Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor.

Abstract

A bstract. Feminization in men occurs when the effective ratio of androgen to estrogen is lowered. Since sufficient estrogen is produced in normal men to induce breast enlargement in the absence of adequate amounts of circulating androgens, it has been generally assumed that androgens exert an antiestrogenic action to prevent feminization in normal men. We examined the mechanisms of this effect of androgens in the mouse breast.Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17#-hydroxy-5a-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast. Within 4 d of castration, the progesterone receptor virtually disappears and estradiol treatment causes a twofold increase above the level in intact animals. Dihydrotes inhibits estradiol-mediated induction of the progesterone receptor. Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosteronetreated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor. IntroductionNormal men produce -45 ,ug of estradiol each day, a sixth of which is secreted by the testes and the remainder of which is derived from the extraglandular aromatization of circulating androgens (1). Extraglandular estradiol formation takes place by two mechanisms, one from the direct conversion of testosterone to estradiol and the other from androgens of adrenal origin by the sequence of androstenedione -estrone -estradiol. The function of estradiol in normal men is unknown, but feminization, commonly manifested by gynecomastia, ensues under conditions of relative or absolute estrogen excess (2).Relative estrogen excess occurs when the synthesis or action of androgen is impaired but estrogen production is maintained at or near normal (as occurs in testicular regression or in testicular failure when testicular androgen production ceases but the formation of estrogens from adrenal androgens is unimpaired (3,4] The mechanism by which androgen inhibits estrogen action is unknown. Evidence has been developed in the MCF7 cell line that 17,3-hydroxy-5a-androstan-3-one (dihydrotestosterone)' functions as an antiestrogen by binding to the estrogen receptor itself and like certain other antiestrogens, that dihydrotestosterone can act as a weak estrogen in high concentration (10). Alternatively, the antiestrogenic actions of androgen on the embryonic mouse breast (11) and on the rodent uterus (12) appear to be mediated via the androgen receptor, e.g., androgen induces some action at the ge...

Osteopenia as a feature of the androgen insensitivity syndrome

“…The recent demonstration of oestrogen receptors on human osteoblasts (Eriksen et al, 1988) and the well documented reduction in bone density accompanying oestrogen deficiency further support the central role of oestrogen in the maintenance of bone density (Biller et al, 1992;Davies et al, 1990). Of potential relevance to AIS are data from a murine mammary cell line suggesting that DHT, at physiological concentrations, has pronounced anti-oestrogenic effects, mediated by its competitive binding to the oestrogen receptor (Casey & Wilson, 1984). Of potential relevance to AIS are data from a murine mammary cell line suggesting that DHT, at physiological concentrations, has pronounced anti-oestrogenic effects, mediated by its competitive binding to the oestrogen receptor (Casey & Wilson, 1984).…”

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Bringing androgens up a NOTCH in breast cancer

“…Therefore, coordinated cell-cell signalling multiple MEC lineages is critical to the normal growth and differentiation of the adult mammary epithelium. During puberty in humans, rodents and non-human primates, various androgenic compounds have been shown to inhibit ductal elongation (Casey & Wilson 1984, Jayo et al 2000, Peters et al 2011) and proliferation of MECs (Pashko et al 1981, Peters et al 2011, suggesting that AR signalling acts to antagonise the stimulatory actions of ERa in the regulation of this developmental process. The broad growth inhibitory, anti-oestrogenic influence of androgens in breast development is exemplified by cases of pubescent girls with adrenal hyperplasia, where breast growth is suppressed due to abnormally highcirculating androgen levels in the presence of normal levels of oestrogens (Forsbach et al 2000).…”

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