Influence of Ovarian Hormones on Exertional Heat Stroke in Mice

Exertional heat stroke (EHS) is the most severe form of heat-related illness. Despite females comprising roughly half of the global population and their expanding participation in sports and military activities, a substantial gap remains in female-specific responses to heat stroke. In a murine model of EHS, females demonstrate greater exercise capacity compared to males. However, the increased exercise capacity is lost in ovariectomized mice. Also, the phase of the female estrous cycle- the rodent equivalent of the menstrual cycle in humans— influences exercise capacity in the heat. Since ovarian hormones (e.g., estrogens and progesterone) levels fluctuate during the estrous cycle we hypothesized that the ovarian hormones could influence exercise capacity in the heat. To test this hypothesis, we compared the exercise capacity, measured as time to loss of consciousness (LOC) in the heat in ovariectomized mice receiving exogenous progesterone or estradiol. Adult C57BL/6 female mice were ovariectomized and implanted with telemetry sensors to measure core temperature (Tc) followed by an implant of an osmotic pump containing progesterone (P, n=33), estradiol (E, n=36), or the respective vehicle solvent saline (V-Sal, n=36) or PEG400 (V-PEG, n=40). Each mouse exercised in an individual forced wheel running device inside an environmental chamber set at 37.5°C and 40% relative humidity. The protocol began at a wheel speed of 2.5 m/min, increasing by 0.3 m/min every 10 minutes until reaching LOC. There were no differences in time to LOC between the hormone and respective vehicles (V-Sal: 132.7 ± 31.8 min, P-Sal 130.5 ± 32.7 min, p= 0.78; V-PEG 119.9 ± 21.7 min, E-PEG 121.8 ± 26.5 min; p=0.74) or maximal speed (Smax; V-Sal: 5.3 ± 1.1 m/min, P-Sal 5.5 ± 1.0 m/min, V-PEG 5.1 ± 0.6 m/min, E-PEG 5.3 ± 0.9 m/min; p=0.28), in spite of the lower initial Tc (V-PEG 37.76 ± 0.46°C, E-PEG 37.41 ± 0.70°C; p=0.01) and higher final Tc (V-PEG 41.97 ± 0.31°C, E-PEG 42.22 ± 0.21°C; p< 0.01) observed in E group. In conclusion, continuous delivery of a single hormone (e.g., estradiol or progesterone) did not restore exercise capacity in ovariectomized animals exposed to EHS. These findings suggest that in our model of EHS, the higher exercise capacity in intact (non-ovariectomized) females observed previously likely depend on the combined, interactive actions of estradiol and progesterone and on the physiological, pulsatile pattern in which these hormones fluctuate across the estrous cycle. Funding: DoD. USAMRAA. HT9425-23-PRMRP-FPA Grant log number BA220322 to OL. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.