Obstructive Sleep Apnea in Women

Recognition, presenting symptoms, and healthcare utilization

Factors contributing to sex differences in the prevalence of SDB include variations in the reporting of symptoms in men compared to women. Snoring and excessive daytime sleepiness are considered primary hallmarks of sleep apnea. Our screening tools (e.g. Stop Bang, Epworth Sleepiness Scale) also target these typical symptoms which are reported less frequently by women compared to men experiencing a similar degree of SDB [9]. Women are more likely to report non-specific symptoms of SDB including headache, fatigue, depression, anxiety, sleep onset insomnia and sleep disruption [3,4]. A population-based sample found that up-to 40% of women with an AHI >15/h did not report any of the classic OSA symptoms (e.g. snoring, witnessed apneas, and day time sleepiness) [7]. These typical symptoms may be deemed less socially acceptable by females, and as a result are underreported. Atypical symptom presentation results in fewer referrals of women to a sleep clinic, delay in diagnosis, and this leads to increased health care utilization [5,6,10]. Additional assessment tools, including fatigue, may be necessary to diagnose sleep apnea in women. Hence, we need more comprehensive and specific screening tools for women in general, and likely in different age-groups of women.

Airway anatomy

There are many factors that contribute to alterations in airway caliber leading to recurrent pharyngeal obstruction during sleep. These include size and stiffness of the pharyngeal lumen, and the pressure gradient across the pharyngeal wall. Differences in properties of the upper airway exist between men and women, and could provide explanation for the dissimilar prevalence [11]. For example the pharyngeal airway in healthy men is longer compared to women independent of height, and a longer airway tends to collapse more [11,12]. Similarly in men thickening of the soft tissue on the lateral walls may increase the susceptibility of airway collapse by increasing extraluminal and reducing intraluminal pressure [13,14]. Sleep apnea is more severe in men compared to women matched for BMI [15]. Consequently, for a given severity of sleep apnea women tend to be more obese than men. One potential explanation for this difference is the fat distribution between the sexes. For the same BMI, men tend to have higher mean body weight, free fat mass, and neck circumference compared with women [14]. Upper airway fat distribution in males tends to be particularly in the posterior tongue, which is important in the pathogenesis of OSA [4].

Ventilatory control and chemo reflex properties

Alongside anatomical differences, variation in neurochemical control of chest wall and upper airway muscle activity contributes to sex differences in the prevalence of sleepdisordered breathing.

The ventilatory response to changes in chemical stimuli (i.e. hypoxia and hypercapnia) is an integrated response of peripheral and central chemoreflexes. The change in ventilation as a function of the change in the partial pressure of end-tidal carbon dioxide (PETCO2) is a measure of chemoreflex sensitivity (i.e. a steeper slope indicates higher sensitivity) [16,17]. Chemoreflex sensitivity during sleep is often measured by obtaining the slope of the decrease in ventilation that occurs in response to step wise reductions in carbon dioxide (CO2). The chemoreflex threshold, which is typically referred to as the apneic threshold during sleep is the point at which ventilation ceases as a consequence of reductions in PETCO2 [18,19]. The CO2 reserve is the difference between baseline levels of PETCO2 and the PETCO2 at which ventilation is abolished. Low CO2 reserve promotes breathing instability, because minor increase in ventilation will drop the PETCO2 below the apneic threshold causing apnea [20]. Hence high chemoreflex sensitivity and decreased CO2 reserve during sleep will promote apnea. There are sex differences in these parameters contributing to the variability in prevalence of SDB. Zhou et al. showed during sleep chemoreflex sensitivity to CO2 is greater in men compared to women [21]. Similar findings were observed in other studies, however during wakefulness, and not sleep [22-31]. Mixed findings have been reported in terms of sex differences in hypoxic ventilatory response [24,25,28].

Respiratory plasticity

Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. In sleep apnea there is recurrent intermittent hypoxia which initiates at least two forms of respiratory plasticity; progressive augmentation of the hypoxic ventilatory response and long-term facilitation of respiratory motor output (i.e. sustained increase in respiratory motor output (hypoglossal and/ or phrenic) that persists even in normoxic condition) following exposure to intermittent hypoxia [32-36]. This can contribute to breathing instability during sleep and indeed supports the findings that apnea severity increases from the beginning to end of the night in individuals with sleep apnea [37-41]. These ventilatory responses to CO2 after episodic hypoxia are seen to be worse in men compared with women [26].

Hormones

It has been reported that women with clinically significant SDB have lower levels of estradiol and/or progesterone when matched for age, menstrual cycle phase or post-menopausal status [42]. Additionally, the prevalence of sleep apnea in postmenopausal women that do not receive hormone replacement therapy is significantly greater compared to those who receive hormone replacement therapy [43]. There are conflicting findings on the potential impact that estrogen/progesterone has on ventilatory sensitivity to hypercapnia and hypoxia [44-47]. Rowley et al. supported that estrogen/progesterone decrease the apneic threshold to CO2 and the sensitivity to hypercapnia or hypoxia, leading to decrease in breathing instability, hence explaining the fact that sleep apnea is less prevalent in menstruating females [44].

The PETCO2 that demarcates the apneic threshold in premenopausal women is further from baseline compared to that of post-menopausal women. Likewise, treatment with medroxyprogesterone acetate and estrogen leads to increased difference between the apneic threshold and baseline PETCO2 in post-menopausal women (i.e. greater CO2 reserve).

Female sex hormones also have a protective effect on upper air way patency. This was supported by findings seen in postmenopausal female volunteers that showed activity of the genioglossus muscle significantly increased after 2 weeks of hormone replacement therapy [48], potentially explaining the marked increase of prevalence and severity of SDB in women after menopause [43,49,50].

Pregnancy is associated with an increase in the ventilatory sensitivity to hypoxia and hypercapnia [45-51]. The increase in sensitivity is due at least in part to the effects of estrogen and progesterone on the carotid body [51]. Pregnancy is a state of increased risk for OSA despite increased sex hormones since hormonal changes may lead to other risk factors such as a larger neck circumference or naso-oropharyngeal edema [52-56]. Anatomical changes related to pregnancy also contribute to OSA risk. For example, a growing uterus leads to elevation in the diaphragm with decrease in functional residual capacity.

Finally, increased prevalence of sleep apnea is reported in women with polycystic ovarian syndrome, which is characterized by elevated testosterone levels, compared to reproductively healthy women. Correlation is seen between the AHI and serum testosterone and unbound testosterone in women with polycystic ovarian syndrome [13,57-59].