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.

BackgroundProstate carcinoma (PCa) is often not diagnosed until advanced disease with bone metastasis. Predictive factors for bone metastasis are required to improve patient outcomes. The study aimed to analyze the factors associated with bone metastases in newly diagnosed patients with PCa.Material/MethodsThis was a retrospective study of 80 patients newly diagnosed with PCa by pathological examination between January 2012 and December 2014. Bone metastases were diagnosed by positron emission computed tomography. Clinical data, serological laboratory results, and pathological examination results were collected.ResultsAmong the 80 patients, 45 (56%) had bone metastases. Age, serum alkaline phosphatase, prostate-specific antigen (PSA), erythrocyte sedimentation rate, PCa tissue Gleason score, androgen receptor (AR) expression, and Ki-67 expression were higher in patients with bone metastasis compared with those without (all P<0.05). Multivariate logistic regression showed that PSA (OR: 1.005; 95%CI: 1.001–1.010; P=0.016), Gleason score (OR: 4.095; 95%CI: 1.592–10.529; P=0.003), and AR expression (OR: 14.023; 95%CI: 3.531–55.6981; P=0.005) were independently associated with bone metastases. Cut-off values for PSA, Gleason score, and AR expression were 67.1 ng/ml (sensitivity: 55.6%; specificity: 97.1%), 7.5 (sensitivity: 75.6%; specificity: 82.9%), and 2.5 (sensitivity: 84.0%; specificity: 91.4%), respectively.ConclusionsPSA, Gleason score, and AR expression in PCa tissues were independently associated with PCa bone metastases. These results could help identifying patients with PCa at high risk of bone metastases.

Somatostatin analogs and their radionuclide and cytotoxic derivatives are recommended as adjuvant treatments for prostate carcinoma, especially in those patients who are at high risk for carcinoma recurrence after radical prostatectomy and who have advanced prostate carcinoma at the time of relapse. Because small-cell carcinomas of the prostate and lung are identical, these analogs may be useful in the detection and treatment of these tumors as well.

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The aim of this study was to elucidate the reproductive toxicity of the coadministration of diltiazem and cyclosporine A or tacrolimus. Testicular development, semen quality, sex hormones and testicular tissues were assessed in unilateral nephrectomised (UN) rats, including the control group, UN group, UN+CsA group, UN+FK506 group, UN+Rapa group, UN+CsA+Dil group and UN+FK506+Dil group. The testicular coefficient, the sperm number and the sperm motility were lower in the treatment groups (except UN+FK506) than in the control and UN groups (all p < 0.05). The lowest sperm number and motility were identified in the UN+CsA+Dil group, followed by the UN+CsA group. The proportion of abnormal sperm was higher in the UN+CsA and UN+CsA+Dil groups than in the control and UN groups, respectively (p < 0.05).The plasma concentrations of sex hormones were changed in the treatment groups. Dil can increase the blood concentrations of CsA and FK506 (◇p < 0.05, ◆p < 0.05). Therapeutic doses of these agents induced morphological changes in the testicular tissue and ultrastructural changes in the testosterone, mesenchymal cells and supporting cells. Our present study suggests that Dil can increase the testicular toxicity of CNIs (calcineurin inhibitors, including CsA and FK506) by enhancing the plasma concentrations of CNIs. K E Y W O R D S calcium channel blockers, immunosuppressive agents, renal transplantation, reproductive function How to cite this article: Lin Y, Zhang J, Lei W, et al. Diltiazem aggravates testicular function impairment induced by cyclosporine A or tacrolimus in unilateral nephrectomised rats.