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ENDOCRINOLOGY BOARD REVIEW MANUAL
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Hypopituitarism
Bruce M. White
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Mayo Clinic and Foundation
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Brigham and Women’s Hospital
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Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Endorsed by the
Association for Hospital
Medical Education
The Association for Hospital Medical Education
endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in
medical education as they affect residency programs and clinical hospital practice.
Diagnosis of Hypopituitarism . . . . . . . . . . . . . . . . . . 2
Treatment of Hypopituitarism . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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Endocrinology Volume 4, Part 3 1
ENDOCRINOLOGY BOARD REVIEW MANUAL
Hypopituitarism
Matthew H. Corcoran, MD
INTRODUCTION
Hypopituitarism refers to the decreased secretion of
one or more anterior pituitary hormones. The clinical
presentation depends on how rapidly the anterior lobe
is affected, the specific cells involved, and the severity of
the functional impairment.
In the classic case of anterior pituitary hormone loss,
gonadotropins are affected first, followed by growth hormone (GH), thyroid-stimulating hormone (TSH; thyrotropin), and finally adrenocorticotropic hormone
(ACTH; corticotropin). Hypopituitarism may develop
acutely, such as pituitary apoplexy following hemorrhage
into a preexisting pituitary adenoma. In contrast, radiation therapy exerts its effects slowly, and the hormone
deficiency may not manifest clinically for months to years.
In assessing the clinical presentation of a patient with
hypopituitarism, one should consider the loss of each
anterior pituitary hormone individually. With some exceptions, the loss of production of an anterior pituitary
hormone results in clinical manifestations similar to
those arising from failure of the target gland the pituitary
hormone controls. The most common presenting symptom of hypopituitarism in men and premenopausal
women is hypogonadism, secondary to gonadotropin
deficiency or hyperprolactinemia.1 The failure to lactate
following parturition may indicate a lack of prolactin
secretion, the only known clinical manifestation of prolactin deficiency. ACTH deficiency causes clinical manifestations of cortisol deficiency and adrenal insufficiency.
TSH deficiency results in symptoms of thyroxine deficiency and hypothyroidism. GH deficiency presents as
short stature in children; adverse consequences in adults
may include an increase in fat mass and a diminution of
lean muscle mass, a decrease in bone mineral density,
and a diminished sense of well-being.
If hypopituitarism is the result of a pituitary or sellar
mass, there may be central symptoms related to the
mass as well as its direction of extension. Symptoms
include headache, visual loss secondary to superior
extension and involvement of the optic chiasm, cranial
nerve involvement and ophthalmoplegia secondary to
2 Hospital Physician Board Review Manual
lateral extension into the cavernous sinus, and epistaxis
or rhinorrhea secondary to inferior extension.
A variety of conditions may affect the pituitary gland
or hypothalamus to cause hypopituitarism (Table 1).
More than 50% of cases are caused by benign pituitary
macroadenomas or their treatment.2 Hypothalamic lesions also may produce hypopituitarism. The hyposecretion of pituitary hormones typically has no diagnostic
value in differentiating between hypothalamic and pituitary causes of hypopituitarism. The exception is the development of spontaneous diabetes insipidus, suggesting
a hypothalamic disease. Because vasopressin-producing
neurons terminate in the median eminence, pituitary
lesions alone will not cause diabetes insipidus.3 In contrast, the hypersecretion of a specific pituitary hormone
identifies the lesion causing hypopituitarism as a pituitary
adenoma, as well as the type of adenoma. It should be
noted, however, that a prolactin level between 20 and
200 ng/dL may result from a lactotroph adenoma or
another mass causing a stalk effect, interrupting dopamine’s inhibitory role in prolactin secretion.3
This manual provides an overview of the clinical and
endocrine approach to partial pituitary failure and panhypopituitarism. The clinical work-up of potential hormone deficiencies using both static and dynamic
endocrine testing are discussed, and key points regarding appropriate hormone replacement therapies are
addressed.
DIAGNOSIS OF HYPOPITUITARISM
CASE PRESENTATION
Initial Presentation
A 39-year-old woman is referred by her primary care
physician to an endocrine clinic for further evaluation
of a 4-month history of worsening frontal headaches
and a suspected pituitary tumor.
History
The patient was well until the onset of the headaches, which were initially relieved by acetaminophen
Hypopituitarism
and nonsteroidal antiinflammatory agents. After
2 months of successful conservative medical management, the patient began to complain of increasing
intensity of the headaches and minimal relief from the
medications. A computed tomography (CT) scan of the
head revealed a homogeneously enhancing, slightly
enlarged pituitary gland (13 mm). This finding
prompted referral for endocrine evaluation.
In the endocrine clinic, the patient complains of a
3- to 6-month history of hot flashes, insomnia, fatigue,
anorexia, and diffuse body aches. She also reports a
7.5-kg loss of body weight during the same time period. On further questioning, the patient admits to cold
intolerance but denies heat intolerance as well as any
change in bowel habits, tremulousness, palpitations,
chest pain, loss of axillary or pubic hair, or change in
her hair, skin, or nails. She has no history of polydipsia, polyuria, or nocturia; galactorrhea; change in
facial appearance; increased shoe, glove, or ring size;
centripetal weight gain; striae; or easy bruising. The
patient had two successful pregnancies, the first when
she was 27 and the second 2 years later. She lactated
and breast-fed without difficulty. Although typically
regular, her menstrual cycles have been irregular for
the past 3 to 6 months; her last menstrual period was
1 month ago. She has no family history of endocrine
or pituitary disorders.
Table 1. Causes of Partial Pituitary Failure and
Panhypopituitarism
Pituitary disease
Mass lesions
Pituitary adenomas
Other benign tumors (craniopharyngiomas, meningiomas)
Cysts
Malignant tumors (rare)
Metastatic disease (rare)
Pituitary surgery or radiation
Infiltrative disease (hemochromatosis, lymphocytic
hypophysitis)
Infarction (Sheehan syndrome)
Infection, abscess
Pituitary apoplexy
Empty sella syndrome
Genetic disease
Hypothalamic disease
Mass lesions
Benign or malignant tumors
Metastatic disease (most commonly from lung or breast)
Radiation therapy for central nervous system and nasopharyngeal malignancies
Infiltrative disease (sarcoidosis, Langerhans cell histiocytosis)
Physical Examination
On physical examination the patient appears fatigued
but otherwise well. Her blood pressure is 130/86 mm Hg,
pulse is 82 bpm, and respiratory rate is 12 breaths/min.
She is not orthostatic and appears well hydrated. Skin
examination is unremarkable, physical stigmata of Cushing’s disease or acromegaly are absent, and no galactorrhea is noted with breast compression. No defect is detected in her visual fields There is a delay in the relaxation
phase of the Achilles deep tendon reflexes.
Laboratory Studies
Routine laboratory studies (ie, electrolytes, blood urea
nitrogen, creatinine, complete blood count with differential, urinalysis) completed recently by the patient’s primary care physician were all within the normal range.
• What is the endocrine differential diagnosis for this
patient?
This patient’s recent history of headaches combined
with hot flashes and menstrual cycle disturbance suggests the possibility of estrogen withdrawal. Estrogen
withdrawal itself has been shown to be the basis of vasomotor lability that accounts for hot flashes.4 Classically,
Trauma (skull base fracture)
Infection
the gonadotropins are the first hormones to be lost in
primary disease of the pituitary gland, as is suspected in
this case.5
The patient’s fatigue, cold intolerance, and general
aches may indicate primary or secondary hypothyroidism. These same symptoms, accompanied by weight loss,
also suggest the possibility of adrenal insufficiency in a
patient with a suspected pituitary disease. There is no reason to believe that the patient previously had insufficient
prolactin secretion, given her ability to lactate. Her history does not suggest diabetes insipidus. These historical
points, in conjunction with an abnormal pituitary gland
visualized on CT, warrant an endocrine evaluation. It is
prudent to perform endocrine testing before proceeding
to magnetic resonance imaging (MRI) due to the prevalence of incidentally discovered pituitary adenomas.
• How are specific anterior pituitary hormone deficiencies diagnosed?
Endocrinology Volume 4, Part 3 3
Hypopituitarism
Testing for hypopituitarism should be done on the
grounds of a clinical suspicion that one or more anterior pituitary hormones may be insufficient. This suspicion may arise from the clinical presentation or from the
knowledge of a sellar or suprasellar lesion that may
involve the pituitary gland or hypothalamus. Under
baseline conditions, some patients with hypopituitarism
may be asymptomatic; therefore, the knowledge of a
pituitary lesion without symptoms is a sufficient reason
to test the pituitary axis. The exception may be a pituitary incidentaloma that is less than 10 mm. In this case,
the most cost-effective approach is to obtain a serum
prolactin level.6 If this is normal and the patient has no
other symptoms of pituitary dysfunction, other significant hormone abnormalities are not likely to exist. Such
a lesion should not be ignored, however, and repeat
MRI after 6 to 12 months is generally recommended to
assess for further growth.
The diagnosis of hypopituitarism depends on the
demonstration of a subnormal secretion of one or
more pituitary hormones via static and dynamic tests of
pituitary function. The status of one pituitary hormone
does not predict the status of another, and each hormone must be tested directly.
GONADOTROPIN DEFICIENCY
Gonadotropin deficiency often presents earlier in
women than in men and is most common in women of
childbearing age. The hypogonadism, or ovarian hypofunction, results in hypo-estrogenemia and a variety of
clinical symptoms (ie, amenorrhea or oligomenorrhea,
fatigue, vaginal dryness, hot flashes). Menopause and/or
primary ovarian failure is documented by the presence of
low estrogen levels and elevated gonadotropin levels.
Secondary hypogonadism is associated with low estrogen
levels and inappropriately normal gonadotropin levels.
After several years, breast tissue and bone mineral density may decline, and the patient may present with fine
facial wrinkles.
In men, testicular hypofunction and resultant decreased testosterone secretion typically cause a decreased libido and fatigue within months. Years of
testosterone deficiency will result in losses to muscle
mass and bone mineral density.
The approach to diagnosing gonadotropin deficiency in a patient with hypopituitarism varies with the gender of the patient. The best test of gonadotroph sufficiency in a premenopausal woman is the menstrual
history. In a woman with known pituitary or hypothalamic disease and normal menses, no tests of luteinizing
hormone (LH) or follicle-stimulating hormone (FSH)
secretion are necessary, as a normal menstrual history is
4 Hospital Physician Board Review Manual
a more sensitive indicator of intact pituitary-gonadal
function than any available biochemical test. In a
woman with oligomenorrhea or amenorrhea, LH and
FSH levels should be measured to distinguish ovarian
disease from pituitary or hypothalamic disease.
LH and FSH are secreted in a pulsatile manner so
that a single measurement may be in the normal range
in a woman with oligomenorrhea; however, normal values are inappropriate in women with amenorrhea and
in postmenopausal women. Estradiol levels may be low
or normal in women with gonadotropin deficiency and
provide little information beyond the menstrual history. Men with gonadal failure may have normal or low
serum LH or low FSH levels, but normal values are
inappropriate if the serum testosterone is decreased,
suggesting pituitary or hypothalamic disease.
Although widely used, the serum LH response to a single bolus of gonadotropin-releasing hormone (GnRH)
does not help distinguish secondary hypogonadism due
to pituitary disease from that resulting from hypothalamic disease. Patients with hypogonadism due to pituitary
disease and those with hypothalamic disease may have a
normal or subnormal LH response to GnRH stimulation.
THYROTROPIN DEFICIENCY
The clinical presentation of TSH deficiency is that of
hypothyroidism, and the degree of clinical signs and
symptoms typically parallels the degree of thyroxine
deficiency. Some patients, however, may present with an
insidious course despite marked TSH deficiency. Some
of the more common nonspecific signs and symptoms
include fatigue, lethargy, cold intolerance, constipation,
dry skin, facial puffiness, bradycardia, a delayed relaxation phase of the deep tendon reflexes, and anemia.
The adequacy of TSH secretion is assessed by the
simple measurement of serum free thyroxine (FT4)
concentration.7 – 9 If the serum FT4 is normal, the TSH
secretion is normal; if the serum FT4 is low, TSH secretion is low. In patients with secondary or tertiary hypothyroidism due to pituitary or hypothalamic disease,
respectively, the TSH alone is not helpful in making the
diagnosis of hypothyroidism, because the TSH is usually in the normal range.
Patients with secondary hypothyroidism usually have
a normal or low TSH concentration. Either is inappropriate for the low serum FT4 concentration. On occasion, such a patient may have an elevated TSH because
the hypothalamic or pituitary disease has caused secretion of TSH that has diminished biologic activity yet
retains immunologic activity. Failure of the serum TSH
concentration to increase following administration of
thyrotropin-releasing hormone (TRH) confirms the
Hypopituitarism
diagnosis of secondary hypothyroidism, but this finding
usually is not necessary to make the diagnosis.
CORTICOTROPIN DEFICIENCY
ACTH deficiency, leading to secondary adrenal insufficiency, presents with signs and symptoms of cortisol
deficiency. In its most severe form, secondary adrenal
insufficiency may lead to death secondary to vascular
collapse, as cortisol is necessary for the maintenance of
peripheral vascular tone. Mild chronic deficiency presents in a more insidious manner, with symptoms including fatigue, anorexia, weight loss, decreased libido,
lassitude, hypoglycemia, and eosinophilia.
Primary and secondary adrenal insufficiency are clinically distinct in two ways. First, secondary adrenal insufficiency is characterized by normal renin-angiotensinaldosterone responses and normal mineralocorticoid
secretion. ACTH deficiency with resultant secondary
adrenal insufficiency does not cause salt wasting, volume
contraction, or hyperkalemia. Hypovolemia is unusual
and is less severe in secondary than in primary adrenal
insufficiency. Second, ACTH deficiency does not result
in hyperpigmentation, which is characteristic of primary
adrenal insufficiency. Both forms of adrenal insufficiency may result in hyponatremia due to the inappropriate
secretion of antidiuretic hormone (ADH; vasopressin).
The hyponatremia results from the impairment of renal
free water excretion and subsequent water retention.
Cortisol deficiency is responsible for the syndrome of
inappropriate ADH secretion (SIADH); corticosteroid
replacement therapy results in a correction in renal concentrating abilities.10
Ninety percent of patients with impaired ACTH
secretion have a decreased response to cosyntropin
(synthetic ACTH 1-24) stimulation. The standard test is
performed by the intravenous or intramuscular administration of a high dose (250 mcg) of cosyntropin. The
adrenal response is evaluated by measuring cortisol levels 30 and 60 minutes following injection. If corticotroph and adrenal secretion are normal, the serum cortisol concentration should rise to an absolute level of
18 mcg/dL or higher.
A subnormal cortisol response to synthetic ACTH
confirms the diagnosis of adrenal insufficiency but does
distinguish between primary and secondary insufficiency.
A low-dose test, using 1 mcg of cosyntropin, may be more
sensitive than the high-dose test. The results of low-dose
testing have been shown to correlate highly with those of
insulin-tolerance testing in the evaluation of a possible
ACTH deficiency.11 The low-dose test may detect partial
adrenal insufficiency that may be missed by the highdose test, which uses a supraphysiologic stimulus.
A normal cortisol response to synthetic ACTH excludes primary adrenal insufficiency but does not exclude secondary adrenal insufficiency of recent onset.
Recent pituitary lesions do not allow sufficient time for
adrenal atrophy to occur, and the adrenal glands may
respond to ACTH stimulation. Therefore, a pituitary
lesion of recent onset with resultant undersecretion of
corticotropin may be missed by relying on the cosyntropin stimulation test. In a similar manner, the cosyntropin stimulation test may miss chronic partial pituitary ACTH deficiency. For these reasons, patients with
a pituitary lesion and a normal response to synthetic
ACTH require a dynamic test of corticotroph reserve.
In patients with severe corticotropin deficiency for
more than a few weeks, the serum cortisol response to
synthetic ACTH will be decreased or absent as a result
of adrenal atrophy.12 – 17
There are several tests of ACTH reserve, including the
metyrapone test and the insulin-induced hypoglycemia
test. The results of the metyrapone test correlate well with
the serum cortisol response to surgical stress. Metyrapone blocks the activity of 11-hydroxylase, the enzyme
that catalyzes conversion of 11-deoxycortisol to cortisol.18
Therefore, metyrapone administration results in an increase in ACTH secretion and 11-deoxycortisol, with a
concomitant reduction in cortisol secretion. Interpretation of the metyrapone test requires adequate inhibition of cortisol secretion. Inadequate inhibition may
result from noncompliance, malabsorption, or rapid metabolism of metyrapone, which may result from medications such as phenytoin therapy.19
Insulin-induced hypoglycemia is a sufficient stress to
stimulate ACTH and therefore cortisol secretion. The
insulin-induced hypoglycemia test involves measuring
serum glucose, cortisol, and GH concentrations before,
at baseline, and at 15, 30, 60, 90, and 120 minutes after
an insulin injection (0.1 unit per kg body weight). The
serum glucose should decrease to less than 50% of the
baseline value or less than 40 mg/dL (2.2 mmol/L) for
adequate hypothalamic-pituitary stimulation.20 The
serum cortisol should increase to 20 mcg/dL or higher,
and the serum GH should increase to 10 ng/mL or
higher. Because of the risks associated with hypoglycemia, this test must be performed under the direct
supervision of a physician. Contraindications include a
history of a seizure disorder, coronary artery disease
with a history of angina, altered mental status, or generalized debility.
GROWTH HORMONE DEFICIENCY
There is increased interest in testing GH secretion
and reserve in patients with hypothalamic or pituitary
Endocrinology Volume 4, Part 3 5
Hypopituitarism
disease, given the recent approval of GH therapy for
treatment of abnormal body composition and dyslipidemia in adults with GH deficiency. The diagnosis of
GH deficiency in adults is likely if the patient has documented panhypopituitarism. In patients with organic
pituitary disease, GH secretion is more likely to be affected than are TSH and ACTH secretion. In patients with
organic pituitary disease and no other pituitary hormone deficits, the likelihood of GH deficiency is 45%.
The likelihood is nearly 100% in patients with multiple
hormone deficits.21 Furthermore, multiple deficiencies
of other pituitary hormones, including TSH, ACTH,
and gonadotropins, correlate highly with an inadequate
GH response to direct stimulation.22
A single GH measurement is not useful in making a
diagnosis of GH deficiency, as GH is secreted in a pulsatile manner and the serum concentration is normally
low during most of the day. Measurement of serum
insulin-like growth factor 1 (IGF-1; somatomedin C),
which is dependent on GH secretion, may indicate a
deficiency of somatotroph function, if the patient is not
malnourished, chronically ill, or elderly (all conditions
that decrease the production of IGF-1).23 However,
serum IGF-1 measurements do not distinguish reliably
between normal and subnormal GH secretion in adults.
In two series of more than 200 adults with proven GH
deficiency, 34% to 51% had a serum IGF-1 within the
normal range.24,25
Provocative tests to diagnose GH deficiency include
insulin-induced hypoglycemia, arginine infusion, and
a single dose of levodopa. A subnormal serum GH
response is considered to be a peak value less than
5 ng/mL.26 Each of the provocative tests should be
completed in the morning after an overnight fast. A
single test of GH reserve may be subnormal in a normal person. It is important to note that obesity blunts
the GH response to all of the provocative tests.
PROLACTIN DEFICIENCY
The only known clinical manifestation of prolactin
deficiency is the inability to lactate postpartum, a potential clue to a previously subclinical pituitary abnormality. The serum prolactin level is rarely low and
may be increased in patients with hypothalamicpituitary disease of almost any cause. Prolactin measurement may provide useful information for identifying the cause of hypopituitarism as well as the potential
cause of hypogonadism. However, testing for prolactin
deficiency is unnecessary. Dynamic testing of lactotroph
reserve with TRH is not useful, because it does not differentiate between the various causes of hyperprolactinemia.
6 Hospital Physician Board Review Manual
ENDOCRINE EVALUATION OF CASE PATIENT
Laboratory evaluation of the patient’s pituitary and
target gland function reveals the following findings:
• Prolactin, 18 ng/mL (normal, less than
20 ng/mL)
• Estradiol, 95 pg/mL (normal, 30 to
400 pg/mL [adult premenopausal]; less than
20 pg/mL [postmenopausal])
• FSH, 4.3 mIU/mL (normal, 0.6 to
13.3 mIU/mL [adult premenopausal]; 31 to
134 mIU/mL [postmenopausal])
• LH, 3.8 mIU/mL (normal, 0.5 to
12.8 mIU/mL [adult premenopausal];
13.8 to 72 mIU/mL [cycle peak]; 15 to
64 mIU/mL [postmenopausal])
• TSH, 0.6 mcU/mL (normal, 0.3 to
3.8 mcU/mL)
• FT4, 0.6 ng/dL (normal, 0.8 to 1.8 ng/dL)
• Cortisol, random, 1.2 mcg/dL (normal, 5 to
25 mcg/dL [8 AM]); after administration of
250 mcg cosyntropin: at 30 min, 3.2 mcg/dL;
at 60 min, 3.6 mcg/dL
• ACTH, 18 pg/mL (normal, 9 to 52 pg/mL
[8 AM])
• GH, 0.9 ng/mL (normal, 0 to 5.6 ng/mL)
• IGF-1, 182 ng/mL (normal, 90 to 360 ng/mL)
• How should these endocrine test results be interpreted?
With normal estradiol and gonadotropin levels, this
patient has no laboratory evidence for the diagnosis of
hypogonadism, suggesting that her symptoms may be
caused by other hormone deficiencies. The patient’s
fatigue, cold intolerance, and general aches may reflect
her hypothyroidism. The FT4 is low, consistent with
hypothyroidism. The TSH is inappropriately normal,
suggesting a pituitary or hypothalamic cause for the
hypothyroidism.
The patient’s low random cortisol value suggests
adrenal insufficiency, which also may have caused her
fatigue, aches, and anorexia. The preservation of axillary and pubic hair suggests that the adrenal insufficiency is not long-standing, as adrenal androgens are necessary for the maintenance of axillary and pubic hair in
women. In the absence of steroid therapy, an undetectable or subnormal morning cortisol concentration
suggests adrenal insufficiency. A serum cortisol of
Hypopituitarism
3 mcg/dL or less (normal, 5 to 25 mcg/dL), confirmed
on a second occasion, is strong evidence of adrenal
insufficiency.27,28 In a patient with a disease known to
result in hypopituitarism, this is usually secondary adrenal insufficiency. If the 8 AM cortisol level is equal to or
greater than 18 mcg/dL, basal ACTH secretion is sufficient, and adrenal insufficiency is excluded. Serum cortisol values between 3 mcg/dL and 18 mcg/dL are intermediate, an indication of the necessity to test pituitary
reserve. This patient’s subnormal response to the cosyntropin stimulation test indicates adrenal insufficiency.
The normal ACTH in this patient is inappropriate for
her low level of circulating cortisol and establishes the
diagnosis of secondary adrenal insufficiency.
Visual Field Testing
The involvement of the optic chiasm on this patient’s MRI prompts visual field testing, which reveals a
subtle bilateral defect of the superior temporal visual
field that is more prominent on right side. No other
abnormalities are noted. These findings are consistent
with a mass effect at the level of the optic chiasm.
• Does this patient require further testing?
Pituitary Adenomas
Benign adenomas of the anterior pituitary are classified based on size (ie, microadenomas if less than 10 mm;
macroadenomas if greater than 10 mm) and function. Any
anterior pituitary cell type may give rise to an adenoma
and result in increased secretion of the hormone or hormones produced by that cell type and/or decreased
secretion of other hormones due to compression of the
other cell types.1 However, impaired vision caused by
suprasellar extension of the adenoma, with subsequent
compression of the optic chiasm (Figure 1), is the most
common reason for a person with a pituitary adenoma to
seek medical attention.29 Some patients may be unaware
of changes in their vision, or the onset of the deficit may
be so gradual that a patient may not seek ophthalmologic consultation for months or even years. The most frequent complaints of patients with chiasmal compression
from pituitary tumors are progressive loss of central acuity and dimming of the visual field, especially in the temporal portion, resulting in peripheral field deficits.
Diplopia may rarely result from involvement of the third,
fourth, or sixth cranial nerves in the cavernous sinus,
resulting in a disturbance of ocular motility.
Given this patient’s endocrine findings and the pituitary abnormality suggested on her earlier CT scan, she
should undergo MRI of the brain and pituitary gland to
identify the specific nature of the abnormality. MRI is the
single best method of visualizing sellar masses, and no
other imaging modality usually is necessary. Normal pituitary tissue—and most sellar masses—emit a signal that is
similar to or slightly greater in intensity than that of central nervous system (CNS) tissue. Normal pituitary tissue
takes up gadolinium to a greater degree than CNS tissue,
resulting in a higher intensity signal than is emitted from
the surrounding CNS tissue.
FURTHER EVALUATION OF CASE PATIENT
The patient’s clinical and biochemical evidence for
secondary hypothyroidism and adrenal insufficiency
and her lack of evidence for other hormone abnormalities lead the endocrinologist to conclude that she has
partial hypopituitarism secondary to a mass lesion in
the sella turcica. MRI studies of the brain are ordered to
evaluate the sellar region.
Brain Imaging
MRI of the brain demonstrates a smooth mass
(14 mm × 22 mm × 13 mm) that fills the sella turcica
and extends superiorly, with a mass effect on the central portion of the optic chiasm. The infundibulum is
buckled and slightly displaced upward and to the right,
without significant thickening or abnormal enhancement. The sphenoid sinus, cavernous sinus, and carotid arteries all appear normal. The mass is isointense
with gray matter on T-1 and T-2 weighted images
before administration of gadolinium, and it displays
homogeneous enhancement after gadolinium administration. The appearance suggests the possibility of a
pituitary adenoma.
• What is the differential diagnosis of this patient’s
MRI findings?
DIFFERENTIAL DIAGNOSIS OF A SELLAR MASS
The differential diagnosis of a sellar mass is summarized in Table 2.
Other Benign or Malignant Tumors
Craniopharyngiomas are solid or mixed solid-cystic
benign tumors that arise from the remnants of Rathke’s
pouch along a line from the nasopharynx to the diencephalon.30 Most are intrasellar or suprasellar. Craniopharyngiomas usually occur in childhood and adolescence, with the most common presentation being growth
retardation; pituitary hormone deficiencies, including
diabetes insipidus, also are common. Meningiomas are
benign tumors that also may occur in or near the sella.
Malignancies that may arise within the parasellar
region include germ cell tumors, sarcomas, and chordomas. Germ cell tumors metastasize readily but are
Endocrinology Volume 4, Part 3 7
Hypopituitarism
Table 2. Differential Diagnosis of a Sellar Mass
Pituitary adenoma
Microadenoma/macroadenoma
Functional versus nonfunctional
Craniopharyngioma
Meningioma
Malignancies
Germ cell tumor
Sarcoma
Chordoma
Pituitary carcinoma (rare)
Metastatic disease
Breast cancer
Lung cancer
Inflammatory lesion
Lymphocytic hypophysitis
Granulomatous hypophysitis
Infection
Abscess (rare)
Cystic lesions
Rathke’s cleft
Arachnoid cyst
Dermoid cyst
Vascular lesions
Arteriovenous fistula
Physiologic pituitary enlargement
highly radiosensitive. Chordomas are aggressive tumors
that often arise in the clivus and present classically with
headaches, visual impairment, and anterior pituitary
deficiencies. Pituitary carcinomas are rare and are characterized by rapid growth, invasiveness, and extrapituitary involvement.31
Metastasis to the sellar region also may occur. Metastases to the pituitary gland are most often associated
with breast cancer in women and lung cancer in men, but
other tumors also metastasize to the pituitary gland.31
Diabetes insipidus is the most common presentation, but
evidence of anterior pituitary dysfunction, headache, visual field abnormalities, fatigue, nausea, vomiting, and cognitive deficits are reported.32 Invasion of the surrounding
tissue, including the cavernous sinus, is common.
Uncommon Causes
Inflammatory, tumor-like lesions of the pituitary
gland and stalk include abscesses (rare) and nonsup-
8 Hospital Physician Board Review Manual
purative lesions, namely lymphocytic hypophysitis
and granulomatous hypophysitis. Lymphocytic hypophysitis is mainly associated with late pregnancy or
the postpartum period, although it may occur in nonpregnant women and, very rarely, in men or postmenopausal women.33 Granulomatous hypophysitis
may be an isolated lesion or a component of systemic
sarcoidosis or other inflammatory disorders (eg,
Takayasu’s arteritis). Rathke’s cleft, arachnoid, and
dermoid cysts also may produce sellar enlargement.
An arteriovenous fistula in the cavernous sinus may
cause modest enlargement of the pituitary gland,
which returns to normal after the fistula is blocked.
Finally, there are a few recognized forms of physiologic pituitary enlargement, including lactotroph
hyperplasia in the peripartum period and thyrotroph
hyperplasia due to long-standing and profound primary hypothyroidism.2,34
• How should this patient be managed?
A biopsy of this patient’s pituitary lesion is necessary
to make a final diagnosis. Given her adrenal insufficiency, she should receive stress doses of corticosteroids prior
to proceeding to the operating room, to protect her
from the stress of general anesthesia and a surgical procedure. Following the surgical procedure the patient
should be treated with replacement doses of corticosteroids and thyroid hormone. It is important to emphasize that thyroxine replacement should not commence
until adrenal function and ACTH reserve have been
tested and treated if necessary. Treatment of hypothyroidism alone, in a patient with coexisting hypothyroidism and hypoadrenalism, may increase the severity of
cortisol deficiency by increasing the metabolic rate and
accelerating the metabolism of the little cortisol that
may still be produced.5
Management of a patient with a pituitary adenoma is
beyond the scope of this manual. An earlier manual in
this volume (see Volume 4 Part 1, Acromegaly and Hyperprolactinemia) provides further details regarding the
management of a pituitary adenoma, including surgical
approaches and alternatives to surgery (ie, radiotherapy, gamma knife therapy).
BIOPSY AND DIAGNOSIS OF CASE PATIENT
The patient is treated with stress doses of corticosteroids. Transsphenoidal surgical exploration of the pituitary gland demonstrates an enlarged, tough, fibrous,
and yellowish gland. No separate mass is seen. The
lower portion of the gland is removed to decompress
the optic chiasm, and residual tissue is left in place with
the hope of maximizing functional pituitary recovery.
Hypopituitarism
Frozen-section biopsy yields a diagnosis of lymphocytic
hypophysitis.
• What are the distinguishing clinical features of lymphocytic hypophysitis?
LYMPHOCYTIC HYPOPHYSITIS
Lymphocytic hypophysitis is an uncommon pituitary
disorder that is considered an autoimmune disease. It
occurs predominantly in women and usually manifests
during the late pregnancy or postpartum period. The
disease has rarely been encountered in men and postmenopausal women.35,36 The pathophysiology is that of
lymphocytic infiltration of the pituitary gland, potentially leading to panhypopituitarism.
Clinically and radiologically, lymphocytic hypophysitis may mimic the presentation of a nonfunctioning
pituitary adenoma, although hyperprolactinemia may
occur. Brain MRI cannot always differentiate lymphocytic hypophysitis from pituitary adenoma; however,
some features may favor lymphocytic hypophysitis, including dural enhancement and extrapituitary involvement within the subarachnoid space.37 Some patients
have evidence of other associated autoimmune disorders (thyroiditis, adrenalitis), and antipituitary antibodies have been found in some cases.38
The pattern of pituitary hormone deficits is somewhat unique in lymphocytic hypophysitis, and the loss
of pituitary function is often out of proportion to the
degree of pituitary enlargement.38 Gonadotroph and
somatotroph function are more likely to be preserved
than corticotroph or thyrotroph function, unlike the
findings of hypopituitarism due to a sizable pituitary
adenoma. An isolated hormone deficiency, particularly
of corticotropin, can occur. Diabetes insipidus is not
characteristic, as the posterior pituitary and the pituitary stalk typically are spared. Definitive diagnosis requires a biopsy demonstrating diffuse infiltration with
lymphocytes, plasma cells, and a few eosinophils.4
The natural history of lymphocytic hypophysitis is
uncertain, and the value of therapy over observation is
debatable. The response to steroid therapy has been
inconsistent, and surgical removal may not be necessary as pituitary size and function may return to normal in any case.38 Surgical treatment is necessary for
decompression of lesions involving the optic chiasm or
other parasellar structures; whether surgery is indicated in the absence of visual field defects remains unclear. Given the anecdotal evidence for regression and
a return of pituitary function, conservative medical
management of lymphocytic hypophysitis may be
appropriate in some cases.
Figure 1. A magnetic resonance imaging scan following administration of gadolinium contrast, showing a coronal section
through the pituitary fossa. Note the large pituitary mass arising
from the fossa, extending into the suprasellar space and displacing the optic chiasm (arrow) superiorly.
TREATMENT OF HYPOPITUITARISM
Treatment of hypopituitarism consists of replacing
the individual hormones that are found to be deficient
when a patient with pituitary-hypothalamic disease is
tested. In many respects, the therapies are the same as
for primary deficiencies of the respective target glands,
but in other ways they are different. The treatment of
GH deficiency is unique to hypopituitarism.
There is a correlation between hypopituitarism and increased mortality. In one retrospective study of 344 patients with hypopituitarism following pituitary surgery, the
age-adjusted long-term mortality was double that of the
general population.39 This increased mortality was almost
entirely due to cardiovascular and cerebrovascular disease. Whether this is reversible with careful hormone
replacement therapy remains unknown at this time.
TREATMENT OF CORTICOTROPIN DEFICIENCY
ACTH deficiency induces cortisol deficiency. Treatment consists of the administration of hydrocortisone
or another glucocorticoid in an effort to mimic the
normal diurnal pattern of cortisol secretion. The average daily secretion of cortisol in normal individuals
is 10 to 20 mg/day.40 Replacement at a rate of 12 to
15 mg/m2/day provides an adequate amount of
Endocrinology Volume 4, Part 3 9
Hypopituitarism
bioactive cortisol. Although small deviations from the
optimal replacement dose usually are not detected, an
excessive dose can lead to symptoms of Cushing’s disease
and bone loss, while an inadequate dose may result in the
persistence or recurrence of the symptoms of cortisol
deficiency. Thus, patients are treated with the lowest dose
that does not result in clinical symptoms (fatigue, orthostasis, weight loss) or biochemical abnormalities consistent with underreplacement. The best guides to adequate replacement include a sense of well-being, a good
appetite, and normal electrolyte levels. The appearance
of signs of Cushing’s disease (hypertension, weight gain,
facial fullness) indicate overreplacement.
Patient education is vital in the treatment of chronic
adrenal insufficiency, as the major risk is the lack of normal serum cortisol in response to stress (surgery, febrile
illness, trauma, emotional or psychological stressors).
The usual recommendation is for patients to double
their replacement dose in such situations and to notify
their physician. Patients also should be encouraged to
wear a medical alert bracelet indicating a diagnosis of
adrenal insufficiency and to have prefilled dexamethasone syringes readily available in the event of an emergency (major injury, inability to tolerate oral medications,
acute adrenal insufficiency and loss of consciousness).
The usual daily dose of hydrocortisone varies according to a patient’s weight, with 30 mg/day sufficient for
a 70-kg patient. Typically, two-thirds of the dose is given
upon awakening, and one-third is given in the late
afternoon.This traditional twice-daily replacement regimen of hydrocortisone may not be as optimal as a
once-daily regimen using a long-acting glucocorticoid.
The oral administration of hydrocortisone does not
mimic the normal daily rhythm of cortisol secretion.
Within 30 minutes of ingestion, the serum cortisol concentration rises rapidly, and levels quickly exceed the
binding capacity of corticosteroid-binding globulin
and reach much higher concentrations than normal.
The kidneys rapidly filter the free or unbound cortisol,
resulting in a rapid decline in serum total cortisol concentrations, after which the decline slows (plasma halflife of 80 minutes). The net effect is a transient marked
elevation in the serum cortisol concentrations followed
by low levels until the next dose.41 Furthermore, by the
time a patient takes the morning dose of hydrocortisone, the normal endogenous cortisol levels would be
peaking or would have already peaked. A transient
morning adrenal insufficiency may account for early
morning symptoms of fatigue, nausea, and headache.
For these reasons, some authors recommend that patients with adrenal insufficiency be treated with a longeracting synthetic glucocorticoid, such as prednisone or
10 Hospital Physician Board Review Manual
dexamethasone.42 The longer duration of action provides a smoother physiologic profile, avoiding the
marked changes in the serum glucocorticoid concentrations that occur with the shorter-acting formulations.
The usual oral replacement doses for dexamethasone
and prednisone are 0.5 mg and 5 mg, respectively. Again,
the goal of therapy is to provide the lowest dose that
relieves the symptoms of glucocorticoid deficiency, while
avoiding the symptoms or signs of Cushing’s disease,
which indicate excessive glucocorticoid replacement.
Unlike the treatment of primary adrenal insufficiency, mineralocorticoid replacement is rarely necessary in
hypopituitarism. The major regulators of aldosterone
secretion are angiotensin II and potassium, not ACTH.
Therefore, aldosterone secretion is usually maintained
in the patient with hypopituitarism.
TREATMENT OF THYROTROPIN DEFICIENCY
The thyroxine deficiency that results from TSH deficiency is treated with levothyroxine. Treatment can be
given once daily, as there is little if any variation in the normal endogenous secretion of thyroxine. The thyroid hormone dose should be adjusted according to the clinical
response, with the goal of therapy being the normalization of the FT4 concentration, usually to the middle or
upper limits of normal. The serum TSH cannot be used
as a guide to the adequacy of levothyroxine therapy in
patients with secondary and tertiary hypothyroidism.
TREATMENT OF GONADOTROPIN DEFICIENCY
Treatment of LH and FSH deficiency depends on
the gender of the patient and whether or not fertility is
desired. In men who are not interested in fertility, testosterone replacement is sufficient. The choices are similar to those for replacement in primary hypogonadism.
Serum testosterone levels must be used to monitor the
adequacy of treatment. Men with secondary hypogonadism who wish to become fertile may be treated with
gonadotropins (if they have pituitary disease) or with
gonadotropins or GnRH (if they have hypothalamic disease).
Women with hypogonadism who are not interested
in fertility can be managed with estrogen-progestin
replacement therapy. Measurements of LH and FSH
cannot be used to monitor the adequacy of treatment.
Women with secondary hypogonadism who wish to
become fertile can be treated with gonadotropins or
GnRH.
TREATMENT OF GROWTH HORMONE DEFICIENCY
Patients with GH deficiency that is acquired in
adulthood must meet at least two criteria for therapy:
Hypopituitarism
a poor GH response to two standard stimuli, and
hypopituitarism due to pituitary or hypothalamic disease.43 There is substantial evidence that GH treatment in these patients increases muscle mass and
decreases fat mass; less convincing evidence exists
regarding improvement in bone mineral density. The
evidence for improved sense of well-being, increased
muscle strength, and improved lipid profiles are conflicting.
Recombinant human GH is administered by subcutaneous injection once daily, usually in the evening. The
optimal dose for adults with hypopituitarism has not
been determined. Most patients over the age of 60 will
have IGF-1 levels in the reference range with a dose of
5 mcg/kg body weight; a few patients will require only
half this dose. A 1998 consensus conference recommended a starting dose of 0.3 to 0.5 mg/day (approximately 2 to 5 mcg/kg body weight).21 Monitoring should
be done by measuring serum IGF-1; after 2 months of
therapy, the IGF-1 level should be in the normal range.
If not, the daily dose should be increased in stepwise
increments every 2 months until the level is normal. If
side effects occur or if the IGF-1 level exceeds the normal
range, the dose should be decreased.
The most common side effects of adult GH therapy
are peripheral edema, arthralgias, carpal tunnel syndrome, paresthesias, and worsened glucose tolerance.
Less common side effects include benign intracranial
hypertension and macular edema and proliferative
retinopathy in the absence of diabetes mellitus. Side
effects are more common in older and heavier patients
and in those who are overtreated, as judged by a high
serum IGF-1 concentration during therapy.
CASE RESOLUTION
Following surgery and discharge from the hospital,
the patient is initially treated with a 2-week course of
high-dose steroids. Her visual field deficits and headaches resolve and she is subsequently placed on a twicedaily hydrocortisone regimen (20 mg in the morning
and 10 mg in the afternoon). Thyroid replacement also
is initiated at this time, beginning with a dose of
100 mcg of levothyroxine and titrating upward, with the
goal of achieving thyroid hormone levels in the middle
to upper limits of normal.
After 3 months of replacement therapy the patient
is feeling well and her clinical symptoms have resolved. A follow-up cosyntropin stimulation test demonstrates persistent hypoadrenalism. Thus, the patient
is continued on daily thyroid hormone and corticosteroid therapy.
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Copyright 2002 by Turner White Communications Inc., Wayne, PA. All rights reserved.
12 Hospital Physician Board Review Manual