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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Clinical Chemistry, Turku University Central Hospital, Turku; Department of Physiology and Biostatistics, University of Turku, Turku; and Department of Clinical Neurophysiology, Satakunta Central Hospital, Pori, Finland.
Address reprint requests to: Päivi Polo-Kantola, MD, PhD, Turku University Central Hospital, Department of Obstetrics and Gynecology, FIN-20520 Turku, Finland; E-mail: paivi.polo-kantola{at}tyks.fi.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A prospective, randomized, placebo-controlled, double-blind, crossover study was completed by 62 of 71 recruited healthy women. The first 3-month treatment period with either estrogen or placebo was followed by placebo washout for a month and then by a second treatment period with crossover to either estrogen or placebo. On a night after each treatment period, sleep was monitored with polysomnography, and breathing was assessed with a static-charge-sensitive bed and oximeter. For the respiratory variables, a sample size of 48 subjects was sufficient to give statistical power of 85% with a significance level of P < .05.
RESULTS: The occurrence of obstructive sleep apnea in all women was low (1.6%), but partial upper airway obstruction, manifesting as an increased respiratory resistance pattern, was more common (17.7%). Estrogen replacement therapy decreased the occurrence (P = .047) and frequency (P = .049) of sleep apnea but had no effect on partial upper airway obstruction or arterial oxyhemoglobin saturation.
CONCLUSION: Partial upper airway obstruction is the most prevalent form of sleep-disordered breathing, occurring ten times more frequently than sleep apnea in postmenopausal women. Unopposed estrogen replacement therapy has only a minor effect on sleep apnea and has no effect on partial airway obstruction.
Sleep-disordered breathing occurs more often in men than in women.1 However, after menopause the prevalence of habitual snoring and obstructive sleep apnea syndrome also increases in women.2 This is often attributed to decreased endogenous production of estrogen and progesterone. Progestogens are potent respiratory stimulants.3 They reduce the partial pressure of arterial carbon dioxide during wakefulness4 and may decrease sleep-disordered breathing alone5 or in combination with estrogen.6
Unopposed estrogen replacement therapy (ERT) is widely used to control the climacteric vasomotor symptoms in hysterectomized postmenopausal women. The incidence of sleep-disordered breathing in this group and whether ERT has any effect on breathing is not known. Estrogen replacement therapy improves sleep quality.7 Alleviation of nocturnal climacteric vasomotor symptoms during ERT is at least partly responsible for this improvement, but alleviation of possible sleep-disordered breathing could also contribute to better sleep. Estrogen could have an impact on breathing during sleep either through the respiratory control system or indirectly by improving the stability of sleep. Estrogen receptors are present in the cerebral frontal cortex, the hypothalamus, the amygdala, and the bulb,8,9 areas that are known to be involved in the control of breathing. In the lung, estrogen receptors10 mediate estrogen-dependent surfactant production. Also, through upregulation of progesterone receptors,11 estrogen may enhance stimulatory effect of progesterone on respiration.12 Finally, as a potent vasodilator, estrogen may increase perfusion of the carotid body and brain.13
Estrogen may, however, negatively affect ventilation. Estrogen replacement therapy may worsen asthma symptoms and lead to increased consumption of bronchodilators.14 In the case of a postmenopausal woman with severe obstructive airways disease, ERT induced bronchospasm.15 The present study had two purposes: 1) to evaluate the prevalence of nocturnal breathing abnormalities in healthy postmenopausal women, and 2) to evaluate the effects of transdermal ERT on nocturnal breathing.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The use of antioxidants or any medication affecting the central nervous system was not allowed before or during the trial. A complete gynecologic examination was carried out on all participants at the beginning of the study. The study was approved by the Ethics Committee of Turku University and Turku University Central Hospital. The subjects provided written, informed consent after receiving both oral and written information. A total of 71 women were admitted to the study.
This was a prospective, randomized, placebo-controlled, double-blind, crossover trial, carried out over 7 months. The first 3-month treatment period with either estrogen or placebo was followed by a 1-month placebo washout period and then by a second treatment period, in which estrogen and placebo treatments were crossed over. The subjects were randomized, in six-person blocks, into two groups with random permuted blocks provided by the companies that supplied the study drugs. Group A received placebo during the first treatment period and estrogen during the second treatment period, whereas group B received estrogen first and then placebo. The estrogen and placebo preparations were similar in appearance. Randomization codes were kept secret at the drug companies until the completion of the data analyses.
Estrogen and placebo were administered transdermally in two different forms, provided by two drug companies. The younger women (aged 47–55 years, n = 30) were treated with gel (Estrogel 2.5 g per day; Leiras, Turku, Finland), whereas the older women (aged 56–65 years, n = 41) used a patch (Evorel 50 µg per 24 hours; Janssen-Cilag/Cilag, Schaffhausen, Switzerland). In this study the results from the two formulae were combined, and no treatment effects were tested across the two formulae. Serum E2 and FSH levels were measured in the morning after each treatment period. Five subjects withdrew from the study. The reasons for withdrawal included intolerable climacteric symptoms with placebo (n = 2), headache with estrogen (n = 1), fear of hormone therapy (n = 1), and personal reasons (n = 1). Four other subjects were excluded: one because she started antidepressant medication and three because of incomplete data. Altogether, data from 62 subjects were acceptable.
The mean (± standard deviation [SD]) age of the subjects was 57.0 ± 4.4 years (range, 47–65) and the mean body mass index (BMI) was 26.8 ± 3.7 kg/m2 (range, 20.4–39.0). Forty-seven (76%) of the 62 subjects had previously used ERT, the mean duration of which was 44.9 months (range, 1 month to 21 years). The time elapsed since interruption of ERT ranged from 5 months to 19 years. Fifteen (24%) of the subjects had a bilateral oophorectomy 5 months to 21 years before entering the study. The group-specific demographic data are presented in Table 1
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Breathing was studied with a combination of a pulse oximeter and a static-charge-sensitive bed (BioMatt, Biorec Oy, Helsinki, Finland), the principle of which has previously been described in detail.16,17 Briefly, the static-charge-sensitive bed consists of a 2-cm-thick movement sensor placed under a foam mattress (Figure 1). Because of its high sensitivity, the sensor enables monitoring of body movements, respiratory movements, and heart beat (ballistocardiogram) without attaching electrodes to the subject. The three-channel, static-charge-sensitive bed method was used because of its capacity to distinguish between several periodic breathing patterns and the increased respiratory resistance pattern.16
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). The frequencies of each breathing abnormality were determined as a percentage of time in bed (Figure 2). Compared with conventional monitoring of breathing during sleep with nasal thermistors and thoracic and abdominal bands, the obstructive periodic breathing types 2 and 3 essentially correspond to episodes of obstructive apnea,16 whereas the other breathing events (periodic breathing type 1 and obstructive periodic breathing type 1) represent periodic breathing with moderate or high respiratory efforts. All these patterns may appear with central apnea at the nadir of respiratory efforts. The increased respiratory resistance episodes correspond to prolonged episodes of obstructive hypoventilation, with slowly increasing intrathoracic pressure variation and increasing intensity of the snoring sound (crescendo snoring). Often, although not always, the increased respiratory resistance episode is accompanied by sustained arterial oxyhemoglobin desaturation of 1% or 2% and is terminated by a movement arousal.16
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Serum E2 and serum FSH levels were measured at four times: at baseline, after both treatment periods, and after the washout period. Serum E2 was measured with Spectria RIA from Orion Diagnostica (Finland) and serum FSH with Delfia TR-IFMA from Wallac (Finland).
The results were analyzed with statistical methods developed for a crossover design of two treatments and two periods by applying nonparametric methods (Wilcoxon rank sums) and methods for binary responses (Hills and Armitage test).18 The potential residual effect after 3 months of estrogen (carryover effect) and the effect of the order of treatment (period effect) were tested first. Carryover and period effects were not expected, and thus P < .10 was considered significant for these effects. The treatment effect was considered significant at P < .05. Spearman correlation coefficients were used to measure the strengths of association between breathing abnormalities and serum E2 or FSH levels. P < .05 was considered to indicate a significant association. A sample size of 48 subjects was sufficient to give a statistical power of 85% with a significance level of P < .05 for the respiratory variables. The statistics were computed with SAS statistical software (SAS Institute, Cary, NC).
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RESULTS |
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No carryover effect was observed, but a period effect was seen in one variable: Increased respiratory resistance events were more frequent during the second study night. The occurrence of the subtypes of breathing abnormalities in the two randomized groups during placebo and during ERT is presented in Table 3. For the entire study group, breathing abnormalities were observed in 20 of 62 subjects (32.3%) taking placebo and in 18 (29.0%) taking ERT. In 14 subjects (23.0 %) taking placebo and in 14 subjects (23.0%) taking ERT (altogether 20 different subjects), the breathing abnormalities represented more than 5% of the time in bed. None of the subjects had obstructive sleep apnea episodes of obstructive periodic breathing type 3; all obstructive episodes were of milder type 2. With placebo, five subjects (8.1%) experienced obstructive periodic breathing type 2 episodes, which accounted for more than 5% of the time in bed in one subject (1.6%). With ERT, only one subject (1.6%) had obstructive periodic breathing type 2 events, which occurred during less than 5% of the time in bed. Although obstructive apnea was rare, increased respiratory resistance was common. With placebo, 18 subjects (29.0%) exhibited episodes of increased respiratory resistance, whereas with ERT 16 subjects (26.0%) had increased respiratory resistance episodes. Increased respiratory resistance accounted for more than 5% of the time in bed in 11 subjects (17.7%) receiving placebo and in 12 subjects (19.4%) receiving ERT.
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). The mean frequencies (percentage of time in bed) of breathing abnormalities in the two randomized groups are presented in Table 4. Estrogen replacement therapy decreased the frequency of obstructive sleep apnea type 2 but had no effect on the other breathing abnormalities. Obstructive sleep apnea type 2 occurred most frequently during stage 1 sleep, whereas increased respiratory resistance was most frequent during slow-wave sleep. The frequencies of the various breathing abnormalities in each sleep stage are illustrated in Figure 3. The mean and minimum arterial oxyhemoglobin saturation in both randomized groups are summarized in Table 5. Irrespective of placebo or ERT treatment, the mean and minimum arterial oxyhemoglobin saturations were similar. Furthermore, ERT had no effect on the arterial oxyhemoglobin desaturation events, assessed as oxyhemoglobin desaturation index 4% or 10% (Table 5).
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DISCUSSION |
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Our observation that clinically significant sleep apnea occurs in 1.6% of healthy postmenopausal women is in agreement with a previous report, which estimated that the prevalence of sleep apnea in postmenopausal women is 2.5%.19 A new finding in this study was that all the apnea episodes in the women were of a moderate type 2; no severe type 3 sleep apnea was observed. Even more striking, however, was our finding that partial upper airway obstruction producing the increased respiratory resistance pattern was the predominant breathing abnormality, manifesting about ten times as often as the apnea episodes. With placebo, 29% of women presented with episodes of increased respiratory resistance, and in 17.7% of these women the increased respiratory resistance was present for more than 5% of time in bed. Clinically significant episodes of arterial oxyhemoglobin desaturation (oxyhemoglobin desaturation index 4% more than 5%) occurred in only two women (3.2%).
Previous studies investigating the effect of estrogen on breathing in postmenopausal women are sparse and have been carried out with only a small number of subjects. In a group of nine healthy, surgically postmenopausal women, Pickett et al6 found that combined estrogen (conjugated equine estrogens 1.25 mg per day) and progestin (medroxyprogesterone acetate 20 mg per day) treatment was superior to placebo in reducing episodes of sleep-disordered breathing and in decreasing the duration of hypopneas. That study did not allow evaluation of the effect of unopposed ERT. Regensteiner et al20 studied 12 healthy, postmenopausal women after 1 week of treatment with placebo, progestin (medroxyprogesterone acetate 20 mg per day), estrogen (conjugated equine estrogens 1.25 mg per day), and combined progestin and estrogen. Progestin alone or in combination with estrogen was found to raise resting ventilation and decrease end-tidal carbon dioxide pressure, as well as to increase the hypoxic and hypercapnic ventilatory responses. Estrogen alone had no effect. Cistulli et al21 also could not show any benefit with estrogen (conjugated equine estrogens 0.625 mg per day, estradiol valerate 1 mg/day, or transdermal E2 8 mg per week) or with combined estrogen–progestin (medroxyprogesterone acetate 2.5–10 mg/day) treatment in 15 postmenopausal women with moderate obstructive sleep apnea.
The female sex hormone–induced improvement of breathing is mainly attributed to progesterone because of its known action as a respiratory stimulant.3,4 However, only a few progesterone receptors are normally present in target tissues unless induced by estrogen acting through estrogen receptors.22 In an ovariectomized animal, unopposed estrogen (E2, 1 µg per day) significantly increased the number of progesterone receptors.11 In fact, estrogen was even more potent alone in upregulating the progesterone receptors than when combined with progestin (medroxyprogesterone acetate 2 mg per day). However, unopposed estrogen did not improve ventilation or the blood gases, whereas in combination with progestin there was a decrease in arterial carbon dioxide pressure. The minor improvement of nocturnal breathing with unopposed estrogen observed in our study is in agreement with the hypothesis that estrogen does not affect breathing directly.
The current understanding about the association between sleep and breathing abnormalities is that the sleep state may uncover upper airway dysfunction, the manifestation of which ranges from partial airway collapse and increased upper airway resistance with snoring to complete airway collapse with episodes of apnea. The reported association of snoring with cardiovascular diseases23 suggests that nocturnal breathing abnormalities may have adverse effects on the cardiovascular system. In women after menopause, there is a marked increase in cardiovascular morbidity.24 On the other hand, there is evidence that estrogen may protect against cardiovascular diseases.25 Against this background, investigation of the prevalence of nocturnal breathing abnormalities as well as of possible interactions between estrogen and nocturnal breathing abnormalities is warranted. The present study, however, provided no evidence that the protective effects of ERT against cardiovascular morbidity are mediated through changes in nocturnal breathing in healthy postmenopausal women.
The conventional method used to assess the severity of sleep-disordered breathing is to determine the apnea–hypopnea index. The choice of the static-charge-sensitive bed method for respiratory monitoring during sleep in our study was crucial for revealing a broader spectrum of breathing abnormalities, ranging from obstructive apnea to partial upper airway obstruction. This method was developed at our sleep unit during 1979–1981.26 Since then it has been widely used for sleep studies and has been validated for respiratory monitoring during sleep.16,17 A particular advantage of the static-charge-sensitive bed is that the sleeping subject is free of disturbing respiratory sensors. With this method, four distinct types of periodic breathing are visually differentiated according to their respiratory movement pattern and body movement content. Compared with the conventional monitoring of breathing during sleep with nasal thermistors and thoracic and abdominal bands, the obstructive periodic breathing type 2 and 3 patterns essentially correspond to episodes of obstructive sleep apnea with major arousal components,16 whereas the periodic breathing type 1 and obstructive periodic breathing type 1 patterns represent periodic breathing with moderate or high respiratory efforts and with less impact on sleep. Because the static-charge-sensitive bed measures effort but not airflow, it does not differentiate between episodes of obstructive apnea and episodes of severe hypopnea.
In addition to recurrent apnea and hypopnea, the static-charge-sensitive bed method reveals episodes of increased respiratory resistance, which correspond to prolonged episodes of obstructive hypoventilation and flow limitation without arousals but with increasing carbon dioxide retention27 and increased intrathoracic pressure variation.28 During carbon dioxide–stimulated breathing, high-frequency respiratory movements (spikes) are generated on the high-frequency channel, which originate from increased respiratory activity, indicating stimulation due to partial airway obstruction.
Our population was recruited for sleep studies through an announcement in a newspaper. Voluntary enrollment in the study could have favored selection of women with sleep problems. Because we aimed to study the occurrence of breathing abnormalities in asymptomatic, postmenopausal women, our inclusion criteria ruled out patients with previously diagnosed sleep apnea. Therefore, none of the subjects presented with severe sleep-disordered breathing. This selection bias could also have partly blunted the possible response to ERT in the women in our study.
The observed period effect (more increased respiratory resistance during the second study night) suggests that the two study nights may not be directly comparable owing to the 4-month interval between study nights. According to previous reports, however, sleep-induced breathing abnormality scores are not influenced by the laboratory environment,29 and night-to-night variation is not significantly different between the first and second laboratory nights.30
Our results allow us to conclude that nocturnal breathing abnormalities, especially partial upper airway obstruction, are common after menopause. In doses used to control climacteric symptoms, unopposed estrogen leads only to a marginal improvement in breathing, which probably has no clinical significance in asymptomatic women.
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Footnotes |
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The authors thank Janssen-Cilag and Leiras Ltd. for supplying estrogen and placebos and for randomizing the subjects. They also thank Anne Kaljonen, MSc, for statistical assistance.
doi:10.1016/S0029-7844(03)00374-0
Received May 28, 2002. Received in revised form December 6, 2002. Accepted December 18, 2002.
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