背景:硫嘌呤是广泛使用的免疫抑制剂。在高剂量,它们抑制嘌呤合成,被认为可能对精子发生有害,随后对男性的生育能力和他们的后代。然而,硫嘌呤暴露与男性生育能力和生殖安全性之间的明确关联,如果有的话,仍然知之甚少。
■这篇综述的目的是系统地总结和荟萃分析现有数据,来自动物和人类研究,关于硫嘌呤暴露对男性及其后代生育能力和受孕安全性的影响。
方法:对MEDLINE和EMBASE数据库进行了系统的文献检索,使用与“硫代嘌呤”相关的相关术语的组合,\'生育能力\',\'概念\',\'复制\',“精液质量”和“出生结果”,结合“男性”,\'男人\',\'父亲\'和\'父亲\'。搜索不仅限于人类受试者,既不是一种疾病或病症,收集有关此主题的所有可用研究。所有发表的关于硫嘌呤和男性生育能力的文章,以英文撰写并出版至2017年5月,我们对其资格进行了筛选.GRADE指南用于评估纳入文章的证据质量。
结果:本综述共纳入28项研究(包括14项人体观察性研究),其中6项纳入荟萃分析。在各种啮齿动物中,硫嘌呤会对生殖细胞产生不利影响(施用剂量为人类等效剂量的2至20倍)。在人类研究中,在83名患有多种基础疾病的男性中,硫嘌呤治疗与睾丸功能或精液质量受损无关。总的来说,975个先天性异常后代中有53个(5.4%,背景患病率为3%),可能是父系硫嘌呤暴露的结果,在所有研究中都有描述。与无父本硫嘌呤暴露的后代相比,先天性异常的风险没有显着增加(4.7%)(合并比值比1.32,95%置信区间0.75,2.34)。
■硫嘌呤对啮齿动物有精子毒性作用。在人类中,总体数据有限,来自动力不足的研究,因此,关于硫嘌呤对精子发生或父亲暴露后代的可能影响尚无定论。较大,流行病学试验评估硫嘌呤对男性生育能力及其后代的安全性是强制性的,以充分建议希望受孕的硫嘌呤治疗的男性。
BACKGROUND: Thiopurines are widely used immunosuppressive agents. In high dosages, they inhibit the purine synthesis and are considered to be possibly harmful to spermatogenesis, and subsequently to men\'s fertility and their offspring. However, the clear association between thiopurine exposure and male fertility and reproduction safety, if any, is still poorly understood.
UNASSIGNED: The aim of this
review was to systematically summarize and meta-analyse the available data, derived from animal and human studies, regarding the influence of thiopurine exposure on fertility and conception safety in men and their offspring.
METHODS: A systematic literature search of the MEDLINE and EMBASE databases was performed using a combination of relevant terms related to \'thiopurines\', \'fertility\', \'conception\', \'reproduction\', \'semen quality\' and \'birth outcome\', combined with \'male\', \'men\', \'father\' and \'paternal\'. The search was not restricted exclusively to human subjects, neither to a type of disease or condition, to gather all available studies with regards to this topic. All published articles on
thiopurines and male fertility, written in English and published until May 2017, were screened for eligibility. The GRADE guidelines were used to assess the quality of evidence of the included articles.
RESULTS: A total of 28 studies (including 14 observational studies in humans) were included in this
review and six of these were included in the meta-analysis. In various rodents, thiopurines adversely affected the germ cells (in administered doses of 2 to 20 times the human equivalent dose). In human studies, thiopurine therapy was not evidently associated with impaired testicular function or semen quality in 83 men with a variety of underlying diseases. In total, 53 out of 975 offspring with congenital anomalies (5.4%, the background prevalence is 3%), possibly as a result of paternal thiopurine exposure, were described in all studies together. The risk of congenital anomalies was not significantly increased when compared with offspring without paternal thiopurine exposure (4.7%) (pooled odds ratio 1.32, 95% confidence interval 0.75, 2.34).
UNASSIGNED: Thiopurines have spermatotoxic effects in rodents. In humans, overall data are limited and derived from underpowered studies, and therefore not conclusive with regards to the possible effects of thiopurines on spermatogenesis or paternally exposed offspring. Larger, epidemiological trials evaluating the safety of thiopurines to men\'s fertility and their offspring are mandatory to adequately counsel thiopurine treated men who wish to conceive.