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Cmp4.8
Clomiphene (Clomid) Research
Mostly mechanism / observationalLimited safety
9 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Clomiphene (Clomid) studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality meta-analyses and randomised trials published 2012–2023 with a typical study size of 750 participants.
Based on 9 studies · 2 meta-analyses · 1 RCT · 2,438 total participants
Confidence
High
By outcome
Testosterone & male hypogonadism
Mostly mechanism / observational7 studies
Safety profile
Mostly mechanism / observational7 studies
Fertility (ovulation & sperm)
Mostly mechanism / observational3 studies
PCOS & ovulation induction
Too few graded studies2 studies
Steady research
2 studies in the last 5 years · Latest meta-analysis: 2023
201220172023
1RCTn=750 · large study2014
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007)... letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. · N Engl J Med (2014)
Double-blind, multicenter RCT (NCT00719186) of 750 women with PCOS randomized 1:1 to letrozole vs clomiphene for up to five cycles; primary outcome live birth
Letrozole beat clomiphene on cumulative live births (27.5% vs 19.1%, P=0.007) and on ovulation rate (61.7% vs 48.3% of cycles, P<0.001)
Clomiphene caused more hot flushes; the honest counter-evidence in clomiphene's own approved indication — the reason letrozole displaced it as PCOS first-line
Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment... Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism.
Huijben M, Lock MTWT, de Kemp VF, de Kort LMO, van Breda HMK. · Andrology (2022)
Systematic review and meta-analysis of clomiphene citrate for male hypogonadism — 19 studies (4 RCTs, 15 observational), 1,642 patients; 17 studies (1,279 patients) in the meta-analysis
Total testosterone rose substantially (standardized increase ~2.60), with increases also in free testosterone, LH, FSH, SHBG and estradiol, plus improved ADAM symptom scores
Side effects were present in under 10% of study populations and no serious adverse events were reported, but the base is dominated by observational studies
First-line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent with clomiphene.
Brown J, Farquhar C. · Cochrane Database Syst Rev (2016)
Cochrane systematic review of clomiphene and other antioestrogens for ovulation induction in anovulatory PCOS subfertility
Frames clomiphene as the established first-line oral ovulation-induction agent while noting clomiphene resistance and limited evidence for adjuncts (dexamethasone, combined oral contraceptives)
Found low-quality evidence that a 10-day clomiphene regimen improves pregnancy rates over a 5-day regimen, but advised caution given low event rates
Treatment with clomiphene citrate and enclomiphene citrate may be an effective and safe alternative to testosterone replacement therapy in men with obesity-related functional androgen deficiency.
Tienforti D, Castellini C, Di Giulio F, Totaro M, Dalmazio G, Spagnolo L, et al. · Andrology (2023)
Systematic review and meta-analysis of SERMs (clomiphene and enclomiphene) in men with obesity-related functional androgen deficiency
Pooled analysis showed a clear rise in testosterone (combined mean difference with tight CI, I²=0%) with no publication bias and no unexpected safety findings
Concludes SERMs may be an effective, safe alternative to testosterone replacement in this population, but calls for long-term studies to define clinical outcomes
Mean testosterone, LH, and FSH levels increased 146%..., 177%..., and 170%..., respectively, during treatment... The zuclomiphene urinary detection window ranged from 121 to >261 days.
Miller GD, Moore C, Nair V, Hill B, et al. · J Clin Endocrinol Metab (2019)
Phase-I controlled-administration study giving healthy men once-daily clomiphene for 30 days, with serial hormone sampling and isomer-specific urinary detection
Testosterone, LH and FSH rose 146-177% over baseline, confirming the HPT-axis mechanism in healthy (non-hypogonadal) men
The slow-clearing zuclomiphene was detectable in urine for 121 to >261 days — a controlled demonstration of the long-lived cis-isomer's persistence
Follow-up T levels were 612 ng/dL at 1 year, 562 ng/dL at 2 years, and 582 ng/dL at 3 years (P < 0.001). Mean femoral neck and lumbar spine BD scores improved significantly... No adverse events were reported by any patients.
Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP. · BJU Int (2012)
Observational study of 46 hypogonadal men on clomiphene citrate for over 12 months, with serial testosterone, estradiol, LH and bone densitometry
Testosterone roughly tripled from a baseline ~228 ng/dL to ~582-612 ng/dL and stayed elevated out to 3 years; femoral neck and lumbar spine bone density improved
ADAM symptom scores fell from a baseline of 7 to a nadir of 3 at one year; no adverse events reported
Clomiphene citrate (CC) may be used as an alternative treatment in these patients with hypogonadism when maintenance of fertility is desired... it appears to be an effective and safe alternative to testosterone supplementation in men wishing to preserve their fertility.
Katz DJ, Nabulsi O, Tal R, Mulhall JP. · BJU Int (2012)
Case series (Level of Evidence 4) of young hypogonadal men treated with clomiphene citrate (typically 50 mg every other day) to preserve fertility instead of exogenous testosterone
All mean testosterone and gonadotropin measurements increased significantly during treatment, with subjective improvement on nearly all ADAM questionnaire items
No major side effects were recorded, and a coexisting varicocele did not affect the response to clomiphene
The CC was effective in stimulating the endogenous production of testosterone... This medication should be considered as a therapeutic option for some patients with symptomatic male testosterone deficiency.
Da Ros CT, Averbeck MA. · Int Braz J Urol (2012)
Prospective study of 25 mg/day clomiphene citrate in men with low sexual desire and testosterone below 400 ng/dL
Clomiphene significantly raised endogenous testosterone and modestly lowered total cholesterol (197→186 mg/dL); HDL, triglycerides, glucose and prolactin were unchanged
All men reported improved quality-of-life scores and no serious adverse events were recorded
The present study suggests that an unopposed high dose of zuclomiphene can have pernicious effects on male mammalian reproductive organs. The deleterious effects seen when administering ZUC in male mice, justifies the case for a monoisomeric preparation and the development of ENC for clinical use.
Fontenot GK, Wiehle RD, Podolski JS. · BJU Int (2016)
Chronic oral-dosing toxicity study in male mice comparing the isolated clomiphene isomers enclomiphene (ENC) and zuclomiphene (ZUC) against placebo
Unopposed high-dose zuclomiphene produced pernicious effects on Leydig cells, epididymis, seminal vesicles and kidneys, whereas isolated enclomiphene raised testosterone with no adverse testicular histology
Provides the mechanistic rationale that the racemic mixture's long-lived zuclomiphene is the liability — justifying the single-isomer enclomiphene