Unique consequences
Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.
A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.
Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.
The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.
The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”
Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.
The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”
Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.
Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.