一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析

李建 , 吴奇 , Ernest Hung Yu Ng , Ben Willem J. Mol , 吴效科 , Chi Chiu Wang

工程(英文) ›› 2022, Vol. 16 ›› Issue (9) : 198 -209.

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工程(英文) ›› 2022, Vol. 16 ›› Issue (9) : 198 -209. DOI: 10.1016/j.eng.2021.07.009
研究论文

一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析

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

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摘要

本研究采用网状荟萃分析对药物和补充剂治疗特发性男性不育症的疗效进行比较,以获得最佳治疗方法。对Medline、EMBASE、OVID和CNKI等数据库中发表于1990年1月至2021年6月的文献进行检索,检索关键词包括'男性不育''药物疗法''补充/营养疗法'及其相关术语等。将研究药物[主要包括促卵泡激素(FSH) 、雄激素、克罗米芬/他莫昔芬(SERM)]或补充剂[主要是锌、硒、维生素C/E、卡尼丁、辅酶Q10(CoQ10)或联合治疗]治疗特发性不育男性的随机对照试验(RCT)纳入meta分析。按PRISMA声明中的报告规范提取数据,并使用偏倚风险工具和适用于网状meta分析的GRADE系统评估证据质量。研究的主要结局是活产率和自然妊娠率(SPR),次要结局是精子参数(包括精子浓度、前向运动百分比和形态)和不良反应。65项RCT被纳入分析,共包括7541名精子参数异常但激素水平正常的育龄男性。36项研究报道SPR,但仅三项研究报道活产率。纳入研究的质量评价为中、高级。与安慰剂或未治疗相比,卡尼汀联合维生素治疗显著增加SPR(RR = 3.7, 95% CI为1.6 ~ 8.5),脂肪酸补充剂显著增加精子浓度(MD = 12.5 × 106 mL–1, 95% CI为3.1 × 106 ~ 22.0 × 106)。SERM联合辅酶Q10显著提升前向活力精子(MD = 11.0%, 95% CI为0.1% ~ 21.9%)和正常形态精子(MD = 11.0%, 95% CI为4.6% ~ 17.4%)。对改善SPR和精子浓度的最佳治疗方案分别是卡尼汀联合维生素和脂肪酸补充剂,即便排除具有高偏倚风险的研究,结果仍保持一致。对于少弱精子症男性,与安慰剂或未治疗相比,FSH(RR = 4.9, 95% CI为1.1 ~ 21.3)显著增加SPR,而SERM联合激肽酶可显著增加精子浓度(MD = 16.5 × 106 mL–1, 95% CI为1.6 × 106 ~ 31.4 × 106),SERM联合辅酶Q10则显著改善前向活力精子(MD = 11.3%, 95% CI为7.3% ~ 15.4%)和正常形态精子(MD = 11.2%, 95% CI为 5.4% ~ 16.9%)。在不良反应方面,脂肪酸补充剂和己酮可可碱分别与口臭或味觉差(RR = 8.1, 95% CI为1.0 ~ 63.5)和呕吐(RR = 8.0, 95% CI为1.0 ~ 63.0)相关。综上所述,对于改善不育男性配偶活产率的最佳治疗方案仍然不清楚。对于所有不孕夫妇和男性少弱精症不孕夫妇,卡尼汀联合维生素和FSH方案在成功实现自然妊娠方面分别优于其他方案。其他治疗方法对妊娠结局的疗效仍需要进一步验证。

Abstract

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. Studies involving 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 (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.

关键词

男性不育症 / 药物 / 补充剂 / 自然妊娠率 / 精子参数

Key words

Male infertility / Medicine / Supplement / Spontaneous pregnancy rate / Sperm parameters

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李建,吴奇,Ernest Hung Yu Ng,Ben Willem J. Mol,吴效科,Chi Chiu Wang. 一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析[J]. 工程(英文), 2022, 16(9): 198-209 DOI:10.1016/j.eng.2021.07.009

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