INTRODUCTION: Progesterone is a crucial hormone for sustaining health in males and females, including maintaining pregnancy, upregulating myelin proliferation, and promoting testosterone biosynthesis. Progesterone is also known to decrease wheel running in mice, an established model of voluntary physical activity, by an estrogen-dependent pathway. Estrogen mediates wheel running through the action of estrogen receptor alpha (ERα), an intracellular transcription factor that upregulates wheel running, but it is not known how progesterone interacts with the ERα pathway to influence wheel running. Given the important role of progesterone in human health, it is valuable to investigate how this hormone interacts with the ERα pathway on a molecular level to identify possible physiological interactions. It is hypothesized that if progesterone interacts with the estrogenic regulatory pathway upstream of ERα, a significant decrease in wheel running distance, duration, and speed will not be expected between the progesterone treatment levels since these progesterone effects will be equalized by subsequent activation of ERα by an administered agonist. If progesterone interacts with the estrogenic regulatory pathway downstream of ERα, a significant decrease in wheel running will be expected with increasing doses of progesterone. METHODS: Female (n=12) C57BL/6J mice were individually housed in environmental exclusion cages with a solid surface running wheel (circumference = 450 mm) and acclimated to running wheel use for 12 days, followed by 7 days of baseline data collection. All mice underwent bilateral ovariectomy surgeries and then had a 10-day recovery period to allow recovery and removal of circulating endogenous estrogen. After recovery all mice received implants of propylpyrazoletriol (PPT), an ERα agonist, which was administered to selectively maintain the ERα receptor in an active conformation. PPT implants were placed concurrently with implants containing varying doses of progesterone: high progesterone with PPT, low progesterone with PPT, and no progesterone with PPT. Post-implant wheel running data were collected for 7 days. Wheel running indices were measured by a turn-by-turn running wheel monitoring system. All mice were provided ad libitum access to food (Teklad Global 18% Protein Rodent Diet) and water throughout the study and were kept on a 12-hour light:12-hour dark cycle. Distance, duration, and speed were assessed by individual 2-way, mixed factor ANOVAs. RESULTS: There was a significant decrease in wheel running following ovariectomies (p< 0.001), but there was no significant difference in wheel running distance, duration, or speed between post-ovariectomy and post-implant phases of the study. Additionally, there was no significant difference in wheel running distance between experimental groups. CONCLUSION: There was a significant drop in wheel running that failed to be recovered by the introduction of PPT with the implant surgeries. While PPT administration mimicked the dosing schedule used in other experiments, wheel running behaviors were unaffected. Higher doses may be required to fully assess progesterone's involvement in regulating this complex phenotype. Support or funding information: This work was supported by an undergraduate research grant from Union University and the Union University Department of Biology. 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.
Cook et al. (2026) studied this question.