Breathe In, Breathe Out
Dr. Adrianne Watson - 12 May 2026
Dr. Silvia Pagliardini
The average person takes about 20 breaths per minute – this equates to a whopping 22 000 breaths per day, or 8 million breaths per year! Luckily for our mental load, this usually happens without much thought. It’s not that we can’t control our breathing – as anyone who has taken a yoga class can attest, we can assume manual breathing at will. But most of the time, our breathing rate adjusts automatically to our body’s needs. Every inhale fills our lungs with oxygen, which goes into our blood and diffuses into our organs, while each exhale removes toxic metabolites like carbon dioxide (CO2). This automatic process keeps us alive and healthy – but what happens when this system is faulty?
Problems with the body’s homeostatic process of breathing are closely associated with respiratory disorders, especially during sleep. They can manifest as obstructive or central apneas (pauses in breathing with or without airway obstructions) or as a very shallow breathing (hypoventilation). Sleep apneas reduce blood oxygen levels and disrupts sleep, causing exhaustion, memory loss, and difficulty concentrating, and is associated with serious cardiometabolic disorders like hypertension and type 2 diabetes.
One rare genetic cause of sleep apnea is congenital central hypoventilation syndrome (CCHS). CCHS patients present with a profoundly impaired CO2 chemoreflex- an automatic process that detects increased CO2 levels in the blood and responds to these changes by increasing ventilation (breathing) to eliminate it. Thus, people with CCHS are at risk of hypoventilation and life-threatening apnea, especially during sleep. Treatment usually means lifelong mechanical ventilation or diaphragm pacemakers. Pharmacological treatments are typically not an option – although this may be beginning to change.
It starts with a molecule many people know - progesterone. While it is largely considered a female hormone, progesterone receptors are present in both sexes. Dr. Pagliardini and others have shown that molecules that bind to these receptors, such as the oral contraceptives desogestrel and etonogestrel (ETO, the active metabolite of desogestrel) can improve chemoreflex in female CCHS patients and female rats.
Which leads to a rather necessary question. Can progesterone-derivatives like ETO be used to treat breathing disorders in males? In newborn rats, ETO can improve breathing in both males and females. While this is promising, the reality is that the amount and location of these receptors changes during sexual maturation. Which is why Dr. Silvia Pagliardini investigated this issue in her most recent publication. This work, led by postdoctoral fellows Drs. Silvia Cardani and Tara Janes, found that ETO causes divergent sex-dependent responses in a rat model that replicates the CO2 reflex impairment observed in CCHS. This provides insights into how breathing may be differently regulated in males and females.
To mimic CCHS in rats, the authors damaged a specialized cluster of neurons in the brainstem called the retrotrapezoid nucleus, or RTN. These neurons are activated by CO2 and stimulate breathing - meaning that they play a big role in driving the CO2 chemoreflex. By damaging the neurons in the RTN, the CO2 chemoreflex is greatly diminished. In normal air, CO2 levels are negligible (0.042%), and the rats had no issues. But in high CO2 environments, it’s a different story. Healthy rats dealt with the elevated CO2 by increasing ventilation-thus expelling the extra CO2. However, both male and female rats with the RTN injury failed to increase their respiration. The level of injury was proportional to their breathing response-the more damage, the greater their impairment.
Like they had seen in their previous study, ETO restored respiration response in female rats. But in male rats, there was no such ventilatory response.
What could the reason be for this striking sex-dependent difference? The authors first asked if ETO was metabolized differently. This was not the case-similar blood levels of ETO were found in both sexes. So they decided to dive deeper. They investigated the expression level of genes related to the CO2 chemoreflex. They discovered that in female rats treated with ETO, the genes Task2 and Gpr4 were elevated in the surviving RTN neurons. These genes are responsible for encoding the pH-sensing channels that detect changes in CO2. However, in ETO-treated males, these genes were unaffected. The authors concluded that it is likely that ETO is acting on a female-specific progesterone pathway to control expression of these genes.
In summary, Cardani, Janes and Pagliardini identify a key difference between males and females in how they respond to progesterone-like treatment in a model of impaired CO2-chemoreflex. Their work tells us why this ETO therapy is so promising in females with CO2-chemoreflex impairment, and-importantly-tells us that males will need a different approach. More broadly, this work gives us insight into how CO2-dependent chemoreflex differs between males and females, and is potentially applicable to a whole range of sleep and breathing disorders.