2-hydroxyestradiol and afimoxifene

Postmenopausal women (PMW) have increased incidence of cardiovascular disease, and estrogen substitution therapy has been shown to have cardioprotective effects. Since abnormal growth of cardiac fibroblasts (CFs) is associated with hypertension and myocardial infarction and estrogen inhibits vascular smooth muscle cell (SMC) growth, it is feasible that estrogen may attenuate cardiac remodeling by inhibiting CF growth, and this possibility was investigated by using cultured CFs. 17Beta-estradiol and progesterone, but not 17alpha-estradiol, estrone, or estriol, inhibited 2.5% FCS-induced proliferation (DNA synthesis and cell number) and collagen synthesis (3H-proline incorporation) in a concentration-dependent manner and to a similar extent in male and female CFs. Compared to 17beta-estradiol, its metabolites 2-hydroxyestradiol and 2-methoxyestradiol were more potent in inhibiting FCS-induced DNA synthesis, collagen synthesis, and cell proliferation. The inhibitory effects of 17beta-estradiol and its metabolites were enhanced in presence of progesterone and 4-hydroxytamoxifen (high-affinity estrogen receptor ligand). Moreover, like estrogens, the dietary phytoestrogens biochanin A and daidzein inhibited FCS-induced growth of CFs. In conclusion, 17beta-estradiol, its metabolites, and progesterone inhibit CF growth in a gender-independent fashion. Moreover, hormone replacement therapy using 17beta-estradiol and progesterone may protect PMW against cardiovascular disease by inhibiting CF growth and cardiac remodeling; whereas estrogens that do not inhibit CF growth may be less effective in protecting PMW against cardiovascular disease. Finally, our studies provide evidence that phytoestrogens inhibit CF growth and may be clinically useful as a substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.

Topics: 2-Methoxyestradiol; Animals; Cell Division; Cells, Cultured; Collagen; DNA; Estradiol; Estrogen Antagonists; Estrogens, Catechol; Female; Fibroblasts; Humans; Kinetics; Male; Myocardium; Progesterone; Proline; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Sex Characteristics; Tamoxifen

Chronic administration of the catecholestrogens 2-OH-estrone (2-OH1) and 2-OH-estradiol (2-OHE2), of tamoxifen and its metabolites and of high concentrations of estradiol have been previously shown to inhibit the growth of the estrogen/progesterone receptor-positive transplantable prolactin (PRL)-secreting rat pituitary tumor 7315a. The mechanism of action of these inhibitory effects on tumor growth is unknown. In the present study we investigated the direct effects of these compounds on PRL release by a tumor cell clone derived from the 7315a tumor. E2 stimulated PRL release in FCSABS (10% estrogen-stripped fetal calf serum)-cultured tumor cells in a biphasic manner: at low concentrations (0.1-100 nM) there was a dose-dependent stimulation of PRL release, which decreased in response to 1 microM E2 and which was greatly inhibited by 10 microM E2. Both 2-OHE2 (100 nM and 1 microM) and 2-OHE2 (1 microM) inhibited PRL release by FCS-cultured tumor cells. In FCSABS-cultured tumor cells, 0.1-10 nM 2-OHE1 and 1 microM 2-OHE2 inhibited PRL release, but 1-100 nM 2-OHE2 stimulated PRL release. Tamoxifen (TMX) and its metabolites dihydroxy (di-OH-TMX) and 4-hydroxytamoxifen (4-OH-TMX) inhibited PRL in a dose-dependent manner. The PRL release inhibiting effect of 4-OH-TMX was 100 times more potent that those of TMX and di-OH-TMX, which were similar in their effect. The inhibitory effects of micromolar concentrations of the catecholestrogens on PRL release could be overcome by estradiol, while the inhibitory effects of high concentrations of tamoxifen were not prevented by estradiol. Both "endogenous" (catecholestrogens) and "exogenous" (tamoxifen and its metabolites) antiestrogens and very high concentrations of estradiol directly inhibit PRL secretion by cultured pituitary tumor cells. The mechanism of their anti-tumor effects, however, seems to differ. The catecholestrogens have direct anti-estrogenic effects on cultured tumor cells, which can be antagonized by estradiol. The final effect of their mixed antagonistic/agonistic action depends on the presence or absence of estrogens in the culture medium. Tamoxifen also affects tumor growth probably mainly via a direct effect, partly involving anti-estrogenic and partly direct toxic effects.

Topics: Animals; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens, Catechol; Female; Hydroxyestrones; Pituitary Neoplasms; Prolactin; Rats; Rats, Inbred BUF; Secretory Rate; Tamoxifen; Tumor Cells, Cultured

Female rats were defeminized by neonatal treatment with estradiol-17beta benzoate, moxestrol (RU 2858), monohydroxytamoxifen ICI 79,280) or the dibenzoate esters of the catecholestrogens, 2-hydroxyestradiol-17beta and 4-hydroxyestradiol-17beta. When ovariectomized as adults and primed with estradiol-17beta benzoate all these rats demonstrated a deficient luteinizing hormone response to progesterone administration. However, estrogen responsiveness of progestin receptor induction was unimpaired in both the pituitary gland, the preoptic-hypothalamic brain and the uterus.

Topics: Animals; Animals, Newborn; Estradiol; Estrogen Antagonists; Estrogens, Catechol; Ethinyl Estradiol; Female; Hypothalamus; Male; Pituitary Gland; Preoptic Area; Rats; Receptors, Progesterone; Tamoxifen; Uterus