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ENDOCRINE DISORDERS
Victor l. Reus, M.D.
Langley Porter Neuropsychiatric Institute,School of Medicine,
Department of Psychiatry, University of California, San Francisco,
California 94143
ABSTRACT
Patients with major endocrine disorders frequently experience significant
changes in mood and mentation. Similarly, many individuals presenting as
psychiatric patients have pathologic alterations in neuroendocrine func­
tion. Although pathognomic behavioral changes are rare, increased recog­
nition of characteristic symptom complexes may lead to earlier diagnosis
and improved treatment planning.
INTRODUCTION
Behavioral symptoms are common in, and in many cases the earliest
manifestations of,hormonal disturbance,but the nature of the relationship
between neuropsychiatric symptomatology and a given endocrine disorder
has historically received inadequate research attention. That this is no
longer the case can be attributed to two recent developments. First, in
animal and, in some cases, human studies a large number of neuropeptides
were found to have specific behavioral effects when administered either
centrally or peripherally. This supports the hypothesis that similar
phenomena occur endogenously in the pathophysiology of primary
disorders of hormonal function (1). Second,the identification of subtle but
specific abnormalities in endocrine function in certain psychiatric popu­
lations indicates that such patient groups may exist on a continuum with
individuals having more severe presentations of endocrine dysfunction. It
should be recognized, however, that because of the complex, often
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206
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reciprocal relationship between hormonal function and behavioral action,
it is premature to attempt to label one set of conditions as "primary" and
exerting a causal effect. To this end, certain "primary" endocrine disorders
may either arise, or be subject to periodic exacerbation, by change in
behavioral circumstance while "primary" psychiatric disorders may either
originate, or be significantly shaped by, a "primary" neuroendocrine
disturbance (2).
Most of the studies in this review suffer from being retrospective or cross­
sectional. The result is that many hormonal disorders seem to exhibit
grossly similar behavioral effects, most commonly a depression of mood
and initiative and a general impairment of cognition. Longitudinal studies,
in which the endocrine dysfunction serves as the independent variable and
in which both the biologic and behavioral factors are examined in a
covariant fashion over time and treatment, are more likely to provide
greater insight into both endocrinologic and psychological function.
Additional reviews of characteristic features of individual syndromes can be
found in the recent literature (3-5).
CUSHING'S SYNDROME
In his original observations, Cushing noted that patients with the syndrome
frequently showed changes in cognitive and affective state. Most systematic
investigations since report evidence for psychiatric disturbance in over 50%
of patients studied, with psychosis and/or suicidal ideation or action
evident in over 10% of patients (6-8). Interestingly, in several studies a
major emotional disturbance appeared to precede the onset of somatic
symptomatology (9). There is some evidence that the character of the mood
disorder varies with stage of illriess; reports and observations of euphoria
and increased motor activity are common early on in the course, and
chronic symptoms of depression, irritability, disturbed concentration and
memory, and anxiety occur later.
Cognitive impairment is most notable in nonverbal visual ideational and
visual memory functions (10). Usually appearing in consort with somatic
changes, the changes in mood and cognition can in certain circumstances
appear independently as the most prominent presenting features of the
syndrome. Particularly in individuals with intermittent or "transient"
Cushing's syndrome, the somatic pathology may be evanescent and mild in
comparison to the mood disturbance. A causal association between
endocrine and behavioral disturbance is supported by data indicating that
reductions in cortisol level and output following clinical intervention
usually result in markedly improved mental states (11). In one published
case, metyrapone rapidly alleviated the neuropsychiatric manifestations of
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BEHAVIORAL DISTURBANCES
207
Cushing's syndrome. This suggests that hypercortisolism caused the
depression, sleep disturbance, and inappropriate behavior (12).
Individuals presenting with the classic stigmata of the disorder seldom
present a diagnostic dilemma. However, it has become clear from
systematic investigations that most of the salient signs of the disorder, such
as obesity, hypertension, hypertrichosis, and osteoporosis, are neither
inevitably found in nor specific to individuals who otherwise meet
laboratory requirements for the diagnosis of Cushing's syndrome (13).
Because many patients with severe depression have associated abnor­
malities in hypothalamic-pituitary-adrenal function, it is not always
possible to discriminate the "psychiatric" patient presenting with such signs
from a patient with mild or "transient" Cushing's syndrome. Several
authors have reported that cortisol response to insulin-induced hypo­
glycemia and to high-dose dexamethasone administration might be
employed successfully in the differential diagnosis (14). These suggestions,
however, do not address other data that indicate that abnormal responses
on these assessments can occur in patients believed to have a "primary"
psychiatric disorder (15).
ADDISON'S DISEASE
Despite their physiologic differences, the psychiatric presentation of
Addison's disease may be similar to that of Cushing's syndrome. Presenting
symptoms include apathy, social withdrawal, fatigue, anhedonia, poverty of
thought, and negativism. A true organic psychosis can also occur,
characterized by cognitive impairment and confusion, and in certain cases
stupor or coma. The relationship of these symptoms to decreased levels of
glucocorticoids is clear in that there is a quick resolution with glucocor­
ticoid replacement. Correction of the electrolyte imbalance does not by
itself result in observable benefit. If psychiatric symptomatology is
profound and antedates the more classic somatic features, misdiagnosis
may occur. In a recent case report, such a patient was initially diagnosed as
suffering from bereavement and conversion disorder after having pre­
sented with a history of weakness, shortness of breath, and a three-week
period of crying, decreased concentration, impaired sleep, nausea, de­
creased appetite,and apathy (16).
Specific changes in sensory function and sleep regulation have also been
reported. In general, in the absence of glucocorticoids, sensory detection
acuity is enhanced, while "integration" of sensory input and recognition
appears decreased. The visual evoked response of Addison's patients is of
small amplitude and short latency at baseline and increases with replace­
ment glucocorticoid. Whether such alterations in physiologic and be-
208
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havioral response should be attributed directly to the adrenal cortical
deficiency itself or to the compensatory increases in corticotropin and
corticotropin-releasing factor is at present unclear; evidence is accumulat­
ing that the latter compounds exert specific effects on a variety of
attentional and affective processes.
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HYPERPARATHYROIDISM
Hyperparathyroidism is commonly associated with a panoply of subtle
changes in affect and cognition. Generalized fatigue, an absence of initiative
and spontaneity, depression, reduced concentration, memory impairment,
and occasionally, irritability and paranoia are the most characteristic
features (17, 18). In some cases, an organic psychosis develops, associated
with true disorientation, delirium, hallucinations, and confusion. Such
changes usually develop over a course of several years and appear to be
generally, although not invariably, related to the degree of hypercalcemia
noted. The individual variation is great, however, and patients with
prominent changes in calcium level may have no observable behavioral
alteration.
Assessments of the neuropsychological deficit associated with primary
hyperparathyroidism indicate that dominant hemispheric functions such as
verbal memory and logic are most likely to be adversely affected (19).
Surgical removal of the parathyroid adenoma in cases of primary
hyperparathyroidism (and reduction of serum calcium in syndromes of
other etiology) usually results in dramatically improved neuropsycholo­
gical function and resolution of the affective disturbance. Clinicians should
be aware, however, that post-parathyroidectomy psychosis has also been
recorded, ostensibly related to the rapid decrease in serum calcium (20). The
differential diagnosis of hyperparathyroidism and hypercalcemia includes
treatment with lithium carbonate. Lithium administration can increase
parathormone and calcium blood levels. In rare cases, this leads to the
discovery of a parathyroid adenoma; it is not clear whether this represents a
coincidental finding.
HYPERTHYROIDISM
Psychopathology in thyrotoxic patients has been recognized since the early
1800s, the clinical picture being that of an acute confusional state or an
activated mood disorder, similar to mania. Less severe behavioral changes
include increased anxiety, hyperactivity, irritability, and emotional lability
(21-23). Atypical presentations consisting of psychomotor retardation and
apathy have been described in rare cases. Isolated hyperthyroxinemia, such
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BEHAVIORAL DISTURBANCES
209
as occurs in "euthyroid sick" syndrome. may be associated with similar
symptomatology in the absence of tissue evidence of thyrotoxicosis (24, 25).
Surv eys of large numbers of unselected psychiatric patients indicate that
levels of serum thyroxine are frequently elevated, although detailed
correlations with specific behavioral symptom clusters have not been
reported . In certain cases, euthyroid h yperthyroxinemia has preceded the
onset of recurrent manic episodes (26). There is some evidence that
hyperthyroidism is uniquely associated with the development of a phobic
disorder in a subgroup of patients and that a reduced TSH response to
TRH occurs more frequently in patients with a past history of violent
suicidal behavior than in matched controls (27, 28).
The impairment in cognitive function in hyperthyroidism is generally
milder than that observed in hypothyroidism. Whybrow et al (29) p resented
objective validation of subjective complaints of diminished recent memory
(principally impaired retrieval) and decreased span of attention. These
disruptions in cognition resolve when thyroid function is normalized.
Starting with a report by Perry in 1825 and with subsequent observations
by Graves himself in 1835, clinicians have recognized that acute thyroid
dysfun ction, in some cases complete with goiter, can be precipitated by
severe psychic stress. Thyroid "hot spots" may disappear during periods of
minimal stress, and may enlarge and result in clinical hyperthyroidism
during periods of prolonged, severe stress (30). Such activation of thyroid
dysfunction by emotional circumstance probably occurs in a clinically
meaningful sense only in individuals who have an underlying endocrino­
logic vulnerability. such as "painless" or "silent" thyroiditis.
HYPOTHYROIDISM
The behavioral changes associated with long-standing hypothyroidism are
classic and seldom misdiagnosed in the current environment of routine
thyroid screening. Signs of fatigue, d ecreased libido, memory impairment,
and disruption of sleep pattern are most characteristic (31-33). In severe or
long-standing cases, patients may present with a true organic psychosis,
characterized frequently by paranoid delusions, or cortical dementia.
It is now recognized that thyroid dysfunction is not an "all-or-none"
phenomenon but exists over a continuum. Individuals with "subclinical
hypothyroidism" whose peripheral hormone levels are within the normal
range and who lack the classic physical features may nonetheless suffer
marked impa irment in emotional and psychological spheres. In patients
whose peripheral thyroxine, triiodothyronine, and thyroid-stimulating
hormone levels faIl within the normal range, the evaluation of TSH
response to thyrotropin-releasing hormone (TRH) is necessary to arrive at
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210
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the proper diagnosis. Increasing utilization of this test of pituitary reserve in
psychiatric diagnosis has revealed that many patients routinely referred for
evaluation and treatment of a "primary" depression have in fact subclinical
hypothyroidism (34--36). Such individuals show a lesser therapeutic
response to mood-altering agents like tricyclic antidepressants and lithium
carbonate and may develop rapid mood cycling in the course of treatment
with these agents. Thyroid replacement generally improves emotional state
and mental functioning. When thyroid replacement is administered either
too quickly or at too high a dose, however, an activated manic-like state can
be precipitated (37). The syndrome is characterized by increased physical
activity, persecutory delusions, an elevated irritable mood, poor judgment,
and anxiety. It lasts from one to two weeks and resolves without sequelae.
The effects of increased or decreased hormonal level on brain function are
different at different stages in life. Deficiency of thyroid hormone at critical
stages of brain development results in aberrant maturation of the cerebral
and cerebellar cortex and the clinical syndrome of cretinism. Subclinical
deficits in motor and cognitive performance measured 10 to 12 years after
birth in the absence of cretinism have been correlated with maternal thyroid
function (38). The mechanism by which thyroid hormone modulates mood
and cognitive function is speculative, but mediation of beta-adrenergic
receptor response is a prime candidate (39).
Although the cause of primary hypothyroidism is in most cases
unknown, the identification of antithyroid antibodies in many patients
indicates an autoimmune etiology (40, 41). Autoimmune thyroiditis not
associated with clinical hypothyroidism, i.e. "symptomless," "silent," or
"transient" thyroiditis, may nonetheless be characterized by behavioral
pathology. An admixture of both hyper- and hypothyroid symptoms can
occur even when the patient is euthyroid by laboratory examination. This
condition is thought to represent an early stage of chronic lymphocytic
thyroiditis and either progresses to true hypothyroidism or is characterized
by recurrent periods of symptomatic remission. Several recent studies
would indicate that 10 to 20% of female patients with "primary" depressive
diagnoses meet the criteria for autoimmune thyroiditis and are not
"symptomless" at all in terms of behavioral function.
In early stages of the syndrome patients will usually experience recurrent
fluctuations in mood state, with short periods of fatigue and anergic
depression punctuated by periods of increased energy and mood. As the
disorder progresses these patients complain of profound mental and
physical sluggishness and a complex of somatic complaints, including
headaches, food allergies, gastrointestinal distress, menstrual irregularities,
decreased libido, and weight gain. Because of the variety of multisystem
complaints and findings of euthyroidism on laboratory examination, these
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BEHAVIORAL DISTURBANCES
211
patients are often formally diagnosed as having somatization disorder or
hysteria. Specific complaints of "being in a fog," or of one's head seeming
"full of cotton or wool," and histories of suicidal ideation or action are
characteristic.
Autoimmune thyroiditis is a common cause of thyroid disease in children
and is associated with severe behavioral pathology in a subgroup of
individuals. The prevalence of transient hypothyroidism and autoimmune
thyroid dysfunction in the postpartum period is quite high, occurring in as
many as 10% of women studied (42,43). Increased complaints of anxiety
and depression in the months following delivery have been reported. In
view of these data and clinical reports of an increased incidence of
postpartum depression in women with chronic lymphocytic thyroiditis, it
would appear that the existence or development of antithyroid antibodies
in the postpartum period increases the risk of depressive symptomatology.
Even when laboratory data indicate an apparent euthyroid state,
patients with autoimmune thyroiditis will usually report modest to
dramatic improvement with thyroid augmentation. Such individuals are
sensitive to small doses of thyroid hormone but chronicle changes in
mentation, mood, and personality often only after months of treatment.
Adjunctive treatment with beta blockers and benzodiazepines is also useful,
particularly with symptoms of anxiety, restlessness, and sleep disturbance.
In a small but significant percentage of cases,thyroid augmentation is of
inadequate benefit and antithyroid antibody titers persist despite maximal
replacement. There is some clinical evidence that such patients respond
beneficially to surgical intervention but this remains a controversial
procedure.
HYPERPROLACTINEMIA
Prolactinomas account for approximately 60% of all primary pituitary
tumors and are commonly associated with symptoms of apathy and
decreased libido, as well as visual disturbance, genital dysfunction, and
headache (44-46). Prominent irritability and impulsiveness are also
sometimes noted. Despite these observations, the relationship of a change
in prolactin level to alteration in behavior is still obscure. Although
dramatic resolution of behavioral symptomatology may occur with
surgical or drug treatment, some patients with extremely elevated prolactin
levels will present with no alteration of mental state. In those patients in
whom behavioral changes are noted, apathy rather than depression per se
seems characteristic. Such patients are less likely to express their internal
sense of distress and may not meet formal diagnostic criteria for a major
affective disorder.
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HYPOPITUITARISM
It is difficult to encompass the full range of adverse behavioral symptoms
that can result from partial or complete destruction of pituitary archi­
tecture. Primary tumors, idiopathic states, or necrosis can produce a
composite of signs and symptoms attributable to loss of individual target
gland hormones (47). Overall, patients with hypopituitarism commonly
become dependent, drowsy, irritable, negativistic, and seem to lose their
drive and initiative. Confusion and true delusions also occur. In cases of
hypogonadotropic hypogonadism, decreased libido and aggressiveness are
salient features. In general, replacement therapy will improve some
dimensions but not others. Chronic fatigue, lack of initiative, and memory
impairment are the most resistant to treatment. Why this should be is
unclear although specific behavioral roles for growth hormone and pro­
lactin deficiency have been suggested.
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