Effect of combined hormonal and insulin therapy on the steroid hormone receptors and growth factors signalling in diabetic mice prostate

Abstract

Diabetes causes harmful effects on prostatic morphology and function. However, there still are doubts about the occurrence of various diseases in the prostate, as well as abnormal angiogenesis in relation to diabetes. Thus, the aim of this study was to correlate and quantify the level of the steroid hormone receptors and the angiogenic and antiangiogenic factors in non-obese diabetic mice (Nod) after combined hormonal and insulin therapy. Sixty mice were divided into six groups after 20 days of diabetes: the control group received 0.9% NaCl, as did the diabetic group. The diabetic-insulin group received insulin, the diabetic-testosterone group received testosterone cypionate, the diabetic-oestrogen group received 17β-oestradiol, and the diabetic-insulin-testosterone-oestrogen group received insulin, testosterone and oestrogen simultaneously. After 20 days, the ventral lobe was processed for immunocytochemical and hormonal analyses. The results showed that the lowest serum testosterone and androgen receptor levels were found in the diabetic group and the highest testosterone and androgen receptor levels in the diabetic-insulin-testosterone-oestrogen group. The serum oestrogen level and its receptor showed changes opposite to those of testosterone and its receptor. The endostatin reactivity was mainly decreased in diabetic mice. The greatest IGFR-1 and VEGF reactivities occurred in diabetic mice. Thus, diabetes led to the prostatic hormonal imbalance, affecting molecular dynamics and angiogenesis in this organ. Combined insulin and steroid hormone therapy partially restored the hormonal and angiogenic imbalance caused by diabetes.

Chronic rapamycin treatment causes diabetes in male mice

“…The dramatic differences in rapamycin-induced glucose intolerance and insulin resistance between the sexes in mice as noted here has previously been alluded to by Lamming et al (21) and Miller et al (28). While much has been done to better elucidate the role of E 2 and T in diabetes induced by various means in rats and mice (6,10,23,24,30,35,36,39,40), little has been done to explore their role in rapamycin-induced diabetes. We show here that E 2 plays a protective role against rapamycin-induced diabetes, with female mice becoming increasingly glucose-intolerant over a period of 10 wk postovariectomy and recovering glucose tolerance over 4 wk post-E 2 replacement.…”

“…Substantial and growing evidence implicates the sex hormones testosterone (T) and 17␤-estradiol (E 2 ) as key drivers of this difference (17, 27, 7a). Although the sum of evidence regarding T is equivocal (6,10,23,30), multiple studies suggest that E 2 confers a protective effect against diabetes. Laboratory-based studies demonstrate that male mice are more prone to developing chemical-or high-fat dietinduced diabetes (30,36) and that diabetic symptoms improve after administration of E 2 (30).…”

Pathological lesions and global DNA methylation in rat prostate under streptozotocin‐induced diabetes and melatonin supplementation

“…The observed alterations in collagen distribution are probably associated with gland shrinkage, which promotes remodeling of the extracellular matrix as there is no evidence of increased collagen synthesis (Ikeda et al, ; Gobbo et al, ). Phenotypic changes in stromal cells such as dilation of organelles and approximation of cytoplasmic dense bodies (observed in electronic microscopy) were also observed in the prostate of diabetic rats (Cagnon et al, ; Carvalho et al, ; Ribeiro et al, , , ; Suthagar et al, ; Fávaro et al, ; Arcolino et al, ; Fávaro and Cagnon, ; Gobbo et al, ). In alloxan‐induced diabetes prostatic smc were weakly immunoreactive to calponin and presented caveolaes (Gobbo et al, ), which are indicative of an acute response to low serum testosterone and intracellular glucose levels.…”

“…Phenotypic changes in stromal cells such as dilation of organelles and approximation of cytoplasmic dense bodies (observed in electronic microscopy) were also observed in the prostate of diabetic rats (Cagnon et al, 2000;Carvalho et al, 2003;Ribeiro et al, 2006Ribeiro et al, , 2008Ribeiro et al, , 2009Suthagar et al, 2009;F avaro et al, 2009;Figure 5 Incidence (%) of tissue alterations and malignant and premalignant lesions in ventral prostate of C2, long-term control (n ¼ 10); M2, long-term control treated with MLT (n ¼ 12); D2, long-term untreated diabetic (n ¼ 15) and MD2, long-term diabetic treated with MLT (n ¼ 10). Arcolino et al, 2010;F avaro and Cagnon, 2010;Gobbo et al, 2012a). In alloxan-induced diabetes prostatic smc were weakly immunoreactive to calponin and presented caveolaes (Gobbo et al, 2012a), which are indicative of an acute response to low serum testosterone and intracellular glucose levels.…”

Obesity and metabolic dysfunction severely influence prostate cell function: role of insulin and IGF1

“…Indeed, testosterone, the main sexual hormone responsible for prostate homeostasis, can be locally converted to dihydrotestosterone, which is involved in increasing proliferation and reducing death of PG cells . Moreover, a growing body of evidence indicates that the endocrine axis comprising growth hormone (GH), insulin and insulin‐like growth factor 1 (IGF1) is locally expressed in the PG and plays a relevant role in its pathophysiology . Thus, earlier studies showed that pituitary‐produced GH is essential for PG development, controlling prostate size , and local expression of IGF1 and its receptor (IGF1R), in vivo and in vitro .…”