Enclomiphene (INN: enclomifene) is the trans isomer of clomiphene, the fertility drug sold as Clomid. It is a selective estrogen receptor modulator (SERM): it blocks estrogen’s “brake” on the brain and pituitary, so the body makes more luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the testes in turn make more testosterone and sperm. Repros Therapeutics developed it as Androxal for men with low testosterone of pituitary or hypothalamic origin (secondary hypogonadism).
The single most important fact is that no regulator has approved it. The FDA never approved the US application, and in January 2018 the European Medicines Agency’s committee recommended refusing the EU application (as EnCyzix). It found that the trials raised testosterone but did not show benefits on symptoms, and it flagged a possible risk of blood clots. In the US it is available off-label through compounding pharmacies. It is also sold online as a “testosterone booster”, and no trial has studied it for recovery after anabolic steroid use.
This page summarizes what the clinical trials, the EMA assessment and the FDA’s compounding review report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Nonsteroidal selective estrogen receptor modulator (SERM); trans isomer of clomiphene |
| Development names | Androxal (Repros Therapeutics, US); EnCyzix (Renable Pharma, EU application) |
| Route | Oral, once daily |
| Doses in trials | 6.25, 12.5 and 25 mg enclomiphene citrate daily; EU application proposed 8.5 and 17 mg capsules of enclomifene base |
| Half-life (EMA) | 8–10 h from plasma |
| Main effect | Raises LH, FSH and the body’s own testosterone; sperm counts are generally kept |
| US status | Not FDA-approved; FDA advisers voted 8–4 in 2022 against adding it to the 503A compounding list; under FDA evaluation as of May 2026 |
| EU status | CHMP negative opinion, January 25, 2018 |
| Anti-doping | Covered by section S4 of the WADA Prohibited List as a component of clomiphene, per the US Department of Defense’s Operation Supplement Safety |
What it is
Clomiphene citrate is a mixture of two geometric isomers. The FDA-approved Clomid label states that it contains 30–50% of the cis isomer (zuclomiphene), with the rest being the trans isomer (enclomiphene) (Clomid label). Enclomiphene is that trans isomer on its own.
Chemically, enclomiphene is (E)-2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine: formula C₂₆H₂₈ClNO, molecular weight 406.0 g/mol (PubChem). In trials it was given as the citrate salt, molecular weight 598.1 g/mol (PubChem). The base therefore makes up about 68% of the salt’s weight. This explains why the EU application used 8.5 mg and 17 mg capsules: they hold the same amount of enclomiphene as the 12.5 mg and 25 mg citrate doses used in US trials (EMA assessment report).
The two isomers behave differently:
| Isomer | Main action | Persistence |
|---|---|---|
| Enclomiphene (trans) | Estrogen receptor antagonist at the hypothalamus and pituitary; raises LH and FSH | Half-life of 8–10 h |
| Zuclomiphene (cis) | More estrogen-like (agonist) activity | Detectable for longer than a month after a single dose, per the Clomid label |
This mismatch has real effects in men taking clomiphene. In 15 men on clomiphene 25 mg daily for at least 6 weeks, the median blood level was 44.0 ng/mL for zuclomiphene and 2.2 ng/mL for enclomiphene, a 20:1 ratio (Helo et al., BJU Int 2017). The idea behind enclomiphene was to give the isomer that raises testosterone without the slowly accumulating one.
Animal data supported this idea but do not prove it in people. In male mice, zuclomiphene caused marked changes in the Leydig cells (the testosterone-producing cells), epididymis, seminal vesicles and kidneys, while enclomiphene did not change testicular tissue (Fontenot et al., BJU Int 2016). This study was run by the drug’s developer.
How it works in the body
In men, estradiol made from testosterone signals the hypothalamus and pituitary to cut LH and FSH output. Enclomiphene blocks that signal. The result is the reverse of testosterone therapy:
- Testosterone therapy raises blood testosterone but suppresses LH and FSH. Without them, the testes make less testosterone and less sperm.
- Enclomiphene raises LH and FSH, so the testes make more testosterone themselves, and sperm production is kept going.
Because of this mechanism, enclomiphene only works if the testes and pituitary can respond. It was studied only in secondary hypogonadism, not in testicular failure (primary hypogonadism).
Pharmacokinetics
The fullest pharmacokinetic data are in the EMA’s public assessment report on the EU application (EMA, 2018):
| Parameter | Finding |
|---|---|
| Time to peak (single dose) | About 2 h fasted, 2.5 h with food (median) |
| Effect of food | Slightly higher peak and exposure; not considered clinically important |
| Elimination half-life | 8–10 h |
| Main metabolism | CYP2D6 (to 4-hydroxy-enclomiphene) and CYP3A4/5 (to desethyl-enclomiphene) |
| Excretion | 71% of a radiolabeled dose recovered in 7 days: 61.5% in feces, 8.2% in urine |
| CYP2D6 poor metabolizers | Peak about 5× higher and total exposure about 7× higher (3 subjects) |
| Moderate or severe kidney impairment | Exposure about 2.1–2.5× higher |
An in-vitro study with human liver microsomes had already shown that CYP2D6 is mainly responsible for breaking down enclomiphene (Ghobadi et al., Drug Metab Pharmacokinet 2008). The EMA also noted that enclomiphene inhibits CYP2D6 in vitro, so it could raise levels of other drugs cleared by that enzyme.
The short half-life does not match the drug’s effects. In a 6-week trial, testosterone and LH stayed raised for at least a week after the last dose, and drug levels did not return to baseline within 24 hours of a dose (Wiehle et al., BJU Int 2013).
About the half-life. A half-life of several days does not fit the regulatory data, which put enclomiphene at 8–10 hours. Multi-week persistence belongs to zuclomiphene, the other isomer in clomiphene.
Regulatory status
United States
No enclomiphene product is FDA-approved. A review of the program describes the history this way (Rodriguez et al., Expert Opin Pharmacother 2016):
- In 2007 the FDA did not accept a rise in testosterone alone as enough to approve a non-testosterone drug for hypogonadism.
- A November 2015 FDA meeting to review the new drug application was canceled over concerns about how the drug-level assays had been validated.
US government and specialist sources report that development was discontinued in 2021 (Operation Supplement Safety; Foster et al., World J Mens Health 2026).
Compounding pharmacies may make drugs only from certain bulk substances. On June 8, 2022, the FDA proposed that enclomiphene citrate not be added to the list of bulk substances allowed under section 503A. The Pharmacy Compounding Advisory Committee voted 8–4 against adding it, with several members citing a lack of clinical efficacy evidence (FDA PCAC minutes). In FDA’s list updated May 14, 2026, enclomiphene citrate remains in Category 1, “under evaluation” (FDA 503A categories). FDA uses this category in its interim compounding policy while it decides.
It cannot legally be sold as a dietary supplement ingredient. Products are nonetheless sold online as “testosterone boosters” or “research chemicals” (Operation Supplement Safety).
European Union and UK
On January 25, 2018, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended refusing EnCyzix for overweight men up to 60 years old with secondary hypogonadism (EMA). Its main reasons were:
- the trials showed higher testosterone but did not test whether symptoms such as libido, erectile function, bone strength or weight improved;
- for most participants the dominant problem was obesity, and it was unclear whether they were truly hypogonadal or had first tried diet and exercise;
- venous thromboembolism (blood clots in the veins) occurred only in enclomiphene-treated patients.
The drug is unlicensed in the UK. A 2026 British Society for Sexual Medicine position statement advises against routine use outside specialist settings. It says that, where it is prescribed, experienced clinicians should manage it, ideally within research frameworks (Foster et al., World J Mens Health 2026).
What the research shows
Almost all controlled data come from the developer’s own trial program in men with secondary hypogonadism, many of them overweight. Trials ran from 6 weeks to 4 months. No trial measured muscle, strength or body composition, and none studied men recovering from anabolic steroid use.
Testosterone levels
In a phase II pharmacokinetic and pharmacodynamic trial, 44 men with testosterone under 350 ng/dL were randomized to enclomiphene citrate 6.25, 12.5 or 25 mg daily or to testosterone gel for 6 weeks (Wiehle et al., BJU Int 2013). The share of men whose 24-hour average testosterone ended above 300 ng/dL was:
| Group | n | 24-h mean testosterone over 300 ng/dL |
|---|---|---|
| Enclomiphene 6.25 mg | 12 | 7 (58%) |
| Enclomiphene 12.5 mg | 7 | 5 (71%) |
| Enclomiphene 25 mg | 12 | 12 (100%) |
| Testosterone gel | 13 | 11 (85%) |
Morning testosterone at day 42 was 604 ± 160 ng/dL on 25 mg and 500 ± 278 ng/dL on the gel (p = 0.23). LH and FSH rose on enclomiphene and fell on the gel.
Two placebo-controlled phase III trials (ZA-301 and ZA-302) treated overweight men for 12 weeks, starting at 12.5 mg and increasing to 25 mg if needed (EMA, 2018):
| Trial | n on enclomiphene / placebo | 24-h average testosterone in normal range (300–1,040 ng/dL) on enclomiphene |
|---|---|---|
| ZA-301 | 113 / 38 | 78.8% (95% CI 70.3–85.3%) |
| ZA-302 | 134 / 47 | 81.3% (95% CI 73.9–87.0%) |
Meta-analyses agree that these drugs raise testosterone:
- All SERM trials. A 2025 meta-analysis of randomized trials pooled clomiphene and enclomiphene. Compared with placebo, they raised total testosterone by 274 ng/dL (95% CI 192–356), LH by 4.7 IU/L and FSH by 4.6 IU/L. Testosterone did not differ significantly from testosterone gel (Hohl et al., Arch Endocrinol Metab 2025).
- Obese men. A 2023 meta-analysis of obesity-related low testosterone found a pooled rise of 7.50 nmol/L (≈216 ng/dL; 95% CI 6.52–8.48 nmol/L) with enclomiphene 12.5–25 mg daily over 1.5–4 months (Tienforti et al., Andrology 2023).
Sperm production
Keeping fertility is the main argument for enclomiphene over testosterone. Two 16-week phase III trials (ZA-304 and ZA-305) compared enclomiphene, testosterone gel 1.62% and placebo in overweight men with normal starting sperm counts (Kim et al., BJU Int 2016; numbers from the EMA assessment report):
| Outcome at 16 weeks | Enclomiphene | Testosterone gel | Placebo |
|---|---|---|---|
| ZA-304: n | 41 | 43 | 45 |
| ZA-304: mean change in sperm concentration | +11.7% | −56.6% | +4.1% |
| ZA-304: testosterone in normal range | 63.4% | 44.2% | 4.4% |
| ZA-305: n | 44 | 42 | 41 |
| ZA-305: mean change in sperm concentration | +15.2% | −32.8% | −7.6% |
| ZA-305: testosterone in normal range | 68.2% | 45.2% | 7.3% |
Sperm counts were not always fully preserved. In ZA-301, sperm concentration fell by 50% or more in 14.2% of men on enclomiphene vs 2.6% on placebo. The EMA concluded that enclomiphene “might not consistently preserve sperm function”.
A small earlier study is the closest to men stopping testosterone. It treated 12 men who had been on testosterone gel (Kaminetsky et al., J Sex Med 2013):
- On enclomiphene, sperm concentrations were 75–334 million/mL in 7 of 7 men at 3 months and 6 of 6 at 6 months.
- On the gel, none of 5 men exceeded 20 million/mL at 3 months.
- Testosterone fell back to pretreatment levels one month after treatment stopped.
Symptoms, body composition and the post-cycle question
There is no controlled evidence that enclomiphene improves symptoms. The pivotal trials did not use validated questionnaires on libido, erectile function or mood. In one supporting study (ZA-003), only testosterone gel improved the libido domain of the International Index of Erectile Function, and enclomiphene was no better than placebo on the other patient-reported measures (EMA, 2018). Effects on fat, muscle, strength and bone density were not studied.
No published trial has tested enclomiphene for recovering hormone production after anabolic steroid use (post-cycle therapy). Any claims for that use are extrapolated from its effect on LH and FSH in men with intact but underactive pituitary signaling.
Enclomiphene vs clomiphene
No randomized head-to-head trial exists. In a retrospective review, 66 men were switched from clomiphene to enclomiphene (Saffati et al., Transl Androl Urol 2024):
- the median testosterone rise was 166 ng/dL on enclomiphene vs 98 ng/dL on clomiphene, a difference that was not significant (p = 0.20);
- estradiol changed by −5.9 vs +17.5 pg/mL;
- documented side effects were less frequent on enclomiphene (OR 0.18; 95% CI 0.07–0.44).
The design (same men, sequential drugs, chart review) means these differences may reflect selection and timing rather than the drug.
Side effects and risks
The EMA reviewed safety data on 1,403 people who took enclomiphene in phase II and III trials. Of these, 482 were treated for more than 6 months and 116 for 12 months or longer (EMA, 2018). Rare or long-term harms could not have been detected in a database this size.
Common effects
In the pooled phase II/III data:
| Measure | Enclomiphene | Testosterone gel (AndroGel) | Placebo |
|---|---|---|---|
| Treatment-emergent adverse events | 17.7% | 19.7% | 8.7% |
| Hot flushes (at least possibly related) | 1.1% | 0% | 0.5% |
| Stopped because of an adverse event | 5.3% | 5.4% | 1.5% |
The most frequent adverse events were headache, hot flushes, nausea and muscle spasms. Blurred vision, muscle spasm, headache and aggression were the most common reasons for stopping. Estradiol rose significantly on both enclomiphene and testosterone gel.
Blood clots
The trials recorded four thromboembolic events, all in patients taking enclomiphene:
- one deep vein thrombosis (DVT) with pulmonary embolism;
- two DVTs;
- one fatal ischemic stroke, in a man with untreated atrial fibrillation.
None occurred on testosterone or placebo. All four patients had other risk factors, and one had a hematocrit (the share of blood made up of red cells) of 55.4% before the event. The EMA noted that SERMs as a class are linked to venous and arterial clots. It judged that a raised risk “cannot be excluded” and named it as a main reason for refusal.
Eyes
Clomiphene’s label warns of blurred vision and other visual symptoms, which increase with total dose and duration (Clomid label). For enclomiphene, cataracts were a topic of special interest after a signal in a dog toxicology study. In the trials:
- eye disorders overall were not more frequent than on placebo (1.6% vs 2.4%);
- “cataract” (0.3% vs 0%) and “vision blurred” (0.5% vs 0%) were reported somewhat more often as at least possibly drug-related (EMA, 2018).
Heart rhythm and other findings
- QT interval. Thorough QT studies found no meaningful QT prolongation at 25 mg or 100 mg. At 250 mg, about 10 times the highest trial dose, QTcF rose by up to 12.2 ms (EMA, 2018).
- Cardiac events. Cardiac events were reported in 1.0% of enclomiphene patients vs 0.4% on placebo in the placebo-controlled pool.
- Hematocrit and PSA. Both can rise as testosterone rises. PSA (prostate-specific antigen) increases were similar to AndroGel.
- IGF-1. In the 6-week trial, IGF-1 (a marker of growth hormone activity) fell from about 94–101 to 50–62 µg/L on enclomiphene, more than on testosterone gel (Wiehle et al., BJU Int 2013). The clinical meaning is unknown.
Interactions and who was excluded
- CYP2D6. Strong CYP2D6 inhibitors, and genetic poor metabolizers, raise exposure severalfold. Enclomiphene itself inhibits CYP2D6 in vitro.
- Kidney and liver disease. Exposure roughly doubles in moderate or severe kidney impairment. Data in liver impairment are limited, and the EMA asked for more.
- Trial exclusions. The phase III trial ZA-301 excluded men with a hematocrit over 54%, uncontrolled hypertension or diabetes, symptomatic cataracts or retinal vein occlusion.
- Clomiphene’s contraindications. The Clomid label lists liver disease or a history of liver dysfunction, uncontrolled thyroid or adrenal dysfunction, and an organic intracranial lesion such as a pituitary tumor.
Key takeaways
- The trans half of clomiphene. Enclomiphene is the estrogen-blocking isomer of Clomid, given alone to avoid the long-lasting zuclomiphene isomer.
- Raises testosterone by restarting the axis. In trials, 12.5–25 mg daily brought most men with secondary hypogonadism into the normal range while raising LH and FSH.
- Usually spares sperm, unlike testosterone. Sperm counts held steady on average while testosterone gel cut them by 33–57%. However, about 1 in 7 men on enclomiphene had a drop of 50% or more in one trial.
- Short half-life. Plasma half-life is 8–10 hours, not days. It is cleared mainly by CYP2D6.
- Benefit on symptoms is unproven, and clots are a concern. Regulators found no evidence of better libido, energy or body composition. All four clot events in the trials occurred on enclomiphene.
- Not approved anywhere. FDA never approved it, the EMA’s committee recommended refusal in 2018, and its US compounding status is still under FDA evaluation.
Sources
- European Medicines Agency. EnCyzix (enclomifene): assessment report, EMA/88321/2018. Committee for Medicinal Products for Human Use; 2018. EMA.
- European Medicines Agency. EnCyzix: refusal of marketing authorisation (CHMP negative opinion, January 25, 2018). EMA.
- Food and Drug Administration. Final summary minutes of the Pharmacy Compounding Advisory Committee meeting, June 8, 2022. FDA.
- Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (updated May 14, 2026). FDA.
- Cosette Pharmaceuticals. Clomid (clomiphene citrate tablets, USP) prescribing information. DailyMed.
- National Center for Biotechnology Information. Enclomiphene, PubChem CID 1548953; enclomiphene citrate, PubChem CID 6420009. PubChem; PubChem.
- Operation Supplement Safety (Uniformed Services University, US Department of Defense). Clomiphene and enclomiphene: drugs, not dietary supplements. Content current as of January 12, 2026. OPSS.
- 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):1188–1200. PubMed; PMC.
- Kaminetsky J, Werner M, Fontenot G, Wiehle RD. 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):1628–1635. PubMed.
- 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):677–685. PubMed.
- Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561–1567. PubMed; PMC.
- 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):e250093. PubMed.
- 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. PubMed.
- 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. PubMed; PMC.
- 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. PubMed.
- Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS. CYP2D6 is primarily responsible for the metabolism of clomiphene. Drug Metab Pharmacokinet. 2008;23(2):101–105. PubMed.
- Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice. BJU Int. 2016;117(2):344–350. PubMed.
- Foster J, Choo L, Patel A, Kirby M, Hackett G. 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. PubMed; PMC.