPAR result tables are images and were read for text only. All four randomised articles report enrolment figures that differ from the registry; this page gives both.

Data and code. The classified census with authors and affiliations, every table on this page, the 25-trial table, the codebook, the double-coding sample and agreement, all queries and the scripts that rebuild every number and figure are published with this page: dataset.json (CC BY 4.0, with data dictionary) and the scripts folder.

How to cite this page

Condor Research Editorial. Enclomiphene Evidence Card, version 1.0-rc, data cut-off 17 October 2026. https://condorresearch.com/research/what-is-enclomiphene/ . Dataset: dataset.json, version 1.0-rc, CC BY 4.0.

Changelog. Version 1.0-rc2 (18 October 2026): RUO review wording changes. Version 1.0-rc (17 October 2026): ZA-203 and ZA-301 extensions reclassified as summarised in the EPAR (12 EPAR-only, 0 without public results); first conclusion rewritten by trial design; combination product separated wherever “eight” appears; Kim 2016 enrolment discrepancy added; ZA-204 dates described as compatible; Key findings box added. Version 0.95 (17 October 2026): eleven full texts read; ZA-201 and ZA-204 matched to their articles, raising the publication rate to 5 of 24; enrolment and conflict-of-interest discrepancies added; ZA-305 comparator figure confirmed by the pooled article; direction of the 1976 cis/trans correction stated and the ten affected articles re-read; isomer table extended with descriptive pharmacokinetics; Tienforti 2023 enclomiphene inputs identified. Version 0.9 (17 October 2026): first evidence-card version of this URL, replacing the June 2026 explainer; census recounted by hand; double coding added; articles, trials and participants reported as separate units; ZA-305 comparator figure reconciled against the EPAR’s own p-values; publication rate given as a range.

Related on this site. A mechanism-level comparison with another catalogue compound is in Tesofensine vs Enclomiphene. The research material is listed at Enclomiphene (research compound).

References

1. Glasier AF, Irvine DS, Wickings EJ et al. A comparison of the effects on follicular development between clomiphene citrate, its two separate isomers and spontaneous cycles. Hum Reprod. 1989;4(3):252-6. PMID 2497133. DOI 10.1093/oxfordjournals.humrep.a136882.
2. Wiehle R, Cunningham GR, Pitteloud N et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU Int. 2013;112(8):1188-200. PMID 23875626. DOI 10.1111/bju.12363.
3. Kaminetsky J, Werner M, Fontenot G et al. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628-35. PMID 23530575. DOI 10.1111/jsm.12116.
4. Wiehle RD, Fontenot GK, Wike J et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-7. PMID 25044085. DOI 10.1016/j.fertnstert.2014.06.004.
5. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-85. PMID 26496621. DOI 10.1111/bju.13337.
6. European Medicines Agency. EnCyzix (enclomifene): EPAR public assessment report, EMA/88321/2018. CHMP opinion 25 January 2018; published 20 April 2018. Source. Accessed 17 October 2026.
7. Thomas J, Suarez Arbelaez MC, Narasimman M et al. Efficacy of Clomiphene Citrate Versus Enclomiphene Citrate for Male Infertility Treatment: A Retrospective Study. Cureus. 2023;15(7):e41476. PMID 37546076. DOI 10.7759/cureus.41476.
8. Saffati G, Kassab J, Orozco Rendon D et al. Safety and efficacy of enclomiphene and clomiphene for hypogonadal men. Transl Androl Urol. 2024;13(9):1984-1990. PMID 39434750. DOI 10.21037/tau-24-238.
9. Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-7. PMID 27337642. DOI 10.1080/14656566.2016.1204294.
10. Warren S. Changes in Serum Testosterone After Sublingual Enclomiphene Citrate Combined With a Mineral Oxide Delivery System: A Retrospective Case Series of 15 Men. Cureus. 2026;18(5):e109299. PMID 42170362. DOI 10.7759/cureus.109299.
11. Tariq MN, Abdel Halim AT, Evans JA. Newly Detected Atrial Flutter After Enclomiphene Dose Escalation in a Patient With Prior Mitral Valve Repair and Chronic Immune Thrombocytopenia: A Case Report. Cureus. 2026;18(8):e114562. PMID 42741668. DOI 10.7759/cureus.114562.
12. Tienforti D, Castellini C, Di Giulio F et al. Selective modulation of estrogen receptor in obese men with androgen deficiency: A systematic review and meta-analysis. Andrology. 2023;11(6):1067-1076. PMID 36604313. DOI 10.1111/andr.13373.
13. Hohl A, Chavez MP, Pasqualotto E et al. Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials. Arch Endocrinol Metab. 2025;69(5). PMID 41066380. DOI 10.20945/2359-4292-2025-0093.
14. ClinicalTrials.gov API v2: records naming enclomiphene (25 interventional trials; NCT numbers in Table 5), including posted results for NCT02651688 (ZA-205). Source. Accessed 17 October 2026.
15. Repros Therapeutics Inc. Form 10-K for fiscal year 2016, filed 31 March 2017. SEC EDGAR. Source. Accessed 17 October 2026.
16. Repros Therapeutics Inc. Form 8-K, Exhibit 99.1: Repros Therapeutics Receives Complete Response Letter From FDA for Enclomiphene. 1 December 2015. SEC EDGAR. Source. Accessed 17 October 2026.
17. Federal Register 2016-22925. Bone, Reproductive and Urologic Drugs Advisory Committee; Notice of Meeting (6 December 2016). Published 23 September 2016. Source. Accessed 17 October 2026.
18. European Medicines Agency. EnCyzix: medicine overview (refused), EMEA/H/C/004198; opinion adopted 25/01/2018, refusal 06/04/2018. Source. Accessed 17 October 2026.
19. European Medicines Agency. Questions and answers on refusal of the marketing authorisation for EnCyzix (enclomifene), EMA/CHMP/54473/2018. Source. Accessed 17 October 2026.
20. Repros Therapeutics Inc. Form 8-K, Exhibit 99.1: Repros Announces Negative Opinion From the EMA for Enclomiphene. 26 January 2018. SEC EDGAR. Source. Accessed 17 October 2026.
21. US Food and Drug Administration. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the FD&C Act (categories list, updated 14 May 2026). Source. Accessed 17 October 2026.
22. World Anti-Doping Agency. International Standard: Prohibited List 2026, in force 1 January 2026 (class S4.2). Source. Accessed 17 October 2026.
23. Foster J, Choo L, Patel A et al. British Society of Sexual Medicine: Position Statement for the Potential Use of Enclomiphene in the Treatment of Male Hypogonadism. World J Mens Health. 2026;44(3):480-483. PMID 41714894. DOI 10.5534/wjmh.250395.
24. Miller GD, Moore C, Nair V et al. Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males. J Clin Endocrinol Metab. 2019;104(3):906-914. PMID 30295816. DOI 10.1210/jc.2018-01159.
25. Franz-Odendaal TA, Bezuhly M. Clomiphene Citrate and Enclomiphene Hydrochloride Exposure Is Associated With Interfrontal Suture Fusion in Zebrafish. Plast Surg (Oakv). 2023;31(4):383-389. PMID 37915340. DOI 10.1177/22925503211057526.
26. Clomid (clomiphene citrate) prescribing information, Cosette Pharmaceuticals; DailyMed set ID 2ca373c1-4dba-4126-8616-5c533d606fe5; Description and Clinical Pharmacology sections (label effective 31 January 2025). Source. Accessed 17 October 2026.
27. PubChem. Enclomiphene, CID 1548953; enclomiphene citrate, CID 6420009; zuclomiphene, CID 1548955. National Library of Medicine. Source. Accessed 17 October 2026.
28. Mikkelson TJ, Kroboth PD, Cameron WJ et al. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986;46(3):392-6. PMID 3091405. DOI 10.1016/s0015-0282(16)49574-9.
29. Adashi EY. Clomiphene citrate: the case for a monoisomeric preparation. Baillieres Clin Obstet Gynaecol. 1993;7(2):331-47. PMID 8358894. DOI 10.1016/s0950-3552(05)80134-8.
30. Ghobadi C, Mirhosseini N, Shiran MR et al. Single-dose pharmacokinetic study of clomiphene citrate isomers in anovular patients with polycystic ovary disease. J Clin Pharmacol. 2009;49(2):147-54. PMID 19033451. DOI 10.1177/0091270008328096.
31. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril. 1999;71(4):639-44. PMID 10202872. DOI 10.1016/s0015-0282(98)00537-8.
32. Helo S, Mahon J, Ellen J et al. Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment. BJU Int. 2017;119(1):171-176. PMID 27511863. DOI 10.1111/bju.13625.
33. Jordan VC, Haldemann B, Allen KE. Geometric isomers of substituted triphenylethylenes and antiestrogen action. Endocrinology. 1981;108(4):1353-61. PMID 6781873. DOI 10.1210/endo-108-4-1353.
34. Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice. BJU Int. 2016;117(2):344-50. PMID 26220499. DOI 10.1111/bju.13244.
35. Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. IDrugs. 2009;12(2):109-19. PMID 19204885.
36. Ernst S, Hite G, Cantrell JS et al. Stereochemistry of geometric isomers of clomiphene: a correction of the literature and a reexamination of structure-activity relationships. J Pharm Sci. 1976;65(1):148-50. PMID 1255423. DOI 10.1002/jps.2600650140.
37. Ramsey RB, Fischer VW. Effects of zuclomiphene in combination with triparanol and ay-9944 on developing rat CNS morphology and biochemistry. Acta Neuropathol. 1977;39(1):97-100. PMID 70952. DOI 10.1007/BF00690391.
38. Bempong DK, Honigberg IL. Multivariate analysis of capillary electrophoresis separation conditions for Z-E isomers of clomiphene. J Pharm Biomed Anal. 1996;15(2):233-9. PMID 8933425. DOI 10.1016/0731-7085(96)01853-5.
39. Crewe HK, Ghobadi C, Gregory A et al. Determination by liquid chromatography-mass spectrometry of clomiphene isomers in the plasma of patients undergoing treatment for the induction of ovulation. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;847(2):296-9. PMID 17085084. DOI 10.1016/j.jchromb.2006.10.019.
40. Trubert J, Garda MR, Matkovska L et al. Comparison between Amorphous States of the Trans/Cis Isomers of Clomiphene: Similarities and Differences. Mol Pharm. 2025;22(11):6932-6940. PMID 41071236. DOI 10.1021/acs.molpharmaceut.5c00888.

Declaration of interest. Condor Research sells enclomiphene as a research-use-only laboratory compound and therefore has a commercial interest in this topic. The page was prepared by Condor Research Editorial; no external funding was received. Every count can be rebuilt from the published dataset and scripts. Enclomiphene is not an approved medicine in the United States or the European Union, and the material Condor Research supplies is for laboratory research use only: not for human or veterinary use or diagnostic application. The human studies and trials on this page are summarised as published literature and regulatory record.