Estrogen replacement therapy (ERT) in the form of conjugated equine estrogens (CEE) is one of the most commonly prescribed medications for post-menopausal women at risk for atherosclerosis and osteoporosis. Decades of use by women have shown it to be very efficacious, however, it also has the undesirable effects of stimulation of breast and uterine tissue. Long term use is assoicated with increased risk of breast and uterine cancer. Therefore the current hope for the future are selective estrogen receptor modulators (SERMS). The properties of this class of drug allow it to act only on certain tissues. Recent studies of a new SERM named Levormeloxifene (LMX) performed in rabbits found in 50 percent reduction in aortic atherosclerosis, reduced plasma cholesterol by 30 percent, and did not stimulate uterine or testicular tissue. Therefore, this is a drug with the potential to inhibit coronary atherosclerosis (CAA) without affecting reproductive tissue. The long- term objective of this proposed study is to determine that Levormeloxifene treatment of surgically post-menopausal Yucatan Micropigs will decrease coronary atherosclerosis and its risk factors without stimulation of uterine and breast tissue. The study design includes three (placebo, LMX, CEE) treatment groups of ovariectomized Microswine fed a high fat and high cholesterol (Western type) diet for six months. The CEE (Premarin) treated group will serve as a positive control. The expectations for the LMX treated group are: a.) decreased coronary artery atherosclerosis quantified by digitization after necropsy. b.) increased prostacyclin and no change in thromboxane production of in vitro isolated arachidonic acid stimulated arterial segments. c.) increased plasma nitrite, decreased endothelin-1 and lower blood pressure. d.) a favorable effect on plasma lipid profiles. e.) no significant stimulatory effect on uterine and breast tissue. In summary, the beneficial health effects of LMX are hypothesized to be similar to conjugated equine estrogens without the adverse effects on the uterus and breast. The data produced by this pilot study will be used for an NIH R01 grant application for a full scale study.
| Goodrich, James A; Clarkson, Thomas B; Cline, J Mark et al. (2003) Value of the micropig model of menopause in the assessment of benefits and risks of postmenopausal therapies for cardiovascular and reproductive tissues. Fertil Steril 79 Suppl 1:779-88 |
| Goodrich, J A; Lackland, D T; Del Signore, M J et al. (2001) Non-invasive measurement of blood pressures in the Yucatan micropig (Sus scrofa domestica), with and without midazolam-induced sedation. Comp Med 51:13-5 |
