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Original Studies |
Sleep Disorders Section, Divisions of Endocrinology (R.B.F., A.M., G.P., S.D.P., A.D., D.P.W.), Pulmonary and Critical Care Medicine (R.B.F., A.M., D.P.W.), and Women’s Health (A.D.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: David P. White, M.D., Sleep Disorders Program, Brigham and Women’s Hospital, RFB 486, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: dpwhite{at}gcrc.bwh.harvard.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several preliminary studies have suggested that androgen levels can directly influence the prevalence and severity of sleep-disordered breathing in both men and women. First, there are several reports demonstrating that administration of exogenous androgens to either men or women can precipitate apnea in a previously unaffected individual, without change in weight (18, 19, 20). Second, there is preliminary evidence that women with OSA have higher circulating androgens than age and weight-matched control women (21, 22). Finally, we have previously demonstrated that in a group of hypogonadal men that short-term testosterone replacement led to a statistically significant increment in the Apnea-Hypopnea Index (AHI, events per hour of sleep) (23). Taken together, these data clearly suggest that androgens can importantly influence the development of OSA.
Polycystic ovary syndrome (PCOS) is a common disorder affecting as many as 5–10% of women of reproductive age (24). This disorder is characterized clinically by oligomenorrhea and clinical signs of androgen excess. Biochemical features of PCOS include chronic annovulation and elevated circulating androgen levels. Obesity is seen in many of these women and is frequently central in nature (increased waist to hip ratio). Insulin resistance is also a common finding. Women with PCOS have an increased prevalence of type 2 diabetes (25) and lipid abnormalities (26). There is also emerging evidence to suggest a link between PCOS and cardiovascular disease (27, 28).
The clinical (obesity) and biochemical (increased serum androgens) features of PCOS suggest that these women may be at increased risk for the development of OSA syndrome. To test this hypothesis, we compared the prevalence of sleep apnea in a group of overweight women with untreated PCOS to that in a group of age and weight matched control women.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We studied 18 overweight women with PCOS and compared them with
18 age- and weight-matched controls. Women with untreated PCOS were
recruited from the Division of Women’s Health at the Brigham and
Women’s Hospital and the Reproductive Endocrine Unit of the
Massachusetts General Hospital. All women were overweight (Body Mass
Index 
28 kg/m2), healthy and between the
ages of 18 and 45 yr. They were not currently taking any medications.
PCOS was defined by chronic oligomenorrhea (six or fewer menses per
year) along with elevated serum androgen levels (total or biologically
available testosterone levels) (29). Nonclassical
21-hydroxylase deficiency was excluded by a 1-h ACTH stimulation test.
No woman had an elevated plasma PRL level. Control women were recruited
by means of advertisement within the community and had normal menstrual
cycles (28–35 days), no clinical signs of androgen excess, and normal
serum levels of androgens. Both groups were recruited consecutively,
and, to avoid any potential recruitment bias no questions regarding
symptoms of any sleep disorder were asked. Women in both groups were
without evidence of other diseases including diabetes and hypertension.
All women gave written informed consent before participation in this
study, which had the approval of the Human Subjects Committee of the
Brigham and Women’s Hospital.
Subject evaluation
Each woman underwent a brief examination by one of the authors (RBF) including measurement of height, weight, minimal waist circumference, and maximal hip circumference. Each filled out a brief sleep questionnaire, which included a subjective evaluation of daytime sleepiness. The Epworth Sleepiness Scale (ESS) (30), asks subjects to rate the probability of falling asleep in eight different situations on a scale of 0 (not likely at all) to 3 (extremely likely). Thus scores can range from 0–24 with higher scores indicating greater sleepiness. This questionnaire has been validated both in normal subjects and in patients with disorders of excessive daytime sleepiness (30, 31).
Measurement of serum hormones
A single fasting blood sample for hormone analysis was obtained between 0800 and 1000 h. Assays for serum Testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) were performed by using Diagnostic Products (Los Angeles, CA) Coat-A-Count kits. Non-SHBG-bound (unbound) testosterone was measured by a modification of the procedure of Tremblay and Dube, as previously described (32).
Polysomnography
Polysomnography was performed according to standard laboratory
protocol. Data recorded included four channels of EEG (two central and
two occipital), two channels of EOG, submental EMG, arterial oxygen
saturation (Healthdyne, Model 930, Marietta, GA.), nasal-oral airflow
(thermistor), nasal pressure (Validyne Engineering Corp., Northridge
CA), EKG, chest and abdominal wall motion (piezo electrodes, Pro-Tech
Services, Woodinville, WA) bilateral anterior tibialis EMG, snoring
(tracheal microphone) and body position (mercury gauge). All signals
were simultaneously recorded and stored using the ALICE 3 digital
polysomnography system (Respironics, Inc., Murraysville, PA). Bedtime
was set between 2200 and 2300 h, and waketime occurred between
0600 and 0700 h. Thus, we attempted to record sleep for
7 h in each subject/patient.
All of the polysomnographic records were scored by one of the authors
(SDP) who was blinded to all subjects’ diagnosis. Sleep was staged
according to standard criteria (33). Arousals were defined
according to American Academy of Sleep Medicine (AASM) guidelines
(34). Respiratory events were scored according to the
recently published AASM guidelines for measurement in clinical research
(35). Specifically, apnea was defined as a complete
cessation in airflow of 10 sec. They were classified as central
if there was no associated effort, and obstructive if respiratory
effort was present. Hypopneas were scored as a clear reduction in
amplitude in the nasal pressure signal for 10 sec that was
associated with either an oxygen desaturation of >3%, EEG arousal or
both. The apnea-hypopnea index (AHI) was calculated as the number of
apneas plus hypopneas divided by the number of hours of sleep.
Data analysis
We quantitatively compared demographic, hormone, and sleep
variables, between patients with PCOS and controls using unpaired
t tests for data that was normally distributed and
nonparametric methods (Mann-Whitney Rank Sum Test) for data that were
not normally distributed (SigmaStat, SPSS, Inc. Chicago,
IL). In addition, the proportion of PCOS women and controls with sleep
apnea syndrome was compared using the Fisher Exact Test. Correlation
analyses were performed using standard least squares linear regression
techniques for single variables, and forward stepwise regression for
multiple variables. Data are presented as the mean ±
SEM. For all analyses, two-tailed significance
was set as 
< 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. PCOS and control women
were well matched for age and BMI. However, as can be seen, women with
PCOS had a significantly higher waist-hip ratio (WHR) than control
women (0.88 ± 0.02 vs. 0.82 ± 0.01,
P = 0.01). Women with PCOS also had significantly
higher circulating testosterone (94.44 ± 8.5 ng/dl vs.
22.77 ± 2.5 ng/dl, P < 0.001) and unbound
testosterone levels (34.06 ± 2.3 ng/dl vs. 5.05
± 0.8 ng/dl P < 0.001) than controls.
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. Women with PCOS had a
significantly higher mean AHI than matched control women (22.5 ±
6.0 vs. 6.7 ± 1.7, P < 0.01) (Fig. 1), a difference that was even more
pronounced during REM sleep (41.3 ± 7.5 vs. 13.5
±3.3, P < 0.01), (Table 2). There was no difference
in other polysomnographic variables including sleep onset latency,
Stages 1 and 2 sleep, slow-wave sleep or REM sleep. Overall, sleep
efficiency appeared lower in the women with PCOS (80.1 ± 3.7%
vs. 88.2 ±2.2%); however, this difference did not reach
statistical significance. Finally, women with PCOS were subjectively
sleepier than control women (mean ESS 9.5 ± 0.9 vs.
5.8 ± 0.8, P < 0.01).
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). Using an AHI cutoff of 5, 10, or 15
as abnormal, the prevalence of sleep apnea was always more common in
women with PCOS. However, this difference only reached statistical
significance at AHI cutoffs of 10 and 15. When OSA syndrome was defined
according to the recently published AASM Task Force Guidelines
(35), women with PCOS were significantly more likely than
control women to suffer from symptomatic OSA (44.4% vs.
5.5%, P < 0.01).
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), total serum testosterone
(r = 0.52, P < 0.001) (Fig. 3), and unbound testosterone (r =
0.50 P < 0.05). There was no significant correlation
between age, weight, waist circumference, or BMI with AHI. In the
control women, AHI correlated significantly with WHR (r = 0.56,
P < 0.01). There was no correlation between serum
androgens and AHI in the control group. Using stepwise regression
analyses to determine the relative importance of WHR, total
testosterone and free testosterone in predicting apnea severity in
women with PCOS, combining WHR and total testosterone improved the
predictive value (r = 0.64, P < 0.001). Free
testosterone did not add significantly to the model.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The reasons for this markedly increased prevalence of sleep-disordered breathing in women with PCOS cannot be determined directly from this study, but several possibilities exist. It could be that the androgen excess associated with PCOS contributes to this finding. Several previous studies have suggested that elevated serum androgens may represent an independent risk factor for the development of OSA. Matsumoto et al. (18) showed that testosterone replacement in 5 hypogonadal men led to the development or substantial worsening of sleep apnea in two. In another such study, Cistulli et al. (20) demonstrated that testosterone administration to a young male with Marfan’s Syndrome was associated with an exacerbation of OSA, along with increased upper airway collapsibility during sleep. A recent case report revealed that an androgen secreting ovarian tumor precipitated clinically significant sleep apnea in a previously unaffected woman, and that apnea disappeared following surgical resection of the tumor (19). Our laboratory has also demonstrated that in a group of hypogonadal men, short-term testosterone replacement led to a statistically significant rise in total nocturnal apneas + hypopneas, with several subjects developing clinical sleep apnea. In addition, there is preliminary evidence that women with OSA have higher circulating androgen levels than age and weight matched normal controls. Mohamed et al. (21) found higher androgen levels in four women with sleep apnea when compared with controls. Schwartz et al. (22) examined hormone levels in six obese women with OSA and compared them to obese and nonobese controls. Women with sleep apnea had higher free testosterone and dihydroepiandrostenedione (DHEAS) than both sets of controls.
It should be noted, however, that not all the available data are consistent in this regard. In fact several studies have found that testosterone levels (free and total) are lower in men with severe sleep apnea and improved with nasal CPAP therapy (36). This same group was also unable to demonstrate a statistically significant improvement in apnea severity using short-term (one month) androgen blockade with flutamide (37). Thus, the exact role of testosterone in sleep apnea pathogenesis is not clear.
In the current study, AHI correlated significantly with both total and free testosterone, although the relationship with free testosterone was no longer significant once waist-hip ratio and total testosterone was included. However, it is well known that sex hormones can affect body fat composition, with androgens leading to central obesity. Evans et al. (38) showed that women with PCOS had an increased WHR compared with weight-matched controls, and that WHR correlated with serum androgen levels. Thus, it is possible that the elevated serum androgens found in women with PCOS leads to increased central obesity, which numerous previous studies (39) have shown to be a better predictor of OSA than BMI. In addition to androgen excess, PCOS is often associated with both insulin resistance and elevated serum glucose levels. Both of these factors may contribute to central obesity and an increased risk of OSA. Thus, central obesity itself, rather than androgen excess, could be the factor that predisposes to OSA.
Elevated androgen levels could predispose to OSA by several potential mechanisms. First, it is well known that testosterone can affect body composition. It is possible that elevated androgen levels leads to increase soft tissue deposition in the pharynx (40). This could change either the size or compliance characteristics of the pharyngeal airway, making it more likely to collapse. Androgen receptors have also been localized in the hypoglossal motor nucleus (41), and it is possible that elevated androgen levels could affect the function of the pharyngeal dilator muscles. We have previously demonstrated differences in the pharyngeal dilator muscles in men when compared with women, a difference that may in part be due to testosterone (16). Finally, it is possible that testosterone could lead to alterations in ventilatory control mechanisms during sleep, rendering the airway more vulnerable to collapse.
These findings have important clinical implications. First, clinical recognition of sleep apnea in women is far from optimal. Both OSA and PCOS are relatively common disorders in the general population and often go undiagnosed. Both are associated with significant morbidity for the affected individual and are readily amenable to therapy. Although OSA is less common in women compared with men, there also appears to be a problem identifying women with sleep apnea. Clinic-based studies have typically reported a much greater difference in sleep apnea rates for men and women than have been seen in epidemiological studies (12). This has raised concerns that there is a selection bias for referral for evaluation that favors men. Based on data from the Wisconsin cohort, Young estimated that > 90% of women with moderate to severe OSA are undiagnosed (42).
Second, OSA may contribute to cardiovascular morbidity in women, an effect that could be greater in women with PCOS. Recent data from the Nurses Health Study has shown that snoring was associated with an increased risk for the development of cardiovascular disease, an association that remained significant after controlling for potential confounding variables (43). Preliminary data from the Wisconsin Sleep Cohort Study has suggested a significantly greater 5-yr mortality rate for women with sleep-disordered breathing than for women without the disorder. This increased mortality was substantially higher in women than in men with OSA (44). In a case-control study, Mooe et al. (45) found sleep apnea (AHI > 5) to be an independent predictor of coronary artery disease (odds ratio = 4.1) that was more powerful than either hypertension or smoking. Although these data are only preliminary, they suggest a gender difference in susceptibility to adverse cardiovascular outcomes from sleep apnea.
Finally, we wonder whether OSA may contribute in small part to the metabolic abnormalities seen in women with PCOS. In some, but not all studies, OSA has been associated with an increased prevalence of insulin resistance and type 2 diabetes, characteristic features of PCOS. Although Stoohs et al. (46) found this relationship to be due entirely to obesity, others have found an increased prevalence of insulin resistance in OSA patients, even after controlling for confounding variables (47, 48). Brooks and colleagues also demonstrated an improvement in insulin responsiveness in patients with type 2 diabetes and OSA following nasal CPAP therapy (49). Clearly, the majority of the metabolic abnormalities in PCOS are due to obesity and androgen excess.
Our study had several limitations, which should be recognized. First, the sample size is relatively small. However, the group differences were sufficiently robust that a larger sample size was not required to demonstrate substantial and significant differences. Second, there might be concern that the prevalence of OSA in the control women was quite low, given their degree of obesity. However, this finding is consistent with several prior studies. Sloan and Shapiro found a prevalence of OSA (AHI >10) in 10% of obese (mean BMI = 39 kg/m2) women referred to an eating disorders clinic. Richman et al. (50) found a higher prevalence of OSA (AHI > 5) in a hospital-based obesity clinic (37.9%), but the women with OSA were substantially more obese (BMI = 46.1 ± 2.3) than those without OSA (37.5 ± 1.3), and the latter group more closely resembles our control women. Third, there may have been a participation bias in that women who agreed to be in this study may have done so because they suspected that they had a sleep problem. However, we doubt this was the case as the vast majority of the women we approached agreed to participate. Approximately 75% of women asked to participate agreed to do so. In addition, any potential bias should have existed for the control group as well. Finally, no questions regarding symptoms of sleep disorders were asked of any subject. Specifically no woman (control or PCOS) was asked about symptoms of snoring, daytime sleepiness or witnessed apneas. All those who completed the sleep study were included in the study, regardless of the results. The final limitation is that as we only studied obese women with PCOS, the results of this study may not be applicable to all women with this disorder.
In summary, we found that overweight women with PCOS were substantially more likely to suffer from the OSA syndrome than a carefully age- and weight-matched group of reproductively normal control women. As a result, women with PCOS, particularly those that are obese, should be carefully questioned regarding symptoms suggestive of sleep apnea. Specifically, these women should be questioned regarding snoring and daytime sleepiness, as these are the most common symptoms found in OSA. The mechanistic relationship between PCOS and OSA is likely complicated, but we suspect that this increased risk is related to chronic androgen excess in these women.
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Footnotes |
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2 Received the Pickwick Fellowship from the National Sleep
Foundation.
Received August 8, 2000.
Accepted November 9, 2000.
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References |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
