A Comparison of Men and Women with Occlusive Sleep Apnea Syndrome

A Comparison of Men and Women with Occlusive Sleep Apnea Syndrome* Judith A Leech, M.D., F.C.C.R;t Ergiln Onal, M.D.; Corrine Dulberg, Ph.D.; and Melvin A Lopata, M.D., F.C.C.R Among 118 patients with occlusive sleep apnea syndrome

(OSA), defined as daytime hypersomnolence and an apnea

hypopnea index (AHI»ten eventslh, 41 women were compared with 77 men. Body mass index, spirometric study, PaO., PaCO., and results from nocturnal polysomnography were examined in a two-way analysis of variance (ANOVA) for the effects of sex, age group, and a sex-age group interaction. The age groups examined were above and below 42 years, the breakpoint for menopause in the women. Younger persons tended to be more obese and to have a higher ABI. Both sexes had similar pulmonary function, Am, and nocturnal desaturation, but women

The preponderance ofcurrent information suggests that sleep-disordered breathing is a predominantly male disorder and that the basis for its gender specificity is partly hormonal. 1-3 A greater frequency and severity of snoring and of apneas and hypopneas in normal men compared with normal women has been described. 1,. During wakefulness, normal women have been shown to have a lower response to hypoxia and hypercapnia than men, albeit with higher resting ventilation." A hormonal basis for gender differences is further supported by three pieces of evidence: differences in prevalence of apneas and hypopneas are observed between normal postmenopausal and premenopausal women;2,3 conflicting results are available,6-8 but there is some evidence that use of pharmacologic doses of progesterone can be successful in alleviating the severity of occlusive sleep apnea (OSA);6,7 and a relationship between testosterone and OSA severity is described in at least one case report. 9 Among 400 patients with OSA seen at a large, general sleep disorders clinic only 16 (4 percent) were women,'? so clinical studies in OSA have either combined the sexes 10-12 or have described results from men only 13-16 *From the Department of Medicine, Section of Bespiratory and Critical Care Medicine, University of Illinois College of Medicine at Chicago; Veterans Administration West Side Medical Center and University of Illinois Hospital, Chicago; Health Care Research Unit, Department of Epidemiology and Community Medicine, and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. tDr. Leech is a recipient of the Career Scientist Award, Ontario Ministry of Health. Supported in part by the Chicago Lung Association and the Medical Research Service of the Veterans Administration. Manuscript received November 24, 1987; revision accepted April 12. Reprint requests: Dr. Leech, Ottawa Hospital, 1053 Carling Avenue, Ottawa, OnttJtio, Caruula KlY 4E9

experienced signi6cantly fewer completely occluded breathing events and had apneas of shorter mean and maximum duration than men of similar ages. No effect of menopausal status per .. was observed. In OSA patients, differences in upper airway occlusion and apnea duration suggest differences between the sexes in upper airway physiology or respiratory control. (Claat 1988; 94:983-88) OSA= occIUSM sleep ~ S)'Ddrome; AID = apnea hypopoea index; ANOVA analYlls of variance; AI = apnea Index; 8M! body mass index; EDS = excesshe daytime sleepiness

=

=

A recent report by Wilhoit and Suratt'" was the first to examine the characteristics of premenopausal women with obstructive sleep apnea syndrome. In eight premenopausal women without structural pharyngeal abnormalities they found a greater prevalence of obesity and hypercapnia than in men and postmenopausal women. Their analysis did not, however, take into account the possible confounding effect of age per see Similarly Guilleminault et all S recently reported that the major difference in premenopausal women with OSA compared with men and postmenopausal women is massive obesity At the University of Illinois Sleep Laboratory which has maintained a sleep apnea patient registry since 1982, we record a higher percentage of women with OSA than that reported elsewhere. We suspect that the higher prevalence of women in our OSA population probably reflects the higher prevalence of obese women in indigent populations such as ours. We undertook an analysis of between-sex differences in the expression of OSA and attempted to sort out the effects of age and menopausal status in the design of the analysis. It was thus possible to use these patients to conduct an analysis of between-sex differences in the expression of OSA from data collected on OSA patients. MATERIAL AND METHODS

The sleep apnea registry is composed of a patient population derived from inpatients and outpatients of the University of Illinois Hospital as well as referrals from community hospitals and clinics. Patients with OSA, defined on the basis of a clinical history of hypersomnolence and snoring and an apnea plus hypopnea index of more than ten eventslh,ll,. are recorded in the register. Patients referred for nocturnal polysomnography but excluded from the registry were those with normal polysomnographg with predominantly central apneas, lIa,. or a mild, frequently asymptomatic sleepCHEST I 94 I 5 I NOVEMBER. 1988

883

induced disorder characterized by occlusive hypopneas and apneas of less than lOIh of total sleep time. At the time of this analysis, 118 patients met this definition of OSA. Each had undergone pulmonary function tests and arterial blood gas determinations at the time of initial evaluation. An analysis of the determinants of hypercapnia in the first III of these patients has been reported elsewhere. II Menopausal status was determined on the basis of reported history in each woman. During a single nights polysomnography sleep was defined by EEG (C4Al), electrooculogram, and submental electromyogram by the criteria of RechtschafIen and Kales. It Airflow at the nose and mouth was recorded by thermocouples fitted into a loose-fitting face mask; the presence of airflow as simultaneously confirmed by monitoring end-tidal COl from a plastic catheter inserted tightly into the face mask; thoracoabdominal motion was monitored by inductive plethysmography (Respitrace), Arterial oxygen saturation was continuously measured by ear oximetry (Hewlett-Packard 4720lA) and all were recorded on a l6-channel strip chart recorder (Beckman Instruments), All patients were advised to discontinue taking any hyponotic, sedative, or stimulant drugs or alcohol at least 72 h before undergoing polysomnography

All patients underwent thyroid function testing (T4, T3 RIU, and Four patients (three women and one man) were hypothyroid by these measures, and two were sick euthyroid.P An apnea episode was defined as the absence of airflow for at least ten seconds, and hypopnea as a fall in airlI~ ribcage, or abdominal motion tracing by greater than 50 percent associated with an oxygen desaturation of greater than 4 percent below the preceding baseline. l 8.JO The apnea index (AI) was defined as the number of apneas divided by the total sleep time, and the apnea plus hypopnea index (AHI) was defined as the sum of apneas plus hypopneas divided by the total sleep time (in hours),18.10 The mean oxygen saturation was defined as the mean measured saturation at the desaturation troughs following apneas. The mean apnea duration was the average duration of airflow cessation recorded throughout the night, and the single longest apnea in each patient was recorded as maximal apnea duration. Arterial blood gases were drawn on room air with the subject

TSH~

Table I-Mean Aga (± SEM) and CeU Sizafor the !-tDafI Age Group 42yr

Factorial Analyaia of VtJriance Men

Women

34 (± 1.0)

33 (±1.7) n=12 58 (±1.6) n=29

n=37 57 (± 1.4) n=4O

>42yr

RESULTS

The study group consisted of 77 (65 percent) men and 41 (35 percent) women. Table 1 shows the mean ages and numbers of persons in the four groups used in the two-way factorial analysis of variance. The mean age was very similar between men and women within each age group. The men were almost equally distributed between the older and younger groups, whereas only about one third of the women were in the younger, premenopausal group. The great majority of the patients were obese. In Figure 1, however, it can be seen that young women were the heaviest group, with a mean BMI of 53 kg/m", Although there was a tendency for women to be heavier than men in both age groups, only the difference in weight between the age groups reached statistical significance (Fig 1). That is, for both men and women, younger individuals with OSA were heavier than their older counterparts; young women were heavier than young men, although not significantly so. A similar effect of age but not of gender was seen in the results for pulmonary function tests and arterial Effect p value Sex .052 Age group .007 Interaction .388

seated and awake. Spirometric study was performed using a pneumotachograph linear to 15 Us and recorded with a digital online computer, and percent predicted values were calculated from reference values. 1M Hypercapnia was defined as an arterial PaCO. of greater than 45 mm Hg. The body mass index (BMI) was selected as the index of obesit}'.15

The differences between sexes were analyzed by a two-way

factorial analysis of variance.- The main factor in question for a

given dependent variable was between-sex differences. However, because of the suggestion in normal subjects of differences between premenopausal and postmenopausal women,· a second factor, age group, was included in the analysis of variance. Menopausal status was determined solely by the individuals medical histOI")t As it happened, women 42 years of age or younger in this patient group were all premenopausal; the women of 43 years of age and more were all postmenopausal. To avoid confounding by age alone, the men were similarly divided into two age groups, above and below age 42. The key to this approach was that if menopausal status per 88 were an important factor, rather than age or sex, it would be expressed as a Significant interaction between age group and sex. In other words, the "age effect," our proxy for hormonal differences, would differ as a function of sex. Given the unequal number of subjects in each group in the analysis, a hierarchical approach was used in the analysis of variance." This method examined first the main effect of sex, then age group, then the interaction of sex and age group in a hierarchical fashion, rather than examining all effects simultaneously

984

55

Body Maaslndex (Kg/m2)

45

35

i

i

s42yr

Age Group

> 42yr

FIGURE 1. Results of hierarchical two-way factorial ANOVA with respect to body mass index: main effects of sex and age group and sex by age group interaction. Mean (~1 SEM) are presented for each sex by age group interaction. Solicllinu. women; broken Una, men.

Comparison of Men and Women with OSA Syndrome (Leech et eJ)

Table I-Baultafrom the J-tDGfI FGctoriGl AnGlfIaU ojVariance (ANOVA) for~,."FunctiQn arad

ArterialBloodea.,,~" Men Grad W(maen*

p Value

..

Women

Men Sex Age group

42yr

"Means

Sexand

42yr

>42yr

Sex

Group

Age Group

77±6 79±6

.172 .190 .901

.049 .005

.199

85~3

59±4 63±4 75±3

.013

Bl±1

66±3 71±3 76±2

.171 .341

70±3 44±1

65±2 43±1

70±3 45±3

62±2 46±1

.lOS

.236

.034 .959

.563 .746

75±3

FEVIIFVCII> B: Blood gas analyses Pa02, mmHg PaC92,mmHg

Interaction

Age

>42yr

A. Pulmonary function tests FEV h II> pred 73±3

FVe, 'I pred

Main Effects

± SEM of the mean for each sex by age group; p values from ANOVA.

blood gas analyses (Table 2). Percent predicted FEV 1, percent predicted FVC, and FEV1/FVC%fell significantly with age, as did awake arterial oxygen tension values. These findings are compatible with age-related changes that have been described in normal persons.18,18 The similar decrease in these variables with age in both men and women resulted in nonsignificant interactions, IQ both sexes, pulmonary function testing results revealed for the most part a mild to moderate restrictive pattern, although a few subjects in each sex group had some"degree of airways obstruction. Only one man and two women bad an FEVI/FVC% of less than 50 percent Oxygenation at initial assessment (PaOt, 'Iable 2B) was also not different between men and Effect

women, a few persons in each group exhibiting severe hypoxemia while awake, For both sexes, PaO. was significantly lower among older individuals. The two-way ANOVA with PaCOI as a continuous variable did not reveal any significant sex or age effect Women were not more likely statistically to be hypercapnic than men; 49 percent of the women had a resting PaCOI of greater than 45 mm Hg in comparison to 30 percent of the men
p y.lue

p·Y.lue

Effect

sex

Sex .343 Age group c.OO1 Int....ctlon .327

.383

Age group

Int.,1M:t1on

AHI

...... C)xygen

(Eventa/hr)

SMuratlon

,/

,,

.248

• eee

J

(7.)

71 10

Age Group FICURE 2. Results of hierarchical two-way factorial ANOVA with respect to AHI and mean oxygen saturation: main effects of sex and age group and sex by age group interaction. Means (± 1 SEM) are presented for each sex by age group interaction. SolitllfneB, women; brokenline&, men.

CHEST I 94 I 5 I NOVEMBER, 1988

..

Effect p value .003 Se. Age group .001 Interaction .839

Effect p value .001 Se• Age group .246 Interaction .718

U••nApnea Duration

AI (Event./hr)

(sec)

40

I//I

eO 18

30

17

18 15

20

14 13

10

12 l'

i

-42yr

i

...

>42yr

I-i i

i

f:42rr >42rr

~f.!!~!. ~alue .010 Sex Age group .840 Interaction .965

M.xirnun Apnea Dur.tion 40 ( .ec)

[---1

35

1-1

30

25 '(

i

i

.42yr >42yr

Age Group FIGURE 3. Results of hierarchical two-way factorial ANOVA with respect to apnea index (AI~ mean and maximum apnea duration: main effects of sex and age groups and sex by age group interaction. Means (± 1 SEM) are presented for each sex by age group interaction. Solid lines, women; broken lines, men.

greater than 40 eventslh demonstrating the overall level of severity of OSA in this population. For both men and women, younger subjects demonstrated a significantly greater frequency of nocturnal events, but not significantly greater nocturnal de saturation. The between-sex differences were observed (Fig 3). When frequency of apneas per se was examined, there was a significant effect of both age and sex. Women of both age groups had a significantly lower percentage of sleep-disordered breathing events where complete occlusion of the upper airway was observed. About 30 percent of nocturnal sleep-disordered breathing events experienced by women were occlusive apneas, but about 70 percent were hypopneas. Although there were some exceptions to the rule, some of the most severely affected women were never observed to have complete cessation of airflow during sleep. By comparison, in men with OSA, about 50 percent of sleepdisordered breathing events were occlusive apneas and 50 percent were hypopneas. At the same time, women exhibited a significantly shorter mean apnea and maximal duration than men in both age groups. It might be expected that longer apneas would be observed on the average in those who had more frequent apneas, and, indeed, AI correlated with mean apnea duration in the whole group (r = 0.37, p<.OOI). To ascertain whether there was a difference in mean apnea duration between sexes independent of the difference in frequency of apneas per se, an analysis of covariance was conducted on the effect of sex and age group on mean apnea duration, controlling for AI. These results indicated that both main effects were statistically significant (sex p= .003, age group p = .031), but the interaction was not. As was the case with the analysis of variance (Fig 3) after controlling for AI, women had shorter apnea durations, as did younger individuals. Similarlj, the average maximal 888

apnea duration was significantly longer in men than in women in both age groups (Fig 3). The absence of an age group interaction with sex suggests that we cannot distinguish any significant effect of menopausal status on any of the variables studied in this OSA group. Any effects seen between premenopausal and postmenopausal women were mirrored in their younger and older male counterparts, suggesting that age rather than hormonal status was important. DISCUSSION

Our findings indicate that women with obstructive sleep apnea are similar to their male counterparts in both the frequency of sleep-disordered breathing events as measured by AHI and in their experience of nocturnal oxygen desaturation accompanying these events. However, the nature of the obstruction differs in that both premenopausal and postmenopausal women tend to experience hypopneas rather than complete apneas and that apneas, when present, tended to be shorter in women than in men. Our findings are similar to those of the report by Wilhoit and Suratt'? and by Guilleminault et al l S in that premenopausal women are more obese than their postmenopausal counterparts but, in our population group, this was thought to be an effect of age as it was also seen in men. The earlier papers cited did not analyze the possibility of confounding by age. Differences in the prevalence of women with OSA in different sleep clinics may reflect population demographics, varying definitions of disease and selection! referral bias as well as the real prevalence of the condition among women. The higher ratio of women to men in our clinic than that reported by others may reflect the provenance of an urban population where women, and especially very obese women, are more Comparison of Men and Women with OSA Syndrome (Leech et 81)

prevalent. 30 In addition, our data suggest that if the earlier criterion of AI rather than AHI is used to define the syndrome, symptomatic women who may have had important degrees of sleep disordered breathing might have been excluded. Women tend less often to be employed in occupations where handling vehicles or machine safety is of paramount importance; that is, where excessive daytime sleepiness (EDS) poses a major occupational hazard and therefore a pressing reason for coming to medical attention. For example, among the men in this patient registry were a taxi driver, four salesmen who drove to customers, a forklift driver, a drill press operator, and a fireman. Only two of the women studied here were employed outside of the home, both at desk jobs. A referral/selection bias based on gender as affecting occupational tolerance ofEDS may therefore also affect prevalence data. Selection or referral bias might also be suggested by the age group effect seen in severity of obesity and AHI. In particular, perhaps a younger individual must be more severely affected before symptoms ensue or simply more obese or hypersomnolent before physicians consider the diagnosis; alternatively perhaps more severely affected individuals die young.P Good epidemiologic data in obese men and women are needed to ascertain the true prevalence of OSA unaffected by the biases of population group, disease definition, and referral patterns. The differences found here between men and women with respect to complete occlusion of the upper airway suggest that women with OSA may have a difference in the upper airway anatomy or physiology (or both) that manifests as incomplete airwayocclusion. A review of the literature on which the understanding of the pathophysiology of airway obstruction during sleep has been based suggests that the groups studied were predominantly male 31-33 or that gender was not stated. 34 ,35 Wilhoit and Suratt'" were unable to demonstrate a relationship between pulse flow resistance of the airway and the degree of OSA in premenopausal women as they had observed in postmenopausal women and men, although again age as a possible confounding variable was not taken into account. On the other hand, Guilleminault et all S found that men with OSA had significantly longer soft palate than women with OSA by cephalometric measurements. The significantly longer duration of apneas in men than women, as reflected in both mean and maximum apnea time, may reflect the predominance of apneas in men; however, the analysis of covariance indicates that beyond that relationship, women still have shorter apneas. Differences in the underlying respiratory rhythmicity or timing36 between men and women may explain the differences in duration of apneas observed here.

It has been suggested that the differences between normal men and women in frequency of snoring, apneas, and hypopneas are on the basis of hormonal differences. l -3 If the differences between men and women with OSAfound here were similarly hormonal, an interaction term should have been observed to be of significance between sex and age group. However, in this group of patients with OSA, all differences between premenopausal and postmenopausal women were seen in younger and older men as well, suggesting that the effects are predominantly those of age rather than hormonal status. The prevalence of women with OSA in our institution gave us the opportunity to study them as a group in comparison to their male counterparts. Similarities to men in severity of OSA as measured by AHI and nocturnal hypoxemia have been confirmed, but it is the differences in the characteristics of sleep-disordered breathing events and frequency of hypercapnia that pose intriguing questions about gender differences in upper airway physiology and respiratory control. REFERENCES

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