5, Issue, Fall 1999
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Complications and Therapeutic Update.
Neurocognitive Dysfunction in Patients
with Pituitary Ademomas.
COMPLICATIONS AND THERAPEUTIC UPDATE
by Laurence Katznelson, M.D.
Acromegaly is characterized by
a number of phenotypic changes including enlargement of the
hands and feet, facial changes such as frontal bossing, enlarged
mandible and increased dental spacing, arthralgias, fatigue,
diaphoresis, sleep apnea, hypertension, diabetes mellitus, and
hypertrophic cardiomyopathy. Because it is a rare disorder and
development of these clinical features is insidious, patients
typically have acromegaly for many years before the diagnosis
is made. Approximately 90% of all somatotroph tumors, which
cause this disorder, are macroadenomas (>1 cm) at diagnosis.
Therefore, these tumors frequently cause local anatomic compression,
resulting in visual field deficits, headaches, hypopituitarism
and cranial nerve palsies.
The pulsatile release of growth
hormone (GH) by normal pituitary somatotroph cells is regulated
by growth hormone releasing hormone (GHRH), which stimulates
GH secretion, and somatostatin, which decreases secretion. At
the liver, GH stimulates secretion of somatomedin C, also known
as insulin-like growth factor I (IGF-I). IGF-I mediates many
of the peripheral somatic effects of GH and feeds back at the
level of the hypothalamus and pituitary resulting in a reduction
in GH secretion. Therefore, GH and IGF-I levels are held in
The diagnosis of acromegaly is
based on three key findings: 1) clinical evidence, 2) demonstration
of an elevated IGF-I level, and 3) inability to suppress serum
GH to less than 2 ng/ml following an oral glucose challenge
(OGTT) using a conventional radioimmunoassay or less than 1
ng/ml using an IRMA or chemiluminescent assay.
Why do we treat? Short term benefits
of therapy include improvement of symptoms such as headaches,
which are often debilitating. In addition, there are long-term
complications of acromegaly that are of concern. There is a
2 to 5 fold increase in the mortality rate in acromegalic patients
and this is largely due to cardiovascular and cerebrovascular
disease. In a recent long-term follow-up of 162 subjects from
the Massachusetts General Hospital, therapy (regardless of modality)
of acromegaly with resultant normalization of IGF-1 was associated
with a 3.5 fold reduction in the risk of mortality compared
to patients with active disease. Therefore, successful management
of acromegaly may negate the increased mortality risk.
There are multiple medical complications
associated with acromegaly. In part because of hypertension,
there is cardiac involvement that includes left ventricular
hypertrophy and congestive heart failure. Sleep apnea syndrome
(both central and obstructive) is detected in up to 80% of subjects
and may result in considerable morbidity. Acromegalics may also
develop significant arthropathy that may lead to pain, deformity,
and necessitate joint replacement. Left ventricular mass, sleep
apnea syndrome, and arthralgias may improve with therapy.
Patients with acromegaly may also
be at enhanced risk for cancer, and colon cancer is the most
prevalent. This risk is particularly increased in men over 40
years with a positive family history of colon cancer and multiple
skin tags. Other malignancies, including breast cancer, have
been described. It is unknown whether successful treatment of
acromegaly will reduce the risk of neoplasia.
The primary mode of therapy for
acromegaly is surgery to reverse the mass effect and attempt
biochemical cure. Surgical cure is dependent on surgical skill
and experience as well as the size of the tumor. Cure, defined
as normalization of IGF-1 levels and normalization of the GH
response to an OGTT, is demonstrated in up to 88% of patients
with microadenomas (<1cm). In contrast, up to 50-65% of acromegalic
patients with macroadenomas are cured following transsphenoidal
surgery. Residual disease following transsphenoidal surgery
is therefore common, indicating the need for adjuvant therapy.
Radiation therapy is a potential adjuvant therapy for patients
with residual disease, however, there is a delayed effect in
that 1/2 to 2/3 of subjects attain GH levels < 5 ng/ml by
10 years and normalization of IGF-1 is more difficult to achieve.
Hypopituitarism is a significant complication of radiation therapy.
Therefore, in most patients, medical management may be necessary
in surgically non-cured patients in lieu of or in combination
Medical management is a highly
useful adjuvant therapy for patients with residual disease or,
in selected subjects, as potential de novo medical therapy.
Dopamine agonists, including bromocriptine (Parlodel) may normalize
GH and IGF-1 levels, but in only 8% of patients. A new longer
acting dopamine agonist, cabergoline (Dostinex) is often better
tolerated than bromocriptine. Cabergoline may have improved
efficacy compared to bromocriptine and should be considered
as an oral, therapeutic option in patients with mild disease.
The most efficacious form of medical
therapy available includes somatostatin analogs, such as octreotide.
Many studies have demonstrated the efficacy of octreotide in
the management of acromegaly. The initial octreotide dose is
usually 50 mcg b.i.d., and doses may be increased to 250 or
500 mcg t.i.d. depending on the response of circulating GH and
IGF-1 levels. However, most studies show 300-900 mcg per day
is an effective dose. Octreotide administration results in a
decrease in GH and IGF-1 levels in a majority of patients with
normalization of IGF-1 levels in up to 60% of patients, indicating
biochemical remission. Most patients note a marked improvement
in their symptoms of acromegaly very soon after starting octreotide
therapy, including headaches, joint pains and diaphoresis. The
most significant adverse effect of somatostatin analogs is the
development of gallstones, so ultrasounds should be obtained
initially. However, the development of symptomatic gallstones
is very rare and the need for serial ultrasounds is controversial.
Other side effects include gastrointestinal disturbances with
nausea, abdominal pain and diarrhea which often occur after
initiation of therapy but usually resolve within 1 to 2 weeks.
A new approach to management of
acromegaly with somatostatin analogs has been the development
of longer acting, depot formulations of somatostatin analogs.
These analogs are administered intramuscularly at 2 to 4 week
intervals. Sandostatin LAR (long acting release formulation
of Sandostatin) was recently approved for use in the United
States. Sandostatin LAR is available in 3 doses: 10 mg, 20 mg,
and 30 mg and is administered once a month. The efficacy and
safety of Sandostatin LAR are similar to that of Sandostatin,
but the benefits of this depot preparation on quality of life
and compliance have been clear. Another depot formulation of
the somatostatin analog lanreotide is available in Europe and
is currently under investigation in the United States.
An exciting and novel therapy for
acromegaly currently under development is a growth hormone antagonist
(GHA). This GHA competes with natural GH for binding to its
receptor and, additionally, prevents receptor activation. This
leads to lowering of IGF-1 levels. In a recent study presented
as an abstract at the Endocrine Society, administration of a
GHA in a randomized, double blind placebo controlled trial to
46 acromegalics resulted in normalization of IGF-1 levels in
92% of subjects. This included patients resistant to somatostatin
analogs. A GHA may have a critical role in the management of
acromegalic patients, particularly in those resistant to or
intolerant of conventional medical therapy.
1. Ho KY, Weissberger AJ, Marbach
P, Lazarus MB. Therapeutic efficacy of the somatostatin analog
SMS 201-995 (Octreotide) in acromegaly. Ann Int. Med. 1990;
2. Serri O, Somma M, Comtois
R, Rasio E, Beauregard H, Jilwan N, Hardy J. Acromegaly: biochemical
assessment of cure after long term follow-up of transsphenoidal
selective adenomectomy. J Clin Endocrinol Metab. 1985; 61:
3. Bates A.S., Vant Hoff
W., Jones J.M. Does treatment of acromegaly affect life expectancy?
Metab. 1995;44: 1-5.
4. Swearingen B, Barker FG (II),
Katznelson L, Biller BMK, Grinspoon S, Klibanski, Moayeri
N, Peter McL. Black, Zervas NT. Long-term mortality after
transsphenoidal surgery and adjunctive therapy for acromegaly.
J Clin Endocrinol Metab. 1998; 83: 3419-26.
5. Lancranjan I, Bruns C, Grass
P, et al. Sandostatin̉ LAR̉ : A promising therapeutic tool
in the management of acromegalic patients. Metabolism. 1996;
6. Barkan A, Dimeraki E, Besser
GM, et al. Treatment of acromegaly with B2036-PEG, a GH receptor
antagonist. Abstract. 1999 Endocrine Society Meeting.
DYSFUNCTION IN PATIENTS WITH PITUITARY ADENOMAS.
by Wesley P.
"It is quite probable that
the psychopathology of everyday life hinges largely upon the
effects of a ductless gland discharge upon the nervous system"
Harvey Cushing, 1913.
Introduction and Overall Concepts
Patients with pituitary adenomas
have a higher prevalence of cognitive dysfunction than found
in the general population. The current literature has evaluated
this association with case control studies and are subject to
the many biases inherent to retrospective analyses. Although
pituitary adenomas account for 10-15% of intracranial tumors,
their relatively low prevalence makes systematic prospective
evaluation difficult. In addition, clinical endpoints to evaluate
cognitive functioning are often poorly standardized. It is entirely
plausible that pituitary adenomas are linked to cognitive changes.
The pituitary gland is situated in a region of the diencephalon
known to be important for memory processing. Patients who have
been diagnosed and treated for a pituitary adenoma may be exposed
to several factors which contribute to changes in cognition
including mass effect, hormone hypersecretion, hormone hyposecretion,
radiation damage, surgical damage and psychiatric issues related
to concomitant medical illness. Given a 9% prevalence of mood
disorders in the general outpatient population, most of the
neurocognitive changes observed in patients with small non-functioning
pituitary adenomas without surgical or radiation therapy are
likely to be coincidental. The prevalence of cognitive dysfunction
in patients with pituitary tumors and the relative contribution
of known variables will be discussed.
Pituitary tumors can present with
raised intracranial pressure, pituitary dysfunction or visual
field compromise. Other tumors commonly located in the region
of the sella turcica include craniopharyngiomas and suprasellar
meningiomas and can present with similar symptoms. Each of these
tumors may produce alteration in mental status that precedes
the aforementioned features. In one retrospective review of
49 patients with cranio-pharyngiomas, the initial presenting
feature was mental status abnormalities in 19% of cases. Attribution
of cognitive changes directly to mass effect is confounded by
the association of large sellar tumors with hypopituitarism
as well as surgical and radiation therapies employed to treat
Some forms of pituitary tumors
may result in psychiatric disturbance attributable to hormone
hypersecretion by the pituitary adenoma in the absence of mass
effect, hypopituitarism, surgical therapy or radiation therapy.
Harvey Cushing in his original description reported emotional
disturbance as a prominent feature of the syndrome bearing his
name. Subsequently many series have documented a high rate of
neuropsychological deficits with endogenous hypercortisolemia
including cognitive changes, affective disorders, disordered
vegetative functions and acute psychoses. In a series of 209
patients with Cushings, nearly 60% had significant psychiatric
illness and while the severity did not correlate with degree
of hypercortisolemia the depression was alleviated with adrenalectomy.
In a study by Dorn et. al., 33 patients with active Cushings
syndrome (29 with pituitary adenomas) were evaluated before
as well as 3, 6 and 12 months after correction of their hypercortisolism.
At baseline, 67% of patients had significant psychopathology
which persisted in 24% of patients at least 12 months after
cure despite recovery of the hypothalamic-pituitary-adrenal
axis by conventional criteria. The authors speculate that long-term
exposure to high levels of cortisol may cause persistent psychiatric
abnormalities through dysregulation of hypothalamic CRH production,
an area of active investigation. Psychiatric symptoms attributable
to hypercortisolemia have also been reported in association
with adrenal ACTH-independent hypercortisolemia as well as ectopic
ACTH-dependent hypercortisolemia arguing against any psychiatric
effect of the pituitary adenoma itself, independent of hypercortisolemia
in Cushings disease. In addition, the neurocognitive and
behavioral effects of exogenous glucocorticoids are well described.
However, the depression observed with Cushings syndrome
is often contrasted with the mood elevation observed with exogenously
administered therapeutic steroids. These differences are presumed
to be related to either the chronicity of hypercortisolemia
or differing levels of biologically active steroids centrally
and peripherally in the two different scenarios.
In several case reports, hyperprolactinemia
has been reported in association with psychiatric disease independent
of the use of psychotropic medications. It is not clear that
an association exists and in many such reports, it is difficult
to determine which effects may be due to estrogen deficiency
or other gonadal steroid changes versus the effects of hyperprolactinemia
The psychiatric accompaniments
of acromegaly have not been studied systematically although
mood lability, apathy and lack of initiative have been reported
in association with this disorder. Determination of an independent
psychiatric effect of having a somatotroph adenoma from the
physical disfigurement and symptoms associated with acromegaly
is likely to be difficult.
Hypopituitarism may result from
impairment of normal pituitary function by a pituitary adenoma.
Neuropsychiatric abnormalities have commonly been reported in
association with hypopituitarism including depression, apathy,
and memory impairment. In addition, cognitive changes are a
well described feature of hypogonadism, hypothyroidism, and
adrenal insufficiency. Some studies have reported neuropsychiatric
abnormalities in patients with growth hormone deficiency which
improve with growth hormone therapy. However in a study conducted
at our center, Baum et. al. investigated the effects of growth
hormone on cognitive function in 40 men treated for hypopituitarism
(32 had pituitary adenomas), all with untreated growth hormone
deficiency. Patients were randomized to receive either physiologic
doses of growth hormone or placebo in a double-blinded fashion.
Patients with growth hormone deficiency tested normally with
respect to cognitive functioning and IQ though scored relatively
lower on tests of memory and learning when compared with a standardized
population. At baseline and after 18 months of therapy, there
were no differences observed in cognitive function testing,
psychometric testing and sense of well being assessments. Neuropsychiatric
abnormalities are subtle (if present) in patients with adult-onset
growth hormone deficiency and neuropsychiatric function does
not appear to improve with growth hormone replacement therapy.
Patients with cognitive defects attributable to hypogonadism,
adrenal insufficiency and hypothyroidism typically respond to
hormone replacement therapy as indicated. However, patients
with long-standing hypopituitarism have been described with
persistent apathy and loss of drive despite the institution
of replacement therapy.
The type of surgery used to remove
pituitary tumors has evolved with advances in technology. The
transfrontal route was the most widely used approach until the
development of the intraoperative microscope resulting in faster
and easier access to the pituitary via the transsphenoidal route
when performed by an experienced neurosurgeon. Transsphenoidal
surgery is considered less traumatic to the patient. Transfrontal
surgery can still be used for very large tumors inaccessible
via a transsphenoidal route and it is speculated that retraction
of the frontal lobe may damage small perforating arteries of
the internal carotid artery resulting in focal infarction and
vasospasm. Any association observed in retrospective studies
linking surgical therapy and neurocognitive changes will be
confounded by selection bias as many larger tumors are more
likely to be treated surgically, often receive adjunctive radiation
therapy, and are associated with hypopituitarism.
Radiation was first used for the
treatment of pituitary tumors in 1909 and remains one of the
primary modalities of therapy for patients particularly with
unresectable pituitary macroadenomas. The existence of long-term
neuropsychological changes directly attributable to previous
radiation therapy is debated in the literature. The incidence
of side effects resulting from radiation therapy in the treatment
of a pituitary adenoma is generally considered to be very low.
However, hypopituitarism as a late sequelae in these patients
is increasingly being recognized. Radiation necrosis is a well-documented
complication of radiation therapy often resulting in severe
impairment in cognition but is considered a rare side effect
in patients receiving radiation therapy for pituitary adenomas.
Neurocognitive and Neuropsychologic
Grattan-Smith et al described the
spectrum of neuropsychological abnormalities in a series of
patients with pituitary tumors. Although their primary interest
was in patients treated with radiotherapy (38 patients), they
extended the study to patients treated medically or surgically
(27 patients) as well as a series of 21 inpatients with chronic
disease used as controls. Specific tests evaluated patients
by using eight neuropsychological tests in three domains: executive
functioning, verbal memory, and visual memory. Both groups of
pituitary tumor patients performed below clinically accepted
norms on seven of eight tests, and performed well below the
level of controls on tests of executive functioning, verbal
and visual memory. Performance on the tests did not differ among
pituitary patients treated with radiation versus other therapy.
Although this study provides helpful descriptive data on neuropsychological
abnormalities in these patients, the authors did not report
the overall prevalence of specific deficits, and the study had
several major limitations. The authors did not assess patients
for depression, nor did they adjust for time interval since
diagnosis and treatment. They were not able to adjust for other
potentially confounding factors associated with poorer function
including type of tumor, medication or recent treatment effects,
and intercurrent illness. A final critical point is that since
most patients had been treated before the study began, it was
impossible to distinguish effects of the tumor from treatment
A recent study by Peace et al examined
69 patients with pituitary tumors (23 each having undergone
either transfrontal surgery, transsphenoidal surgery, or medical
treatment), and 23 healthy controls . Some of the patients in
both surgical groups received radiotherapy as well, and all
surgeries were performed at least two years prior to the study.
Attention, memory, and executive function were assessed using
seven specific tests, in addition to a test for overall intelligence.
The authors reported deficits in executive function and memory
among patients with tumors, although patients treated medically
had milder memory deficits. Patients treated with transfrontal
surgery had the greatest degree of cognitive impairment, with
43.5% having three or more test scores below the 10th
percentile. Among transsphenoidal patients, 30.4% scored below
the 10th percentile on three or more tests, compared
with 21.7% of medically treated patients, and 5% of controls.
The authors do not report when surgery was performed and may
overestimate the impact of surgical therapy given recent developments
of new neurosurgical techniques resulting in less damage and
less frequent use of anti-seizure medications which can also
interfere with cognition. Radiotherapy treatment did not appear
to affect test scores. Since treatment decisions are necessarily
nonrandom, differences between treatment groups are subject
to substantial selection bias and are not directly comparable.
The strength of this study is that it highlights the high prevalence
of cognitive abnormalities among patients with pituitary tumors,
including those treated non-surgically.
In the largest study, Guinan described
neuropsychological testing among 90 patients treated for pituitary
adenoma of any etiology. Treatment groups included transfrontal
surgery, transsphenoidal surgery with or without radiotherapy,
radiotherapy only, and bromocriptine only. The investigators
assessed general intellectual function, memory, executive function,
language comprehension, and speed of mental processing. The
authors of this study also found substantial memory deficits
in all treatment groups compared with healthy controls. Anterograde
memory was most substantially affected. Treatment group did
not correlate with degree of impairment in general, although
bromocriptine-treated patients had less impairment on one test
of anterograde memory. Additional analyses showed no association
between cognitive function and tumor type or time elapsed since
treatment. This study was able to control for psychiatric disease
and examine effects of interval since treatment. As with the
reports from Grattan-Smith and Peace, the retrospective design
limits evaluation of treatment effects, since selection bias
is expected to strongly influence treatment choice and outcome.
Nonetheless, these reports suggest that neuropsychological deficits,
particularly memory impairment, are common among patients with
pituitary tumors and persist long after treatment completion.
Patients with pituitary adenomas
appear to be at risk for the development of neuropsychiatric
abnormalities. Patients with Cushings disease appear to
be particularly at risk for the development of psychiatric abnormalities.
The available literature has not established an independent
association between having a pituitary adenoma and cognitive
changes when accounting for mass effect, hormone hypersecretion,
hypopituitarism, surgical therapy and radiation therapy. Patients
who report impaired memory or other neuropsychiatric symptoms
should be evaluated with formal neuropsychiatric testing and
referred appropriately based upon the results.
- Cushing H. Psychic disturbances
associated with disorders of the ductless glands. Am J Insanity
- Crane TB, Yee RD, Hepler RS,
Hallinan JM. Clinical manifestations and radiologic findings
in craniopharyngiomas in adults. Am J Ophthalmol 1982; 94:220-8.
- Cushing H. Basophilic adenomas
of the pituitary body and their clinical manifestations. Bull
Johns Hopkins Hosp 1932; 50:137.
- Dorn LD, Burgess ES, Dubbert
B, et al. Psychopathology in patients with endogenous Cushing's
syndrome: 'atypical' or melancholic features. Clin Endocrinol
(Oxf) 1995; 43:433-42.
- Kelly WF. Psychiatric aspects
of Cushing's syndrome. QJM 1996; 89:543-51.
- Dorn LD, Burgess ES, Friedman
TC, Dubbert B, Gold PW, Chrousos GP. The longitudinal course
of psychopathology in Cushing's syndrome after correction
of hypercortisolism. J Clin Endocrinol Metab 1997; 82:912-9.
- Baum HB, Katznelson L, Sherman
JC, et al. Effects of physiological growth hormone (GH) therapy
on cognition and quality of life in patients with adult-onset
GH deficiency. J Clin Endocrinol Metab 1998; 83:3184-9.
- Grattan-Smith PJ, Morris JG,
Langlands AO. Delayed radiation necrosis of the central nervous
system in patients irradiated for pituitary tumours. J Neurol
Neurosurg Psychiatry 1992; 55:949-55.
- Peace KA, Orme SM, Padayatty
SJ, Godfrey HP, Belchetz PE. Cognitive dysfunction in patients
with pituitary tumour who have been treated with transfrontal
or transsphenoidal surgery or medication. Clin Endocrinol
(Oxf) 1998; 49:391-6.
- Guinan EM, Lowy C, Stanhope
N, Lewis PD, Kopelman MD. Cognitive effects of pituitary tumours
and their treatments: two case studies and an investigation
of 90 patients. J Neurol Neurosurg Psychiatry 1998; 65:870-6.
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