Kisspeptin and enclomiphene come up in the same searches because they promise the same thing: a higher testosterone level made by the man's own testes, without the shutdown of the hormone signal that taking testosterone causes. Mechanistically they are neighbours — both act upstream of the testis, on the brain's control of LH. On the record they are very different. Enclomiphene went through a full drug-development programme, was taken by mouth for weeks by hundreds of men, and was then refused by both FDA and the European Medicines Agency. Kisspeptin has been given to small groups of volunteers by injection or infusion for minutes to hours, in academic studies. This page sets out what each record shows and what neither does. It does not recommend either.
How each acts on the same chain
The male hormone chain runs: kisspeptin neurons → GnRH → LH and FSH from the pituitary → testosterone and sperm from the testes. Testosterone and oestrogen feed back to switch the top of the chain down.
| Kisspeptin | Enclomiphene | |
|---|---|---|
| What it is | Peptide hormone (kisspeptin-10, -54) | Small molecule; the trans isomer of clomiphene |
| Where it acts | Stimulates GnRH neurons directly (KISS1 receptor) | Blocks oestrogen receptors in the hypothalamus and pituitary, lifting oestrogen's brake |
| Route in the human record | Intravenous or subcutaneous | Oral capsule, once daily |
| Duration studied in men | Single doses to an 11-hour infusion | 6 weeks and longer, including a registered extension study |
| Regulatory status | No approval anywhere | FDA Complete Response Letter 2015; EMA refusal 2018 |
| What changes with repetition | Response fades; continuous exposure suppresses | Not reported to fade over weeks in the studies below |
Enclomiphene's relationship to an approved drug is worth stating exactly. The US clomiphene citrate label describes the product as "a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer", approved for ovulatory dysfunction in women. Men who are prescribed clomiphene off-label take enclomiphene plus zuclomiphene; enclomiphene alone is the isomer its developer, Repros Therapeutics, tried to approve.
The enclomiphene record
Repros ran a registered programme of more than a dozen studies. One with posted results compared three doses against testosterone gel for six weeks (NCT01386606, 60 men; its brief title describes men with secondary hypogonadism):
| Arm (6 weeks) | 24-h average testosterone, baseline → week 6 | Morning LH, baseline → week 6 |
|---|---|---|
| Enclomiphene 6.25 mg (n = 16) | 262 → 392 ng/dL | 3.6 → 6.1 mIU/mL |
| Enclomiphene 12.5 mg (n = 14) | 374 → 461 ng/dL | 4.8 → 8.2 mIU/mL |
| Enclomiphene 25 mg (n = 16) | 298 → 587 ng/dL | 5.0 → 14.5 mIU/mL |
| AndroGel (n = 14) | 322 → 544 ng/dL | 3.6 → 2.2 mIU/mL |
Values are the posted means. The table shows the mechanism working as designed: testosterone rose on both drug and gel, but LH rose on enclomiphene and fell on the gel. No serious adverse events were posted in any arm; minor events were one or two per arm (diarrhoea, insomnia, urinary hesitancy among them).
Then the regulators. On November 30, 2015 FDA sent a Complete Response Letter; the sponsor reported FDA's view that "the design of enclomiphene Phase 3 studies is no longer adequate to demonstrate clinical benefit", plus concerns about entry criteria, titration and the validation of the hormone assays. In Europe the application as EnCyzix drew a negative opinion on 25 January 2018 (EMA): four main studies in 588 patients had shown higher testosterone and measured sperm output, but "did not look at whether EnCyzix would improve symptoms such as bone strength, weight gain, impotence and libido", and there is "a risk of venous thromboembolism". The committee concluded the benefits did not outweigh the risks. FDA's adverse-event database held 12 reports naming enclomiphene when queried on 2026-10-11.
The regulators' point is the one a reader needs: a higher testosterone number is not the same as a man feeling or functioning better, and that second question was never answered for enclomiphene.
The kisspeptin record in men
Kisspeptin's human research comes mostly from academic groups in London and Edinburgh. The clearest test of the testosterone question is a small proof-of-concept study in men with type 2 diabetes and low testosterone (George et al., Clinical Endocrinology 2013):
- A single intravenous bolus of kisspeptin-10 (0.3 mcg/kg) raised LH from 4.7 to 10.7 IU/L in five men with diabetes, and from 5.5 to 13.9 IU/L in seven healthy men.
- An 11-hour intravenous infusion at 4 mcg/kg/h in four of the men raised LH from 3.9 to 20.7 IU/L and testosterone from 8.5 to 11.4 nmol/L — about 245 to 329 ng/dL in US units (our conversion, × 28.84), a rise of about a third within the day.
That is four men, for one day, by vein. It shows the axis responds; it says nothing about weeks of use.
What happens over weeks points the other way. In women given kisspeptin-54 under the skin twice a day, the LH rise fell from 24.0 IU/L on day 1 to 2.5 IU/L on day 14. And Takeda's kisspeptin analogue TAK-448, infused continuously into healthy men, first raised testosterone and then pushed it into the castration range by day 8 — the property that made it a candidate prostate-cancer drug. Constant stimulation of the kisspeptin receptor switches the chain off. Our kisspeptin side-effects page gives both studies and the posted adverse-event tables; our kisspeptin dosage page covers the units the studies used, which no vial label uses. The approved peptides that lower testosterone on purpose, and by how much, are compared on our peptides and testosterone page.
Comparing the two numbers honestly
It is tempting to set 587 ng/dL beside 329 ng/dL and call one stronger. The studies cannot carry that:
- Population. Enclomiphene's study enrolled men with secondary hypogonadism; kisspeptin's infusion was in four obese men with type 2 diabetes.
- Duration. Six weeks of daily dosing against eleven hours of infusion.
- Route. Oral capsule against continuous intravenous drip — not the subcutaneous vial route research kisspeptin is sold for.
- Direction over time. Enclomiphene's LH rise was still present at week 6; kisspeptin's is known to fade with repetition.
No head-to-head study exists. Our hCG vs kisspeptin page compares kisspeptin with the other drug that acts on the same chain, at the testis end.
What neither record contains
- Any trial showing improvement in symptoms — libido, erections, energy, bone or body composition — which is the gap the EMA named for enclomiphene and which kisspeptin has not been tested against at all.
- Any study of kisspeptin used daily for weeks to raise testosterone in men.
- Any sperm-count data for kisspeptin in men.
- Any regulator's approval of either for this use.
- Anything about research-labelled vials or "enclomiphene" sold outside a pharmacy, whose contents no study has assayed — see how to read a COA and what research-use-only labelling means.
Low testosterone has causes a clinician needs to find, and both drugs act on a system that also governs fertility; any decision about either belongs with a clinician. MuscleLedger's kisspeptin page covers the gym-side discussion, and Peptide Lexicon's kisspeptin entry covers what the hormone is.
Sources and dates
- ClinicalTrials.gov, NCT01386606, The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Repros Therapeutics), posted outcome and adverse-event tables. Read via API v2, 2026-10-11.
- European Medicines Agency. EnCyzix (enclomifene): refusal of the marketing authorisation, overview and Q&A EMA/CHMP/54473/2018. https://www.ema.europa.eu/en/medicines/human/EPAR/encyzix. Read 2026-10-11.
- Repros Therapeutics announcement of FDA's Complete Response Letter, 1 December 2015, as reported by BioSpace (FDA Denies Approval of Repros Therapeutics' Enclomiphene). Read 2026-10-11.
- Clomiphene citrate tablets, US prescribing information (openFDA label, effective 2025-09-18), description and indications. Read 2026-10-11.
- George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clin Endocrinol (Oxf). 2013;79(1):100-4. PMID 23153270.
- Jayasena CN et al. 2009 (PMID 19820030) and MacLean DB et al. 2014 (PMID 24762108), as recorded on our kisspeptin side-effects page.
- openFDA drug adverse event endpoint, medicinal product "enclomiphene": 12 reports, queried 2026-10-11.