Nonprimate animal models of menopause: workshop report

Menopause, an understudied, normal biological process in middle-aged women, is associated with loss of fertility and increased risk for osteoporosis and cardiovascular disease. Appropriate animal models allow in-depth investigation of biological mechanisms that underlie the increased risk for adverse health events in menopausal women. Although some species of older female nonhuman primates experience a menopause-like condition, with cessation of reproductive cycles, decreased bone density, and perhaps an increased risk for atherosclerosis, several factors restrict their usefulness for research (e.g., expense of purchase and care, relatively small numbers of animals available, risk for disease transmission to humans, limited facilities for experimentation). Thus, it may be useful to consider nonprimate animal species as potential models for pathophysiological changes associated with loss of reproductive function.

A workshop was convened in June 1998 at the National Institutes of Health to explore the suitability of nonprimate animal species in this context. The focus of this workshop was on middle-aged, ovariectomized females of various laboratory animal species and the ability of exogenous estrogen to reverse pathophysiological changes in the skeleton, cardiovascular system, and thermoregulatory control mechanisms in these species.

Of the species considered (mice, rats, dogs, rabbits, pigs, and sheep) and because of the limitations of relatively small amounts of research in ovariectomized, middle-aged animals for most of these species, mice (largely because of transgenic technology) have the potential to be good models for the effect of ovariectomy and estrogen replacement on associated bone and cardiovascular changes. Rats are an excellent model for bone but a poor model for the cardiovascular system changes associated with loss of reproductive function. Usefulness of the pig, which is usually considered to be a good model for the human cardiovascular system, is limited by the dearth of information available on ovariectomized mature pigs in cardiovascular and bone studies, sensitivity of bone density to dietary calcium, the difficult-to-manage size of regular pigs, and the relatively high cost of minipigs. Rabbits show good potential as a cardiovascular model despite the limited numbers of studies and the difference from primates in coronary artery structure. Although rabbits are the smallest species known to have Haversian bone remodeling processes, the limited number of bone studies in ovariectomized rabbits is confounded by effects of dietary calcium. Although there are virtually no studies on the cardiovascular system of the ovariectomized dog, bone studies that have been conducted suggest that it is a poor model for the menopausal human. Furthermore, the role of estrogen in bone and cardiovascular physiology is difficult to interpret because of the limitation of two estrus cycles per year in the dog. The sheep seems to be a promising large animal model for the bone and cardiovascular systems, but more research is needed. Of the species examined for estrogen effects on vasomotor symptoms (guinea pig, mouse, rat, and monkey), only rats and monkeys show evidence of hot flashes associated with loss of reproductive function.