Menopause is an inevitable consequence of aging in women, and it affects the quality of life of millions of women all over the world. Menopausal symptoms including hot flushes, a decline in cognitive function, sleep disorders, depression/anxiety, cardiovascular disease, genitourinary conditions, and osteoporosis. These symptoms have been shown to be causally linked to a decline in circulating sex steroid concentrations, which is particularly dramatic after menopause. Consequently, menopausal symptoms are considerably more problematic in elderly women than in elderly men. The most immediate and unbearable symptoms of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood and behavior and in general, the quality of life. Among current treatments of hot flushes, only estrogen therapy and hormone therapy (estrogens and progestins have satisfactory efficacies. Although estrogens prevent hot flashes, they have unwanted side effects in the periphery, including the stimulation of the uterus and breast, and the increased risk of cancer risk in these organs. Although there has been a great effort to develop safer estrogens, the lack of animal model(s) reminiscent for the symptoms, their pathomechanism, temporal pattern, etc. of women's menopause has had a tremendous negative impact on the success of this effort. We have recently shown that nonhuman primates, such as the rhesus macaque, undergo a menopausal process that is hormonally identical to that of women. They, therefore, hold great promise for studies aimed at elucidating the mechanisms that underlie hot flushes in women, and for the development of safe and effective therapies. Although the use of NHPs for studies aimed at developing novel treatments for menopausal symptoms is critical, due to high costs and technical problems, there have been only two studies utilizing them in the last 30 years. This proposal has been written in response to PA-13-156: Development and characterization of animal models for aging research (R21). We propose to develop a novel, non-invasive NHP model of hot flush, using novel non-invasive technology. Specifically, our primary goal here is to evaluate a primate model of hot flush, by examining the effects of ovariectomy and subsequent treatment with estrogen, on adult rhesus monkey facial skin temperature, using infrared thermal imaging (FLIR T650sc) without restraining the animals. Once the monkey hot flush model is established and the new non-invasive thermal imaging methodologies validated, we intend to submit a new R01 application to evaluate our novel and innovative approach to treat menopausal hot flushes with a brain-selective estrogen which would not have side effects in peripheral organs such as the uterus and breast.
The most immediate and unbearable symptoms of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood and behavior. Although there has been a great effort to develop novel therapies to alleviate these unbearable menopausal symptoms, the lack of animal model(s) reminiscent for those menopausal women experiencing has had a tremendous negative impact on the success of this effort. We propose to develop a novel, non-human primate model of hot flush, using thermo-imaging, an innovative, non- invasive technology to measure skin temperature following estrogen therapy. Once the primate model has been established and validated, we will introduce a novel brain-selective estrogen therapy, free of side effects in uterus and breast for the treatment of menopausal symptoms.
| Merchenthaler, Istvan; Lane, Malcolm; Sabnis, Gauri et al. (2016) Treatment with an orally bioavailable prodrug of 17?-estradiol alleviates hot flushes without hormonal effects in the periphery. Sci Rep 6:30721 |
