Ameliorative effect of combined low dose of Pioglitazone and omega‐3 on spermatogenesis and steroidogenesis in diabetic rats

BACKGROUND: Chronic hyperglycemia is linked to either subfertility or infertility among diabetic males. Pioglitazone is one of the thiazolidinediones (TZDs) drugs that are selective peroxisome proliferator-activated receptor (PPAR-gamma agonists used for treating type 2 diabetes mellitus (T2DM). AIM: This study aims to explore the possible effect of low Pioglitazone dose and omega (omega-3) on rat male reproductive function. Furthermore, we evaluated the add-on effect of combined use of low Pioglitazone dose of and omega-3 on reproductive functions in adult male T2DM rats. METHODS: Fifty adult male rats were included and subdivided into control and four test subgroups. T2DM was induced in test groups and subdivided into non-treated T2DM, omega-3 treated, 0.6 mg/kg Pioglitazone treated, and combined treated group (orally by gavage). Following 16 weeks, final body weight, testicular weight, fasting plasma glucose, and serum testosterone levels were measured. Semen analysis, testicular testosterone, malondialdehyde (MDA) concentrations, superoxide dismutase (SOD) activity, immunohistochemistry staining for apoptosis marker B-cell lymphoma protein 2 (Bcl-2), proliferation marker as proliferating cell nuclear antigen (PCNA), estrogen receptor alpha (ERalpha), androgen receptor (AR) were determined. Caspase-3, nuclear factor-kappa B (NF-kB), glucose transporter 3 (GLUT3), 17beta-hydroxysteroid dehydrogenases (17beta-HSD) PPARgamma, and PPARalpha genes expression were analyzed by real-time polymerase chain reaction (RT-PCR). RESULTS: Our findings revealed that treatment with low dose of Pioglitazone or omega-3 significantly lowered fasting plasma glucose and MDA levels, ameliorated diabetes effects on histological damage, improved antioxidant activity (SOD), significantly improved anti-apoptosis BCL-2 and proliferation (PCNA), remarkably elevated ERalpha, AR, 17beta-HSD PPARgamma, and PPARalpha expression with significant reduction in caspase-3, NF-kB genes expression and improved semen quality as well. Combined use of low dose of and omega-3 has better effects on all measured parameters. CONCLUSION: Small Pioglitazone dose and omega-3 possess beneficial effects on spermatogenic and steroidogenic functions in adult diabetic rat; while combined use of both has an add-on effect.