2896 PART 12 Endocrinology and Metabolism

Deficient production of anterior pituitary hormones leads to features

of hypopituitarism. Impaired production of one or more of the anterior pituitary trophic hormones can result from inherited disorders;

more commonly, adult hypopituitarism is acquired and reflects the

compressive mass effects of tumors or the consequences of local

pituitary or hypothalamic traumatic, autoimmune, inflammatory,

or vascular damage. These processes also may impair synthesis or

secretion of hypothalamic hormones, with resultant pituitary failure

(Table 379-1).

379 Hypopituitarism

Shlomo Melmed, J. Larry Jameson

■ DEVELOPMENTAL CAUSES OF HYPOPITUITARISM

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.

A large number of transcription factors and growth factors are critical for the development of the hypothalamus and pituitary gland and

the function of differentiated anterior pituitary cell lineages. mutations

have been described in the HESX1, SOX2, SOX3, LHX3, LHX4, OTX,

GLI2, PAX6, BMP4, ARNT2, FGF8, FGFR1, SHH, PROKR2, GPR161,

IGSF1, PITX2, and CHD7 genes, among others. Heterozygous loss-offunction or autosomal recessive mutations disrupt hypothalamic and

pituitary development at different developmental stages, causing a wide

array of phenotypes ranging from severe syndromic midline and other

defects to combined pituitary hormone defects or isolated hormone

deficiencies. Depending on the gene involved, the pituitary may be

hypoplastic, hyperplastic, or ectopic. Midline defects include variable

combinations of abnormal development of the eyes, corpus collosum,

vertebrae, and genital systems. Pituitary dysfunction ranges from isolated hormone deficiency to combined pituitary hormone deficiency

(CPHD) and diabetes insipidus (DI).

In addition to these syndromic developmental disorders, some

mutations affect specific pituitary cell lineages. For example, Pit-1

mutations cause combined growth hormone (GH), prolactin (PRL),

and thyroid-stimulating hormone (TSH) deficiencies. These patients

usually present with growth failure and varying degrees of hypothyroidism. The pituitary may appear hypoplastic on magnetic resonance

imaging (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 adrenocorticotropic hormone (ACTH)

deficiency. Because of gonadotropin deficiency, these individuals do

not enter puberty spontaneously. In some cases, the pituitary gland

appears enlarged on MRI. TPIT mutations result in ACTH deficiency

associated with hypocortisolism. Mutations in NR5A1 (also known as

steroidogenic factor 1 [SF1]) impair development of gonadotrope cells,

as well as adrenal/gonadal development.

■ HYPOTHALAMIC ENDOCRINE DYSFUNCTION

Hypothalamic disorders can affect temperature regulation, appetite,

sleep-wake cycles, autonomic systems, behavior, and memory, as well

as multiple endocrine systems. Selected examples of hypothalamic disorders that affect the endocrine system are described below.

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. 391). Classically, the syndrome may also be associated with color blindness, optic atrophy, nerve deafness, cleft palate,

renal abnormalities, cryptorchidism, and neurologic abnormalities

such as mirror movements. The initial genetic cause was the X-linked

KAL gene, mutations of which impair embryonic migration of GnRH

neurons from the hypothalamic olfactory placode to the hypothalamus. Since then, more than a dozen additional genetic abnormalities,

in addition to KAL mutations, have been found to 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 (including

GNRH1, PROK2, PROKR2, CHD7, PCSK1, FGF8, NELF, WDR11,

TAC3, TACR3, and SEMA3E). Some patients have oligogenic mutations in which mutations in a combination of different genes lead to

the phenotype. Associated clinical features, in addition to GnRH deficiency, vary depending on the genetic cause. GnRH deficiency prevents

progression through puberty. Males present with delayed puberty and

pronounced hypogonadal features, including micropenis, probably the

TABLE 379-1 Etiology of Hypopituitarisma

Development/structural

Midline cerebral defect syndromes

Pituitary dysplasia/aplasia

Primary empty sella

 Congenital hypothalamic disorders (septo-optic dysplasia, Prader-Willi

syndrome, Bardet-Biedl syndrome, Kallmann syndrome)

Congenital central nervous system mass, encephalocele

Genetic

Combined pituitary hormone deficiencies

Isolated primary hormone deficiencies

Traumatic

Surgical resection

Radiotherapy damage

Head injuries

Neoplastic

Pituitary adenoma

Parasellar mass (germinoma, ependymoma, glioma)

Rathke’s cyst

Craniopharyngioma

Hypothalamic hamartoma, gangliocytoma

Pituitary metastases (breast, lung, colon carcinoma)

Lymphoma and leukemia

Meningioma

Infiltrative/inflammatory

Lymphocytic hypophysitis

Hemochromatosis

Sarcoidosis

Histiocytosis X

Granulomatous hypophysitis

Transcription factor antibodies

Immunotherapy

Vascular

Pituitary apoplexy

Pregnancy-related (infarction with diabetes; postpartum necrosis)

Subarachnoid hemorrhage

Sickle cell disease

Arteritis

Infections

Fungal (histoplasmosis)

Parasitic (toxoplasmosis)

Tuberculosis

Pneumocystis jirovecii

a

Trophic hormone failure associated with pituitary compression or destruction

usually occurs sequentially: growth hormone > follicle-stimulating hormone >

luteinizing hormone > thyroid-stimulating hormone > adrenocorticotropic hormone.

During childhood, growth retardation is often the presenting feature, and in adults,

hypogonadism is the earliest symptom.

2897Hypopituitarism CHAPTER 379

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 luteinizing hormone (LH) and

follicle-stimulating hormone (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 known causes of hypothalamic-pituitary dysfunction have been

eliminated. Repetitive GnRH administration restores normal pituitary

gonadotropin responses, pointing to a hypothalamic defect in these

patients.

Long-term treatment of males with human chorionic gonadotropin

(hCG) or testosterone restores pubertal development and secondary

sex characteristics; women can be treated with cyclic estrogen and

progestin. Fertility may be restored by the administration of gonadotropins or by using a portable infusion pump to deliver subcutaneous,

pulsatile GnRH.

Bardet-Biedl Syndrome This very rare genetically heterogeneous

disorder is characterized by intellectual disability, renal abnormalities,

obesity, and hexadactyly, brachydactyly, or syndactyly. Central DI 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. 401).

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. 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; autoimmune hypophysitis

associated with checkpoint inhibitor cancer immunotherapy; infiltrative disorders such as sarcoidosis, hemochromatosis (Chap. 414), and

tuberculosis; or irradiation.

Patients with brain injury, including from contact sports trauma,

motor vehicle accidents, explosive causes, subarachnoid hemorrhage,

and irradiation, can experience transient or long-term hypopituitarism. Long-term periodic endocrine follow-up is indicated because

hypothalamic or pituitary dysfunction will develop in 25–40% of these

patients.

Hypothalamic Infiltration Disorders Sarcoidosis, histiocytosis X,

amyloidosis, and hemochromatosis frequently involve both hypothalamic and pituitary neuronal and neurochemical tracts. Consequently,

DI is a common presentation, reported in half of patients with these

disorders. Growth retardation is seen if attenuated GH secretion occurs

before puberty. Hypogonadotropic hypogonadism and hyperprolactinemia are also common.

Inflammatory Lesions Pituitary damage and subsequent secretory dysfunction can be seen with chronic site infections such as

tuberculosis, with opportunistic fungal infections associated with

AIDS, and in tertiary syphilis. Other inflammatory processes, such as

granulomas and sarcoidosis, should be considered in the differential

diagnosis of imaging studies suggestive of a pituitary adenoma. These

lesions may cause extensive hypothalamic and pituitary damage, leading to 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 subsequent 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, thyroid, 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. Because

it may be indistinguishable from a pituitary adenoma on MRI, 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.

Immunotherapy and Hypophysitis Pituitary cells express

cytotoxic T lymphocyte antigen-4 (CTLA-4), and up to 20% of

patients receiving cancer immunotherapy with CTLA-4 inhibitors

(e.g., ipilimumab) may develop hypophysitis with heterogeneously

associated thyroid, adrenal, islet, and gonadal failure. Hypophysitis is

also reported with PD-1/PD-L1 inhibitors (e.g., pembrolizumab and

nivolumab) and may show delayed presentation. Pituitary hormone

replacement, with or without high-dose glucocorticoids, may be safely

tolerated with continued immunotherapy.

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 pituitary 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 computed tomography (CT) or MRI may

reveal signs of intratumoral or sellar hemorrhage, with pituitary stalk

deviation 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, cranial nerve

2898 PART 12 Endocrinology and Metabolism

palsy, 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

common after apoplexy.

Empty Sella A partial or apparently totally empty sella is often

an incidental MRI finding and may sometimes be associated with

intracranial hypertension. These patients usually have normal pituitary function, implying that the surrounding rim of pituitary tissue is

fully functional. Hypopituitarism, however, may develop insidiously.

Pituitary adenomas 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 normal

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 (see below).

GH deficiency causes growth disorders in children and leads to abnormal body composition in adults. 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 deficiencies 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. In patients with long-standing pituitary damage,

epidemiologic studies document an increased mortality rate, primarily

from increased cardiovascular and cerebrovascular disease. Previous

head or neck irradiation is also a determinant of increased mortality

rates in patients with hypopituitarism, especially from cerebrovascular

disease.

■ LABORATORY INVESTIGATION

Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of respective pituitary trophic hormones in the

setting of low levels of target organ 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 379-2). GH responses to insulin-induced hypoglycemia, arginine,

TABLE 379-2 Tests of Pituitary Sufficiency

HORMONE TEST BLOOD SAMPLES INTERPRETATION

Growth hormone (GH) Insulin tolerance test: Regular insulin

(0.05–0.15 U/kg IV)

–30, 0, 30, 60, 120 min for glucose and

GH

Glucose <40 mg/dL; GH should be >3 μg/L

GHRH test: 1 μg/kg IV 0, 15, 30, 45, 60, 120 min for GH Normal response is GH >3 μg/L

l-Arginine test: 30 g IV over 30 min 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L

l-Dopa test: 500 mg PO 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L

Prolactin TRH test: 200–500 μg IV 0, 20, and 60 min for TSH and PRL Normal prolactin is >2 μg/L and increase

>200% of baseline

ACTH Insulin tolerance test: regular insulin

(0.05–0.15 U/kg IV)

–30, 0, 30, 60, 90 min for glucose

and cortisol

Glucose <40 mg/dL

Cortisol should increase by >7 μg/dL or to >20 μg/dL

CRH test: 1 μg/kg ovine CRH IV at 8 a.m. 0, 15, 30, 60, 90, 120 min for ACTH

and cortisol

Basal ACTH increases 2- to 4-fold and peaks at

20–100 pg/mL

Cortisol levels >20–25 μg/dL

Metyrapone test: Metyrapone

(30 mg/kg) at midnight

Plasma 11-deoxycortisol and cortisol at

8 a.m.; ACTH can also be measured

Plasma cortisol should be <4 g/dL to assure an

adequate response

Normal response is 11-deoxycortisol >7.5 μg/dL or

ACTH >75 pg/mL

Standard ACTH stimulation test: ACTH

1-24 (cosyntropin), 0.25 mg IM or IV

0, 30, 60 min for cortisol and aldosterone Normal response is cortisol >21 g/dL and aldosterone

response >4 ng/dL above baseline

Low-dose ACTH test: ACTH 1-24

(cosyntropin), 1 μg IV

0, 30, 60 min for cortisol Cortisol should be >21 μg/dL

3-day ACTH stimulation test consists

of 0.25 mg ACTH 1-24 given IV over 8 h

each day

Cortisol >21 μg/dL

TSH Basal thyroid function tests: T4

, T3

, TSH Basal measurements Low free thyroid hormone levels in the setting of TSH

levels that are not appropriately increased indicate

pituitary insufficiency

TRH test: 200–500 μg IV 0, 20, 60 min for TSH and PRLa TSH should increase by >5 mU/L unless thyroid

hormone levels are increased

LH, FSH LH, FSH, testosterone, estrogen Basal measurements Basal LH and FSH should be increased in

postmenopausal women

Low testosterone levels in the setting of low LH and

FSH indicate pituitary insufficiency

GnRH test: GnRH (100 μg) IV 0, 30, 60 min for LH and FSH In most adults, LH should increase by 10 IU/L and FSH

by 2 IU/L

Normal responses are variable

Multiple hormones Combined anterior pituitary test: GHRH

(1 μg/kg), CRH (1 μg/kg), GnRH (100 μg),

TRH (200 μg) are given IV

–30, 0, 15, 30, 60, 90, 120 min for GH,

ACTH, cortisol, LH, FSH, and TSH

Combined or individual releasing hormone responses

must be elevated in the context of basal target gland

hormone values and may not be uniformly diagnostic

(see text)

a

Evoked PRL response indicates lactotrope integrity.

Abbreviations: T3

, triiodothyronine; T4

, thyroxine; TRH, thyrotropin-releasing hormone. For other abbreviations, see text.

2899Hypopituitarism CHAPTER 379

glucagon, l-dopa, growth hormone–releasing hormone (GHRH),

or growth hormone–releasing orally active ghrelin receptor agonist

macimorelin 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. 386).

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 known

seizure disorders.

TREATMENT

Hypopituitarism

Hormone replacement therapy, including glucocorticoids, thyroid

hormone, sex steroids, GH, 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 379-3.

Patients in need of glucocorticoid replacement require especially

careful dose adjustments during stressful events such as acute illness, dental procedures, trauma, and hospitalization.

■ DISORDERS OF GROWTH AND DEVELOPMENT

Skeletal Maturation and Somatic Growth The growth plate is

dependent on a variety of hormonal stimuli, including GH, insulinlike growth factor (IGF)-1, sex steroids, thyroid hormones, paracrine

and circulating growth factors (e.g., fibroblast growth factor family),

and cytokines. The growth-promoting process also requires caloric

energy, amino acids, vitamins, and trace metals and consumes ~10% of

normal energy production. Malnutrition impairs chondrocyte activity,

increases GH resistance, and leads to reduced circulating IGF-1 and

IGF binding protein (IGFBP)-3 levels.

Linear bone growth rates are very high in infancy and are pituitary

dependent. Mean growth velocity is ~6 cm/year in later childhood and

usually is maintained within a given range on a standardized percentile

chart. Peak growth rates occur during midpuberty when bone age is

12 (girls) or 13 (boys). Secondary sexual development is associated

with elevated sex steroids that cause progressive epiphyseal growth

plate closure. Bone age is delayed in patients with all forms of true GH

deficiency or GH receptor defects that result in attenuated GH action.

Short stature may occur as a result of constitutive intrinsic growth

defects or because of acquired extrinsic factors that impair growth. In

general, delayed bone age in a child with short stature is suggestive of

a hormonal or systemic disorder, whereas normal bone age in a short

child is more likely to be caused by a genetic cartilage dysplasia or

growth plate disorder (Chap. 413).

GH Deficiency in Children Isolated GH deficiency is characterized by short stature, micropenis, increased fat, high-pitched voice,

and a propensity to hypoglycemia due to relatively unopposed insulin

action. Familial modes of inheritance are seen in at least one-third

of these individuals and may be autosomal dominant, recessive, or

X-linked. About 10% of children with GH deficiency have mutations

in the GH-N gene, including gene deletions and a wide range of point

mutations. Mutations in transcription factors Pit-1 and Prop-1, which

control somatotrope development (see above), result in GH deficiency

in combination with other pituitary hormone deficiencies, which may

become manifest only in adulthood. The diagnosis of idiopathic GH

deficiency should be made only after known molecular defects have

been rigorously excluded.

GHRH RECEPTOR MUTATIONS Recessive mutations of the GHRH

receptor gene in subjects with severe proportionate dwarfism are associated with low basal GH levels that cannot be stimulated by exogenous

GHRH, GH-releasing peptide, or insulin-induced hypoglycemia, as

well as anterior pituitary hypoplasia. The syndrome exemplifies the

importance of the GHRH receptor for determining somatotrope cell

proliferation and hormonal responsiveness.

GH INSENSITIVITY This is caused by defects of GH receptor structure

or signaling. Homozygous or heterozygous mutations of the GH receptor are associated with partial or complete GH insensitivity and growth

failure (Laron syndrome). The diagnosis is based on normal or high

GH levels, with decreased circulating GH-binding protein (GHBP),

and low IGF-1 levels. Very rarely, defective IGF-1, IGF-1 receptor, or

IGF-1 signaling defects are also encountered. STAT5B mutations result

in both immunodeficiency as well as abrogated GH signaling, leading

to short stature with normal or elevated GH levels and low IGF-1 levels.

Circulating GH receptor antibodies may rarely cause peripheral GH

insensitivity.

NUTRITIONAL SHORT STATURE Caloric deprivation and malnutrition, uncontrolled diabetes, and chronic renal failure represent secondary causes of abrogated GH receptor function. These conditions

also stimulate production of proinflammatory cytokines, which act to

exacerbate the block of GH-mediated signal transduction. Children

with these conditions typically exhibit features of acquired short stature

with normal or elevated GH and low IGF-1 levels.

PSYCHOSOCIAL SHORT STATURE Emotional and social deprivation

lead to growth retardation accompanied by delayed speech, discordant

hyperphagia, and an attenuated response to administered GH. A nurturing environment restores growth rates.

■ PRESENTATION AND DIAGNOSIS

Short stature is commonly encountered in clinical practice, and

the decision to evaluate these children requires clinical judgment

in association with auxologic data and family history. Short stature

should be evaluated comprehensively if a patient’s height is >3 standard

deviations below the mean for age or if the growth rate has decelerated. Skeletal maturation is best evaluated by measuring a radiologic

bone age, which is based mainly on the degree of wrist bone growth

plate fusion. Final height can be predicted using standardized scales

(Bayley-Pinneau or Tanner-Whitehouse) or estimated by adding

6.5 cm (boys) or subtracting 6.5 cm (girls) from the midparental height.

TABLE 379-3 Hormone Replacement Therapy for Adult

Hypopituitarisma

HORMONE DEFICIT HORMONE REPLACEMENT

ACTH Hydrocortisone (10–20 mg/d in divided doses)

Cortisone acetate (15–25 mg/d in divided doses)

Prednisone (5 mg a.m.)

TSH l-Thyroxine (0.075–0.15 mg daily)

FSH/LH Males

Testosterone gel (5–10 g/d)

Testosterone skin patch (5 mg/d)

Testosterone enanthate (200 mg IM every 2 weeks)

Females

Conjugated estrogen (0.65–1.25 mg qd for 25 days)

Progesterone (5–10 mg qd) on days 16–25

 Estradiol skin patch (0.025–0.1 mg every week),

adding progesterone on days 16–25 if uterus intact

 For fertility: menopausal gonadotropins, human

chorionic gonadotropins

GH Adults: Somatotropin (0.1–1.25 mg SC qd)

Children: Somatotropin (0.02–0.05 mg/kg per day)

Vasopressin Intranasal desmopressin (5–20 g twice daily)

Oral 300–600 μg qd

a

All doses shown should be individualized for specific patients and should

be reassessed during stress, surgery, or pregnancy. Male and female fertility

requirements should be managed as discussed in Chaps. 391 and 392.

Note: For abbreviations, see text.

2900 PART 12 Endocrinology and Metabolism

■ LABORATORY INVESTIGATION

Because GH secretion is pulsatile, GH deficiency is best assessed by

examining the response to provocative stimuli, including exercise,

insulin-induced hypoglycemia, and other pharmacologic tests that

normally increase GH to >7 μg/L in children. Random GH measurements do not distinguish normal children from those with true GH

deficiency. Adequate adrenal and thyroid hormone replacement should

be assured before testing. Age-matched IGF-1 levels are not sufficiently

sensitive or specific to make the diagnosis but can be useful to confirm

GH deficiency. Pituitary MRI may reveal pituitary mass lesions or

structural defects. Molecular analyses for known mutations should be

undertaken when the cause of short stature remains cryptic or when

additional clinical features suggest a genetic cause.

TREATMENT

Disorders of Growth and Development

Replacement therapy with recombinant GH (0.02–0.05 mg/kg

per day SC) restores growth velocity in GH-deficient children to

~10 cm/year. If pituitary insufficiency is documented, other associated hormone deficits should be corrected, especially adrenal steroids. In selected situations, GH treatment may be combined with

strategies to delay puberty (e.g., GnRH agonist) or reduce sex steroids (e.g., aromatase inhibitors) as a means to mitigate sex steroid

effect on epiphyseal closure. GH treatment is also moderately effective for accelerating growth rates in children with Turner syndrome

and chronic renal failure. Treating psychosocial or constitutional

(idiopathic) short stature with GH is not uniformly recommended

as these children may only experience modest additive growth,

which should be weighed against GH cost and side effect profiles.

In patients with GH insensitivity and growth retardation due to

mutations of the GH receptor, treatment with IGF-1 bypasses the

dysfunctional GH receptor.

ADULT GH DEFICIENCY

Adult GH deficiency (AGHD) usually is caused by acquired hypothalamic or pituitary somatotrope damage. Acquired pituitary hormone

deficiency follows a typical pattern in which loss of adequate GH

reserve foreshadows subsequent hormone deficits. The sequential

order of hormone loss is usually GH → FSH/LH → TSH → ACTH.

Patients previously diagnosed with childhood-onset GH deficiency

should be retested as adults to affirm the diagnosis.

■ PRESENTATION AND DIAGNOSIS

The clinical features of AGHD include changes in body composition,

lipid metabolism, and quality of life and cardiovascular dysfunction

(Table 379-4). Body composition changes are common and include

reduced lean body mass, increased fat mass with selective deposition

of intraabdominal visceral fat, and increased waist-to-hip ratio. Hyperlipidemia, left ventricular dysfunction, hypertension, and increased

plasma fibrinogen levels also may be present. Bone mineral content

is reduced, with resultant increased fracture rates. Patients may experience social isolation, depression, and difficulty maintaining gainful

employment. Adult hypopituitarism is associated with a threefold

increase in cardiovascular mortality rates in comparison to age- and

sex-matched controls, and this may be due to GH deficiency, as

patients in these studies were replaced with other deficient pituitary

hormones.

■ LABORATORY INVESTIGATION

AGHD is rare, and in light of the nonspecific nature of associated

clinical symptoms, patients appropriate for testing should be selected

carefully on the basis of well-defined criteria. With few exceptions,

testing should be restricted to patients with the following predisposing factors: (1) pituitary surgery, (2) pituitary or hypothalamic

tumor or granulomas, (3) history of cranial irradiation, (4) radiologic

evidence of a pituitary lesion, and (5) childhood requirement for GH

replacement therapy. The transition of a GH-deficient adolescent to

adulthood requires retesting to document subsequent AGHD. Up to

20% of patients previously treated for childhood-onset GH deficiency

are found to be GH sufficient on repeat testing as adults.

A significant proportion (~25%) of truly GH-deficient adults have

low-normal IGF-1 levels. Thus, as in the evaluation of GH deficiency in

children, valid age-matched IGF-1 measurements provide a useful index

of therapeutic responses but are not sufficiently precise for diagnostic

purposes. The most validated test to distinguish pituitary-sufficient

patients from those with AGHD is insulin-induced (0.05–0.1 U/kg)

hypoglycemia. After glucose reduction to ~40 mg/dL, most individuals experience neuroglycopenic symptoms (Chap. 406), and peak GH

release occurs at 60 min and remains elevated for up to 2 h. About 90%

of healthy adults exhibit GH responses >5 μg/L; AGHD is defined by

a peak GH response to hypoglycemia of <3 μg/L. Although insulininduced hypoglycemia is safe when performed under appropriate supervision, it is contraindicated in patients with diabetes, ischemic heart

disease, cerebrovascular disease, or epilepsy and in elderly patients.

Alternative stimulatory tests include intravenous arginine (30 g), GHRH

(1 μg/kg), oral ghrelin receptor agonist (0.5 mg/kg), and glucagon

(1 mg). Combinations of these tests may evoke GH secretion in subjects who are not responsive to a single test.

TREATMENT

Adult GH Deficiency

Once the diagnosis of AGHD is unequivocally established, replacement of GH may be indicated. Contraindications to therapy include

the presence of an active neoplasm, intracranial hypertension, and

uncontrolled diabetes and retinopathy. The starting adult dose of

0.1–0.2 mg/d should be titrated (up to a maximum of 1.25 mg/d)

to maintain IGF-1 levels in the mid-normal range for age- and

TABLE 379-4 Features of Adult Growth Hormone Deficiency

Clinical

Impaired quality of life

Decreased energy and drive

Poor concentration

Low self-esteem

Social isolation

Body composition changes

Increased body fat mass

Central fat deposition

Increased waist-to-hip ratio

Decreased lean body mass

Reduced exercise capacity

Reduced maximum O2

 uptake

Impaired cardiac function

Reduced muscle mass

Cardiovascular risk factors

Impaired cardiac structure and function

Abnormal lipid profile

Decreased fibrinolytic activity

Atherosclerosis

Omental obesity

Imaging

Pituitary: mass or structural damage

Bone: reduced bone mineral density

Abdomen: excess omental adiposity

Laboratory

Evoked GH <3 ng/mL

IGF-1 and IGFBP3 low or normal

Increased LDL cholesterol

Concomitant gonadotropin, TSH, and/or ACTH reserve deficits may be present

Abbreviation: LDL, low-density lipoprotein. For other abbreviations, see text.

2901Hypopituitarism CHAPTER 379

sex-matched controls (Fig. 379-1). Women require higher doses

than men, and elderly patients require less GH. Long-term GH

maintenance sustains normal IGF-1 levels and is associated with

persistent body composition changes (e.g., enhanced lean body

mass and lower body fat). High-density lipoprotein cholesterol

increases, but total cholesterol and insulin levels may not change

significantly. Lumbar spine bone mineral density increases, but

this response is gradual (>1 year). Many patients note significant

improvement in quality of life when evaluated by standardized

questionnaires. The effect of GH replacement on mortality rates in

GH-deficient patients is currently the subject of long-term prospective investigation. Recently approved long-acting GH preparations

for patients with AGHD require weekly injections. Ideally, dosing

should be titrated to achieve normal but not supra-normal IGF-1

levels. Early reports indicate that side effects appear similar to subcutaneous formulations.

About 30% of patients exhibit reversible dose-related fluid retention, joint pain, and carpal tunnel syndrome, and up to 40%

exhibit myalgias and paresthesia. Patients receiving insulin require

careful monitoring for dosing adjustments, as GH is a potent

counterregulatory hormone for insulin action. Patients with type

2 diabetes mellitus may initially develop further insulin resistance.

However, glycemic control usually improves with the sustained

loss of abdominal fat associated with long-term GH replacement.

Headache, increased intracranial pressure, hypertension, and tinnitus occur rarely. Pituitary tumor regrowth and progression of skin

lesions or other tumors have not been encountered in long-term

surveillance programs with appropriate replacement doses.

ACTH DEFICIENCY

■ PRESENTATION AND DIAGNOSIS

Secondary adrenal insufficiency occurs as a result of pituitary ACTH

deficiency. It is characterized by fatigue, weakness, anorexia, nausea,

vomiting, and, occasionally, hypoglycemia. In contrast to primary

adrenal failure, hypocortisolism associated with pituitary failure usually is not accompanied by hyperpigmentation or mineralocorticoid

deficiency.

ACTH deficiency is commonly due to glucocorticoid withdrawal after treatment-associated suppression of the hypothalamicpituitary-adrenal (HPA) axis. Isolated ACTH deficiency may occur

after surgical resection of an ACTH-secreting pituitary adenoma that

has suppressed the HPA axis; this phenomenon is in fact suggestive of

a surgical cure. The mass effects of other pituitary adenomas or sellar

lesions may lead to ACTH deficiency, usually in combination with

other pituitary hormone deficiencies. Partial ACTH deficiency may

be unmasked in the presence of an acute medical or surgical illness,

when clinically significant hypocortisolism reflects diminished ACTH

reserve. Rarely, TPIT or POMC mutations result in primary ACTH

deficiency.

■ LABORATORY DIAGNOSIS

Inappropriately low ACTH levels in the setting of low cortisol levels are

characteristic of diminished ACTH reserve. Low basal serum cortisol

levels are associated with blunted cortisol responses to ACTH stimulation and impaired cortisol response to insulin-induced hypoglycemia

or testing with metyrapone or CRH. For a description of provocative

ACTH tests, see Chap. 386.

TREATMENT

ACTH Deficiency

Glucocorticoid replacement therapy improves most features of

ACTH deficiency. The total daily dose of hydrocortisone replacement preferably should generally not exceed 20 mg daily, divided

into two or three doses. Prednisone (5 mg each morning) is longer

acting and has fewer mineralocorticoid effects than hydrocortisone. Some authorities advocate lower maintenance doses in an

effort to avoid cushingoid side effects. Doses should be increased

severalfold during periods of acute illness or stress. Patients should

wear medical alert bracelets and/or carry identification cards with

information about their glucocorticoid requirements.

GONADOTROPIN DEFICIENCY

Hypogonadism is the most common presenting feature of adult hypopituitarism even when other pituitary hormones are also deficient. It

is often a harbinger of hypothalamic or pituitary lesions that impair

GnRH production or delivery through the pituitary stalk. As noted

below, hypogonadotropic hypogonadism is a common presenting feature of hyperprolactinemia.

A variety of inherited and acquired disorders are associated with

isolated hypogonadotropic hypogonadism (Chap. 391). Hypothalamic

defects associated with GnRH deficiency include Kallmann syndrome

and mutations in more than a dozen genes that regulate GnRH neuron migration, development, and function (see above). Mutations in

GPR54, DAX1, NR5A1, kisspeptin, the GnRH receptor, and the LHβ

or FSHβ subunit genes also cause pituitary gonadotropin deficiency.

Acquired forms of GnRH deficiency leading to hypogonadotropism

are seen in association with anorexia nervosa, stress, starvation, and

extreme exercise but also may be idiopathic. Hypogonadotropic hypogonadism in these disorders is reversed by removal of the stressful

stimulus or by caloric replenishment.

■ PRESENTATION AND DIAGNOSIS

In premenopausal women, hypogonadotropic hypogonadism presents

as diminished ovarian function leading to oligomenorrhea or amenorrhea, infertility, decreased vaginal secretions, decreased libido, and

breast atrophy. In hypogonadal adult men, secondary testicular failure

is associated with decreased libido and potency, infertility, decreased

muscle mass with weakness, reduced beard and body hair growth, soft

testes, and characteristic fine facial wrinkles. Osteoporosis occurs in

both untreated hypogonadal women and men.

■ LABORATORY INVESTIGATION

Central hypogonadism is associated with low or inappropriately normal

serum gonadotropin levels in the setting of low sex hormone concentrations (testosterone in men, estradiol in women). Because gonadotropin secretion is pulsatile, valid assessments may require repeated

measurements or the use of pooled serum samples. Men have reduced

sperm counts.

History of pituitary pathology

Clinical features present

Evoked GH <3 µg/L

Treat with

 GH 0.1–0.3 mg/d

Exclude contraindications

Titrate GH dose

 up to 1.25 mg/d

Check IGF-1 after 1 mo

No

response Response

6 mo

Discontinue Rx Monitor

 IGF-1 Levels

FIGURE 379-1 Management of adult growth hormone (GH) deficiency. IGF, insulinlike growth factor; Rx, treatment.

2902 PART 12 Endocrinology and Metabolism

HYPOTHALAMIC, PITUITARY, AND

OTHER SELLAR MASSES

■ EVALUATION OF SELLAR MASSES

Local Mass Effects Clinical manifestations of sellar lesions vary,

depending on the anatomic location of the mass and the direction of

its extension (Table 380-1). The dorsal sellar diaphragm presents the

least resistance to soft tissue expansion from the sella; consequently,

pituitary adenomas frequently extend in a suprasellar direction. Bony

invasion may occur as well, especially through the sellar floor to the

sphenoid sinus (Fig. 380-1).

Headaches are common features of small intrasellar tumors, even

with no demonstrable suprasellar extension. Because of the confined

nature of the pituitary, small changes in intrasellar pressure stretch the

dural plate; however, headache severity correlates poorly with adenoma

size or extension.

Suprasellar extension can lead to visual loss by several mechanisms,

the most common being compression of the optic chiasm. Rarely, direct

invasion of the optic nerves or obstruction of cerebrospinal fluid

(CSF) flow leading to secondary visual disturbances can occur. Pituitary stalk compression by a hormonally active or inactive intrasellar

mass may compress the portal vessels, disrupting pituitary access to

380 Pituitary Tumor

Syndromes

Shlomo Melmed, J. Larry Jameson

TABLE 380-1 Features of Sellar Mass Lesionsa

IMPACTED STRUCTURE CLINICAL IMPACT

Pituitary Hypogonadism

Hypothyroidism

Growth failure, adult growth hormone deficiency

Hypoadrenalism

Hyperprolactinema (stalk compression)

Optic chiasm Loss of red perception

Bitemporal hemianopia

Superior or bitemporal field defect

Scotoma

Blindness

Hypothalamus Temperature dysregulation

Appetite and thirst disorders

Obesity

Diabetes insipidus

Sleep disorders

Behavioral dysfunction

Autonomic dysfunction

Cavernous sinus Ophthalmoplegia with or without ptosis or diplopia

Facial numbness

Frontal lobe Personality disorder

Anosmia

Brain Headache

Hydrocephalus

Psychosis

Dementia

Laughing seizures

a

As the intrasellar mass expands, it first compresses intrasellar pituitary tissue,

then usually invades dorsally through the dura to lift the optic chiasm or laterally

to the cavernous sinuses. Bony erosion is rare, as is direct brain compression.

Microadenomas may present with headache.

Intravenous GnRH (100 μg) stimulates gonadotropes to secrete

LH (which peaks within 30 min) and FSH (which plateaus during the

ensuing 60 min). Normal responses vary according to menstrual cycle

stage, age, and sex of the patient. Generally, LH levels increase about

threefold, whereas FSH responses are less pronounced. In the setting

of gonadotropin deficiency, a normal gonadotropin response to GnRH

indicates intact pituitary gonadotrope function and suggests a hypothalamic abnormality. An absent response, however, does not reliably

distinguish pituitary from hypothalamic causes of hypogonadism. For

this reason, GnRH testing usually adds little to the information gained

from baseline evaluation of the hypothalamic-pituitary-gonadotrope

axis except in cases of isolated GnRH deficiency (e.g., Kallmann

syndrome).

MRI examination of the sellar region and assessment of other

pituitary functions usually are indicated in patients with documented

central hypogonadism.

TREATMENT

Gonadotropin Deficiency

In males, testosterone replacement is necessary to achieve and

maintain normal growth and development of the external genitalia,

secondary sex characteristics, male sexual behavior, and androgenic

anabolic effects, including maintenance of muscle function and

bone mass. Testosterone may be administered by intramuscular

injections every 1–4 weeks or by using skin patches or testosterone gels (Chap. 391). Gonadotropin injections (hCG or human

menopausal gonadotropin [hMG]) over 12–18 months are used to

restore fertility. Pulsatile GnRH therapy (25–150 ng/kg every 2 h),

administered by a subcutaneous infusion pump, is also effective for

treatment of hypothalamic hypogonadism when fertility is desired.

In premenopausal women, cyclical replacement of estrogen and

progesterone maintains secondary sexual characteristics and integrity of genitourinary tract mucosa and prevents premature osteoporosis (Chap. 392). Gonadotropin therapy is used for ovulation

induction. Follicular growth and maturation are initiated using

hMG or recombinant FSH; hCG or human luteinizing hormone

(hLH) is subsequently injected to induce ovulation. As in men,

pulsatile GnRH therapy can be used to treat hypothalamic causes of

gonadotropin deficiency.

DIABETES INSIPIDUS

See Chap. 381 for diagnosis and treatment of DI.

■ FURTHER READING

Chanson P et al: Adrenal insufficiency: Screening methods and confirmation of diagnosis. Ann Endocrinol (Paris) 78:495, 2017.

Fleseriu M et al: Hormonal replacement in hypopituitarism in adults:

An Endocrine Society clinical practice guideline. J Clin Endocrinol

Metab 101:3888, 2016.

Garcia JM et al: Macimorelin as a diagnostic test for adult GH deficiency. J Clin Endocrinol Metab 103:3083, 2018.

Higham CE et al: Hypopituitarism. Lancet 388:2403, 2016.

Melmed S: Pathogenesis and diagnosis of growth hormone deficiency

in adults. N Engl J Med 380:2551, 2019.

Miller BS et al: Long-acting growth hormone preparations-current

status and future considerations. J Clin Endocrinol Metab 105:e2121,

2020.

Tanriverdi F et al: Pituitary dysfunction after traumatic brain injury:

A clinical and pathophysiological approach. Endocr Rev 36:305,

2015.

Xatzipsalti M et al: Congenital hypopituitarism: Various genes, various phenotypes. Horm Metab Res 51:81, 2019.

Yamamoto M et al: Autoimmune pituitary disease: New concepts with

clinical implications. Endocr Rev 41:261, 2020.

2903Pituitary Tumor Syndromes CHAPTER 380

hypothalamic hormones and dopamine; this results in early hyperprolactinemia and later concurrent loss of other pituitary hormones. This

“stalk section” phenomenon may also be caused by trauma, whiplash

injury with posterior clinoid stalk compression, or skull base fractures. Lateral mass invasion may impinge on the cavernous sinus and

compress its neural contents, leading to cranial nerve III, IV, and VI

palsies as well as effects on the ophthalmic and maxillary branches of

the fifth cranial nerve (Chap. 441). Patients may present with diplopia,

ptosis, ophthalmoplegia, and decreased facial sensation, depending

on the extent of neural damage. Extension into the sphenoid sinus

indicates that the pituitary mass has eroded through the sellar floor

(Fig. 380-1). Aggressive tumors rarely invade the palate roof and cause

nasopharyngeal obstruction, infection, and CSF leakage. Temporal and

frontal lobe involvement may rarely lead to uncinate seizures, personality disorders, and anosmia. Direct hypothalamic encroachment by

an invasive pituitary mass may cause important metabolic sequelae,

including precocious puberty or hypogonadism, diabetes insipidus,

sleep disturbances, dysthermia, and appetite disorders.

Magnetic Resonance Imaging Sagittal and coronal T1-weighted

magnetic resonance imaging (MRI) before and after administration

of gadolinium allows precise visualization of the pituitary gland with

clear delineation of the hypothalamus, pituitary stalk, pituitary tissue

and surrounding suprasellar cisterns, cavernous sinuses, sphenoid

sinus, and optic chiasm. Pituitary gland height ranges from 6 mm in

children to 8 mm in adults; during pregnancy and puberty, the height

may reach 10–12 mm. The upper aspect of the adult pituitary is flat or

slightly concave, but in adolescent and pregnant individuals, this surface may be convex, reflecting physiologic pituitary enlargement. The

stalk should be midline and vertical.

Anterior pituitary gland soft tissue consistency is slightly heterogeneous on MRI, and signal intensity resembles that of brain matter on

T1-weighted imaging (Fig. 380-2). Adenoma density is usually lower

than that of surrounding normal tissue on T1-weighted imaging, and the

signal intensity increases with T2-weighted images. Computed tomography (CT) scan is reserved to define the extent of bony erosion or the

presence of calcification.

Sellar masses are encountered commonly as incidental findings

on MRI, and most are pituitary adenomas (incidentalomas). In the

absence of hormone hypersecretion, these small intrasellar lesions can

be monitored safely with MRI, which is performed annually and then

less often if there is no evidence of further growth. Resection should be

considered for incidentally discovered larger macroadenomas, because

about one-third become invasive or cause local pressure effects. If

hormone hypersecretion is identified, specific therapies are indicated

as described below. When larger masses (>1 cm) are encountered, they

A

B

FIGURE 380-1 Expanding pituitary mass. Pituitary mass expansion may (A) impinge vital soft tissue structures and (B) invade the sphenoid sinus. (Reproduced with

permission from P Cappabianca et al: Size does not matter. The intrigue of giant adenomas: a true surgical challenge. Acta Neurochir (Wien) 156:2217, 2014.)

2904 PART 12 Endocrinology and Metabolism

FIGURE 380-2 Pituitary adenoma. Coronal T1-weighted postcontrast magnetic

resonance image shows a homogeneously enhancing mass (arrowheads) in the

sella turcica and suprasellar region compatible with a pituitary adenoma; the small

arrows outline the carotid arteries.

should also be distinguished from nonadenomatous lesions. Meningiomas often are associated with bony hyperostosis; craniopharyngiomas

may have calcifications and are usually hypodense, whereas gliomas are

hyperdense on T2-weighted images.

Ophthalmologic Evaluation Because optic tracts may be contiguous to an expanding pituitary mass, reproducible visual field assessment

using perimetry techniques should be performed on all patients with

sellar mass lesions that impinge the optic chiasm (Chap. 32). Bitemporal hemianopia, often more pronounced superiorly, is observed

classically. It occurs because nasal ganglion cell fibers, which cross

in the optic chiasm, are especially vulnerable to compression of the

ventral optic chiasm. Occasionally, homonymous hemianopia occurs

from postchiasmal compression or monocular temporal field loss from

prechiasmal compression. Invasion of the cavernous sinus can produce

diplopia from ocular motor nerve palsy. Early diagnosis reduces the

risk of optic atrophy, vision loss, or eye misalignment.

Laboratory Investigation The presenting clinical features of functional pituitary adenomas (e.g., acromegaly, prolactinoma, or Cushing’s

disease) should guide the laboratory studies (Table 380-2). However,

for a sellar mass with no obvious clinical features of hormone excess,

laboratory studies are geared toward determining the nature of the

tumor and assessing the possible presence of hypopituitarism. When

a pituitary adenoma is suspected based on MRI, initial hormonal

evaluation usually includes (1) basal prolactin (PRL); (2) insulin-like

growth factor (IGF)-1; (3) 24-h urinary free cortisol (UFC) and/or

overnight oral dexamethasone (1 mg) suppression test; (4) α subunit,

follicle-stimulating hormone (FSH), and luteinizing hormone (LH);

and (5) thyroid function tests. Additional hormonal evaluation may

be indicated based on the results of these tests. Pending more detailed

assessment of hypopituitarism, a menstrual history, measurement of

testosterone and 8 a.m. cortisol levels, and thyroid function tests usually identify patients with pituitary hormone deficiencies that require

hormone replacement before further testing or surgery (Chap. 379).

Histologic Evaluation Immunohistochemical staining of pituitary tumor specimens obtained at transsphenoidal surgery for hormones as well as cell-type specific transcription factors confirms

clinical and laboratory studies and provides a histologic diagnosis

when hormone studies are equivocal and in cases of clinically nonfunctioning tumors.

TABLE 380-2 Screening Tests for Functional Pituitary Adenomas

TEST COMMENTS

Acromegaly Serum IGF-1

Oral glucose tolerance

test with GH obtained at

0, 30, and 60 min

Interpret IGF-1 relative to ageand sex-matched controls

Normal subjects should

suppress growth hormone to

<1 μg/L

Prolactinoma Serum PRL Exclude medications

MRI of the sella should be

ordered if PRL is elevated

Cushing’s disease 24-h urinary free cortisol

Dexamethasone

(1 mg) at 11 p.m. and

fasting plasma cortisol

measured at 8 a.m.

Late night salivary

cortisol

ACTH assay

Ensure urine collection is total

and accurate

Normal subjects suppress to

<5 μg/dL

Distinguishes adrenal adenoma

(ACTH suppressed) from

ectopic ACTH or Cushing’s

disease (ACTH normal or

elevated)

Gonadotropinoma Baseline FSH, LH, free

α subunit, ovarian

hyperstimulation,

estrogen (females),

testosterone (males)

TRH stimulation test with

assays for LH, FSH, free

α subunit, free LHβ, free

FSHβ subunits

Rare; more commonly

nonfunctioning adenomas

Consider screening for

hypopituitarism

Some gonadotropinomas exhibit

an inappropriate gonadotropin

response to TRH

TSH-producing

adenoma

Free T4

, free T3

, TSH, free

α subunit

Key feature is an

inappropriately normal or high

TSH in the setting of elevated

free T4

 and T3

Abbreviations: ACTH, adrenocorticotropin hormone; FSH, follicle-stimulating

hormone; GH, growth hormone; IGF-I, insulin-like growth factor I; LH, luteinizing

hormone; MRI, magnetic resonance imaging; PRL, prolactin; TSH, thyroidstimulating hormone.

TREATMENT

Hypothalamic, Pituitary, and Other Sellar Masses

OVERVIEW

Successful management of sellar masses requires accurate diagnosis

as well as selection of optimal therapeutic modalities. Most pituitary tumors are benign and slow growing. Clinical features result

from local mass effects and hormonal hyper- or hyposecretion

syndromes caused directly by the adenoma or occurring as a consequence of treatment. Thus, lifelong management and follow-up are

necessary for these patients.

MRI with gadolinium enhancement for pituitary visualization, new advances in transsphenoidal surgery and in stereotactic

radiotherapy, and novel therapeutic agents have improved pituitary tumor management. The goals of pituitary tumor treatment

include normalization of excess pituitary secretion, amelioration of

symptoms and signs of hormonal hypersecretion syndromes, and

shrinkage or ablation of large tumor masses with relief of adjacent

structure compression. Residual anterior pituitary function should

be preserved during treatment and sometimes can be restored by

removing the tumor mass. Ideally, adenoma recurrence should be

prevented.

TRANSSPHENOIDAL SURGERY

Transsphenoidal resection is the desired surgical approach for

pituitary tumors, except for the rare invasive suprasellar mass

surrounding the frontal or middle fossa or the optic nerves or

invading posteriorly behind the clivus, which may require transcranial approaches. Intraoperative microscopy facilitates visual

distinction between adenomatous and normal pituitary tissue as

well as microdissection of small tumors that may not be visible by

MRI (Fig. 380-3). Endoscopic techniques with three-dimensional

2905Pituitary Tumor Syndromes CHAPTER 380

Optic chiasm

Pituitary tumor

Venus plexus

of cavernous

sinus

Sphenoid

sinus

Sphenoid

bone

Surgical curette

Nasal septum

Oculomotor

nerve

Trochlear

nerve

Internal carotid

artery

Pituitary

tumor

Sphenoid

sinus

Trigeminal

nerve

FIGURE 380-3 Transsphenoidal resection of pituitary mass via the endonasal

approach.

intraoperative localization enable better visualization and access to

tumor tissue. Transsphenoidal surgery also avoids cranial invasion

and manipulation of brain tissue required by subfrontal surgical

approaches. Individual surgical experience is a major determinant

of outcome efficacy with these techniques.

In addition to correction of hormonal hypersecretion, pituitary

surgery is indicated for mass lesions that impinge on surrounding structures. Surgical decompression and resection are required

for an expanding pituitary mass, which may be asymptomatic

or accompanied by persistent headache, progressive visual field

defects, cranial nerve palsies, hydrocephalus, and, occasionally,

intrapituitary hemorrhage and apoplexy. Transsphenoidal surgery

rarely is used for pituitary tissue biopsy to establish a histologic

diagnosis. Whenever possible, the pituitary mass lesion should be

selectively excised; normal pituitary tissue should be manipulated

or resected only when critical for effective mass dissection. Nonselective hemihypophysectomy or total hypophysectomy may be

indicated if no hypersecreting mass lesion is clearly discernible,

multifocal lesions are present, or the remaining nontumorous pituitary tissue is obviously necrotic. This strategy, however, increases

the likelihood of postoperative hypopituitarism and the need for

lifelong hormone replacement.

Preoperative mass effects, including visual field defects and compromised pituitary function, may be reversed by surgery, particularly when the deficits are not long-standing. For large and invasive

tumors, it is necessary to determine the optimal balance between

maximal tumor resection and preservation of anterior pituitary

hormonal function, especially for preserving growth and reproductive function in younger patients. Tumor invasion outside the sella

is rarely amenable to surgical cure, and the surgeon must judge the

risk-versus-benefit ratio of extensive tumor resection.

Side Effects Tumor size, the degree of invasiveness, and experience of the surgeon largely determine the incidence of surgical

complications. Operative mortality rate is ~1%. Transient diabetes

insipidus and hypopituitarism occur in up to 20% of patients.

Permanent diabetes insipidus, cranial nerve damage, nasal septal

perforation, or visual disturbances may be encountered in up to

10% of patients. CSF leaks occur in 4% of patients. Less common

complications include carotid artery injury, loss of vision, hypothalamic damage, and meningitis. Permanent side effects are rare after

surgery for microadenomas.

RADIATION

Radiation is used either as a primary therapy for pituitary or

parasellar masses or, more commonly, as an adjunct to surgery or

medical therapy. Focused megavoltage irradiation is achieved by

precise MRI localization, using a high-voltage linear accelerator

and accurate isocentric rotational arcing. A major determinant of

accurate irradiation is reproduction of the patient’s head position

during multiple visits and maintenance of absolute head immobility. A total of <50 Gy (5000 rad) is given as 180-cGy (180-

rad) fractions divided over ~6 weeks. Stereotactic radiosurgery

delivers a large single high-energy dose from a cobalt-60 source

(Gamma Knife), linear accelerator, or cyclotron. Long-term effects

of Gamma Knife surgery appear to be similar to those encountered

with conventional radiation. Proton beam therapy is available in

some centers and provides concentrated radiation doses within a

localized region.

The role of radiation therapy in pituitary tumor management

depends on the nature and anatomic location of the tumor, the age

of the patient, and the availability of surgical and radiation expertise. Because of its relatively slow onset of action, radiation therapy

is usually reserved for postsurgical management. As an adjuvant to

surgery, radiation is used to treat residual tumor in an attempt to

prevent persistent growth or recurrence. Irradiation offers the only

means for potentially ablating significant postoperative residual

nonfunctioning tumor tissue. By contrast, PRL-, growth hormone

(GH)–, adrenocorticotropin hormone (ACTH)–, and thyrotropin

(thyroid-stimulating hormone [TSH])–secreting residual tumor tissues are amenable to medical therapy.

Side Effects In the short term, radiation may cause transient nausea and weakness. Alopecia and loss of taste and smell may be more

long-lasting. Failure of pituitary hormone synthesis is common in

patients who have undergone head and neck or pituitary-directed

irradiation. More than 50% of patients develop loss of GH, ACTH,

TSH, and/or gonadotropin secretion within 10 years, usually due to

hypothalamic damage. Lifelong follow-up with testing of anterior

pituitary hormone reserve is therefore required after radiation

treatment. Optic nerve damage with impaired vision due to optic

neuritis is reported in ~2% of patients who undergo pituitary irradiation. Cranial nerve damage is uncommon now that radiation doses

are <2 Gy (200 rad) at any one treatment session and the maximum

dose is <50 Gy (5000 rad). The use of stereotactic radiotherapy

reduces the risk of damage to adjacent structures. Conventional

radiotherapy for pituitary tumors has been associated with adverse

mortality rates, mainly from cerebrovascular disease. The cumulative risk of developing a secondary tumor after conventional radiation is 1.3% after 10 years and 1.9% after 20 years.

MEDICAL

Medical therapy for pituitary tumors is highly specific and depends

on tumor type. For prolactinomas, dopamine agonists are the

treatment of choice. For acromegaly, somatostatin receptor ligands (SRLs) and a GH receptor antagonist are indicated. For

TSH-secreting tumors, SRLs and occasionally dopamine agonists

2906 PART 12 Endocrinology and Metabolism

are indicated. ACTH-secreting tumors may respond to SRLs, and

adrenal-directed therapy may also be of benefit. Nonfunctioning

tumors are generally not responsive to medications and require

surgery and/or irradiation.

■ SELLAR MASSES

Sellar masses may arise from brain, hypothalamic, or pituitary tissues.

Each exhibit features related to the lesion location but also unique to

the specific etiology. Unique MRI characteristics inform the differential diagnosis of pituitary masses (Fig. 380-4).

Lesions involving the anterior and preoptic hypothalamic regions

cause paradoxical vasoconstriction, tachycardia, and hyperthermia.

Acute hyperthermia usually is due to a hemorrhagic insult, but

poikilothermia may also occur. Central disorders of thermoregulation result from posterior hypothalamic damage. The periodic

hypothermia syndrome is characterized by episodic attacks of rectal temperatures <30°C (86°F), sweating, vasodilation, vomiting,

and bradycardia (Chap. 464). Damage to the ventromedial hypothalamic nuclei by craniopharyngiomas, hypothalamic trauma, or

inflammatory disorders may be associated with hyperphagia and

obesity. This region appears to contain an energy-satiety center

where melanocortin receptors are influenced by leptin, insulin, proopiomelanocortin (POMC) products, and gastrointestinal peptides

(Chap. 401). Polydipsia and hypodipsia are associated with damage

to central osmoreceptors located in preoptic nuclei (Chap. 381).

Slow-growing hypothalamic lesions can cause increased somnolence

and disturbed sleep cycles as well as obesity, hypothermia, and emotional outbursts. Lesions of the central hypothalamus may stimulate

sympathetic neurons, leading to elevated serum catecholamine and

cortisol levels. These patients are predisposed to cardiac arrhythmias,

hypertension, and gastric erosions.

Craniopharyngiomas are benign, suprasellar cystic masses that

present with headaches, visual field deficits, and variable degrees of

hypopituitarism. They are derived from Rathke’s pouch and arise near

the pituitary stalk, commonly extending into the suprasellar cistern.

Craniopharyngiomas are often large, cystic, and locally invasive. Many

are partially calcified, exhibiting a characteristic appearance on skull

x-ray and CT images. More than half of all patients present before

age 20, usually with signs of increased intracranial pressure, including

headache, vomiting, papilledema, and hydrocephalus. Associated

symptoms include visual field abnormalities, personality changes

and cognitive deterioration, cranial nerve damage, sleep difficulties,

and weight gain accompanied by features of the metabolic syndrome.

Hypopituitarism is documented in ~90%, and diabetes insipidus

occurs in ~10% of patients. About half of affected children present

with growth retardation. MRI is generally superior to CT for evaluating

cystic structure and tissue components of craniopharyngiomas. CT is

useful to define calcifications and evaluate invasion into surrounding

bony structures and sinuses.

Treatment usually involves transcranial or transsphenoidal surgical resection followed by postoperative radiation of residual tumor.

Surgery alone is curative in less than half of patients because of recurrences due to adherence to vital structures or because of small tumor

deposits in the hypothalamus or brain parenchyma. The goal of surgery

is to remove as much tumor as possible without risking complications

associated with efforts to remove firmly adherent or inaccessible tissue.

In the absence of radiotherapy, ~75% of craniopharyngiomas recur,

and 10-year survival is <50%. In patients with incomplete resection,

radiotherapy improves 10-year survival to 70–90% but is associated

with increased risk of secondary malignancies. Most patients require

lifelong pituitary hormone replacement. As some craniopharyngiomas

(particularly papillary) are associated with activated BRAF V600E

mutations, use of BRAF inhibitors (dabrafenib or vemurafenib) either

alone or in combination with MEK inhibitors (trametinib or cobimetinib) has resulted in long-term growth responses in some patients.

Developmental failure of Rathke’s pouch obliteration may lead to

Rathke’s cysts, which are small (<5 mm) cysts entrapped by squamous

epithelium and are found in ~20% of individuals at autopsy. Although

Rathke’s cleft cysts do not usually grow and are often diagnosed

incidentally, about a third present in adulthood with compressive

symptoms, diabetes insipidus, and hyperprolactinemia due to stalk

compression. Rarely, hydrocephalus develops. The diagnosis is suggested preoperatively by visualizing the cyst wall on MRI, which distinguishes these lesions from craniopharyngiomas. Cyst contents range

from CSF-like fluid to mucoid material. Arachnoid cysts are rare and

generate an MRI image that is isointense with CSF.

Sella chordomas usually present with bony clival erosion, local

invasiveness, and, on occasion, calcification. Normal pituitary tissue

may be visible on MRI, distinguishing chordomas from aggressive

A B

C

D

FIGURE 380-4 Imaging differential diagnosis of sellar masses. A. Microadenoma. B. Macroadenoma. C. Craniopharyngioma. D. Hypophysitis with stalk thickening.

(C: Reproduced with permission from Muller HL: Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. Horm Res 69:193, 2008. A, B, D: Used

with permission from Vivien Bonert, MD.)

2907Pituitary Tumor Syndromes CHAPTER 380

pituitary adenomas. Mucinous material may be obtained by fineneedle aspiration.

Meningiomas arising in the sellar region may be difficult to distinguish from nonfunctioning pituitary adenomas. Meningiomas typically enhance on MRI and may show evidence of calcification or bony

erosion. Meningiomas may cause compressive symptoms.

Histiocytosis X includes a variety of syndromes associated with foci

of eosinophilic granulomas. Diabetes insipidus, exophthalmos, and

punched-out lytic bone lesions (Hand-Schüller-Christian disease) are

associated with granulomatous lesions visible on MRI, as well as a characteristic axillary skin rash. Rarely, the pituitary stalk may be involved.

Pituitary metastases occur in ~3% of cancer patients. Bloodborne

metastatic deposits are found almost exclusively in the posterior pituitary. Accordingly, diabetes insipidus can be a presenting feature of

lung, gastrointestinal, breast, and other pituitary metastases. About half

of pituitary metastases originate from breast cancer; ~25% of patients

with metastatic breast cancer have such deposits. Rarely, pituitary

stalk involvement results in anterior pituitary insufficiency. The MRI

diagnosis of a metastatic lesion may be difficult to distinguish from

an aggressive pituitary adenoma; the diagnosis may require histologic

examination of excised tumor tissue. Primary or metastatic lymphoma,

leukemias, and plasmacytomas also occur within the sella.

Hypothalamic hamartomas and gangliocytomas may arise from astrocytes, oligodendrocytes, and neurons with varying degrees of differentiation. These tumors may overexpress hypothalamic neuropeptides,

including gonadotropin-releasing hormone (GnRH), growth hormone–

releasing hormone (GHRH), and corticotropin-releasing hormone

(CRH). With GnRH-producing tumors, children present with precocious puberty, psychomotor delay, and laughing-associated seizures.

Medical treatment of GnRH-producing hamartomas with long-acting

GnRH analogues effectively suppresses gonadotropin secretion and

controls premature pubertal development. Rarely, hamartomas also

are associated with craniofacial abnormalities; imperforate anus;

cardiac, renal, and lung disorders; and pituitary failure as features of

Pallister-Hall syndrome, which is caused by mutations in the carboxy

terminus of the GLI3 gene. Hypothalamic hamartomas are often contiguous with the pituitary, and preoperative MRI diagnosis may not

be possible. Histologic evidence of hypothalamic neurons in tissue

resected at transsphenoidal surgery may be the first indication of a

primary hypothalamic lesion.

Hypothalamic gliomas and optic gliomas occur mainly in childhood

and usually present with visual loss. Adults have more aggressive

tumors; about a third are associated with neurofibromatosis.

Brain germ cell tumors may arise within the sellar region. They

include dysgerminomas, which frequently are associated with diabetes

insipidus and visual loss. They rarely metastasize. Germinomas, embryonal carcinomas, teratomas, and choriocarcinomas may arise in the

parasellar region and produce human chorionic gonadotropin (hCG).

These germ cell tumors present with precocious puberty, diabetes

insipidus, visual field defects, and thirst disorders. Many patients are

GH deficient with short stature.

■ PITUITARY ADENOMAS AND

HYPERSECRETION SYNDROMES

Pituitary adenomas are the most common cause of pituitary hormone

hypersecretion and hyposecretion syndromes in adults. They account

for ~15% of all intracranial neoplasms and have been identified with

a population prevalence of ~80/100,000. At autopsy, up to one-quarter

of all pituitary glands harbor an unsuspected microadenoma (<10 mm

diameter). Similarly, pituitary imaging detects small clinically inapparent pituitary lesions in at least 10% of individuals.

Pathogenesis Pituitary adenomas are benign neoplasms that arise

from one of the five anterior pituitary cell types. The clinical and biochemical phenotypes of pituitary adenomas depend on the cell type

from which they are derived. Thus, tumors arising from lactotrope

(PRL), somatotrope (GH), corticotrope (ACTH), thyrotrope (TSH), or

gonadotrope (LH, FSH) cells hypersecrete their respective hormones

(Table 380-3). Plurihormonal tumors express various combinations of

GH, PRL, TSH, ACTH, or the glycoprotein hormone α or β subunits.

They may be diagnosed by careful immunocytochemistry of specific

hormone and transcription factor expression or may manifest as clinical syndromes that combine features of these hormonal hypersecretory

syndromes. Morphologically, these tumors may arise from a single

polysecreting cell type or include cells with mixed function within the

same tumor.

Hormonally active tumors are characterized by autonomous hormone secretion with diminished feedback responsiveness to physiologic inhibitory pathways. Hormone production does not always

correlate with tumor size. Small hormone-secreting adenomas may

cause significant clinical perturbations, whereas larger adenomas that

produce less hormone may be clinically silent and remain undiagnosed

(if no central compressive effects occur). About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical

hypersecretory syndrome. Most of them arise from gonadotrope cells

and may secrete small amounts of α- and β-glycoprotein hormone

subunits or, very rarely, intact circulating gonadotropins. True pituitary

carcinomas with documented extracranial metastases are exceedingly

rare.

Almost all pituitary adenomas are monoclonal in origin, implying

the acquisition of one or more somatic mutations that confer a selective growth advantage. Consistent with their clonal origin, complete

surgical resection of small pituitary adenomas usually cures hormone

hypersecretion. Nevertheless, hypothalamic hormones such as GHRH

and CRH also enhance mitotic activity of their respective pituitary target cells in addition to their role in pituitary hormone regulation. Thus,

patients who harbor rare abdominal or chest tumors that elaborate

ectopic GHRH or CRH may present with somatotrope or corticotrope

hyperplasia with GH or ACTH hypersecretion.

Several etiologic genetic events have been implicated in the development of pituitary tumors. The pathogenesis of sporadic forms of acromegaly has been particularly informative as a model of tumorigenesis.

GHRH, after binding to its G protein–coupled somatotrope receptor,

uses cyclic adenosine monophosphate (AMP) as a second messenger

to stimulate GH secretion and somatotrope proliferation. A subset

(~35%) of GH-secreting pituitary tumors contains sporadic mutations

in Gs

α. These mutations attenuate intrinsic GTPase activity, resulting

in constitutive elevation of cyclic AMP, Pit-1 induction, and activation

of cyclic AMP response element binding protein (CREB), thereby promoting somatotrope cell proliferation and GH secretion.

TABLE 380-3 Classification of Pituitary Adenomasa

ADENOMA CELL ORIGIN

HORMONE

PRODUCT CLINICAL SYNDROME

Lactotrope PRL Hypogonadism, galactorrhea

Gonadotrope FSH, LH, subunits Silent, ovarian

hyperstimulation,

hypogonadism

Somatotrope GH Acromegaly/gigantism

Corticotrope ACTH/none Cushing’s disease or silent

Mixed growth hormone

and prolactin cell

GH, PRL Acromegaly, hypogonadism,

galactorrhea

Other plurihormonal cell Any Mixed

Acidophil stem cell PRL, GH Hypogonadism, galactorrhea,

acromegaly

Mammosomatotrope PRL, GH Hypogonadism, galactorrhea,

acromegaly

Thyrotrope TSH Thyrotoxicosis

Null cell None Hypopituitarism/none

Oncocytoma None Hypopituitarism/none

a

Hormone-secreting tumors are listed in decreasing order of frequency. All tumors

may cause local pressure effects, including visual disturbances, cranial nerve

palsy, and headache.

Note: For abbreviations, see text.

Source: Adapted with permission from S Melmed: Pathogenesis of pituitary tumors.

Nat Rev Endocrinol 7:257, 2011.