10/12/2020 Causes of hypopituitarism - UpToDate

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Causes of hypopituitarism
Author: Peter J Snyder, MD
Section Editor: David S Cooper, MD
Deputy Editor: Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2020. | This topic last updated: Sep 24, 2019.

INTRODUCTION

Hypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the
pituitary gland or from diseases of the hypothalamus. The latter cause diminished secretion of
hypothalamic-releasing hormones, thereby reducing secretion of the corresponding pituitary hormones (
table 1).

The clinical manifestations of hypopituitarism depend upon the cause as well as the type and degree of
hormonal insufficiency. Patients may be asymptomatic or present with symptoms related to hormone
deficiency or a mass lesion, or nonspecific symptoms such as fatigue.

The causes of hypopituitarism will be reviewed here. The clinical manifestations and treatment of
hypopituitarism are discussed separately. (See "Clinical manifestations of hypopituitarism" and "Treatment
of hypopituitarism".)

EPIDEMIOLOGY

In a study that comprised two cross-sectional surveys (from 1992 and 1999) of over 146,000 adults in
northern Spain, the prevalence of hypopituitarism was 29 of 100,000 in the first survey and 45.5 of 100,000
in the second [1]. A longitudinal survey was also performed; the average annual incidence of
hypopituitarism was 4.2 cases of 100,000 (similar for men and women). In the second survey (which
included most cases registered in the first survey), the causes of hypopituitarism included pituitary tumor
(61 percent), nonpituitary tumor (9 percent), and a nontumor cause (30 percent).

A study of 773 adults with hypopituitarism found the following distribution of etiologies [2]:

● Nontumoral causes (approximately 50 percent)

● Pituitary tumors (43.6 percent) (hypopituitarism due to direct effects of the tumor and/or treatment)

● Extrapituitary tumors (7.2 percent)

HYPOTHALAMIC DISORDERS

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Any disease involving the hypothalamus can affect secretion of one or more of the hypothalamic hormones
that influence secretion of corresponding pituitary hormones. Unlike diseases that involve the pituitary
directly, any of these conditions can also diminish the secretion of vasopressin, resulting in diabetes
insipidus. Pituitary lesions alone do not cause diabetes insipidus, since some vasopressin-producing
neurons terminate in the median eminence. (See "Clinical manifestations and causes of central diabetes
insipidus".)

Tumors — These include benign tumors that arise in the hypothalamus, such as craniopharyngiomas, and
malignant tumors that metastasize there, such as lung and breast carcinomas. (See 'Epidemiology' above
and "Causes, presentation, and evaluation of sellar masses".)

Radiation therapy — Hypothalamic hormone deficiency often ensues when brain tumors or

nasopharyngeal carcinomas are treated by radiation in children or adults [3-8]. Radiation-induced damage
is usually due to injury at the level of the hypothalamus, which results in secondary deficiencies or
dysregulation of the anterior pituitary hormones growth hormone (GH), luteinizing hormone (LH), follicle-
stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and corticotropin (ACTH).

Children treated with radiation doses ≥18 Gy to the hypothalamic-pituitary axis are at risk for GH deficiency.
Those treated with doses >30 to 40 Gy are at risk for deficiencies of LH, FSH, TSH, and ACTH.

The risk of pituitary dysfunction after cranial radiation is both dose- and time-dependent and may not
become apparent until many years after treatment. It is likely that systematic, risk-based screening will
uncover large numbers of previously undiagnosed hormonal deficiencies in at-risk adult survivors of
childhood cancer [9,10]. It is thus imperative for at-risk survivors of childhood cancer to have lifelong risk-
based screening for hormonal abnormalities. (See "Endocrinopathies in cancer survivors and others
exposed to cytotoxic therapies during childhood".)

In a retrospective study of 748 adult survivors of childhood cancer who were treated with cranial radiation
and followed for a mean of 27 years, the prevalence of anterior pituitary hormone deficiencies was 46.5,
10.8, 7.5, and 4 percent for GH, LH/FSH, TSH, and ACTH respectively [11]. (See "Endocrinopathies in cancer
survivors and others exposed to cytotoxic therapies during childhood".)

Infiltrative lesions — Infiltrative disorders such as sarcoidosis and Langerhans cell histiocytosis can cause
deficiencies of anterior pituitary hormones and diabetes insipidus. In a series of 12 patients with
Langerhans cell histiocytosis, eight developed one or more anterior pituitary hormone deficiencies at a
median of 4.5 years after their initial diagnosis of diabetes insipidus [12]. Magnetic resonance imaging
(MRI) of the sella region in patients who have hypopituitarism due to these infiltrative diseases often shows
marked thickening of the infundibulum [13].

Infections — Hypopituitarism can follow meningitis, which can be caused by many different kinds of
infectious agents, including tuberculosis [14], candida [15], and hantavirus. It is more likely in
immunocompromised patients, such as by human immunodeficiency virus (HIV) [16] and high-dose
glucocorticoids [15].

Traumatic brain injury — Head trauma of sufficient severity to fracture the skull base can cause
hypothalamic hormone deficiencies, resulting in deficient secretion of anterior pituitary hormones and
vasopressin [17]. A number of studies also report hormonal deficiencies associated with trauma that does
not fracture the skull base, but the frequency of such deficiencies is difficult to determine because some of
the criteria for diagnosis of decreased secretion are less stringent than generally used to diagnose

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hypopituitarism [18-23]. Nonetheless, some generalizations can be made about hormonal abnormalities
following traumatic brain injury [24-26]:

● Anterior pituitary deficiencies are common acutely but much less common 3 and 12 months
afterwards. In a study of 46 consecutive patients with traumatic brain injury, 35 patients (76 percent)
had deficiencies in the acute phase, but only six (13 percent) and five (11 percent) had deficiencies 3
and 12 months afterwards [27].

● The likelihood of hormonal deficiency is directly related to the severity of the injury. In the same study
noted above, deficiencies 12 months after injury were found in 4 of 15 (27 percent) who had severe
trauma and only 1 of 35 (3 percent) who had mild or moderate trauma [27].

● Hypoadrenalism, hypothyroidism, and hypogonadism are less common than decreased GH response
to an arginine-gonadotropin-releasing hormone (GHRH) stimulus. In the study cited above, 12 months
after the trauma, three had hypoadrenalism, one hypothyroidism, one hypogonadism, and all five a
subnormal GH response to stimulation [27].

● Abnormalities of vasopressin secretion are also common in the acute phase of the illness and less
common later. In a study of 122 consecutive patients who experienced moderate to severe traumatic
brain injury [22], 22 (18 percent) had diabetes insipidus acutely, but persistent diabetes insipidus was
only seen in seven patients (6 percent) 6 to 36 months later. Thirteen patients (10.6 percent) had the
syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the acute period, but only one
did later.

Stroke — Both ischemic stroke [28,29] and subarachnoid hemorrhage [18] may be associated with pituitary
dysfunction, although not commonly.

Ischemic stroke — In one report of 48 patients who underwent endocrine evaluation 12 to 15 months
after an ischemic stroke, none were hypothyroid, one was hypoadrenal, three were hypogonadal, and 15
had subnormal GH response to GHRH stimulation [28].

Subarachnoid hemorrhage — Patients with subarachnoid hemorrhage may also be at risk for

developing hypopituitarism. The prevalence varies widely from study to study [18,30-33].

PITUITARY DISORDERS

Any disease that affects the pituitary gland can result in diminished secretion of one or more pituitary
hormones. These diseases include mass lesions, surgery and radiation to treat mass lesions, and many
other disorders.

Mass lesions — Mass lesions that can cause hypopituitarism include pituitary adenomas, cysts, metastatic
cancer, and other lesions. The early stage of lymphocytic hypophysitis is characterized by lymphocytic
infiltration and enlargement of the pituitary.

A mass lesion in the sella can cause temporary or permanent damage by exerting pressure on pituitary
cells. Conversely, reducing the size of the mass may relieve the pressure and restore pituitary function. (See
"Causes, presentation, and evaluation of sellar masses".)

Pituitary macroadenomas — Among pituitary mass lesions, pituitary adenomas are most commonly
associated with hypopituitarism, in particular, clinically nonfunctioning pituitary adenomas (see

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'Epidemiology' above and "Clinical manifestations and diagnosis of gonadotroph and other clinically
nonfunctioning pituitary adenomas"). In a retrospective study of 305 patients who were to have
transsphenoidal surgery for a clinically nonfunctioning pituitary adenoma, 50 percent had hormonal
deficits preoperatively; 26 percent were hypothyroid, 20 percent of men and 16 percent of women were
hypogonadal, and 13 percent were hypoadrenal [34].

Pituitary surgery — A surgeon who excises a pituitary adenoma attempts to preserve the adjacent
nonadenomatous pituitary, but that goal may not be possible if the two cannot be distinguished visually. If
sufficient normal tissue is inadvertently excised, hypopituitarism will occur. Consequently, pituitary function
may be better or worse afterwards (see "Transsphenoidal surgery for pituitary adenomas and other sellar
masses", section on 'Hormonal deficiencies'). In the same review above [34], pituitary function improved six
weeks and six months after surgery in 26 and 36 percent of men who had been hypogonadal, 13 and 13
percent of women who had been hypogonadal, 30 and 49 percent of those who had been hypothyroid, and
3 and 3 percent of those who had been hypoadrenal.

Pituitary radiation — Radiation of a pituitary adenoma, usually to prevent regrowth of residual tissue after
surgery, exposes the nonadenomatous pituitary to the same radiation. In one report of 22 patients who
received supervoltage radiation (46 Gy) of residual adenoma tissue after surgery, over 50 percent
developed new corticotropin (ACTH), thyroid-stimulating hormone (TSH), or gonadotropin (luteinizing
hormone [LH]/follicle-stimulating hormone [FSH]) deficiency during the subsequent four years [35]. The
results of other studies were similar [36,37].

Because single high-dose radiation from a gamma or proton beam source or linear accelerator
(stereotactic "radiosurgery") is usually administered to a smaller volume of tissue than fractionated
radiation, the expectation was that the risk of hypopituitarism would be less. However, these forms of
radiation also cause a similar, high rate of hypopituitarism in the subsequent decade [38]. In a report based
upon a prospective database of patients who had gamma radiation for acromegaly or Cushing's disease at
least five years and a median of more than 13 years earlier, the actuarial rates of hypopituitarism at 3, 5,
and 10 years were 10, 21.7, and 53.3 percent [39]. Because loss of any pituitary hormone can occur from a
few months to at least 10 years after radiation, hormonal evaluation should be performed six months
afterwards and then yearly. (See "Radiation therapy of pituitary adenomas".)

Hereditary hemochromatosis — Hemochromatosis in the pituitary is characterized by iron deposition in

pituitary cells. Gonadotropin deficiency is the most common endocrine abnormality; other pituitary
hormone deficiencies may occur but are much less common [40]. Repeated phlebotomy to remove iron
may reverse the gonadotropin deficiency [41]. (See "Clinical manifestations and diagnosis of hereditary
hemochromatosis" and "Management and prognosis of hereditary hemochromatosis".)

Hypophysitis — Several uncommon forms of hypophysitis (inflammation of the pituitary) are recognized

histologically, including lymphocytic, granulomatous, plasmacytic, and xanthomatous [42,43]. The clinical
and hormonal manifestations are similar for all of them and are described below.

Lymphocytic hypophysitis — Lymphocytic hypophysitis is the most common form of hypophysitis; the

cause is usually unknown. It is initially characterized by lymphocytic infiltration and enlargement of the
pituitary; this stage is followed by destruction of the pituitary cells [44-46]. It often occurs in late pregnancy
or the postpartum period. In a report of 16 patients, there were 14 women and two men; the clinical
presentation was associated with pregnancy in 10 of the women. The frequent postpartum occurrence and

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the lymphocytic infiltration suggest that this disorder has an autoimmune etiology [44]. One report,
however, showed a majority of patients whose diagnosis was independent of pregnancy [47].

Affected patients typically present with headaches of an intensity out of proportion to the size of the lesion
and hypopituitarism. Preferential hypofunction of ACTH- and TSH-secreting cells has been described in
many papers, leading to adrenal insufficiency and hypothyroidism [48], but hypogonadism was most
common in a more recent study [47]. Diabetes insipidus, hyperprolactinemia, growth hormone (GH) excess,
and associated autoimmune thyroiditis can also occur [11,44,49].

Magnetic resonance imaging (MRI) typically reveal features of a pituitary mass, mimicking an adenoma
[11,44]. MRI also shows diffuse and homogeneous contrast enhancement of the anterior pituitary [48], but
enhancement may be delayed or even absent in the posterior pituitary area [11].

The natural history typically involves progressive pituitary atrophy with replacement of pituitary tissue by
fibrosis [45]. However, at least partial spontaneous recovery of both anterior and posterior pituitary
function can occur [44,45]. High-dose pulse glucocorticoid therapy has been reported to reduce the mass
effect in a small number of patients [50,51].

Complication of immunotherapy — Hypophysitis may also occur as a complication of anti-cytotoxic

T-lymphocyte-associated antigen 4 (CTLA-4) immunotherapy, mostly with ipilimumab. In a review of three
studies of more than 100 patients each who were treated with ipilimumab, hypophysitis was diagnosed in
11 to 17 percent based on the combination of headache, pituitary enlargement ( image 1), and
hypopituitarism [52]. Most patients had all three conditions. The pituitary enlargement was not associated
with visual impairment. The diagnosis was made a median of 8 to 10 weeks after beginning treatment. In
most patients, the pituitary enlargement eventually resolved, but hypopituitarism was usually permanent.
(See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Hypophysitis'.)

Granulomatous hypophysitis — This condition is characterized histologically by infiltration by

histiocytes and giant cells [42,43]. It sometimes accompanies a known systemic granulomatous condition,
such as Wegener granulomatosis and tuberculosis, and has been reported following treatment of hepatitis
C with interferon alfa and ribavirin [53], but the cause is often unknown. The clinical and hormonal
manifestations are similar to those of lymphocytic hypophysitis, although one report described a greater
percentage of chiasmal involvement with granulomatous hypophysitis [47].

Plasmacytic (IgG4-associated) hypophysitis — Histologically, this is characterized by infiltration by

plasma cells, which produce immunoglobulin G4 (IgG4) [42]. Infiltration of the pituitary is often associated
with infiltration of other organs, such as the pancreas. This disorder may be more common than previously
thought. In a report of 170 patients with hypopituitarism, of whom 23 had hypophysitis, seven were
diagnosed with IgG4-related hypophysitis, giving a prevalence of 30 and 4 percent of hypophysitis and all
hypopituitarism cases, respectively [54].

Xanthomatous hypophysitis — This condition, the most rare form of hypophysitis, is characterized

histologically by infiltration by foamy histiocytes [42,43].

Pituitary infarction (Sheehan syndrome) — Infarction of the pituitary gland after postpartum

hemorrhage has long been recognized as a cause of hypopituitarism and is called Sheehan syndrome
[55,56]. In developed countries, postpartum hemorrhage now less often results in Sheehan syndrome than
previously, largely due to improvements in obstetrical care [57], but it does still occur. However, in
underdeveloped and developing countries, postpartum pituitary infarction remains a common cause of

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hypopituitarism [58]. Less commonly, infarction may occur immediately postpartum even in the absence of
obvious hemorrhage. (See "Overview of postpartum hemorrhage".)

In a report of 114 patients with Sheehan syndrome, 53, 31, and 10 percent of women had nonspecific
symptoms, symptoms suggestive of adrenal insufficiency, or symptoms of hypogonadism, respectively [59].
The mean diagnostic delay was 19.7 years, possibly related to the high percentage of women with
nonspecific symptoms. At the time of diagnosis, 55 percent had panhypopituitarism and 45 percent had
partial hypopituitarism.

Clinical features of Sheehan syndrome include the following:

● A history of postpartum hemorrhage so severe as to cause hypotension and require transfusion of

multiple units of blood.

● When the hypopituitarism is severe, development of lethargy, anorexia, weight loss, and inability to
lactate during the first days or weeks after delivery [60].

● When the hypopituitarism is less severe, failure of postpartum lactation and failure to resume menses
in the weeks and months after delivery [56,60,61] and loss of sexual hair, as well as milder degrees of
fatigue, anorexia, and weight loss.

● When the hypopituitarism is mild, possible delay in recognition for many years after the inciting event
[56,60].

● Loss of all anterior pituitary hormones. In two reports of a total of 48 women with Sheehan syndrome
due to severe postpartum hemorrhage, all patients had GH, prolactin, and gonadotropin deficiency,
and the majority had TSH and ACTH deficiency [60,61].

● Rare development of overt diabetes insipidus, although subclinical vasopressin deficiency is common
[62-64]. (See "Clinical manifestations and causes of central diabetes insipidus".)

● Eventual development of a small pituitary within a sella of normal size, sometimes read as an "empty
sella" on MRI [56,65].

Evaluation of postpartum hypopituitarism should be performed whenever it is suspected after a delivery

associated with unusually heavy blood loss. If the blood loss is severe and especially if it is associated with
hypotension, the patient should be evaluated and treated for adrenal insufficiency immediately. Other
hormonal deficiencies can be evaluated four to six weeks later. (See "Diagnostic testing for
hypopituitarism".)

Treatment is the same as for other causes of hypopituitarism (see "Treatment of hypopituitarism").
Prolactin deficiency results in inability to breastfeed, but no treatment is available. The value of measuring
prolactin shortly after postpartum hemorrhage to predict the ability to breastfeed has not been studied.

Rare causes of pituitary infarction include:

● Vascular insufficiency occurring during coronary artery bypass surgery in older patients [66].

● Snake bites in Southeast Asia (Russell's viper bites) – 49 cases of acute and/or chronic hypopituitarism
have been reported [67]. Autopsy studies of most patients have shown hemorrhagic necrosis of the
pituitary. (See "Snakebites worldwide: Clinical manifestations and diagnosis", section on 'Additional
resources' and "Snakebites worldwide: Management", section on 'Additional resources'.)

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Pituitary apoplexy — Sudden hemorrhage into the pituitary gland is called pituitary apoplexy.
Hemorrhage often occurs into a pituitary adenoma. In one report, the prevalence of pituitary apoplexy
among patients with nonfunctioning pituitary macroadenomas was 8 percent [68]. In its most dramatic
presentation, apoplexy causes the sudden onset of excruciating headache, diplopia due to pressure on the
oculomotor nerves, and hypopituitarism. All pituitary hormonal deficiencies can occur, but the sudden
onset of ACTH and therefore cortisol deficiency is the most serious because it can cause life-threatening
hypotension.

The sudden enlargement of the pituitary mass, due to acute hemorrhage, results in a range of acute
clinical findings (severe headache, visual loss, diplopia, hypopituitarism) [69]. The acute symptoms and
imaging evidence of a pituitary mass confirms the diagnosis.

In a series of 35 patients with pituitary apoplexy seen at one center, 97 percent had headache, 71 percent
had visual field impairment, and 66 percent had decreased visual acuity [70]. Only a minority had clinical
manifestations of hormonal excess or deficiency, but there was biochemical evidence of gonadotropin
deficiency in 79 percent, ACTH deficiency in 76 percent, and TSH deficiency in 50 percent. MRI revealed
hemorrhage more often than did computed tomography (CT).

Surgical decompression of the pituitary is often performed in cases with severe or progressive impairment
of vision or neurologic symptoms [69]. The hypopituitarism, like the diplopia, may improve after surgical
decompression [70,71]. Both problems may also improve spontaneously, as blood is resorbed, over a
course of weeks to months after the hemorrhage. Other treatments that can be used include high doses of
corticosteroids and, for patients with a lactotroph adenoma, administration of a dopamine agonist to
reduce adenoma size. (See "Management of hyperprolactinemia".)

Pituitary infection/abscess — Infections in the pituitary are rare and can be due to a variety of organisms,
as infections in the hypothalamus (see 'Infections' above). Some infections result in an abscess of the
pituitary [72]. These present with headaches, and MRI shows a mass of >1 cm in diameter. Most patients
have panhypopituitarism, and several have diabetes insipidus. In a few cases, culture of the pus aspirated
at transsphenoidal surgery identifies the apparent infectious agent.

Genetic diseases — For many years, congenital deficiencies of one or more pituitary hormones have been
recognized. Only recently have genetic defects responsible for some of the congenital deficiencies been
identified. These defects are in the genes that encode the transcription factors whose expression is
necessary, in cascade, for the differentiation of anterior pituitary cells ( table 2).

Mutations have so far been detected in the genes encoding many of these transcription factors, including:

● ROBOS guidance receptors (ROBOS) determine axonal guidance in the central nervous system [73].

● BMP4 induces Rathke's pouch formation, which is necessary for anterior pituitary development [74].

● HESX1 [75,76], LHX3 [77], and LHX4 [78], transcription factors that are important for pituitary
organogenesis and early differentiation of pituicytes.

● PROP-1, which is necessary for the differentiation of a cell type that is a precursor to somatotroph,
lactotroph, thyrotroph, and gonadotroph cells.

● PIT-1 (called POU1F1 in the human), which acts temporally just after PROP-1 and is necessary for the
differentiation of a cell type that is a precursor of somatotroph, lactotroph, and, to a lesser degree,
thyrotroph cells [79-82].
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● TPIT, which is required for specific differentiation of the corticotroph cells. (See "Basic genetics
concepts: DNA regulation and gene expression".)

ROBO1 — A ROBO1 mutation has been reported to cause combined anterior hormone deficiencies and
severe central nervous system abnormalities [73].

BMP4 — Mutation in BMP4 has been reported to result in combined anterior pituitary hormone
deficiencies and central nervous system abnormalities [83].

HEXS1, LHX3, LHX4 — Mutations in HEXS1, LHX3, and LHX4, because they act early in pituicyte
differentiation, cause combined pituitary hormone deficiency, which refers to deficiencies of GH, prolactin,
TSH, LH, and FSH [75,77,78]. Mutations in LHX3 also lead to neurologic abnormalities due to expression in
the central nervous system (CNS) [84].

PROP-1 — Mutations in PROP-1 appear to be the most common cause of both familial and sporadic
congenital combined pituitary hormone deficiency [79,85-87]. This was illustrated in a study of 195 patients
with sporadic or familial combined pituitary hormone deficiency [80], in whom PROP1 mutations were
identified in 20 of 109 patients without extrapituitary abnormalities, POU1F1 and LHX4 mutations in one
patient each, and no mutations in LHX3 or HESX1. ACTH deficiency has been described in several older
patients with PROP-1 mutations [88], but it is not known whether ACTH deficiency in these patients is a
result of corticotroph attrition or pituitary hypertrophy followed by pituitary degeneration, which has been
described in some patients with these mutations.

Several different mutations have been detected, and the phenotypic results are variable, even in patients
who have the same mutation. The age of onset of the first hormonal deficiency, the order of the onset of
the various pituitary hormone deficiencies, and the severity of the deficiencies all vary. Almost invariably,
however, GH deficiency begins sometime in infancy or childhood and results in short stature. Most patients
receive GH therapy during childhood. However, in a family of three individuals with PROP-1 mutations who
did not receive GH therapy until adulthood, significant linear growth occurred in spite of their fairly
advanced bone age [89].

PIT-1 — Both dominant and recessive mutations of the gene that encodes PIT-1 (POU1F1) lead to
congenital deficiencies of GH, prolactin, and sometimes TSH [80,81]. The secretion of ACTH, FSH, and LH is
preserved. A study of four affected siblings found that all had complete deficiency of GH diagnosed in early
childhood, while central hypothyroidism and hypoprolactinemia developed later [80].

Circulating anti-PIT-1 antibodies may also result in hypopituitarism. This was illustrated in a report of three
patients with adult onset GH, prolactin, and TSH deficiency and antibodies against the PIT-1 gene [90].
None had evidence of the autoantibodies described with autoimmune polyglandular syndrome-associated
hypophysitis (anti-GH, anti-alpha-enolase, anti-TDRD6), suggesting that these are different autoimmune
disorders.

TPIT — Because the TPIT gene is necessary for differentiation of the corticotroph cell, mutations of the
gene are one cause of isolated ACTH deficiency, which results in neonatal death if not detected early [91].
Other genetic causes of isolated ACTH deficiency are discussed elsewhere. (See "Causes of secondary and
tertiary adrenal insufficiency in adults", section on 'Isolated ACTH deficiency'.)

Pituitary stalk interruption syndrome — Congenital hypopituitarism is often associated with the imaging
abnormalities of a small pituitary, thinned or interrupted stalk, and ectopic neurohypophysis, together
called the pituitary stalk interruption syndrome (PSIS) [92,93], although it is a radiologic constellation and
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not clinical syndrome. This constellation may also be associated with one of the mutations above [92]; there
is also some evidence for a polygenic cause of PSIS [94].

Empty sella — An empty sella refers to an enlarged sella turcica that is not entirely filled with pituitary
tissue. It is a radiologic description and not a clinical condition. There are two types:

● Secondary empty sella is characterized by association of the empty sella with an identifiable disease of
the pituitary gland. One example of an identifiable disease is a mass, such as a pituitary adenoma, that
enlarges the sella but then is removed by surgery, radiation, or infarction. In this type of empty sella,
hypopituitarism can result from the adenoma itself, its treatment, or infarction. A remnant of a partially
removed pituitary adenoma could have residual function. Another example is a congenital abnormality
of a transcription factor necessary for pituitary differentiation, where the sella turcica is normal but the
pituitary gland is small [95]. (See 'PROP-1' above.)

● Primary empty sella is characterized by a defect in the diaphragm sella that is thought to allow
cerebrospinal fluid (CSF) pressure to enlarge the sella [96]. Although some papers claim deficiencies of
one or more pituitary hormones [97], the evidence for such deficiencies is not convincing, ie, there is
no consistent evidence of the existence of an "empty sella syndrome."

● Evaluation of a patient whose MRI shows an empty or partially empty sella, therefore, depends on what
else is seen in the sella and the clinical situation. The presence of a sellar mass, especially a lesion more
than 1 cm in size, requires evaluation for hormonal hypersecretion and hyposecretion, as does any
other sellar mass. Clinical evidence of hormonal excess or deficiencies requires biochemical evaluation
of all pituitary hormones. In the absence of a sellar mass and clinical evidence of hormonal excess or
deficiency, measurement of thyroxine (T4) and early morning cortisol could be performed, but the
likelihood is that they will be normal. (See "Causes, presentation, and evaluation of sellar masses".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they
answer the four or five key questions a patient might have about a given condition. These articles are best
for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at
the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Panhypopituitarism (The Basics)")

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SUMMARY

Hypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the
hypothalamus or pituitary gland ( table 1). The majority of cases are due to a pituitary adenoma or
treatment of the adenoma or, less commonly, an extrapituitary tumor (eg, craniopharyngioma).

● Any disease involving the hypothalamus can affect secretion of one or more of the hypothalamic
hormones that influence secretion of corresponding pituitary hormones (see 'Hypothalamic disorders'
above). This includes:

• Benign tumors such as craniopharyngiomas (see 'Tumors' above)

• Malignant tumors that metastasize to the hypothalamic area, such as lung and breast carcinomas
(see "Causes, presentation, and evaluation of sellar masses")

• Cranial radiation for brain tumors, which can result in hypothalamic hormone and, therefore,
pituitary hormone deficiency (see 'Radiation therapy' above)

• Infiltrative diseases such as sarcoidosis and Langerhans cell histiocytosis (see 'Infiltrative lesions'
above)

• Other causes of hypopituitarism include traumatic brain injury and stroke (ischemic and
subarachnoid hemorrhage) (see 'Traumatic brain injury' above and 'Stroke' above)

● In addition to pituitary adenomas and their treatment (surgery or radiation therapy), other pituitary
causes include (see 'Pituitary disorders' above):

• Other types of pituitary masses, including metastatic disease

• Infiltrative lesions (hemochromatosis, lymphocytic hypophysitis) (see 'Hereditary

hemochromatosis' above and 'Hypophysitis' above)

• Pituitary infarction (Sheehan syndrome) or hemorrhage (see 'Pituitary infarction (Sheehan

syndrome)' above and 'Pituitary apoplexy' above)

• Mutations in genes that encode transcription factors, such as PROP-1, POU1F1, TPIT, HESX1, LHX3,
and LHX4, that are important for differentiation of different pituitary cell types and/or pituitary
organogenesis (see 'Genetic diseases' above)

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GRAPHICS

Major causes of hypopituitarism

Hypothalamic diseases
Mass lesions – Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc)

Radiation – For CNS and nasopharyngeal malignancies

Infiltrative lesions – Sarcoidosis, Langerhans cell histiocytosis

Infections – Tuberculous meningitis

Other – Traumatic brain injury, stroke

Pituitary diseases
Mass lesions – Pituitary adenomas, other benign tumors, cysts

Pituitary surgery

Pituitary radiation

Infiltrative lesions – Hypophysitis, hemochromatosis

Infection/abscess

Infarction – Sheehan syndrome

Apoplexy

Genetic mutations

Empty sella 

CNS: central nervous system.

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Hypophysitis associated with checkpoint inhibition

Sagittal MRI section from patient 7 before anti-CTLA-4 antibody treatment and after onset of clinical symptoms. Pituitary height is in parentheses.

MRI: magnetic resonance imaging.

Reproduced with permission from: Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in
patients with metastatic melanoma and renal cancer. J Immunother 2005; 28:593. Copyright © 2005 Lippincott Williams & Wilkins. Unauthorized reproduction of this
material is prohibited.

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Genetic disorders of hypothalamopituitary development in humans

Gene Phenotype Inheritance

Isolated hormone abnormalities

GH1 Isolated GH deficiency AR, AD

GHRHR Isolated GH deficiency AR

TSHB Isolated TSH deficiency AR

TRHR Isolated TSH deficiency AR

TPIT Isolated ACTH deficiency AR

GnRHR HH AR

PC1 ACTH deficiency, hypoglycemia, HH, obesity AR

POMC ACTH deficiency, obesity, red hair AR

DAX1 Adrenal hypoplasia congenital and HH XL

CRH CRH deficiency AR

KAL1 Kallman syndrome, renal agenesis, synkinesia XL

FGFR1 Kallman syndrome, cleft lip and palate, facial dysmorphism AD, AR

Leptin HH, obesity AR

Leptin-R HH, obesity AR

GPR54 HH AR

Kisspeptin HH AR

FSHB Primary amenorrhea, defective spermatogenesis AR

LHB Delayed puberty AR

PROK2 Kallman syndrome, severe sleep disorder, obesity AD

PROKR2 Kallman syndrome AD, AR

AVP-NPII Diabetes insipidus AR, AD

Combined pituitary hormone deficiency

POU1F1 GH, TSH, and prolactin deficiencies AR, AD

PROP1 GH, TSH, LH, FSH, prolactin, and evolving ACTH deficiencies AR

Specific syndrome

HESX1 Septo-optic dysplasia AR, AD

LHX3 GH, TSH, LH, FSH, prolactin deficiencies, limited neck rotation AR

LHX4 GH, TSH, ACTH deficiencies with cerebellar abnormalities AD

SOX3 Hypopituitarism and mental retardation XL

GLI2 Holoprosencephaly and multiple midline defects AD

SOX2 Anophthalmia, hypopituitarism, oesophageal atresia AD

GLI3 Pallister-Hall syndrome AD

PITX2 Rieger syndrome AD

GH: growth hormone; AR: autosomal recessive; AD: autosomal dominant; TSH: thyroid-stimulating hormone; ACTH: corticotropin; HH: hypogonadotropic
hypogonadism; XL: X-linked; CRH: corticotropin-releasing hormone; R: receptor; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

Reproduced from: Mehta A, Dattani MT. Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism. Best Pract
Res Clin Endocrinol Metab 2008; 22:191. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Contributor Disclosures
Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism]; Novartis [Cushing's].
Consultant/Advisory Boards: AbbVie [Hypogonadism]; Novartis [Cushing's]; Pfizer [Acromegaly]; Teva Pharmaceuticals
[Cushing's]. David S Cooper, MD Nothing to disclose Kathryn A Martin, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

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