When CO2 sensing fails: Protective effects of sex hormones and potential mechanisms

Abstract

Breathing movements driven by the brainstem rhythmogenic neural networks rely on chemosensory inputs to produce a motor output that is homeostatically adjusted to the prevailing metabolic demand. The central CO₂ chemoreflex is a critical component of respiratory neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably, a potent progestin drug, etonogestrel (ETO), has been shown to enhance CO₂-chemosensitivity in animal models and in a subset of female patients affected by congenital central hypoventilation syndrome. Our recent work shows that systemic chronic ETO treatment recovered the CO₂ chemoreflex in female rats in which <80% of neurons of the key CO₂ chemosensory structure of the retrotrapezoid nucleus (RTN) were eliminated, whereas male rats with similar lesions and ETO serum levels did not show recovery of the CO₂ chemoreflex. Interestingly, female respiratory recovery was associated with increased expression of the pH sensors Task2 and Gpr4 mRNA in the surviving RTN neurons, suggesting that progestin drugs may recover the CO₂ chemoreflex responses in a sex-specific fashion.