Differential response in cell proliferation to beta estradiol in coronary arterial vascular smooth muscle cells obtained from mature female versus male animals.

Although the cardioprotective effect of estrogen is well recognized, the mechanisms by which this sex steroid provides a reduction in coronary artery disease are not fully understood. Vascular smooth muscle cells (VSMC) are present in early atherosclerosis and become the dominant cell type. VSMC contain estrogen receptors and may have specific responses to estrogen. We studied the effect of beta-estradiol on the proliferation of coronary VSMC obtained from sexually mature male, female, and oophorectomized pigs. Alpha-estradiol, an inactive isomer of estradiol, had no effect on cells obtained from male or female animals. In vascular smooth muscle cells obtained from sexually mature female animals, significant inhibition of proliferation of coronary vascular smooth muscle cells was noted at physiologic concentrations of beta-estradiol. Progesterone inhibited VSMC proliferation at concentrations of 10(-9)M. In contrast, beta-estradiol did not alter proliferation in porcine coronary vascular smooth muscle cells obtained from sexually mature male or from oophorectomized female animals. This study is the first to indicate, in an animal model, specific gender-related differences in cell proliferation in response to sex steroid hormones.

Prevention and treatment of osteoporosis in women with breast cancer.

Women who have had breast cancer may be at higher risk for osteoporosis than other women. First, they are more likely to undergo early menopause, due to chemotherapy-induced ovarian failure or oopherectomy. In addition, chemotherapy may have a direct adverse effect on bone mineral density (BMD), and osteoclastic activity may increase from the breast cancer itself. While estrogen therapy is considered standard for the prevention and treatment of osteoporosis, use of estrogen in women with a history of breast cancer is usually contraindicated. The approach to osteoporosis in women with breast cancer is also affected by the use of tamoxifen in many, as this drug appears to have opposite effects on BMD in premenopausal and postmenopausal women. We have reviewed therapeutic alternatives for the prevention and treatment of osteoporosis, focusing on patients with a history of breast cancer. Alendronate and raloxifene are currently approved in the United States for the prevention of osteoporosis; alendronate, raloxifene, and calcitonin are approved for treatment. Alendronate has the greatest positive effect on BMD and reduces the incidence of vertebral and nonvertebral fractures. Raloxifene and calcitonin appear to reduce the incidence of vertebral fractures; their effects on the incidence of nonvertebral fractures are not yet proven. Although no published studies specifically address the use of these approved agents for osteoporosis in women with breast cancer, understanding their relative effects on BMD in postmenopausal women in general will facilitate therapy selection in this population. Postmenopausal women with a history of breast cancer should undergo bone mineral analysis. Normal results and absence of other risk factors ensure that calcium and vitamin D intake are adequate. If osteopenia or other risk factors are present, preventive therapy with alendronate or raloxifene should be considered. For osteoporosis, treatment with alendronate should be strongly considered. Raloxifene and calcitonin are alternatives when alendronate is contraindicated. Further studies are needed to evaluate the optimal timing of initial bone mineral analysis in premenopausal women after breast cancer diagnosis and to determine the value of preventive treatment in women scheduled to undergo chemotherapy.

Gender-related differences in vascular smooth muscle cell proliferation: implications for prevention of atherosclerosis.

Premenopausal women have a significant reduction in coronary artery disease compared to age-matched males. Little is known about the mechanism underlying this cardioprotective effect of estrogen. Contradictory evidence has been published and our lack of basic understanding of hormone interactions and bioavailability of different estrogens prevents definitive interpretation of these data. We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature animal model. Vascular smooth muscle cells are an integral component of the atherosclerotic plaque, and inhibition of cell proliferation by estrogen may be one mechanism by which estrogen exerts its cardioprotective effect. Various types of estrogen may also have different mechanistic actions on the vascular system. No differences are demonstrated in overall estradiol binding in vascular smooth muscle cells obtained from male or female animals: however, differences in c-jun, c-fos and TIEG gene expression were gender related. Inhibition of vascular smooth muscle cell proliferation may have important implications in the prevention of atherosclerotic disease and these studies may provide evidence for the cardioprotective effect of estrogen.