ReviewMetabolic dysfunction in PCOS: Relationship to obstructive sleep apnea☆
Highlights
► PCOS is among the most common endocrine disorders in women. ► Women with PCOS are highly predisposed to develop impaired glucose tolerance and type 2 diabetes. ► Obstructive sleep apnea (OSA) contributes to the metabolic disturbances associated with PCOS. ► Correction of OSA is associated with amelioration of metabolic dysfunction in PCOS.
Introduction
It is now well established that the average duration of sleep has declined over the past several decades for most Americans. During the 1960s, the mean sleep duration was between 7 and 8 h per night; current estimates place the average duration at less than 6 h per night [1]. Chronic sleep loss imposes a significant negative impact upon individual health as well as an enormous economic cost to society. Shortened sleep duration is associated with increased mortality [2], [3], even after adjusting for age, smoking, alcohol, exercise, depression, snoring, obesity, and history of cancer and cardiovascular disease [3]. Reduced sleep time has also been reported as a risk factor for the development of obesity and for type 2 diabetes [4], [5], [11], [12]. Results of the Sleep Heart Health Study showed that subjects sleeping 5 h or less per night had an adjusted odds ratios for diabetes of 2.51 (95% CI, 1.57–4.02) when compared to those who slept 7–8 h per night [5]. This trend in shorter sleep duration mirrors the progressive rise in overweight and obesity in the United States [6] and evidence continues to emerge to support a causal link between these two conditions. Should either or both trends continue along their current trajectory, the metabolic and cardiovascular health consequences as well as economic costs will be staggering.
Obstructive sleep apnea (OSA) is a highly prevalent, chronic condition that is characterized by recurrent episodes of complete (apnea) or partial (hypopnea) obstruction of the upper airway leading to intermittent hypoxia, cortical microarousals, sleep fragmentation and chronic sleep loss [7], [8], [9]. The severity of OSA is defined by the number of obstructive events per hour of sleep [apnea–hypopnea index or AHI], and is usually characterized as mild, moderate, or severe. Obstructive sleep apnea is now well-documented to be an important contributor to both metabolic disturbances (insulin resistance, type 2 diabetes) and adverse cardiovascular events [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] even in milder forms of OSA [25], [28], [29], [30].
Obstructive respiratory events can occur throughout the sleep cycle and can also cluster in REM sleep or NREM sleep [31]. Studies have consistently demonstrated that REM-related OSA occurs more commonly in younger individuals, women, children, and in patients with mild or moderate OSA rather than severe OSA [32], [33], [34], [35]. Although gender is known to impact upon the distribution (REM vs. NREM) of obstructive events, the physiologic basis for this gender-based difference has not been established. Likewise, whether the cardiometabolic consequences of OSA differ in frequency or severity as a consequence of the distribution of obstructive events (REM vs. NREM) has not been established.
The majority of patients (approximately 80%) with OSA have either mild (AHI < 15) or moderate (AHI < 30) disease [36], [37]. Among these individuals, obstructive events often cluster in REM sleep [32] (so-called “REM-related OSA”) leading to selective fragmentation of REM sleep [32]. While the precise prevalence of REM-related OSA has not been established, based upon data from a number of clinical studies in which polysomnography has been utilized, it appears to be between 10% and 36% of those having OSA [32], [33]. Recently, it has been reported that among the 14% of individuals studied as part of the Sleep Heart Health Study (SHHS) who had an overall AHI ⩾ 5.5, the AHI in REM sleep was ⩾13, while the AHI in non-REM sleep was <8 [17].
REM sleep is associated with greater sympathetic activity and cardiovascular instability in healthy human subjects and patients with OSA when compared to NREM sleep [38], [39]. These acute hemodynamic changes of REM sleep could play a part in triggering ischemic events in patients with cardiovascular disease [39], [40], [41], [42]. Indeed, obstructive apneas and hypopneas during REM sleep tend to be longer in duration, lead to greater degrees of hypoxemia [43], [44] and higher levels of sympathetic activity compared to events in NREM sleep [38]. Despite the more significant degrees of hypoxemia and sympathetic activity, patients with REM-related OSA generally have overall milder OSA due to REM sleep occupying only 15–25% of sleep time in adults. Moreover, the majority of studies thus far have failed to demonstrate an association between AHI in REM and subjective or objective measures of sleepiness [16], [17], [20], [45].
Section snippets
Sex differences in prevalence of OSA
In a recent study conducted by Mokhlesi et al. [46] out of 1019 consecutive adults referred for their first in-laboratory clinical PSG for suspicion of OSA over a 10 month period, 931 patients (91.4%) had OSA (AHI ⩾ 5). Obstructive sleep apnea was mild to moderate (AHI < 30) in 61% of women in contrast to 37% of men (P < 0.0001). The prevalence of REM-related OSA was 13.5% [47]. These data confirmed previous reports that REM-related OSA was more prevalent in women (78% vs. 48%; P < 0.001) and among
Obstructive sleep apnea in women with PCOS
Women with PCOS have been documented to develop OSA at rates that equal and may even exceed those in men. The high prevalence of OSA has been thought to be a function of both elevated levels of testosterone (a defining feature of PCOS) as well as the obesity that commonly accompanies the disorder. However, it appears that the high prevalence of OSA in PCOS cannot be fully accounted for on the basis of these two factors alone. In two studies [52], [53], the severity of sleep apnea did not
Sex differences in PSG findings in OSA
There are a limited number of well-controlled studies comparing PSG findings in women vs. men. Generally, women have a higher BMI for a given AHI level than men and weight changes have a lesser impact on AHI in women than in men. REM-related OSA is disproportionately more common in women than in men and, for the same BMI, OSA is less severe in women because of milder OSA during NREM sleep. Because REM sleep is a state of elevated sympathetic nervous activity, it is possible that REM-related OSA
Role of progesterone
Progestins have been generally characterized as protective against the development of OSA in women. Much of the evidence to support this view is derived from studies in which sleep was evaluated in relation to pregnancy status [58], [59], age and phase of the menstrual cycle [60], [61], menopausal status [62], or in response to hormone replacement therapy [62]. Progesterone is the key hormone thought to underlie the differences in sleep measures that exist across the normal menstrual cycle.
Cardiovascular disease in PCOS
Women with PCOS have multiple risk factors for cardiovascular disease, including dyslipidemia, hypertension, impaired glucose tolerance/type 2 diabetes, subclinical vascular disease, and even significant reductions in maximal oxygen consumption and lower maximal workload [72]. It now appears that OSA can be added to the list of cardiovascular risk factors in PCOS and the treatment of OSA appears to ameliorate some of the cardiovascular dysfunction seen in these women [73].
Women with PCOS appear
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Studies conducted with support from NIH Grants: HL-075079 (DAE), P50-HD057796 (DAE), P60-DK20595 (The University of Chicago DRTC Laboratory) and M01-RR000555 (The University of Chicago CTSA – GCRC).