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. Author manuscript; available in PMC: 2021 Aug 5.
Published in final edited form as: Curr Opin Endocr Metab Res. 2021 Feb 3;17:46–51. doi: 10.1016/j.coemr.2021.01.002

Role of obstructive sleep apnea in metabolic risk in PCOS

Susan Sam 1, Esra Tasali 1,2
PMCID: PMC8341449  NIHMSID: NIHMS1698166  PMID: 34368492

Abstract

Women with polycystic ovary syndrome (PCOS) have a substantially increased risk for diabetes and cardiovascular disease. Obstructive sleep apnea (OSA) is the most common sleep disorder in PCOS. Recent population-based studies indicate a high incidence of OSA among adult women with PCOS. Obesity and increasing age are the main factors for this association. There is strong evidence indicating that OSA is an important modulator of metabolic risk in the general population. There is also some evidence to suggest that OSA may contribute to insulin resistance and glucose intolerance among women PCOS, and thus increase their metabolic risk. The potential mechanisms for adverse metabolic consequences of OSA are likely to be multiple. Whether treatment of OSA in PCOS improves metabolic outcomes requires further rigorous research.

Keywords: PCOS, Obstructive sleep apnea, Glucose, Insulin resistance, Diabetes, Metabolic, Cardiovascular

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The syndrome was initially defined in the 1930s by reproductive abnormalities including oligomenorrhea, anovulation, and infertility [1]. Decades later, insulin resistance and related metabolic derangements were identified as key features in PCOS [2]. It is now well-established that affected women are at a high risk for early-onset diabetes and cardiovascular disease [3]. In addition, it is increasingly recognized that sleep disturbances, particularly obstructive sleep apnea (OSA) are highly prevalent in PCOS [46]. There is also some evidence to suggest that the presence and severity of OSA may worsen insulin resistance and glucose intolerance in this high-risk population [4,7,8].

OSA is characterized by recurring complete (i.e., apnea) or partial (i.e., hypopnea) upper airway obstruction leading to intermittent hypoxia (i.e., repetitive cycles of oxygen drops and reoxygenation), sleep fragmentation, and poor sleep quality. OSA is a treatable disorder that is pervasive in overweight and obese individuals [9]. Continuous positive airway pressure (CPAP) is the recommended first-line treatment for individuals who are diagnosed with OSA. However, it is estimated that, in the general population, about 80% of those who have OSA remain undiagnosed, and thus not receive CPAP treatment [911]. The gold standard for establishing OSA diagnosis is by polysomnography when the apnea-hypopnea index, that is, the total number of obstructive apneas and hypopneas per hour of sleep, is greater than five [12]. Typical symptoms of OSA include snoring, witnessed apneas, daytime sleepiness, and cognitive impairment. Clinically, women with OSA may often present with insomnia, fatigue, or mood disturbances, rather than snoring or daytime sleepiness. Obesity and increasing age are major risk factors for OSA. Also, men are more likely to have OSA than women [13]. Over the past 20 years, numerous studies have demonstrated that beyond the effects of excess weight, OSA may be an important determinant of insulin resistance and glucose intolerance, and thus may contribute to the development of diabetes and cardiovascular disease (reviewed in Refs. [1416]). In lean individuals, OSA was associated with insulin resistance and higher glucose as compared to controls that were matched for BMI and visceral adiposity [17,18].

Herein, we review the current evidence for associations between OSA and PCOS with a particular focus on the impact of OSA on insulin resistance and glucose intolerance in affected women. We also briefly discuss the potential mechanisms by which OSA can result in metabolic dysfunction, and thus may contribute to heightened metabolic risk in PCOS.

Prevalence of OSA in PCOS: clinical and population-based studies

The associations between and OSA and PCOS were first identified in clinical studies reporting an increased prevalence of OSA, estimated on average at ~40%, among women with PCOS (reviewed in the study by Kahal et al. [19]). Notably, the clinical studies were limited by small sample size and inclusion of mostly overweight or obese women with PCOS [2026]. A few studies also reported that this association was stronger particularly during rapid eye movement sleep [23,27], a sleep stage when predisposition to upper airway collapse is increased particularly in the presence of excess weight. In a recent meta-analysis of 12 clinical studies (8 in adults and 5 in adolescents) that used polysomnography [6], adult women with PCOS had a 9.7 times higher risk for OSA than control women of similar age. However, obesity was not accounted for in this meta-analysis and in most studies, PCOS women were heavier than controls. Furthermore, this association was not observed among adolescent girls, suggesting that increased age may be an important determinant of OSA in PCOS. More specifically, the prevalence of OSA was not increased in obese adolescents with PCOS compared with normal weight or obese girls without PCOS [2830]. Nevertheless, abnormalities in sleep architecture with reduced sleep efficiency, reduced rapid eye movement sleep, and increased sleep latency were found among girls with PCOS compared with lean or obese controls [30]. In a retrospective chart review, the prevalence of OSA was increased in obese adolescents with PCOS compared with obese controls, with estimates similar to that reported in obese adolescent boys [31].

More recently, population-based studies have shown an association between PCOS and OSA [32,33] and other sleep disturbances, for example, difficulty initiating and maintaining sleep or insomnia [3436]. These associations were not entirely explained by excess weight alone in these population-based longitudinal analyses. The high rates of insomnia symptoms in PCOS may reflect, at least in part, an unrecognized OSA diagnosis, because women frequently present with OSA with atypical symptoms [37]. In a longitudinal analysis of the large Taiwan National Health Insurance Research Database, using formal diagnosis codes women with PCOS (n = 4595) had greater incidence of OSA during a 2- to 8-year follow-up period, compared with age-matched control women, after adjusting for obesity, other demographics, and comorbidities (adjusted hazard ratio 2.6, 95% confidence interval 1.6–4.0) [32]. Similarly, another large population–based study from the UK, The Health Improvement Network, reported higher incidence of OSA in women with PCOS (n = 76 978) over a median follow-up of 3.5 years, as compared with age- and weight-matched women without PCOS (n = 143 077; adjusted hazard ratio 2.3, 95% confidence interval 1.9–2.7) [33]. In the UK cohort, the increased risk of OSA in PCOS was evident among overweight or obese women, but this association did not reach statistical significance in the normal weight group. Potential mechanisms other than obesity that might increase the likelihood of OSA in PCOS may involve intrinsic features such as central adiposity, hyperandrogenism, low progesterone, and low estradiol levels, which all have been implicated in OSA pathophysiology [7,38]. Hyperandrogenism, a cardinal feature of PCOS [39] can predispose to OSA via effects on neural control of breathing [40] and upper airway mechanics [41]. High androgen levels in PCOS have been associated with increased risk for OSA in some [20,26,42] but not all studies [24]. In addition, low progesterone and low estrogen concentrations can possibly contribute to this risk because low levels might increase frequency of apneic events in women across a broad age spectrum [43,44].

In summary, clinical studies suggest that the prevalence of OSA is increased in women with PCOS, but this association occurs in later life and appears to be mostly dependent on excess weight. Recent large population–based reports indicate a higher incidence of OSA in PCOS, which is not merely accounted for by obesity. Future rigorous research is necessary to elucidate the putative role of altered sex steroid production in elevated OSA risk seen in PCOS.

Impact of OSA on insulin resistance and glucose intolerance in PCOS

A few clinical studies have investigated the effects of OSA on metabolic outcomes in PCOS. In an earlier study, women with PCOS who were recommended treatment for OSA showed higher fasting insulin levels and a lower glucose-to-insulin ratio as compared with control women, and the difference between the insulin levels remained significant after adjustment for BMI [27]. More recent studies reported significant associations between the presence of OSA and fasting glucose [26] or insulin resistance by homeostatic model assessment (HOMA) index [42] among women with PCOS, after statistical adjustments for BMI. Similarly, among adolescent girls with PCOS and OSA, the degree of insulin resistance (HOMA index) was higher compared to girls with PCOS without OSA [31]. In an earlier study, we have reported that the risk and severity of OSA (respiratory events and oxygen desaturations) are highly correlated with insulin levels and measures of glucose tolerance [23]. Among women with normal glucose tolerance, the insulin response to an oral glucose challenge was more than two-fold greater in those at high risk for OSA per Berlin Questionnaire, as compared with those at low risk [23]. In a follow-up study, we have found that the presence and severity of OSA predicts insulin resistance and glucose intolerance in nondiabetic women with PCOS, after controlling for age, BMI, and ethnicity [24]. The increasing apnea-hypopnea index was a significant predictor of fasting glucose and insulin, HOMA index as well as 2-h glucose levels during an oral glucose challenge. Interestingly, among PCOS women with normal glucose tolerance, the presence of OSA was associated with a nearly 2-fold higher fasting insulin level and HOMA index [24]. To date, in the only interventional study involving women with PCOS and OSA, our group has found that 8 weeks of CPAP treatment of OSA in young and morbidly obese PCOS women improves metabolic and cardiovascular outcomes [45]. Among women who were compliant with CPAP treatment (average use ~ 6.6 h per night), we found a modest improvement in insulin sensitivity as assessed by intravenous glucose tolerance test, after controlling for BMI. In addition, in this cohort, we observed reductions in markers of sympathetic activity (i.e., plasma norepinephrine and heart rate variability) and diastolic blood pressure after OSA treatment [45]. These beneficial effects were of greater magnitude with longer hours of CPAP use and of lesser magnitude in those with higher degrees of obesity. The potential mechanisms by which OSA may worsen metabolic outcomes could be multiple [4648]. Intermittent hypoxia and sleep fragmentation can lead to metabolic disturbances via an interplay of intermediate pathways (Fig. 1) including sympathetic activation [49], alterations in lipid metabolism [50,51], oxidative stress and mitochondrial dysfunction [52], release of proinflammatory markers [53,54], and endothelial dysfunction [55,56]. In fact, the animal and human models mimicking OSA provide strong evidence to support these putative pathways. These models utilized experimental exposures to intermittent hypoxia and sleep fragmentation and revealed direct mechanistic links between OSA, insulin resistance, glucose intolerance, and beta-cell dysfunction [5765].

Figure 1. Potential mechanisms linking OSA to adverse metabolic consequences.

Figure 1

Intermittent hypoxia and sleep fragmentation are two main characteristics of OSA, which can result in sympathetic overactivity, alterations and lipid metabolism, oxidative stress and mitochondrial dysfunction, inflammation, and endothelial dysfunction. These metabolic disturbances may subsequently contribute to insulin resistance, glucose intolerance and beta-cell dysfunction, leading to diabetes, and cardiovascular disease.

Overall, a limited number of clinical studies suggest that the presence of OSA may exacerbate the degree of insulin resistance and glucose intolerance in PCOS, after statistical adjustments for BMI. It is noteworthy that these findings should be interpreted with caution considering small number of patients and higher degree of obesity among women with PCOS and OSA. Thus, the potential role of OSA in worsening metabolic risk in PCOS needs to be further investigated. Nevertheless, the current evidence in OSA populations without PCOS and experimental models mimicking OSA strongly supports a biological plausibility linking OSA to metabolic disturbances seen in PCOS.

Summary and future research agenda

OSA is a highly common sleep disorder particularly among overweight or obese populations. Yet, it is often overlooked and undertreated. Current evidence from clinical and population-based studies indicate that OSA occurs at increasing frequency among women with PCOS. Age and obesity appear to be major determinants in this association. In addition, observational evidence in a limited number of studies suggests that metabolic outcomes are worsened among PCOS women who have OSA. Numerous studies support a strong biological plausibility that OSA may be an important modulator of metabolic risk. Current guidelines recommend screening overweight or obese adolescents and adult women with PCOS for symptoms suggestive of OSA and to provide appropriate treatment if OSA is diagnosed [66]. The question of whether the presence of OSA may exacerbate the metabolic risk in PCOS requires further rigorous research to better understand the underlying pathophysiology. Large-scale randomized controlled trials of CPAP treatment of OSA with robust assessments of insulin sensitivity and glucose tolerance of are also warranted. In addition, future mechanistic studies can provide novel pathophysiologic insights to the associations between OSA and heightened metabolic risk in PCOS.

Funding declaration

Dr.Tasali’s research is funded by R01 DK120312-01A1 and R01DK115471 from the National Institute of Health.

Footnotes

Conflict of interest statement

Nothing declared.

References

Papers of particular interest, published within the period of review, have been highlighted as:

* of special interest

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