The difference in prevalence of sleep apnea in men versus women may be explained by variations in chemoresponsiveness.

 There is increasing recognition that sleep-disordered breathing is a major public health burden for both genders and that it should be recognized and treated. Sleep apnea/hypopnea is more common in men than in women. The gender difference in the prevalence of sleep apnea is, however, much smaller than sleep-laboratory clinical experience and clinic-based studies indicate. For example, the Wisconsin Sleep Cohort Study1 showed the prevalence of sleep apnea as 24% in men and 9% in women. The gender difference persisted when sleep apnea/hypopnea syndrome, defined as an apnea/hypopnea index (AHI) of five or more events per hour of sleep combined with daytime sleepiness, was considered; prevalence was 2% for women and 4% for men. A more recent study by Bixler et al2 reached similar conclusions regarding prevalence, regardless of the definition used to identify the disorder. The authors also noted less central apnea in women. Overall, the small gender difference indicates that gender cannot be used in diagnosis as an exclusionary criterion.

Why Women Are Missed
Epidemiological clinic-based studies have consistently shown a large difference between men and women in the prevalence of sleep apnea. This may reflect differences in the clinical manifestations or in the consequences of the disorder, leading to the erroneous conclusion that sleep apnea syndrome is a male disease. This systematic error has been corrected in community-based epidemiological studies.1-3 The consistent difference between clinical and community-based studies raises the likelihood that women are missed diagnostically either because of differences in presentation or because physicians fail to recognize the symptoms in women.4,5 Some studies have shown that women report more fatigue6 or more difficulty in initiating and maintaining sleep.7 In fact, women in the working population enrolled in the Wisconsin Sleep Cohort Study reported more daytime sleepiness even in cases of mild (or no) sleep apnea.8 Therefore, it is imperative that inquiries regarding sleep habits, snoring, daytime sleepiness, and fatigue be included routinely in any review of systems.

There is agreement that AHI is lower in women than men matched for body weight. This is mostly due to a higher AHI during non–rapid-eye-movement (NREM) sleep in men. Apneas and hypopneas tend to occur during REM sleep in women; several studies9,10 have investigated whether polysomnographic features are different in men and women. Men also tend to demonstrate more supine dependence. There is no clear explanation for the difference in polysomnography results between genders, but it may reflect differences in mechanisms between REM and NREM sleep.

Obstructive sleep apnea is characterized by recurrent episodes of apnea or hypopnea accompanied by pharyngeal narrowing or occlusion. Upper-airway patency depends on the caliber of the pharyngeal lumen, the length of the collapsible segment, the stiffness of the pharyngeal wall, and the pressure gradient across the pharyngeal wall. The sleep state is conducive to pharyngeal narrowing or closure due to narrowing of the upper airway and increased upper-airway collapsibility.

Differences in upper-airway dimensions alone cannot account for the gender difference in the prevalence of sleep apnea. In fact, there is no consistent gender difference in pharyngeal cross-sectional area. In contrast, there is evidence of a gender difference in pharyngeal airway length. Using MRI scanning, Malhotra et al11 demonstrated a greater pharyngeal airway length in men, even when this was corrected for height. This is particularly interesting because the upper airway is composed of soft tissue, with no solid structural support. The length of the airway represents the length of the susceptible segment and may correlate with the tendency to develop upper-airway obstruction.

Upper-airway function during sleep represents the net effect of a complex interplay between the intrinsic mechanical properties of the pharynx and the neural regulation of pharyngeal dilator muscle activities. Upper-airway resistance, collapsibility, compliance, and critical closing pressure are distinct properties of the pharyngeal airway. There is a lack of concordance between these properties, indicating that they may have distinctly different determinants and physiological implications. The effect of gender on pharyngeal structure and function during sleep depends on the specific index measured. For example, there is no conclusive evidence of gender differences in upper-airway resistance or collapsibility during NREM sleep.12-14 Pillar et al15 found, however, that hypoventilation in response to an external inspiratory load is more pronounced in men. Pharyngeal compliance during sleep is also higher in men, suggesting a greater susceptibility to collapse.16 Compliance differences are due to differences in neck circumference between genders. Therefore, increased pharyngeal compliance in men is attributable to differences in the passive structures surrounding the upper airway, not to intrinsic differences in upper-airway function.

Gender differences in upper-airway structure and function cannot explain the prevalence of sleep apnea in men versus women. Therefore, exploration of differences in ventilatory control may shed light on the underlying mechanisms. Chemoresponsiveness during sleep may be a critical determinant of breathing stability in response to transient perturbation, especially during sleep. An excessive ventilatory response to hypoxia may cause a reduction in arterial carbon dioxide below normal levels. This may be inconsequential during wakefulness because the wakefulness drive to breathe maintains stable rhythmic respiration, despite hypocapnia. The removal of the wakefulness drive to breathe during NREM sleep, however, renders ventilation critically dependent on central and peripheral chemoreflexes. In fact, sleep unmasks a highly sensitive, hypocapnic apneic threshold. If arterial Pco2 is lowered sufficiently, central apnea ensues. The level of Paco2 associated with central apnea is the apneic threshold.17 The hypocapnic apneic threshold is elevated in men18 and can be elevated toward male values in women receiving testosterone.19 Conversely, the apneic threshold is reduced toward female values in men receiving leuprolide acetate to suppress androgen production.20 A higher apneic threshold indicates that induction of central apnea in men is more feasible and requires less hyperventilation.

The occurrence of central apnea may contribute to recurrent apnea and breathing instability. A common adage is that apnea begets apnea. Central apnea may initiate several processes, including hypoxia and transient arousal with subsequent ventilatory overshooting, hypocapnia, and recurrent central apnea. A less recognized phenomenon is that central apnea may also influence the development of obstructive sleep apnea. There is evidence that central apnea is associated with pharyngeal narrowing or occlusion in patients with susceptibility to upper-airway collapse,21 such as patients with obstructive sleep apnea. The occurrence of complete pharyngeal collapse during central apnea, combined with mucosal and gravitational factors, may impede pharyngeal opening and necessitate a substantial increase in drive.

Composite Picture
The gender difference in the prevalence of sleep apnea can be explained by a combination of anatomical and physiological differences. Anatomically, the upper airway in men is more vulnerable owing to increased compliance (due to increased neck circumference) and to increased pharyngeal airway length. Physiologically, men are more susceptible to the development of central apnea in response to a mild perturbation and modest hypocapnia . The gender differences in the basic mechanisms of breathing instability and upper-airway function may provide insight into the underlying pathophysiology of sleep apnea and could, perhaps, guide future efforts toward new, effective therapy.

Safwan Badr, MD, is professor and chief, division of pulmonary, critical care, and sleep medicine, Harper University Hospital, Wayne State University, Detroit.

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