Men looking for a way to raise testosterone without the fertility cost of testosterone therapy keep arriving at the same two names. Enclomiphene is a pill; hCG is an injection. Both raise the body's own testosterone production rather than replacing it, and both are prescribed off-label for that purpose. They do it from opposite ends of the same hormone chain, and they have very different regulatory records.
This page sets the two side by side and reports what has been measured. The fuller hCG record in men — label, the testosterone-therapy adjunct studies, fertility recovery — is on our hCG for men page; enclomiphene's dose-by-dose trial table and its two regulatory refusals are on our kisspeptin vs enclomiphene page. Nothing here is a recommendation.
Side by side
| Enclomiphene | hCG (chorionic gonadotropin) | |
|---|---|---|
| What it is | Small molecule, the trans-isomer of clomiphene | Glycoprotein hormone, 237 amino acids in two chains |
| Where it acts | Hypothalamus and pituitary — blocks oestrogen feedback | Testis — binds the LH receptor on Leydig cells |
| What rises | The body's own LH and FSH, then testosterone | Testosterone directly; the label notes "a small degree of FSH activity" |
| Route | Oral, daily in trials | Injection, several times a week in trials |
| Needs a working pituitary? | Yes | No |
| US status | Not approved; FDA Complete Response Letter, 30 Nov 2015 | Approved prescription biologic (Pregnyl, Novarel, generic) |
| EU status | Negative CHMP opinion as EnCyzix, 25 Jan 2018 | Not reviewed for this page |
| Labelled male use | None | Selected hypogonadotropic hypogonadism; prepubertal cryptorchidism |
The mechanism row decides most of what follows. Enclomiphene only works if the pituitary can respond — it turns up a signal that already exists. hCG replaces the signal, which is why it is used when the pituitary is suppressed, as it is during testosterone therapy. The hCG labels put it plainly: "The action of HCG is virtually identical to that of pituitary LH" (Fresenius Kabi, DailyMed, effective 11 April 2025, read 26 October 2026).
What enclomiphene's trials measured
Enclomiphene was developed by Repros Therapeutics for men with secondary hypogonadism — low testosterone with low or normal LH. Its trials compared it with testosterone gel, not with hCG:
- Phase 2, ZA-203 (Wiehle 2014, Fertility and Sterility, NCT01270841): enclomiphene raised morning testosterone, oestradiol and LH to levels similar to those on 1% testosterone gel, raised FSH, and "sperm counts were conserved".
- Phase 3, ZA-304 and ZA-305 (Kim 2016, BJU International): two parallel, double-blind 16-week trials in overweight men aged 18 to 60 with testosterone at or below 300 ng/dL. Testosterone rose in every arm; LH and FSH rose on enclomiphene and fell on AndroGel 1.62%; enclomiphene "maintained sperm concentration in the normal range" while the gel group showed "a marked reduction in spermatogenesis".
Those trials measured hormone levels and sperm counts. They did not show that men felt or functioned better, which is the gap the European committee named when it declined the drug (details on the kisspeptin vs enclomiphene page).
What hCG's record measured
hCG's male indications come from its label, not from trials against testosterone: selected cases of hypogonadotropic hypogonadism, and prepubertal cryptorchidism. Its off-label use alongside testosterone therapy rests on a different kind of evidence — studies showing that low-dose hCG keeps testosterone inside the testis close to baseline while testosterone injections suppress LH, and case series in which sperm production returned. Those studies, with their sizes and designs, are tabled on our hCG for men page.
The one trial that compared them — and why it is not quite this comparison
Only one randomised trial has put an oestrogen-receptor modulator against hCG, and it used clomiphene, the older mixture from which enclomiphene is purified, not enclomiphene itself.
Habous 2018 (BJU International) randomised 282 men with hypogonadism who wanted to preserve fertility to one of three arms for 12 weeks:
| Arm | n | What they received |
|---|---|---|
| Clomiphene | 95 | 50 mg daily, oral |
| hCG | 94 | 5,000 IU twice weekly, injected |
| Both | 94 | the two together |
Mean testosterone rose from 2.31 nmol/L at baseline to 5.17 nmol/L at three months — a 223% increase — "with no statistically significant difference among the groups". Symptom scores on the qADAM questionnaire rose in every arm (by 12.73 on clomiphene, 11.82 on hCG and 15.13 on the combination at three months), with the combination significantly ahead of either drug alone. The authors concluded that single-agent clomiphene "is simple, cheap" and as effective as hCG for restoring testosterone.
Two cautions travel with that result. First, the baseline is unusually low: 2.31 nmol/L is about 67 ng/dL (our conversion, at 28.84 ng/dL per nmol/L), far below the 300 ng/dL cut-off most trials use, and the final mean of 5.17 nmol/L is about 149 ng/dL — still low by that standard. Second, the trial was open-label, and the 2025 meta-analysis below rated its risk of bias as very serious.
What a systematic review found
A 2025 meta-analysis (Hohl 2025, Archives of Endocrinology and Metabolism) searched for every randomised trial comparing clomiphene or enclomiphene with placebo, testosterone gel or hCG up to July 2024. It found 10 trials with 819 men: 374 assigned to a modulator, 133 to gel, 94 to hCG, 13 to anastrozole and 205 to placebo. The 94 hCG patients were all from Habous 2018. Against placebo, the modulators raised testosterone by a mean of about 274 ng/dL; against gel, testosterone was similar but LH and FSH were higher. The single comparison with hCG was graded low certainty.
So the position is reproducible in one sentence: there is no randomised trial of enclomiphene against hCG, and the one trial of its parent compound against hCG found no difference in testosterone.
Side effects, from what each record holds
- hCG: the label lists gynecomastia, headache, irritability, restlessness, depression, fatigue, oedema and injection-site pain, and advises caution where fluid retention would matter. The detail is on our hCG side effects page.
- Enclomiphene: the European committee cited a risk of venous thromboembolism. FDA's adverse-event database held 12 reports naming enclomiphene, all in men where sex was recorded, when queried through openFDA on 26 October 2026. A 2026 case report described atrial flutter detected after a man took 50 mg daily instead of 25 mg (Tariq 2026, Cureus); the authors rated the link "possible" only, given a pre-existing heart-valve repair.
Neither drug has been studied against the other for safety.
Why the comparison keeps coming up
Testosterone therapy suppresses LH and FSH, which shuts down sperm production. Both drugs are attractive because they avoid that — enclomiphene by raising the body's own signals, hCG by replacing the testicular one. A 2025 review of fertility-preserving options (Hochu 2025, Translational Andrology and Urology) lists both side by side for that reason and calls for "larger, long-term studies" of each. Further along the same chain sit gonadorelin, which acts on the pituitary (our gonadorelin vs hCG page), and kisspeptin, which acts above it. Our map of peptides that move testosterone up or down places all of them.
What is not established
- Enclomiphene against hCG, head to head — no trial.
- Enclomiphene as a substitute for hCG during testosterone therapy — no trial, and the mechanism argues against assuming it works there.
- Symptom benefit from enclomiphene — not shown to regulators' satisfaction.
- Long-term safety of either drug used off-label for low testosterone.
Choosing between them, or using either, is a decision for a clinician who can measure LH, FSH and testosterone first and knows why they are low.
Sources and dates
- Chorionic gonadotropin for injection, Fresenius Kabi, DailyMed set f93b2baa-03ac-4650-b35a-20b818d712d6, effective 11 April 2025 — clinical pharmacology read via openFDA 26 October 2026.
- Wiehle RD et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia. Fertil Steril. 2014;102(3):720–7. PMID 25044085; NCT01270841.
- Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone. BJU Int. 2016;117(4):677–85. PMID 26496621.
- Habous M et al. Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study. BJU Int. 2018;122(5):889–97. PMID 29772111.
- Hohl A 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. PMID 41066380 (PMC12510335, full text read 26 October 2026).
- Hochu G, Geyer-Kim I, Kim E. Preserving spermatogenesis in testosterone deficiency. Transl Androl Urol. 2025;14(12):3975–87. PMID 41522318.
- Tariq MN et al. Newly detected atrial flutter after enclomiphene dose escalation. Cureus. 2026;18(8):e114562. PMID 42741668.
- FDA Complete Response Letter (30 November 2015, as reported by the sponsor) and EMA EnCyzix refusal (25 January 2018) — as documented on our kisspeptin vs enclomiphene page.
- openFDA drug adverse events, "enclomiphene": 12 reports, all male where recorded — 26 October 2026. Abstracts read 26 October 2026.