Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model

ABSTRACT Menopause is an inevitable stage in normal human aging, affecting the quality of life of millions of women all over the world. Menopausal symptoms including hot flushes, sleep disorders, depression/anxiety, decline in cognitive function (Alzheimer’s disease is more prevalent in women and linked to estrogen), cardiovascular disease, genitourinary conditions, and osteoporosis. These symptoms have been shown to be causally linked to a sharp decline in circulating sex steroid concentrations after menopause. While men have similar decline in sex hormones, andropause symptoms are usually infrequent and mild. Consequently, menopausal symptoms are of considerably more pressing medical concern in elderly women than andropause in elderly men. Thus, this proposal focuses on women’s health and improved therapies for menopause. The most immediate and patient reported ‘unbearable’ symptom of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood, behavior and general quality of life. Among current treatments of hot flushes, only estrogen therapy (ET) and hormone therapy (HT, estrogens and progestins) have satisfactory efficacy. Although ET/HT prevents hot flushes, they have unwanted side effects in the periphery, including the stimulation of the uterus and breast leading to a significantly increased cancer risk in these organs. Although there have been extensive efforts to develop safer estrogens, the lack of animal model(s) that naturally recapitulate the symptoms and pathophysiology of human menopause has had a tremendous negative impact on the success of this effort. Only humans and our close mammalian cousins exhibit menopausal hot flush symptoms in normal aging or with ovariectomy. However, the most commonly utilized model for thermoregulation is rodent, which is limited for translational drug discovery with human menopause as rodents do not normally flush and do not sweat. We developed an old-world advanced translational animal model which undergoes a menopausal process that is hormonally identical to that of human women. We show that ovariectomy induces hot flushes that are exacerbated by niacin and nearly eliminated by estrogen therapy. This also involved development of novel use of non-invasive thermal imaging to detect these events, alleviating the need for older train-and-restrain models used in this species for hot flush research in the past. Using this model, we propose to test a novel estrogen prodrug therapy using 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED). DHED has ideal properties for a translational therapy for hot flushes. In the prodrug form it is highly shelf-stable at room temperature, can be taken orally, has no peripheral bioactive properties in the prodrug form and it is selectively converted to estrogen only in the brain, resulting in no peripheral side effects on uterus/breast. We propose a comprehensive testing of the pharmacological effectiveness of DHED to treat hot flushes in our advanced translational model as a key step to human clinical trials.