Clinical Endocrinology (2004) 60, 41–48
doi: 10.1046/j.1365-2265.2003.01938.x
Obese patients with obstructive sleep apnoea syndrome
show a peculiar alteration of the corticotroph but not of
the thyrotroph and lactotroph function
Blackwell Publishing Ltd.
F. Lanfranco*, L. Gianotti*, S. Pivetti†, F. Navone†,
R. Rossetto*, F. Tassone*, V. Gai†, E. Ghigo* and
M. Maccario*
*Division of Endocrinology and Metabolism, Department
of Internal Medicine, University of Turin, †Emergency
Department-Emergency Medicine, A.O. S.G. Battista,
Molinette Hospital, Turin, Italy
(Received 17 April 2003; returned for revision 19 May 2003;
finally revised 11 September 2003; accepted 22 September 2003)
Summary
OBJECTIVE Obstructive sleep apnoea syndrome (OSAS)
is strongly associated with obesity (OB) and is characterized by several changes in endocrine functions,
e.g. GH/IGF-I axis, adrenal and thyroid activity. It is still
unclear whether these alterations simply reflect overweight or include peculiar hypoxia-induced hormonal
alterations. Hormonal evaluations have been generally
performed in basal conditions but we have recently
reported that OSAS is characterized by a more severe
reduction of the GH releasable pool in comparison to
simple obesity. We aimed to extend our evaluation of
anterior pituitary function to corticotroph, thyrotroph
and lactotroph secretion under dynamic testing in OSAS
in comparison with simply obese and normal subjects.
SUBJECTS AND METHODS In 15 male patients with
OSAS [age, mean ± SEM 43·5 ± 1·6 years; body mass
index (BMI) 39·2 ± 3·1 kg /m2; apnoea /hypopnoea index,
(AHI) 53·4 ± 8·7], 15 male patients with simple obesity
(OB, age 39·7 ± 1·2 years; BMI 41·2 ± 2·0 kg /m2; AHI
3·1 ± 1·2 events/h of sleep) and in 15 normal lean male
subjects (NS, age 38·2 ± 1·4 years; BMI 21·2 ± 0·8 kg/
m2; AHI 1·9 ± 0·8 events /h of sleep) we evaluated: (a)
the ACTH and cortisol responses to CRH [2 µg / kg intravenously (i.v.)] and basal 24 h UFC levels; (b) the TSH
and PRL responses to TRH (5 µg /kg iv) as well as FT3
and FT4 levels.
Correspondence: Mauro Maccario, Division of Endocrinology and
Metabolism, Department of Internal Medicine, University of Turin,
Corso Dogliotti 14, 10126 Torino, Italy. Tel.: +39 011 633 4317;
Fax: +39 011 664 7421; E-mail: [email protected]
© 2004 Blackwell Publishing Ltd
RESULTS Twenty-four-hour UFC levels in OSAS and
OB were similar and within the normal range. Basal
ACTH and cortisol levels were similar in all groups.
∆peak:
However, the ACTH response to CRH in OSAS (∆
30·3 ± 3·8 pmol/l; ∆AUC: 682·8 ± 128·4 pmol* h/ l) was
∆peak: 9·3 ± 1·4
markedly higher (P < 0·001) than in OB (∆
pmol/l; ∆AUC 471·5 ± 97·3 pmol*h/l), which, in turn, was
∆peak: 3·3 ± 0·9 pmol / l;
higher (P < 0·05) than in NS (∆
∆AUC 94·7 ± 76·7 pmol* h/l). On the other hand, the
cortisol response to CRH was not significantly different
in the three groups. Basal FT3 and FT4 levels as well
as the TSH response to TRH were similar in all groups.
Similarly, both basal PRL levels and the PRL response
to TRH were similar in the three groups.
CONCLUSIONS With respect to patients with simple
abdominal obesity, obese patients with OSAS show a
more remarkable enhancement of the ACTH response
to CRH but a preserved TSH and PRL responsiveness
to TRH. These findings indicate the existence of a peculiarly exaggerated ACTH hyper-responsiveness to CRH
that would reflect hypoxia- and/or sleep-induced alterations of the neural control of corticotroph function;
this further alteration is coupled to the previously
described, peculiar reduction of somatotroph function.
Obstructive sleep apnoea syndrome (OSAS) is a common disorder with important clinical consequences for affected individuals. It is characterized by repetitive episodes of upper airway
occlusion leading to apnoea and asphyxia, typically occurring
100–600 times/night, with arousal being required to re-establish
airway patency (Sullivan & Issa, 1980). The most important epidemiological risk factors for sleep apnoea are obesity and male
gender (Block et al., 1979; Davies & Stradling, 1990). In particular, the disorder is estimated to affect up to 7% of the adult
male population and its prevalence increases with advancing age,
though clinical severity of apnoea decreases (Sullivan & Issa,
1980; Bixler et al., 1998). The increased risk of sleep apnoea in
men compared to women is poorly understood, with prior
studies focusing on differences in airway anatomy (White et al.,
1985; Brown et al., 1986), pharyngeal dilator muscle function
(Grunstein, 1996) and ventilatory control mechanisms (Onal &
Lopata, 1982; Cherniak, 1984). OSAS is associated with daytime
41
42 F. Lanfranco et al.
somnolence, cardiovascular disease, decreased quality of life
and an increased risk of automobile accidents (Remmers et al.,
1978).
Like simple obesity, OSAS is characterized by several metabolic and endocrine abnormalities (Glass et al., 1981), including
insulin resistance, changes in the activity of GH /IGF-I axis
(Grunstein et al., 1989; Saini et al., 1993; Cooper et al., 1995),
adrenal (Cooper et al., 1995; Bratel et al., 1999), thyroid (Bratel
et al., 1999) and gonadal axis (Grunstein et al., 1989; Bratel
et al., 1999). These studies focused mostly on hormonal evaluations in basal conditions, while the GH /IGF-I axis has been
more extensively investigated. In OSAS as well as in obesity a
clear decrease in spontaneous and stimulated GH secretion
(Glass et al., 1981; Kopelman et al., 1985; Grunstein et al., 1989;
Veldhuis et al., 1991; Ghigo et al., 1992; Saini et al., 1993;
Cooper et al., 1995; Maccario et al., 1997) is coupled to normal
or low-normal IGF-I levels (Grunstein et al., 1989; Maccario
et al., 1999). However, we have recently demonstrated that, with
respect to simple obesity, OSAS is characterized by a more severe
impairment of the GH releasable pool surprisingly coupled to a
reduction of peripheral GH sensitivity (Gianotti et al., 2002).
These findings further triggered our interest about the endocrine function in OSAS; as a first step we therefore decided to
extend the evaluation of anterior pituitary function in these
patients by testing the corticotroph, thyrotroph and lactotroph
secretion under dynamic conditions.
A disrupted function of HPA axis has been described in patients
with simple obesity who show an ACTH hyper-responsiveness
to provocative stimuli and alterations in cortisol metabolism and
sensitivity (Pasquali et al., 1993; Weaver et al., 1993; Pasquali
et al., 1996; Arvat et al., 2000a; Arvat et al., 2000b; Tassone
et al., 2002). On the other hand, in OSAS an enhanced cortisol
secretion has been reported by some (Bratel et al., 1999) but not
by others (Grunstein et al., 1989).
Simple obesity is also associated with some derangement in
prolactin secretion and thyroid axis function. These would reflect
changes in body composition as they are usually reversed by
weight loss (Kopelman et al., 1979; Cavagnini et al., 1981; Weaver
et al., 1990; Lin et al., 1994; Winkelman et al., 1996; Kopelman,
2000). Studies on PRL secretion and thyroid axis in OSAS provided
conflicting results (Clark et al., 1979; Grunstein et al., 1989; Lin
et al., 1994; Winkelman et al., 1996; Bratel et al., 1999).
The impairment of pituitary function in OSAS could well be
due to factors other than simply overweight. It could depend upon
hypoxia and/or sleep fragmentation, which are peculiar to the
syndrome (Goodday et al., 2001). Supporting this hypothesis,
endocrine alterations are often reverted to normality after 3
months of nasal continuous positive airway pressure (nCPAP)
treatment without any change in body weight (Grunstein et al.,
1989). In fact, in OSAS spontaneous GH secretion, IGF-I, cortisol and testosterone levels too have been found restored by
nCPAP treatment independently of any change in body weight
(Grunstein et al., 1989; Saini et al., 1993; Cooper et al., 1995).
Based on the foregoing, in the present study we evaluated the
corticotroph, thyrotroph and lactotroph function under dynamic
stimulation by CRH and TRH in OSAS in comparison to patients
with simple obesity and normal subjects.
Subjects and methods
Subjects
The subjects who participated to this study were recruited in the
Outpatient Clinic for weight disorders of our Division among
obese patients. These subjects were reporting symptoms such as
nocturnal snoring and daytime sleepiness and fatigue, suggesting
possible sleep apnoea syndrome. After a polysomnographic study
was performed, the first consecutive 15 male patients with
OSAS aged 30–50 years [OSAS, age, mean ± SEM, 43·5 ± 1·6
years; body mass index (BMI) 39·2 ± 3·1 kg/m2; waist–hip ratio
(WHR) 1·05 ± 0·04; apnoea /hypopnoea index (AHI) 53·4 ± 8·7
events /h of sleep] and the first consecutive 15 male obese patients
without OSAS aged 30–50 years (OB, age 39·7 ± 1·2 years; BMI
41·2 ± 2·0 kg/m2; WHR 1·00 ± 0·02; AHI 3·1 ± 1·2 events / h of
sleep) were enrolled.
Fifteen normal lean male subjects aged 30–50 years (NS, age
38·2 ± 1·4 years; BMI 21·2 ± 0·8 kg/m2; WHR 0·89 ± 0·03; AHI
1·9 ± 0·8 events /h of sleep) were recruited among staff members
and studied as controls.
The present study follows our previous one focussed on the
function of GH/IGF-I axis in obese patients with OSAS; these
results have been already published elsewhere (Gianotti et al.,
2002). Thus, nine OSAS, 11 OB and 10 NS herein studied have
participated also in the previous investigation.
In all subjects we evaluated: (a) basal cortisol, ACTH and UFC
levels and the ACTH and cortisol responses to CRH (CRH
Ferring, Kiel, Germany, 2 µg/ kg i.v. at 0 min); (b) basal FT3, FT4,
TSH and PRL levels and the TSH and PRL responses to TRH
(TRH UCB, S.A. UCB N.V., Bruxelles, Belgium, 5 µg/ kg i.v. at
0 min).
Exclusion criteria included cardiopulmonary diseases, malignancies, recent surgery of the upper airways, diabetes mellitus,
thyroid disorders, glucocorticoid treatment, renal or hepatic failure.
Patients were also excluded if the period of sleep during polysomnographic study was fewer than 4 h or if they were diagnosed
or receiving medical treatment for sleep-disordered breathing.
All subjects underwent
Polysomnography. Sleep state and respiratory and cardiac variables
were assessed using a 16-channel polysomnographic recording
system (Compumedics Sleep, Abbotsford, Australia).
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41– 48
Pituitary function in sleep apnoea syndrome 43
All the patients and controls underwent a standard overnight
polysomnography (American Thoracic Society Consensus
Conference, 1989; AARC-APT, 1995) with continuously recording
of electroencephalogram, electromyogram and electrooculogram, electrocardiogram, nasal airflow, body position, thoracic
and abdominal respiratory efforts and arterial oxyhaemoglobin
saturation (SaO2) recorded by a pulse oximeter. Apnoea was
defined as cessation of airflow for at least 10 s; a reduction in
the amplitude of the ribcage and abdominal excursions with a
decrease in ventilation exceeding 50% that lasted at least 10 s
associated with a SaO2 reduction of at least 4% was defined as
hypopnoea.
The AHI was defined as the average number of episodes of
apnoea and hypopnoea per hour of sleep. The threshold of more
than five episodes of apnoea or hypopnoea per hour of sleep to
define OSAS was chosen according to the most recent recommendations (Littner, 2000).
All subjects gave their written informed consent to participate
to the study, which had been approved by the local Ethical
Committee.
Hormonal assays. In each subject the following variables were
studied:
• basal ACTH, cortisol, FT3, FT4, TSH and PRL levels;
• 24 hour urinary free cortisol (UFC);
• ACTH and cortisol responses to CRH (2 µg / kg i.v.);
• TSH and PRL responses to TRH (5 µg / kg i.v.);
CRH and TRH were injected consecutively between 08·30 and
09·00 h after an overnight fasting and 30 min after and 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 ACTH, cortisol, PRL and TSH levels were measured at
each time point.
Methods and characteristics of hormonal evaluations are
reported in Table 1.
All samples from the same subject were analysed together.
Statistical analysis
Data are expressed as mean (± SEM) of absolute values, delta
peaks and delta areas under curves (∆AUC) calculated by
trapezoidal integration.
The statistical analysis of the data was carried out by anova,
ancova using age and basal hormonal values as covariates where
appropriate, Newman–Keuls test as posthoc analysis, where
appropriate.
Results
BMI in OSAS and OB was similar (39·2 ± 3·1 and 41·2 ± 2·0 kg/
m2) and in both groups it was higher than in NS (21·2 ± 0·8 kg/
m2, P < 0·005). Similarly, WHR in OSAS and OB did not differ
(1·05 ± 0·04 and 1·00 ± 0·02) and in both groups it was higher
Table 1 Hormonal evaluations: methods and characteristics
Hormone
Assay and supplier
ACTH (pmol/l)
IRMA
Allegro HS-ACTH
Nichols Institute, Diagnostics, San Juan
Capistrano, USA
RIA
CORT-CTK 125, Sorin, Saluggia, Italy
RIA
Biodata Diagnostics, s.p.a., Guidonia
Montecelio (RM), Italy
RIA
Techno Genetics, Cassina de’ Pecchi
(MI), Italy
RIA
Techno Genetics, Cassina de’ Pecchi
(MI), Italy
IRMA
TSH IRMA C.T., Biocode, Liege, Belgium
IRMA
PROLCTK, Sorin, Saluggia, Italy
Cortisol (nmol/l)
UFC (nmol/day)
Free T3 (pmol/l)
Free T4 (pmol/l)
TSH (mU/l)
PRL (µg/l)
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41–48
Interassay
coefficient of
variation (%)
Intra-assay
coefficient of
variation (%)
Sensitivity
2·4–8·9
3·9–9·9
0·22 pmol/l
6·6–7·5
3·8–6·6
11·0 nmol/l
1·80–9·17
3·24–4·62
7·36 nmol/l
4·2–7·4
3·2–4·0
0·46 pmol/l
6·6–8·7
2·6–7·3
0·39 pmol/l
4·2–7·1
4·0–6·2
0·05 mU/l
3·1–5·8
0·9–5·8
0·45 µg/l
44 F. Lanfranco et al.
Table 2 Polysomnographic features of OSAS, OB and NS
OSAS
OB
NS
AHI (events/h sleep)
53·4 ± 8·7
3·1 ± 1·2
1·9 ± 0·8
Mean SaO2 (%)
85·3 ± 1·9
92·9 ± 1·1
96·4 ± 0·8
Minimum SaO2 (%)
70·3 ± 1·8
85·2 ± 2·4
87·3 ± 2·1
269·6 ± 40·3
288·5 ± 29·4
326·2 ± 28·5
97·8 ± 1·2
92·6 ± 2·0
80·2 ± 3·0
REM sleep time (%)
3·6 ± 1·5
6·3 ± 2·4
17·8 ± 3·2
Stage 1 (%)
8·7 ± 1·2
6·6 ± 2·2
5·7 ± 1·2
Stage 2 (%)
34·8 ± 5·4
32·3 ± 5·6
36·3 ± 3·6
Stage 3 (%)
45·4 ± 5·5
44·5 ± 5·0
35·4 ± 5·2
Stage 4 (%)
6·6 ± 2·4
9·3 ± 2·5
5·2 ± 1·4
27·4 ± 3·2
7·3 ± 1·4
8·5 ± 1·4
Total sleep time (min)
Non-REM sleep time (%)
Arousals (events/h sleep)
P-value
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
< 0·001
< 0·001
n.s.
< 0·005
< 0·001
n.s.
< 0·005
< 0·005
n.s.
n.s.
n.s.
n.s.
n.s.
< 0·005
< 0·005
n.s.
< 0·005
< 0·005
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
< 0·005
< 0·005
n.s.
REM, rapid eye movement; n.s., not significant; OSAS, obstructive sleep apnoea syndrome; OB, obesity; NS, normal subjects.
than in NS (0·89 ± 0·03, P < 0·001). No significant age difference
was recorded between the three groups studied.
Polysomnographic features of the three groups are reported in
Table 2.
Twenty-four-hour UFC levels in OSAS and OB were similar
to those in normal subjects (Table 3). Moreover, basal ACTH
and cortisol levels were similar in all groups (6·47 ± 1·45 vs.
3·55 ± 0·75 vs. 5·57 ± 1·01 pmol/l and 250·5 ± 25·7 vs. 225·1
± 30·6 vs. 326·9 ± 24·0 nmol/l, in OSAS, OB and NS, respectively;
Table 3).
Basal FT3, FT4 and TSH levels were similar in the three groups
(5·0 ± 0·2 pmol/l; 16·3 ± 1·3 pmol/l; 1·1 ± 0·22 mU/l in OSAS;
4·4 ± 1·7 pmol/l; 14·2 ± 1·4 pmol/l; 0·74 ± 1·1 mU/l in OB; 4·7
± 0·2 pmol/l; 17·6 ± 0·7 pmol/l; 1·1 ± 0·1 mU/l in NS; Table 3).
Similarly, basal PRL levels were similar in all groups (5·4 ± 0·6,
7·2 ± 1·6 and 5·0 ± 0·7 µg /l in OSAS, OB and NS, respectively;
Table 3).
The ACTH response to CRH in both OB and OSAS was
significantly higher (P < 0·05 and 0·001, respectively) than that
in NS (∆peak: 3·3 ± 0·9 pmol/l; ∆AUC 94·7 ± 76·7 pmol*h/ l)
while all groups showed a similar cortisol response (∆peak: 292·5
± 36·9, 276·2 ± 43·6 and 193·7 ± 128·6 nmol/l, ∆AUC: 14 520·1
± 2498·6, 15 806·9 ± 2857·8, 100 14·6 ± 2588·5 nmol*h/l in
OSAS, OB and NS, respectively) although a trend toward a
greater cortisol increase was evident in both groups of obese
subjects. The ACTH response to CRH in OSAS was even higher
(P < 0·001) than in OB (∆peak: 30·3 ± 3·8 vs. 9·3 ± 1·4 pmol / l;
∆AUC: 682·8 ± 128·4 pmol*h/l vs. ∆AUC 471·5 ± 97·3 pmol*h/ l;
Fig. 1).
No significant difference was evident among OSAS, OB and
NS in term of TSH response to TRH (∆peak: 10·0 ± 2·2, 6·8 ± 0·9
and 9·9 ± 3·0 mU/l; ∆AUC: 490·6 ± 94·6, 352·2 ± 47·6 and
445·6 ± 64·9 mU*h/l in OSAS, OB and NS, respectively; Fig. 2).
Moreover, OSAS, OB and NS showed a similar PRL response
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41– 48
Pituitary function in sleep apnoea syndrome 45
Table 3 Basal UFC, ACTH, Cortisol, FT3, FT4, TSH and PRL levels in OSAS, OB and NS
OSAS
OB
NS
UFC (nmol/day)
194·2 ± 22·6
189·5 ± 27·9
171·9 ± 22·6
ACTH (pmol/l)
6·47 ± 1·45
3·55 ± 0·75
5·57 ± 1·01
cortisol (nmol/l)
250·5 ± 25·7
225·1 ± 30·6
326·9 ± 24·0
FT3 (pmol/l)
5·0 ± 0·2
4·4 ± 1·7
4·7 ± 0·2
FT4 (pmol/l)
16·3 ± 1·3
14·2 ± 1·4
17·6 ± 0·7
TSH (mU/l)
1·1 ± 0·22
0·74 ± 1·1
1·1 ± 0·1
PRL (µg/l)
5·4 ± 0·6
7·2 ± 1·6
5·0 ± 0·7
P-value
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
OSAS vs OB
OSAS vs NS
OB vs NS
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s., not significant; OSAS, obstructive sleep apnoea syndrome; OB, obesity; NS, normal subjects.
Fig. 1 Mean (± SEM) ACTH and cortisol responses
expressed as ∆ change above baseline (left panels)
and ∆AUC (right panels) to CRH (2 µg / kg i.v. at
0 min) in OSAS (), OB () and NS ().
to TRH (∆peak: 30·3 ± 7·5, 31·1 ± 9·9 and 20·7 ± 3·1 µg/l;
∆AUC: 1183·9 ± 280·3, 1114·7 ± 357·3 and 838·2 ± 107·0 µg*h/
l in OSAS, OB and NS, respectively; Fig. 2).
BMI, AHI and SaO2 in OSAS did not associate to any of the
hormonal parameters.
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41–48
Side-effects
A transient facial flushing, tachicardia and urinary urgency was
observed in nine OSAS, 10 OB and 12 NS after CRH and TRH
administration.
46 F. Lanfranco et al.
Fig. 2 Mean (± SEM) PRL and TSH responses
expressed as ∆ change above baseline (left panels)
and ∆ AUC (right panels) to TRH (5 µg / kg i.v. at
0 min) in OSAS (), OB () and NS ().
Discussion
The results of the present study demonstrate that, with respect
to patients with simple obesity, obese patients with OSAS show
a more remarkable ACTH response to CRH, while both thyrotroph and lactotroph secretion are preserved.
We have recently demonstrated that, in comparison to patients
with simple obesity, obese patients with OSAS show a more
marked reduction of GH response to a provocative stimulus as
potent and reproducible as GHRH plus arginine; this severe
reduction of the GH releasable pool was surprisingly coupled
with a reduced peripheral sensitivity to GH (Gianotti et al.,
2002). These findings supported the hypothesis that OSAS is a
clinical condition characterized by peculiar hormonal abnormalities that cannot simply be explained as the result of weight
excess; hypoxia and/or sleep fragmentation could play a role
causing peculiar neurohormonal alterations.
Besides a deeper GH insufficiency, we now demonstrate that
OSAS patients show a corticotroph hyper-responsiveness to
CRH that, in fact, is even more remarkable than that occurring
in patients with simple obesity.
The presence of an exaggerated ACTH response to provocative
stimuli in simple obesity has been already shown by several studies addressing the corticotroph responsiveness to CRH and/or
AVP as well as glucagon (Pasquali et al., 1993, 1996; Weaver
et al., 1993; Arvat et al., 2000a). The mechanisms underlying
this hyper-responsiveness in obesity are still unclear but would
reflect alterations in the neurotransmitter control of ACTH and
POMC secretion and action as well as an impaired sensitivity
to the negative feedback action of glucocorticoids (Cone, 1999;
Bjorntorp & Rosmond, 2000). Metabolic alterations such as
chronic elevation in FFA levels and insulin resistance could also
play a role altering in opposite ways both corticotroph and
somatotroph function (Maccario et al., 1995; Widmaier et al.,
1995; Morishita et al., 2000).
Once again, the evidence that OSAS patients show an even
more remarkable ACTH hyper-responsiveness than patients with
simple obesity indicates that factors other than obesity per se
have a role in this clinical condition.
Hypoxia itself is likely to directly or indirectly play a critical
role. In fact, hypoxia has been shown able to reduce GH synthesis
and release in animals (Nelson & Cons, 1975; Nessi & Bozzini,
1982; Zhang & Du, 2000) and to induce hypothalamic–pituitary–
adrenal (HPA) axis activation both in animals and in humans
(Raff et al., 1981; Matthews & Challis, 1995; Chen & Du, 1996;
Basu et al., 2002). Thus, an hypoxic state is likely to represent
a stressful condition that, in turn, would well trigger HPA axis.
Qualitative and quantitative sleep alterations in OSAS have
been well demonstrated (Bradley & Phillipson, 1985) and are
improved by nCPAP treatment (Grunstein et al., 1989; Saini
et al., 1993). Thus, sleep-related alterations of the neuroendocrine control of anterior pituitary function could contribute to the
peculiar, opposite alteration of ACTH and GH secretion in obese
patients with OSAS.
Differently from some (Pasquali et al., 1999) but not from
other studies (Arvat et al., 2000b; Tassone et al., 2002), ACTH
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41– 48
Pituitary function in sleep apnoea syndrome 47
hyper-responsiveness to provocative stimulation was uncoupled
to the enhancement of the cortisol response. This agrees with the
evidence that cortisol secretion is somehow independent of
ACTH stimulation (Oelkers, 1996; Arvat et al., 2000c; Maccario
et al., 2000) and could reflect a more extensive disturbance in
the control of POMC and related peptides such as melanocortins
and agouti-related peptides. These latter are important mediators
in the regulation of feeding behaviour, insulin levels and body
weight (Cone, 1999; Boston, 2001). Moreover, the absence of
cortisol hypersecretion in association to the enhanced ACTH
response to CRH could reflect a reduced adrenal sensitivity to
ACTH even more marked in OSAS than in simple obesity.
Finally, our results do not show any alteration of either thyrotroph or lactotroph function, in agreement with some but not
other studies; in fact, some derangement in TSH or PRL secretion
in obesity with or without OSAS has been demonstrated after
administration of different stimuli, such as arginine or insulininduced hypoglycaemia (Clark et al., 1979; Kopelman et al.,
1979; Cavagnini et al., 1981; Chomard et al., 1985; Grunstein
et al., 1989; Weaver et al., 1990; Bratel et al., 1999; Roti et al.,
2000).
In conclusion, with respect to patients with simple abdominal
obesity, obese patients with OSAS show a more remarkable
enhancement of the ACTH response to CRH but a preserved TSH
and PRL responsiveness to TRH. These findings indicate the existence of a peculiarly exaggerated ACTH hyper-responsiveness
to CRH that would reflect hypoxia- and/or sleep-induced alterations of the neural control of corticotroph function; this further
alteration is coupled to the previously described, peculiar reduction
of somatotroph function.
References
AARC-APT (1995) clinical Practice Guideline: Polysomnography. Respiratory Care, 40, 1336–1343.
American Thoracic Society. (1989) Consensus Conference on Indications and Standards for Cardiopulmonary Sleep Study. American
Review of Respiratory Disease, 139, 559–568.
Arvat, E., Maccagno, B., Ramunni, J., Giordano, R., Broglio, F., Gianotti,
L., Maccario, M., Camanni, F. & Ghigo, E. (2000a) Interaction
between glucagon and human corticotropin-releasing hormone or
vasopressin on ACTH and cortisol secretion in humans. European
Journal of Endocrinology, 143, 99–104.
Arvat, E., Maccagno, B., Ramunni, J., Giordano, R., Di Vito, L., Broglio,
F., Maccario, M., Camanni, F. & Ghigo, E. (2000b) Glucagon is an
ACTH secretagogue as effective as hCRH after intramuscular administration while it is ineffective when given intravenously in normal
subjects. Pituitary, 3, 169–173.
Arvat, E., Di Vito, L., Lanfranco, F., Maccario, M., Baffoni, C., Rossetto,
R., Aimaretti, G., Camanni, F. & Ghigo, E. (2000c) Stimulatory effect
of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: dose–response study.
Journal of Clinical Endocrinology and Metabolism, 85, 3141–
3146.
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41–48
Basu, M., Sawhney, R.C., Kumar, S., Pal, K., Prasad, R. & Selvamurthy, W. (2002) Hypothalamic–pituitary–adrenal axis following
glucocorticoid prophylaxis against acute mountain sickness. Hormone
and Metabolic Research, 34, 318–324.
Bixler, E.O., Vgontzas, A.N., Ten Have, T., Tyson, K. & Kales, A. (1998)
Effects of age and sleep apnea in men. I. Prevalence and severity.
American Journal of Respiratory and Critical Care Medicine, 157,
144–148.
Bjorntorp, P. & Rosmond, R. (2000) Obesity and cortisol. Nutrition, 16,
924–936.
Block, A.J., Boysen, P.G., Wynne, J.W. & Hunt, L.W. (1979) Sleep apnea,
hypopnea and oxygen desaturation in normal subjects: a strong male
predominance. New England Journal of Medicine, 300, 513–517.
Boston, B.A. (2001) Pro-opiomelanocortin and weight regulation: from
mice to men. Journal of Pediatric Endocrinology and Metabolism, 14,
1409–1416.
Bradley, T.D. & Phillipson, E.A. (1985) Pathogenesis and pathophysiology of obstructive sleep apnoea syndrome. Medical Clinics of North
America, 69, 1169–1185.
Bratel, T., Wennlund, A. & Carlstrom, K. (1999) Pituitary reactivity,
androgens and catecholamines in obstructive sleep apnea. Effects of
continuous positive airway pressure treatment (CPAP). Respiratory
Medicine, 93, 1–7.
Brown, I.G., Zamel, N. & Hoffstein, V. (1986) Pharyngeal cross-sectional
area in normal men and women. Journal of Applied Physiology, 61,
890–895.
Cavagnini, F., Maraschini, C., Pinto, M., Dubini, A. & Polli, E.E. (1981)
Impaired prolactin secretion in obese patients. Journal of Endocrinological Investigation, 4, 149–153.
Chen, Z. & Du J.Z. (1996) Hypoxia effects on hypothalamic corticotropin-releasing hormone and anterior pituitary cAMP.
Zhongguo Yao Li Xue Bao, 17, 489–492.
Cherniak, N. (1984) Sleep apnea and its causes. Journal of Clinical Investigation, 73, 1501–1506.
Chomard, P., Vernhes, G., Autissier, N. & Debry, G. (1985) Serum
concentrations of total T4, T3, reverse T3 and free T4, in moderately
obese patients. Human Nutrition. Clinical Nutrition, 39, 371–378.
Clark, R.W., Schmidt, H.S. & Malarkey, W.B. (1979) Disordered growth
hormone and prolactin secretion in primary disorders of sleep.
Neurology, 29, 855–861.
Cone, R.D. (1999) The Central Melanocortin System and Energy Homeostasis. Trends in Endocrinology and Metabolism, 10, 211–216.
Cooper, B.G., White, J.E.S., Ashworth, L.A., Alberti, K.G. & Gibson,
G.J. (1995) Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the acute effects of nasal continuous
positive airway pressure (CPAP) treatment. Sleep, 18, 172–179.
Davies, R.J. & Stradling, J.R. (1990) The relationship between neck
circumference, radiographic pharyngeal anatomy, and the obstructive
sleep apnea syndrome. European Respiratory Journal, 3, 509–514.
Ghigo, E., Procopio, M., Boffano, G.M., Arvat, E., Valente, F., Maccario,
M., Mazza, E. & Camanni, F. (1992) Arginine potentiates but does
not restore the blunted growth hormone response to growth hormone
releasing hormone in obesity. Metabolism, 41, 560–563.
Gianotti, L., Pivetti, S., Lanfranco, F., Tassone, F., Navone, F., Vittori, E.,
Rossetto, R., Gauna, C., Destefanis, S., Grottoli, S., De Giorgi,
R., Gai, V., Ghigo, E. & Maccario, M. (2002) Concomitant impairment
of growth hormone secretion and peripheral sensitivity in obese
patients with obstructive sleep apnea syndrome. Journal of Clinical
Endocrinology and Metabolism, 87, 5052–5057.
Glass, A.R., Burman, K.D., Dahms, W.T. & Boehm, T.M. (1981) Endocrine function in human obesity. Metabolism, 130, 89–104.
48 F. Lanfranco et al.
Goodday, R.H.B., Precious, D.S., Morrison, A.D. & Robertson, C.G.
(2001) Obstructive sleep apnea syndrome: diagnosis and management.
Journal of the Canadian Dental Association, 67, 652–658.
Grunstein, R.R. (1996) Metabolic aspects of sleep apnea. Sleep, 19,
S218–S220.
Grunstein, R.R., Handelsman, D.J., Lawrence, S.J., Blackwell, C.,
Caterson, J. & Sullivan, C.E. (1989) Neuroendocrine dysfunction in
sleep apnea: reversal by continuous positive airways pressure therapy.
Journal of Clinical Endocrinology and Metabolism, 68, 352–358.
Kopelman, P.G. (2000) Physiopathology of prolactin secretion in obesity.
International Journal of Obesity and Related Metabolic Disorders, 24,
S104–S108.
Kopelman, P.G., White, N., Pilkington, T.R. & Jeffcoate, S.L. (1979)
Impaired hypothalamic control of prolactin secretion in massive obesity. Lancet, 7, 747–750.
Kopelman, P.G., Noonan, K., Guolton, R. & Forrest, A.J. (1985) Impaired
growth hormone response to growth hormone releasing factor and
insulin-hypoglycemia in obesity. Clinical Endocrinology, 23, 87–94.
Lin, C.C., Tsan, K.W. & Chen, P.J. (1994) The relationship between sleep
apnea syndrome and hypothyroidism. Chest, 105, 1296–1297.
Littner, M. (2000) Polysomnography in the diagnosis of the obstructive
sleep apnea–hypopnea syndrome: where do we draw the line? Chest,
118, 286–288.
Maccario, M., Procopio, M., Grottoli, S., Oleandri, S.E., Razzore, P.,
Camanni, F. & Ghigo, E. (1995) In obesity the somatotrope response
to either growth hormone-releasing hormone or arginine is inhibited
by somatostatin or pirenzepine but not by glucose. Journal of Clinical
Endocrinology and Metabolism, 80, 3774–3778.
Maccario, M., Valetto, M.R., Savio, P., Aimaretti, G., Baffoni, C., Procopio, M., Grottoli, S., Oleandri, S.E., Arvat, E. & Ghigo, E. (1997)
Maximal secretory capacity of somatotrope cells in obesity: comparison with GH deficiency. International Journal of Obesity and
Related Metabolic Disorders, 21, 27–32.
Maccario, M., Ramunni, J., Oleandri, S.E., Procopio, M., Grottoli, S.,
Rossetto, R., Savio, P., Aimaretti, G., Camanni, F. & Ghigo, E. (1999)
Relationships between IGF-I and age, gender, body mass, fat
distribution, metabolic and hormonal variables in obese patients.
International Journal of Obesity and Related Metabolic Disorders, 23,
612–618.
Maccario, M., Grottoli, S., Di Vito, L., Rossetto, R., Tassone, F.,
Ganzaroli, C., Oleandri, S.E., Arvat, E. & Ghigo, E. (2000) Adrenal
responsiveness to high, low and very low ACTH 1–24 doses in obesity.
Clinical Endocrinology, 53, 437–444.
Matthews, S.G. & Challis, J.R. (1995) Regulation of CRH and AVP mRNA
in the developing ovine hypothalamus. effects of stress and glucocorticoids. American Journal of Physiology, 268, E1096 –E1107.
Morishita, M., Iwasaki, Y., Yamamori, E., Nomura, A., Mutsuga, N.,
Yoshida, M., Asai, M., Olso, Y. & Saito, H. (2000) Antidiabetic
sulfonylurea enhances secretagogue-induced adrenocorticotropin
secretion and proopiomelanocortin gene expression in vitro.
Endocrinology, 141, 3313–3318.
Nelson, M.L. & Cons, J.M. (1975) Pituitary hormones and growth
retardation in rats raised at simulated high altitude (3800 m). Environmental Physiology and Biochemistry, 5, 273–282.
Nessi, A.C. & Bozzini, C.E. (1982) Ultrastructural changes in somatotropic cells induced by anemic or hypoxic hypoxia. Acta Physiologica
Latino Americana, 32, 175–183.
Oelkers, W. (1996) Dose–response aspects in the clinical assessment of
the hypothalamo–pituitary–adrenal axis, and the low-dose adrenocorticotropin test. European Journal of Endocrinology, 135, 27–33.
Onal, E. & Lopata, M. (1982) Periodic breathing and the pathogenesis
of occlusive sleep apneas. American Review of Respiratory Disease,
126, 676–680.
Pasquali, R., Cantobelli, S., Casimirri, F., Capelli, M., Bortoluzzi, L.,
Flamia, R., Labate, A.M. & Barbara, L. (1993) The hypothalamicpituitary-adrenal axis in obese women with different patterns of body
fat distribution. Journal of Clinical Endocrinology and Metabolism,
77, 341–346.
Pasquali, R., Anconetani, B., Chattat, R., Biscotti, M., Spinucci, G.,
Casimirri, F., Vicennati, V., Carcello, A. & Labate, A.M. (1996)
Hypothalamic-pituitary-adrenal axis activity and its relationship to
the autonomic nervous system in women with visceral and subcutaneous obesity: effects of the corticotropin-releasing factor/argininevasopressin test and of stress. Metabolism, 45, 351–356.
Pasquali, R., Gagliardi, L., Vicennati, V., Gambineri, A., Colitta, D.,
Ceroni, L. & Casimirri, F. (1999) ACTH and cortisol response to combined corticotropin releasing hormone-arginine vasopressin stimulation in obese males and its relationship to body weight, fat distribution
and parameters of the metabolic syndrome. International Journal of
Obesity and Related Metabolic Disorders, 23, 419–424.
Raff, H., Tzankoff, S.P. & Fitzgerald, R.S. (1981) ACTH and cortisol
responses to hypoxia in dogs. Journal of Applied Physiology, 51,
1257–1260.
Remmers, J.E., deGroot W.J., Sauerland E.K. & Anch A.M. (1978)
Pathogenesis of upper airway occlusion during sleep. Journal of
Applied Physiology, 44, 931–938.
Roti, E., Minelli, R. & Salvi, M. (2000) Thyroid hormone metabolism
in obesity. International Journal of Obesity and Related Metabolic
Disorders, 24, S113–S115.
Saini, J., Krieger, J., Brandenberger, G., Wittersheim, G. & Follenius, M.
(1993) Continuous positive airway pressure treatment effects on
growth hormone, insulin, and glucose profiles in obstructive sleep
apnoea patients. Hormone and Metabolic Research, 25, 375–381.
Sullivan, C.E. & Issa, F.C. (1980) Pathophysiological mechanism in
obstructive sleep apnea. Sleep, 3, 235–246.
Tassone, F., Grottoli, S., Rossetto, R., Maccagno, B., Gauna, C.,
Giordano, R., Ghigo, E. & Maccario, M. (2002) Glucagon administration elicits blunted GH but exaggerated ACTH response in obesity.
Journal of Endocrinological Investigation, 25, 551–556.
Veldhuis, J.D., Iranmanesh, A., Ho, K.K., Waters, M.J., Johnson, M.L.
& Lizarralde, G. (1991) Dual defects in pulsatile growth hormone
secretion and clearances subserve the hyposomatropism of obesity in
man. Journal of Clinical Endocrinology and Metabolism, 72, 51–59.
Weaver, J.U., Noonan, K., Kopelman, P.G. & Coste, M. (1990) Impaired
prolactin secretion and body fat distribution in obesity. Clinical Endocrinology, 32, 641–646.
Weaver, J.U., Kopelman, P.G., McLoughlin, L., Forsling, M.L. &
Grossman, A. (1993) Hyperactivity of the hypothalamo–pituitary–
adrenal axis in obesity: a study of ACTH, AVP, beta-lipotrophin and
cortisol responses to insulin-induced hypoglycaemia. Clinical
Endocrinology, 39, 345–350.
White, D.P., Lombard, R.M., Cadieux, R.J. & Zwillich, C.W. (1985)
Pharyngeal resistance in normal humans: influence of gender, age and
obesity. Journal of Applied Physiology, 58, 365–371.
Widmaier, E.P., Margenthaler, J. & Sarel, I. (1995) Regulation of
pituitary–adrenocortical activity by free fatty acids in vivo and in vitro.
Prostaglandins, Leukotrienes, and Essential Fatty Acids, 52, 179–183.
Winkelman, J.W., Goldman, H., Piscatelli, N., Lukas, S.E., Dorsey, C.M.
& Cunningham, S. (1996) Are thyroid function tests necessary in
patients with suspected sleep apnea? Sleep, 19, 790–793.
Zhang, Y.S. & Du, J.Z. (2000) The response of growth hormone and
prolactin of rats to hypoxia. Neuroscience Letters, 279, 137–140.
© 2004 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 41– 48