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(Chest. 2001;120:151-155.)
© 2001 American College of Chest Physicians

Impact of Menopause on the Prevalence and Severity of Sleep Apnea*

David R. Dancey, MD; Patrick J. Hanly, MD, FCCP; Christine Soong, BSc; Bert Lee, BSc and Victor Hoffstein, MD, FCCP

* From the Department of Medicine, University of Toronto, Division of Respirology, St. Michael’s Hospital, Toronto, Canada.

Correspondence to: Victor Hoffstein, MD, FCCP, St. Michael’s Hospital, 30 Bond St, Suite 6–015, Toronto, Ontario, Canada M5B 1W8; e-mail: victor.hoffstein{at}utoronto.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To compare the prevalence and severity of sleep apnea between premenopausal and postmenopausal women, and to determine whether these differences are affected by the body mass index (BMI) and neck circumference.

Design: Cross-sectional study utilizing a sleep clinic patient database.

Setting: University hospital.

Patients: A total of 1,315 women, classified into premenopausal and postmenopausal groups based on age (< 45 years and > 55 years, respectively).

Measurements: Anthropometric measurements included height, weight, and neck circumference. Sleep measurements included full nocturnal polysomnography. Sleep apnea was defined as an apnea-hypopnea index (AHI) > 10/h.

Results: There were 797 premenopausal and 518 postmenopausal women. The latter group was more obese (mean ± SE BMI, 32.2 ± 0.4 kg/m2 vs 30.2 ± 0.4 kg/m2; p < 0.0001) and had larger neck circumference (37.1 ± 0.2 cm vs 35.8 ± 0.2 cm; p < 0.0001). The prevalence of sleep apnea was greater in postmenopausal women than premenopausal women (47% vs 21%; {chi}2 < 0.0001). There were proportionately more postmenopausal than premenopausal women in all ranges of apnea severity (AHI, 10 to 30/h, 30 to 50/h, and > 50/h). Postmenopausal women had a significantly higher mean AHI compared to premenopausal women (17.0 ± 0.9/h vs 8.7 ± 0.6/h; p < 0.0001); this significant difference persisted even after adjusting for BMI and neck circumference.

Conclusion: There may be functional, rather than anatomic, differences in the upper airway between premenopausal and postmenopausal women, which may account for the observed differences in apnea prevalence and severity.

Key Words: menopause • sleep apnea • women


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although it is commonly assumed that the prevalence and severity of sleep apnea in women increase after the menopause, examination of the available data does not support this conclusion, because of the conflicting or incomplete information, as may be illustrated by several examples. The first study comparing breathing during sleep in premenopausal and postmenopausal women was carried out by Block et al.1 2 It showed a significantly higher prevalence of apneas, hypopneas, and episodes of oxygen desaturation in the postmenopausal group, suggesting that lack of progestational hormones may affect breathing during sleep; however, treatment of postmenopausal women with medroxyprogesterone for 1 month did not significantly alter their breathing, although there were some individual subjects who exhibited a reduction in sleep-disordered breathing events following hormonal replacement. Ancoli-Israel et al3 examined postmenopausal women residing in a nursing home and showed high prevalence of sleep apnea in this group. A study4 compared young, middle-age, and older women and demonstrated increased frequency of apneas; however, this effect was inconsistent and present only in stage 2 sleep. Millman et al5 studied premenopausal and postmenopausal women and did not find any differences in sleep variables; however, the study was limited to only about 12 women in each group.

Since the effect of menopause on sleep is still a matter of controversy, it is not surprising that the potential mechanisms that may account for possible differences are highly speculative. Some authors6 7 8 9 have suggested that estrogen and progesterone exert a protective effect on the upper airway, preventing premenopausal women from developing sleep apnea. Carskadon et al10 found that differences in body fat distribution explain the increase in sleep apnea seen in postmenopausal women. However, all of these studies are limited by small patient numbers. Consequently, the purpose of this study was to compare the prevalence and severity of sleep apnea in premenopausal and postmenopausal women in a large clinic population, after adjusting for such common confounders as body mass index (BMI) and neck circumference.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Population
The patient population included women referred to a university-based sleep clinic because of symptoms suggestive of sleep-related abnormality. The data collected included age, BMI, neck circumference, medical history, list of medications, reason for referral, diagnosis, and overnight polysomnography.

Overnight Polysomnography
Overnight polysomnography was performed in all patients and included monitoring of EEG, electro-oculograms, submental and tibial electromyograms, ECG, oxygen saturation using pulse oximeter (Biox 3700/3740; Ohmeda; Boulder, CO), respiratory effort using inductance plethysmography (Respitrace; Ambulatory Monitoring; Ardsley, NY), and airflow. Two surrogate measures of airflow were used: either (1) expired CO2 at the nose and mouth through cannulas adapted for this purpose and attached to a CO2 analyzer (CD 102 Normocap; Datex; Helsinki, Finland), or (2) monitoring of oronasal temperature using thermistors. All variables were recorded either on a polygraph (models 78D or 78E; Grass Instruments; Quincy, MA) at a paper speed of 10 mm/s, or using a computerized acquisition system (Sandman; Mallinckrodt Nellcor Puritan Bennett; Melville, Ottawa, Ontario).

Polysomnograms were scored manually. Sleep stage and arousals were determined according to established criteria.11 An obstructive apnea was defined as a cessation of airflow for > 10 s despite persistent respiratory effort. Hypopnea was defined as a reduction in the amplitude of respiratory effort by at least 50% of the baseline sleeping level, for > 10 s. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep.

Menopausal Status
We defined women as being premenopausal if they were < 45 years of age and postmenopausal if they were > 55 years of age. This was based on evidence by McKinlay et al12 that the median age of onset of the perimenopausal transition is 47.5 years, and that the median age of menopause is 51.3 years. Women were excluded if they were between 45 years and 55 years of age, were receiving the birth control pill or hormone replacement therapy, and if they had a history of premature ovarian failure, polycystic ovaries, or iatrogenic menopause.

Statistical Analysis
Data are reported as the mean ± SE. The prevalence of sleep apnea (defined as AHI > 10) in premenopausal and postmenopausal women was compared using {chi}2 tests. The severity of sleep apnea was compared using unpaired t test. However, AHI is generally correlated with BMI and neck circumference. These two variables may be significantly different in the premenopausal and postmenopausal groups. Consequently, in order to correct for this mismatch, we performed analysis of covariance, with BMI and neck circumference as the covariate variables. All statistical analyses were carried out using statistical software (SAS Statistical Software, Version 7; SAS Institute; Cary, NC). The level of significance was assumed to be equal to 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were a total of 1,967 women; of these, 652 women were excluded: 72 women were excluded because they were either receiving hormone replacement therapy or had undergone gynecologic surgery, and 580 women were excluded because they were between 45 years and 55 years old. This left us with 1,315 women available for analysis; of these, 797 women were premenopausal (mean age, 35 ± 0.2 years) and 518 women were postmenopausal (mean age, 65 ± 0.3 years). Table 1 shows that premenopausal women had a significantly lower mean AHI, BMI, and neck circumference compared to postmenopausal women.


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  		Table 1. Anthropometric Data and AHI for Premenopausal and Postmenopausal Women*

 
The prevalence of sleep apnea was significantly lower in premenopausal women than in postmenopausal women: 20% of the premenopausal women had AHI > 10/h, vs 49% of the postmenopausal group ({chi}2 < 0.0001); with a more strict definition of sleep apnea based on AHI > 20/h, the prevalence among postmenopausal women dropped to 28% vs 10% in premenopausal women ({chi}2 < 0.0001).

Furthermore, we found proportionally more postmenopausal than premenopausal women in all ranges of apnea severity (AHI > 10/h but <= 30/h; AHI >30/h but <= 50/h, and AHI > 50/h). Among nonapneic women (AHI <= 10), the opposite was true: more premenopausal than postmenopausal women (Fig 1 ).



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  		Figure 1. Frequency of premenopausal and postmenopausal women according to apnea severity.

 
Correlation analysis demonstrated significant associations between AHI and BMI (Pearson correlation coefficient, r = 0.38; p < 0.0001), as well as between AHI and neck circumference (r = 0.49; p < 0.0001). Multiple regression analysis showed that neck circumference, BMI, and menopause status together accounted for 27% of the variability in AHI (p < 0.0001).

The relationship between AHI and BMI (Fig 2 ) was more linear in postmenopausal women than in premenopausal women; the latter showed more rapid increase in AHI with BMI in the most obese range. However, the relationship between AHI and neck circumference (Fig 2) was similar in the two groups.



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  		Figure 2. Apnea severity as a function of BMI (top panel) and neck circumference (bottom panel) in premenopausal (Pre) and postmenopausal (Post) women.

 
We used analysis of covariance to compare AHI in the premenopausal and postmenopausal groups after adjusting for neck circumference and BMI. The results showed that there continued to be a significant difference in AHI between the two groups (least-squares mean, 10.2 ± 0.8/h vs 16.4 ± 1.0/h, p < 0.0001, for premenopausal and postmenopausal women, respectively).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study suggests that the prevalence and severity of sleep apnea increase in women after menopause, even after controlling for BMI and neck circumference. Its uniqueness lies in (1) its large sample size, (2) the availability of polysomnography in all participants, and (3) careful control of the two most important confounders influencing apnea severity (neck circumference and BMI).

The most serious limitation of our study is our definition of menopause. Ideally, either serum hormone levels or the date of the last menstrual period are necessary to determine menopausal status. Unfortunately, we did not have either to help us distinguish premenopausal from postmenopausal women. Instead, we used age (< 45 years and > 55 years) as a surrogate marker of menopausal status. The support for this approach comes from the Massachusetts Women’s Health Study.12 In this large, prospective cohort study of 2,565 middle-age women, the median age of menopause was 51.3 years, and the median age of onset of the transition to menopause was 47.5 years.

Nevertheless, it is theoretically possible, although unlikely, that some women < 45 years old are in fact postmenopausal, while others > 55 years are premenopausal. This would obviously alter the composition of our assumed premenopausal and postmenopausal groups, conceivably affecting our results and conclusions. We attempted to estimate the error caused by this possible misclassification by performing the following calculation. We assumed the "worse case scenario," ie, 5% of women 40 to 45 years old with the lowest AHI are postmenopausal, and 5% of women 55 to 60 years old with the highest AHI are premenopausal. We then recalculated the prevalence and severity of sleep apnea for the two groups. Even with this assumption, we still found that the prevalence of sleep apnea in the premenopausal group was significantly lower than in the postmenopausal group (19% vs 53%). In addition, premenopausal women still had significantly lower AHI than postmenopausal women (10.3 ± 0.7/h vs 14.3 ± 0.8/h, respectively).

Another important limitation of the analysis is that due to the definition for menopausal status, the role of aging cannot be addressed. Consequently, we cannot be sure that the differences in AHI between premenopausal and postmenopausal women are due to menopause or age. An indirect way to assess the effect of age on AHI is to determine whether prevalence and severity of sleep apnea vary by age within each menopausal group. We therefore classified all premenopausal women into three age groups (< 30 years, 30 to 40 years, and > 40 years). Similarly, all postmenopausal women were classified into three age groups (< 60 years, 60 to 70 years, and > 70 years). We used analysis of variance to compare AHI between the age groups (separately for premenopausal and postmenopausal women), after adjusting for BMI and neck circumference. We found no difference in AHI as a function of age group.

Clearly, we do not advocate using age as a substitute measure to determine the menopausal status, but we believe that in our patient population, age-related differences in sleep apnea prevalence and severity relatively accurately reflect the differences due to menopausal status. Another potential confounding factor affecting our results relates to a possible referral bias. It is conceivable that most of the premenopausal women were referred because of a nonrespiratory sleep disorder, whereas most of the postmenopausal women were referred because of suspicion of sleep apnea. If this were the case, it would not be surprising that premenopausal women have a lower prevalence and less severe sleep apnea than postmenopausal women. To deal with this possibility, we examined the chief complaints of all patients. Those who presented with the chief complaint suggestive of obstructive sleep apnea (OSA; ie, snoring, gasping, choking, observed episodes of cessation of breathing, and excessive daytime tiredness, sleepiness, or fatigue) were termed "OSA symptoms +," and all others were termed "OSA symptoms -." We found that 67% of premenopausal women presented with symptoms of OSA, vs 69% of postmenopausal women ({chi}2, 0.52). This indicates that referral bias in unlikely to account for our findings.

The effect of menopause on sleep apnea prevalence and severity has been a matter of debate in the literature. For example, contrary to our results, Millman et al5 found no significant differences in AHI, BMI, or anthropometric measurements between premenopausal and postmenopausal women. However, the study included only 12 premenopausal women and 13 postmenopausal women. Ware et al4 recently studied the influence of age and gender on the duration and frequency of apnea events. Although the authors4 found no difference in the apnea index between young (ages 18 to 39 years) and middle-aged (ages 40 to 59 years) women, it doubled when comparing middle-aged with older (ages 60 to 88 years) women. A relatively high prevalence of sleep apnea among postmenopausal women has been observed in the general population as well as in the clinic population. For example, Zamarron et al13 found the prevalence of sleep-disordered breathing (AHI > 5/h) in a general population of women aged 50 to 70 years to be 30%.

We controlled for BMI and neck circumference when comparing the severity of apnea in premenopausal and postmenopausal women. This was done because of overwhelming evidence indicating that these two variables constitute the most important determinants of apnea severity. Several previous investigations14 15 have pointed out the importance of regional (ie, upper airway) and generalized obesity in affecting the severity of sleep apnea. Much of the relationship between obesity and sleep apnea is explained by neck size, upper-airway compliance, and fat content in the neck. When patients are matched for BMI, apneic patients have larger neck circumferences compared with nonapneic patients.16 Obese patients with larger necks tend to have a more collapsible velopharynx during wakefulness, predisposing them to upper-airway obstruction during sleep.17 A study18 using CT to assess visceral fat accumulation found that patients with increased visceral fat also tended to have larger fluctuations in upper-airway size between inspiration and expiration. MRI studies19 20 have shown that the thickness of the lateral pharyngeal walls in the neck accounts for most of the airway narrowing found in apneic subjects. Even nonobese subjects with sleep apnea have larger neck volumes and fat content than those who are normal or only have simple snoring.21

Our results show that BMI and neck circumference status do not entirely explain the differences in apnea prevalence and severity between premenopausal and postmenopausal women. Clearly, there must be other factors that influence the observed differences. Some of these factors have been pointed out by other investigators6 7 8 9 ; one common hypothesis is that differences in estrogen and progesterone levels may explain the differences in apnea.

There are five studies2 6 7 8 9 of postmenopausal women receiving treatment with female sex hormones, in the hope of abolishing sleep apnea. However, the results are inconsistent. In two of the studies,4 5 administration of estradiol, estrogen, or progestin to 16 postmenopausal women resulted in a reduction of time awake, an increase in the proportion of rapid eye movement sleep, a reduction in AHI, and an improvement in oxygen saturation. This improvement may have been due to increased upper-airway dilator muscle activity mediated by estrogen and progesterone, as supported in a study by Popovic and White.8 However, Block et al2 and Cistulli et al9 administered hormone replacement therapy to a group of postmenopausal women and found no reduction in sleep-disordered breathing events. All of these studies suffer from small sample size. Only one study2 had a placebo-controlled group. Carskadon et al10 hypothesized than nasal obstruction, which is a risk factor for snoring and apnea, may be influenced by the menopausal status. However, although application of nasal occlusion to premenopausal and postmenopausal women did increase AHI, it was independent of the menopausal status.

In summary, using the largest sample of a female clinic population to date, we found that sleep apnea is more prevalent and more severe in postmenopausal women compared to the premenopausal women. However, menopause status, BMI, and neck circumference account for < 30% of the variability in sleep apnea. It is therefore possible, although it remains to be proven, that hormonal replacement may not fully abolish sleep apnea in postmenopausal women. Further investigations are required to elucidate the factors that account for the differences in apnea activity between premenopausal and postmenopausal women.


   Footnotes
 
Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; OSA = obstructive sleep apnea

Received for publication September 1, 2000. Accepted for publication February 22, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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