Effects of Medicines and Supplements on Spontaneous Pregnancy and Semen Parameters in Male Infertility: A Systematic Review Update and Network Meta-Analysis

In this study, we used a network meta-analysis (NMA) to compare the effectiveness of medicines and supplements for idiopathic male infertility and to identify the best treatment. Medline, Excerpta Medica Database (EMBASE), Ovid, and China National Knowledge Infrastructure (CNKI), were searched for the period from January 1990 to June 2021 using the keywords “male infertility,” “medical therapy,” “supplement/nutrient therapy,” and related terms. Randomized controlled trials (RCTs) investigating medicines (mainly follicle-stimulating hormone (FSH), androgen, and clomiphene/tamoxifen) or supplements (mainly zinc, selenium, vitamin C or E, carnitine, coenzyme Q10 (CoQ10), or combined treatment) for idiopathic infertile men were selected for meta-analysis. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) was used for data extraction, and a risk-of-bias tool and grades of recommendation, assessment, development, and evaluation (GRADE) system adapted to the NMA were employed to assess the quality of the evidence. The primary outcomes were live birth and spontaneous pregnancy rate (SPR). The secondary outcomes were sperm parameters (including concentration, progressive motility, and morphology) and side effects. In total, 65 RCTs involving 7541 men with sperm abnormalities but normal hormone levels were included. A total of 36 studies reported SPR but only three reported live birth rates. The quality of the included studies was found to be moderate to high. Compared with a placebo or being untreated, carnitine plus vitamins significantly improved SPR (relative risk (RR) = 3.7, 95% confidence interval (95%CI), 1.6–8.5); fatty acids significantly increased sperm concentrations (mean difference (MD) = 12.5 × 10⁶ mL⁻¹, 95%CI, 3.1 × 10⁶–22.0 × 10⁶); and selective estrogen receptor modulators (SERM) plus CoQ10 significantly improved sperm progressive motility (MD = 11.0%, 95%CI, 0.1%–21.9%) and normal sperm morphology (MD = 11.0%, 95%CI, 4.6%–17.4%). The most optimal intervention was carnitine plus vitamins and fatty acids for SPR and sperm concentrations, respectively, even after excluding trials at a high risk of bias. Compared with a placebo or being untreated, FSH (RR = 4.9, 95%CI, 1.1–21.3) significantly increased SPR, whereas SERM plus kallikrein increased sperm concentration (MD = 16.5 × 10⁶ mL⁻¹, 95%CI, 1.6 × 10⁶–31.4 × 10⁶), and SERM plus CoQ10 significantly improved sperm progressive motility (MD = 11.3%, 95%CI, 7.3%–15.4%) and normal morphology (MD = 11.2%, 95%CI, 5.4%–16.9%) in men with oligoasthenozoospermia (OA). In terms of side effects, fatty acids and pentoxifylline were associated with foul breath and/or a bad taste (RR = 8.1, 95%CI, 1.0–63.5) and vomiting (RR = 8.0, 95%CI, 1.0–63.0), respectively. In conclusion, the optimal treatment for male infertility for live birth is still unknown. Carnitine plus vitamins and FSH are likely to be better than other therapies in achieving successful spontaneous pregnancy in couples overall and in couples with men with OA, respectively. The efficacy of other treatments on pregnancy outcomes warrants further verification.