Immunosuppressants and Male Reproduction

Abstract

Prolonged use of immunosuppressant medications is occasionally seen in infertile men with chronic inflammatory conditions; autoimmune disorders; or an organ or hematopoietic stem cell transplant. Chronic inflammation impacts negatively on male reproductive endpoints, so immunosuppressant therapy can produce improvements. Corticosteroids have been used to treat antisperm antibodies and even as an empirical treatment for male infertility in general. Trials of these methods have provided mixed results on semen quality and fertility, with improvement, no change and negative effects reported by different investigators. In a substantial number of observational studies, patients on long-term therapy with prednisone for chronic inflammatory disease, testosterone levels were lower compared to untreated controls, though randomized controlled trials have not been conducted. Similarly decreases in testosterone have been reported in men receiving corticosteroids to minimize transplant rejection; however, most were treated with multiple immunosuppressive medications that may have contributed to this effect. A large number of trials of healthy men treated with corticosteroids have shown some disruption in reproductive hormone levels, but other studies reported no effect. Studies in monkeys, rats (at human equivalent dose), cattle, sheep, and horses have shown endocrine disruption, including low testosterone with dexamethasone treatment. Of the cytostatic immunosuppressives, which have high potential for cellular damage, cyclophosphamide has received the most attention, sometimes lowering sperm counts significantly. Methotrexate may decrease sperm numbers in humans and has significant negative impacts in rodents. Other chemotherapeutic drugs used as immunosuppressants are likely to impact negatively on male fertility endpoints, but few data have been collected. The TNF-α Inhibitors have also received little experimental attention. There is some evidence that the immunophilin modulators: cyclosporine, sirolimus, and everolimus cause endocrine disruption and semen quality impairment. As we review in this chapter, results in experimental species are concerning, and well-designed studies are lacking for the effects of these medications on reproductive endpoints in men.

The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: a systematic review

“…Because of the scope of our systematic review, studies that reported the effect of corticosteroids on the male reproductive health of healthy controls were excluded. A review on this topic can be found elsewhere ( Drobnis and Nangia, 2017 ).…”

“…These studies reported mixed results and overall the risks associated with glucocorticoid therapy outweighed the benefits. In-depth information can be found elsewhere ( Drobnis and Nangia, 2017 ).…”

Sex differences in COVID-19: the role of androgens in disease severity and progression

“…Dexamethasone, a glucocorticosteroid drug, reduced the mortality rate by one-third in mechanically ventilated patients and by one-fifth for those receiving oxygen without ventilation [ 26 ]. Notably, dexamethasone has been shown to lower testosterone synthesis in animal models [ 35 , 36 ] and human patients [ 36 ]. Lower androgen levels might be a contributor to dexamethasone observed beneficial effects; however, these preliminary results should be interpreted with caution.…”

Amelioration of cyclosporine‐induced testicular toxicity by carvedilol and/or alpha‐lipoic acid: Role of TGF‐β1, the proinflammatory cytokines, Nrf2/HO‐1 pathway and apoptosis

“…The mechanisms of cyclosporine‐induced testicular toxicity include increased release of reactive oxygen species (ROS), increased formation of the proinflammatory cytokines and induction of apoptosis in the spermatogenic cells. These effects may lead to serious toxic events in the gonads which may significantly affect male fertility 4 …”