Endocrine Abstracts

Introduction: Selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) potentially increase endogenous gonadotrophin and testosterone secretion in men. They are used off-label in men with hypogonadism and/or infertility. There is a lack of guidance on using these agents in men with secondary hypogonadism, though these agents are widely used in these people as a cheaper alternative to gonadotrophins.

Methods: Systematic search was conducted in PubMed, MEDLINE, Cochrane library and ClinicalTrials.gov for randomised controlled trials (RCTs) and non-randomised studies of intervention (NRSI) reporting SERM and/or AI effects on semen parameters or fertility in men with secondary hypogonadism (PROSPEROCRD42022306535). Study selection and data extraction were performed by two reviewers independently. The risk of bias (ROB) was assessed using ROB-2 and ROBINS-I tools. Results of RCTs were summarised using vote counting while summarising effect estimates where available. NRSI meta-analysis was conducted using the random-effect model. Certainty of evidence was assessed using GRADE.

Results: Five NRSIs (n=105) of SERMs showed an increase in sperm concentration [pooled mean difference 6.64 million/ml; 95% CI 1.54, 11.74] and three NRSIs (n=3) of SERMs showed an increase in total motile sperm count [pooled mean difference 10.52; 95% CI 1.46-19.59], with very low certainty of evidence due to critical ROB. All participants had infertility, however, the aetiology of hypogonadism was not specified in four studies and the mean BMI of participants in those studies was >30 kg/m². All three RCTs (n=275) comparing SERMs to testosterone gel showed the benefit of SERMs on sperm concentration. Four RCTs (n=591) comparing SERMs to placebo showed a heterogeneous effect on sperm concentration. Three RCTs included men with overweight/obesity, whereas participants in the other studies also had a mean BMI >28 kg/m². Results were of very low/low certainty of evidence due to the high ROB. Limited pregnancy or live birth data were available. No AI data on sperm parameters or fertility compared placebo or testosterone were found. Single cases of fatal stroke and venous thromboembolism were associated with SERMs and AIs, respectively; however, no causality could be established.

Conclusions: Current studies are of limited size and quality but suggest that SERMs may improve semen quality in men having low testosterone with low/normal gonadotrophins, particularly when associated with obesity. Well-designed, randomised studies recruiting men with a clear diagnosis of secondary hypogonadism are needed to determine whether SERMs improve spermatogenesis and live-birth rates in couples affected by secondary hypogonadism.