Editorial Comment on Efficacy and Safety of Clomiphene Citrate for Late‐Onset Hypogonadism as Evaluated by Aging Male Symptom Rating Scale Over 1 Year

The management of late-onset hypogonadism (LOH) presents a persistent clinical challenge. While testosterone replacement therapy (TRT) is the established standard of care [1], its limitations—most notably the suppression of endogenous spermatogenesis and the risk of testicular atrophy—render it unsuitable for a significant subset of patients, particularly younger men who wish to preserve their fertility. The search for effective and safe alternatives is of paramount importance. Anno et al. [2] provide a valuable contribution to this field with their study, “Efficacy and Safety of Clomiphene Citrate for Late-Onset Hypogonadism as Evaluated by Aging Male Symptom Rating Scale over One Year.” This retrospective analysis of 54 men offers important real-world insights into the use of clomiphene citrate (CC), an oral selective estrogen receptor modulator that stimulates the endogenous hypothalamic–pituitary-gonadal axis. The authors are to be commended for being the first, to our knowledge, to utilize the comprehensive Aging Males' Symptoms (AMS) rating scale to assess clinical efficacy, moving beyond the simpler, less nuanced ADAM questionnaire used in many previous studies. Anno et al. demonstrate that CC (50 mg every other day) effectively and sustainably increased serum testosterone levels to nearly double the baseline over a one-year period. Crucially, this biochemical improvement was mirrored by a significant reduction in AMS scores, indicating a tangible improvement in the general psychological and physical symptoms that often degrade the quality of life for men with LOH. Furthermore, the treatment was well-tolerated, with no adverse events reported. However, the study also reveals the complexities inherent in LOH management. Despite the robust increase in testosterone, there was no significant improvement in sexual function as measured by the SHIM and EHS scores. This finding, coupled with the lack of correlation between the magnitude of testosterone increase and the degree of AMS score improvement, powerfully underscores that the symptomatology of LOH is not solely dictated by androgen levels. Psychological factors, comorbidities, and the multifactorial nature of sexual dysfunction likely play a significant role. This dissociation highlights that simply “normalizing the number” is not always sufficient to resolve all patient complaints. The authors acknowledge the limitations of their work, including its retrospective design, relatively small sample size, and the lack of estradiol monitoring—a key parameter given CC's mechanism of action. These limitations temper definitive conclusions but pave a clear path for future investigation. A large-scale, prospective, randomized controlled trial is urgently needed to corroborate these findings. Such a trial should ideally compare CC not only to a placebo but also head-to-head with TRT, with long-term follow-up to rigorously assess safety profiles, including cardiovascular and metabolic outcomes. Perhaps the most clinically actionable finding from Anno et al. is that a lower baseline luteinizing hormone (LH) level was the only independent predictor of a robust testosterone response. This suggests a potential biomarker for patient selection, allowing clinicians to identify individuals most likely to benefit from CC. In conclusion, this study provides compelling evidence that clomiphene citrate is a viable and safe alternative to TRT for a carefully selected group of men with LOH. It is a critical tool for personalized medicine—an excellent option for men concerned with fertility, especially those with lower baseline LH. Anno et al. have provided a solid foundation upon which future, more definitive research can be built to further refine the role of CC in the therapeutic armamentarium for LOH. Shinichiro Fukuhara: conceptualization, writing – original draft, writing – review and editing. The author has nothing to report. The author has nothing to report. The author declares no conflicts of interest. This article is linked to Anno et al. papers. To view this articles, visit https://doi.org/10.1111/iju.70289.