Clomiphene and enclomiphene show comparable efficacy to testosterone in functional hypogonadism

Daniela Barros, post graduate student, Surgical Clinic Program at Ribeirão Preto Medical School, University of São Paulo (FMRP-USP). Ribeirão Preto, SP, Brasil.

The study Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials, conducted by researchers from the Federal University of Santa Catarina (UFSC) and published in the Archives of Endocrinology and Metabolism (vol. 69 no. 5, 2025), demonstrated that the use of selective estrogen receptor modulators (SERMs), clomiphene and enclomiphene, is effective in increasing testosterone levels in men with functional hypogonadism, with the additional benefit of preserving spermatogenesis.

This systematic review and meta-analysis of ten randomized controlled trials evaluated 819 patients and found that treatment with SERMs led to a significant increase in total testosterone (mean difference: 273.76 ng/dL; 95% CI: 191.87–355.66; p < 0.01), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with placebo.

The effect was comparable to that achieved with testosterone gel, but with the advantage of maintaining male fertility, an important limitation of conventional testosterone replacement therapy (TRT). “Selective estrogen receptor modulators offer a safe and effective alternative to testosterone replacement in men with functional hypogonadism, particularly those wishing to preserve fertility,” the authors stated.

Searches were performed in international databases (PubMed, Embase, Cochrane Library, and ClinicalTrials.gov) up to April 2024, comparing SERMs with placebo, testosterone gel (T gel), and human chorionic gonadotropin (hCG).

In addition to increasing testosterone, SERM therapy resulted in higher LH and FSH levels, indicating endogenous stimulation of the hypothalamic–pituitary–gonadal axis, and, compared with testosterone gel, showed a significant improvement in sperm concentration parameters. No significant differences were observed in fasting glucose, insulin, glycated hemoglobin, or body mass index (BMI), and no substantial adverse events were reported across the included studies.

The authors also performed sensitivity and meta-regression analyses, which revealed a reduced treatment benefit among older men and those with higher BMI.

According to the GRADE assessment, the quality of evidence ranged from moderate (for total testosterone and LH) to low (for FSH) in comparisons with testosterone gel.

Imagem: Via Pixabay

Functional hypogonadism is an increasingly prevalent condition, particularly among men with obesity, type 2 diabetes, or metabolic syndrome (ARAUJO, A.B. et al., 2007; ZAROTSKY, V. et al., 2014; HARMAN, S.M. et al., 2001). Although conventional testosterone replacement therapy effectively raises serum testosterone, it may suppress sperm production and increase risks such as polycythemia and elevated PSA (BHASIN, S. et al., 2018).

In this context, SERMs, originally developed for treating female infertility, have been increasingly used off-label in men to stimulate endogenous testosterone production while preserving fertility (WHEELER, K.M. et al., 2019; SURAMPUDI, P. et al., 2014). The findings of the UFSC meta-analysis reinforce this advantage, suggesting that clomiphene and enclomiphene enclomiphene may represent clinically relevant therapeutic options for younger men with obesity-related or insulin-resistance–associated hypogonadism, also known as functional or secondary hypogonadism.

“The use of SERMs restores testosterone levels physiologically by stimulating the body’s own hormonal axis and avoids the risks associated with exogenous replacement,” the authors emphasized. The study also noted that the modest increase in estradiol levels observed with SERM therapy was not associated with adverse sexual effects and may even contribute positively to bone health, which is a favorable outcome in men with androgen deficiency (WU, F.C.W. et al., 2010; AL-SHAREFI, A. et al., 2020).

Another clinically relevant implication is the potential role of SERMs in transient forms of hypogonadism, such as those following anabolic steroid use or in cases of relative energy deficiency in athletes (HABOUS, M. et al., 2018; KIM, E.D. et al, 2016).

However, the authors emphasize that treatment should be individualized and monitored by an endocrinologist, since long-term data on safety and clinical outcomes remain limited. Further randomized controlled trials are warranted to consolidate the role of SERMs as a definitive alternative to testosterone replacement therapy across different patient populations.

Finally, the authors acknowledged several methodological limitations. Two of the included trials employed a cross-over design, which may introduce a unit-of-analysis error and widen confidence intervals, resulting in more conservative estimates. Considerable between-study heterogeneity was also observed, particularly for total testosterone levels. Although trial sequential analysis indicated robust evidence supporting the benefit of SERM therapy over placebo and testosterone gel for LH and FSH, results for total testosterone remained inconclusive. The authors highlight the need for longer and larger randomized trials to confirm the efficacy and safety profile of SERMs compared with traditional testosterone replacement therapy.

To read the article, access

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. [online]. 2025, vol. 69, no. 5, e250093 [viewed 02 December 2025]. https://doi.org/10.20945/2359-4292-2025-0093. Available from: https://www.scielo.br/j/aem/a/jyRkLt4MbHqk3tpgvsMfMmP/

References

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External links

Archives of Endocrinology and Metabolism – AEM