PPAR-γ agonist pioglitazone improves semen quality and testicular histomorphometrics with partial reversal of hyperglycaemia in alloxan-induced diabetic rats

Objective: Chronic hyperglycaemia is associated with subfertility and infertility in male diabetic subjects, possible as a result of perturbed testicular antioxidant defence system. Recent evidence however shows that some testicular cells produce insulin and this raises the possibility of a role for this hormone in spermatogenesis. Moreover, isoforms of the nuclear peroxisome proliferator activated receptor (PPAR) have been detected in testicular tissue, suggesting a role for insulin sensitisation in testicular function. In this study, we report the ameliorative effects of the PPAR γ agonist pioglitazone on testicular morphologic aberrations and impaired semen profile induced by diabetes in rats treated with intraperitoneal alloxan (150 mg/kg). Setting: This is an in vivo experimental study. Methods: Diabetic rats were randomized to receive oral pioglitazone at 10 or 30 mg/kg once daily for 6 weeks, after which rats were euthanised under anaesthesia. Caudal epididymal sperm was analysed for count, motility and morphology, and testosterone levels were measured in testicular homogenates by the enzyme immunoassay technique. Portions of the testes were fixed and processed by the H&E and Gordon and Sweet techniques. Blood glucose was estimated weekly during oral pioglitazone treatment using the glucometer. Results: Weekly blood glucose measurement showed weak effect of pioglitazone on hyperglycaemia in our model. Nonetheless, findings from caudal epididymal sperm analysis showed significantly high sperm density in the pioglitazone-treated rats at the two doses tested (P < 0.05 compared with diabetic controls). Moreover, pioglitazone at 10 mg/kg improved sperm motility and lowered the percentages of deformed and dead sperm cells in the treated diabetic rats. Haematoxylin and eosin (H&E) sections of the testes showed significantly reduced seminiferous tubule diameter and lumen size, as well as diminished height of the germinal epithelium in the untreated diabetic rats, but not in rats on pioglitazone intervention. Furthermore, Gordon and Sweet section of the testes showed thickened interstitial compartment only in the untreated diabetic group. Meanwhile, interstitial cells of Leydig appeared undisturbed in testicular sections of all the groups, while intratesticular testosterone levels were not significantly different between the treated and control rats (P > 0.05). Conclusion: These findings show that increased sensitivity of testicular cells to insulin mediated by the PPAR γ agonist pioglitazone restores testicular histomorphometry and improves semen quality in diabetic rats, despite the weak effect of this glitazone on blood glucose. This suggests a role for insulin sensitizers and improved insulin signalling in the amelioration of testicular lesions and regulation of spermatogenesis in the diabetic state, and lends support for insulin at promoting testicular functions.