Local transformations of androgens into estradiol by aromatase P450 is involved in the regulation of prolactin and the proliferation of pituitary prolactin-positive cells.

María José García Barrado,José Carretero,Marta Carretero Hernández,Deborah Jane Burks,María Carmen Iglesias Osma,Julio J Herrero,Enrique J Blanco,Manuel Carretero,Raul M Luque

doi:10.1371/journal.pone.0101403

Abstract

In previous studies we demonstrated the immunohistochemical expression of aromatase in pituitary cells. In order to determine whether pituitary aromatase is involved in the paracrine regulation of prolactin-producing pituitary cells and the physiological relevance of pituitary aromatase in the control of these cells, an in vivo and in vitro immunocytochemical and morphometric study of prolactin-positive pituitary cells was carried out on the pituitary glands of adult male rats treated with the aromatase antagonist fadrozole. Moreover, we analyzed the expression of mRNA for the enzyme in pituitary cells of male adult rats by in situ hybridization. The aromatase-mRNA was seen to be located in the cytoplasm of 41% of pituitary cells and was well correlated with the immunocytochemical staining. After in vivo treatment with fadrozole, the size (cellular and nuclear areas) of prolactin cells, as well as the percentage of prolactin-positive cells and the percentage of proliferating-prolactin cells, was significantly decreased. Moreover, fadrozole decreased serum prolactin levels. In vitro, treatment with fadrozole plus testosterone induced similar effects on prolactin-positive cells, inhibiting their cellular proliferation. Our results suggest that under physiological conditions aromatase P450 exerts a relevant control over male pituitary prolactin-cells, probably transforming testosterone to estradiol in the pituitary gland.

Highlights

Of the two pathways through which androgens are metabolized -reduction and aromatization- the latter depends on the presence of an enzyme belonging to the family of cytochrome P450.There is growing awareness that androgens and estrogens play general metabolic roles that are not directly involved in reproductive processes
Previous findings from our laboratory suggest an important role of aromatase in the regulation of pituitary hormones, because we observed that aromatase P450 is expressed in the rat pituitary gland; that this expression is modified by sex and age, and that it could be involved in the genesis of spontaneous prolactinomas in old rats [3] or humans [4,5,6,7,8,9,10,11,12]
Aromatase mRNA has been reported in pituitary cells using in situ hybridization in trout [5]

Summary

Introduction

Of the two pathways through which androgens are metabolized -reduction and aromatization- the latter depends on the presence of an enzyme (aromatase P450) belonging to the family of cytochrome P450.There is growing awareness that androgens and estrogens play general metabolic roles that are not directly involved in reproductive processes. Estrogen is no longer considered solely an endocrine factor, but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and autocrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, the action of aromatase can generate high levels of estradiol locally, without significantly affecting circulating levels [1,2]. We have demonstrated the expression of aromatase in the rat pituitary gland. This expression was related to the sex and age of the animals. The physiological relevance of aromatase and the possible aromatization of testosterone to estradiol in the regulation of pituitary hormones are not well known

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