SAT-015 Brain-Selective Estrogen Therapy to Prevent Menopausal Hot Flushes in a Primate Model

Abstract Disclosure: H. Hoorfar: None. M. Lane: None. V. Nguyen: None. G. Aberdeen: None. H.F. Urabanski: None. A. Puche: None. L. Prokai: None. I. Merchenthaler: None. Brain-Selective Estrogen Therapy to Prevent Menopausal Hot Flushes in a Primate Model The most immediate and patient-reported ‘unbearable’ symptom of the menopause is hot flush (HF). Among current treatments, only estrogen therapy is effective but is associated with unwanted side effects in the periphery, including the stimulation of the uterus and breast leading to significantly increased cancer risk. Recently, the FDA approved the neurokinin-3 antagonist fezolinetant for HF treatment, which modulates the activity of the neurokinin-B neurons involved in thermoregulation. While having reasonable efficacy in reducing severe HFs, the presence of any liver or renal disease is a contraindication for this medication. Fezolinetant however has none of the other beneficial effects of estrogen (improving cognition and sleep, reducing depression/anxiety). What is needed is a treatment that is intrinsically safer, broadly acting to address the multiple roles of estrogen in the brain and has no side effects in peripheral organs. This study investigates the effectiveness of a brain-selective 17β-estradiol (E2) therapy using the E2 prodrug DHED (10β,17β-dihydroxyestra-1,4-dien-3-one) to reduce HF frequency in rhesus macaques. DHED can be taken orally and has no bioactive properties until it is selectively converted to E2 in the brain. This approach putatively eliminates negative side effects of circulating E2 by restricting the formation of E2 only to the brain, thus avoiding undue uterus/breast exposure to circulating E2 present with current therapies. In rhesus macaques, HF manifest appears as elevated nose and face temperature of a range like humans, 4–6 °C elevation. We monitored HFs continuously using non-invasive infrared imaging taking an image every five seconds in undisturbed animals. In these longitudinal studies, animals served as their own control. Imaging started with intact animals, followed by ovariectomy (OVX), washout, ethinyl estradiol (EE), washout, and DHED treatment. Each of these segments lasted six to eight weeks. Like EE, DHED was administered orally using a twice daily oral dosing regimen applicable to a human relevant regimen and based on preliminary assessment of its pharmacokinetics.Both EE (positive control) and DHED were highly effective in reducing HF frequency. The highest HF rates occurred during the post-OVX (7.67 ± 1.69/day) and washout periods between treatments (6.76 ± 2.13/day). As expected, EE reduced HF frequency to 2.02 ± 1.23/day and DHED to a comparable 1.91 ± 0.98/day compared to OVX. Post OVX peripheral E2 levels were low/undetectable and DHED treatment did not result in any increase, indicating DHED treatment yields negligible circulating E2 despite being as effective as oral EE for HF. These findings underscore the effectiveness of DHED as a novel, innovative, and safe therapy of menopausal HFs without unwanted side effects in the periphery. Presentation: Saturday, July 12, 2025