Male Infertility in Renal Failure and Transplantation

Scott D. Lundy; Sarah C. Vij

Disclosures

Transl Androl Urol. 2019;8(2):173-181. 

In This Article

The Effect of Immunosuppression on Male Fertility

In addition to the rapid and profound physiological changes associated with renal transplantation and clearance of uremia itself, the selection of an immunosuppression regimen likely plays a critical role in the recovery of male fertility following renal transplant. Numerous drugs and regimens are now available, and each agent has a side effect profile that must be considered when making this decision.

Calcineurin Inhibitors (CNIs)

Representing the backbone of most modern immunosuppressive regimens, CNIs modulate immunity via blocking the nuclear factor of activated T cells (NFAT) dephosphorylation and interrupting IL-2 synthesis. The two main agents in this class in the modern era include cyclosporine (CsA) and tacrolimus. Data from the basic science literature suggests that in a solitary kidney rodent model, tacrolimus exerts minimal detrimental effects on spermatogenesis.[31] This is in contrast to regimens containing cyclosporine or sirolimus, both of which caused oligospermia with diminished motility and morphology, decreased testosterone levels, and altered testicular architecture on histological analysis.[31] In humans, however, small studies have shown relatively normal semen parameters and successful paternity on male renal transplant recipients on a cyclosporine regimen.[18,21,26,32] Another larger contemporary study showed successful paternity in 212 male transplant recipients on a CsA regimen showed relatively normal paternity at most doses. It appears the effects of cyclosporine on sperm parameters occurs in a dose dependent fashion.[33] For an excellent more detailed summary of this literature, the reader is directed towards a recent review article by Georgiou and colleagues.[34] Despite the widespread use of tacrolimus, there is a paucity of data in the literature on its effects on male reproductive health. Animal studies on relatively high doses of tacrolimus have shown testicular changes including cell death and diminished numbers of Sertoli cells and spermatocytes.[35] A small comparative study between cyclosporine and tacrolimus, however, found no differences in hormonal parameters between transplant recipients receiving each regimen.[36] While early studies are promising and suggest that paternity is certainly possible on CNIs, further work will be required to fully elucidate whether therapeutic doses of tacrolimus suppress male fertility to a meaningful degree. Interestingly, specific isoforms of calcineurin in sperm have been proposed as a candidate target for a male infertility pill,[37] further suggesting this pathway may plan an important role in male infertility.

mTOR Inhibitors

Sirolimus, everolimus, and temsirolimus are inhibitors of the mammalian target of rapamycin (mTOR) and PI3K pathways and thus suppresses immunity as well as neoplastic processes. An anti-HPG effect has also been described,[38] resulting in modest levels hypogonadism. In theory, both of these effects could have significant deleterious effects on spermatogenesis, and indeed this has been seen in practice. Patients receiving mTORs such as sirolimus appear to have diminished sperm counts, poorer motility, and significantly decreased spontaneous pregnancy rates with unknown additional risk of birth defects.[39] Whether these changes are reversible remains controversial,[40] but based upon this data, patients should be counseled on the risks of mTOR-based regimens on male fertility.

Antimetabolites

Mycophenolate is a reversible noncompetitive inhibitor of purine synthesis, which exerts its immunosuppressive effect by inhibiting DNA synthesis in lymphocytes. While mycophenolate appears to be teratogenic during pregnancy,[41] the effect on spermatogenesis and paternity is less clear. Studies in animal models have demonstrated a decreased sperm count and motility, but this has not been studied in humans. The National Transplantation Pregnancy Registry (NTPR) recently published paternity data on 152 male transplant patients maintained on mycophenolic acid-based medications.[42] The rates of spontaneous abortion, prematurity, live births, and structural anomalies were all similar to the general population.[42] This finding has been confirmed with another large cohort from Norway, which also found no evidence of adverse events in the setting of mycophenolate.[43]

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