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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 11 5052-5057
Copyright © 2002 by The Endocrine Society

Original Article

Concomitant Impairment of Growth Hormone Secretion and Peripheral Sensitivity in Obese Patients with Obstructive Sleep Apnea Syndrome

L. Gianotti, S. Pivetti, F. Lanfranco, F. Tassone, F. Navone, E. Vittori, R. Rossetto, C. Gauna, S. Destefanis, S. Grottoli, R. De Giorgi, V. Gai, E. Ghigo and M. Maccario

Division of Endocrinology (L.G., F.L., F.T., R.R., C.G., S.D., S.G., E.G., M.M.), Department of Internal Medicine, University of Turin, 10126 Turin, Italy; and Emergency Department–Emergency Medicine (S.P., F.N., E.V., R.D.G., V.G.), Azienda Ospedaliera San Giovanni Battista, Molinette Hospital, 10126 Turin, Italy

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Università di Torino, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it.

Abstract

To clarify the impairment of the GH/IGF-I axis in obstructive sleep apnea syndrome (OSAS), in 13 adult male patients with OSAS (OSA) as well as 15 weight-matched patients with simple obesity (OB) and 10 normal lean male subjects (NS), we studied: 1) the GH response to GHRH (1 µg/kg iv) plus arginine (30 g iv); and 2) the IGF-I and IGF binding protein-3 responses to a very low dose recombinant human (rh)GH treatment (5.0 µg/kg sc per day for 4 d). The GH response to arginine plus GHRH in OSA was lower than in OB (P < 0.05), which in turn was lower than in NS (P < 0.001). Basal IGF-I levels in OSA were lower than in OB (P < 0.05), which in turn were lower than in NS (P < 0.03). As opposed to OB and NS, in OSA a very low rhGH dose did not affect IGF-I. Adjusting for age and basal values, rhGH-induced IGF-I rise in OSA was lower than in OB (P < 0.01). IGF binding protein-3, glucose, and insulin levels in the three groups were not modified by rhGH. OSA show a more marked impairment of the maximal secretory capacity of somatotroph cells together with reduced IGF-I sensitivity to rhGH stimulation. These findings suggest that OSAS is connoted by a concomitant impairment of GH secretion and sensitivity.

OBSTRUCTIVE SLEEP APNEA SYNDROME (OSAS) is characterized by repetitive upper airway occlusion leading to apnea and asphyxia, typically occurring 100–600 times per night (1). It is estimated to affect up to 7% of the adult male population, and its prevalence increases with advancing age, although clinical severity of apnea decreases (1, 2). It is associated with daytime somnolence, cardiovascular disease, and obesity (1, 2, 3, 4). Moreover, as in simple obesity (OB), it is characterized by several endocrine abnormalities (5), including changes in the activity of GH/IGF-I axis (6, 7, 8). In fact, both in obesity and in OSAS, spontaneous GH secretion is reduced (5, 6, 7, 8, 9), whereas IGF-I levels are reported normal or slightly reduced in OB and reduced in OSAS (6, 10). It is still unclear whether these alterations in OSAS simply reflect overweight or include hypoxia-induced hormonal changes that are peculiar to this syndrome. In fact, concerning GH/IGF-I axis, the reduced spontaneous GH secretion as well as the reduced IGF-I levels have been found restored by nocturnal nasal continuous positive airway pressure (nCPAP) treatment in the absence of any change in body weight (6, 7, 8).

On the basis of the foregoing, we aimed to throw further light on the activity of GH/IGF-I axis in obese patients with OSAS (OSA) in comparison with that in patients with OB and in normal subjects (NS). To this goal, in a group of obese OSA, we studied the maximal secretory capacity of somatotroph cells as well as the peripheral sensitivity to GH. The GH releasable pool was evaluated by the GHRH plus arginine (ARG) test, which is one of the most potent and reproducible stimuli available so far (11). On the other hand, to evaluate peripheral GH sensitivity, we assessed the IGF-I response to a short treatment with the minimal recombinant human (rh)GH effective dose (12). The same study protocol was also performed in a group of weight-matched patients with OB and a group of lean NS.

Subjects and Methods

Subjects

The subjects enrolled in this study belonged to a cohort of outpatients with obesity reporting symptoms such as daytime somnolence and nocturnal snoring, suggesting possible sleep apnea syndrome. After a polysomnographic study was performed, the first consecutive 13 male OSA [age, 52.6 ± 2.8 yr (mean ± SEM); body mass index (BMI), 38.5 ± 2.9 kg/m2; waist to hip ratio (WHR), 1.01 ± 0.03; apnea/hypopnea index (AHI), 51.6 ± 9.2 events/h of sleep] and the first consecutive 15 male obese patients without OSAS (OB; age, 38.4 ± 1.8 yr; BMI, 43.2 ± 2.2 kg/m2; WHR, 0.99 ± 0.01; AHI, 3.4 ± 1.4 events/h of sleep) were recruited. Exclusion criteria included unstable or uncompensated cardiopulmonary disease, malignancies, recent surgery of the upper airways, diabetes mellitus, or thyroid disorders. Patients were also excluded if they had sleep studies with an inadequate period of sleep (less than 4 h) or if they were diagnosed or receiving medical treatment for sleep-disordered breathing. Ten normal lean male subjects (NS; age, 39.6 ± 0.9 yr; BMI, 22.2 ± 0.6 kg/m2; WHR, 0.90 ± 0.03; AHI, 2.2 ± 0.6 events/h of sleep) were studied as controls.

Methods

All subjects underwent the following:

Anthropometric measurements. Height (to the nearest 0.5 cm) and weight (to the nearest 0.5 kg) were recorded while subjects were wearing only underwear garments. BMI was calculated as weight/height (2). Each subject’s waist was measured with a soft tape midway between the lowest rib and the iliac crest. The hip circumference was measured at the widest part of the gluteal region.

Blood pressure evaluation. Blood pressure was measured to the nearest millimeter with a sphygmomanometer in the right arm after at least 10 min of rest in the sitting position in the morning before the beginning of hormonal assays. Systolic and diastolic pressures were defined as Korotkoff phases I and V. The mean of three measurements taken at 2-min intervals were averaged and used for the analysis. Diagnosis of hypertension was defined according to conventional criteria (13).

Polysomnography. A 16-channel polysomnographic recording system (Compumedics Sleep Pty. Ltd., Abbotsford, Australia) was used to assess sleep state and respiratory and cardiac variables. All of the patients and controls underwent a standard overnight polysomnography (14, 15) with continuous recording of electroencephalogram, electromyogram, electrooculogram, electrocardiogram, nasal airflow (by stalk-mounted thermocouples), body position, thoracic and abdominal respiratory efforts (recorded by respiratory inductive plethysmography using mercury strain gauge), and arterial oxyhemoglobin saturation (SaO2) recorded by a pulse oximeter. Sleep state was measured by electroencephalogram, electromyogram, and electrooculogram, according to conventional criteria (16). Arterial SaO2, nasal airflow, and ribcage and abdominal respiratory motion were used to assess episodes of sleep-disordered breathing. Apnea was defined as cessation of airflow for at least 10 sec; hypopnea was defined as a reduction in the amplitude of the ribcage and abdominal excursions with a decrease in ventilation exceeding 50% that lasted at least 10 sec, associated with a SaO2 reduction of at least 4%. The AHI was defined as the average number of episodes of apnea and hypopnea per hour of sleep. The threshold of more than five episodes of apnea or hypopnea per hour of sleep to define OSAS was chosen according to the most recent recommendations (17). All subjects gave their written informed consent to participate in the study, which had been approved by the local Ethical Committee.

Hormonal assays. In each subject, the following variables were studied: 1) GH response to GHRH (1.0 µg/kg iv) plus ARG (30 g iv); and 2) IGF-I and IGF binding protein-3 (IGFBP-3) responses to a very low rhGH dose (5.0 µg/kg given sc at 2100 h for 4 d). The GHRH plus ARG tests were begun in the morning at 0830–0900 h, after an overnight fasting and 30 min after an indwelling catheter had been placed into an antecubital vein of the forearm kept patent by slow infusion of isotonic saline. Blood samples were drawn at baseline and then every 15 min from -15 up to +90 min. Serum GH levels were measured at each time point. The night after the test, at 2100 h, the first rhGH treatment was administered after a standardized meal. The following rhGH administrations were repeated at the same hour from d 1 to d 4. A blood sample was taken at 0900 h, 12 h after the first and the last rhGH administration. IGF-I, IGFBP-3, glucose, and insulin levels were assayed at each time point.

Serum GH levels (micrograms per liter) were measured in duplicate by immunoradiometric assay (HGH-CTK IRMA, Sorin, Saluggia, Italy). The sensitivity of the assay was 0.15 µg/liter; the inter- and intra-assay coefficients of variation were 2.9–4.5% and 2.4–4.0%, respectively. Serum IGF-I levels (nanomoles per liter) were measured in duplicate by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA) after acid-ethanol extraction to avoid interference by binding proteins. The sensitivity of the assay was 0.013 nmol/liter. The inter- and intra-assay coefficients of variation were 10.1–15.7% and 7.6–15.5%, respectively. Serum IGFBP-3 levels (nanomoles per liter) were measured by RIA (Nichols Institute Diagnostics). The sensitivity of the assay was 0.009 nmol/liter. The inter- and intra-assay coefficients of variation were 5.3–8.0% and 3.8–8.0%, respectively. Plasma glucose (millimoles per liter) was determined by the glucose oxidase colorimetric method (Glucofix; Menarini Diagnostics, Firenze, Italy). Serum insulin levels (picomoles per liter) were measured in duplicate by immunoradiometric assay (INSIK-5, Sorin). The sensitivity of the assay was 0.018 pmol/liter. The inter- and intra-assay coefficients of variation were 6.2–10.8% and 5.5–10.6%, respectively.

Statistical analysis

Data are expressed as mean (±SEM) of absolute values and area under the curve (AUC) of GH response to GHRH plus ARG. The statistical analysis of the data was performed by ANOVA, analysis of covariance using age and basal hormonal values as covariate where appropriate, Newman-Keuls test as post hoc analysis, and {chi}2 test where appropriate.

Results

OSA were older (P < 0.005) than OB (52.6 ± 2.8 vs. 38.4 ± 1.8 yr) and NS (39.6 ± 0.9 yr), whereas no significant age difference was recorded between OB and NS. BMI was similar in OSA and OB (38.5 ± 2.9 and 43.2 ± 2.2 kg/m2), and in both groups it was higher than in NS (22.2 ± 0.6 kg/m2; P < 0.005). Similarly, WHR did not differ in OSA and OB (1.01 ± 0.03 and 0.99 ± 0.01), and in both groups it was higher than in NS (0.90 ± 0.03; P < 0.001). Seven of 15 OB subjects and 11 of 13 OSA had hypertension. The number of hypertensive subjects was significantly higher in OSA than in the OB group (P < 0.005). NS showed normal blood pressure levels. Polysomnographic features of the three groups are reported on Table 1Go.


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  		Table 1. Polysomnographic features of OSAS patients (OSA), obese patients (OB), and normal subjects (NS)

 
Basal GH levels in OSA were similar to those in OB (0.2 ± 0.1 vs. 0.9 ± 0.2 µg/liter), and both were lower (P < 0.05) than in NS (2.5 ± 0.5 µg/liter; Fig. 1Go). The GH response to ARG plus GHRH in OSA was lower than in OB (AUC, 440.5 ± 85.6 vs. 1050.9 ± 201.7 µg/liter·h; P < 0.05), which in turn was clearly lower than in NS (5222.0 ± 441.7 µg/liter·h; P < 0.001; Fig. 2Go).



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  		Figure 1. Basal GH, IGF-I, and IGFBP-3 levels in NS, OB, and OSA.

 


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  		Figure 2. Mean (±SEM) peak (left) and AUC (right) of GH responses to GHRH (1 µg/kg iv at 0 min) plus ARG (30 g iv from 0–30 min) in NS, OB, and OSA.

 
Basal IGF-I levels in OSA (17.5 ± 1.9 nmol/liter) were lower than in OB (21.3 ± 1.6 nmol/liter; P < 0.05), which in turn were lower than in NS (28.0 ± 2.1 nmol/liter; P < 0.03; Fig. 1Go). In OSA, rhGH administration did not significantly affect IGF-I levels (18.2 ± 1.2 and 21.6 ± 1.5 nmol/liter, 12 h after the first and last dose, respectively), although it induced a significant increase (P < 0.001) in OB (27.8 ± 1.5 and 33.6 ± 1.8 nmol/liter) and in NS (31.4 ± 1.8 and 35.5 ± 1.9 nmol/liter; Fig. 3Go). Adjusting for age and basal values, IGF-I levels in OB were similar to those in NS (28.6 vs. 28.8 nmol/liter) after the first rhGH administration, whereas they were significantly higher (P < 0.05) after the last rhGH dose (34.3 vs. 28.9 nmol/liter). At each time point, IGF-I responses to rhGH in OB and NS were clearly greater than in OSA (22.1 and 25.2 nmol/liter; Fig. 3Go).



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  		Figure 3. IGF-I levels before and 12 h after the first and last rhGH administration (5 µg/kg sc per day for 4 d) in NS, OB, and OSA. Left, the absolute curves of IGF-I response; right, the IGF-I response after the last rhGH dose after adjusting for basal values. Arrows represent rhGH administrations. {alpha}, P < 0.001 vs. OSA; ß, P < 0.05 vs. NS.

 
Basal IGFBP-3 levels in OSA, OB, and NS were similar (0.11 ± 0.02, 0.11 ± 0.01, and 0.10 ± 0.01 nmol/liter, respectively; Fig. 1Go). During rhGH treatment, no significant change in IGFBP-3 levels was found in the three groups 12 h after the first (0.11 ± 0.02, 0.10 ± 0.01, and 0.11 ± 0.01 nmol/liter in OSA, OB, and NS, respectively) and last rhGH administration (0.12 ± 0.02, 0.11 ± 0.01, and 0.11 ± 0.02 nmol/liter in OSA, OB, and NS, respectively).

Basal glucose levels were similar in the three groups (5.39 ± 0.06, 4.97 ± 0.11, and 4.59 ± 0.14 mmol/liter in OSA, OB, and NS, respectively) and were not modified 12 h after the first (4.91 ± 0.24, 4.87 ± 0.16, and 4.60 ± 0.09 mmol/liter in OSA, OB, and NS, respectively) and last (5.49 ± 0.29, 4.90 ± 0.15, 4.64 ± 0.11 mmol/liter in OSA, OB, and NS, respectively) rhGH administration.

Basal insulin levels were similar in OSA and OB (184.4 ± 15.8 vs. 170.8 ± 20.1 pmol/liter), and in both groups were higher than in NS (93.3 ± 9.3 pmol/liter; P < 0.05). rhGH treatment did not modify insulin levels in the three groups 12 h after the first (211.7 ± 30.1, 227.4 ± 30.1, and 107.6 ± 12.9 pmol/liter in OSA, OB, and NS, respectively) and last administration (261.9 ± 56.7, 259.0 ± 33.0, 83.2 ± 5.7 pmol/liter in OSA, OB, and NS, respectively). Thus, insulin levels in OSA and OB persisted higher than in NS.

Both basal and stimulated IGF-I and IGFBP-3 levels did not show significant correlation with BMI, AHI, and SaO2 in OSA, whereas a trend toward a negative association was found between AHI and rhGH-induced IGF-I levels 12 h after the last hormone administration.

No side effects were recorded during either the ARG plus GHRH test or rhGH treatment.

Discussion

The results of the present study demonstrate that, with respect to OB, obese OSA show a deeper reduction of the GH response to a maximal provocative test. Interestingly, this impairment occurred in the presence of basal IGF-I levels significantly lower than in OB and not responsive to a short-term administration of a very low rhGH dose.

Obesity per se is likely to concur with the pathogenesis of GH insufficiency of overweight OSA. In fact, obesity is connoted by an impairment of somatotroph secretion, reflecting a decrease in GH production rate (5, 9, 18). Besides clear reduction of spontaneous GH pulsatility (9, 18), obese patients also show a marked impairment of the somatotroph responsiveness to all provocative stimuli known so far (19, 20, 21). GH insufficiency in obesity could reflect neuroendocrine abnormalities, including somatostatinergic hyperactivity (22) and/or, more likely, GHRH hypoactivity (23, 24), although peripheral hormone abnormalities and/or metabolic factors can also be involved (25, 26, 27, 28, 29, 30). The original observation of this study is that obese OSA showed a more marked reduction of the maximal secretory capacity of somatotroph cells, suggesting that factors other than obesity affect somatotroph activity in OSAS. Accordingly, the reduction of nocturnal GH secretion of overweight OSA is reversed by nCPAP, before any significant variation in body weight occurs (7, 8). Notice that in the present study a slight difference, although not significant, between groups in terms of BMI was present, OSA showing BMI levels lower than OB; this fact, however, would have predicted more marked GH response in OSAS, but the opposite occurred.

Together with GH insufficiency, obese OSA are connoted by a marked reduction in IGF-I levels; this reduction is associated with disease severity but not with age or adiposity (6). On the other hand, despite marked GH insufficiency, total IGF-I levels in OB are generally normal or slightly reduced (10), whereas free IGF-I levels are even elevated (27, 31), thus suggesting an increased peripheral GH sensitivity (32). This has been confirmed in a recent study in which women with OB show enhanced IGF-I response to a very low rhGH dose (33). Notice that nCPAP has been found able to restore IGF-I levels in OSA before any variation in body weight occurred (6).

Altogether, these findings suggest the hypothesis that OSAS per se impairs GH/IGF-I axis activity, independently of adiposity. This hypothesis is fully demonstrated by the present study, which shows a clear difference in the functional profile of GH/IGF-I axis between obese patients with and without OSAS. In fact, obese OSA showed a greater reduction in the GH response to a provocative test as potent and reproducible as GHRH plus ARG (11) coexisting with lower basal IGF-I levels that showed scarce sensitivity to the stimulatory effect of a very low rhGH dose.

OSA were older than subjects with OB, and it is known that spontaneous GH and IGF-I secretion undergo an age-related reduction (34, 35). However, after adjusting for age, OSA still showed the impairment of GH/IGF-I parameters. Moreover, it has already been demonstrated that the GH response to GHRH plus ARG and the sensitivity to rhGH are both independent of aging (11, 35, 36).

In the present study, we did not measure sex steroid levels. Actually, it has been demonstrated that testosterone has positive influence on IGF-I synthesis and release, whereas estradiol positively influences GH secretion but negatively affects IGF-I synthesis and release, at least at pharmacological doses (37, 38). It is also accepted that obesity in males is associated with a relative hypoandrogenic state (39). Moreover, there is evidence that OSA show more severe impairment in sex steroid secretion with respect to OB, and the more severe OSAS is, the more severe the impairment of gonadal axis seems to be (6), although discordant evidence is present (40). The possibility that the peculiar alteration in the activity of GH/IGF-I axis in OSAS reflects some gonadal alteration is, however, at present only speculative.

Insulin resistance can be proposed to explain the impairment of GH/IGF-I axis activity in OSAS. In fact, insulin is able to inhibit GH synthesis and secretion (41) and to enhance GH-induced hepatic IGF-I production (42). We did not find significant difference in terms of insulin levels between OSA and OB, and this would seem against the hypothesis that insulin resistance plays a major role in the peculiar alteration of GH/IGF-I axis we found in OSA. However, it is widely accepted that OSA have insulin resistance (43) and that sleep apnea is more frequent in disorders connoted by insulin resistance, e.g. polycystic ovary syndrome (44). It could be that in the present study insulin levels in OSAS were not significantly different from those in OB just because the obese group was characterized by a slight difference in BMI. Thus, the possibility that insulin resistance plays a role in the peculiar alterations of GH/IGF-I axis in OSAS is open.

The mechanisms controlling sleep and GH secretion are tightly associated (45, 46, 47), and the amplification of somatotroph secretion during sleep, e.g. III-IV stages, is well known (48). Qualitative and quantitative sleep alterations in OSAS have been well demonstrated (49); they are associated with the reduction of GH/IGF-I secretion (50), and both are improved by nCPAP treatment (6, 7). Thus, sleep-related alterations of the neuroendocrine control of GH secretion could also contribute to the peculiar impairment of GH release in obese OSA.

Finally, hypoxia itself might further impair both somatotroph function and the peripheral sensitivity to GH. In fact, recent evidence in animals shows that acute as well as prolonged hypoxia reduces GH synthesis and release (51). Moreover, hypoxia reduces IGF-I mRNA expression in endothelial cells in vitro (52), and low IGF-I levels have been shown in patients with ischemic dilated cardiomyopathy (53). Indeed, in the present study, IGF-I levels in OSAS showed a trend toward negative association with the AHI.

In conclusion, obese OSA show a peculiar reduction of the maximal secretory capacity of somatotroph cells coupled with reduced IGF-I sensitivity to stimulation with a very low rhGH dose. These findings suggest that OSAS is connoted by concomitant impairment of GH secretion and peripheral sensitivity, which can both be responsible for metabolic alterations, increasing the risk of cardiovascular events as well as mortality (54).

Acknowledgments

We thank Prof. F. Camanni for his support; Drs. G. Aimaretti, S. E. Oleandri, G. Corneli, L. Di Vito, and M. Procopio for their participation in the study; and Mrs. M. Taliano for her skillful technical assistance.

Footnotes

The present study was supported by the University of Turin, Ministero dell’Università e della Ricerca Scientifica e Tecnologica, and Fondazione per lo Studio delle Mallattie Endocrino Metaboliche.

Abbreviations: AHI, Apnea/hypopnea index; ARG, arginine; AUC, area under the curve; BMI, body mass index; IGFBP-3, IGF binding protein-3; nCPAP, nasal continuous positive airway pressure; NS, normal subjects; OB, patients with simple obesity; OSA, patients with OSAS; OSAS, obstructive sleep apnea syndrome; rh, recombinant human; SaO2, oxyhemoglobin saturation; WHR, waist to hip ratio.

Received August 31, 2001.

Accepted July 26, 2002.

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