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Hypothalamus and pituitary volume in schizophrenia: a structural MRI
Anne Klomp, P. Cédric M. P. Koolschijn, Hilleke E. Hulshoff Pol, René S. Kahn and Neeltje E. M. Van Haren
The International Journal of Neuropsychopharmacology / Volume 15 / Issue 02 / March 2012, pp 281 288
DOI: 10.1017/S1461145711000794, Published online: 20 May 2011
Link to this article: http://journals.cambridge.org/abstract_S1461145711000794
How to cite this article:
Anne Klomp, P. Cédric M. P. Koolschijn, Hilleke E. Hulshoff Pol, René S. Kahn and Neeltje E. M. Van Haren (2012).
Hypothalamus and pituitary volume in schizophrenia: a structural MRI study. The International Journal of
Neuropsychopharmacology,15, pp 281288 doi:10.1017/S1461145711000794
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Hypothalamus and pituitary volume in
schizophrenia: a structural MRI study
Anne Klomp, P. Ce ´dric M. P. Koolschijn, Hilleke E. Hulshoff Pol, Rene ´ S. Kahn
and Neeltje E. M. Van Haren
Rudolf Magnus Institute for Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands
Volumetric differences of the hypothalamus and/or the pituitary gland tend to support involvement of
the HPA axis in psychotic disorders. These structures were manually outlined in 154 schizophrenia
patients and 156 matched healthy comparison subjects by MRI brain images. Linear regression analyses
were performed to investigate differences in volume between groups. Moreover, the effects of illness
duration and type of medication were investigated. No significant differences were found between
patients and healthy controls in volumes of the hypothalamus and pituitary gland. In addition, there were
no differences in volumes between patients with short and long illness duration. There was a trend
towards patients receiving typical antipsychotic medication at the time of scanning having larger pituitary
volumes than patients receiving atypical medication. These findings indicate that volume decreases
in brain structures important for the normal functioning of the HPA axis are not present, either in
recent-onset or chronically ill patients.
Received 29 January 2011; Reviewed 2 March 2011; Revised 22 April 2011; Accepted 25 April 2011;
First published online 20 May 2011
Key words: Hypothalamus, pituitary gland, schizophrenia, structural magnetic resonance imaging.
There is convincing evidence that stressful life events
can trigger psychosis in individuals with a genetic
predisposition to be vulnerable for stress (Corcoran
et al. 2003; Gispen-de Wied & Jansen, 2002). An
important model aiming to explain the underlying
(neuro)biological mechanisms is the neural diathesis-
stress model for schizophrenia (Walker & Diforio,
plays a leading role in this model. In response to
psychological and/or physiological stressors, neural
signals are converted into an endocrine response at the
level of the hypothalamus, which results in activation
of the pituitary gland and finally release of the stress
hormone cortisol by the adrenal gland. A prominent
role for the HPA axis in the development of psychotic
disorders like schizophrenia has been suggested
(Walker et al. 2008).
Volumetric differences of the hypothalamus and/or
the pituitary gland tend to support involvement of
the HPA axis in psychotic disorders. As reviewed by
Pariante (2008), the most notable findings so far are:
(1) increases in pituitary volume during the prodromal
phase and shortly after psychosis onset; (2) decreases
in volume in chronically ill patients; and (3) additional
enlarging effects as a result of antipsychotic medi-
cation intake, particularly for typical antipsychotics
(Nicolo et al. 2010). Smaller (Goldstein et al. 2007) as
well as larger (Hulshoff Pol et al. 2005; Koolschijn et al.
2008) hypothalamus volumes have been reported.
However, these studies consisted only of small sam-
ples of patients and the latter two studies differed
notably from the Goldstein et al. study in segmentation
procedures and boundaries that were used. The aim
of the current study is to compare the volumes of
the pituitary gland and the hypothalamus between
patients with schizophrenia and healthy comparison
subjects by means of structural magnetic resonance
brain images. To our knowledge, this is the first study
to investigate the volumes of both these structures in
the same group of subjects and to include a relatively
large sample. Since it has been suggested that disease
duration and medication intake (typical/atypical and
Address for correspondence: N. E. M. Van Haren, Ph.D., Rudolf
Magnus Institute of Neuroscience, Department of Psychiatry,
A.01.126, University Medical Center Utrecht, Heidelberglaan 100,
3584 CX Utrecht, The Netherlands.
Tel.: +31887557130Fax: +31887555443
International Journal of Neuropsychopharmacology (2012), 15, 281–288. f CINP 2011
prolactin enhancing/sparing) might affect pituitary
volume (Pariante, 2008), these variables were taken
A total of 159 patients with schizophrenia and
158 healthy comparison subjects were included. All
subjects received a magnetic resonance imaging
(MRI) scan of the brain as part of a study investi-
gating structural brain abnormalities in schizophrenia
(Hulshoff Pol et al. 2002). For the current study, 154
patients and 156 controls were included (some data
were lost because the quality of scans was too poor to
perform manual segmentation).
The presence or absence of psychopathology was
established for all subjects using the Comprehensive
Andreasen et al. 1992) and was assessed by two inde-
pendent raters; diagnostic consensus was achieved in
the presence of a psychiatrist. Age at onset of illness
was defined as the first time a patient experienced
psychotic symptoms, as obtained from the CASH
interview. Duration of illness was defined as the time
between age of onset and age at scan acquisition.
Details of recruitment have been described previously
(Hulshoff Pol et al. 2002). All patients were receiving
antipsychotic medication at the time of their scan.
(See Table 1 for the demographic characteristics.) This
study was approved by the medical ethics committee
for research in humans of the University Medical
Center Utrecht, The Netherlands. Written informed
consent was obtained from all subjects.
All images were acquired on a Philips NT scanner
operating at 1.5 T. T1-weighted three-dimensional
fast-field echo (3D-FFE) scans with 160–180 contigu-
ous coronal slices [echo time (TE)=4.6 ms, repetition
time (TR)=30 ms, flip angle=30x, 1r1r1.2 mm3
voxels], and T2-weighted dual echo–turbo spin echo
(DE-TSE) scans with 120 contiguous coronal slices
(TE1=14 ms, TE2=80 ms, TR=6350 ms, flip angle=
90x, 1r1r1.6 mm3voxels) of the whole head were
used for quantitative measurements. MRI processing
methods have been described previously (Hulshoff
Pol et al. 2002). Images were coded to ensure investi-
gator blindness to subject identification and diagnosis;
scans were placed into Talairach frames without
scaling and corrected for inhomogeneities in the
magnetic field. Segmentation of the hypothalamus, its
mamillary bodies and the pituitary gland were
performed following protocols developed at our in-
stitute, using Display (http://www.bic.mni.mcgill.ca/
ServicesSoftware/MINC). A segmentation protocol
for the hypothalamus had been developed previously
(Hulshoff Pol et al. 2006), but was changed to include
the separate segmentation of the mamillary bodies.
For 119 subjects a hypothalamus segment was already
present; these were adjusted according to the new
protocol. Tracing was performed slice by slice on
T1-weighed images in coronal orientation. Axial and
sagittal orientations were used for reference when the
segmentation boundaries in the coronal view were
Mamillary bodies (Fig. 1a,b):
Anterior: first coronal slice in which the mamillary
bodies ‘pop up’ as part of the hypothalamus.
Lateral: darker grey of the hypothalamus or the
bundles of white matter that surrounds it.
Dorsal: floor of the 3rd ventricle.
Ventral: CSF-filled suprasellar cistern.
Posterior: very last slice in which the mamillary
bodies are still visible.
This resulted in an average of five slices in which
the mamillary bodies could be traced.
Hypothalamus (Fig. 1a,b):
Anterior: first coronal slice after the anterior com-
Posterior: mamillary bodies.
Dorsal: AC–PC (posterior commissure) plane in
transversal section, which approximates the hypo-
Ventral: where the optic chiasm, infundibular stalk
or the mamillary bodies begin.
Lateral: bundles of white matter.
This resulted in an average of 10 slices in which the
hypothalamus could be traced. The third ventricle
is removed from the segments by multiplying the
segment with the whole brain mask.
Pituitary gland (Fig. 1c, d):
Anterior and ventral: sphenoid sinus.
Lateral: cavernous sinuses.
Posterior: dorsum sellae.
Dorsal: diaphragma sellae.
The infundibular stalk was excluded from the
segment. This resulted in an average of 10 slices in
which the pituitary gland could be traced.
All segmentations were performed by A.K. The
intra-rater reliability of the volume measurements
282A. Klomp et al.
determined by the intra-class correlation coefficient
(ICC) in 10 brains was as follows: hypothalamus
pituitary gland (ICC=0.96).
Groups were compared on demographic variables,
using an independent-samples t test for continuous
variables and Pearson’s x2for categorical variables.
Group differences in the volumes of the hypothalamus
(including and excluding the mamillary bodies), the
mamillary bodies and pituitary gland were examined
using linear regression analysis with the volume of
interest as dependent variable, and group, age, sex,
and intracranial (IC) volume as independent variables.
For significant group differences the analyses were
repeated adding total brain (TB) volume instead of
IC volume as an independent variable. In addition,
main effects of age and sex and their interaction with
group were investigated.
The patient group was divided in two subgroups
based on the type of medication used at the time of
scan (typical or atypical antipsychotic medication) or
on illness duration (<2 yr or o2 yr). For a subsample
of patients (n=106), detailed information about
medication intake was available making it possible to
investigate the effect of using prolactin-enhancing (all
typical medication and the atypicals risperidone and
amisulpiride) or prolactin-sparing (all other atypicals)
antipsychotic medication. Volumes of interest were
compared between groups using linear regression
analyses with volume of interest as dependent vari-
able, group [typical/atypical or prolactin-enhancing/
prolactin-sparing or illness duration (<2 yr or o2 yr)],
Table 1. Demographic, clinical and volumetric information for both groups
Characteristic or measure
Healthy control subjects
Level of educationa(yr)
Parental level of education (yr)
Age of first symptoms (yr)
Illness duration (yr) (range)
Medication at time of scan (typical/atypical/unknown)
Patients with extended information on (lifetime)
Medication freecor unknown
Cumulative medication intake (HEQ)d(range)
Hypothalamus (no mamillary bodies)e
N gives the total number of reliable segments per structure in each group.
aNot matched for subject’s level of education.
bProlactin-enhancing: typical antipsychotics, risperidone, and amisulpiride. Prolactin-sparing: any of the other atypical anti-
cMedication free: no medication for at least 1 month at the time of scan acquisition.
dCumulative antipsychotic medication intake: the total amount of medication (lifetime) used at the time of scan acquisition in
haloperidol equivalents (HEQ).
eDue to segmentation difficulties (e.g. blood vessels blocking view of the structure, poor quality scans, borders indefinable, etc.),
it was not possible to obtain a reliable segment of all three structures in every participating subject.
Hypothalamus in schizophrenia283
age, sex and IC as independent variables. Finally,
within each illness-duration group those on typical
antipsychotic medication were compared to those
on atypical medication, and those with prolactin-
enhancing medication were compared to those with-
out for all volumes (for numbers per group see Table 2.
The SPSS 17.0 statistical package for Windows
(SPSS Inc., USA) was used for all statistical analyses.
All linear regression analyses were performed with a
two-tailed alpha level of 0.05.
Uncorrected mean volumes of the hypothalamus,
mamillary bodies and pituitary gland for both groups
are shown in Table 1. There were no significant
and healthy control subjects for the hypothalamus
[b=x0.01 (S.E.=0.01) ml, p=0.49], mamillary bodies
[b=x0.002 (S.E.=0.004) ml, p=0.53], and the pituitary
gland [b=0.02 (S.E.=0.01) ml, p=0.26].
Main effects for sex were found for the hypo-
thalamus [including the mamillary bodies; b=0.05
(S.E.=0.02) ml, p=0.01; larger volumes in males
compared to females]and
[b=x0.09 (S.E.=0.02) ml, p<0.001; larger volumes in
females compared to males]. For the mamillary bodies
separately a main effect for sex was significant at trend
level (p=0.065). No grouprsex interaction effects
A main effect for age was found for hypothalamus
[b=x0.004 (S.E.=0.001) ml, p<0.001]. While no sig-
nificant main effect for age was found in the mamillary
bodies, there was a significant interaction effect
Fig. 1. The hypothalamus, mamillary bodies and pituitary gland by magnetic resonance imaging (MRI). The hypothalamus
(red) and the mamillary bodies (green) in a coronal T1-weighed MR image, (a) without and (b) with segment. The pituitary gland
(red) in (c) coronal-oriented and (d) sagittal-oriented T1-weighed MR image.
Table 2. Number of patients on typical/atypical or
prolactin-enhancing/sparing medication for both
recent-onset (illness duration <2 yr) and chronically ill
(illness duration o2 yr) patients
Five patients did not receive medication at the time of scan
(i.e. they were not medication-naive). One patient received
both typical and atypical antipsychotic medication at the
time of scan.
284A. Klomp et al.
between group and age [b=0.001 (S.E.=0.001) ml,
p=0.02] representing an larger increase of 0.001 ml/yr
(0.4%) in patients compared to controls. Controls
showed only a very subtle decrease with increasing
age. No main effects of age or grouprage interaction
were found for the pituitary gland.
No significant differences in hypothalamus or
pituitary volumes were found between patients with
short-duration of illness (<2 yr, n=26) and long-
duration of illness (o2 yr, n=127). The patient group
with an illness duration of <2 yr [mean 1.19 yr
(S.D.=0.43)] represents a recent-onset sample. The
two patient groups that resulted after dividing on
illness duration were, due to the high correlation be-
tween illness duration and age (Spearman’s r=0.87
p<0.001) not matched for age.
Patients receiving typical antipsychotic medication
at time of scanning (n=75) had larger pituitary
volumes than patients receiving atypical medication
(n=67) [b=x0.04 (S.E.=0.02) ml, p=0.05]. No differ-
ences in hypothalamus or pituitary volumes were
found between patients taking prolactin-enhancing
medication (n=80) and patients taking medication
that did not affect prolactin levels (n=26).
In recent-onset or chronically ill patients no signifi-
cant differences were found in any of the brain
volumes between patients on typical or atypical
medication. In recent-onset patients, pituitary volume
was significantly smaller in those taking prolactin-
sparing medication (n=10) compared to those taking
prolactin-enhancing medication (n=12) [b=x0.11
(S.E.=0.05) ml, p=0.05]. No further significant differ-
ences were found for any of the volumes in either of
the illness-duration groups between those patients
taking typical vs. atypical or prolactin-enhancing vs.
Findings of abnormal HPA axis functioning in
schizophrenia have suggested an important role for
the biological stress system. Volumetric abnormalities
in hypothalamus and/or pituitary gland in patients
would strengthen this theory. No significant volu-
metric differences between patients with schizo-
phrenia and healthy controls were found in these
Presuming abnormal HPA activity in this sample of
schizophrenia patients, our findings suggest that this
does not necessarily influence the size of some of the
crucial structures involved. This brings us to an im-
portant limitation of this and previous studies: none of
the studies that looked at volumetric differences of the
pituitary or hypothalamus in schizophrenia have
looked at hormonal levels at the time of scan acqui-
sition. Therefore, it cannot be verified whether HPA
axis activity was indeed abnormal in these patient
groups; this can only be presumed on the basis of the
available literature (for reviews see Walker & Diforio,
1997; Walker et al. 2008).
Previous studies of our group (Hulshoff Pol et al.
2005; Koolschijn et al. 2008) excluded the mamillary
bodies from the hypothalamus segment, because of
their distinct morphology and origin in relation to
other hypothalamic nuclei (Keyser, 1979). However,
the study of Goldstein et al. (2007) included the
mamillary bodies and suggested that the increase
they found in hypothalamic volume could, at least
partially, be explained by enlargement of these nuclei.
This is in line with post-mortem findings of enlarged
mamillary bodies in schizophrenia (Briess et al. 1998).
Therefore, we changed our segmentation protocol to
include the mamillary bodies but we were unable to
replicate their findings.
Considering the HPA axis and the role of the
hypothalamus, the main focus should probably not be
on the mamillary bodies, but on the paraventricular
nucleus (PVN). The PVN lies adjacent to the third
ventricle in the periventricular zone of the front half of
the hypothalamus. The PVN is functionally associated
with the posterior lobe of the pituitary gland. It is the
hypothalamic nucleus that produces the precursor of
cortisol, corticotropin-releasing hormone (CRH). The
PVN is, however, a small nucleus and is difficult to
detect on the T1-weighted images that are acquired at
1.5 T. Whether changes in the volume of this nucleus
alone affects the volume of the entire hypothalamus is
The pituitary gland is not part of the brain but it is a
hormonal gland and is known to vary in size when
activated (e.g. in pregnancy). We found no effect of
disease or illness duration on pituitary volume. It has
been suggested that effects of illness duration and
medication use influence pituitary volume in schizo-
phrenia (for review see Pariante, 2008). Indeed,
volumetric increase has been found in high-risk
individuals that made the transition to psychosis, in
the prodromal phase, during early psychosis and in
schizotypal patients (Buschlen et al. 2011; Garner et al.
2005; Takahashi et al. 2009). It is not clear yet if this
is an effect of HPA axis activation caused by the
upcoming disease or that there is a genetic predis-
position to heightened HPA axis activity, since en-
larged pituitary volumes were also found in family
members of psychosis patients (Mondelli et al. 2008).
The effects on pituitary volume in chronically ill
Hypothalamus in schizophrenia285
patients remain unclear, as both smaller (Pariante et al.
2004; Upadhyaya et al. 2007) and normal volumes
(Tournikioti et al. 2007) have been reported. It has been
suggested that chronic activation of the HPA axis
will lead to a decrease in pituitary volume in those
that have been ill for a long time, but that this can
be masked by an increase in volume due to chronic
prolactin-enhancing medication use (MacMaster et al.
2007; Pariante, 2008). Longitudinal studies showed
excessive volume increases in the pituitary gland over
time during the early course of the schizophrenia
spectrum (MacMaster et al. 2007; Takahashi et al.
2011), but a non-significant loss has also been reported
(Nicolo et al. 2010).
Recently, reviews of the literature concluded that
there is an association between intake of antipsychotic
medication and brain volume (change) in patients
Most likely, effects of medication are dependent on
type of medication as well as location in the brain
(Moncrieff & Leo, 2010; Navari & Dazzan, 2009;
Smieskova et al. 2009). Indeed, in a large longitudinal
study it was shown that typical antipsychotics appear
to be associated with larger brain volume loss over
time while atypical antipsychotics tend to ameliorate
the tissue loss (Van Haren et al. 2007, 2008). This is in
line with findings from a randomized control trial
showing greater loss of grey-matter volume in those
patients who were taking haloperidol compared to
those on olanzapine (Lieberman et al. 2005). In con-
trast, there are both human and animal studies that
provide evidence for volume loss being associated
with higher dose of atypical antipsychotic medication
(Dorph-Petersen et al. 2005; Ho et al. 2011; Vernon et al.
2011). Relevant for the current study are the findings
from Nicolo et al. (2010) and Pariante et al. (2005).
Using a cross-sectional design, little volume differ-
ences were found between medication-free patients
and those receiving atypical antipsychotics. However,
those patients that received typical antipsychotics had
the largest pituitary volumes. Interestingly, Nicolo
et al. (2010) showed a negative correlation between
change in pituitary volume dose of atypical anti-
psychotic, indicating a larger tissue loss in the pitu-
itary gland in the presence of a higher dose of atypical
antipsychotics. In addition, MacMaster et al. (2007)
found a pituitary volume increase over time in
patients that were neuroleptic-naive at baseline. This
increased seemed driven by the prolactin-enhancing
Our findings on the effects of medication use sup-
port this notion. We see a trend towards an enlarging
effect of typical medication use on pituitary volume in
the total sample. Moreover, in recent-onset patients
only, those who were taking prolactin-sparing medi-
cation had smaller pituitary volumes relative to those
on prolactin-enhancing medication, which is in
line with previous findings (MacMaster et al. 2007).
However, the groups were rather small to reliably in-
vestigate the effects of type of medication, cumulative
dose of antipsychotic medication or illness duration.
Next to including hormonal levels, all future studies
should therefore control for conditions that could en-
hance neuroendocrine activity, such as (antipsychotic)
In the patient group, mamillary body volume in-
crease was more pronounced with age compared to
the control group (on average 0.4%/yr). Since age
had almost no effect on mamillary body volume in
healthy subjects and because age and disease duration
are highly correlated, the excessive increase could
be an effect of disease duration. However, age-related
decreases of the mamillary bodies have also been
described (Raz et al. 1992; Sheedy et al. 1999). In the
total sample, hypothalamic volume decreased with
age, with an average decrease of 0.004 ml/yr. As far as
we know, no studies have looked into the effects of
ageing in the volume of this structure.
Pituitary volume was significantly increased in fe-
males compared to males; their pituitary volume was
on average 0.09 ml higher (y14%). Males were found
to have significantly greater hypothalamus volumes
than females (on average 0.05 ml; y4%). These sex
effects are in line with previous findings (Hulshoff Pol
et al. 2005; Koolschijn et al. 2008; Pariante et al. 2004,
2005; Upadhyaya et al. 2007).
In conclusion, our findings indicate that volume
decreases in the hypothalamus and pituitary gland,
which are important brain structures for normal
functioning of the HPA axis, are not present, either in
recent-onset or chronically ill patients.
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