Interaction of testosterone with inhibin α and βA subunits to regulate prostate gland growth

Abstract

Testosterone regulation of prostate gland growth has been shown to involve reciprocal interaction with inhibin and activin. This study was therefore conducted to correlate the effect of testosterone on prostate gland proliferation and differentiation with the level of expression of inhibin alpha and betaA subunits. Immature dogs were treated with testosterone for 0, 3, 7, and 14 days and prostate gland growth was assessed by morphological and immunohistological localization of differentiation and proliferation markers. The results showed that testosterone treatment resulted in an initial significant increase in PCNA proliferation index by days 3 and 7, followed by a significant decrease by day 14 post-treatment. Interestingly, the decrease of cell proliferation was associated with structural and biochemical changes characteristic of glandular and stromal differentiation of the prostate gland. These changes include progressive glandular ductal canalization and inter-ductal stroma differentiation which were apparent from a gradual shift from vimentin expression to vimentin and alpha-actin expression. Testosterone also had a differential effect on inhibin alpha and beta subunits. Although testosterone treatment resulted in significant and constant inhibition of alpha subunit mRNA expression, it resulted in a significant increase of betaA mRNA expression by day 3, followed by a decrease by days 7 and 14. These results indicated that testosterone acts first to drive proliferation of undifferentiated prostatic cells and then to maintain a low proliferation turnover of differentiated cells. Because it has been shown that activin is an antagonistic regulator of androgens, the attenuated stimulatory effect of testosterone on cell proliferation by day 14 might be mediated, at least in part, by interplay between testosterone and activin.

Activin A in Mammalian Physiology

“…This antiproliferative role of prostatic activin A may also be a defense mechanism against excess proliferation and hyperplasia. Activin ␤A subunit is present in the glandular epithelium of benign prostate hyperplasia in humans (278,420) and is induced by testosterone treatment in prepuberal dogs (389). However, many gaps remain in our knowledge of how activin A is regulated and whether it is implicated in the genesis of human prostatic disease.…”

Activins and Inhibins: Expression and Role in Normal and Pathological Canine Reproductive Organs: A review

“…The canine prostate does not seem to produce inhibin (Garde and Sheth, ), while the glandular epithelium synthesises activin A and TGF‐beta receptor II, whose expression declines rapidly after castration, demonstrating that their synthesis is androgen dependent (Al‐Omari et al., ). Indeed, treatment with testosterone increases the expression of activin in the prostate gland (Shidaifat et al., ). Activins act by inhibiting the proliferation of prostate cells both during and after morphogenesis (Cancilla et al., ).…”

Testosterone effect on the expression of genes that mediate testosterone metabolism and genes that mediate the effect of those metabolites on the prostate

“…Previous results from rats (Mirosevich et al, 1999) and dogs (Shidaifat et al, 2007b) showed that testosterone treatment exerts a dual effect on prostatic cell proliferation characterized by an initial stimulation, followed by inhibition, of proliferation. The proliferation rate of the prostate gland in response to testosterone treatment appeared to be related to the differentiation status of prostatic cells (Shidaifat et al, 2007b). These results suggested that testosterone treatment acts to first drive prostatic cell proliferation and differentiation and then, when the cells become differentiated, it acts to maintain a low proliferation turnover rate of differentiated cells.…”