gender-specific differences in a patient population with obstructive sleep apnea-hypopnea syndrome

Gender-Specific Differences in a Patient Population with Obstructive Sleep Apnea-Hypopnea Syndrome

Dietlind L. Wahner-Roedler, MD, MScl; Eric J. Olson, MD2; Sujata Narayanan, MBBS1; Richa Sood, MD3; Andrew C. Hanson, BS4; Laura L. Loehrerl; and Amit Sood, MD, MSc 1

1Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; 2Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota; 3Women's Health Clinic, Mayo Clinic, Rochester, Minnesota; and 4Division of Biostatistics, Mayo Clinic, Rochester, Minnesota

ABSTRACT

Background: Sleep-related breathing disorders are increasingly recognized as an impor tan t cause of morbidi ty and mortality. Women wi th obstructive sleep apnea-hypopnea syndrome (OSA) are less likely to be assessed or to receive a diagnosis, and they may have poorer survival rates.

Objective: This study assessed gender-specific differences in patients wi th OSA. Methods: Data were collected wi th a prospective, point-of-care, anonymous 2S-question survey

about basic medical in format ion and therapies for patients undergoing po lysomnography at the sleep center of a US tertiary care center f rom January 1 th rough March 31, 2005.

Results: Of the 646 consecutive patients who received the survey, 522 (80.8%) patients completed it, and 406 subsequently received a diagnosis of OSA. Of those 406 patients, 267 (65.8%) were men. Overall mean age was 57 years (56.4 years for men; 56.7 years for women). Alcohol use was more c o m m o n in m e n (132 [49.4%]) t h a n in w o m e n (43 [30.9%]) (P < 0.001). Women were more likely to have the following associated comorbidities: obesity (body mass index >_30) (P = 0.047), fibromyalgia (P < 0.001), migraine (P < 0.001), depression (P = 0.01), and irritable bowel syndrome (P = 0.01). The 4 most frequently reported sleep-related symptoms in bo th sexes were snoring (279 [68.7%]), lack of energy (235 [57.9%]), difficulty staying asleep (206 [50.7%]), and dayt ime sleepiness (204 [50.2%]). Lack of energy (P = 0.01), difficulty falling asleep (P = 0.02), and night sweats (P = 0.01) were observed more frequently in w o m e n t h a n in men. There was no significant gender difference in the recalled duration of sleep-related symptoms. The mean (SD) apnea-hypopnea index (AHI) was 26.6 (26.6) for m e n and 22.1 (26.5) for w o m e n (P = 0.02). Convent ional medicat ions ( including prescription and over-the-counter medications) for sleep-related problems were used more by w o m e n (35 [25.2%]) t h a n by men (29 [10.9%]) (P < 0.001).

Conclusions: The majori ty of patients who received a diagnosis of OSA were m e n (male-female ratio, 2:1), and the m e a n AHI was higher in m e n t h a n in women. However, w o m e n presented wi th more nonspecif ic symptoms t h a n did men, a l though there was no significant gender-specific difference in the recalled durat ion of symptoms. In addition, w o m e n reported more comorbidities and used significantly more convent ional medicat ions for sleep-related problems. (Gend Med. 2007;4:329- 338) Copyr ight © 2007 Excerpta Medica, Inc.

Key words: gender, polysomnography, sex, sleep apnea, sleep hypopnea , surveys.

Presented in part at the 2nd World Congress on Gender-Specific Medicine and Aging: The Endocrine Impact; March 8-11, 2007; Rome, Italy.

Accepted for publication August 13, 2007. Printed in the USA. Reproduction in whole or part is not permitted. 1550-8579/$32.00

Copyright © 2007 Excerpta Medica, Inc. 329

Gender Medicine

INTRODUCTION Sleep-related breathing disorders are increasingly recognized as an important cause of mor- bidity and mortality. These disorders include several distinct syndromes defined by clinical and polysomnographic criteria. The common obstructive sleep apnea-hypopnea syndrome (OSA) is defined as an apnea-hypopnea index (AHI) of at least 5 events per hour. OSA is char- acterized by episodic collapse or narrowing of the upper airway during sleep, resulting in apnea or hypopnea, gas-exchange abnormali- ties, and sleep fragmentation.

The prevalence of OSA has been estimated in several large studies. 1-4 Comparison of the male- female ratio of OSA in clinic populations (8:1) with that in communi ty populations (2:1) indicates that women with OSA are less likely to be evaluated and to receive a diagnosis, s Further- more, some data show poorer survival among female OSA patients, suggesting that OSA in women may be diagnosed late in the course of the disease or may not be treated aggressively. 6

To further assess this gender issue, we exam- ined gender-specific differences among patients with a diagnosis of OSA in a population referred to our institution's sleep disorder center. We report on gender-specific differences in disease symptoms, comorbidities, and use of conventional medications (including prescription and over-the-counter agents) for sleep-related symptoms before the diagnosis of OSA.

METHODS Survey Questionnaire

All patients undergoing polysomnography at the Mayo Clinic Sleep Disorder Center were asked to fill out a survey questionnaire during their overnight stay.* This 25-question survey was developed with input from the survey research group at Mayo Clinic, Rochester, Minnesota. The survey included questions regarding basic demographics, sleep-related symptoms (snoring, difficulty falling asleep, difficulty staying asleep, daytime sleepiness, restless sleep, lack of energy,

*Survey is available on request.

morning headache, and inability to concentrate), details about alcohol (CAGE questions 7) and tobacco use, and medical conditions (14 were l isted--high blood pressure, diabetes, heart attack, angina, heart failure, depression, fibromyalgia, irritable bowel syndrome, anxiety, chronic obstructive pulmonary disease, impotence, migraine, stomach ulcers, and stroke--and a free-text entry area was provided to list additional medical conditions). There were specific questions about current use of conventional medications for sleep-related problems (20 items, including zolpidem, trazodone, alprazolam, diphenhydramine, ace taminophen-d iphenhydramine , diazepam, temazepam, lorazepam, clonazepam, zaleplon, hydrocodone, triazolam, and hormone replacement therapy). The survey had a free-text entry area for conventional medications not covered elsewhere in the survey.

CAGE Questionnaire Developed by Ewing 7 in 1984, the CAGE ques-

tionnaire is a widely used instrument for detecting alcohol abuse or dependence. The acronym CAGE represents the 4 yes/no items (in italics) constituting the screening test: (1) Have you ever felt that you ought to cut down on your drinking?; (2) Have people annoyed you by criti- cizing your drinking?; (3) Have you ever felt bad or guilty about your drinking?; and (4) Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)? Individual item responses are scored 0 if the person answers "no" or 1 if the person answers "yes." The total score ranges from 0 to 4.

Population Studied From January I through March 31, 2005, the

survey was administered to patients consecu- tively before they underwent overnight polysomnography. These patients had been assessed in consultation with a sleep disorder center physician and were judged to need polysomnography for further evaluation of their sleep problems.

The data were collected in an anonymous fa- shion; thus, no informed consent was obtained.

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The study was approved by the Mayo Clinic Institutional Review Board.

Polysomnography Polysomnography was performed using digi-

tal polygraph equipment (NCI-LAMONT Medi- cal Inc., Madison, Wisconsin, or Bio-Logic Systems Corporation, Mundelein, Illinois) in a laboratory and at tended by a sleep technologist. OSA was defined by an AHI of at least 15 or an AHI of 5 to 14 plus insomnia, excessive daytime sleepiness, mood disorder, impaired cognition, hypertension, ischemic heart disease, or history of stroke. Split-night sleep studies were performed in nearly all cases, with the diagnostic portion including a m i n i m u m of 120 minutes of sleep. Obstructive apnea was defined as ces- sation of airflow for at least 10 seconds despite respiratory effort. Hypopnea was defined as a decrease in airflow of at least 30% for at least 10 seconds, despite respiratory effort, accompa- nied by a decrease in oxyhemoglobin saturation of at least 4%. Airflow was analyzed using a nasal pressure transducer. The polysomnograms were analyzed by board-certified sleep physicians blinded to the survey data. Sleep stages 8 and arousals 9 were scored using recognized standards.

Data Analysis Data were analyzed for only the patients who

had received a confirmed diagnosis of OSA. Tabular summaries of survey responses were generated both overall and according to sex. Differences between men and women were assessed using the t test (or rank sum test) for continuous variables and the Fisher exact test for categorical variables. In all cases, 2-tailed P values of ___0.05 were considered statistically significant. All analyses were performed using SAS software, version 9.1.3 (SAS Institute Inc., Cary, North Carolina).

RESULTS Demographics

Of the 646 consecutive patients who were invited to participate in the study, 522 (80.8%)

completed the survey, and OSA was subse- quent ly diagnosed in 406. Of those 406 patients, 267 (65.8%) were men. The overall mean age was 57 years (range, 18-76 years), with no significant difference be tween the

sexes (56.4 years for men; 56.7 years for women). Most patients (217/402 [54.0%]) lived wi th in 120 miles of Mayo Clinic in Rochester. There were no significant differences in level of education or insurance providers (private, Medicare, Medicaid, or none) be tween the sexes.

Social History Current alcohol intake was reported by

132 (49.4%) men and 43 (30.9%) women (P < 0.001). CAGE questionnaire scores did not differ significantly between men and women. Of the men and women who indicated current use of alcohol, 22 (16.7%) and 5 (11.6%), respectively, had a CAGE score _>1. The mean (SD) CAGE score was 0.32 (0.83) for men and 0.16 (0.48) for women (P = NS).

Twenty-one (7.9%) of the men and 12 (8.6%) of the women were current smokers (P = NS). Of the men and women who indicated current use of cigarettes, 10 (30.3%) reported smoking __.10 cigarettes per day, 20 (60.6%) reported smoking 11 to 20 cigarettes per day, and 3 (9.1%) reported smoking >20 cigarettes per day. Stratified by sex, the respective numbers and percentages were 7 (33.30/0), 13 (61.9O/o), and 1 (4.8°/6) for men and 3 (25.0%), 7 (58.3%), and 2 (16.7%) for women (P = NS).

Comorbidities On the basis of body mass index (BMI; cal-

culated as kg/m 2) de te rmined by the sleep disorder center staff, 68.0% of the populat ion studied were obese (BMI _>30), including 160 of 248 men (64.5%) and 95 of 127 women (74.8%) (P = 0.047). Severe obesity (BMI >35) was sig- n i f icant ly more c o m m o n in w o m e n (67 [52.8%]) t han in men (71 [28.6%]) (P < 0.001) (Table I).

Hypertension was the associated medical problem most frequently reported by both men

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Table I. Comorbidities of patients with obstructive sleep apnea-hypopnea syndrome.

Patients

Total (N -- 406) Men (n = 267) Women (n = 139)

Comorbidity* No. % No. % No. % pt

Obesity (BMI >30 kg/m2) ~ 255 68.0 160 64.5 95 74.8 0.047

Severe obesity (BMI >35 kg/m2) $ 138 36.8 71 28.6 67 52.8 <0.001

Hypertension 213 52.5 135 50.6 78 56.1 0.30

Depression 122 30.0 69 25.8 53 38.1 0.01

Diabetes mellitus 83 20.4 51 19.1 32 23.0 0.37

Anxiety 73 18.0 41 15.4 32 23.0 0.08

CAD 54 13.3 41 15.4 13 9.4 0.12

Impotence 48 11.8 46 17.2 2 1.4 <0.001

Migraine 44 10.8 15 5.6 29 20.9 <0.001

IBS 40 9.9 19 7.1 21 15.1 0.01

Fibromyalg ia 28 6.9 6 2.2 22 15.8 <0.001

COPD 27 6.7 18 6.7 9 6.5 1.00

Heart failure 22 5.4 13 4.9 9 6.5 0.50

Stroke 16 3.9 11 4.1 5 3.6 1.00

BMI = body mass index; CAD = coronary artery disease; IBS = irritable bowel syndrome; COPD -- chronic obstructive pulmonary disease. *All comorbidities were self-reported, except for BMI, which was determined by the Mayo Clinic Sleep Disorder Center staff. tDetermined by Fisher exact test. ~:BMI was calculated for 248 men and 127 women who indicated both height and weight. Percentages reflect available data.

(135 [50.6%]) and women (78 [56.1%]). Women were more likely than men to have the following associated comorbidities: fibromyalgia (P < 0.001), migraine (P < 0.001), depression (P = 0.01), and irritable bowel syndrome (P = 0.01) (Table I).

Sleep-Related Symptoms The 4 most frequently reported sleep-related

symptoms in the populat ion were snoring (279 [68.7%]), lack of energy (235 [57.9%]), difficulty staying asleep (206 [50.7%]), and dayt ime sleepiness (204 [50.2%]) (Table II). Women complained more frequently than men about lack of energy (P = 0.01), difficulty falling asleep (P = 0.02), and night sweats (P = 0.01). About half of the patients (125/246 [50.8%]

men and 63/129 [48.8°/6] women) had symptoms for 6 to 10+ years before their assessment at the sleep disorder center (Table Ill). There was no significant gender difference in the recalled duration of sleep-related symptoms.

Treatment for Sleep-Related Problems at Time of Evaluation

At the time of assessment, conventional medications (prescription or over the counter) were used for sleep-related problems by 64 patients (15.8°/6 of the entire population), with women reporting significantly greater use (35 [25.2%]) compared with men (29 [10.9%]) (P < 0.001). The conventional drug used most frequently by men and women was diphenhydramine (Table IV).

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Table II. Sleep-related symptoms reported by patients with obstructive sleep apnea-hypopnea syndrome.

Patients

Total (N = 406)

Sleep-Related Symptom No. %

Men (n = 267) Women (n = 139)

No. % No. % P*

Snoring 279 68.7 186 69.7 93 66.9 0.57

Lack of energy 235 57.9 142 53.2 93 66.9 0.01

Difficulty staying asleep 206 50.7 134 50.2 72 51.8 0.83

Daytime sleepiness 204 50.2 132 49.4 72 51.8 0.68

Restless sleep 183 45.1 116 43.4 67 48.2 0.40

Difficulty falling asleep 109 26.8 62 23.2 47 33.8 0.02

Inability to concentrate 95 23.4 59 22.1 36 25.9 0.39

Night sweats 65 16.0 33 12.4 32 23.0 0.01

Morning headaches 58 14.3 34 12.7 24 17.3 0.23

*Determined by Fisher exact test.

Table III. Duration of sleep-related symptoms reported by patients with obstructive sleep apnea-hypopnea syndrome (OSA).

Patients*

Duration of Sleep- Related Symptoms, y

Total (N = 406) Men (n -- 267) Women (n = 139)

No. % No. % No. %

< 1 40 10.7 22 8.9 18 14.0 1-3 78 20.8 49 19.9 29 22.5 4-5 69 18.4 50 20.3 19 14.7 6-1 O+ 188 50.1 125 50.8 63 48.8

*The sum of the number of patients within each column is less than the sample size (406 patients with OSA) because of missing data.

Sleep Study Results The mean (SD) AHI was 26.6 (26.6) for 267 men

with OSA and 22.1 (26.5) for 139 women with

OSA (P = 0.02).

DISCUSSION OSA is a c o m m o n disorder that represents a considerable public health problem. 1° Evidence from methodological ly strong cohort studies indicates that OSA is independent ly associated with an increased likelihood of hypertension, n

heart failure, 12 cardiac arrhythmias, 13 stroke and death, 14 diabetes mellitus, 15,16 dayt ime sleepiness, 17 motor vehicle accidents, 18,19 and

diminished quality of life. 2° It is estimated that

OSA with dayt ime impairment occurs in 1 of

20 adults and that minimal ly symptomatic or asymptomatic OSA is found in 1 of 5 adults, s

C o m m o n to all reports is a higher prevalence of OSA in men than in women. Interestingly, the ratio of men to women with OSA in clinical studies 3,21,22 appears to be considerably higher

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Table IV. Conventional medication use for sleep-related problems reported by patients with obstructive sleep apnea-hypopnea syndrome.

Patients

Total (N --- 406) Men (n -- 267) Women (n = 139)

Medication No. % No. % No. % P*

Diphenhydramine 27 6.7 13 4.9 14 10.1 0.06

Zolpidem 16 3.9 8 3.0 8 5.8 0.19

Trazodone hydrochloride 12 3.0 4 1.5 8 5.8 0.03

Clonazepam 5 1.2 1 0.4 4 2.9 0.049

Lorazepam 3 0.7 3 1.1 0 0 0.55

Acetarninophen/ hydrocodone 3 0.7 1 0.4 2 1.4 0.27

AIprazolam 2 0.5 1 0.4 1 0.7 1.00

Zaleplon 2 0.5 0 0 2 1.4 0.12

Hormone replacement therapy 2 0.5 0 0 2 1.4 0.12

Diazeparn 1 0.2 0 0 1 0.7 0.34

Any 64 15.8 29 10.9 35 25.2 <0.001

*Determined by Fisher exact test.

than in the c o m m u n i t y 1,3 (-5 to 8:1 vs 2 to 3:1,

respectively). The reason for the apparent gender discrepancy between clinic and community populations is not clear. A number of explanations have been discussed in the litera- ture, including the possibility that OSA is undiagnosed in large numbers of women because: (1) they are unaware of their condition; (2) they do not present for treatment; or (3) having sought help, they are turned away or

the condition is misdiagnosed (eg, as depression) by their physician, z3,z4

Gender-based heal th care inequities have been associated with m a n y disorders, and OSA is far from being unique in this respect. 2s The clinical underrecogni t ion of cardiovascular disease in women and the resolute pursuit of this issue with the recognition of how clinical biases arise in general has been a major concern for at least 20 years. 2s Several studies have shown that the presenting symptoms of OSA are different

in men and women, suggesting that greater awareness of these differences could improve the underdiagnosis of OSA in women. 2,24-27

The 2:1 male-female ratio in our population reflects ratios previously reported for communi ty studies 1,3 rather t han for clinic populations. 21,22 Therefore, the ratio in our study was reassuring, in that it indicated there were relatively more referrals of female patients from the c o m m u n i t y (217/402 [54.0%] of patients

lived wi th in 120 miles of Mayo Clinic in Rochester, Minnesota) to our sleep center.

Obesity has been identified as a strong risk factor for OSA. Women are more likely to be obese (BMI ___30) than are men, 28 as w a s found in our population. The distribution of body fat, however, is probably more important than the overall BMI. Men have greater upper body obesity, including greater subscapular skinfold thickness, 29 which increases the resistive load of the upper airway. A significant relationship

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has been noted between neck size and OSA.30,sl

Studies have shown that postmenopausal women have a significantly greater risk of OSA than do either premenopausal women or postmenopausal women taking hormone replacement therapy. Therefore, sex hormones may protect against OSA and contribute to the observed gender difference in its prevalence.2,32, 33

The men in our survey reported significantly higher alcohol intake than the women did. Alcohol use to self-treat insomnia has been reported to be more common in men than in women. 1 Although large quantities of alcohol have long been known to aggravate severe OSA, more recent reports have documented that even modest alcohol consumption (resulting in a mean blood alcohol concentration of 0.07 g/dL) significantly increases OSA frequency. 34

Most clinic-based OSA studies from North America have reported that on presentation, females are about the same age as males, 3s,36

similar to our observation. In a study of 1010 patients with OSA (844 men and 166 women) from Greece, 37 the female patients were significantly older than the male patients (mean [SD] age, 56.9 [10.6] years vs 50.6 [11.7] years; P = 0.001). Women in the Greek study had weights similar to those of their male counter- parts, whereas women were much heavier than men in the North American studies. The Greek study authors postulated that although older women may have OSA without being morbidly obese, younger females with OSA are more likely to be obese.

In both the men and women of our cohort, the most frequent sleep-related symptom was snoring. Similar to the results in other reports, 23,24,27 less-

specific symptoms such as lack of energy, head-

ache, insomnia, and depression were more common in our female population. Women may perceive and report symptoms as frequently as men do, but having sought help, they are often turned away by their physician or receive a mis- diagnosis (eg, depression). 23 The frequent reporting of excessive sleepiness, headache, and fatigue

by women without OSA may mask women

with OSA. However, in our population with no significant age difference between the sexes, there was no reported significant gender difference in the recalled duration of sleep-related symptoms, implying that women did not experience strikingly longer delays in the diagnosis of OSA.

The most commonly self-reported medical

condition in our OSA population was hypertension, which had been diagnosed in 135 (50.6%) of the men and 78 (56.1%) of the women. The association between sleep apnea and hypertension has been well documented. 11,38 Medical

conditions that were significantly more commonly reported by women than by men in our OSA population included depression, fibromyalgia, irritable bowel syndrome, and migraine. These differences, however, are in concordance with the findings in the general population and might not be unique to our OSA population. The symptoms of these comorbidities could eas- ily lead primary care and specialist physicians to underdiagnose or misdiagnose OSA. Complex relationships between some of these medical conditions and sleep problems have been postulated. 39-43

Ohayon 44 underscored the evidence for a link between depression and OSA in the general population, noting that 800 of 100,000 individ- uals had both a breathing-related sleep disorder and a major depressive disorder, with up to 20% of the subjects presenting with one of these disorders also having the other. May et al 4° described 92 women and 25 men with newly diagnosed fibromyalgia and sleep complaints who underwent polysomnography. Among these patients, 2.2% of the women and 44.0% of the men had significant sleep apnea at formal assessment. The authors postulate that fibromyalgia may be a

marker for occult sleep apnea in males. The 2% prevalence of fibromyalgia in the men in our OSA population is quite high compared with the reported 0.5% prevalence in men in the general population45; thus, it is quite possible that in some of these men, the primary medical problem is OSA and not fibromyalgia.

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In our study, impotence was self-reported by 46 (17.2%) of the men with documented OSA. A strong correlation between the severity of sleep apnea and the severity of erectile dysfunct ion has been reported. 46,47

The mean (SD) AHI in our study was 26.6 (26.6) events per hour for m e n and 22.1 (26.5) events per hour for women (P -- 0.02). The f inding of a higher AHI in men than in women is in concordance with observations reported by Vagiakis et a137 in a large study of Greek subjects. The mean AHI during total sleep time in their study was 42.4 (28.2) events per hour in men versus 32.6 (27.7) events per hour in women (P < 0.001); however, during rapid eye movement (REM) sleep there was no significant difference between men and women. Clustering of respiratory events during REM sleep in female patients may explain this finding. 26

Pharmacotherapy for sleep problems was used by 64 (15.8%) patients in our study population before the diagnosis of OSA, with women reporting significantly higher use compared with men (P < 0.001). Diphenhydramine was the most frequently used sleep medicat ion by both sexes.

The strengths of this study include our ability to survey consecutive patients and the excellent response rate. The limitations include the study site: a tertiary care center, with its inherent re- ferral bias and limited generalizability.

CONCLUSIONS In this study, the majority of patients who received a diagnosis of OSA were men. The male-female ratio (2:1) corresponded to male- female ratios in communi ty samples, in con- trast to the ratios reported for clinic populations (8:1). There was no significant gender difference in the recalled duration of symptoms; however, there was a significant gender- specific difference in reported sleep-related symptoms, wi th w o m e n present ing more frequently with nonspecific complaints such as lack of energy, insomnia, and night sweats. The mean AHI was higher in men than in women. Women with OSA had more comor-

bidities and used significantly more conventional medications.

It is critical that an increased level of awareness for OSA in both sexes continues in pr imary care settings; that pr imary care providers refer patients suspected of having OSA to sleep cen- ters for fur ther evaluation; that resources be increased for OSA diagnosis and therapy; and that public heal th initiatives target OSA across its severity spectrum for recognition, preven- tion, and surveillance.

ACKNOWLEDGMENT Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic, Rochester, Minnesota.

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Address c o r r e s p o n d e n c e to: Dietlind L. Wahner-Roedler, MD, MSc, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]

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