38th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: Granada, Spain, April 7-8, 2006 (Hormone Research)

229 Pages·2007·4.37 MB·English

by  H. P. F. Koppeschaar

HORMONE
RESEARCH
38th International Symposium on
Growth Hormone and Growth Factors
in Endocrinology and Metabolism
Granada, Spain, April 7–8, 2006
Guest Editors
Hans P.F. Koppeschaar, Utrecht
Torsten Tuvemo, Uppsala
Peter Trainer, Manchester
Philip Zeitler, Denver, Colo.
80 figures, 33 in color, and 35 tables, 2007
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ogy and Metabolism, the organization of the program was devel-
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Vol. 67, Suppl. 1, 2007
HORMONE
RESEARCH
Contents
1 Foreword KIGS Highlights
43 KIGS Highlights
Plenary Lecture 1
Darendeliler, F. (Istanbul); Ferrández Longás, Á. (Zaragoza)
2 Impact of Sleep and Sleep Loss on Neuroendocrine and 45 Noonan Syndrome: Genetics and Responsiveness to
Metabolic Function Growth Hormone Therapy
Van Cauter, E.; Holmbäck, U.; Knutson, K.; Leproult, R.; Binder, G.; Wittekindt, N.; Ranke, M.B. (Tübingen)
Miller, A.; Nedeltcheva, A.; Pannain, S.; Penev, P.; Tasali, E.
50 Idiopathic Short Stature: Reflections on Its Definition
(Chicago, Ill.); Spiegel, K. (Brussels)
and Spontaneous Growth
Wit, J.M. (Leiden)
Plenary Lecture 2
58 Hormonal Treatment of Idiopathic Short Stature
10 The Genomic Approach to Growth Prediction Reiter, E.O. (Springfield, Mass.)
Clayton, P.E.; Whatmore, A.J. (Manchester)
Pediatric Workshop 1
Plenary Lecture 3
64 How Proinflammatory Cytokines May Impair Growth
16 Factors Predisposing to Osteoporosis in Childhood: and Cause Muscle Wasting
New Concepts in Diagnostics Thissen, J.-P. (Brussels)
Schoenau, E.; Fricke, O. (Cologne)
23 Skeletal Health in Adulthood Pediatric Workshop 2
Eastell, R. (Sheffield)
71 Disorders of Salt and Water Balance in Children
Maghnie, M.; Ambrosini, L.; di Iorgi, N.; Napoli, F. (Genova)
Plenary Lecture 4
28 Use of Embryonic Stem Cells for Endocrine Disorders Pediatric Workshop 3
Trounson, A. (Clayton, Vic.)
77 ABCs of Natriuretic Peptides: Cardiac Aspects
Nir, A. (Jerusalem)
Plenary Lecture 5
81 ABCs of Natriuretic Peptides: Growth
32 Controversial Debate: Growth Hormone and Glucose Espiner, E.A.; Prickett, T.C.; Yandle, T.G.; Barrell, G.K.;
Metabolism Wellby, M.; Sullivan, M.J.; Darlow, B.A. (Christchurch)
Hardin, D.S. (Columbus, Ohio)
33 Growth Hormone and Insulin Resistance Pediatric Workshop 4
Jørgensen, J.O.L.; Larsen, R.L.; Møller, L.; Krag, M.; Jessen, N.;
91 Disorders of Sexual Differentiation
Nørrelund, H.; Christiansen, J.S.; Møller, N. (Aarhus)
Hughes, I.A. (Cambridge)
37 Growth Hormone Effects on Glucose Metabolism
Dunger, D. (Cambridge); Yuen, K. (Portland, Oreg.); Salgin, B.
Pediatric Clinical Case Sessions
(Cambridge)
96 Pediatric Clinical Case Sessions
Dacou-Voutetakis, C. (Athens); Latronico, A.C. (São Paulo)
98 Diagnosis and Long-Term Human Growth Hormone
Treatment of a Boy with Noonan Syndrome
de Lima Jorge, A.A. (São Paulo)
© 2007 S. Karger AG, Basel
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102 Isolated Growth Hormone Deficiency due to GH1 Gene Adult Workshop 4
Deletion: Central Nervous System Hypertension during
Growth Hormone Treatment 165 Ten Essential Points about Body Water Homeostasis
Verbalis, J.G. (Washington, D.C.)
Antonini, S.R.; Faleiros, L.; Machado, H.R.;
Carlos dos Santos, A.; de Castro, M. (São Paulo)
Adult Clinical Case Sessions
106 Hepatic Enzyme Abnormalities in Turner Syndrome:
A Case Report
173 Adult Clinical Case Sessions
Pervanidou, P.; Xekouki, P.; Dacou-Voutetakis, C. (Athens)
Casanueva, F.F. (Santiago de Compostela); Ghigo, E. (Turin)
109 PROP1 Gene Mutations and Pituitary Size: A Unique 174 Positive Metabolic Impact of Treatment
Case of Two Consecutive Cycles of Enlargement and
with Pegvisomant in an Acromegalic Patient
Regression
Grottoli, S.; Gasco, V.; Mainolfi, A.; De Giorgio, D.; Ghigo, E.
Xekouki, P.; Sertedaki, A.; Livadas, S. (Athens); (Turin)
Argyropoulou, M.; Voutetakis, A. (Ioannina)
177 Depression following Traumatic Brain Injury
Associated with Isolated Growth Hormone Deficiency:
Hot Topics in Pediatric Endocrinology
Two Case Reports
114 Hot Topics in Pediatric Endocrinology Maric, N.; Pekic, S.; Doknic, M.; Jasovic-Gasic, M.; Zivkovic, V.;
Stojanovic, M.; Djurovic, B.; Popovic, V. (Belgrade)
Deal, C. (Montreal)
115 Leptin Reversal of the Metabolic Phenotype: 180 Hypodipsic Hypernatremia after Hypothalamic Infarct
Evidence for the Role of Developmental Plasticity Marazuela, M.; López-Gallardo, G.; López-Iglesias, M.;
in the Development of the Metabolic Syndrome Manzanares, R. (Madrid)
Gluckman, P.D.; Beedle, A.S. (Auckland); Hanson, M.A.;
Vickers, M.H. (Southampton) Hot Topics in Adult Endocrinology
121 Gain-of-Function Mutations in the V2 Vasopressin 184 Hot Topics in Adult Endocrinology
Receptor
Johannsson, G. (Gothenburg)
Rosenthal, S.M.; Gitelman, S.E.; Vargas, G.A.; Feldman, B.J.
(San Francisco, Calif.) 186 The Endocannabinoid System in the Physiopathology
of Metabolic Disorders
Pagotto, U.; Vicennati, V.; Pasquali, R. (Bologna)
Clinical Practice in Adult Growth Hormone Deficiency:
Learnings from KIMS 191 Klotho , an Aging-Suppressor Gene
Rosenblatt, K.P.; Kuro-o, M. (Dallas, Tex.)
126 Clinical Practice in Adult Growth Hormone Deficiency:
Learnings from KIMS
Abstract Winners
Fideleff, H. (Buenos Aires)
204 Vitamin D Stimulates Growth Hormone-Insulin-Like
Adult Workshop 1 Growth Factor (GH-IGF) Gene Axis Expression and
Potentiates GH Effect to Reverse the Inhibition
128 T4 versus T3 and T4: Is It a Real Controversy? Produced by Glucocorticoids in Human Growth Plate
Weetman, A.P. (Sheffield) Chondrocytes
132 Recombinant Human Thyroid-Stimulating Hormone: Fernández-Cancio, M.; Andaluz, P.; Torán, N.; Esteban, C.;
Use in Papillary and Follicular Thyroid Cancer Carrascosa, A.; Audí, L. (Barcelona)
Schlumberger, M.; Borget, I.; De Pouvourville, G. (Villejuif); 206 Abnormalities of Pituitary Function after Traumatic
Pacini, F. (Siena) Brain Injury in Children
Niederland, T.; Makovi, H.; Gál, V.; Andréka, B. (Győr);
Adult Workshop 2 Ábrahám, C.S. (Debrecen); Kovács, J. (Szeged)
143 Novel Medical Approaches to the Treatment of
TBI Monograph
Pituitary Tumors
van der Lely, A.J. (Rotterdam) 208 Hypopituitarism in Adults and Children following
Traumatic Brain Injury
Adult Workshop 3 Casanueva, F.F. (Santiago de Compostela); Ghigo, E. (Turin);
Polak, M. (Paris); Savage, M.O. (London)
149 Genetics of Hypogonadotropic Hypogonadism
Simoni, M.; Nieschlag, E. (Münster)
222 Author Index
155 Management of Glucocorticoid Replacement in Adult 223 Subject Index
Growth Hormone Deficiency
Filipsson, H.; Johannsson, G. (Gothenburg)
IV Contents
HORMONE
Horm Res 2007;67(suppl 1):1 Published online: February 15, 2007
RESEARCH
DOI: 10.1159/000097542
Foreword

Pfizer’s 38th International Symposium on Growth of sexual differentiation. Internal medicine topics includ-
Hormone and Growth Factors in Endocrinology and Me- ed thyroid replacement therapy, treatment of pituitary
tabolism was held on April 7 and 8, 2006, in Granada, tumors, disorders of salt and water balance in adults, ge-
Spain. Endocrinologists from around the world were wel- netics of hypogonadotropic hypogonadism and manage-
comed to this beautiful historic city by Fernando Esco- ment of glucocorticoid replacement. Presentations also
bar-Jiménez, Professor of Medicine-Endocrinology, Uni- included pediatric and adult clinical cases, highlights
versity Hospital San Cecilio in Granada. from KIGS (Pfizer International Growth Study Data-
This conference exemplified Pfizer Endocrine Care’s base), and the impact of KIMS (Pfizer International Met-
ongoing commitment to providing an educational forum abolic Database) on clinical practice for patients with
for both pediatric and internist endocrinologists. The adult growth hormone deficiency. ‘Hot’ topics of current
broad scope of topics and the structure of the programme interest to the pediatric endocrine community included
were designed to provide opportunities for interaction leptin and related strategies for preventing metabolic dis-
and debate. The symposium was accredited by the Euro- ease and the nephrogenic syndrome of inappropriate an-
pean Accreditation Council for Continuing Medical Ed- tidiuresis: a paradigm for activating mutations causing
ucation. endocrine dysfunction. ‘Hot’ topics for internal medicine
The first of five plenary lectures addressed the role of endocrinology included the relations between the canna-
sleep in neuroendocrine and metabolic functions. Other binoid receptor and weight loss and the involvement of
lectures considered the genomic approach to growth pre- the Klotho gene in the process of aging.
diction, the role of growth hormone in glucose metabo- Sincere thanks go to the outstanding symposium fac-
lism, skeletal health, and use of embryonic stem cells for ulty who so willingly shared their insights and expertise.
endocrine applications. Their excellent presentations provided invaluable infor-
Parallel workshops were conducted on issues specifi- mation for the international community of clinicians and
cally pertinent to pediatric and internal medicine endo- researchers contending with the challenges of pediatric
crinology. Pediatric topics included the endocrinology of and internal medicine endocrinology on a daily basis.
critical illness, disorders of salt and water balance in chil- The Scientific Planning Committee
dren, new advances in natriuretic peptides and disorders
© 2007 S. Karger AG, Basel
0301–0163/07/0677–0001$23.50/0
Fax [phone]
E-Mail [email protected] Accessible online at:
www.karger.com www.karger.com/hre
Plenary Lecture 1
HORMONE
Horm Res 2007;67(suppl 1):2–9 Published online: February 15, 2007
RESEARCH
DOI: 10.1159/000097543
Impact of Sleep and Sleep Loss on
Neuroendocrine and Metabolic Function
Eve Van Cauter a Ulf Holmbäck a Kristen Knutson a Rachel Leproult a

Annette Miller a Arlet Nedeltcheva a Silvana Pannain a Plamen Penev a

Esra Tasali a Karine Spiegel b

a Departments of Medicine and Health Studies, University of Chicago, Chicago, Ill. , USA; b Laboratory of Physiology,

Université Libre de Bruxelles, Brussels , Belgium
Key Words Hormones and Sleep: An Introduction
Ghrelin (cid:1) Leptin (cid:1) Insulin resistance (cid:1) Obesity (cid:1) Diabetes
It has been known for several decades that sleep exerts
profound modulatory effects on hormones and metabo-
Abstract lism. The secretion of growth hormone (GH) and prolac-
Background: Sleep exerts important modulatory effects on tin (PRL) is markedly increased during sleep, whereas the
neuroendocrine function and glucose regulation. During release of cortisol and thyrotropin (TSH) is inhibited.
the past few decades, sleep curtailment has become a very Conversely, awakenings interrupting sleep inhibit noc-
common behavior in industrialized countries. This trend to- turnal GH and PRL secretions and are associated with
ward shorter sleep times has occurred over the same time increased cortisol and TSH concentrations. Modulatory
period as the dramatic increases in the prevalence of obesity effects of sleep on endocrine release are not limited to the
and diabetes. Aims: This article will review rapidly accumu- hormones of the hypothalamic-pituitary axis. Indeed the
lating laboratory and epidemiologic evidence indicating hormonal control of carbohydrate metabolism and water
that chronic partial sleep loss could play a role in the current and electrolyte balance is also different during total sleep
epidemics of obesity and diabetes. Conclusions: Laboratory deprivation as compared with normal sleep.
studies in healthy young volunteers have shown that exper- The release of GH is particularly dependent on the oc-
imental sleep restriction is associated with a dysregulation currence and quality of sleep. In the late 1960s it was rec-
of the neuroendocrine control of appetite consistent with ognized that the most reproducible GH pulse occurs
increased hunger and with alterations in parameters of glu- shortly after sleep onset [1]. In men, the sleep-onset GH
cose tolerance suggestive of an increased risk of diabetes. pulse is generally the largest, and often the only, secre-
Epidemiologic findings in both children and adults are con- tory pulse observed over the 24-hour span. In women,
sistent with the laboratory data. daytime GH pulses are more frequent, and the sleep-as-
Copyright © 2007 S. Karger AG, Basel sociated pulse, although still present, does not account
for the majority of the 24-hour secretory output. As illus-
trated in figure 1 , stimulation of GH release during sleep
is evident in children as well. Sleep onset elicits a pulse in
© 2007 S. Karger AG, Basel Eve Van Cauter, MD
0301–0163/07/0677–0002$23.50/0 Department of Medicine
Fax [phone] University of Chicago, 5841 S. Maryland Ave.
E-Mail [email protected] Accessible online at: Chicago, IL 60637 (USA)
www.karger.com www.karger.com/hre Tel. [phone], Fax [phone], E-Mail [email protected]
25 9-year-old girl 25 10-year-old boy
20 20
15 15
10 10
5 5
0 0
25 15-year-old girl 25 14.5-year-old boy
20 20
Growth
15 15
Hormone
(ng/ml) 10 10
5 5
0 0
25 22-year-old woman 25 21-year-old man
20 20
Fig. 1. 24-hour profiles of plasma GH in
15 15
prepubertal children, pubertal children
and adults. The black bar represents the 10 10
sleep period. Note that a large pulse of GH 5 5
release consistently follows sleep onset, ir-
0 0
respective of age or gender. Data in chil-
14 18 22 02 06 10 14 14 18 22 02 06 10 14
dren were obtained courtesy of Professor
Clock Time Clock Time
Zvi Zadik (Kaplan Medical Center, Reho-
vot, Israel).
GH secretion whether sleep is advanced, delayed or inter- During deep NREM sleep (stages III and IV), the EEG
rupted and reinitiated. Current evidence is consistent for becomes synchronized with low frequency (in the 0.5–
a combined and probably synergic role of GH-releasing 4 Hz range), high-amplitude waveforms, referred to as
hormone stimulation and decreased somatostatinergic slow waves or delta waves. Stages III and IV are therefore
tone in the control of GH secretion during sleep. Noctur- referred to as ‘slow-wave sleep’ (SWS). During a normal
nal levels of ghrelin, a powerful GH secretagogue, are also night in healthy young subjects, approximately 20% of
higher during sleep than during wake, but it is unclear the night is spent in SWS, 25% in REM, 50% in stages I
whether the nighttime elevation of ghrelin levels plays a and II NREM and only 5% awake. In adults over 60 years
role in the control of sleep-related GH release. of age, SWS is generally reduced to only 5–10% and REM
Hormonal events during sleep are dependent upon sleep to 10–15% while the proportion of time awake may
sleep quality. Sleep involves two states of distinct neuro- occupy as much as 30% of the night.
nal activity that are each actively generated in specific The quantification of EEG recordings by spectral
brain regions, and in the course of a normal night of sleep, analysis provides useful information regarding sleep
brain activity oscillates between non-rapid eye move- depth or sleep intensity that is not captured by stage scor-
ment (NREM) stages and REM stages. The periodicity of ing because, in contrast to stage scoring, spectral analysis
this oscillation is approximately 90 min and is normally is more sensitive to the amplitude of the waveform. The
repeated four to six times per night. During REM sleep, EEG signal is digitalized and, after appropriate filtering,
a cortical electroencephalogram (EEG) resembles that of spectral power is estimated in standard frequency bands.
active waking, with mixed high-frequency, low-ampli- The low-frequency waves that are apparent during SWS
tude waveforms; muscle tone is inhibited and bursts of are reflected in an increase in spectral power in the delta
REMs are present. NREM sleep is subdivided into stages range (typically 0.5–4 Hz), often referred to as slow-wave
I, II, III and IV, with the higher stages corresponding to activity (SWA). Higher SWA reflects more intense, deep-
deeper sleep that requires stronger stimuli for arousal. er NREM sleep.
Impact of Sleep and Sleep Loss Horm Res 2007;67(suppl 1):2–9 3
Self-reported sleep duration in adolescents
8.4
8.5
8.1 8.1
8
7.6
7.5 7.3
Hours
7.0
6.9
7
6.5
Fig. 2. Self-reported sleep duration during
weekdays in American adolescents from
6th grade (11–12 years old) to 12th grade 6
Grade 6th 7th 8th 9th 10th 11th 12th
(17–18 years old). Data from the National
Sleep Foundation ‘2006 Sleep in America Age 11-12 y 12-13 y 13-14 y 14-15 y 15-16 y 16-17 y 17-18 y
Poll’.
Several of the more robust peripheral effects of sleep Chronic Partial Sleep Loss: An Endemic Condition of
occur during SWS and are dependent on the intensity of Modern Society
SWS, as quantified by SWA. In particular, the stimula- Sleep curtailment is a behavior that seems to have de-
tion of GH release occurs during SWS and is proportion- veloped during the past few decades and has become
al to SWA [1] . Pharmacological stimulation of SWA re- highly prevalent, particularly among Americans. In 1960,
sults in a dose-dependent stimulation of nocturnal GH the American Cancer Society conducted a survey study
secretion. But sleep, and particularly SWS, is associated in adults that found modal sleep duration to be 8.0 to
with multiple peripheral and central effects besides stim- 8.9 h [2]. In 1995, a survey conducted by the National
ulation of GH release, including stimulation of PRL re- Sleep Foundation concluded that the mean had dropped
lease, inhibition of corticotropic and thyrotropic activity, to 7 h [3] . In 2004, more than 30% of adult men and wom-
decreased heart rate, decreased blood pressure, decreased en between the ages of 30 and 64 years reported sleeping
sympathetic nerve activity, increased vagal tone and de- less than 6 h/night [4] .
creased cerebral glucose utilization. While sleep depriva- Sleep need varies between individuals and is likely to
tion has been clearly demonstrated to be associated with be influenced by age. Several authors have distinguished
profound reductions in neurobehavioral performance, between ‘sleep need’ and ‘sleep capacity or ability’, par-
the multiple peripheral effects of sleep suggest that sleep ticularly in older populations [5–7] . Sleep ‘capacity’ may
loss might be associated with deleterious health effects. be estimated as the stable total sleep time achieved after
Until recently, nearly all studies of the peripheral impact several consecutive nights of extended bedtimes. A
of sleep loss examined the effects of acute total sleep month-long experimental extension of the bedtime pe-
deprivation, a condition that is necessarily of short dura- riod to 14 h/day has provided evidence that a ‘normal’ 8-
tion in humans and invariably followed by sleep recovery. hour night does not meet the sleep capacity of healthy
Alterations evidenced during acute total sleep depriva- young adults who may carry a substantial sleep debt even
tion are readily corrected following sleep recovery and in the absence of obvious efforts at sleep curtailment [8] .
therefore the possibility that sleep loss may result in long- This study estimated ‘sleep capacity’ in young adults to
term adverse effects appeared unlikely. Most individuals be 8 h, 14 min with an SD of 51 min, suggestive of large
experience a full night of sleep loss only occasionally, if interindividual differences. Several independent studies
ever at all. As indicated below, a much more common have consistently indicated that the average sleep capac-
condition that appears to have become increasingly prev- ity of young adults is between 8 and 9 h/night [9, 10] . Us-
alent in both adults and children is chronic partial sleep ing a similar approach, Carskadon and Acebo [11] showed
curtailment, i.e., having too little sleep night after night. that sleep ‘need’, operationally defined as the amount of
4 Horm Res 2007;67(suppl 1):2–9 Van Cauter et al.
4 Hours in Bed 8 Hours in Bed 12 Hours in Bed
3h48' of Sleep 6h52' of Sleep 8h52' of Sleep
6.5
5.5
4.5
Leptin
3.5
(ng/ml)
2.5
1.5
40
30
HOMA
(Insulin (mU/L)* 20
Glucose (mmol/L)/22.5) 10
0
9 13 17 21 1 5 9 9 13 17 21 1 5 9 9 13 17 21 1 5 9
Clock Time Clock Time Clock Time
Fig. 3. 24-hour profiles of plasma leptin (upper panels) and ho- files represent the area under the curve for the first 90 min after
meostatic model assessment (HOMA; lower panels) in 11 healthy the morning meal. The vertical line at each time point represents
lean young men under three bedtime conditions. The black bars the SEM. Note the progressive increase in leptin levels and de-
represent the bedtime period. The shaded areas in the lower pro- crease in breakfast response with increasing bedtime duration.
sleep obtained in a 10-hour sleep opportunity, does not subjects submitted to repeated curtailment of the bed-
change across the adolescent span (aged 10 to 17 years) time period in the laboratory have demonstrated that
and is about 9 h. chronic partial sleep loss is associated with deleterious
In 2005 the National Sleep Foundation conducted a hormonal and metabolic alterations that are consistent
poll regarding sleep duration among US children and ad- with an increased risk of obesity and diabetes.
olescents. This 25-min telephone survey of 1,602 indi- The first detailed laboratory study that examined the
viduals aged 11–17 years assessed sleep habits based on neuroendocrine and metabolic effects of recurrent par-
responses to questions addressed to the children as well tial sleep deprivation on glucose metabolism involved
as to the parent or caregiver. The sample was representa- healthy young men who were subjected to 6 nights of 4 h
tive of the distribution of home telephones in the U.S. and in bed (‘sleep debt’) followed by 7 nights of 12 h in bed
included similar proportions of boys and girls. The mar- (‘sleep recovery’) [12] . The subjects ate identical carbohy-
gin of error was estimated at 8 2.5%. As shown in figure drate-rich meals and were on continuous bed rest on the
2 , modern-day US adolescents do not satisfy their sleep last 2 days of each condition. They underwent an intra-
need, as mean self-reported sleep duration is under 9 h at venous glucose tolerance test (ivGTT) followed by a 24-
all ages and decreases markedly from 11 to 18 years of age. hour period of frequent blood sampling to assess hor-
Adolescents 16 to 18 years of age appeared to have an av- monal levels [12] . A control condition with 8-hour bed-
erage sleep deficit of roughly 2 h during the week. The times was performed on a separate occasion and involved
poll further revealed that the adolescents were well aware similar experimental procedures.
that they had insufficient sleep. An astounding 28% of Figure 3 illustrates the highlights of the findings. The
high school students admitted falling asleep at school at levels of leptin, a secretory product of the adipocytes that
least once a week. Those reporting that they had suffi- signals energy balance to the brain and promotes satiety,
cient sleep ( 6 9 h) were more likely to have better grades were clearly and markedly dependent on sleep duration
than those with insufficient sleep. (upper panels). When the subjects had only 4 h in bed for
6 nights, mean leptin levels were 19% lower, the noctur-
Neuroendocrine and Metabolic Implications of Short nal acrophase was 26% lower and the amplitude of the
Sleep: Clinical Studies diurnal variation was 20% lower than when sleep had
While the concept that ‘sleep is for the brain, not for been extended to 12 h in bed for 7 nights [13] . These
the rest of the body’ has long prevailed, recent studies of changes occurred despite similar levels of caloric intake
Impact of Sleep and Sleep Loss Horm Res 2007;67(suppl 1):2–9 5