A systematic overview of the spermatotoxic and genotoxic effects of methotrexate, ganciclovir and mycophenolate mofetil

Abstract

Introduction Immunosuppressant drugs are increasingly being used in the reproductive years. Theoretically, such medications could affect fetal health either through changes in the sperm DNA or through fetal exposure caused by a presence in the seminal fluid. This systematic overview summarizes existing literature on the spermatotoxic and genotoxic potentials of methotrexate (MTX), a drug widely used to treat rheumatic and dermatologic diseases, and mycophenolate mofetil (MMF), which alone or supplemented with ganciclovir (GCV) may be crucial for the survival of organ transplants. Material and methods The systematic overview was performed in accordance with the PRISMA guidelines: A systematic literature search of the MEDLINE and Embase databases was done using a combination of relevant terms to search for studies on spermatotoxic or genotoxic changes related to treatment with MTX, GCV or MMF. The search was restricted to English language literature, and to in vivo animal studies (mammalian species) and clinical human studies. Results A total of 102 studies were identified, hereof 25 human and 77 animal studies. For MTX, human studies of immunosuppressive dosages show transient effect on sperm quality parameters, which return to reference values within 3 months. No human studies have investigated the sperm DNA damaging effect of MTX, but in other organs the genotoxic effects of immunosuppressive doses of MTX are fluctuating. In animals, immunosuppressive and cytotoxic doses of MTX adversely affect sperm quality parameters and show widespread genotoxic damages in various organs. Cytotoxic doses transiently change the DNA material in all cell stages of spermatogenesis in rodents. For GCV and MMF, data are limited and the results are indeterminate, for which reason spermatotoxic and genotoxic potentials cannot be excluded. Conclusions Data from human and animal studies indicate transient spermatotoxic and genotoxic potentials of immunosuppressive and cytotoxic doses of MTX. There are a limited number of studies investigating GCV and MMF.

Selective Depletion of Adult GFAP-Expressing Tanycytes Leads to Hypogonadotropic Hypogonadism in Males

“…These reduced levels of testosterone are also likely the cause of the strong alteration in sexual behavior seen in Tg+GCV males. Several studies have reported that prenatal or adult exposure to GCV can be spermatotoxic and induce drastic effects on testes ( 56 , 57 ) even if a recent systematic overview indicates a limited number of studies investigating the effect of GCV and could not conclude on the spermatotoxic effects of this substance ( 58 ). In all cases, effects of GCV on testes and germ lines were found when high doses were administered subcutaneously (100 – 300 mg/kg) ( 56 , 57 ).…”

Long-Term Follow-Up after Testicular Torsion: Prospective Evaluation of Endocrine and Exocrine Testicular Function, Fertility, Oxidative Stress and Erectile Function

“…Medication with antioxidants can improve semen quality through reducing OS [ 35 ]. However, several medications have been reported to have a negative impact on spermiogenesis, such as antidepressants, antibiotics, and antihypertensive agents [ 36 ]. Increased scrotal temperature due to fever or varicocele can cause a temporary decrease in sperm quality, where OS may play a role [ 37 ].…”

What benefit–risk trade-offs are acceptable to rheumatoid arthritis patients during treatment selection? Evidence from a multicountry choice experiment

“…1 For example, sulfasalazine and methotrexate are effective first-line conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but have been linked to adverse events, including gastrointestinal complications, infections, skin reactions, neurotoxicity, malignancies, infertility, and negative effects on sperm that may or may not be reversible. [3][4][5][6][7] Treatment selection is especially challenging among advanced therapies. While the American College of Rheumatology and EULAR align on recommendations for first-line therapies, approximately one-third of patients have an inadequate response to conventional csDMARDs, such as methotrexate and sulfasalazine, and often progress to one of multiple available advanced treatments.…”