Gender differences may figure in sleeping disorder

Gender hormones may be a key factor in the onset of a common human disorder called sleep apnea, suggest findings from a new study by researchers at the School of Veterinary Medicine.

Sleep apnea, which typically occurs when the tongue blocks the airway during sleep, affects more than 18 million Americans, a majority of whom are middle-aged men.

UW–Madison scientists Andrea Zabka and Mary Behan studied how age affects a female rat’s response to hypoxia, or oxygen deprivation, and compared the results to those from a previous study focusing on male rats’ responses. The gender-specific responses, they found, are completely different.

In the earlier study published last summer, the researchers deprived male rats of oxygen for brief periods and then monitored nerve activity from the brain to the tongue and diaphragm, two major muscles involved in respiration. The results showed that young and middle-aged rats reacted differently to hypoxia.

“A normal, young male rat will respond to episodic hypoxia by actually increasing its output of neuronal activity to the muscles,” says Behan.

The increased activity, which leads to deeper and more frequent breaths, can protect the body from future episodes of hypoxia. But, as the results showed, only young male rats had a hyped-up protective response. “The older male rats didn’t respond in the same way,” says Behan. “Their neuronal activity was the same as before hypoxia.”

Zabka and Behan, wondering if age would affect the respiratory control of female rats in a similar way, started a new study, the results of which are published in the December issue of the Journal of Applied Physiology. Now, the researchers compared the respiratory long-term facilitation — plasticity in each rat’s neuronal response to episodic hypoxia — of young female rats to middle-aged ones. Additionally, they monitored LTF in female rats during two stages of their estrus cycle.

“Looking at male and female rats side-by-side, they’re totally different,” Behan notes. “With aging, the female rats, unlike the males, had an increased response to episodic hypoxia,” Zabka adds. In other words, older female rats had an improved protective reaction to oxygen deprivation. Plus, female rats during one stage of their reproductive cycle had an even better response.

This result, says Zabka, suggests that female gender hormones definitely play a role in the female’s response to hypoxia. “This raises the possibility that male gender hormones might also be playing a role in the male’s response,” she adds. Behan says, “When you see a difference between males and females, the first thing you need to consider is hormones.”

Hormones, particularly the female gender hormone estrogen, influence serotonin, a chemical in the brain that transmits nerve signals. “We know from the literature,” says Behan, “that serotonin levels change during the estrus cycle.” When estrogen levels are higher, so too are serotonin levels.

To confirm this, Zabka and Behan removed the ovaries from rats, thus depleting estrogen levels and mimicking the effects of menopause. When the researchers measured the amount of the chemical found in the region of the brain controlling the tongue, they found less serotonin. Less serotonin, says Zabka, directly impacted how well the rats responded to hypoxia. “We now have data to support that gender hormones influence the neurocontrol of breathing in female rats,” Behan adds.

That gender hormones control something as fundamental as breathing is a new idea. “When you think of the benefits of estrogen, you think of protecting the body against osteoporosis, Alzheimer’s disease and depression,” Zabka explains. “No one thinks of breathing.”

But, as the latest research shows, female rats with greater levels of estrogen have better responses to LTF, possibly protecting them against future episodes of hypoxia.

These findings help explain the common human disorder called obstructive sleep apnea. Potentially fatal, this sleeping disorder occurs when air doesn’t flow into a person’s airway, usually because the tongue or other muscles near the airway relax and block it. Apnea’s side effects — heavy snoring, brief periods of hypoxia (up to 60 per hour) and frequent awakenings — can lead to high blood pressure, daytime sleepiness, poor concentration and sexual dysfunction.

Epidemiological evidence shows that middle-aged men are more likely than middle-aged women to develop sleep apnea. Such evidence also shows that the incidence in women increases after they reach menopause, a period marked by lower levels of estrogen. Post-menopausal women on hormone replacement therapy, however, are less likely to have sleep apnea.

“The data in humans is very compelling,” says Behan. “And the similarities between our findings and the evidence of sleep apnea in humans are striking.”

Though the research by Zabka and Behan did not directly investigate obstructive sleep apnea, it does point to gender hormones as a possible cause. “We are investigating the underlying mechanisms of respiratory control,” says Zabka, “that will give us better insight into the underlying mechanisms of breathing disorders that have a distinct gender and age pattern.”

In a study already underway, Zabka and Behan turn their attention back to male rats to examine the role of testosterone in respiratory control.

Their research is funded by a five-year, $1.25 million grant from the National Institute of Aging, part of the National Institutes of Health.