Novel Mouse Model of Human Menopause Available Soon at Bar Harbor Facility

JAX® NOTES Issue 505, Spring 2007

JAX® Services offers our novel menopause mouse model (formerly available only through JAX® West, Sacramento, Calif.) from our Bar Harbor, Maine facility. The model, known as the VCD-induced model (after the industrial chemical 4-vinylcyclohexene diepoxide used to induce the menopause state), was developed by Drs. Loretta Mayer and Patricia Hoyer at the University of Arizona College of Medicine (Mayer et al. 2002). Other models for human menopause are considered less appropriate or feasible. Non-human primates are too long-lived, and rodents neither menstruate nor experience human-like menopause. The ovariectomized (OVX) rodent model (either the rat or the mouse), the only non-genetically manipulated rodent model of menopause previously available, begins menopause too abruptly, skips perimenopause (the 1-10 year period of irregular menstrual cycles when women experience most of their discomforts), and doesn't simulate the hormonal cycling of perimenopausal women. Additionally, unlike OVX rodents, 90% of menopausal women still have their ovaries. Mayer and Hoyer discovered that VCD selectively accelerates the natural loss of the small primordial and primary ovarian follicles of mice and rats without affecting other tissues. Specifically, the B6C3F1/J mice (100010) used in their research develop persistent acyclic diestrus (the equivalent of human menopause) approximately 58 days after receiving intraperitoneal (IP) injections containing 160mg/kg body weight VCD for 15 days. Furthermore, 127 days after the 15-day VCD injection protocol, the endocrine state of these mice mimics that of ovary-intact post-menopausal women (Fig. 1): plasma estrogen levels are non-detectable, follicle stimulating hormone (FSH) levels are 10 times higher, ovarian and uterine weights are significantly lower, plasma leutenizing hormone (LH) levels are significantly higher, and plasma progesterone and androstenedione levels are significantly lower than those of controls (JAX® NOTES. 2004; Mayer et al. 2004, 2002).

VCD-induced menopause is a particularly powerful tool not only because it mimics human menopause, but because it works with most mouse strains, including models of atherosclerosis, osteoporosis, diabetes, Alzheimer's, cancer, and other diseases common among menopausal women. JAX® Services in Bar Harbor will offer the VCD-induced menopause model on at least 5 genetic backgrounds: C57BL/6J (000664), an atherosclerosis-susceptible strain; C3H/HeJ (000659), an atherosclerosis-resistant strain; B6.129S7-Ldlrtm1Her/J (002207), a strain with normally high serum cholesterol levels and extremely high levels when fed an atherogenic diet; B6.129P2-Apoetm1Unc/J (002052), another strain with high serum cholesterol levels; and NZBWF1/J (100008), a model of systemic lupus erythematosus. For additional cost, this service can be adapted to other strains.

A study recently conducted by our Animal Husbandry and Performance Group demonstrated the efficacy of VCD-induced menopause in these strains. A group of 10 4-week old females from each strain received IP injections containing 160 mg/kg of VCD daily, 5 days a week, for 3 weeks, and a group of 10 controls from each strain were injected with vehicle (sesame seed oil) only. On day 22, 150 ยตl of blood were collected from the periorbital sinus of each mouse. The blood was allowed to clot, and serum was removed, stored at -20 or -80oC, and later analyzed for FSH levels. Three mice from each group were euthanized, and their ovaries were removed and fixed in Bouin's solution for histological analysis. Blood samples and ovaries were similarly collected and handled on days 37 and either 51 or 58. VCD treatments significantly decreased the number of primordial and primary follicles (Fig. 2), resulting in a significant increase in FSH levels (Fig. 3).

Through an agreement with the University of Arizona, we have the exclusive right to inject VCD into appropriate mouse models and distribute them to the biomedical research community. The availability of the VCD-induced menopause model from our Bar Harbor facility should facilitate research of menopausal physiology, the efficacy of hormone replacement therapy, and the hypersusceptibility of menopausal women to various diseases.

For more information on this service, please contact your regional field manager (see back page of JAX® NOTES), visit the JAX® Services Web site, send an e-mail to jaxservices@jax.org, or call JAX® Services at 1-800-422-MICE (6423) or 1-207-288-5845.

Fig. 1. Cyclicity, estrogen levels, and FSH levels are similar in VCD-induced mouse and human menopause. The OVX mouse begins menopause quickly and skips peri-menopause, typically 1 to 10 years before human menstrucal cycles cease (post-menopause refers to the year after peri-menopause). Values for VCD-induced menopause are relative to the beginning of the 15-day VCD injection protocol.

Fig. 2. Number of follicles in VCD-treated vs. control NZBWF1 females on days 22, 37, and 51. Results in the other 4 strains tested were comparable.

Fig. 3. Serum FSH levels (ng/ml) in VCD-treated vs. control C57BL/6J females on days 22, 37 and 58. Data for other strains is unavailable.

References

Mayer L.P, Devine PJ, Dyer CA, Hoyer PB. 2004. The follicle-depleted mouse ovary produces androgen. Biology of Reproduction 71:130-8.

Mayer LP, Pearsall NA, Christian PJ, Devine PJ, Payne CM, McCusskey MK, Marion SL, Sipes IG, Hoyer, PB. 2002. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Repro Tox 16:775-81.

JAX® NOTES. 2004. A new mouse model for ovarian follicle loss in post-menopausal women. JAX® NOTES 494:6.