Circadian timing of serum cortisol in patients with anorexia nervosa.

A.tti del I I Simposio Internazionale su
Aspetti medico - sociali della
Cronobiologia
Proceedings of I I International Symposium on
Chronobiologic approach
to social
A cura di / Edited
medicine
by
F. H A L B E R G - L . R E A L E - B. TARQUINI
Promosso ed organizzato
DALL'ISTITUTO ITALIANO D I MEDICINA SOCIALE
con i l patrocinio
DELL'ASSESSORATO ALLA SANITA' DELLA REGIONE TOSCANA
DELL'UNIVERSITA' D I FIRENZE
Ε DELLA SOCIETA' ITALIANA D I CRONOBIOLOGIA
con la collaborazione
DELL'ISTITUTO D I CLINICA MEDICA I I
DELL'UNIVERSITA' D I FIRENZE
Firenze,
2 ottobre 1984
ISTITUTO ITALIANO D I MEDICINA SOCIALE
E D I T O R E - ROMA
Circadian timing of serum Cortisol in patients with anorexia
nervosa /
Timing
del
ritmo circadiano
in pazienti con anoressia
del
cortisolo
sierico
nervosa
Boguslawa Baranowska *, Maria Lazicka-Frelek *, Barbara Migdalska *,
Stefan Zgliczynski*, Barnett Zumoff**, R.$. Rosenfeld**,
Germaine Cornelissen***, Helmut Arbogast****,
Elke Eckert***, Franz Halberg***
* Endocrinology Clinic, Medical Center of Postgraduate Education,
Bielanski Hospital - Ceglowska 80 - 01-809 Warsaw, Poland
** Department of Medicine, Beth Israel Medical Center, New York, N Y , USA
*** University of Minnesota, Minneapolis, MN, USA
**** Kinderzentrum, University of Munich, F R G
Introduction
The hypothalamic-pituitary-adrenal network i n patients w i t h anorexia nervosa (AN) appears to be unusually active. Time-unspecified
fasting or other serum Cortisol concentrations are reported as elevated
in virtually all studies investigating plasma Cortisol i n patients w i t h AN
(3, 6, 8, 10, 11, 19, 36, 37). Elevated serum Cortisol has been regarded
as a differential diagnostic feature distinguishing AN from Addison's
disease. This elevated serum Cortisol has been associated w i t h a decrease
i n the rate of Cortisol metabolism i n the form of an increased, i f circadian stage-unspecified Cortisol half-life (3, 8), probably related to a reduced capacity of the liver for ring A reduction of Cortisol.
Elevated serum Cortisol has also been associated w i t h an increased
S U P P O R T : Scientific Programme R M Z - V I I / 9 ; National Institute of
Medical Sciences (GM-13981); Medtronic Inc., Minneapolis, MN, USA
General
535
rate of Cortisol production relative to body size (35). There is an increase i n the excretion of unconjugated or « free » Cortisol i n the urine,
usually a very sensitive indicator of adrenal overactivity (3, 35). Adrenocortical activity is not as readily suppressed in patients w i t h AN (8, 12)
as i n clinical health (CH), a finding suggesting fhat the hypothalamic
and pituitary centers coordinating adrenal activity have an altered sensitivity.
I t has been suggested (7, 29) that malnutrition i n anorexia nervosa
patients is responsible for alterations seen i n Cortisol metabolism. A
more recent review (35), however, has concluded that additional changes
i n A N are not accounted for by protein-calorie malnutrition (29).
There are differing reports concerning the circadian variation of
circulating Cortisol i n A N . Some authors report an absence of the usual
circadian variation (10, 11, 18, 33, 36), suggesting a disturbance of the
hypothalamic coordination of pituitary-adrenal function i n patients w i t h
AN. Other authors report the usual circadian variation of Cortisol (3,
6, 8). Studies reporting usual (non-deviant) and deviant results i n circadian variation of serum Cortisol are listed i n Table 1.
Materials and methods
We studied 22 women w i t h AN, ranging i n age from 17 to 29 years
(mean: 23 years) w i t h weight deficiency ranging from 24% to 57%
(mean 39%), and 18 CH women, 19 to 58 years of age (mean: 35 years)
whose body weights were w i t h i n accepted limits. AN was diagnosed
based on criteria described elsewhere (9, 25):
1) a pattern of behavior aimed at inducing weight loss,
2) emaciation to a body weight at least 20% below standard,
3) cessation of menstruation for at least 3 months,
4) absence of other (overt) physical or psychiatric illness.
Ideal body weight was calculated in kg from the formula: height
i n cm - 100. The clinical data are presented i n Table 2.
The subjects w i t h A N or i n CH were examined on the 4th day
of their hospitalization. The subjects slept or rested from about 23°°
u n t i l 07°°. Meals were served at 08°°, 13°° and 17°°. No drugs were administered. Activity was limited to that compatible with standard hos536
Table 1
CIRCADIAN VARIATION OF S E R U M CORTISOL IN ANOREXIA NERVOSA
Authors
Sampling
Studies reporting deviant results
•Frankel and
Jenkins (10)
00
09°°, 00
08 , low
Morning &
afternoon
30
Garfinkel et al. (11)
Hurd et al. (18)
Vigersky et al, (33)
Warren & V a n de
Wiele (36)
00
08 , 17°°
00
09 , 16
00
# Samples
/24h
# of
subjects
Age (yrs)
2
2
4
9
16-28
13-25
23.3-34.6 kgx
26-48XX
2
101
11-61
2
11
23.7+8.1
0-59
33.6+10.5xx
15-54
2
23
10-23
°/o loss in
body weight
Comment (% deviant)
50
Data regarded as
insufficient by authors
53
55
48°/o deviant & 22% with
« reversal » of circadian
rhythm
Studies reporting non-deviant results
Boyar et al. (3)
Casper et al. (6)
Doerr et al. (8)
q 20 min
Ö8 , 20
q 30 m i n
30
00
72
2
48
10
20
16
16-28
14-32
13-29
23.8 —40.1xx
16 —48xxx
23 —49xx
0
0
0
x% loss not reported
xx% loss from ideal body weight taken from the Metropolitan Life Insurance Co. Statistical Bullettin, 1959
xxx°/o loss from « normal »
Table 2
C L I N I C A L DATA O F P A T I E N T S W I T H A N O R E X I A N E R V O S A (AN)
Case
number
Age
(years)
Height
(cm)
Body weight
(kgQ
Deficit of body
weight* (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
27
26
25
29
25
22
25
22
19
26
22
28
24
19
16
18
18
17
20
26
22
27
156
160
165
161
162
167
168
158
163
166
172
154
160
162
165
154
155
164
160
154
161
164
24
28
31
31
33
37
38
34
37
39
44
34
39
40
43
38
40
48
45
41
47
49
57
53
52
49
47
45
44
41
41
41
39
37
36
35
34
29
27
25
25
24
23
23
* in relation to ideal body weight in kg computed as height in cm -lOO
pital conditions. The patients did not exhibit any body weight gain prior
to blood sampling for Cortisol determinations. Blood samples were taken
from the antecubital vein at 08°°, 12°°, 16°° and 22 . Serum Cortisol concentrations were measured by a fluorometric method (30). The data
were analyzed by the single cosinor procedure (15, 17). Time-specified
reference intervals, notably prediction intervals, were computed, as noted elsewhere (13, 21, 22), from the data on CH women and also from
a data base used for international reference standards (14). Calculations
were made by computer (Mera 400 and PDP11/34) w i t h Fortran I V
programs.
00
538
Results
The mean 24-h Cortisol concentrations i n the CH women ranged
from 6.10 to 25.55 μg/dl (Table 3). The mean 24-h Cortisol concentra­
tions of the AN subjects were higher, from 12.12 to 43.28 μg/dl (Ta­
ble 4). The difference between the mean of serum Cortisol in AN patients
of 20.9 as compared to 13.2 in CH subjects is 7.8 ± 2.1 (SE), the cor­
responding t is 3.65 (p <0.01).
A group rhythm is demonstrated by the population-mean cosinor
technique for AN and CH, as shown in Table 5. The P-values ( < . 0 1 )
in testing the zero-amplitude (no rhythm) assumption demonstrate the
prominence of circadian rhythmicity.
The timing of the Cortisol rhythm in each individual is shown i n
Figure 1 by acrophases alone. These are plotted along a circular scale,
irrespective of amplitude. The acrophases of the CH women (dots) ran­
ged from 06 to 10 (hrs min) from local midnight. Acrophases similar
to those of the healthy group are also found i n 16 of the women w i t h
AN (triangles). The acrophases of the six remaining patients w i t h A N
lie far outside the range of CH women (15° = 1 h). I n these women
( w i t h outlying acrophases), the body weight deficit rangefj from 39%
to 57% of ideal body weight. The weight deficits of those;AN patients
w i t h acrophases within or outside the CH limits averaged 33.4% and
48.8%, respectively, The difference of 15.4 + 3.8% (SE) i$ associated
w i t h a t of 4.06 and is significant below the 1% level. One may also use
a reference prediction region (ellipse) or conservative prediction limits
(i.e., the tangents drawn to the ellipse) instead of a range for inter­
preting the acrophase. The institutional reference ellipse and the indi­
vidual (A, 0 ) pairs for AN patients are shown in Figs. 2a and 2b. I n
Fig. 2a, the amplitude is used in original units, whereas in Fig. 2b, i t
is expressed as percent of MESOR. W i t h either approach, the results are
discriminating in that the difference in body weight loss of patients
whose Cortisol (A, 0 ) pair lies inside or outside the reference prediction
ellipse (or the prediction limits for 0 ) is statistically significant below
the 1% level.
24
41
Both approaches are given (for completeness), but a priori, i t was
decided to interpret results on the basis of the amplitude as percentage
of the MESOR, since, earlier, such reference regions, as compared to
those based on the amplitude expressed in original units, had been found
to be more reliable and internationally valid (21). Figs. 2a and 2b allow
539
Table 3
R H Y T H M O M E T R I C SUMMARY O F S E R U M C O R T I S O L I N
CLINICALLY HEALTHY WOMEN*
Subject
ID
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
teg/dl)
MESOR
Amplitude
2.08
3.14
5.70
6.98
3.33
5.74
2.94
3.16
3.41
2.69
3.57
2.35
4.70
7.15
6.67
3.98
4.65
4.28
10.52
6.10
14.25
10.98
10.70
11.23
10.80
12.33
10.72
13.80
11.78
7.55
11.23
25.55
22.75
22.50
10.78
13.22
Acrophase 360° ss 24 h 0° =
degrees
hour
132
142
120
102
110
131
149
129
133
106
122
96
144
124
109
148
118
160
00
51
30
02
50
22
47
57
39
52
07
11
24
38
16
17
52
55
41
08
09
08
06
07
08
09
08
08
07
08
06
09
08
07
09
07
10
00
* E a c h subject contributed 4 samples at 06 , 12 ; 16
00
midnight
minute
00
and 22 .
an examination of the AN subjects ranked i n order of decreasing seve­
rity of body weight loss. Most of the A N patients with the largest deficit
( w i t h the lowest numbers shown in Figs. 2a and 2b) are outside the
90% prediction region.
A Kruskal-Wallis test was performed to compare the body weight
loss i n A N patients ( i n Warsaw) having their Cortisol (A, 0 ) pair inside
or outside the reference, region. A statistically significant difference is
thus demonstrated ( X D = 9.136; Ρ <.01). This result is in keeping w i t h
that of the Student t-test reported above. A linear regression of only
borderline statistical significance (P = .065) was found between relative
body weight loss and the extent of departure of the Cortisol rhythm
from « normalcy » (di), as gauged by the euclidean distance between the
patients' (Ai/Mi, 0i)s and the CH population rhythm estimate ( A / M , 0 ) :
2
(
A
Μ
540
sin 0 .
Table 4
R H Y T H M O M E T R I C SUMMARY O F S E R U M C O R T I S O L I N
WOMEN W I T H ANOREXIA N E R V O S A *
Case
#
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
teg/dl)
MESOR
Amplitude
3.70
3.61
0.86
2.57
10.48
7.98
4.58
4.26
6.14
3.96
6.25
4.42
5.22
3.74
5.29
1.68
1.64
4.26
12.73
0.87
1.87
2.17
18.88
12.32
16.28
23.28
28.07
25.72
15.33
24.63
23.33
19.52
17.33
15.03
17.22
43.28
15.40
15.22
24.70
24.33
36.07
12.12
16.67
15.35
Acrophase 360°==24 h, 0° = midnight
degrees
hour
minute
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
00
17
209
9
94
244
183
113
113
139
97
261
121
125
95
127
93
99
113
105
145
112
106
01
13
00
06
16
12
07
07
09
06
17
08
08
06
08
06
06
07
07
09
07
07
00
* E a c h subject contributed 4 samples at 06 , 12 , 16
00
08
58
38
16
18
13
35
32
16
30
25
04
20
21
28
13
37
Ρ3
2
ί
h
07
00
and 22 .
Table 5
P O P U L A T I O N - M E A N C O S I N O R O F 24-h P R O F I L E O F S E R U M C O R T I S O L
C O N C E N T R A T I O N I N C L I N I C A L H E A L T H AND A N O R E X I A N E R V O S A *
Population
Anorexia
nervosa
Clinically
healthy
women
Ν
subj.
22
18
m i n
M±SE
A (95% C L )
0hr
.003
20.93 + 1.70
2.55 (1.04,4.06)
08
<.001
13.16+1.23
4.07 (3.29,4.86)
0823 (0748, 09 )
Ρ
48
(95%CL)
(07«\ 1152)
00
* Ν subj. = number of subjects
Μ = MESOR
A = amplitude
0 = acrophase
95°/o C L = confidence limits
Ρ = P-value in testing zero-amplitude (no-rhythm) hypothesis
541
Figure 1
Acrophases from cosinor summaries of 24-h profiles of serum Cortisol concentration
in clinical health ( · ) and anorexia nervosa ( ^ ) .
Until more data are available, one cannot say whether there may
not be a gradual departure from « normalcy » as a function of body
weight loss or, rather, that abnormality occurs more abruptly once body
weight loss has reached a critical point.
With 4 samples, 4 to 8 hours apart, on 18 to 22 subjects, i t is
tempting to ignore individual behavior altogether and to restrict one's
attention to groups only, unless a reference group of more than 18 clinically healthy subjects (sampled sparsely) can be found as an additional reference standard. Additional data for use as standards for women
542
Figure 2a
Circadian Amplitude (A)- Acrophase (0) Pair
of Serum Cortisol in Women with
Anorexia Nervosa (0 in Relation to 90%
Prediction Region for Clinically Healthy Women*
Computed with A in original units.
For 0 in degrees
360°= 24 hours
Numbers accompanying outliers indicate rank in relation to
decreasing severity of body weight loss, the loss itself being given
in parentheses as percentage of ideal body weight.
Institutional elliptical reference region for acrophase-amplitude pair of serum
Cortisol concentrations estimated for clinically healthy women against which
individual values for patients with anorexia nervosa are shown. Numbers show
ranks in order of decreasing severity of body weight deficit. Deficits also given
in parentheses as percentage of ideal body weight. Reference region based on
amplitude in original units (a), left, and on amplitude expressed in percentage
of mesor (b), middle. Results shown against international reference standard (c),
right.
Figure 2b
Circadian Amplitude (A)- Acrophase (0) Pair
of Serum Cortisol in Women with
Anorexia Nervosa (*) in Relation to 90%
Prediction Region for Clinically Healthy Women
%
Computed
with A as percentage of mesor.
For 0 in degrees
360°= 24 hours
0°=00
00
Meals
% of Mesor
Rest-Activity
Schedule
Numbers accompanying
outliers indicate rank in relation to
decreasing severity of body weight loss, the loss itself being given
in parentheses as percentage of ideal body weight.
544
in CH are indeed available from a study involving 134 series sampled
at 20-minute intervals for 24 hours, Figure 3 (14). International validity
has been documented for such a reference standard i n the form of the
90% prediction region for the amplitude and acrophase pair, when the
amplitude is expressed as a percentage of the MESOR. Such a Minnesotan prediction region, computed to contain 90% of a population, contains
the (anticipated) majority of amplitude-acrophase pairs from studies
of clinically healthy individuals in Japan (23), Italy and Germany (13).
Moreover, all 18 of the Polish women in CH fall within this interna­
tional reference standard (not shown). By contrast, one-half of the
Polish women w i t h AN fall outside this international standard (Fig. 2c).
Until proof is offered to the contrary, a local institutional reference
region is preferred to an international one. I n our case, the results
obtained w i t h the use of an international standard support the infe­
rences based upon the use of a local standard.
Whichever standard is used, certain AN patients, but not all of
them, have atypical acrophase-amplitude pairs. I t is of interest to see
whether such differences are due to amplitude only, to acrophase only,
or to both characteristics. Student's t-tests for any difference i n body
weight loss between those w i t h amplitudes inside and outside the
(A, 0 ) prediction region or inside and outside the reference interval
for A, computed on the basis of the amplitude in original units, or on
the basis of the amplitude expressed as percent of MESOR, were all
associated w i t h a Ρ above the 10% level (the corresponding t-values
are 0.98, 0.43, 1.39 and 0.99).
A procedure similar to that practiced for examining discrimination
of extent of body weight loss by the use of acrophases as criterion was
also applied to the mean 24-h Cortisol concentrations or MESORS. Four
patients w i t h AN had their rhythm-adjusted means outside the range
of those of CH women by more than 1 μg/dl. These four subjects had
a mean weight deficit of 38%, whereas the other A N patients, who had a
Cortisol MESOR w i t h i n the range of MESORS for CH, had a mean weight
deficit of 37.5% (t = 0.08; Ρ >0.50). Until proof is offered to the con­
trary, the increase i n mean Cortisol concentration seen i n AN patients
may be non-specific i n reflecting a low body weight, while a change
in acrophase is more specific i n this context. I t is concluded, i n the light
of such results, that the best criterion among the three parameters ex­
amined here- -MESOR, amplitude and acrophase- -is indeed the acrophase.
The value of a combination of these indices and of the waveform (when
denser data allow its assessment, e.g., by harmonics), however, remains
545
Figure 2c
Circadian Characteristics of Serum Cortisol in 11 of 22
Women with Anorexia Nervosa in Poland Lie Outside
90% Prediction Region for Clinically Healthy Minnesotans
to be investigated. For the time being, the finding of deviant Cortisol
acrophases relative to body weight loss is based on sparse data, whereas
the similarity of circadian Cortisol acrophases examined by objective
cosinor methods throughout the year in women of different ages, in
different populations, and on different continents (14), rests on dense
data obtained every 20 minutes for 24 hours, Figure 3.
546
Figure 3
CIRCADIAN RHYTWS OF PLASMA CORTISOL IN CLINICALLY HEALTHY WOMEN:
AGREEMENT AMONG SUBJECTS*
J a p a n e s e and American Women ot Three Age Groups
• IT
aaottsctar t a o u * . ι · ) » - ·
KWftBaOMlT t a O U ' . I O t
aosT-a«ia>»«wsai * » O U * . I * I ι
•
WMHSO'*
» wv« yv»
Results of fit of 24-h cosine curve to 24-h plasma Cortisol profiles a j 100-minute
intervals. With data at 20-minute intervals, over 99% of series allow rejection of
the no-rhythm assumption at the 1% level and all do so at the 10% level.
Discussion
W i t h Rotable exceptions (3, 8, 37) (Table 1), much earlier discussion
in the literature on Cortisol i n AN vs. CH is based on samples that were
even more) limited than those i n the present study. Sampling limited to
a single time-unspecified determination described as « f a s t i n g » , w i t h
added determinations apparently stemming from response tests, can be
cited (17). There is also a case when dense sampling is used only for
computing a reliable mean (37). Others sampled twice a day, Table 1.
I t is on that basis that some authors discuss a deviant circadian varia­
tion, whereas still others feel that the variation is w i t h i n the expecta­
tion for clinically healthy subjects. H u r d et al. (18) report that i n 42%
of their patients, serum corticosteroid concentration was elevated and
circadian variation lost or reversed i n 53%, and that weight loss was
correlated w i t h the urinary excretion of ketogenic steroids: the greater
the weight loss, the higher the systemic steroid excretion. These authors
refer to a discrepancy i n AN between the serum concentration and the
urinary excretion of corticosteroids, on the basis of data limited to
547
serum samples from 2 timepoints, i n keeping with the practice of others
(Table 1).
I t is noteworthy that the most extensive sampling--every - 20 o r
every 30-minute sampling (3, 8}·-yielded the overall (macroscopic) i m ­
pression of no deviant result. I t is possible that the unaided eye, seeking
to interpret small differences i n pattern of variation (macroscopically)
i n a time plot, may often be in the same position as the eye unaided
by histologic microscopy, trying to find a cell (macroscopically) i n a
tissue. Rhythmometric (microscopic) procedures such as the cosinors
used herein provide objective point and (confidence) interval estimates
of rhythms when the data are sufficiently dense. When the data are
relatively sparse (for a rigorous individualized assessment), an imputed
characteristic in AN, such as the amplitude-acrophase pair, may be
interpreted by reference to a prediction region established on the basis
of institutional sampling, in Figures 2a and 2b, or on the basis of inter­
national reference standards (Figure 2c).
I t is also possible that other factors account for the difference i n
outcome. Further analyses are needed before one can conclude that the
sparser sampling discriminates better and, i f so, to determine to what
extent alterations of waveform may be involved.
Whereas the finding of a statistically significantly different behavior
as a function of the extent of weight loss experienced by the A N patients
(those w i t h the deviant acrophases showing, on the average, a greater
deficit) is apparently original, it complements earlier focus by Gerner
and Gwirtsman (12) upon the extent of weight loss i n the light of
dexamethasone suppression tests. The Cortisol concentration after dexamethasone suppression was correlated with the percentage of ideal
weight (r = .35); there was a trend for the Cortisol concentrations of
the 11 women who were less than 65% of their ideal weight to be
higher than the concentrations of the 5 women who were 74% — 8 0 %
of their ideal weight (17.3 + 2.2 versus 9.5 + 2.1 μg/dl, t = 2.12, ρ ~
0.05).
Differences in the circadian and circannual timing of the periodic
production of aldosterone, Cortisol, dehydroepiandrosterone ( D H E A ) and
DHEA-sulfate (DHEA-S) are noteworthy; they suggest the periodic ope­
ration of a 4-way switch in the pathway of adrenocortical steroid bio­
synthesis preferred at a given stage. Thus, in human beings, along the
24-hour scale, high values of aldosterone precede those of Cortisol, with
the latter preceding high DHEA, w i t h high DHEA-S concentrations lag­
ging behind all of these. Although the concentrations of these hormones
548
i n blood are vastly different, their time relations, notably of DHEA-S,
along the scale of a year as well as of a day may be important markers
of enzymatic adrenocortical activities. The pineal may contribute to
this timing, since i t is already known that it rhythmically modulates
(attenuates, leaves unaffected or amplifies) a pituitary tropic hormone
(ACTH) effect upon adrenal corticosterone production (26-28). This modulation may be impaired i f not absent in some patients w i t h A N .
Deviant acrophases, such as those here noted for AN, can also be
seen i n our analyses of data obtained w i t h a sampling similar to that
here practiced on 3 out of 4 children w i t h AN i n Munich, Federal Republic of Germany (13), as well as i n very young CH children (less than
1 year of age) in M i k i , Japan (23). I n CH children two years of age or
older, the amplitude-acrophase pair is within the international reference
standard for Cortisol, computed w i t h the amplitude as a percentage of
the MESOR. I t seems pertinent that a statistically significantly higher
Cortisol concentration i n anorexia nervosa found earlier (3, 6, 8, 10, 11,
19, 36, 37) was shown by Zumoff et al. (37) to be associated w i t h a
lowering of adrenal androgen (p < 0.05). The DHEA-to-cortisol ratio
representing the relative activities of pathways from 17-hyroxy^regnenolone to DHEA vs. Cortisol averaged less than half of the reference
value i n A N , while i n relapse, whereas i n partial remission, theffe was
an increase i n DHEA-to-cortisol ratio. The failure of DHEA concentrations to rise i n response to ACTH i n AN patients resembles the picture
seen i n pre-adrenarcheal children and is probably due to low activity
of 17, 20 - lyase. What is physiological i n pre-adrenarche may be pathological i n A N . The lowered DHEA-to-cortisol ratio then, constitutes a
hormonal parameter of ontogenic regression (34). Even earlier evidence
that A N may represent a regression to pre-puberty was found by Boyar
et al. (4), who report that the 24-h plasma luteinizing hormone secretory pattern was similar to that seen i n pre-pubertal children.
Along the same line of thought, our analyses of systematic data
from Japan by Onishi et al. (23) show that i n the first year of life as
compared to later i n life, the timing of the circadian variation i n
Cortisol is drastically different. One could postulate that some of the
patients w i t h AN might be regressed into the circadian pattern of very
early childhood.
More than serum and even urinary Cortisol w i l l have to be determined for those who wish to look at the mechanisms of A N . I n view
of the failure of the mean to discriminate (in this study and i n those
of others) between patients w i t h large and small deficits in body weight,
549
any endocrine focus upon AN w i l l have to include an objective measure
of timing, since an alteration of timing, established w i t h the cosinor
method herein, is also implied macroscopically by others, referring,
e.g., to a reversed pattern, Table 1.
The data herein, limited to four samples a day, have served pri­
marily for the comparison of patients w i t h AN and subjects i n CH,
but they also achieve subgroupings as a first step by weight deficit.
The question whether a change in Cortisol acrophase, the discriminant
found, and perhaps some change in a rhythm characteristic of another
hormone (yet to be demonstrated) is an unspecific concomitant of A N ,
or rather an important co-determinant of the condition, is a topic for
further research, to be planned i n the light of this work. Our findings
are in keeping w i t h an alteration of cephalo-adrenal interaction (16).
A direct pineal effect upon pituitary-adrenal interactions, rather than
necessarily a hypothalamically-mediated pineal effect, has recently been
demonstrated as a so-called feed-sideward (16, 26-28), apart from any
feedbacks from the adrenal to the pituitary or hypothalamus. The pineal,
in a rhythmic sequence, attenuates, leaves unaffected or amplifies the
pituitary (or the ACTH) effect upon the adrenal in vitro (and thus in
the absence of the hypothalamus) (16, 26-28). What is particularly per­
tinent to the findings of this study, under certain conditions, the pineal
shifts a rhythm that, for one reason or another, is out of phase (26).
Could this aspect of pineal modulation be deficient i n AN? This possi­
bility is a matter for further consideration to be explored w i t h frequent
sampling on the several variables that reflect not only the Cortisol
pathway but also competing pathways coordinating electrolyte and sex
hormone metabolism i n the adrenal itself and also i n its superimposed
and juxtaposed coordinators, the pituitary, hypothalamus and pineal,
now known to interact i n a time-dependent fashion and w i t h important
consequences in terms of body defense and behavior (1φ, 26-28).
Since the hormones involved i n CH as a reference standard for AN
exhibit a set of rhythmic changes with several frequencies, the work
herein may be used to suggest that rather than being 3 vexing source
of variability, the study of circadian, circannual and other rhythms
can yield novel and useful parameters that thus far have discriminated
between AN patients w i t h large or small body weight deficit, pointing
to mechanisms of cephaloendocrine interactions and suggesting the need
to test i n particular a possible alteration of a pineal feed-sideward upon
pituitary-adrenal interaction. Answers to whether cephaloadrenal inte­
ractions constitute a determinant of AN w i l l have to be explored with
550
strategically-placed cost-effective sampling (14) on the several variables
implicated by the new finding of a quantitative change i n timing of the
Cortisol rhythm, here interpreted i n the light of the voluminous literature on adrenocortical function and steroids more broadly i n A N , w i t h
only a citation ( 1 , 2, 5, 20, 24, 31, 32, 34, 35, 38) to some other pertinent
endocrine and metabolic studies.
Conclusion
Reliance i n this paper, of necessity rather than choice, upon a less
specific fluorometric method, as compared to a radioimmunoassay, forestalls definitive inferences. A set of radioimmunoassays on much denser data but on a different population (37) warrants the inference that
serum Cortisol in patients w i t h anorexia nervosa and a certain extent
of body weight loss, and in healthy subjects, is similarly timed. Whether
or not this inference is to be extended to data from Warsaw, the
present study, by being fluorometric and thereby picking up additional
fluorogens, should prompt focus upon rhythms in substances other than
Cortisol that may also exhibit deviant characteristics i n anorexia nervosa.
1
Institutional
in relation to reference limits, in the context of this paper,
specifies 1) a population of women studied in Warsaw, 2) the fluorometric method used for Cortisol determination and 3) a certain approach in determining
body weight status for the diagnosis of anorexia nervosa. The Varsovian institutional reference standard differs from that in New York, also discussed in this
paper, by all three criteria, i.e., geography and methodologies for Cortisol determination and for assessing body weight loss. Whether any one or several of the
three differences in possibly contributing to the results here found remains to
be elucidated.
551
RlASSUNTO
Variazioni del ritmo circadiano del cortisolo plasmatico possono
indicare alterazioni della regolazione cefalo-ipotalamo-ipofisi-surrenalica
i n corso di anoressia nervosa (A.N.). I I cortisolo plasmatico e stato dosato con metodo fluorimetrico i n 22 donne con A.N. e 18 donne clinicamente sane ai tempi 06, 12, 16 e 22. Sulla base dei gruppi i livelli medi
di cortisolo erano significativamente piü alti nel gruppo di A.N. i n raffronto al gruppo d i controllo, ma i l MESOR non differisce nei pazienti
con A.N. con i l MESOR dei controlli sani. Un ritmo circadiano significativo e stato riscontrato i n entrambi i gruppi con i l metodo del « single
cosinor ». Sono stati valutati i l i m i t i di riferimento istituzionale per le
donne sane come regioni di predizione al 90% per le misure di ampiezza/
acrofase. Sei delle pazienti con A.N. hanno mostrato caratteristiche circadiane del cortisolo fuori dei l i m i t i istituzionali di riferimento per i l
paio ampiezza/acrofase dei normali. Le pazienti con A.N. le cui acrofasi
di cortisolo erano fuori dei l i m i t i di riferimento istituzionale avevano
i piü gravi deficit ponderali. I I tempo di deviazione, misurato con l'ampiezza/acrofase pesato, e i n accordo con altri comportamenti regressiv! riscontrati nelle pazienti con A.N.
552
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555
DEDICATIÖN/D£D/CA
Pag.
5
PREFAZIONE/PJRJEFACE
LORIO
REALE
LETTURA
»
MAGISTRALE
PLENARY
8
LECTURE
FRANZ HALBERG, ERHARD H A U S , E R N A HALBERG, G E R M A I N E C O R N E L I S S E N , PAOLO
SCARPELLI, BRUNETTO TARQUINI, MARIO CAGNONI, DOUGLAS W I L S O N , K E I T H
GRIFFITHS,
H U G SIMPSON,
ESTER
BALESTRA,
LORIO
REALE:
Chrono-
biologic challenges in social medicine: illustrative tasks in cardiology and oncology / Sfide cronobiologiche in medicina sociale:
enunciazione di compiti in cardiologia e oncologia
.
.
.
.
PRIMA SESSIONE
FIRST
SESSION
Cronobiologia clinica
Clinical
chronobiology
UGO MANZOLI, ANTONIO
G . R E B U Z Z I , M I C H E L E L U C E N T E : Aspetti cronobio-
logici della cardiopatia ischemica / Chronobiological
the ischemic heart disease
P.T.
SCARPELLI, L . S C A R P E L L I , R . L I V I ,
features
of
» 4 5
E . CROPPI, M . CAGNONI,
LONI, V . G I A C H E T T I , A. SEMERARO, G . FANGHI:
M . PAMPA-
Utilizzazione delle au-
tomisure multiple della pressione arteriosa e del polso nella diagnosi e nel trattamento dell'ipertensione / Utilization of multiple
blood pressure and heart rate self-measurement in diagnosis and
treatment of hypertension
CHRISTIAN BARTSCH - E L L A BARTSCH:
» 6 5
The link between the pineal gland
and cancer an interaction involving chronobiological mechanimsms /
Correlazioni tra epifisi e cancro: una interazione che coinvolge
meccanismi circadiani
BRUNETTO TARQUINI, FRANZ HALBERG:
Altered circannual
prolactin
M A U R I Z I O C E C C H E T T I N , ANGELO CARIDDI, DONATELLA CALVANI, LAURA
»105
and
T S H and circadian melatonin rhythm and risk of developing breast
cancer / Alterazioni del ritmo circannuale della prolattina e del
TSH e del ritmo circandiano della melatonina e rischio di sviluppo
del cancro della mammella
»127
MASI,
BRUNETTO TARQUINI: Aspetti cronobiologici di alcuni markers circolanti di patologia ossea / Marker rhythms in bone diseases .
.
786
» 1 3
»
149
SERGIO S E N S I ,
MARIA T E R E S A GUAGNANO,
F A B I O CAPANI:
circadian time structure / Ritmo di assunzione
temporale circadiana
GERMAINE
CORNELISSEN,
FRANZ
HALBERG, R U D O L F
Meal-timing
dei pasti e
and
struttura
Pag. 171
ENGEL,
ERNA
HALBERG,
PIERRE PASSOUANT: Chronobiology of paroxysmal central nervous
system disorders / Aspetti cronobiologici in affezioni
parossistiche
del Sistema Nervoso Centrale
» 1 8 5
BRUNETTO TAROUINI: L'ulcera peptica: cronobiologia da costrizione /
Peptic ulcer: forced chronobiology
» 195
PAOLA GALVAN, ALFONSO GRANATI, RENATO L E N Z I , G U S M A N O POGGINI, SERGIO
SQUARCIALUPI, BRUNETTO TAROUINI:
cronobiologico sociale / Shift-Work:
PIETRO C U G I N I :
nescence
II lavoro a turni:
Cronobiologia e senescenza / Chronobiology
model
and se­
C O R N E L I S S E N / FRANCA
SECOND
SESSION
Workshop on Chronobiological
Methodology
CARANDENTE,
FRANZ
HALBERG:
Circadian
and circaseptan periodicity in differential skin surface temperature
automatically monitored by polychronor / Periodicita circadiana e
circasettana nella temperatura differenziale cutanea registrata automaticamente con polychronor
MARCO C A V A L L I N I , FRANZ HALBERG, TAO L I U , G U I D O MAGNUS:
C. H E R M I D A D O M I N G U E Z ,
C.
HERMIDA
» 289
ROBERT B . SOTHERN, F R A N Z HALBERG, TODD
R . LANGEVIN: Variability of circadian acrophase of urinary potas­
sium excretion as a potential marker for cancer chronotherapy /
Variabilitä
dell'acrofase circadiana nelVescrezione di potassio urinario come marker Potenziale nella cronoterapia del cancro .
.
RAMON
» 271
Coordinated
optimization of device, administration pattern, route and time scale
for (e.g., cyclosporine) chronotherapy / Ottimizzazione
coordinata
degli strumenti, schemi di somministrazione,
vie e tempo per una
cronoterapia
(ciclosporina)
RAMON
» 209
» 229
SECONDA S E S S I O N E
Aspetti di Metodologia
Cronobiologica
GERMAINE
un modello
α social chronobiological
DOMINGUEZ,
FRANZ
HALBERG,
TODD
» 3 1 3
R . LANGEVIN:
Serial
whthe blood
cell
counts
and chronochemiotherapy
according to highest values (macrophases*) or by model characteristics (acrophases) / Conta seriata dei Globuli Bianchi e cronochemioterapia in funzione dei valori piü alti (macrofasi) ο delle caratteristiche del modello (acrofasi)
» 327
P . T . S C A R P E L L I , S . ROMANO, Μ . CAGNONI,
F . B I G I O L I , W . MÄRZ, F . HALBERG:
R . L I V I , L . S C A R P E L L I , E . CROPPI,
Blood pressure self-measurement
as part of instruction in the Regione Toscana /
della pressione arteriosa come parte dell'istruzione
Regione Toscana
KATHLEEN
L . JOHNS,
FRANZ
HALBERG, G E R M A I N E
Automisurazione
scolastica η ell a
Pag. 345
CORNELISSEN,
WOLFGANG
M Ä R Z : Chronobiology at the American international school in
Lisbon, Portugal / La cronobiologia nella Scuola
Internaz'ionale
Americana di Lisbona
VITTORIO DE LEONARDIS, M A U R I Z I O D E S C A L Z I , PIERO C I N E L L I :
»
367
»
385
»
395
Lautoritmo-
metria come guida indispensabile alia cronoterapia deH'ipertensione
arteriosa / Autorhythmometry
as an essential guide to chronotherapy of hypertension
ROBERT Β. SOTHERN, FRANZ HALBERG: Circadian and infradian blood pres­
sure rhythms of a man 20 to 37 years of age / Ritmi circadiani e
infradiant della pressione sanguigna in tin uomo, da 20 a 37 anni
dL.pta
N E L S O N MARQUES, M I R I A N D . MARQUES, F R A N Z HALBERG, ROBERT Β.
SOTHERN:
Ambulatory cardiovascular monitoring by an adult man for 16
days after transequatorial-transmeridian flight / Monitoraggio car­
diovascular e ambulatoriale di un uomo adulto per 16 giorni dopo
un volo transequatoriale-transmeridiano
G . SLOVER, R . B . SOTHERN, L . E . S C H E V I N G , T . S . T S A I , F . HALBERG:
»
417
»
427
Urinary
and self-measured circadian and circatrigintan rhythms before
and after a human manic episode / Ritmi circadiani e circatrigintani urinari, automisurati,
prima e dopo un episodio maniacale nell'uomo
SALVATORE ROMANO: Alcuni metodi cronobiologici di analisi statistica
utili in fase diagnostica e terapeutica / Some chronobiological me­
thods of statistical analysis usefull in diagnostic and
therapeutic
approaches
»445
MARCO B O S S I N I : Le applicazioni del personal computer in cronobiologia /
The personal computer in chronobiology
»511
TERZA
SESSIONE
THIRD
a) Comunicazioni
BOGUSLAWA
BARANOWSKA,
a)
MARIA
SESSION
Communications
LAZICKA-FRELEK,
BARBARA
MIGDALSKA.
STEFAN Z G L I C Z Y N S K I , BARNETT Z U M O F F , R . S . ROSENFELD, G E R M A I N E COR­
N E L I S S E N , H E L M U T ARBOGAST, E L K E E C K E R T , FRANZ HALBERG: Circadian
timing of serum Cortisol in patients with anorexia nervosa / Timing
del ritmo circadiano del cortisolo sierico in pazienti con anoressia nervosa
»535
PlETRO CüGINI, PlERNATALE LUCIA, GlULIA MüRANO, CLAUDIO LETIZIA, DOMENICO SCAVO: Contributo cronobiologico clinico alio studio dei
determinanti del ritmo circadiano della pressione arteriosa / A
chronobiologic
contribution
to the scrutiny of determinants for
blood pressure circadian rhythmicity
PAUL J . MEIS,
F R A N Z HALBERG, FRANCE B O Y E T T E - K O U R I : Hyperbaric index
guages excess blood pressure during pregnancy / La misurazione
dell'indice iperbarico sovrastima
la pressione sanguigna in gravidanza
RICHARD D O E , H E L E N H R U B Y , P H I L I P GOLDMAN,
MAURO
D E S C A L Z I , VITTORIO DE LEONARDIS,
GUICCIARDI,
PIERO
CINELLI:
»
569
»
575
FRANZ HALBERG: Circannual
rhythm in glucocorticoid receptors of circulating polyomorphonuclears in clinically healthy adults / Ritmo circannuale dei ricettori dei glicocorticoidi nei polimorfonucleati
in soggetti adulti clinicamente sani
MAURIZIO
Pag. 557
FRANCO
SALVATORE
Elettrocardiografia
FABIANO,
dinamica
e
fattori di rischio per la cardiopatia coronarica: un approccio cronobiologico / 24 - Hour electrocardiogram
monitoring
in the
assessment
of the influence on chrono electrocardiographic
parameters by risk factors for coronary heart disease .
.
.
.
» 5 8 1
V I N C E N Z O E S P O S I T O , MARIA ROSARIA CAFARO, SERGIO D E A N G E L I S , ALDO E R A M O ,
G I U S E P P E L O I U D I C E , BRUNO D'ALESSANDRO: Variazioni circadiane della
secrezione di L H ed F S H in pazienti affetti da ipogonadismo ipogonadotropo « isolato » ( I H H ) / Twenty four hours rhythm of LH
and FSH release in patients with « isolated»
hypo gonadotropic
hypogonadism (IHH)
VINCENZO
ESPOSITO,
MAZZELLA,
GIUSEPPE
ANNUNZIATA
L O IUDICE, MAURIZIO
OFFICIOSO,
CARMELA
LOMBARDI,
RISPOLI,
BRUNO
CARMINE
D'ALES-
SANDRO: Variazioni circadiante della secrezione di T S H , Prolattina
e Cortisolo in pazienti affetti da ipogonadismo ipogonadotropo
« isolato » ( I H H ) / Circadian variations of TSH, proclactin
(PRL),
Cortisol secretion in patiens with « isolated»
hypo gonadotropic
hypogonadism (IHH)
E T T O R E F E R R A R I , P I E R ANGELO BOSSOLO,
PETRAGLIA, ANDREA
» 595
ALBERTO V A I L A T I , L U I G I MAGNANI,
G I U S E P P E M A R E L L I , E M I L I A MARTIGNONI,
NAPPI, F E L I C E
* 589
GIUSEPPE MICIELI,
R . GENAZZANI:
GIUSEPPE
Crono-patologia
en-
docrina e neuro-vegetativa nelle cefalee primarie / Endocrine and
autonomic chrono-pathology in primary headache syndromes .
.
» 603
FRANK W . FINGER: The effect of age on circadian pattern of activity /
Effetto delVetä sul comportamento
circadiano delVattiviia .
.
» 619
K A L V A SHANKARAIAH,
FRANZ
HALBERG, EDMOND Y U N I S ,
ADA L . M . WATSON:
Alternate-day feeding alters the circadian system, reduces breast
cancer incidence and prolongs life / La nutrizione a giorni alterni
789
modified il sistema circadiano, riduce la incidenza
della mammella e allunga la vita, nel ratio
E R N A HALBERG, FRANZ HALBERG, S H A H I D RAMAM,
SHIRIN
del
cancro
Pag. 633
I . R A M , DEVENDRA
P. D U B E Y , FRANCA CARANDENTE: Circadian rhythmic aspects of gastric
ulcerogenesis in rats / Aspetti ritmici circadiani
nell'ulcerogenesi
gastrica nel ratio
»
649
»
657
M O R T I M E R L I P S E T T , GEORGE CHROUSOS, F R A N Z HALBERG: Alteration of circa-
dian serum Cortisol rhythm characteristics in a father and son /
Alterazioni delle caratteristiche del ritmo circadiano del cortisolo
serico nel padre e nel figlio
GIUSEPPE
L O IUDICE,
VINCENZO
PERNA, ADA ROMANO, B R U N O
ESPOSITO,
PASOUALINA
D'ALESSANDRO:
FEDERICO,
Comportamento
BIANCA
nelle 24
ore della tiroxina libera e della frequenza cardiaca in pazienti con
adenoma tiroideo funzionante e eutiroidismo / The 24-hour plasma
free thyroxine and heart rate profile in euthyroid patients
with
functioning adenoma of the thyroid
GIOVANNI
MURIALDO, ANDREA
D E MARIA,
MARIA
» 6 7 1
L U I S A BONURA, PAOLA M A -
STURZO, ALESSANDRO POLLERI: L a periodicitä secretoria degli adenomi
ipofisari / The secretory
periodicity of pituitary adenomas .
.
G A B R I E L E N E N C I , ANGELO CARIDDI, PAOLA GALVAN, MARIA
RIZIO C E C C H E T T I N , BRUNETTO T A R Q U I N I :
BENVENUTI,
jyiAU-
Valutazione della gastrina e
del pepsinogeno sierico in turnisti / Serum gastrin and pepsinogen
in shift-workers
ALESSANDRO
BIANCO,
PANCONESI,
BRUNO
ANSELMI,
GIANCARLO F R A N C H I ,
CARLO CURRADI,
PASQUALETTI, P I E R L U I G I A C I T E L L I ,
RAFFAELE
LANTONIO, VITTORIO F E S T U C C I A , LAURA N A T A L I :
TARQUINI:
/
.
RYBA,
FRANZ
HALBERG, ROBERT
C A S A L E , DOMENICO C O -
B . SOTHERN,
OLGA
9
SALTI,
FIORELLA
G A L L U Z Z I , GIANNA
CHITI,
CARMELO L A C A U Z A ,
ANGELO CARIDDI, ANTONIO P I E R I , BRUNETTO TARQUINI,
SALVATORE S E M I -
NARA: Variazioni circannuali del T S H sierico in un gruppo di bam-
790
» 7 1 5
PETRE-QUADENS,
P . J . WALTER, F . LOSKOT: Chronobiologic cardiovascular and other
monitoring before and after coronary bypass surgery / Monitoraggio cardiovascolare cronobiologico e non, prima e dopo bypass
coronarico
ROBERTO
» 701
R i t m i circannuali della
prolattina e del testosterone in soggetti sani anziani ed in pazienti
con ipertrofia prostatica benigna prima e dopo adenomiomectomia /
Circannual rhythms of prolactin and testosterone in healty elderly
subjects and in patients whit benign prostatic hypertrophy
before
and after removal of adenoma
RENE
» 693
PIER LUIGI D E L
FEDERICO S I C U T E R I , BRUNETTO
Bioritmi della reattivitä vasculare alia serotonina nell'uomo
Biological rhythms of vascular reactivity to serotonin in man .
PAOLO
» 679
» 729
bini obesi / Circannual
variations
in serum TSH of obese children
THIRD
b) Short
TERZA SESSIONE
b) Intervent!
MARY C . GANNON, FRANK Q. N U T T A L L , FRANZ HALBBRG:
Pag. 741
SESSION
Reports
Circannual changes
in murine cardiac glycogen, glycogen synthase, phosporylase, plasma
insulin and glucose and body weight / Variazioni circannuali del
glicogeno, della glicogeno-sintetasi e della fosforilasi cardiaci, delVinsulina e glucosio plasmatici e del peso corporeo nel topo .
»
749
H. ARBOGAST, R . SOTHERN, F . HALBERG : Cosinor assessment of differences
in M E S O R and acrophase of plasma luteinizing hormone ( L H ) in
teenagers with Stein-Leven thai syndrome (S) and clinically healthy
(H) girls / Valutazione con il cosinor delle differenze nel MESOR e
nella acrofase deU'ormone luteinizzante (LH) nel plasma in giovani
con sindrome di Stein-Leventhal
(S) ed in ragazze
clinicamente
sane (H)
JAIME
I G L E S I A S , ROBERTO V I L L A E S C U S A , V I C E N T E GOYANES,
C A M I L L O V E I R A S , JOSE" OTERO R A I C E S , FRANZ HALBERG:
LORENZO
O. M A R E L L I , R. M A U R I ,
M. R E S E N T I N I ,
G . E S P O S T I , F . FRASCHINI, F . HALBERG:
P . FRANCO, D .
of
»
761
»
763
»
767
»
771
ESPOSTI,
Chronomodulatory sequence
of stimulation and inhibition of human N K cell activity by melato­
nin given in the afternoon to nocturnally resting subjects / Sequenza
cronomodulatoria
della stimolazione
e dell'inibizione
dell'attivitä
delle cellule NK umane da parte della melatonina data nel pomeriggio a soggetti che riposano di notte
K R I S T I N A ORTH-GOMER,
759
OTERO,
Comparison
circadian variation in blood of patients with cancer and in appa­
rent clinical health / Confront ο fra variazioni circadiane di alcuni
parametri circolanti in pazienti con cancro e pazienti clinicamen­
te sani
P. LISSONI,
»
G E R M A I N E C O R N E L I S S E N , F R A N Z HALBERG, ROBERT B .
SOTHERN, TORBJÖN AKERSTEDT: Relative merits of chronobiologic vs.
conventional monitoring of ventricular ectopic beats ( V E B ) / Vantaggi del monitoraggio cronobiologico nei confronti di quello convenzionale nella valutazione dei battiti ventricolari ectopici .
SALVADOR
SANCHEZ
DE LA PENA, N E L S O N
MARQUES,
FRANZ
HALBERG:
Inf ra-
dian modulation of corticosterone production by hamster adrenals
in vitro / Modulazione infradiana della produzione di corticosterone
nella surrenale di criceto in vitro
CONCLUSIONI
BRUNETTO
CONCLUSIONS
TAROUINI
791