Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques

Abstract

The purpose of this work was to examine the mammary glands of adult, ovariectomized female cynomolgus macaques (Macaca fascicularis) in a long-term study of the effects of hormone treatments on chronic disease. Treatments included conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE+MPA, and tamoxifen. Doses were scaled from those given women. Treatments were given in the diet for three years, followed by necropsy and tissue collection. Endpoints evaluated included glandular histology, histomorphometry, and immunohistochemical detection of the proliferation marker Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in mammary epithelial cells. Major findings were as follows: CEE induced PR expression and focal to diffuse lobuloalveolar proliferation. Proliferation was increased by the addition of MPA, but was not induced by MPA alone. Tamoxifen induced ER and PR but not Ki-67 expression or glandular hyperplasia. Neoplasms were not seen. These findings indicate that progestogens may exacerbate, not antagonize mammary gland proliferation induced by estrogen replacement therapy, and that tamoxifen has both estrogen agonist and antagonist effects on sex steroid receptor expression in the normal primate breast.

Dietary Soy Isoflavones Inhibit Estrogen Effects in the Postmenopausal Breast

“…In this study, high physiologic isoflavone doses inhibited estrogen-induced proliferation in the breast and induced divergent effects on ER-mediated targets as seen with synthetic SERMs. Tamoxifen, for example, has been shown to decrease proliferation (38), increase PR expression (20,39), and decrease pS2 expression (40) in the breast, providing a similar profile to that seen with high-dose isoflavone treatment. These data indicate that dietary soy isoflavones, rather than simply blocking ER transactivation, may induce unique ER-driven expression patterns in breast tissue.…”

“…The primary end point of this study was breast epithelial proliferation as determined by Ki-67 (MIB-1) immunostaining. Ki-67 expression is an important prognostic indicator in human breast cancer (19) and has been used extensively in our model to predict risk associated with hormonal agents (20,21). Secondary end points included key markers of ER activity in the breast, serum estrogens, and measures of estrogen exposure in other reproductive tissues.…”

Progestin Treatment Induces Apoptosis and Modulates Transforming Growth Factor-β in the Uterine Endometrium

“…Test compounds were administered daily in the diet throughout the study period at human equivalent doses on a caloric basis to 0.625 mg/d/woman for CEE and 2.5 mg/d/woman for MPA. This dosing strategy is metabolically based and thus results in relative doses similar to those produced by allometric calculations (29); most importantly, it produces serum concentrations in the range of those seen in women taking hormone therapy (30,31). The duration of treatment was 36 months.…”

Expressão dos fatores de proliferação celular PCNA e Ki-67 e receptores de estrogênio e progesterona em tecido mamário normal de mulheres na pós-menopausa submetidas a dois esquemas de terapia de reposição hormonal

“…Apenas dois trabalhos na pós-menopausa com estímulo de TRHM foram encontrados na literatura disponível (39)(40)(41), talvez em decorrência de questão ética que dificulta a obtenção de amostras para o estudo. No presente trabalho, por exemplo, sete pacientes não desejaram repetir o procedimento de realização da segunda bióp -sia por fragmento.…”