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Panhypopituitarism may result from pituitary tumors, traumatic brain injury, intracranial aneurysm, and
pituitary surgery or radiotherapy. Up to 30% of patients with head trauma experience pituitary
dysfunction months or years after the initial insult. Less often, panhypopituitarism can be caused by
infection (tuberculosis, histoplasmosis), infiltrative diseases, and autoimmune lymphocytic hypophysitis.
Although pituitary metastases are frequently found in patients with disseminated cancer, these
metastases rarely impede hormone secretion. Sheehan syndrome is massive peripartum blood loss
precipitating hypovolemic shock and anterior pituitary infarction. Pituitary apoplexy from hemorrhage
into an enlarging pituitary adenoma may also lead to panhypopituitarism during or after pregnancy
(principles and practise of hospital medicine )
CURRENT Medical Diagnosis & Treatment 2014
Maxine A. Papadakis, Editor, Stephen J. McPhee, Editor, Michael W. Rabow, Associate Editor
Combined pituitary hormone deficiency and panhypopituitarism
The conditions refer to a deficiency of several or all pituitary hormones. Combined pituitary hormone
deficiency gradually develops in patients with PROP 1 gene mutations, usually presenting with short
stature and growth failure due to GH and TSH deficiency; lack of pubertal development occurs due to
deficiencies in FSH and LH. ACTH-cortisol deficiency also gradually develops in patients with PROP 1 gene
mutations; these patients typically require corticosteroid replacement therapy by age 18 years. In
addition to the manifestations noted above, patients with long-standing hypopituitarism tend to have
dry, pale, finely textured skin. The face has fine wrinkles and an apathetic countenance.
Other manifestations
Patients with long-standing hypopituitarism tend to have dry, pale, fine, wrinkled facial skin and an
apathetic countenance. Hypothalamic damage can cause obesity and cognitive impairment. Local tumor
effects can cause headache or optic nerve compression with visual field impairment.
Laboratory Findings
The fasting blood glucose may be low. Hyponatremia is often present due to hypothyroidism or

hypoadrenalism. Hyperkalemia usually does not occur, since aldosterone production is not affected.
For men, an accurate serum total testosterone measurement must be obtained. For older men, free
testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone
binding globulin. If the serum testosterone is low, then serum gonadotropins (FSH and LH) are obtained
to distinguish pituitary dysfunction from primary hypogonadism.
The free thyroxine (FT4) level is low, but TSH is usually not elevated in patients with hypothalamic
hypopituitarism. Plasma levels of sex steroids (testosterone and estradiol) are low or low normal, as are
the serum gonadotropins. Elevated prolactin (PRL) levels are found in patients with prolactinomas,
acromegaly, and hypothalamic disease.
ACTH deficiency usually causes functional atrophy of the adrenal cortex within 2 weeks of pituitary
destruction. Therefore, the diagnosis of secondary hypoadrenalism can usually be confirmed with the
cosyntropin test. For the cosyntropin test, patients should be either taking no corticosteroids or a short-
acting corticosteroid (such as hydrocortisone), which is held after midnight on the morning of the test. At
8 am, blood is drawn for serum cortisol, ACTH, and dehydroepiandrosterone (DHEA); then 0.25 mg of
cosyntropin (synthetic ACTH1–24) is administered intramuscularly or intravenously. Another blood
sample is obtained 45 minutes after the cosyntropin injection to measure the stimulated serum cortisol
levels. A stimulated serum cortisol of < 20 mcg/dL (550 nmol/mL) indicates adrenal insufficiency. With
gradual pituitary damage and early in the course of ACTH deficiency, patients can have a stimulated
serum cortisol of ≥ 20 mcg/dL but a baseline 8 am serum cortisol < 5 mcg/dL (137.5 nmol/L), which is
suspicious for adrenal insufficiency. The baseline ACTH level is low or normal in secondary
hypoadrenalism, distinguishing it from primary adrenal disease. The serum DHEA levels are usually low in
patients with adrenal deficiency, helping confirm the diagnosis. For patients with symptoms of secondary
adrenal insufficiency (hyponatremia, hypotension, pituitary tumor) but borderline cosyntropin test
results, treatment can be instituted empirically and the test repeated at a later date. Insulin tolerance
testing and metyrapone testing are usually unnecessary.
Epinephrine deficiency occurs with secondary adrenal insufficiency, since high local concentrations of
cortisol are required to induce the production of the enzyme phenylethanolamine N-methyltransferase
(PNMT) in the adrenal medulla that catalyzes the conversion of norepinephrine to epinephrine.
GH deficiency diagnosis is difficult since GH secretion is normally pulsatile and serum GH levels are nearly
undetectable for most of the day. Also, adults normally tend to produce less GH as they age. Therefore,

GH deficiency is often inferred by symptoms of GH deficiency in the presence of pituitary destruction or
other pituitary hormone deficiencies. GH deficiency is present in 96% of patients with three or more
other pituitary hormone deficiencies. While GH stimulates the production of IGF-I, the serum IGF-I level
is neither a sensitive (about 50%) nor specific test for GH deficiency in adults. While very low serum IGF-I
levels (< 84 mcg/L) are usually indicative of GH deficiency, they also occur in malnutrition, prolonged
fasting, oral estrogen, hypothyroidism, uncontrolled diabetes mellitus, and liver failure. In GH deficiency
(but also in most adults over age 40), exercise-stimulated serum GH levels remain at < 5 ng/mL and
usually fail to rise.
Provocative GH-stimulation tests (eg, insulin hypoglycemia, intravenous arginine and growth hormone–
releasing hormone (GHRH), and oral clonidine or carbidopa/levodopa (combination) tests) are often
performed but are in fact poor tests for GH deficiency. The insulin hypoglycemia test is now rarely used.
Other GH stimulation tests require the administration of intravenous arginine and GHRH and oral
clonidine or carbidopa/levodopa (combination) in patients pretreated with propranolol or estrogen.
However, these tests do not discriminate well between normal individuals and patients with presumed
GH deficiency (patients with three or more other pituitary hormone deficiencies). Also, normal
overweight adults (body mass index [BMI] ≥ 25 kg/m2) typically have blunted peak GH levels after
arginine-GHRH administration.
Despite the limitations of intravenous GHRH/arginine stimulation testing, some insurance companies
insist that patients have an abnormal test before covering the costs of GH replacement therapy.
However, the latter test has a sensitivity of only 66% for GH deficiency. Therefore, when patients have a
serum IGF-I < 84 mcg/L or three other pituitary hormone deficiencies, the likelihood of GH deficiency is
so high that symptomatic patients should have a therapeutic trial of GH therapy.
The differential diagnosis of GH deficiency is congenital GH resistance with deficiency of IGF-I; at its
worst, IGF-I deficiency results in Laron dwarfism that is resistant to GH therapy.
Patients with hypopituitarism without an established etiology should be screened for hemochromatosis
with a serum iron and transferrin saturation or ferritin since hemochromatosis can cause
hypopituitarism.
Imaging
MRI provides the best visualization of pituitary and hypothalamic tumors. Thickening of the pituitary

stalk can be caused by sarcoidosis or hypophysitis.
Differential Diagnosis
The failure to enter puberty may simply reflect delayed puberty, also known as constitutional delay in
growth and puberty. Reversible hypogonadotropic hypogonadism may occur with serious illness,
malnutrition, anorexia nervosa, or morbid obesity. Men typically develop partial secondary
hypogonadism with aging. The clinical situation and the presence of normal adrenal and thyroid function
allow ready distinction from hypopituitarism. Profound hypogonadotropic hypogonadism develops in
men who receive GnRH analog therapy (leuprolide) for prostate cancer; it usually persists following
cessation of therapy. Hypogonadotropic hypogonadism usually develops in patients receiving opioid
therapy, including high-dose methadone or long-term intrathecal infusion of opioids; both GH deficiency
and secondary adrenal insufficiency occur in 15% of such patients. Secondary adrenal insufficiency may
persist for many months following high-dose corticosteroid therapy.
Severe illness causes functional suppression of TSH and T4 . Hyperthyroxinemia reversibly suppresses
TSH. Administration of triiodothyronine (Cytomel) suppresses TSH and T4. Bexarotene, used to treat
cutaneous T cell lymphoma, suppresses TSH secretion, resulting in temporary central hypothyroidism.
Corticosteroids or megestrol treatment reversibly suppresses endogenous ACTH and cortisol secretion.
GH deficiency normally occurs with aging. Physiologic GH deficiency that develops in obese patients may
return to normal with sufficient weight loss.
Complications
Among patients with craniopharyngiomas, diabetes insipidus is found in 16% preoperatively and in 60%
postoperatively. Hyponatremia often presents abruptly during the first 2 weeks following pituitary
surgery. Visual field impairment may occur. Hypothalamic damage may result in morbid obesity as well
as cognitive and emotional problems. Conventional radiation therapy results in an increased incidence of
small vessel ischemic strokes and second tumors.
Patients with untreated hypoadrenalism and a stressful illness may become febrile and comatose and die
of hyponatremia and shock.
Adults with GH deficiency have experienced an increased cardiovascular morbidity. Rarely, acute

hemorrhage may occur in large pituitary tumors, manifested by rapid loss of vision, headache, and
evidence of acute pituitary failure (pituitary apoplexy) requiring emergency decompression of the sella.
Treatment
Transsphenoidal removal of pituitary tumors will sometimes reverse hypopituitarism. Hypogonadism due
to PRL excess usually resolves during treatment with cabergoline or other dopamine agonists.
GH-secreting tumors may respond to octreotide (see Acromegaly). Radiation therapy with x-ray, gamma
knife, or heavy particles may be necessary but increases the likelihood of hypopituitarism.
The mainstay of substitution therapy for pituitary insufficiency is lifetime hormone replacement.
Corticosteroid Replacement
Hydrocortisone tablets, 15–35 mg/d orally in divided doses, should be given. Most patients do well with
10–20 mg in the morning and 5–15 mg in the late afternoon. Patients with partial ACTH deficiency (basal
morning serum cortisol above 8 mg/dL [220 mmol/L]) require hydrocortisone replacement in lower
doses of about 5 mg orally twice daily. Some clinicians prefer prednisone (3–7.5 mg/d orally) or
methylprednisolone (4–6 mg/d orally), given in divided doses. A mineralocorticoid is rarely needed. To
determine the optimal corticosteroid replacement dosage, it is necessary to monitor patients carefully
for over- or underreplacement. A white blood cell count (WBC) with a relative differential can be useful,
since a relative neutrophilia and lymphopenia can indicate corticosteroid overreplacement, and vice
versa. Additional corticosteroids must be given during stress, eg, infection, trauma, or surgical
procedures. For mild illness, corticosteroid doses are doubled or tripled. For trauma or surgical stress,
hydrocortisone 50 mg is given every 6 hours intravenously or intramuscularly and then reduced to usual
doses as the stress subsides. Patients with adrenal insufficiency are advised to wear a medical alert
bracelet describing their condition and treatment.
Patients with secondary adrenal insufficiency due to treatment with corticosteroids at supraphysiologic
doses require their usual daily dose of corticosteroid during surgery and acute illness; supplemental
hydrocortisone is not usually required.
Thyroid Hormone Replacement

Levothyroxine is given to correct hypothyroidism only after the patient is assessed for cortisol deficiency
or is already receiving corticosteroids. (See Hypothyroidism.) The typical maintenance dose is about 1.6
mcg/kg body weight. However, dosage requirements vary widely, averaging 125 mcg daily with a range
of 25–300 mcg daily. The optimal replacement dose of thyroxine for each patient must be carefully
assessed clinically. Serum FT4 levels usually need to be in the high-normal range for adequate
replacement. Assessment of serum TSH is useless for monitoring patients with hypopituitarism, since
TSH levels are always low.
Sex Hormone Replacement
Hypogonadotropic hypogonadism often develops in patients with hyperprolactinemia and resolves with
its treatment (see Hyperprolactinemia).
Androgen and estrogen replacement are discussed below (see Male Hypogonadism and Female
Hypogonadism). Patients with idiopathic hypogonadotropic hypogonadism, who have received several
years of hormone replacement therapy (HRT), may have a trial off hormonal therapy to assess whether
spontaneous sexual maturation may have occurred.
Women with hypopituitarism and secondary adrenal insufficiency whose serum DHEA levels are < 400
ng/mL may be treated with compounded DHEA in doses of about 25–50 mg/d orally. DHEA therapy
tends to increase pubic and axillary hair and may modestly improve libido, alertness, stamina, and
overall psychological well-being after 6 months of therapy.
To improve spermatogenesis, human chorionic gonadotropin (hCG) (equivalent to LH) may be given at a
dosage of 2000–3000 units intramuscularly three times weekly and testosterone replacement
discontinued. The dose of hCG is adjusted to normalize serum testosterone levels. After 6–12 months of
hCG treatment, if the sperm count remains low, hCG injections are continued along with injections of
follitropin-beta (synthetic recombinant FSH) or urofollitropins (urine-derived FSH). An alternative for
patients with an intact pituitary (eg, Kallmann syndrome) is the use of leuprolide (GnRH analog) by
intermittent subcutaneous infusion. With either treatment, testicular volumes double within 5–12
months, and spermatogenesis occurs in most cases. With persistent treatment and the help of
intracytoplasmic sperm injection for some cases, the total pregnancy success rate is about 70%.
Clomiphene, 25–50 mg orally daily, can sometimes stimulate a man’s own pituitary gonadotropins (when
his pituitary is intact), thereby increasing testosterone and sperm production.

For fertility induction in females, ovulation may be induced with clomiphene, 50 mg daily for 5 days
every 2 months. Follitropins and hCG can induce multiple births and should be used only by those
experienced with their administration. (See Hypogonadism.)
Human Growth Hormone (hGH) Replacement
Symptomatic adults with severe GH deficiency (serum IGF-I < 85 mcg/L) may be treated with a
subcutaneous recombinant human growth hormone (rhGH, somatropin) injections starting at a dosage
of about 0.2 mg/d (0.6 international units/d), administered three times weekly. The dosage of rhGH is
increased every 2–4 weeks by increments of 0.1 mg (0.3 international units) until side effects occur or a
sufficient salutary response and a normal serum IGF-I level are achieved. A sustained-release injectable
suspension of depot GH is available (Nutropin Depot). It can be given twice monthly and is therefore
more convenient than standard rhGH preparations. In a study of 20 Brazilian GH-deficient adults, depot
GH, given in doses of 13.5 mg subcutaneously twice monthly over 6 months, improved body morphology
and lipid profiles but was associated with an increase in carotid plaque. If the desired effects (eg,
improved energy and mentation, reduction in visceral adiposity) are not seen within 3–6 months at
maximum tolerated dosage, rhGH therapy is discontinued.
During pregnancy, rhGH may be safely administered during pregnancy to women with hypopituitarism at
their usual pregestational dose during the first trimester, tapering the dose during the second trimester,
and discontinuing rhGH during the third trimester.
Oral estrogen replacement reduces hepatic IGF-I production. Therefore, prior to commencing rhGH
therapy, oral estrogen should be changed to a transdermal or transvaginal estradiol.
Treatment of adult GH deficiency usually improves the patient’s emotional sense of well-being, increases
muscle mass, and decreases visceral fat and waist circumference. Long-term treatment with rhGH does
not appear to affect mortality.
Side effects of rhGH therapy may include peripheral edema, hand stiffness, arthralgias, myalgias,
headache, pseudotumor cerebri, gynecomastia, carpal tunnel syndrome, tarsal tunnel syndrome,
hypertension, and proliferative retinopathy. Side effects are more common in patients who are older,
those with higher BMI, and those with adult-onset GH deficiency. Such symptoms usually remit promptly
after a sufficient reduction in dosage. Excessive doses of rhGH could cause acromegaly; patients
receiving long-term therapy require careful clinical monitoring. Serum IGF-I levels should be kept in the

normal range.
GH should not be administered during critical illness since, in one study, administration of very high
doses of rhGH to patients in an intensive care unit was shown to increase overall mortality. There is no
role for GH replacement in the somatopause of aging.
IGF-I (mecasermin) is available to treat patients with Laron syndrome.
Other Treatment
Selective transsphenoidal resection of pituitary adenomas can often restore normal pituitary function.
Cabergoline, bromocriptine, or quinagolide may reverse the hypogonadism seen in hyperprolactinemia.
(See Hyperprolactinemia.) Disseminated Langerhans cell histiocytosis may be treated with
bisphosphonates to improve bone pain; treatment with 2-chlorodeoxyadenosine (cladribine) has been
reported to produce remissions.
Patients with lymphocytic hypophysitis may be treated with corticosteroid therapy; pituitary surgery or
low-dose external beam radiation therapy may be required for aggressive cases.
Prognosis
The prognosis depends on the primary cause. Hypopituitarism resulting from a pituitary tumor may be
reversible with dopamine agonists or with careful selective resection of the tumor. Spontaneous
recovery from hypopituitarism associated with pituitary stalk thickening has been reported. Patients can
also recover from functional hypopituitarism, eg, hypogonadism due to starvation or severe illness,
suppression of ACTH by corticosteroids, or suppression of TSH by hyperthyroidism. Spontaneous reversal
of isolated idiopathic hypogonadotropic hypogonadism occurs in about 10% of patients after several
years of HRT. However, hypopituitarism is usually permanent, and lifetime HRT is ordinarily required..
Functionally, most patients with hypopituitarism do very well with hormone replacement. Men with
infertility who are treated with hCG/FSH or GnRH are likely to resume spermatogenesis if they have a
history of sexual maturation, descended testicles, and a baseline serum inhibin level over 60 pg/mL.
Women under age 40 years, with infertility due to hypogonadotropic hypogonadism, can usually have
successful induction of ovulation.

Hypothalamic and Anterior Pituitary Insufficiency
Hypopituitarism results from impaired production of one or more of the anterior pituitary trophic
hormones. Reduced pituitary function can result from inherited disorders; more commonly,
hypopituitarism is acquired and reflects the compressive mass effects of tumors or the consequences of
inflammation or vascular damage. These processes also may impair synthesis or secretion of
hypothalamic hormones, with resultant pituitary failure (Table 339-2).
Table 339-2 Etiology of Hypopituitarism*
View Large | Save Table
Developmental and Genetic Causes of Hypopituitarism
Pituitary Dysplasia
Pituitary dysplasia may result in aplastic, hypoplastic, or ectopic pituitary gland development. Because
pituitary development follows midline cell migration from the nasopharyngeal Rathke's pouch, midline
craniofacial disorders may be associated with pituitary dysplasia. Acquired pituitary failure in the
newborn also can be caused by birth trauma, including cranial hemorrhage, asphyxia, and breech
delivery.
Septo-Optic Dysplasia
Hypothalamic dysfunction and hypopituitarism may result from dysgenesis of the septum pellucidum or
corpus callosum. Affected children have mutations in the HESX1 gene, which is involved in early
development of the ventral prosencephalon. These children exhibit variable combinations of cleft palate,
syndactyly, ear deformities, hypertelorism, optic atrophy, micropenis, and anosmia. Pituitary dysfunction
leads to diabetes insipidus, GH deficiency and short stature, and, occasionally, TSH deficiency.
Tissue-Specific Factor Mutations

Several pituitary cell–specific transcription factors, such as Pit-1 and Prop-1, are critical for determining
the development and committed function of differentiated anterior pituitary cell lineages. Autosomal
dominant or recessive Pit-1 mutations cause combined GH, PRL, and TSH deficiencies. These patients
usually present with growth failure and varying degrees of hypothyroidism. The pituitary may appear
hypoplastic on MRI.
Prop-1 is expressed early in pituitary development and appears to be required for Pit-1 function. Familial
and sporadic PROP1 mutations result in combined GH, PRL, TSH, and gonadotropin deficiency. Over 80%
of these patients have growth retardation; by adulthood, all are deficient in TSH and gonadotropins, and
a small minority later develop ACTH deficiency. Because of gonadotropin deficiency, these individuals do
not enter puberty spontaneously. In some cases, the pituitary gland is enlarged. TPIT mutations result in
ACTH deficiency associated with hypocortisolism.
Developmental Hypothalamic Dysfunction
Kallmann Syndrome
Kallmann syndrome results from defective hypothalamic gonadotropin-releasing hormone (GnRH)
synthesis and is associated with anosmia or hyposmia due to olfactory bulb agenesis or hypoplasia
(Chap. 346). The syndrome also may be associated with color blindness, optic atrophy, nerve deafness,
cleft palate, renal abnormalities, cryptorchidism, and neurologic abnormalities such as mirror
movements. Defects in the X-linked KAL gene impair embryonic migration of GnRH neurons from the
hypothalamic olfactory placode to the hypothalamus. Genetic abnormalities, in addition to KAL
mutations, also can cause isolated GnRH deficiency. Autosomal recessive (i.e., GPR54, KISS1) and
dominant (i.e., FGFR1) modes of transmission have been described, and there is a growing list of genes
associated with GnRH deficiency (GNRH1, PROK2, PROKR2, CH7, PCSK1, FGF8, TAC3, TACR3). GnRH
deficiency prevents progression through puberty. Males present with delayed puberty and pronounced
hypogonadal features, including micropenis, probably the result of low testosterone levels during
infancy. Females present with primary amenorrhea and failure of secondary sexual development.
Kallmann syndrome and other causes of congenital GnRH deficiency are characterized by low LH and FSH
levels and low concentrations of sex steroids (testosterone or estradiol). In sporadic cases of isolated
gonadotropin deficiency, the diagnosis is often one of exclusion after other causes of hypothalamic-
pituitary dysfunction have been eliminated. Repetitive GnRH administration restores normal pituitary
gonadotropin responses, pointing to a hypothalamic defect.

Long-term treatment of men with human chorionic gonadotropin (hCG) or testosterone restores
pubertal development and secondary sex characteristics; women can be treated with cyclic estrogen and
progestin. Fertility also may be restored by the administration of gonadotropins or by using a portable
infusion pump to deliver subcutaneous, pulsatile GnRH.
Bardet-Biedl Syndrome
This is a rare genetically heterogeneous disorder characterized by mental retardation, renal
abnormalities, obesity, and hexadactyly, brachydactyly, or syndactyly. Central diabetes insipidus may or
may not be associated. GnRH deficiency occurs in 75% of males and half of affected females. Retinal
degeneration begins in early childhood, and most patients are blind by age 30. Numerous subtypes of
Bardet-Biedl syndrome (BBS) have been identified, with genetic linkage to at least nine different loci.
Several of the loci encode genes involved in basal body cilia function, and this may account for the
diverse clinical manifestations.
Leptin and Leptin Receptor Mutations
Deficiencies of leptin or its receptor cause a broad spectrum of hypothalamic abnormalities, including
hyperphagia, obesity, and central hypogonadism (Chap. 77). Decreased GnRH production in these
patients results in attenuated pituitary FSH and LH synthesis and release.
Prader-Willi Syndrome
This is a contiguous gene syndrome that results from deletion of the paternal copies of the imprinted
SNRPN gene, the NECDIN gene, and possibly other genes on chromosome 15q. Prader-Willi syndrome is
associated with hypogonadotropic hypogonadism, hyperphagia-obesity, chronic muscle hypotonia,
mental retardation, and adult-onset diabetes mellitus (Chap. 62). Multiple somatic defects also involve
the skull, eyes, ears, hands, and feet. Diminished hypothalamic oxytocin- and vasopressin-producing
nuclei have been reported. Deficient GnRH synthesis is suggested by the observation that chronic GnRH
treatment restores pituitary LH and FSH release.
Acquired Hypopituitarism
Hypopituitarism may be caused by accidental or neurosurgical trauma; vascular events such as apoplexy;
pituitary or hypothalamic neoplasms, craniopharyngioma, lymphoma, or metastatic tumors;
inflammatory disease such as lymphocytic hypophysitis; infiltrative disorders such as sarcoidosis,
hemochromatosis (Chap. 357), and tuberculosis; or irradiation.

Increasing evidence suggests that patients with brain injury, including sports trauma, subarachnoid
hemorrhage, and irradiation, have transient hypopituitarism and require intermittent long-term
endocrine follow-up, as permanent hypothalamic or pituitary dysfunction will develop in 25–40% of
these patients.
Hypothalamic Infiltration Disorders
These disorders—including sarcoidosis, histiocytosis X, amyloidosis, and hemochromatosis—frequently
involve both hypothalamic and pituitary neuronal and neurochemical tracts. Consequently, diabetes
insipidus occurs in half of patients with these disorders. Growth retardation is seen if attenuated GH
secretion occurs before pubertal epiphyseal closure. Hypogonadotropic hypogonadism and
hyperprolactinemia are also common.
Inflammatory Lesions
Pituitary damage and subsequent dysfunction can be seen with chronic infections such as tuberculosis,
with opportunistic fungal infections associated with AIDS, and in tertiary syphilis. Other inflammatory
processes, such as granulomas and sarcoidosis, may mimic the features of a pituitary adenoma. These
lesions may cause extensive hypothalamic and pituitary damage, leading to trophic hormone
deficiencies.
Cranial Irradiation
Cranial irradiation may result in long-term hypothalamic and pituitary dysfunction, especially in children
and adolescents, as they are more susceptible to damage after whole-brain or head and neck
therapeutic irradiation. The development of hormonal abnormalities correlates strongly with irradiation
dosage and the time interval after completion of radiotherapy. Up to two-thirds of patients ultimately
develop hormone insufficiency after a median dose of 50 Gy (5000 rad) directed at the skull base. The
development of hypopituitarism occurs over 5–15 years and usually reflects hypothalamic damage
rather than primary destruction of pituitary cells. Although the pattern of hormone loss is variable, GH
deficiency is most common, followed by gonadotropin and ACTH deficiency. When deficiency of one or
more hormones is documented, the possibility of diminished reserve of other hormones is likely.
Accordingly, anterior pituitary function should be continually evaluated over the long term in previously
irradiated patients, and replacement therapy instituted when appropriate (see below).
Lymphocytic Hypophysitis

This occurs most often in postpartum women; it usually presents with hyperprolactinemia and MRI
evidence of a prominent pituitary mass that often resembles an adenoma, with mildly elevated PRL
levels. Pituitary failure caused by diffuse lymphocytic infiltration may be transient or permanent but
requires immediate evaluation and treatment. Rarely, isolated pituitary hormone deficiencies have been
described, suggesting a selective autoimmune process targeted to specific cell types. Most patients
manifest symptoms of progressive mass effects with headache and visual disturbance. The erythrocyte
sedimentation rate often is elevated. As the MRI image may be indistinguishable from that of a pituitary
adenoma, hypophysitis should be considered in a postpartum woman with a newly diagnosed pituitary
mass before an unnecessary surgical intervention is undertaken. The inflammatory process often
resolves after several months of glucocorticoid treatment, and pituitary function may be restored,
depending on the extent of damage.
Pituitary Apoplexy
Acute intrapituitary hemorrhagic vascular events can cause substantial damage to the pituitary and
surrounding sellar structures. Pituitary apoplexy may occur spontaneously in a preexisting adenoma;
postpartum (Sheehan's syndrome); or in association with diabetes, hypertension, sickle cell anemia, or
acute shock. The hyperplastic enlargement of the pituitary, which occurs normally during pregnancy,
increases the risk for hemorrhage and infarction. Apoplexy is an endocrine emergency that may result in
severe hypoglycemia, hypotension and shock, central nervous system (CNS) hemorrhage, and death.
Acute symptoms may include severe headache with signs of meningeal irritation, bilateral visual
changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness.
Pituitary CT or MRI may reveal signs of intratumoral or sellar hemorrhage, with deviation of the pituitary
stalk and compression of pituitary tissue.
Patients with no evident visual loss or impaired consciousness can be observed and managed
conservatively with high-dose glucocorticoids. Those with significant or progressive visual loss or loss of
consciousness require urgent surgical decompression. Visual recovery after sellar surgery is inversely
correlated with the length of time after the acute event. Therefore, severe ophthalmoplegia or visual
deficits are indications for early surgery. Hypopituitarism is very common after apoplexy.
Empty Sella
A partial or apparently totally empty sella is often an incidental MRI finding. These patients usually have
normal pituitary function, implying that the surrounding rim of pituitary tissue is fully functional.
Hypopituitarism, however, may develop insidiously. Pituitary masses also may undergo clinically silent
infarction and involution with development of a partial or totally empty sella by cerebrospinal fluid (CSF)
filling the dural herniation. Rarely, small but functional pituitary adenomas may arise within the rim of

pituitary tissue, and they are not always visible on MRI.
Presentation and Diagnosis
The clinical manifestations of hypopituitarism depend on which hormones are lost and the extent of the
hormone deficiency. GH deficiency causes growth disorders in children and leads to abnormal body
composition in adults (see below). Gonadotropin deficiency causes menstrual disorders and infertility in
women and decreased sexual function, infertility, and loss of secondary sexual characteristics in men.
TSH and ACTH deficiency usually develop later in the course of pituitary failure. TSH deficiency causes
growth retardation in children and features of hypothyroidism in children and adults. The secondary
form of adrenal insufficiency caused by ACTH deficiency leads to hypocortisolism with relative
preservation of mineralocorticoid production. PRL deficiency causes failure of lactation. When lesions
involve the posterior pituitary, polyuria and polydipsia reflect loss of vasopressin secretion.
Epidemiologic studies have documented an increased mortality rate in patients with long-standing
pituitary damage, primarily from increased cardiovascular and cerebrovascular disease. Previous head or
neck irradiation is also a determinant of increased mortality rates in patients with hypopituitarism.
Laboratory Investigation
Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of trophic hormones
in the setting of low levels of target hormones. For example, low free thyroxine in the setting of a low or
inappropriately normal TSH level suggests secondary hypothyroidism. Similarly, a low testosterone level
without elevation of gonadotropins suggests hypogonadotropic hypogonadism. Provocative tests may be
required to assess pituitary reserve (Table 339-3). GH responses to insulin-induced hypoglycemia,
arginine, l-dopa, growth hormone–releasing hormone (GHRH), or growth hormone–releasing peptides
(GHRPs) can be used to assess GH reserve. Corticotropin-releasing hormone (CRH) administration
induces ACTH release, and administration of synthetic ACTH (cosyntropin) evokes adrenal cortisol
release as an indirect indicator of pituitary ACTH reserve (Chap. 342). ACTH reserve is most reliably
assessed by measuring ACTH and cortisol levels during insulin-induced hypoglycemia. However, this test
should be performed cautiously in patients with suspected adrenal insufficiency because of enhanced
susceptibility to hypoglycemia and hypotension. Administering insulin to induce hypoglycemia is
contraindicated in patients with active coronary artery disease or seizure disorders.
Hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, growth
hormone, and vasopressin, is usually safe and free of complications. Treatment regimens that mimic
physiologic hormone production allow for maintenance of satisfactory clinical homeostasis. Effective
dosage schedules are outlined in Table 339-4. Patients in need of glucocorticoid replacement require
careful dose adjustments during stressful events such as acute illness, dental procedures, trauma, and

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