Neurotransmitter impairments in MDI can also affect
hormonal neuroregulation. Therefore, we decided to study
the integrated concentration of growth hormone (IC-GH)
and its 24-h secretory profile in this pathology. Ten
women with major depressive illness (MDI) (three premenopausal
and seven postmenopausal) were evaluated. Samples were
obtained every 30 min using a constant withdrawal pump.
Growth hormone (GH) pulses were analyzed by Cluster System.
Twenty-four IC-GH was evaluated as area under the curve
(AUC) and the following results were found:
Depressed (D) = 429.15 + 367.9 vs. controls (C) = 1281.07
+ 379.77 (p < .008); nocturnal IC-GH: D = 220 + 274.0
vs. C = 739.52 + 378.15 (p < .02). No statistically
significant differences were found between D and C in
diurnal IC-GH or in the number of nocturnal or diurnal
pulses. Adrenal (cortisol at 0800h, 2300h and post-suppression
1 mg of dexamethasone) and thyroid (T3, T4 0800h and 1700h
TSH) evaluations did not show statistically significant
differences between D and C women. In conclusion, patients
with MDI present a decrease in total GH secretion at the
expense of the nocturnal period, probably due to changes
in the neurotransmitters that would be involved in depression.
Keywords-Depression; Endogenous depression; Growth hormone;
GH neurosecretory dysfunction; GH secretory profiles.
It is known that the changes in neurotransmission occurring
in major depressive illness can also affect the neuroregulation
of the various hormonal axes. The most consistent neuroendocrine
abnormalities present in endogenous depression have
been hypercortisolism, lack of cortisol suppression
by dexamethasone, and blunted TSH response to TRH. The
results obtained from studies of other axes, such as
the prolactin and dynamic tests have been performed
to study the hypothalamic-pituitary-somatotropic axis,
and the GH response to insulin-induced hypoglycemia,
l-dopa, clonidine and other hypothalamic neuropeptides
such as TRH, GHRH and LHRH have been described. Even
though basal GH levels are normal (Brambilla et al.,
1988, some studies have described different alterations
in the 24-h GH secretory profile. Mendlewicz et al.
(1985) reported diurnal hypersecretion with no changes
in the amount of GH secreted at night, whereas Rubin
et al. (1990) did not find significant differences in
the 24-h secretory profiles. Other authors studied only
the nocturnal period (Jarret et al., 1990; Schildkraut
et al., 1975; Steigert et al., 1989) agreeing that GH
secretion appeared to be lower during this period. Because
of these contradictory results, we decided to study
diurnal and nocturnal GH secretion in woman with major
depressive illness in order to gain better knowledge
of the somatotropic impairments that may occur in this
SUBJECTS AND METHODS
Ten women with major depressive illness (three premenopausal
and seven postmenopausal), normal weight and no systemic
illness were evaluated. None of the patients had any
history of alcoholism, drug addiction or endocrinopathies.
Four volunteer women (one premenopausal and three postmenopausal)
were studied as controls. They did not have a personal
or family history of psychiatric illness.
The psychiatric diagnosis was made in accordance with
the criteria established by the Diagnostic and Statistically
Manual III Edition Revised (DSMIII R) for major depressive
illness (1987). The severity of depression was assessed
using the Hamilton Scale (Hamilton, 1987) the same day
hormonal study was performed. Patients 1, 2, 5, 7, 8,
9 and 10 were diagnosed as unipolar and nos 3, 4 and
6 as bipolar. Five of them had never received antidepressant
medication and the remaining five were studied after
a 30-day drug-free period. These patients received different
associations of a tricyclic antidepressive (desipramine,
imipramine or clomipramine), neuroleptics (levomepromazine
or clozapine) and benzodiazepines (clobazam, flunitrazepam
or clonazepam). Patients 4, 5 and 6 received eight series
of electroconvulsive therapy (ECT). In the case of patient
no. 6 it was associated to carbamazepine.
The mean age for patients was 49.8 years (range: 40-59
years) and for controls 49.5 years (range: 45-54 years).
The patients reported no major alterations in their
alimentary behavior and their body mass index (BMI)
was 24.72 (range: 20.5-28.2). Control subjects had normal
weight and BMI of 24.8 (range: 20.8-27).
For GH evaluation, patients entered the laboratory at
0800h the day test was performed. A sterile non-thrombogenic
catheter was inserted into a forearm superficial vein
and connected to a constant withdrawal pump to determine
integrated concentrations (CORMED ML-6) (Kowarsky et
al., 1971). The first sample was discarded to avoid
possible effects related to the venipuncture stress.
Samples were collected every 30 min and frozen at –20°C
until assayed. Patients were ambulatory during daytime
and their food intake was not restricted.
The thyroid and adrenal axes were also studied. Morning
T3 and T4 (0800h) and TSH (0800h and 1700h) were measured
to evaluated the thyroid axis. In patient no.5 a TRH
test was performed because she presented elevated 0800h
TSH levels. We administered 200µg of TRH (Elea
lab., Buenos Aires, Argentina) intravenously obtaining
blood samples cortisol with samples obtained at 0800h
and 2300h. Dexamethasone (1.0 mg) was administered at
2300h, measuring plasma cortisol the next day at 1600h.
GH was measured by a double antibody radioinmunoassay
(RIA) with reagents from Diagnostic Products Corporation
(DPC, California, USA). The interassay quality control
showed the following coefficients of variation (CV):
CV % GH: 10.2% (mean =2.6 ng/ml) and 6.3% (mean = 18
ng/ml) with a sensitivity of: 0.76 ng/ml.
T3 and T4 were measured by RIA with reagents from DPC
and TSH was measured by IRMA with two monoclonal antibodies
and a magnetic solid-phase separation (reagents from
SERONO Diagnostic S.A., Coinsins, Switzerland).
The interassay quality control showed the following
3 coefficients of variation:
CV % T3: 6.1%(mean = 115 ng/dl) and 4.5 % (mean = 207
CV % T4: 4.1 % (mean = 3.95 µg/dl); 4.2 % (mean
= 9.8 µg/dl and 5.5 % mean = 16 µg/dl.
CV % TSH: 5.8 % (mean = 1.02 µIU/ml); 4.4 % (mean
= 2.8 µIU/ml) and 4.6 % (mean 15.5 µIU/ml).
Cortisol was measured with DPC reagents and the interassay
coefficients of variation were as follows: CV % cortisol:
5.2 % (mean = 16.5 µg/dl and 9 % (mean =1 µg/dl).
Pulses were evaluated using the Cluster Analysis program
described by Veldhius & Johnson (1986). The total
number of pulses, diurnal (1000-2200h) and nocturnal
(2200-1000h) area under the curve (AUC) were evaluated
in all patients. The statistical calculations were made
using the Mann-Whitney and Wilcoxon tests.
Depressed patients secreted less GH over 24 h than controls.
The statistical analysis of the results obtained showed
that the 24-h IC-GH, evaluated as AUC, was 429.15 +
367.9 in depressives vs. 1281.07 + 379.77 in controls
(p < .008). This difference persisted for the nocturnal
period, being 220 + 274.01 in depressed patients vs.
739.52 + 378.15 in controls (p < .02).
All the sleep periods occurred during this time.
Conversely, no significant differences were found between
both groups in the amount of GH secreted during the
diurnal period (Fig. 1). There were no significant differences
between depressives and controls in the number of diurnal,
nocturnal and 24-h pulses. No significant differences
were found in diurnal vs. nocturnal IC-GH. The decrease
in the 24-h AUC found in patients vs. normal controls
is shown individually in Fig. 2, following a sequential
order based on the amount of GH secreted, and in the
secretory profiles of each subject. We found that the
severity of depressive symptoms evaluated by the Hamilton
Rating Scale did not correlate with the IC-GH in 24
h ( r_ = .3590) nor with the nocturnal IC-GH (r_ = .2529).
Adrenal evaluation was normal in nine of the 10 patients
studied, but one of them did not achieve good post-dexamethasone
suppression at 1600h. No significant differences were
found between depressives and controls for cortisol
levels at 0830h, 2300h or post-dexamethasone. The TSH
morning measurement (0830h) was elevated in one of the
10 patients studied, with no changes in the evening
concentration (1700h). This patient showed a normal
TSH response to the TRH test. No abnormalities were
observed in any of the parameters evaluated in controls.
No significant differences were found between depressed
patients and controls in T3, T4 morning TSH and evening
TSH levels. Evening TSH in depressed patients was significantly
decreased with respect to morning levels (p < 0.2).
1: Growth Hormone (GH) relationship between depressive
patients (n=10) and controls (n=4)
GH daily production (measured as AUC) shows that depressed
patients present a statistically significant decreased
in hormonal production over 24 h. This decreased in
total GH occurred mainly at the expense of nocturnal
GH. Diurnal secretion also showed a trend towards decreased
but did not attain statistical significance when compared
with the control group. These findings are in partial
agreement with those of other authors (Galard et al.,
1988; Jarret et al., 1990; Schildkraut et al., 1975).
Jarret et al. (1990) reported a decrease in GH during
the nocturnal period without evaluating the 24-h secretory
profile. However, Mendlewicz et al. (1985) found a diurnal
hypersecretion which did not decreased during the nocturnal
period. These discrepancies could be attributed both
to the different methods used for the research and to
the heterogeneity of the patients evaluated. Mendlewicz
divided depressed patients into unipolar and bipolar,
finding changes in unipolar patients more marked than
in bipolar ones. Other authors make no distinction between
both groups (Rocatagliata et al., 1982; Zohar et al.,
1985), which, together with the diversity of criteria
used in research methods, makes it impossible to obtain
comparable results. The bipolar patients included in
our study were not found to show secretory profile that
differentiated them from the rest of the group. What
is worth highlighting is the case of patient no. 5,
whose secretory profile is similar to those of the control
group. All possibilities of diagnostic error are excluded
in this patient, since she presented the most severe
depression picture, melancholia and history of suicide
The marked difference between this secretory profile
and the rest of the depressed patients suggest that
there might be other factors ----hitherto unidentified----
that could be related to various inherent neurochemical
abnormalities. On the basis of this hypothesis, different
subpopulation could be detected by studying a significantly
larger number of cases. Besides, due to individual characteristics
of the patient, the wash-out period for the previously
received drug (carbamazepine) may have been insufficient
or the electroconvulsive therapy may have been produced
Another variable to be considered in depressed patients
is the frequency of pulses or secretory peaks. Mendlewicz
found a larger number of peaks associated with diurnal
hypersecretion, while we did not find any differences
in the number of peaks as compared with the control
group. It should be noted that peak detection is directly
related to the sampling method, since the sampling frequency
can bring about differences in peak detection. On this
basis, implementing what Albertsson-Wikland & Rosberg
(1988) had described and according to our own experience
in short stature (Fideleff et al., 1992), we considered
a 30 min frequency to be the most appropriate to identify
the detectable GH performed every 20 min, Holl et al.
(1991) observed a 64 % decrease in the pulses detected
by the Cluster System. Hence, our system might not have
been sensitive enough to detect small variations in
Other factors, such as hormonal status, nutritional
intake and sleep patterns influence GH secretion.
As to hormonal status, some investigators (Mendlewicz
et al.,1985; Rocatagliata et al., 1982) performed their
studies in male patients in order to prevent estrogens
from influencing the GH secretory profile. Others (Rubin
et al., 1990) included patients of both sexes but analysed
both groups separately. In spite of the known stimulatory
effects of estrogens on GH (Faria et al., 1992) we did
not find that premenopausal women secreted more GH than
postmenopausal women. Ho et al. (1987) report that elderly
women secrete less GH than young women and that difference
is unrelated to estrogen effects. On the other hand,
according to Iranmanesh et al. (1991), the age and the
body mass index (BMI) account for 60 % of the variability
observed in the GH production rate. For this reason,
our study included only female patients with a small
age range, since it was limited to women between 40
and 59 years.
Regarding the GH-sleep relationship, it is known that
GH is secreted with the EEG slow waves. Even thought
we did not evaluated this phenomenon, we observed that
all controls and eight of the 10 depressed patients
presented a secretory period in the first half if the
night. The remaining two depressed patients (case nos
9 10) showed a dissociation of the sleep/GH release
relationship, which is not striking, since it is usually
observed from 50 years of age (Carlson et al., 1972)
which affects their quality of life, leading to social
isolation, emotional instability and disturbances in
their sexual life, all these being symptoms also observed
in depression. Symptoms improved in these patients after
treatment with recombinant GH (Almqvist et al., 1986;
Bengtsson et al., 1993; McGauley, 1989).
With regard to thyroid evaluation, only one patient
showed increased TSH values. However, she had no clinical
manifestations of hypothyroidism, normal T3 and T4 values,
negative antibodies, normal TSH response to TRH, and
a decrease in evening TSH. The depressed patients studied
by our group also presented this decrease in evening
values. Which would confirm the normality of the thyroid
We conclude that under the conditions of this research,
patients with major depressive illness show a decrease
in total GH, especially at the expense of the nocturnal
period. This decrease in GH could have contributed to
the depressive symptomatology of the patients studied.
Such impairments in the secretory pattern could be due
to changes in the activity of one or more neurotransmitter
system which would be involved in the pathophysiology
of this disease.
2: Integrate concentration of Growth Hormone (IC-GH)
in depressive patients (n=10) and controls (n=4)