Not your mother's hormone therapy: Highly selective estrogen receptor beta agonists as next-generation therapies for menopausal symptom relief

Although the menopausal transition causes a panoply of unpleasant and disruptive symptoms, many women are reluctant to use estrogen-based treatments due to risks of cancer, cardiovascular disease, and stroke. As we learn more about how estrogens regulate the cellular and circuit mechanisms underlying menopausal symptoms such as hot flashes and brain fog, drug development that specifically targets these mechanisms could provide the therapeutic benefits of estrogens without adverse health effects. This review discusses the rationale for targeting estrogen receptor beta (ERß) with highly selective synthetic agonists to alleviate two common menopausal symptoms: memory dysfunction and hot flashes. We begin by reviewing the history of estrogen-based menopausal hormone therapy, including conjugated equine estrogens and related products. We then describe the neurobiological mechanisms underlying estrogenic regulation of memory and hot flashes, with a particular focus on the role of ERß. Finally, we discuss past and current clinical trials of ERß agonists and highlight pre-clinical data showing that a highly potent and selective synthetic ERß agonist can enhance object recognition and spatial memory, and reduce a drug-induced hot flash, in mouse models of ovarian hormone loss and Alzheimer's disease. Collectively, this work supports the targeted development of highly selective ERß agonists to relieve memory and vasomotor symptoms of menopause.