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Enc4.2
Enclomiphene Research
Mostly mechanism / observational
12 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Enclomiphene 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 2013–2026 with a typical study size of 15 participants.
Based on 12 studies · 1 meta-analysis · 3 RCTs · 75 total participants
Confidence
Moderate confidence
By outcome
Testosterone & male hormonesPhase-2/3 RCTs show oral enclomiphene raises total testosterone into the normal range, comparably to topical testosterone · Weeks to a few months · Raises LH-driven endogenous testosterone production in hypogonadal men · Weeks to a few months
Mostly mechanism / observational11 studies
Fertility (sperm preservation)Unlike testosterone gel, raises FSH/LH and keeps sperm concentration in the normal range (fertility-sparing) · Within 3-6 months
Mostly mechanism / observational6 studies
Active research area
5 studies in the last 5 years · Latest meta-analysis: 2025
201320192026
1Review2025
In plain English: Continued research with larger, long-term studies is essential to confirm their safety, efficacy, and fertility outcomes.
Hochu G, Geyer-Kim I, Kim E. · Translational andrology and urology (2025)
Multiple studies demonstrate that hCG maintains sperm production even with full gonadotropin suppression from TRT.
Finally, enclomiphene citrate, a purified trans-isomer of clomiphene, stimulates the hypothalamic-pituitary-gonadal (HPG) axis, increasing endogenous testosterone while maintaining spermatogenesis.
This paper provides an updated overview of these evolving modalities and advances since our 2013 publication, highlighting short-acting testosterone delivery, concomitant gonadotropin support, and selective estrogen receptor modulation.
In plain English: This narrative review synthesizes current evidence on CC in post-cycle therapy and highlights key challenges in defining safe and standardized approaches to endocrine recovery following AAS use.
Bandura A, Furka S, Hromníková D, Kalafutová I, Furka D, Böhmer D. · Andrology (2026)
Clinical studies consistently show improvements in hormonal parameters across different types of study participants, although symptomatic recovery varies and concerns remain regarding adverse metabolic and long-term efficacy.
Monitoring is further complicated by the limited specificity of immunoassays, with mass spectrometry offering superior reliability for assessing hormonal recovery and detecting residual AAS metabolites.
Emerging approaches, including kisspeptin analogues, the enclomiphene isomer, and genotype-guided interventions, suggest potential future directions but lack validation in ASIH populations.
In plain English: The findings suggest that SERM therapy effectively increases TT levels in men with functional hypogonadism and should be considered as an alternative to T gel therapy.
Hohl A, Chavez MP, Pasqualotto E, Ferreira ROM, Sande-Lee SV, Ronsoni MF. · Archives of endocrinology and metabolism (2025)
Weighted mean differences (MDs) and risk ratios (RRs) were calculated for continuous and binary endpoints, respectively, with 95% confidence intervals (CIs).
TT levels were significantly higher with SERM therapy and the combined treatment of SERM and hCG compared to hCG alone (158 vs. 153 vs. 134 ng/dL, respectively; p < 0.002 for both comparisons).
In plain English: Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production.
In plain English: Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range.
Kim ED, McCullough A, Kaminetsky J. · BJU Int (2016)
Two parallel randomized, double-blind, double-dummy, placebo-controlled, multicentre Phase-3 trials (ZA-304/ZA-305) of 12.5 mg and 25 mg enclomiphene vs testosterone gel (AndroGel 1.62%) in overweight men 18-60 with secondary hypogonadism
Total testosterone rose in all groups; FSH and LH rose with enclomiphene but fell with testosterone gel at 16 weeks
Enclomiphene maintained sperm concentration in the normal range, while spermatogenesis was markedly reduced in the testosterone-gel group
In plain English: After six weeks of continuous use, the mean concentration of total testosterone was 604 ng/dL for men taking the highest dose of enclomiphene citrate (25 mg daily) and 500 ng/dL in those treated with transdermal testosterone.
Wiehle R, Cunningham GR, Pitteloud N, Wike J, Hsu K, Fontenot GK, Rosner M, Dwyer A, Podolski J. · BJU Int (2013)
Randomized, single-blind, two-center Phase-2 study of three enclomiphene doses (6.25, 12.5, 25 mg Androxal) vs transdermal testosterone in 48 men with secondary hypogonadism, with 24-hour LH/TT sampling
Defined the dose-response: 25 mg/day produced mean Day-42 testosterone ~604 ng/dL, comparable to or above transdermal testosterone
Characterized the pharmacokinetics of enclomiphene and the LH/testosterone pharmacodynamic profile over 6 weeks
In plain English: Enclomiphene citrate increased testosterone and sperm counts. Concomitant changes in LH and FSH suggest normalization of endogenous testosterone production and restoration of sperm counts through the hypothalamic-pituitary-testicular axis.
Kaminetsky J, Werner M, Fontenot G, Wiehle RD. · J Sex Med (2013)
Proof-of-principle randomized, open-label, active-control, two-center Phase-2B study in 12 men with secondary hypogonadism previously on topical testosterone
At 6 months total testosterone was ~525 (enclomiphene) vs ~545 pg/dL (gel) — comparable restoration
Only the enclomiphene group showed increased LH and FSH; enclomiphene raised sperm counts (75-334 million/mL) while the gel failed to do so
In plain English: Enclomiphene has been shown to increase testosterone levels while stimulating FSH and LH production... [it] maintains the androgenic benefit of clomiphene citrate without the undesirable effects attributable to zuclomiphene.
Earl JA, Kim ED. · Expert Rev Endocrinol Metab (2019)
Drug-profile review of the trans-isomer enclomiphene, noting that most of clomiphene's benefit comes from the trans-isomer while zuclomiphene contributes little
Summarizes that enclomiphene raises testosterone while stimulating FSH and LH and maintaining fertility
Explicitly reviews the difficulties associated with FDA approval of enclomiphene as a new molecular entity — the honest regulatory caveat
Review of enclomiphene as the trans-isomer of clomiphene — a non-steroidal estrogen-receptor antagonist — for secondary male hypogonadism
Synthesizes the evidence that it raises testosterone via LH/FSH while maintaining semen parameters, supporting use where testosterone therapy is unsuitable
Frames the fertility-sparing rationale against the fertility-suppressing effect of exogenous testosterone
In plain English: After at least 6 weeks of clomiphene therapy, the median zuclomiphene:enclomiphene serum concentration ratio was 20:1.
Helo S, Mahon J, Ellen J, Wiehle R, Fontenot G, Hsu K, Feustel P, Welliver C, McCullough A. · BJU Int (2017)
Observational study measuring enclomiphene (ENC) and zuclomiphene (ZUC) isomer levels in 15 men on long-term clomiphene citrate 25 mg daily for secondary hypogonadism
On long-term clomiphene the slow-clearing ZUC dominates the serum, with a median ZUC:ENC ratio of ~20:1 — the rationale for using the pure trans-isomer enclomiphene instead
Total testosterone rose from a median 205 to 488 ng/dL on therapy (P<0.001); age, BMI, and duration did not predict isomer levels