Endocrinology. 2021 May 3;bqab087. doi: 10.1210/endocr/bqab087.
Declining and variable levels of estrogens around the time of menopause are associated with a suite of metabolic, vascular, and neuroendocrine changes. The archetypal adverse effects of peri-menopause are vasomotor symptoms, which include hot flashes and night sweats. Although vasomotor symptoms are routinely treated with hormone therapy, the risks associated with these treatments encourage us to seek alternative treatment avenues. Understanding the mechanisms underlying the effects of estrogens on temperature regulation is a first step toward identifying novel therapeutic targets. Here we outline findings in rodents that reveal neural and molecular targets of estrogens within brain regions that control distinct components of temperature homeostasis. These insights suggest that estrogens may alter the function of multiple specialized neural circuits to coordinate the suite of changes after menopause. Thus, defining the precise cells and neural circuits that mediate the effects of estrogens on temperature has promise to identify strategies that would selectively counteract hot flashes or other negative side effects without the health risks that accompany systemic hormone therapies.
Several estrogen-sensitive regions have been revealed as candidates for mediating the effects of estrogens on body temperature, but evidence suggests these areas work synergistically, antagonistically, and/or in parallel to modulate whole-body thermoregulation. Whereas estrogens affect body temperature by modulating both heat production and dissipation, many of these effects are mediated specifically or simultaneously via different estrogen-sensitive regions (13). We recommend a systems-level, circuit-based approach to dissect the distinct thermal effectors modulated by estrogens. Further, it is important to note that other hormones, such as leptin, insulin, and thyroid hormone, potently affect metabolism and thermoregulation through these estrogen-sensitive sites. Thus, it is of interest to decipher the potential interactions of estrogens and these hormones and their coordinated effects on temperature and energy balance. Future studies taking a circuit-based approach should also pay heed to connections and crosstalk between the thermoregulation and energy homeostasis systems, particularly as they both exhibit circuit-level modulation by estrogens.
Given the widespread impact of menopausal hot flashes on quality of life, it has become imperative to try to better understand the neural circuits responsible for the physiological effects of estrogens on body temperature. A deeper understanding of the modular and circuit-level consequences of estrogens will help to identify new potential targets for the development of therapeutics that could mimic the thermoregulatory effects of estrogens and avoid the detrimental side effects of hormone therapy.