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

Abstract

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.

Keywords: Cognition; Drug development; Estrogen therapy; Hippocampus; Hot flash; Hot flush; Memory; Menopause; Vasomotor.

Figure 1.. Timeline illustrating several seminal events in the development of estrogen-based hormone therapies for alleviating menopausal symptoms.

The bars proceed forward chronologically from top to bottom. However, the distance between each pair of bars does not accurately represent elapsed time between them. See text for discussion of each event. Created in BioRender. Frick, K. (2025) https://BioRender.com/vgpjbgv

Figure 2.. Overview of primary ERβ impacts on hippocampal function and hippocampus-dependent memory.

Upward arrow represents “increased”. Created in BioRender. Frick, K. (2025) https://BioRender.com/rx55gx1

Figure 3.. The gonadal-hypothalamic circuit regulating hot flashes.

See text for detailed description of the circuit. FSH = follicle stimulating hormone; GnRH = gonadotrophin releasing hormone; KNDy = kisspeptin/neurokinin/dynorphin; LH = luteinizing hormone; NKB = neurokinin B; NK3R = neurokinin 3 receptor. Created in BioRender. Frick, K. (2025) https://BioRender.com/b058dwt

Figure 4.. Long-term EGX358 treatment improves memory and alleviates a drug-induced hot flash in wild-type mice.

A, B: Schematic illustrations of the training and testing phases of the object placement and object recognition tasks. C, D: OVX C57BL/6 mice receiving long-term oral gavage treatments of 17β-estradiol (E2) or EGX358 spent significantly more time than chance (15 sec) with the moved (C) or new (D) objects, whereas vehicle-treated mice did not, indicating that these treatments enhanced memory in both tasks. Diarylpropionitrile (DPN) significantly enhanced memory in object placement. *p<0.05, **p<0.01 relative to chance. E: Structure of EGX358. F: Thermal imaging showing mice injected with vehicle (left) or the NK3R agonist senktide (right). Note the differences in tail skin temperature (tail on vehicle mouse outlined in dashes). G: Change in tail skin temperature (T_skin) relative to the 10 min baseline recording period (shown to the left of the y axis). Senktide was injected at time 0 (y-axis) and T_skin recorded every minute for 20 minutes. E2, DPN, and EGX358 reduced the magnitude of the change in T_skin during minutes 5–10 after senktide injection and produced faster returns to baseline. Horizontal lines above specific data points indicate the times at which that colored group was significantly different (*p<0.05) from vehicle (e.g., the EGX358 group had lower T_skin in minutes 5–9, 16, and 19 compared with vehicle, indicated by red horizontal lines). Figure adapted from open access article Fleischer et al., 2021, which is freely available under the Creative Commons CC-BY license.

Figure 5.. The efficacy of long-term EGX358 treatment on memory and hot flashes in an Alzheimer’s mouse model depends on APOE genotype.

Six month-old mice of the APOE^+/+/5xFAD^+/− (EFAD) transgenic model of Alzheimer’s received long-term oral vehicle or EGX358 via hydrogel. EFAD mice exhibit at this age exhibit substantial Alzheimer’s-like pathology in the hippocampus and cortex. A: EGX358 significantly enhanced object recognition memory in both E3FAD and E3/4FAD OVX mice, suggesting that this type of memory is responsive to ERβ activation in mice with one or two copies of APOE3. *p<0.05 and **p<0.01 relative to chance; #=significant main effect of treatment in ANOVA. B: EGX358 reduced the magnitude of the senktide-induced hot flash (change in T_skin) in E3FAD mice only, indicating that one copy of APOE4 blunts the thermoregulatory response to ERβ activation. $$$=significant main effect of time (p<0.0001), ###=significant main effect of treatment (p<0.0001); &&&=significant main effect of genotype (p<0.0001); # × &=significant treatment × time interaction (p<0.05). Figure adapted from open access article Schwabe et al., 2024, which is freely available under the Creative Commons CC-BY license.