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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0774
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4199-4207
Copyright © 2007 by The Endocrine Society

Hypothalamic-Pituitary-Adrenal Axis Activity in Obese Men with and without Sleep Apnea: Effects of Continuous Positive Airway Pressure Therapy

A. N. Vgontzas, S. Pejovic, E. Zoumakis, H.-M. Lin, C. M. Bentley, E. O. Bixler, A. Sarrigiannidis, M. Basta and G. P. Chrousos

Sleep Research and Treatment Center, Department of Psychiatry (A.N.V., S.P., E.O.B., A.S., M.B.), and Health Evaluation Sciences (H.-M.L., C.M.B.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and First Department of Pediatrics and Unit on Endocrinology, Metabolism and Diabetes (E.Z., G.P.C.), University of Athens, GR-157-84 Athens, Greece

Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Department of Psychiatry, H073, Penn State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: avgontzas{at}psu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited.

Objective: In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients.

Design and Participants: In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory.

Results: The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 ± 0.4 vs. 8.1 ± 0.3 vs. 7.5 ± 0.3 µg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference –0.7 ± .4 µg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response.

Conclusions: Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBSTRUCTIVE SLEEP APNEA is associated with repetitive episodes of breathing cessation, nocturnal hypoxia, and continuous brief electroencephalographic arousals and sleep fragmentation (1). These pathophysiological changes should be associated with an activation of both the systemic sympathetic/adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axis limbs of the stress system (2). Indeed, urinary catecholamines, nocturnal plasma catecholamines, and apnea-related surges of sympathetic nerve activity, determined by microneurography, are all elevated in obese sleep apneic patients, compared with obese controls (3, 4). Interestingly, however, the effects of sleep apnea on the HPA axis have not been studied adequately to allow concrete conclusions. There have been only a few studies, primarily assessing the effects of continuous positive airway pressure (CPAP) on the axis, and most of them have not shown an association between sleep apnea and HPA axis activity (5, 6, 7, 8). None of these studies have factored out the effects of obesity per se, the strongest risk factor for sleep apnea, on the HPA axis, and most of them implemented an incomplete assessment of the HPA axis, e.g. plasma cortisol measures at a single time point, which might not have been informative.

Obstructive sleep apnea in obese patients is associated with abdominal (visceral) obesity and insulin resistance and may itself be a manifestation of the metabolic syndrome (9, 10). Chronic stress-related activation of the HPA axis has been proposed as a risk factor in the development of visceral obesity and metabolic syndrome (11). Indeed, it is plausible that sleep apnea, through nocturnal hypoxia and repetitive electroencephalographic arousals, may lead to increased secretion of cortisol, which in turn may contribute to and accelerate the worsening of visceral obesity and the metabolic syndrome (2).

The goal of this study was to evaluate HPA axis function at the basal state by 24-h serial plasma sampling of cortisol and after a challenge test, i.e. ACTH and cortisol responses to CRH administration, in well-characterized, psychologically healthy obese men with sleep apnea, obese controls, and nonobese controls. We hypothesized that obese patients with sleep apnea would show HPA axis hyperactivity, compared with their controls, and that CPAP would have a beneficial effect on cortisol hypersecretion. Furthermore, we expected no differences in terms of plasma cortisol levels and response to CRH test between nondistressed obese and nonobese individuals studied under the strictly controlled conditions of the sleep laboratory.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Overall, 83 subjects, including obese patients with sleep apnea, nonapneic obese controls, and nonobese controls, participated in two studies for the assessment of the HPA axis in obesity and sleep apnea. All subjects were screened for psychiatric comorbidity by a psychiatrist, and those who met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria of a current mental disorder (i.e. psychotic disorders, mood disorders, anxiety disorders, substance abuse disorders) or insomnia and narcolepsy were excluded from the study. The first study (study I) evaluated the 24-h basal circadian secretory pattern of plasma cortisol and was completed in 16 obese, middle-aged men with sleep apnea; 13 nonapneic obese controls, of similar age and body mass index (BMI); and 16 nonobese controls. One of the nonobese controls was excluded from the analysis as an outlier because of abnormally high values of cortisol. The second study (study II) assessed the response of the HPA axis to the administration of ovine (o) CRH and was completed in 14 obese, middle-aged men with sleep apnea; 12 nonapneic obese controls, of similar age and BMI; and 12 nonobese controls. In each study, two groups of controls were included: the nonobese group to control for the effects of obesity per se on HPA axis function and the obese group to control for the effects of obesity on HPA axis in obese patients with sleep apnea.

Subjects

The subjects were recruited from the Sleep Disorders Clinic and through advertisement from the community. The participants in the two studies were similar in terms of age and BMI (see Tables 1Go and 3Go).


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  		TABLE 1. Demographic, sleep, and respiratory data in sleep apneic patients, obese controls, and nonobese controls in study I

 

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  		TABLE 3. Demographic, sleep, and respiratory data in sleep apneics, obese controls, and nonobese controls in study II

 
To qualify for the study, apneic patients had to have apnea of sufficient severity to warrant recommendation for treatment (9). Obese or nonobese control subjects who 1) presented a sleep complaint, i.e. difficulty in falling or staying asleep, excessive daytime sleepiness, 2) had an apnea/hypopnea index of more than five events per hour of sleep, and 3) during the screening night their percentage sleep time less than 75% were excluded from the study. Because of the high comorbidity of obesity and sleep apnea in men, a much larger group of obese men (almost twice as high as the number of participants) had to be screened to end with the group of obese controls. Based on data from the Penn State Cohort, a general random sample, it appears that about 50% of the adult obese men would have fit the definition of normally sleeping nonpsychologically distressed obese men of our study (Bixler, E. O., unpublished data). Also, apneic patients and control subjects with a diagnosis of diabetes mellitus or who were receiving treatment with psychotropics, steroids, sympathomimetics, or sympatholytics, including ß-blockers, were excluded from the study. In study I, two of the sleep apneic patients, two of the obese controls, and two of the nonobese controls were treated for hypertension. In study II, five of the sleep apneic patients and none of the nonapneic obese or the nonobese controls were treated for hypertension. The studies were approved by the institutional review board, and each subject signed a written consent form.

Procedures

Sleep laboratory. A thorough medical assessment, including physical examination, routine laboratory tests (including complete blood cell count, urinalysis, thyroid function tests, electrocardiography, and urine drug screen), and sleep history, was completed for each patient and control subject. Those who were positive for abnormal findings in the battery of clinical tests were excluded from the study. Blood pressure was measured in the evening during the physical examination using a pneumoelectric microprocessor-controlled instrument. The recorded blood pressure was the average of three consecutive readings during a 5-min period after 10 min of rest in the supine position. All potential participants in the study were screened in the sleep laboratory for 1 night for 8 h (2300–0700 h) using standard polysomnographic procedures (12). Throughout the night, respiration was monitored by thermocouples and/or pressure transducers at the nose and mouth (model TCT1R; Grass Instrument Co., Quincy, MA) and thoracic strain gauges. All-night recordings of hemoglobin oxygen saturation (SaO2) were obtained using a cardiorespiratory oximeter (model 8800; Nonin Medical, Inc., Plymouth, MN) attached to the finger. The subjects who met the inclusion criteria were monitored in the sleep laboratory for 4 consecutive nights (1 adaptation and 3 baseline nights). The patients with sleep apnea were reassessed with the same protocol after at least 3 months of closely monitored nightly use of CPAP. The sleep records were scored independently of any knowledge of the experimental conditions according to standardized criteria (12). Also, the respiratory data were quantified as previously described (13).

CPAP use. All 16 patients with sleep apnea used CPAP for 3 months. The optimal nasal CPAP pressure was determined during a full night polysomnographic study as the pressure necessary to abolish all respiratory events and snoring, secondary arousals, and episodes of SaO2 desaturation during rapid eye movement (REM) sleep and in the supine position. To assure adherence, we monitored closely the CPAP use on a daily basis by calculating the time that the patient is breathing through the machine and not just the time the machine is on (AutoSet T, SmartStart; ResMed, Poway, CA). Furthermore, a respiratory therapist visited the home of each patient weekly for the first 4 wk and monthly thereafter to provide us with information regarding CPAP usage (number of hours used each day), pressure setting, and mask leakage. The average nightly use of CPAP was 4.6 ± 1.7 h, whereas 15 of the 16 met the criteria of regular users (14).

Twenty-four-hour blood sampling (study I)

Twenty-four-hour blood sampling was performed serially, every 30 min, on the fourth day and night in the sleep laboratory in the participants of study I and repeated in the patients with sleep apnea after 3 months of regular nightly use of CPAP as previously described (15). During the sleep periods, blood samples were obtained from an adjacent room by connecting external tubing to the indwelling catheter through a perforation in the wall.

Ovine CRH stimulation test (study II)

The participants of study II were given oCRH as an iv bolus injection at 2000 h, when the HPA axis is normally quiescent in the evening (16), on d 5 after the fourth night in the sleep laboratory. An indwelling catheter was inserted in the antecubital vein about 30 min before the first blood draw. Blood was drawn 30 and 15 min before the administration of CRH; at the time of the injection; and 5, 15, 30, 60, 90, and 120 min afterward for measurement of ACTH and cortisol.

Hormone assays

Blood collected from the indwelling catheter was transferred to an ethylenediamine tetraacetate-containing tube and refrigerated until centrifugation (within 3 h). The supernatant was frozen at –20 C until hormone assay. ACTH and cortisol levels were measured by specific immunoassay techniques as previously described (17). The lower limit of detection was 5 pg/ml for ACTH and 0.7 µg/dl for cortisol. The intra- and interassay coefficients were, respectively, 4.6 and 6.0% for cortisol and 10.0 and 12.0% for ACTH. Also, single measures of cortisol binding globulin (CBG) were obtained with a double antibody/immunoabsorbent RIA (Labor Diagnostika Nord, Nordhorn, Germany). The lower detection limit was 11.5 µg/ml, and the intra- and interassay coefficients ranged from 2.9 to 3.9% and 2.4 to 5.5%, respectively.

Statistical analyses

The sleep variables were calculated based on the mean values from nights 2 and 3 for the 24-h blood draw study (night 4 was not included due to potential blood draw-induced sleep disturbance) and from nights 2 to 4 in the CRH study. For comparisons of age, BMI, and sleep variables among the three groups, the ANOVA or Kruskal-Wallis test, when the variable displayed high level of skewness, was used. If the overall test was significant, pairwise comparisons among the three groups were further conducted using the Student t test or Wilcoxon rank-sum test. For comparisons before and after the CPAP treatment for the apnea group, the paired t test was used. We note that the conclusions for the tests were essentially the same, regardless of whether parametric or nonparametric tests were used.

For study I the cortisol values among the three groups (see Table 4Go), and before and after CPAP treatment for the apnea group, were compared using the repeated measurements analysis assuming the within-subject observations followed a group-specific autoregressive variance-covariance structure. The results were analyzed for the entire 24 h, daytime (0800–2200 h), and nighttime (2300–0700 h), respectively, and adjusted for age and race for the three-group comparisons but not for the before and after CPAP treatment comparison.


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  		TABLE 4. Twenty-four-hour plasma cortisol values in sleep apneic patients, obese controls, and nonobese controls in study I

 
For study II the total integrated ACTH and cortisol responses to oCRH were expressed as the area beneath the concentration-time curve from –30 to 120 min. The net integrated ACTH and cortisol responses were expressed as the area beneath the concentration-time curve from 0 to 120 min minus the area corresponding to the mean of the two baseline values multiplied by 120 min. The ACTH values were transformed logarithmically because their distribution was skewed. The peak ACTH and cortisol responses corresponded to the highest levels of ACTH and cortisol achieved during the test, which occurred in all instances during the first hour after the administration of the oCRH. For comparisons of net, total and net peak ACTH and cortisol responses among the three groups, the linear model that allowed for heterogeneous variances for the three groups using the maximum likelihood methods was used (18). Because there were no differences in any of the ACTH response variables between obese patients with sleep apnea and obese controls, they were further combined and contrasted to the nonobese controls. The analysis adjusted only for age due to incomplete race data.

Alternatively, the repeated-measurement analyses were also performed for the post-oCRH administration cortisol and log-transformed ACTH data, in which the models adjusted for age and the mean of the baseline values and assumed group-specific autoregressive variance-covariance structure. The overall and time-specific differences among the three groups were contrasted.

The data are expressed as the mean ± SE, except for age and BMI, which are expressed as the mean ± SD. The statistical significance level selected for all analyses was set to be 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Sleep, respiratory, and blood pressure data

Study I. The group of sleep apneic patients, compared with both nonapneic obese and nonobese controls, demonstrated a significantly higher percentage of stage 1 sleep and significantly lower percentages of stage 2 and REM sleep (Table 1Go). There were no significant differences between nonapneic obese and nonobese controls in any of the sleep variables. After the use of CPAP for 3 months, there was a significant improvement of wake time after sleep onset, percent stage 1 sleep, percent stage 2 sleep, percent REM sleep and a significant shortening of REM latency (Table 2Go). Also, the apnea/hypopnea index and minimum SaO2 were significantly and markedly improved while on CPAP (53.3 ± 7.0 vs. 4.5 ± 1.9 and 72.4 ± 2.1 vs. 85.9 ± 1.6, both P < 0.001).


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  		TABLE 2. Sleep and respiratory data in sleep apneic patients at baseline and after treatment with CPAP for 3 months

 
Finally, systolic blood pressure was significantly higher in the sleep apneic group, compared with nonobese controls (141.7 ± 3.4 vs. 129.9 ± 2.8, P < 0.05). After the use of CPAP, there was a significant lowering of diastolic and mean arterial pressures (87.7 ± 2.6 vs. 79.9 ± 1.9 and 105.7 ± 2.8 vs. 98.4 ± 2.0, both P < 0.05).

Study II. The group of sleep apneic patients, compared with both nonapneic obese and nonobese controls, demonstrated a significantly higher wake time after sleep onset, total wake time, and percentage stage 1 sleep (P < 0.01) (Table 3Go). The same patients demonstrated a significantly lower percentage of sleep time and stage 2 sleep (P < 0.05) than either control groups. There were no differences between obese and nonobese controls in any of the sleep variables. Finally, systolic, diastolic, and mean arterial pressures were significantly higher in the sleep apneic patients group (144.3 ± 7.0, 89.4 ± 3.6 and 107.7 ± 4.6, respectively), compared with the nonobese controls (123.0 ± 1.6, 76.3 ± 1.4, and 91.9 ± 1.0) (P < 0.01 for all three blood pressure variables).

HPA axis

Basal function of the HPA axis (study I). The 24-h mean values of cortisol were highest in nonobese controls, intermediate in obese apneic patients, and lowest in nonapneic obese controls (8.8 ± 0.4 vs. 8.1 ± 0.3 vs. 7.5 ± 0.3 µg/dl, overall P < 0.05 and P = 0.013 between nonobese and obese controls) (Fig. 1Go and Table 4Go). Similar nonsignificant trends were observed for the daytime period (0800–2200 h). During the nighttime period (2300–0700 h), the difference between obese sleep apneic patients and obese controls became significant, whereas the cortisol levels of obese sleep apneic patients and nonobese controls were very similar (Table 4Go). The association of BMI and mean 24-h cortisol levels in the groups of nonobese and obese controls was negative (r = –0.4, P = 0.03). Three months of CPAP use was associated with a trend to reduce plasma cortisol levels in the apneic group (difference: –0.7 ± 0.4 µg/dl, P = 0.1), bringing it closer to the levels of the nonapneic obese controls (Fig. 2Go). This effect was uniformly present throughout the 24-h period. There was no correlation between average nightly use of CPAP and the reduction of cortisol levels after CPAP. There were no differences of CBG levels among the three groups studied (42.1 ± 1.7 µg/ml for sleep apneics, 42.2 ± 1.5 for obese controls, and 42.9 ± 2.0 for nonobese controls).


Figure 1
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  		FIG. 1. Twenty-four-hour baseline secretory pattern of cortisol in obese ({blacksquare}) and nonobese controls (•) and in patients with sleep apnea ({blacktriangleup}). The thick black bar on the abscissa represents the sleep-recording period. Inserted panel depicts mean ± SE of 24-h plasma concentration of cortisol. The vertical arrows at the bottom indicate the time points of the meals. The asterisk indicates a significant difference between obese controls and nonobese controls (*, P < 0.05). SA, Sleep apnea.

 

Figure 2
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  		FIG. 2. Twenty-four-hour secretory pattern of cortisol in sleep apneic patients before and after 3 months of CPAP treatment. Pre-CPAP ({blacktriangleup}) and post-CPAP (•). The thick black bar on the abscissa represents the sleep-recording period. The vertical arrows at the bottom indicate the time points of the meals. Inserted panel depicts mean ± SE of 24-h cortisol concentration for the two groups.

 
Cortisol secretion was circadian in all three groups without any significant differences in terms of amplitude or the acrophases of the rhythm.

Responses to CRH (study II)

Basal plasma levels of ACTH and cortisol were not different among the three groups. However, both obese sleep apneic patients and nonapneic obese controls had enhanced ACTH responses to the administration of CRH (Fig. 3Go). Specifically, net integrated ACTH was increased in the two obese groups, compared with the nonobese controls (log difference of means: 0.61 ± 0.24, P < 0.05 between apneic patients and nonobese controls and 0.41 ± 0.23, P = 0.09 between nonapneic obese and nonobese controls). Similar increases were observed in total integrated ACTH (log difference of means: 0.43 ± 0.22, P = 0.06 apneic patients vs. nonobese controls and 0.30 ± 0.19, P = 0.10 nonapneic obese controls vs. nonobese controls) and net peak ACTH secretion (log difference of means: 0.49 ± 0.26, P = 0.07 apneics vs. nonobese controls and 0.40 ± 0.23, P = 0.10 nonapneic obese vs. nonobese). There were no differences in any of the ACTH response variables (net integrated, total integrated, peak secretion) between obese patients with sleep apnea and obese controls. After collapsing the obese apneic patients and nonapneic obese controls, a comparison of the obese group (apneic patients and nonapneic controls) vs. nonobese controls showed a significant difference in all three variables of ACTH response. Specifically, net integrated ACTH (log difference of means: 0.56 ± 0.20 P < 0.01), total integrated ACTH (log difference of means: 0.39 ± 0.17 P < 0.05), and net peak ACTH secretion (log difference of means: 0.48 ± 0.20 P < 0.05) were all significantly increased in obese vs. nonobese controls.


Figure 3
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  		FIG. 3. Log ACTH (A) and cortisol concentration (B) over time in sleep apneic patients ({blacktriangleup}), obese (•), and nonobese controls ({blacksquare}) in response to CRH administration at zero time point. Inserted panel depicts the corresponding areas under the curve in each group. The asterisk above the nonobese group (nonobe) indicates a significant difference in terms of log ACTH net area under the curve between obese sleep apneic patients (SA) and nonobese controls (*, P < 0.05).

 
Similar results were observed using the repeated measurement analyses for the post-oCRH administration ACTH data. As before, there was a significant overall difference in the log-transformed ACTH means between apneic patients and nonobese controls (P = 0.004) and close to significant difference between nonapneic obese and nonobese controls (P = 0.068). However, there was no difference between obese patients with sleep apnea and obese controls. Furthermore, the differences among the three groups remain relatively constant throughout the entire time course (i.e. no time and group interaction), except for the responses at the first 15 min.

Finally, there were no differences among the three groups in terms of cortisol responses to oCRH administration, including net integrated cortisol, total integrated cortisol, net peak cortisol, and results based on the repeated measurement analysis (Fig. 3Go). The peak ACTH and cortisol values occurred, respectively, 30 and 60 min after CRH administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The two major findings of our two studies are that: 1) in nondepressed, nonapneic obese men, HPA axis activity is decreased, compared with that of matched nonobese controls; and 2) sleep apnea is associated with a mild but significant at-night elevation of cortisol levels, compared with nonapneic obese controls, which is corrected after the use of CPAP for 3 months. These differences are not explained by variable circulating CBG concentrations, which were similar in the three groups.

We were partially surprised by the results, which showed that obesity is associated with a decreased cortisol secretion and an exaggerated response of ACTH to CRH, suggesting a hyposecretion of hypothalamic CRH. These findings challenge the notion supported by studies that the HPA axis in obesity, particularly central obesity, is hyperactive or normal (19, 20, 21, 22, 23). In the majority of these studies, the psychological profile, including emotional distress, anxiety, and/or depression, of the subjects was not assessed formally, and/or the evaluation of the function of the HPA axis was not based on serial 24-h plasma sampling for cortisol in a strictly controlled environment. Our findings are consistent with reports of significantly lower levels of plasma cortisol in adults and children (24, 25) or 24-h urinary free cortisol in women with abdominal obesity that, similar to our study, were screened for depression (26). This lower HPA axis activity in obese subjects is consistent with the hypoalertness and daytime sleepiness and fatigue of obese individuals (27, 28).

In our study, obese individuals without sleep apnea slept at night as well as nonobese individuals. Previous studies by us and others reported that severely obese individuals, compared with normal-weight subjects, sleep poorly at night (13, 27, 29). However, in this study, obese subjects were carefully selected not to have poor sleep and especially insomnia, a condition that has been associated with an activated HPA axis (30). Our decision not to include emotionally distressed insomniac subjects is supported by an analysis of objective sleep measures of 73 obese individuals without sleep apnea that showed that less sleep was associated with psychological distress, whereas more sleep was associated with absence of distress (31).

Are the lower plasma cortisol values in obese subjects secondary to central or peripheral alterations of the HPA axis? Vicennati and Pasquali (26) suggested that the lower urinary free cortisol values they found in obese, nondepressed women were most likely secondary to subtle abnormalities of cortisol transport, metabolism, and/or target tissue activity. Admittedly, hypersensitivity of tissues to glucocorticoids could result in both low circulating cortisol, due to increased cortisol-negative feedback, and central obesity analogous to mild Cushing syndrome (11).

Reports of the ACTH and/or cortisol response to exogenous CRH in obese patients have been inconsistent, ranging from a blunt to an exaggerated response or no difference, compared with nonobese controls (23). Our oCRH study showed that obese subjects with and without sleep apnea had a higher response of ACTH but not cortisol, which is consistent with two previous reports (32, 33). These results suggest that in nondepressed, nonapneic obese men, the HPA axis is chronically slightly hypoactive, associated with hypotrophic adrenal cortices requiring compensatorily elevated amounts of ACTH to produce normal amounts of cortisol. These findings are reminiscent of data in patients with hypothalamic adrenal insufficiency and are against the glucocorticoid hypersensitivity hypothesis in obesity, in which we would have expected a lower rather than a higher ACTH response to oCRH.

Our CRH stimulation data are also compatible with an increased peripheral clearance of cortisol in obese subjects, which might have led to compensatory increases of CRH and ACTH secretion in an attempt to maintain free cortisol within a minimum normal range (34, 35). This type of ACTH and cortisol response to CRH was observed in AIDS patients with insulin resistance and lipodystrophy (36). In these patients, there was a mild early ACTH hypersecretion response and a normal cortisol response to CRH.

There are only a few studies on the effects of sleep apnea on the HPA axis, and most of these have primarily focused on the effects of CPAP on cortisol secretion (5, 6, 7, 8, 37). Several studies have reported that CPAP does not reduce cortisol levels or that acute withdrawal of CPAP therapy does not result in an increase in cortisol levels (5, 6, 8, 37). In contrast, another study reported that CPAP corrected preexisting hypercortisolemia, particularly after prolonged use (7). Several of these studies were limited in that cortisol was measured at a single time point, they did not use appropriate controls, and were not done under controlled conditions. Our study demonstrated that sleep apnea in obese men is associated with increased cortisol level during the night, compared with nonapneic obese controls, which is corrected after the use of CPAP for 3 months. The correction of the increased cortisol appears to be related to the elimination, through CPAP, respectively, of the stress of repetitive respiratory pausing (apnea) and sleep fragmentation and/or better oxygen saturation. The decrease of cortisol levels after CPAP use may also be related to the beneficial effect of CPAP on blood pressure, via a decrease in sympathetic activity, reported in these patients. Our findings on the effect of CPAP on blood pressure are consistent with randomized controlled trials that have shown that CPAP treatment of severe sleep apnea reduces blood pressure (38).

The pathogenesis of airway collapse during sleep in patients with sleep apnea is not well understood; however, there is evidence of decreased excitatory stimuli from neural systems to respiratory centers (39). CRH is a potent stimulus of respiration (40), and its inferred hyposecretion in obese patients may explain why such patients are at higher risk for sleep apnea. Furthermore, prolonged exercise is associated with increased CRH levels (41), which may explain the beneficial effect of exercise in sleep apneics (42). Fatigue and sleepiness are common complaints of obesity, and we and others have reported that obesity, even without sleep apnea, is associated with objective sleepiness and hypoalertness (19, 29). The inferred low levels of CRH secretion, the low levels of 24-h cortisol secretion, combined with high plasma levels of the proinflammatory cytokines IL-6 and TNF{alpha} are consistent with the hypoalertness and daytime sleepiness and fatigue of obese individuals (9, 10, 43).

Finally, our data, that obesity in nondepressed individuals is associated with lower cortisol secretion, whereas in psychologically stressed, obese individuals, there is HPA axis activation albeit from a lower baseline, may provide the basis for a meaningful phenotyping of obesity. One phenotypic subtype may be associated with depression/anxiety, HPA axis hyperactivity, and less sleep and the other with HPA axis normalcy or hypoactivity, normothymia, and more sleep; this subtyping is supported further by our recent study of the association between amount of sleep and psychological distress in the obese (31). This proposed subtyping may have important therapeutic implications and lead to the development of novel treatment approaches specific for each subtype.


   Acknowledgments
 
We thank the nursing staff of the General Clinical Research Center and Carrie Criley at the Pennsylvania State University College of Medicine for their technical assistance. We also thank Barbara Green for the overall preparation of the manuscript. Finally, we thank Young’s Medical Equipment, a division of Air Products Healthcare, for providing the CPAP devices and the compliance monitoring throughout the study.


   Footnotes
 
This work was supported by National Institutes of Health Grants R01 HL64415, RR010732, and RR016499.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 4, 2007

Abbreviations: BMI, Body mass index; CBG, cortisol binding globulin; CPAP, continuous positive airway pressure; HPA, hypothalamic-pituitary-adrenal; o, ovine; REM, rapid eye movement; SaO2, oxygen saturation.

Received April 4, 2007.

Accepted August 27, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Vgontzas AN, Kales A 1999 Sleep and its disorders. Annu Rev Med 50:387–400[CrossRef][Medline]
  2. Buckley TM, Schatzberg AF 2005 On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 90:3106–3114[Abstract/Free Full Text]
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