Long-Term Impact of Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral Nephrectomized Rats: A Comparative Study

Abstract

Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged.

Costus afer leaf extract protects against testicle damage caused by cyclosporine A in adult male Wistar rats through an antioxidant mechanism

“…This study results showed that cyclosporine A decreased the weight of the reproductive organs: testis, prostate and seminal vesicle compared with the control rats. Similarly, many previous studies stated that the consumption of cyclosporine A induces a dose‐dependent decline in the male reproductive organs' weights in rats (Chen et al, 2013; Pan et al, 2018; Türk et al, 2007). The results of this study showed that C. afer extract significantly increased weight of the reproductive organs (testis, prostate and seminal vesicle) during cyclosporine A toxicity.…”

Testicular Function, Semen Quality, and Fertility in Young Men After Renal Transplantation During Childhood or Adolescence

“…Experimental studies on rats treated with Tac and CsA have shown testicular histology with various degrees of atrophy of seminiferous tubes and problems with spermiation (15,17). CsA and sirolimus at doses equivalent to the therapeutic levels are reported to have even stronger toxicity on rat spermatogenesis than Tac (34). In the present study, the limited number of patients and higher cumulative doses of CTX among the Tac-treated patients did not allow us to compare the effect of CsA and Tac on semen quality.…”

Mammalian target of rapamycin complex 1 (mTORC1) Is required for mouse spermatogonial differentiation in vivo

“…These drugs can cause reversible human male infertility with unclear etiology [50-54]. Specifically, rapamycin analog treatments caused a block in spermatogonial differentiation in a human patient [55] as well as in a study using rats, although no detailed analyses were performed [56]. Both treated humans and rats exhibit reduced testosterone (T) levels due to inhibition of the hypothalamic-pituitary-gonadal axis.…”