Impacts of progesterone and estradiol levels on ventilatory chemoreflexes measured by rebreathing in premenopausal women

The hypoxic and hypercapnic ventilatory responses (HVR, HCVR, respectively) are the reflex increases in breathing in response to decreases in arterial oxygen or increases in arterial carbon dioxide partial pressures. These reflexes are highly variable both within individuals as a result of pathologies or environmental exposures, as well as across populations. However, the mechanisms underlying individual variation in these responses are still under investigation. Despite decades of research examining the effects of sex hormones progesterone and estrogen on ventilatory chemoreflexes, there remains no strong consensus and data are conflicting. Some studies have reported differences in the HVR in menstruating women compared to men and postmenopausal women, but few studies investigate this link further, and data within menstruating non-pregnant women are less conclusive. One reason for this includes the common use of self-reported cycle information to estimate menstrual phases. However, this method is unreliable due to large variability in individual cycle and phase lengths. We directly measured plasma progesterone and estradiol levels, as well as the HVR and HCVR using the Duffin modified rebreathing chemoreflex method, in 40 healthy, nonpregnant menstruating women. We hypothesized that higher progesterone levels would be associated with elevated HVR as previously reported in some studies. Our results indicate that higher progesterone levels, were either not associated with HVR, or associated with a moderate decrease in HVR depending on the level of isocapnia during testing (HVR at 50 mmHg ETPCO 2 : r s = 0.12, p = 0.47; HVR at 55 mmHg ETPCO 2 : r s = -0.43, p = 0.03). Similar results were obtained for progesterone/estradiol ratios (HVR at 50 mmHg ETPCO 2 : r s = -0.02, p = 0.92; HVR at 55 mmHg ETPCO 2 : r s = -0.47, p = 0.02). However, since progesterone levels in our sample peaked near 10-20 ng/ml, it is possible that higher progesterone levels, such as those observed in pregnancy, would be linked to higher HVRs as observed in other studies with higher progesterone ranges and treatments. There was no association between progesterone and HCVR or the ventilatory recruitment threshold when measured in hyperoxic (inspired PO 2 = 228 mmHg) or hypoxic (end-tidal PO 2 = 50 mmHg) conditions. Overall, these findings indicate that the impact of progesterone on the isocapnic HVR in menstruating women may be moderate at lower hormone levels. This work was supported by a UC Riverside Health Disparities Research Center subaward and UC Riverside OASIS award to ECH, and an Undergraduate Mini Grant to TS. This abstract was presented at the American Physiology Summit 2025 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.