Increased androgen receptor and remodeling in the prostatic stroma after the inhibition of 5‐alpha reductase and aromatase in gerbil ventral prostate

Prostate require high levels of steroidogenic enzymes such as 5α‐reductase (5α‐r) and Aromatase (Aro) for the formation of active steroids. Dihydrotestosterone (DHT), the prostate dominant androgen, is converted from testosterone (T) by the action of 5α‐r. Aro provides an alternative pathway for estrogen, via T aromatization. Since prostatic maintenance is dependent on both reciprocal stromal–epithelial interaction and regulation by steroids, this study aimed to elucidate what the absence of 5α‐r and Aro enzymes provokes in the prostate microenvironment after their long‐term inhibition. Data obtained 1 day after the 30 consecutive days of enzymatic inhibition with Finasteride (5α‐r inhibitor) and Letrozole (Aro inhibitor) demonstrated a marked stromal remodeling, with an increased deposition of extracellular matrix (ECM) proteins besides androgen receptor (AR) overexpression in the three phases of postnatal development analyzed. The subepithelial area of acini from ventral prostate presented collagen and reticular fibers accumulation, besides various altered and active fibroblasts. The AR content immunostaining was elevated after enzymatic inhibition therapy, mainly in the nuclei of epithelial cells. Similar data were observed in the ventral prostates even 21 days after the end of treatments. Results obtained following the long‐term inhibition of 5α‐r and Aro are relevant and highlight the actions of these enzymes as crucial not only for the maintenance of tissue architecture and ECM arrangement but also for androgen and AR function. The long‐term absence of their action imposes a novel situation on the prostate from which its normal physiology could not be restored by the conclusion of the treatments. Microsc. Res. Tech., 2009. © 2009 Wiley‐Liss, Inc.     

Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils

There is an increasing variety of endocrine disrupting chemicals (EDCs) either with (anti)estrogenic or (anti)androgenic potential widely present in the environment. These xenosteroids may mimic endogenous steroid hormones disrupting the homeostasis of physiological pathways and leading to several disturbances, especially in tissues highly dependent on steroid hormones such as the prostate. Taking this into account, this comparative study aimed to verify the potential of ethinylestradiol (EE) and testosterone acting as ECDs on the prostate of both male and female adult gerbils exposed to these agents during the embryonic phase. Consequently, pregnant gerbils were treated either with 10 μg/kg/day of EE or with a single dose of 1 mg of testosterone cypionate. The pups that were born 6-8 days after testosterone exposure and the pups that were born after 3 days of EE exposure were allowed to grow but were sacrificed within 4 months. Serological, morphological, stereological, and immunohistochemical analyses were used. Overall, the results showed that both sexes exposed to testosterone and EE during gestation had a prostatic gland with an increased stromal and epithelial and a reduced luminal compartment. Moreover, we observed that glands affected with prostatic intraepithelial neoplasia showed intense stromal reshuffling. In conclusion, although these alterations were observed in both sexes, more relevant to this study was the differential responsiveness of males and females exposed to these different drugs. Whereas the EE affected males more, the testosterone was more harmful to the females.     

Changes of inducible nitric oxide synthase in aortic cells during the development of hypertension: Effect of angiotensin II

Nitric oxide (NO) generation by inducible nitric oxide synthase (iNOS) in the vascular smooth muscle cells (VSMC), may play a role in blood vessel tone regulation. Lipopolysaccharide (LPS) induced iNOS activity and subsequent nitrite production by cultured aortic VSMC, from SHR with an established chronic blood pressure elevation (adult SHR) or during the period preceding the development of hypertension (young SHR) and from age-matched normotensive Wistar (W) rats were compared. Angiotensin II (Ang II) effect was also evaluated. Both basal LPS-induced iNOS activity and nitrite accumulation were significantly lower in young SHR VSMC compared to young W rat cells. In contrast, adult hypertensive and normotensive rat cells did not differ in NO generation. Besides, young SHR cells exhibited a significant smaller iNOS activity and nitrites than adult SHR cells. After 24h-incubation with Ang II, both variables were markedly reduced in all groups. The proportional reduction of iNOS activity and nitrites by Ang II was not different between hypertensive and normotensive rat cells, at any age. However, this Ang II inhibitory effect was greater in both adult SHR and W cells than in VSMC from young rats. In conclusion, a reduced LPS-induced iNOS activity and NO generation was observed in VSMC form spontaneously hypertensive rats before the raise of blood pressure, but not in adult hypertensive rat cells. Additionally, an inhibitory effect of angiotensin II on these variables is described. We can speculate that the impairment in vascular smooth muscle NO production precedes the development of hypertension in SHR and may play a pathophysiologic role in the early blood pressure elevation in genetically hypertensive rats.