Table Of ContentI
HUMAN PITUITARY HORMONES
II
DEVELOPMENTS IN ENDOCRINOLOGY
VOLUME 1
III
HUMAN PITUITARY
HORMONES
Circadian and episodic variations
A Workshop Symposium held in Brussels, Belgium, November 29-30, 1979.
Sponsored by the Commission of the European Communities, as advised by the
Committee on Medical and Public Health Research
edited by
E. VAN CAUTER, Ph. D.
School of Medicine,
Free University of Brussels,
and Thyroid Study Unit,
The University of Chicago
and
G. COPINSCHI, M.D., Ph. D.
School of Medicine,
Free University of Brussels
1981
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v
FOREWORD
During the last decade, circadian and episodic fluctuations
of the plasma levels of pituitary hormones have been demon~
trated in man. The interest in the time dependence of the
pituitary secretions partially originates from their close
functional relation with the neuroendocrine mechanisms pre
sumably responsible for the control of the circadian.rhyth
micity in man.
High frequency blood sampling techniques and specific radio
immunoassays have allowed to describe in detail the varia
tions over the 24-h cycle of the hormonal concentrations in
healthy individuals under basal conditions as well as after
manipulation of external synchronizers such as the sleep
wake cycle, the dark-light cycle and the feeding schedule.
Alterations in normal hormonal var~ions have been sugges
ted to play a role in the etiopathogeny of several metabo
lic and mental diseases, such as obesity or manic-depressio~
Important clinical implications regarding treatment and pre
vention are expected to be developed in the near future.
However, so far, data obtained in different groups are dif
ficult to compare because different hormones were studied
using different protocols and statistical methods. As a
result, unclear or controversial issues are not uncommon.
Also, because of the interdisciplinary nature of biological
rhythm research, studies on 24-h profiles of pituitary hor
mones have appeared in a wide variety of publications inclu
ding journals specialized not only in clinical endocrinolo
gy and neuroendocrinology but also in psychiatry, chronobio
logy, sleep or behavioural research and general clinical
investigation. Early in 1977, when this Workshop was propo
sed to the Committee of Medical Research and Public Health
of the Commission of the European Communities, not a single
reference volume on endocrine rhythms was available. A
unique opportunity to assess the present state of knowledge
and methodology in the field by fostering the discussion
and the exchange of data between leading investigators was
thus provided. The present volume gathers the contributions
of the participants and includes a straightforward trans
cription of all the discussions. It constitutes an invalua
ble reference tool for endocrinologists as well as for all
interested in the clinical aspects of biological rhythm
research.
We thank the Committee of Medical Research and Public
Health for evaluation of the Workshop and the Commission of
European Communities for sponsorship. We are grateful to
Mrs. C. Demesmaeker for careful secretarial and editorial
help.
G. COPINSCHI E. VAN CAUTER
VII
CONTENTS
Foreword v
E. van Cauter and G. Copinschi
1. Quantitative methods for the analysis of circadian and
episodic hormone fluctuations
E. van Cauter
Discussion 26
Moderators: J, Aschoff and G. Copinschi
2. The sleep-wake pattern of cortisol and growth hormone 29
secretion during non-entrained (free running) conditions
in man
E.D. Weitzman, C.A. Czeisler, J.C. Zimmerman and J. Ronda
3. Search for a primate model of human sleep-related hormone 42
secretion
H.J. Quabbe
Discussion 64
Moderators: D.S. Minors and E. van Cauter
4. Adaptation of 24-hour hormonal patterns and sleep to jet lag 68
E. van Cauter, S. Refetoff, D. Desir, C. Jadot,
M. Fevre-Montange, V.S. Fang, J. Golstein, M. L'Hermite,
C. Robyn, P. Noel, J.P. Spire and G. Copinschi
Discussion 89
Moderators: E.D. Weitzman and C. Robyn
5. Effect of an imposed 21-hour sleep-wake cycle upon the 96
rhythmicity of human plasma thyrotropin
L.G. Rossman, D.C. Parker, A.E. Pekary and J. Hershman
Discussion 114
Moderator: L. Vanhaelst
6. Physiological factors influencing the nyctohemeral 118
pattern of TSH
J. Golstein, L. Vanhaelst and E. van Cauter
7. Circadian and ultradian variations in serum TSH and thyroid 132
hormones in normal man and in patients with treated and
untreated primary hypothyroidism
J. Weeke
Discussion 152
Moderator: L. Vanhaelst
VIII
8. Control of pituitary-adrenal periodicity 161
D.T. Krieger
Discussion 178
Moderators: A. Reinberg and J. GoZstein
9. Influence of drug administration on ACTH circadian rhytm 184
F. Ceresa
Discussion 203
Moderators: A. Reinberg and J. ~oZstein
10. Hormonal rhythms in pituitary tumors 207
P. Jaquet, M. Guibout, E. Castanas, E. Goldstein, C. Jaquet
F. Grisoli and P. Bert
Discussion 230
Moderators: C.W. Bardin and J. MendZewicz
11. Circadian variation of plasma growth hormone in normal subjects 233
and diabetic patients. Effects of somatostatin infusion, age
and body weight
A.P. Hansen and S.E. Christensen
Discussion 257
Moderators: C.W. Bardin and J. MendZewicz
12. Circadian and circannual changes of pituitary and other 261
hormones in healthy human males: their relationship with
gonadal activity
M. Lagoguey and A. Reinberg
Discussion 277
Moderators: C.W. Bardin and J. MendZewicz
13. Clinical implications of gonadotropin rhythms 279
C.W. Bardin
Discussion 291
Moderator: M. L'Hermite
14. Pituitary and pineal hormone rhythms in manic depression 295
J. Mendlewicz, E. van Cauter, J. Golstein, L. Vanhaelst
P. Linkowski, M. L'Hermite, C. Robyn, U. Weinberg and
E.D. Weitzman
Discussion 306
Moderator: M. L'Hermite
IX
15. Circadian rhythm of plasma gonadotropins, prolactin and 310
growth hormone levels in anorexia nervosa: Correlations
with hypophysial tests
R. Roulier, B. Conte-Devolx, E. Castanas, J. Bert and
J.L. Codaccioni
Discussion 328
Moderator: M. L'Hermite
General Discussion 330
Moderators: D.T. Krieger and G. Copinschi
List of participants 351
QUANTITATIVE METHODS FOR THE ANALYSIS OF
CIRCADIAN AND EPISODIC HORMONE FLUCTUATIONS
Eve Van Cauter
Institut de Recherche Interdisciplinaire, School of Medicin~
The University of Brussels, Belgium and
The Thyroid Study Unit, Department of Medicine, The
University of Chicago, Illinois, USA
INTRODUCTION
The development of sensitive radioimmunoassays and of high
frequency blood sampling techniques has made possible to
measure accurately the variations in plasma levels of pitui
tary and other hormones over the 24-h cycle. Data gener
ated challenged the concept of hormonal homeostasis and in
troduced the notion that time of sampling is an important
factor in defining normal and pathological levels. The in
vestigators of hormonal rhythms are faced with the interpre
htion of data of a new type, namely, time series where at
least two types of temporal variation are present: (1) a
circadian periodicity (low frequency variation); and (2)
short-term, episodic fluctuations (high frequency variation).
Because of the complexity of the data and of their depen
dence upon time, classical statistical methods currently
used in clinical investigation cannot be generally applied.
The majority of reports on the 24-h profile of blood con
stituents have therefore been largely descriptive. The
determination of possible correlations between hormonal
variations and sleep stages has also been often based on
visual examination of the data. The sophistication of
the sampling procedures and of the biochemical determina
tions in plasma is thus far greater than that of the quantitative
2
interpretation of the observations. It seems likely that
results well documented by the data could be overlooked or
misinterpreted and that more information could be extracted
from the available data provided suitable quantitative pro
cedures for their interpretation were available.
This paper describes and illustrates methods for the
analysis of 24-h profiles of blood components developed
over the last few years to interpret data collected at the
University of Brussels, Belgium and at the University of
Chicago, USA. Procedures for the analysis of low frequency
(e.g., circadian) components and high frequency (e.g., epi
sodic) components and a preliminary approach to the analy
sis of correlations between sleep and hormonal variations
will be described separately in the next three sections.
THE CHARACTERIZATION OF THE CIRCADIAN COMPONENT
Several statistical procedures have been combined to derive
a method suitable for the characteristics of 24-h profiles
of hormones and other plasma constituents. The method has
been described in detail elsewhere (1). This presentation
illustrates its potential applications since
its statistical background has been previously discussed (1,
2, 3).
Because 24-h profiles may not present a definite pat
tern, the first step in the analysis consists of testing
the significance of the observed temporal fluctuations
against the hypothesis of their pure random occurrence.
So-called "white noise" tests are used to determine whether
the profile consists of a random succession of uncorrelated
levels, each data being independent of past and future va
lues, or whether consistent trends, periodicities or ten
dencies for certain patterns to recur at regular intervals
exist (1).
If the hypothesis of white noise is rejected, a best
fit pattern describing the low frequency variation of the
profile is built using repeated periodogram calculations.
The periodogram method consists of fitting a sum of sinusoid
