Clomiphene citrate versus testosterone replacement therapy in male hypogonadism: a systematic review of literature and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Primary outcome (overall testosterone): not significant (CI crosses zero); libido outcome: P=0.009

• Effect Size: Overall MD = 6.64 ng/dL favouring clomiphene; injectable TRT subgroup MD = -290.50 ng/dL favouring injectable TRT; libido (ADAM 1-5) MD = -0.54 favouring TRT

• Primary Outcome: Change in serum testosterone levels: no statistically significant difference between clomiphene citrate and TRT overall (predominantly gel-based formulations)

• Nnt Or Sensitivity: No NNT calculable from available data. The libido finding (MD=-0.54 on ADAM scale) favours TRT but the clinical meaningfulness of this difference on a multi-item questionnaire scale requires contextualisation against the MCID for the ADAM instrument

• Confidence Interval: Overall testosterone: 95% CI -35.35 to 48.63 ng/dL; injectable TRT: 95% CI -518.78 to -62.22 ng/dL; libido: 95% CI -0.87 to -0.21

Clinical Application

Clomiphene citrate is orally administered, generally well-tolerated, and does not suppress the hypothalamic-pituitary-gonadal axis, making it logistically simpler than injectable TRT. Gel-based TRT requires daily application with transference precautions. Injectable TRT requires clinic attendance or self-administration. Monitoring requirements differ: clomiphene requires LH/FSH/testosterone and ophthalmological awareness; TRT requires haematocrit, PSA, and cardiovascular monitoring. In Australia, clomiphene citrate is not TGA-approved for male hypogonadism and is used off-label, which limits PBS subsidy and requires informed consent documentation. Testosterone formulations available on the PBS include testosterone undecanoate injection (Reandron), testosterone gel (Testogel, AndroForte), and testosterone implants. The RACGP and Andrology Australia guidelines recommend TRT as first-line for symptomatic hypogonadism with confirmed biochemical deficiency, but acknowledge clomiphene as an option for men desiring fertility preservation. The absence of fertility outcome data in this meta-analysis is particularly relevant to Australian urologists and endocrinologists managing younger men with functional hypogonadism. Prescribers should note that off-label clomiphene use requires individual clinical justification and cannot be PBS-subsidised in this indication. Adult males with confirmed hypogonadism (age-related or functional), particularly those with concurrent obesity or metabolic syndrome, and especially those in whom fertility preservation is a clinical priority

Abstract

INTRODUCTION: Male hypogonadism, including age-related and functional forms, is characterized by insufficient testosterone production often associated with obesity and metabolic comorbidities. Testosterone replacement therapy (TRT) increases serum testosterone but suppresses spermatogenesis and may cause adverse effects. Selective estrogen receptor modulators (SERMs), such as clomiphene citrate, have emerged as an alternative approach to restore endogenous testosterone while preserving fertility. This study aimed to compare the efficacy of clomiphene citrate versus testosterone replacement therapy (TRT) in increasing serum testosterone levels in men with hypogonadism. METHODS: We conducted a systematic review of the literature in PubMed, Embase, Scopus, The Cochrane Library, and Google Scholar to identify studies comparing clomiphene citrate and testosterone replacement therapy (TRT) in men with male hypogonadism'. The primary outcome was the change in serum testosterone levels before and after treatment. Secondary outcomes included variations in other hormonal parameters, and clinical symptom improvement assessed through standardized instruments. RESULTS: A total of 11 studies with 1512 patients were included (764 on clomiphene citrate; 748 on testosterone replacement therapy, TRT). For serum testosterone, the overall pooled effect showed no significant difference between clomiphene and TRT (MD = 6.64 ng/dL; 95% CI -35.35 to 48.63; I² = 80.6%). Subgroup analyses indicated injectable testosterone achieved higher levels than clomiphene (1 study, 62 patients; MD = -290.50; 95% CI -518.78 to -62.22), whereas gel-based TRT showed no difference (8 studies, 1012 patients; MD = 24.29; 95% CI -18.91 to 67.48; I² = 76.1%). For sexual function, three studies (199 patients; 85 on clomiphene; 114 on TRT) assessing post-treatment libido (ADAM 1-5) showed lower libido scores with clomiphene than TRT (MD = - 0.54; 95% CI - 0.87 to - 0.21; P = 0.009; I² = 18.8%). CONCLUSIONS: No statistically significant difference in serum testosterone levels was observed between clomiphene citrate and testosterone gel, although the evidence is limited by high heterogeneity and some concerns to high risk of bias. TRT was associated with greater improvements in libido. These findings should be interpreted as preliminary, and large-scale randomized trials incorporating clinical and fertility endpoints are needed.

References

1. 1.Constantinou, B. T., Benedicto, B. C., Galligani, L., Schiavon, B. N., Mendes, C. M. O., Petri, M. M. G., Uzueli, B., Maia, R. S., da Sardenberg, R. A. S., Fraietta, R., & Shiomi da Cruz, J. A. (2026). Clomiphene citrate versus testosterone replacement therapy in male hypogonadism: a systematic review of literature and meta-analysis. European Journal of Clinical Pharmacology. Advance online publication. https://doi.org/10.1097/JU.0000000000000396