SERM / Oral / 12.5-25mg daily
Enclomiphene
Enclomiphene is one half of clomiphene, the 1960s fertility drug, separated out and sold on its own. The entire history is an argument about whether the other half is doing anything worth keeping.
In plain words
Enclomiphene is one of the two closely related forms that make up clomiphene, an old fertility tablet, separated out and sold on its own. Taken by mouth, it blocks estrogen's shut-off signal to the brain, so the body raises its own testosterone instead of having it replaced from outside, and that is why sperm counts hold up on it while testosterone gel drives them down. Randomized trials, including two completed phase III trials, back the hormone and sperm findings, though a pooled analysis of ten trials rated the evidence moderate quality and said the trials were too short and too small to judge safety. Despite finishing phase III it has never been approved by the FDA or the European regulator, the developer dropped the program in 2021, and it is unlicensed in the United Kingdom, so people get it from compounding pharmacies through telehealth clinics or from research-chemical sellers with no release testing behind them. The usual reason given for preferring it to clomiphene, that the other form causes mood and vision problems as it builds up over weeks, has never been tested head to head in people; it is an inference from how long each form lasts in the body.
At a glance
| Half-life | 0.42 days |
|---|---|
| Tmax | 0.083 days |
| Route(s) | Oral |
| Published dosing range | 12.5-25mg daily |
Reference data from the DosePlot canon -- not a protocol recommendation.
Serum curve
Single 18.8 mg dose by Oral, rendered from the same engine that powers the interactive chart. Relative levels, not lab values.
What does the evidence show?
Two things are labeled separately here because they answer different questions. The tier is how a study was built. The distance chips are whether that study touched this molecule, by this route, in a population resembling the reader. A randomized trial of a different molecule keeps its tier and still says nothing about this compound.
| Finding | Tier | Distance from use | Study |
|---|---|---|---|
| Two parallel randomized, double-blind, double-dummy, placebo-controlled phase III trials tested enclomiphene against testosterone gel in overweight men aged 18 to 60 whose morning total testosterone was at or below 300 ng/dL with low or normal luteinizing hormone. At 16 weeks, testosterone had risen in every treatment group. Enclomiphene raised LH and FSH; the gel lowered them. Enclomiphene held sperm concentration in the normal range, while the gel group showed a marked reduction in spermatogenesis. | rct | not recorded | 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 International 117(4):677-685, 2016 |
| Pooling 10 randomized trials and 819 men, a selective estrogen receptor modulator (clomiphene or enclomiphene) raised total testosterone by 273.76 ng/dL against placebo (95 percent confidence interval 191.87 to 355.66), luteinizing hormone by 4.66 IU/L and follicle stimulating hormone by 4.59 IU/L. Against testosterone gel there was no meaningful difference in total testosterone. Sperm concentration did not differ from placebo (mean difference 7.50 million/mL, 95 percent confidence interval -20.01 to 35.02). The authors rated the evidence moderate quality, with treatment periods of 2 to 30 weeks and too few patients to judge safety. | rct | not recorded | Hohl A, Chavez MP, Pasqualotto E, Ferreira ROM, Sande-Lee SV, Ronsoni MF. Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials.Archives of Endocrinology and Metabolism 69(5):e250093, 2025 |
| In a randomized two-center phase II study, 44 men with secondary hypogonadism took 6.25, 12.5 or 25 mg of enclomiphene citrate daily or applied transdermal testosterone. At day 42 the morning total testosterone on the 25 mg dose was 604 ng/dL (standard deviation 160) against 500 ng/dL (standard deviation 278) on the gel. Enclomiphene pushed LH and FSH above the normal range while testosterone suppressed them, and the effect on LH and testosterone persisted for at least a week after the last dose. | rct | not recorded | Wiehle R, Cunningham GR, Pitteloud N, et al. Testosterone restoration by enclomiphene citrate in men with secondary hypogonadism: pharmacodynamics and pharmacokinetics.BJU International 112(8):1188-1200, 2013 |
| The sperm result is the one that separates enclomiphene from testosterone. In a six-month randomized open-label study of 12 men with secondary hypogonadism who had been using topical testosterone, enclomiphene raised sperm counts in 7 of 7 men at 3 months and 6 of 6 at 6 months, with concentrations in the 75 to 334 million/mL range. The gel did less on the same endpoint. It left all five men in its arm at or below 20 million/mL at 3 months and raised counts in two of the five at 6 months. Only the enclomiphene arm showed raised LH and FSH. Twelve men is a small study, and it was not blinded. | rct | not recorded | 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.Journal of Sexual Medicine 10(6):1628-1635, 2013 |
| The case for isolating the isomer rests on a measurement. In 15 men taking clomiphene citrate 25 mg daily for at least six weeks, median serum zuclomiphene was 44.0 ng/mL against 2.2 ng/mL for enclomiphene, a ratio of 20 to 1 in favor of the isomer that is not doing the work. Median total testosterone had risen from 205 to 488 ng/dL and estradiol from 17 to 34 pg/mL. Age, body mass index, duration of treatment and testosterone level all failed to predict the ratio. | clinical | not recorded | 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 International 119(1):171-176, 2017 |
| Given separately to male mice by oral gavage at 4 or 40 mg/kg/day, the two isomers behaved differently. Zuclomiphene alone produced changes in Leydig cells, epididymis, seminal vesicles and kidneys and altered testosterone, LH and FSH. Enclomiphene raised testosterone and left testicular histology unchanged. These are mouse doses far above human use, and no equivalent head-to-head toxicology comparison exists in people. | preclinical | not recorded | Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice.BJU International 117(2):344-350, 2016 |
| The only direct human comparison of the two drugs is retrospective. Among 46 men given enclomiphene and 32 given clomiphene for at least three months, both raised total testosterone, but only enclomiphene raised FSH and LH significantly and only enclomiphene significantly raised total motile sperm count. Semen volume and sperm concentration changed significantly with neither. Nobody was randomized and nobody was blinded. | clinical | not recorded | Thomas J, Suarez Arbelaez MC, Narasimman M, et al. Efficacy of clomiphene citrate versus enclomiphene citrate for male infertility treatment: a retrospective study.Cureus 15(7):e41476, 2023 |
| Enclomiphene is used off-label in community practice as a testosterone restart after a steroid cycle and as an alternative to clomiphene for men who want to keep sperm counts. The reason given for choosing it over clomiphene is almost always the same: mood flatness, irritability and visual symptoms reported on clomiphene are attributed to the accumulating zuclomiphene isomer. No trial has compared the isolated isomers head to head for mood or vision in people, so this attribution is inference from the kinetics, not a measured result. | anecdotal | not recorded | community reports aggregated from reddit, MESO-Rx, and similar forumsno study |
How did it get here?
- preclinical1958
- At the William S. Merrell Company in Cincinnati, Leonard Lerner tests a compound whose structure resembles the triphenylethylene estrogens and finds the opposite of what he expected: no estrogen activity in any species, and weak but consistent antiestrogenic action in every animal model. That compound, MER-25, is the first nonsteroidal antiestrogen. Clomiphene, coded MRL-41, comes out of the same program. Unlike MER-25 it is not one substance but a mixture of an estrogenic and an antiestrogenic geometric isomer of the same skeleton.
- first-human1961
- Greenblatt and colleagues report in JAMA that MRL-41 induces ovulation in women who were not ovulating. The preliminary report runs four pages. The mixture works, and nobody separates it.
- clinical-adoption1967
- The FDA approves Clomid for ovulatory dysfunction on 1 February under new drug application 016131. The label describes the product as a mixture of two geometric isomers, cis (zuclomiphene) and trans (enclomiphene), and specifies the cis content only as a range: between 30 and 50 percent. Fifty-nine years later the current label still gives it as a range.
- clinical-adoption1986-1993
- Single-dose studies in volunteers establish that zuclomiphene has the longer half-life and that detectable levels persist for more than a month, which the label attributes to possible enterohepatic recycling. In 1993 a review in Baillieres Clinical Obstetrics and Gynaecology is titled, flatly, the case for a monoisomeric preparation. The argument for separating the isomers is two decades older than any trial of the separated drug.
- clinical-adoption2013-2016
- Repros Therapeutics develops the isolated trans isomer as Androxal and runs it against transdermal testosterone. Phase II work in 44 men and a 12-man open-label study report the same pattern: enclomiphene raises testosterone into the normal range while raising LH and FSH, and testosterone gel raises testosterone while shutting them down. Two parallel phase III trials, ZA-304 and ZA-305, run in 2014 in overweight men and find the same split on sperm concentration at 16 weeks. On the hormone endpoints the drug does what it was designed to do.
- grey-market2021-present
- The developer discontinues the program in 2021. Enclomiphene has never been approved by the FDA or the EMA, no approved US product contains the isolated isomer, and in the United Kingdom the drug is unlicensed. What that leaves in the United States is a compounding question rather than a settled route. Section 503A of the Federal Food, Drug, and Cosmetic Act lets a pharmacy compound from a bulk substance only if the substance complies with an applicable USP or NF monograph, is a component of an FDA-approved drug, or appears on the 503A bulks list. Enclomiphene citrate is not on that list: FDA's Pharmacy Compounding Advisory Committee reviewed it as a nominee in 2022, and the regulation naming the listed substances still names six, none of them enclomiphene. Whether a single isomer counts as a component of the approved isomer mixture is the reading the compounding route rests on, and no rule has resolved it. The consumer market sits in that gap. Telehealth clinics prescribe compounded capsules, and research-chemical vendors sell powder and dropper bottles with no release testing behind them. A drug with completed phase III trials is now bought mostly from suppliers who publish no certificate at all.
How is it made?
Enclomiphene is made the way clomiphene is made, with one extra step.
1. Building the skeleton. Clomiphene is a triarylethylene: a carbon-carbon double bond carrying two phenyl rings, a chlorine, and a third ring whose oxygen holds a short basic side chain. The textbook outline is a Grignard addition to a substituted benzophenone, dehydration to the double bond, chlorination, alkylation of the phenol oxygen to attach the side chain, and salt formation with citric acid. The chemistry is old and undemanding.
2. Separating the isomers. The double bond can form either way, so both geometries come out together; the marketed clomiphene mixture is reported at about 62 percent enclomiphene to 38 percent zuclomiphene. The two have the same atoms bonded in the same order, so neither mass nor ordinary crystallization of the free base tells them apart. Separation depends on small differences in how the two geometries form salts, move through a chromatography column, and fit inside a host molecule such as a cyclodextrin. That step is the entire difference between enclomiphene and clomiphene, and the expensive one.
3. Filling the capsule. This is an oral solid, so there is no sterile filtration and no endotoxin risk. The quality variable is isomeric purity. A lot that assays at 90 percent enclomiphene is 10 percent zuclomiphene, and because zuclomiphene accumulates over weeks while enclomiphene clears in hours, a contaminant that looks small on a certificate becomes the majority isomer in serum. Outside regulated manufacturing that is the number nobody measures.
Worth knowing
The cis and trans labels on clomiphene's two isomers were wrong in print for years. In 1976 a paper appeared in the Journal of Pharmaceutical Sciences whose stated purpose was to correct the stereochemistry in the clomiphene literature and re-examine the structure-activity relationships that had been built on it; a companion paper by the same group did the same job that year for a related bromo analogue. A decade of published reasoning about which half of the drug did what had the two halves swapped. The names now in use encode the corrected answer: enclomiphene is the E isomer, zuclomiphene the Z.
Ernst S, Hite G, Cantrell JS, Richardson A Jr, Benson HD. Stereochemistry of geometric isomers of clomiphene: a correction of the literature and a reexamination of structure-activity relationships.Journal of Pharmaceutical Sciences 65(1):148-150, 1976
Twelve healthy men took 50 mg of clomiphene daily for 30 days in a study built to establish how long the drug stays findable in urine. Testosterone rose 146 percent, LH 177 percent and FSH 170 percent during dosing. The interesting number is the tail. Zuclomiphene remained detectable in urine from 121 days to more than 261 days after the last tablet, meaning that for at least one participant it was still there roughly eight and a half months later. One month of dosing left a marker that outlasted the effect by most of a year.
Miller GD, Moore C, Nair V, et al. Hypothalamic-pituitary-testicular axis effects and urinary detection following clomiphene administration in males.Journal of Clinical Endocrinology and Metabolism 104(3):906-914, 2019
Clomiphene came out of the laboratory that made triparanol, a cholesterol drug withdrawn after it caused rapid cataracts in young women. Triparanol blocks the last step of cholesterol synthesis, so desmosterol accumulates, and the desmosterol was thought to be what clouded the lenses. Clomiphene is structurally close and also raises desmosterol, and that is why its development as a breast cancer treatment was discontinued while its fertility use went ahead. The visual symptoms that appear in the clomiphene labeling have a family resemblance to an older problem.
Jordan VC, McDaniel R, Agboke F, Maximov PY. The evolution of nonsteroidal antiestrogens to become selective estrogen receptor modulators.Steroids 90:3-12, 2014
Written and reviewed by Evan Marlow, developer of DosePlot · Updated 2026-08-27
Not medical advice. DosePlot is an informational tool, not a healthcare provider, and using it creates no provider-patient relationship. Do not start, stop, or change any protocol without the approval of a licensed healthcare professional.
Your whole protocol, in one place.
Free to start. Runs in your browser today.
14-day Premium trial inside, no card required.
Launch the web app