Is Better Sleep Beneficial for Metabolic Outcomes in Obese Female Adolescents with Polycystic Ovarian Syndrome?

Polycystic ovarian syndrome (PCOS) entails a combination of reproductive, metabolic, and psychological complications worsened by obesity that can be improved by weight management. Metabolic syndrome (MS) is a complication of PCOS that is strongly linked to abdominal obesity and insulin resistance that increases the risk for diabetes and cardiovascular disease development. Adolescence is a critical stage in PCOS where lifestyle management—including sleep health—can be introduced earlier in life to prevent further worsening of weight, features of PCOS, and subsequent development of diabetes. Thus, there is emerging interest in the role of sleep disorders in women with PCOS and their association with the complications of PCOS.

Sleep can be considered as a multidimensional construct with key features of quantity, timing, and quality and intertwined with circadian rhythm health. The sleep disorder that has perhaps received the most attention in terms of associations with metabolic function in the pediatric population is obstructive sleep apnea (OSA). Although no large-scale pediatric-focused epidemiologic studies dedicated to examining sleep measures are available, a compilation of clinic-based studies has revealed an OSA prevalence estimate of 0.8% to 2.8% (1). Increased oxidative stress during obstructive respiratory events affects inflammatory signaling, which in turn disrupts normal metabolism. Similarly, OSA and PCOS share common comorbidities such as obesity and may be linked via common pathophysiologic mechanisms including but not limited to insulin resistance, sympathetic hyperactivity, and hormonal disturbance (2). Although conclusive evidence of such pathophysiologic links is lacking, adult women with PCOS and OSA have been shown to have a higher body mass index, insulin resistance, systolic and diastolic blood pressure (BP), unfavorable lipid profiles, and impaired glucose tolerance compared with women with PCOS without OSA. Even in adults, directionality of OSA and PCOS and confounding or effect modification of obesity remains unclear (3). A single prior retrospective study of 28 adolescent females reported that the prevalence of OSA was significantly higher in females with PCOS (57%) compared with females without PCOS (14.3%) (4). In the same study, females with PCOS and OSA had a significantly higher proportion of MS, insulin resistance, elevated daytime systolic BP, elevated triglycerides and lower high-density lipoprotein levels compared with females without OSA (4). Furthermore, the influence of insufficient sleep or circadian variability such as “social jet lag” may lead to fatigue and sleepiness, which in turn can decrease activity levels and increase risk of developing of obesity, MS, or PCOS. A bidirectional or multidirectional complex relationship may exist between MS, PCOS, and sleep, mediated via obesity, which has not been longitudinally examined in prior studies in the pediatric population.

Study findings are consistent in demonstrating an association of OSA and higher levels of triglycerides, insulin, and BP and lower levels of high-density lipoprotein cholesterol in adolescents (5). Although the impact of OSA on metabolic derangements in adolescents appears to be moderate, these relationships independent of obesity still remain difficult to parse out because of residual confounding (5). However, the influence of quantity and timing of sleep on MS as well as PCOS has not been extensively reported in children and adolescents. Recent studies in adolescents show that reduced or prolonged sleep duration ascertained by self-report or objectively measured with actigraphy devices are associated with MS (6). Moreover, the timing of bedtime-wake up time and variability between weekdays and weekends are variably associated with individual components of MS (6). Age-appropriate adequate sleep duration is associated with decreased fasting glucose, whereas short sleep duration (less then recommended) is associated with insulin resistance (homeostatic model assessment for insulin resistance) and hyperinsulinemia. Additionally, children with later bedtime and short sleep duration have been identified to have a higher systolic BP (7). Therefore, the association between sleep duration and timing appear to be associated with individual components of MS instead of MS when considered globally in children.

In the current issue of the Journal of Clinical Endocrinology and Metabolism, Simon and colleagues prospectively examine the relationship across various dimensions of sleep quantity, timing, quality determined by sleep efficiency, as well as presence or absence of sleep-disordered breathing in relation to MS in obese females with PCOS. Therefore, it addresses an existing knowledge gap by extending our current quite limited scientific knowledge of the relationship between sleep and MS in obese adolescents with PCOS. This is also the first study to report multiple dimensions of sleep and MS combined. Although this study is limited by a small sample size, as acknowledged by the authors, a clear strength resides in the robust phenotyping. Objective sleep measures were derived from standard testing (i.e., actigraphy and polysomnography) albeit in a subset. Also, systematic laboratory testing and hepatic fat measures from abdominal magnetic resonance imaging scans were used to define PCOS and MS. The authors concluded that sleep-disordered breathing was more common in those with MS in adolescents with PCOS. Also observed, was greater OSA severity (defined by the apnea hypopnea index) and reduction in sleep efficiency was associated with poorer metabolic health. A strength of the study is attempting to minimize the influence of confounding factors such as menstrual cycle (studied in adolescent females in the follicular phase only) with reduced physical activity, although there was no obvious notation of statistical adjustment for variations in activity and dietary differences. Results of this study do not establish causality between sleep disruption or sleep disorders and MS in females with PCOS. Importantly, however, it sets the stage for researchers to further explore such relationships. Additionally, correlation between quantity and efficiency of sleep with individual markers of MS are statistically significant but are not a strength of this study. Although this is likely because of a small sample size, these findings are consistent with prior studies in children, as discussed earlier. As pointed out by the authors, the directionality of the relationship of PCOS and sleep disruption remains unclear because this cannot be concluded confidently from the results of this cross-sectional analysis. Rather, this study provides early insights into potential directionality of such a relationship, upon which further research can be conducted.

It is clear from this and prior studies that, in obese adolescents, the prevalence of OSA is higher in females with PCOS than without PCOS and with MS compared with those without MS. Taken together with biologically plausible OSA-PCOS-MS relationships, screening and early detection of OSA in obese adolescents with PCOS should be considered by clinicians in this population. Additionally, unhealthy sleep behaviors adversely affecting duration and timing of sleep were associated with a greater number of MS components, suggestive of monotonic relationships thus supporting a tenant of causality. There is a need for large-scale studies focused on further investigation of dose-response relationship as well as effects of interventions to improve sleep duration and regularize timing on metabolic factors and PCOS in adolescents. Counseling pertaining to sleep duration and timing, sleep hygiene measures, and its impact on metabolic health are encouraged. Given that effective treatments for OSA are available, these interventions when implemented in adolescence may mitigate development of components of MS and obesity over time. Last, early prevention via targeting sleep factors of obesity-related metabolic consequences including PCOS, MS, and diabetes mellitus can substantially improve long-term health outcomes of an individual, particularly if addressed during childhood. Ultimately, however, to definitively change our clinical approach and paradigm, interventional controlled clinical trials designed to investigate the merit and impact of targeting sleep apnea and behavioral interventions on metabolic outcomes in adolescents with PCOS and obesity are needed.

Additional Information

Disclosure Summary: R.M. reports receiving National Institutes of Health funding support from the National Heart, Lung, and Blood Institute [U01HL125177, UG3HL140144] and the American Heart Association. Her institution has received positive airway pressure devices and equipment from Philips Respironics, ResMed, GE Healthcare, and Natus for research. She has served as a consultant for Respicardia and Merck; received funds for service on the American Board of Medicine Sleep Medicine Exam test writing committee and royalties from UpToDate. S.K. has previously obtained research funding from Ethicon endo-surgery and Janssen and serves on an advisory board for GI dynamics Inc.

Data availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.