Department of Rheumatology, Erasmus Medical Center, Rotterdam, Netherlands
Department of Rheumatology, Erasmus Medical Center, Rotterdam, Netherlands.
Ann Rheum Dis. 2023 Aug;82(8):1068-1075. doi: 10.1136/ard-2023-224032. Epub 2023 Jun 1.
Current scientific evidence guiding the decision whether men with an active desire to become a father should be treated with methotrexate (MTX) remains controversial. We aimed to prospectively evaluate the testicular toxicity profile of MTX focusing on several markers of male fertility, including semen parameters and sperm DNA fragmentation index (sDFI). As a secondary outcome, we aimed to evaluate whether MTX-polyglutamates can be detected in spermatozoa and seminal plasma and to evaluate the enzymatic activity in spermatozoa of folylpolyglutamate synthetase (FPGS).
In a prospective cohort study, men ≥18 years who started therapy with MTX were invited to participate (MTX-starters). Participants were instructed to produce two semen samples (a pre-exposure and a post-exposure sample after 13 weeks). Healthy men ≥18 years were invited to participate as controls. Conventional semen analyses, male reproductive endocrine axis and sDFI were compared between groups. FPGS enzymatic activity and MTX-PG1-5 concentrations were determined by mass spectrometry analytical methods.
In total, 20 MTX-starters and 25 controls were included. The pre-exposure and postexposure semen parameters of MTX-starters were not statistically significant different. Compared with healthy controls, the conventional semen parameters and the sDFI of MTX-starters were not statistically significant different. These data were corroborated by the marginal accumulation of MTX-PGs in spermatozoa, consistent with the very low FPGS enzymatic activity associated with the expression of an alternative FPGS splice-variant.
Treatment with MTX is not associated with testicular toxicity, consistent with the very low concentration of intracellular MTX-PG. Therefore, therapy with MTX can be safely started or continued in men and with a wish to become a father.
指导有生育意愿的男性是否应接受甲氨蝶呤（MTX）治疗的当前科学证据仍存在争议。我们旨在前瞻性评估 MTX 的睾丸毒性特征，重点关注几项男性生育力标志物，包括精液参数和精子 DNA 碎片化指数（sDFI）。作为次要结果，我们旨在评估 MTX-多聚谷氨酸是否可在精子和精浆中检测到，并评估精子中叶酸多聚谷氨酸合成酶（FPGS）的酶活性。
在一项前瞻性队列研究中，邀请≥18 岁开始 MTX 治疗的男性参加（MTX 开始者）。告知参与者产生两份精液样本（暴露前样本和暴露后 13 周后的样本）。邀请≥18 岁的健康男性参加作为对照组。比较各组间常规精液分析、男性生殖内分泌轴和 sDFI。通过质谱分析方法测定 FPGS 酶活性和 MTX-PG1-5 浓度。
共纳入 20 名 MTX 开始者和 25 名对照组。MTX 开始者的暴露前和暴露后精液参数无统计学差异。与健康对照组相比，MTX 开始者的常规精液参数和 sDFI 无统计学差异。这些数据得到了精子中 MTX-PGs 的微量积累的佐证，这与与表达替代 FPGS 剪接变体相关的非常低的 FPGS 酶活性一致。
MTX 治疗与睾丸毒性无关，与细胞内 MTX-PG 的低浓度一致。因此，在有生育意愿的男性中可以安全地开始或继续 MTX 治疗。
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