Combined Effects of Dehydroepiandrosterone and EM-800 on Bone Mass, Serum Lipids, and the Development of Dimethylbenz(A)Anthracene-Induced Mammary Carcinoma in the Rat

Abstract

Although treatment with dehydroepiandrosterone (DHEA) and the antiestrogen EM-800 alone decreased dimethylbenz(A)anthracene (DMBA)-induced mammary tumor incidence from 95% to 57% and 38%, respectively, approximately 9 months after DMBA administration, only two tumors developed in the group of animals that received the combination of DHEA and EM-800, and these two tumors disappeared before the end of the experiment (P < 0.01 vs. DHEA or EM-800 alone). Average tumor number per tumor-bearing animal as well as average tumor area per tumor-bearing animal were further decreased in animals that received the combination therapy compared with the effect of each treatment alone (P < 0.01). DHEA induced 6.9% (P < 0.01), 10.6% (P < 0.05), and 8.2% (P < 0.01) increases in bone mineral density of total skeleton, lumbar spine, and femur, respectively. The addition of EM-800 to DHEA did not affect the enhancing effect of DHEA on bone mass. The combination of the two drugs had important inhibitory effects on the urinary excretion of calcium and phosphorus as well as on the urinary hydroxyproline/creatinine ratio. Serum total alkaline phosphatase was stimulated by DHEA. Treatment with EM-800 decreased both serum triglyceride and cholesterol levels, whereas DHEA had an inhibitory effect on serum triglycerides. Although treatment with EM-800 caused a marked atrophy of the mammary gland, DHEA alone reduced lobular hyperplasia seen in aged intact rats while causing an androgen-specific stimulation of the same structures in animals already receiving the antiestrogen EM-800. The combination of DHEA and EM-800 lowered ovarian weight by 24% (P < 0.01) and decreased serum estradiol concentrations to intact control levels, whereas each compound alone had no effect on ovarian weight and stimulated serum estradiol levels by 45% (P < 0.05) and 46% (P < 0.05), respectively. Treatment with EM-800 caused a marked inhibition of uterine and vaginal weight. The present data show the additive inhibitory effects of DHEA and EM-800 on the development of DMBA-induced mammary carcinoma in the rat, thus suggesting the potential benefits of such a combination for the prevention of breast cancer in women while preserving or even increasing bone mass and maintaining a favorable lipid profile.

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

“…11,12 The present study extends these ®ndings by demonstrating that treatment of OVX rats with EM- HCl is at least as effective as estrogen replacement therapy in reverting obesity and its related lipid and glucoseainsulin abnormalities induced by OVX. Estrogen removal through OVX profoundly altered energy balance and lipid metabolism, as previously described by us and others 4 ± 7,19,20 In brief, OVX increased energy intake and food ef®ciency, which resulted in a larger deposition of body energy, mainly in the form of fat.…”

“…10 Despite its pure antiestrogenic activity in the mammary gland and endometrium, EM-652.HCl can be classi®ed as a selective estrogen receptor modulator, based on some`estrogen-like' properties of EM-800, the prodrug of EM-652, such as the prevention of bone loss and the lowering of plasma cholesterol and triglycerides. 11,12 In the course of studies on the action of EM-800, the prodrug of EM-652, collateral observations have suggested that these compounds may exert effects upon metabolic pathways associated with energy balance, glucose and lipid metabolism. 11,12 These observations, which suggested that the estrogen antagonist EM-652.HCl may exert effects that mimic, rather than antagonize, those of estrogen on energy and lipid metabolism, prompted us to undertake the present study to assess in detail such actions in a rat model.…”

“…11,12 In the course of studies on the action of EM-800, the prodrug of EM-652, collateral observations have suggested that these compounds may exert effects upon metabolic pathways associated with energy balance, glucose and lipid metabolism. 11,12 These observations, which suggested that the estrogen antagonist EM-652.HCl may exert effects that mimic, rather than antagonize, those of estrogen on energy and lipid metabolism, prompted us to undertake the present study to assess in detail such actions in a rat model. The experimental strategy consisted of evaluating the potential of EM-652.HCl to antagonize the effects of OVX on energy balance and lipid metabolism, and to compare its action with that of estrogen replacement.…”

A Comparitive Study to Evaluate the Role of Serum Lipid Levels in Aetiology of Carcinoma Breast

“…Studies have shown that obese women are more likely to have large tumors, greater lymph node involvement, and poorer breast cancer prognosis with 30% higher risk of mortality [5]. Levels of circulating lipids and lipoproteins have also been associated with high breast cancer risk, though published results have been varying [6][7][8].…”

The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats

“…SCH 57068 and its pro-drug, SCH 57050, significantly inhibit growth and prevent development of DMBAinduced mammary carcinomas in the Sprague-Dawley rat [3][4][5]. SCH 57050 also prevents bone loss and decreases serum cholesterol levels in the ovariectomized (OVX) rat [2,6].…”