Menopause in women is an understudied normal aspect of the aging process that is associated with a loss of estrogen production and increased risk of cardiovascular disease and other health problems. Estrogen is generally considered to be cardioprotective. There are currently unprecedented numbers of women, about 50 million, in the United States reaching menopause; cardiovascular disease is the number one killer of postmenopausal women. Animal models provide a means of performing critical studies of the biological mechanisms and responses to existing and emerging therapies for this condition (i.e. soy protein/isoflavones). A nonprimate animal model of menopause is needed to provide a research tool that is: 1) readily available to many researchers; 2) low in risk for zoonotic disease; 3) domesticated; 4) a low cost rapidly renewable resource; 5) possess a similar coronary artery anatomy; and 6) atherosclerotic lesion to that of women. The ovariectomized Yucatan Micropig has the potential to fill this void, and will serve the interests of both the NIA and NHLBI. The overall objective of this application is to develop, characterize, and improve the Yucatan Micropig Model of Menopause for use in cardiovascular studies. This will be approached by Aim 1 clarifying the cardioprotective effects of soy protein in this model by measuring the extent of the reduction in coronary artery atherosclerosis, serum lipids, inflammatory risk factors (C-reactive Protein, Interleukin-6) and blood pressure among soy, control, and conjugated equine estrogen treated groups. Establishing that soy protein can reduce coronary artery atherosclerosis in Micropigs, like it does in monkeys, would provide foundation data helpful to future soy isoflavone mechanistic studies in the Micropig model. Studies to determine how soy isoflavones and soy protein interact to reduce serum cholesterol and subsequently coronary artery atherosclerosis are needed. The next step is Aim 2, to examine the effects of these treatments on reproductive tissue. The investigators approach this aim by comparing uterine weights, and mammary and uterine immunohistology among these groups. The third step Aim 3, is to determine if and to what extent there is a natural female cardioprotection in the Yucatan Micropig. The investigators will approach this by comparing groups of male, ovariectomized female, and intact female Micropigs fed an atherogenic diet. The end points will be identical to those of the first aim. Finally, Aim 4, is to determine if and to what extent ovariectomized female Yucatan Micropigs experience vasomotor symptoms or hot flashes related to estrogen deficiency. This will be approached through continuous telemetric monitoring of skin temperature spikes before and after ovariectomy and then with and without estrogen replacement therapy. The future plans for this model are to use it to study the cardiovascular benefits/risks of new progestins, selective estrogen receptor modulators, tissue selective estrogens, and isoflavone products, as well as the mechanism by which soy protein lowers serum cholesterol and coronary artery atherosclerosis.
