Influence of exogenous melatonin on rat prostate response under experimental diabetes and testosterone supplementation

Prostate damage induced by diabetes is due to perturbations in insulin signaling, increment of oxidative stress and androgenic scarcity. Because of its antioxidant activity, melatonin (MLT) is a potential agent to be used in prevention of prostate impairment due to diabetes. MLT also inhibits testosterone testicular synthesis and its action on androgen-dependent organs must be better evaluated. In this regard, we investigated the influence of therapeutic doses of MLT in morphology and proliferative activity on ventral prostate of healthy and diabetic rats. Testosterone treatment was used to discriminate the MLT inhibitory effect on androgen synthesis and to better clarify the MLT specific action on this gland. The experiment was approved by the Ethics Committee of Experimental Animals of Sao Paulo State University (Protocol number: 137/2016). Wistar rats (12 weeks old) were divided into 6 groups (n=15 per group): control (C), MLT treatment (M), diabetic (D), diabetic treated with MLT (DM), diabetic treated with testosterone (DT) and diabetic treated with MLT and testosterone. Diabetes was induced at 12th week by streptozotocin injection (40mg/Kg body weight, ip) and the animals which showed glucose levels over 200mg/dL were considered diabetic. Animals were treated for one week with MLT (0.1mg/kg/day, gavage), testosterone (200ug/day/animal, sc) or both and were euthanized at 13th week of age. Serum testosterone levels were measured by ELISA, prostate histological sections were stained with Hematoxylin and Eosin for stereological analysis and submitted to immunohistochemistry for proliferating cell nuclear antigen (PCNA). Our results indicated that MLT treatment did not influence glycemic levels of healthy animals but increased these levels ~70% at D and DM group. There was a drastic prostate atrophy in D (p=0.002) and DM (p=0.007) that did not occurred in DT and DMT groups. Stereological analysis indicated that M group displayed a reduction in absolute frequency of epithelial component and D group showed a decrease of epithelial relative weight (~43%) and lumen (~42%), possibly due to the decline of epithelial cell secretory capacity. Proliferative rates declined ~70% after one week of induceddiabetes. The MLT treatment to diabetic rats did not avoid epithelial and lumen atrophy however there was an increased ~32% the relative stromal weight. This effect could be explained by the fact that MLT preserved testosterone serum levels in DM group. As expected, testosterone treatment to diabetic rats attenuated acinar atrophy of prostate. DMT group displayed a reduction of acinar epithelial and stromal hyperplasia as well an increase of mitotic rate which surpassed DT group. In conclusion, the main effect of treatment of healthy rats with therapeutic doses of MLT for short-term was a discrete epithelial atrophy. Such doses ameliorated prostate atrophy induced by experimental diabetes but also induced stromal hyperplasia of the gland in this rodent. Besides, our results indicate a synergistic action of MLT and testosterone on proliferative activity of rat prostate under hyperglycemic conditions.