2908 PART 12 Endocrinology and Metabolism

Growth factors may also promote pituitary tumor proliferation.

Basic fibroblast growth factor (bFGF) is abundant in the pituitary and

stimulates pituitary cell mitogenesis, whereas epidermal growth factor

receptor (EGFR) signaling induces both hormone synthesis and cell

proliferation. Mutations of USP8 may result in overexpressed EGFR in

a subset of ACTH-secreting tumors. Other factors involved in initiation

and promotion of pituitary tumors include loss of negative-feedback

inhibition (as seen with primary hypothyroidism or hypogonadism)

and estrogen-mediated or paracrine angiogenesis. Growth characteristics and neoplastic behavior also may be influenced by activated oncogenes, including RAS and pituitary tumor transforming gene (PTTG),

or inactivation of growth suppressor genes, including MEG3. Pituitary

adenomas exhibit lineage-specific features of cell-cycle disruption,

including cellular senescence, with chromosomal instability and copy

number alterations as well as elevated levels of CDK inhibitors. These

features underlie the invariably benign nature of these adenomas.

Genetic Syndromes Associated with Pituitary Tumors Several familial syndromes are associated with pituitary tumors, and

the genetic mechanisms for some of them have been unraveled

(Table 380-4).

Multiple endocrine neoplasia (MEN) 1 is an autosomal dominant

syndrome characterized primarily by a genetic predisposition to parathyroid, pancreatic islet, and pituitary adenomas (Chap. 388). MEN

1 is caused by inactivating germline mutations in MENIN, a constitutively expressed tumor-suppressor gene located on chromosome

11q13. Loss of heterozygosity or a somatic mutation of the remaining

normal MENIN allele leads to tumorigenesis. About half of affected

patients develop prolactinomas; acromegaly and Cushing’s disease are

less commonly encountered.

Carney complex is characterized by spotty skin pigmentation, myxomas, and endocrine tumors, including testicular, adrenal, and pituitary

adenomas. Acromegaly occurs in ~20% of these patients. A subset of

patients has mutations in the R1α regulatory subunit of protein kinase

A (PRKAR1A).

McCune-Albright syndrome consists of polyostotic fibrous dysplasia,

pigmented skin patches, and a variety of endocrine disorders, including acromegaly, adrenal adenomas, and autonomous ovarian function

(Chap. 412). Hormonal hypersecretion results from constitutive cyclic

AMP production caused by inactivation of the GTPase activity of Gs

α.

The Gs

α mutations occur postzygotically, leading to a mosaic pattern

of mutant expression.

Familial acromegaly is a rare disorder in which family members may

manifest either acromegaly or gigantism. A subset of families with a

predisposition for familial pituitary tumors, especially acromegaly,

has been found to harbor germline mutations in the AIP gene, which

encodes the aryl hydrocarbon receptor interacting protein.

■ HYPERPROLACTINEMIA

Etiology Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. PRLsecreting pituitary adenomas (prolactinomas) are the most common

cause of PRL levels >200 μg/L (see below). Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly

caused by drugs, pituitary stalk compression, hypothyroidism, or renal

failure (Table 380-5).

Pregnancy and lactation are the important physiologic causes of

hyperprolactinemia. Sleep-associated hyperprolactinemia reverts to

normal within an hour of awakening. Nipple stimulation and sexual

orgasm also may increase PRL. Chest wall stimulation or trauma

(including chest surgery and herpes zoster) invokes the reflex suckling

arc with resultant hyperprolactinemia. Chronic renal failure elevates

PRL by decreasing peripheral clearance. Primary hypothyroidism is

associated with mild hyperprolactinemia, probably because of compensatory TRH secretion. Mutation of the PRL receptor is a rare cause

of hyperprolactinemia.

Lesions of the hypothalamic-pituitary region that disrupt hypothalamic dopamine synthesis, portal vessel delivery, or lactotrope

responses are associated with hyperprolactinemia. Thus, hypothalamic

tumors, cysts, infiltrative disorders, and radiation-induced damage cause elevated PRL levels, usually in the range of 30–100 μg/L.

Plurihormonal adenomas (including GH and ACTH tumors) may

hypersecrete PRL directly. Pituitary masses, including clinically nonfunctioning pituitary tumors, may compress the pituitary stalk to cause

hyperprolactinemia.

Drug-induced inhibition or disruption of dopaminergic receptor

function is a common cause of hyperprolactinemia (Table 380-5).

Thus, antipsychotics and antidepressants are a relatively common

cause of mild hyperprolactinemia. Most patients receiving risperidone

have elevated PRL levels, sometimes exceeding 200 μg/L. Methyldopa

inhibits dopamine synthesis, and verapamil blocks dopamine release,

also leading to hyperprolactinemia. Hormonal agents that induce PRL

include estrogens and thyrotropin-releasing hormone (TRH).

Presentation and Diagnosis Amenorrhea, galactorrhea, and

infertility are the hallmarks of hyperprolactinemia in women. If hyperprolactinemia develops before menarche, primary amenorrhea results.

More commonly, hyperprolactinemia develops later in life and leads to

oligomenorrhea and ultimately to amenorrhea. If hyperprolactinemia

is sustained, vertebral bone mineral density can be reduced compared

with age-matched controls, particularly when it is associated with pronounced hypoestrogenemia. Galactorrhea is present in up to 80% of

hyperprolactinemic women. Although usually bilateral and spontaneous, it may be unilateral or expressed only manually. Patients also may

complain of decreased libido, weight gain, and mild hirsutism.

In men with hyperprolactinemia, diminished libido, infertility, and

visual loss (from optic nerve compression) are the usual presenting

symptoms. Gonadotropin suppression leads to reduced testosterone,

impotence, and oligospermia. True galactorrhea is uncommon in men

with hyperprolactinemia. If the disorder is long-standing, secondary

effects of hypogonadism are evident, including osteopenia, reduced

muscle mass, and decreased beard growth.

The diagnosis of idiopathic hyperprolactinemia is made by exclusion of known causes of hyperprolactinemia in the setting of a normal

pituitary MRI. Some of these patients may harbor small microadenomas below visible MRI sensitivity (~2 mm).

■ GALACTORRHEA

Galactorrhea, the inappropriate discharge of milk-containing fluid

from the breast, is considered abnormal if it persists longer than

6 months after childbirth or discontinuation of breast-feeding. Postpartum galactorrhea associated with amenorrhea is a self-limiting

disorder usually associated with moderately elevated PRL levels.

Galactorrhea may occur spontaneously, or it may be elicited by nipple

TABLE 380-4 Familial Pituitary Tumor Syndromes (see Chap. 388)

GENE MUTATED CLINICAL FEATURES

Multiple endocrine

neoplasia 1 (MEN 1)

MEN1

(11q13)

Hyperparathyroidism

Pancreatic neuroendocrine

tumors

Foregut carcinoids

Adrenal adenomas

Skin lesions

Pituitary adenomas (40%)

Multiple endocrine

neoplasia 4 (MEN 4)

CDKNIB

(12p13)

Hyperparathyroidism

Pituitary adenomas

Other tumors

Carney complex PRKAR1A

(17q23-24)

Pituitary hyperplasia and

adenomas (10%)

Atrial myxomas

Schwannomas

Adrenal hyperplasia

Lentigines

Familial pituitary

adenomas

AIP

(11q13.2)

Acromegaly/gigantism (~15% of

afflicted families)

2909Pituitary Tumor Syndromes CHAPTER 380

pressure. In both men and women, galactorrhea may vary in color

and consistency (transparent, milky, or bloody) and arise either unilaterally or bilaterally. Mammography or ultrasound is indicated for

bloody discharges (particularly from a single nipple), which may be

caused by breast cancer. Galactorrhea is commonly associated with

hyperprolactinemia caused by any of the conditions listed in Table

380-5. Acromegaly is associated with galactorrhea in about one-third

of patients. Treatment of galactorrhea usually involves managing the

underlying disorder (e.g., replacing T4

 for hypothyroidism, discontinuing a medication, treating prolactinoma).

Laboratory Investigation Basal, fasting morning PRL levels

(normally <20 μg/L) should be measured to assess hypersecretion.

Both false-positive and false-negative results may be encountered. In

patients with markedly elevated PRL levels (>1000 μg/L), reported

results may be falsely lowered because of assay artifacts; sample

dilution is required to measure these high values accurately. Falsely

elevated values may be caused by aggregated forms of circulating PRL,

which are usually biologically inactive (macroprolactinemia). Hypothyroidism should be excluded by measuring TSH and T4

 levels.

TREATMENT

Hyperprolactinemia

Treatment of hyperprolactinemia depends on the cause of elevated

PRL levels. Regardless of the etiology, however, treatment should

be aimed at normalizing PRL levels to alleviate suppressive effects

on gonadal function, halt galactorrhea, and preserve bone mineral

density. Dopamine agonists are effective for most causes of hyperprolactinemia (see the treatment section for prolactinoma, below)

regardless of the underlying cause.

If the patient is taking a medication known to cause hyperprolactinemia, the drug should be withdrawn, if possible. For psychiatric

patients who require neuroleptic agents, supervised dose titration

or the addition of a dopamine agonist can help restore normoprolactinemia and alleviate reproductive symptoms. However, dopamine agonists may worsen the underlying psychiatric condition,

especially at high doses. Hyperprolactinemia usually resolves after

adequate thyroid hormone replacement in hypothyroid patients or

after renal transplantation in patients undergoing dialysis. Resection

of hypothalamic or sellar mass lesions can reverse hyperprolactinemia caused by stalk compression and reduced dopamine tone.

Granulomatous infiltrates occasionally respond to glucocorticoid

administration. In patients with irreversible hypothalamic damage,

no treatment may be warranted. In up to 30% of patients with hyperprolactinemia—usually without a visible pituitary microadenoma—

the condition may resolve spontaneously.

■ PROLACTINOMA

Etiology and Prevalence Tumors arising from lactotrope cells

account for about half of all functioning pituitary tumors, with a population prevalence of ~10/100,000 in men and ~30/100,000 in women.

Mixed tumors that secrete combinations of GH and PRL, ACTH and

PRL, and rarely TSH and PRL are also seen. These plurihormonal

tumors are usually recognized by immunohistochemistry, sometimes

without apparent clinical manifestations from the production of additional hormones. Microadenomas are classified as <1 cm in diameter

and usually do not invade the parasellar region. Macroadenomas are

>1 cm in diameter and may be locally invasive and impinge on adjacent structures. The female-to-male ratio for microprolactinomas is

20:1, whereas the sex ratio is near 1:1 for macroadenomas. Tumor

size generally correlates directly with PRL concentrations; values

>250 μg/L usually are associated with macroadenomas. Men tend to

present with larger tumors than women, possibly because the features

of male hypogonadism are less readily evident. PRL levels remain stable

in most patients, reflecting the slow growth of these tumors. About 5%

of microadenomas progress in the long term to macroadenomas.

Presentation and Diagnosis Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside the

sella, visual field defects or other mass effects may be seen. Men often

present with impotence, loss of libido, infertility, or signs of central

nervous system (CNS) compression, including headaches and visual

defects. Assuming that physiologic and medication-induced causes of

TABLE 380-5 Etiology of Hyperprolactinemia

I. Physiologic hypersecretion

Pregnancy

Lactation

Chest wall stimulation

Sleep

Stress

II. Hypothalamic-pituitary stalk damage

Tumors

 Craniopharyngioma

 Suprasellar pituitary mass

 Meningioma

 Dysgerminoma

 Metastases

Empty sella

Lymphocytic hypophysitis

Adenoma with stalk compression

Granulomas

Rathke’s cyst

Irradiation

Trauma

 Pituitary stalk section

 Suprasellar surgery

III. Pituitary hypersecretion

Prolactinoma

Acromegaly

IV. Systemic disorders

Chronic renal failure

Hypothyroidism

Cirrhosis

Pseudocyesis

Epileptic seizures

V. Drug-induced hypersecretion

Dopamine receptor blockers

 Atypical antipsychotics: risperidone

 Phenothiazines: chlorpromazine, perphenazine

 Butyrophenones: haloperidol

 Thioxanthenes

 Metoclopramide

Dopamine synthesis inhibitors

 α-Methyldopa

Catecholamine depletors

 Reserpine

Opiates

H2

 antagonists

 Cimetidine, ranitidine

Imipramines

 Amitriptyline, amoxapine

Serotonin reuptake inhibitors

 Fluoxetine

Calcium channel blockers

 Verapamil

 Estrogens

 Thyrotropin-releasing hormone

Note: Hyperprolactinemia >200 μg/L almost invariably is indicative of a prolactinsecreting pituitary adenoma. Physiologic causes, hypothyroidism, and drug-induced

hyperprolactinemia should be excluded before extensive evaluation.

2910 PART 12 Endocrinology and Metabolism

hyperprolactinemia are excluded (Table 380-5), the diagnosis of prolactinoma is likely with a PRL level >200 μg/L. PRL levels <100 μg/L

may be caused by microadenomas, other sellar lesions that decrease

dopamine inhibition, or nonneoplastic causes of hyperprolactinemia.

For this reason, an MRI should be performed in all patients with

hyperprolactinemia. It is important to remember that hyperprolactinemia caused secondarily by the mass effects of nonlactotrope lesions is

also corrected by treatment with dopamine agonists despite failure to

shrink the underlying mass. Consequently, PRL suppression by dopamine agonists does not necessarily indicate that the underlying lesion

is a prolactinoma.

TREATMENT

Prolactinoma

Because microadenomas rarely progress to become macroadenomas, no treatment may be needed if patients are asymptomatic

and fertility is not desired; these patients should be monitored by

regular serial PRL measurements and MRI scans. For symptomatic

microadenomas, therapeutic goals include control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility,

and resolution of galactorrhea. Dopamine agonist doses should be

titrated to achieve maximal PRL suppression and restoration of

reproductive function (Fig. 380-5). A normalized PRL level does

not ensure reduced tumor size. However, tumor shrinkage usually is

not seen in those who do not respond with lowered PRL levels. For

macroadenomas, formal visual field testing should be performed

before initiating dopamine agonists. MRI and visual fields should

be assessed at 6- to 12-month intervals until the mass shrinks and

annually thereafter until maximum size reduction has occurred.

Oral dopamine agonists (cabergoline and bromocriptine) are

the mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis

as well as lactotrope cell proliferation. In patients with microadenomas who have achieved normoprolactinemia and significant

reduction of tumor mass, the dopamine agonist may be withdrawn after 2 years. These patients should be monitored carefully

for evidence of prolactinoma recurrence. About 20% of patients

(especially males) are resistant to dopaminergic treatment; these

adenomas may exhibit decreased D2

 dopamine receptor numbers

or a postreceptor defect. D2

 receptor gene mutations in the pituitary

have not been reported.

Cabergoline An ergoline derivative, cabergoline is a long-acting

dopamine agonist with high D2

 receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and

induces prolactinoma shrinkage in most patients. Cabergoline (0.5–

1.0 mg twice weekly) achieves normoprolactinemia and resumption

of normal gonadal function in ~80% of patients with microadenomas; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes PRL and shrinks ~70% of macroprolactinomas.

Mass effect symptoms, including headaches and visual disorders,

usually improve dramatically within days after cabergoline initiation; improvement of sexual function requires several weeks of

treatment but may occur before complete normalization of PRL levels. MRI should be repeated within 16 weeks after initial therapy of

macroadenomas as shrinkage of invasive adenomas may be striking

(Fig. 380-6). After initial control of PRL levels has been achieved,

cabergoline should be reduced to the lowest effective maintenance

dose. In ~5% of treated patients harboring a microadenoma, hyperprolactinemia may resolve and not recur when dopamine agonists

are discontinued after long-term treatment. Cabergoline also may

be effective in patients resistant to bromocriptine. Adverse effects

and drug intolerance are encountered less commonly than with

bromocriptine.

Bromocriptine The ergot alkaloid bromocriptine mesylate is a

dopamine receptor agonist that suppresses PRL secretion. Because

it is short-acting, the drug is preferred when pregnancy is desired.

Therapy is initiated by administering a low bromocriptine dose

(0.625–1.25 mg) at bedtime with a snack, followed by gradually

increasing the dose. Most patients are controlled with a daily dose

of <7.5 mg (2.5 mg tid).

SIDE EFFECTS

Side effects of dopamine agonists include constipation, nasal stuffiness, dry mouth, nightmares, insomnia, and vertigo; decreasing

the dose usually alleviates these problems. Nausea, vomiting, and

postural hypotension with faintness may occur in ~25% of patients

after the initial dose. These symptoms may persist in some patients.

In general, fewer side effects are reported with cabergoline. For

the ~15% of patients who are intolerant of oral bromocriptine,

ELEVATED PROLACTIN LEVELS

Symptomatic Prolactinoma

Microadenoma Macroadenoma

Exclude secondary causes of hyperprolactinemia

MRI evidence for pituitary mass

Test visual

 fields

Test pituitary

 reserve function

Titrate

 dopamine agonist Drug intolerance Titrate

 dopamine agonist

Repeat MRI

 within 4 months

Tumor shrinkage

 and prolactin

 normalized

Monitor PRL

 and repeat

 MRI annually

No tumor shrinkage

 or tumor growth

 or persistent

 hyperprolactinemia

Change

 dopamine agonist Serum PRL

<20 20–50 >50 (µg/L)

Maintenance

Rx

Consider Surgery

Reassess

 diagnosis

Increase dose

FIGURE 380-5 Management of prolactinoma. MRI, magnetic resonance imaging; PRL, prolactin.

2911Pituitary Tumor Syndromes CHAPTER 380

cabergoline may be better tolerated. Intravaginal administration

of bromocriptine is often efficacious in patients with intractable

gastrointestinal side effects. Auditory hallucinations, delusions, and

mood swings have been reported in up to 5% of patients and may

be due to the dopamine agonist properties or to the lysergic acid

derivative of the compounds. Rare reports of leukopenia, thrombocytopenia, pleural fibrosis, cardiac arrhythmias, and hepatitis

have been described. Patients with Parkinson disease who receive at

least 3 mg of cabergoline daily have been reported to be at risk for

development of cardiac valve regurgitation. Studies analyzing >500

prolactinoma patients receiving recommended doses of cabergoline (up to 2 mg weekly) have shown no evidence for an increased

incidence of valvular disorders. Nevertheless, because no controlled

prospective studies in pituitary tumor patients are available, it is

prudent to perform echocardiograms before initiating standarddose cabergoline therapy.

Surgery Rarely, surgical adenoma debulking may be indicated

for dopamine resistance or intolerance as well as the presence of

an invasive macroadenoma with compromised vision that fails to

improve after drug treatment. Initial PRL normalization is achieved

in ~70% of microprolactinomas after surgical resection, but only

30% of macroadenomas can be resected successfully. Follow-up

studies have shown that hyperprolactinemia recurs in up to 20%

of patients within the first year after surgery; long-term recurrence rates may exceed 50% for macroadenomas. Radiotherapy for

prolactinomas is reserved for patients with aggressive tumors that

do not respond to maximally tolerated dopamine agonists and/or

surgery.

PREGNANCY

The pituitary increases in size during pregnancy, reflecting the

stimulatory effects of estrogen and perhaps other growth factors

on pituitary vascularity and lactotrope cell hyperplasia. About 5%

of microadenomas significantly increase in size, but 15–30% of

macroadenomas grow during pregnancy. Bromocriptine has been

used for >30 years to restore fertility in women with hyperprolactinemia, without evidence of teratogenic effects. Nonetheless, most

authorities recommend strategies to minimize fetal exposure to

the drug. For women taking bromocriptine who desire pregnancy,

mechanical contraception should be used through three regular

menstrual cycles to allow for conception timing. When pregnancy

A B

C D

FIGURE 380-6 Large invasive prolactinoma successfully treated with cabergoline. A–B. Prolactin-secreting macroadenoma in a 32-year-old male measuring 5.6 × 6.9 cm

invading the skull base. PRL level was 122,260 μg/L. Four days after cabergoline was started, PRL was 10,823 μg/L and dropped to 772 μg/L after 3 weeks. C–D. Substantial

tumor regression after 40 months of treatment, with PRL levels stable at 25 μg/L. (Reproduced with permission from M Ahmed, O Al-Nozha: Images in clinical medicine.

Large prolactinoma. N Engl J Med 363:177, 2010.)

2912 PART 12 Endocrinology and Metabolism

is confirmed, bromocriptine should be discontinued and PRL levels

followed serially, especially if headaches or visual symptoms occur.

For women harboring macroadenomas, regular visual field testing

is recommended, and the drug should be reinstituted if tumor

growth is apparent. Although pituitary MRI may be safe during

pregnancy, this procedure should be reserved for symptomatic

patients with severe headache and/or visual field defects. Surgical

decompression may be indicated if vision is threatened. Although

comprehensive data support the efficacy and relative safety of

bromocriptine-facilitated fertility, patients should be advised of

potential unknown deleterious effects and the risk of tumor growth

during pregnancy. Because cabergoline is long-acting with a high

D2

-receptor affinity, it is not recommended for use in women when

fertility is desired.

■ ACROMEGALY

Etiology GH hypersecretion is usually the result of a somatotrope adenoma but may rarely be caused by extrapituitary lesions

(Table 380-6). In addition to the more common GH-secreting somatotrope adenomas, mixed mammosomatotrope tumors and acidophilic

stem cell adenomas secrete both GH and PRL. In patients with acidophilic stem cell adenomas, features of hyperprolactinemia (hypogonadism and galactorrhea) predominate over the less clinically evident

signs of acromegaly. Occasionally, mixed plurihormonal tumors are

encountered that also secrete ACTH, the glycoprotein hormone α

subunit, or TSH in addition to GH. Patients with partially empty sellae

may present with GH hypersecretion due to a small GH-secreting

adenoma within the compressed rim of pituitary tissue; some of these

may reflect the spontaneous necrosis of tumors that were previously

larger. GH-secreting tumors rarely arise from ectopic pituitary tissue

remnants in the nasopharynx or midline sinuses.

There are case reports of ectopic GH secretion by tumors of pancreatic, ovarian, lung, or hematopoietic origin. Rarely, excess GHRH

production may cause acromegaly because of chronic stimulation of

somatotropes. These patients present with classic features of acromegaly, elevated GH levels, pituitary enlargement on MRI, and pathologic

characteristics of pituitary hyperplasia. The most common cause of

GHRH-mediated acromegaly is a chest or abdominal carcinoid tumor.

Although these tumors usually express positive GHRH immunoreactivity, clinical features of acromegaly are evident in only a minority of

patients with carcinoid disease. Excessive GHRH also may be elaborated by hypothalamic tumors, usually choristomas or neuromas.

Presentation and Diagnosis Protean manifestations of GH and

IGF-1 hypersecretion are indolent and often are not clinically diagnosed for 10 years or more. Acral bony overgrowth results in frontal

bossing, increased hand and foot size, mandibular enlargement with

prognathism, and widened space between the lower incisor teeth.

In children and adolescents, initiation of GH hypersecretion before

epiphyseal long bone closure is associated with development of pituitary gigantism (Fig. 380-7). Soft tissue swelling results in increased

heel pad thickness, increased shoe or glove size, ring tightening,

characteristic coarse facial features, and a large fleshy nose. Other

commonly encountered clinical features include hyperhidrosis, a deep

and hollow-sounding voice, oily skin, arthropathy, kyphosis, carpal

tunnel syndrome, proximal muscle weakness and fatigue, acanthosis

nigricans, and skin tags. Generalized visceromegaly occurs, including

cardiomegaly, macroglossia, and thyroid gland enlargement.

The most significant clinical impact of GH excess occurs with

respect to the cardiovascular system. Cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, and

hypertension ultimately occur in most patients if untreated. Upper

airway obstruction with sleep apnea occurs in >60% of patients and

is associated with both soft tissue laryngeal airway obstruction and

central sleep dysfunction. Diabetes mellitus develops in 25% of patients

with acromegaly, and most patients are intolerant of a glucose load (as

GH counteracts the action of insulin). Acromegaly is associated with

an increased risk of colon polyps and mortality from colonic malignancy; polyps are diagnosed in up to one-third of patients. Overall

mortality is increased about threefold and is due primarily to cardiovascular and cerebrovascular disorders and respiratory disease. Unless

GH levels are controlled, survival is reduced by an average of 10 years

compared with an age-matched control population.

Laboratory Investigation Age-matched serum IGF-1 levels are

elevated in acromegaly. Consequently, an IGF-1 level provides a

useful laboratory screening measure when clinical features raise the

possibility of acromegaly. Owing to the pulsatility of GH secretion,

measurement of a single random GH level is not useful for the diagnosis or exclusion of acromegaly and does not correlate with disease

severity. The diagnosis of acromegaly is confirmed by demonstrating

the failure of GH suppression to <0.4 μg/L within 1–2 h of an oral

glucose load (75 g). When ultrasensitive GH assays are used, normal

nadir GH levels are even lower (<0.05 μg/L). About 20% of patients

exhibit a paradoxical GH rise after glucose. PRL should be measured,

as it is elevated in ~25% of patients with acromegaly. Thyroid function,

gonadotropins, and sex steroids may be attenuated because of tumor

mass effects. Because most patients will undergo surgery with glucocorticoid coverage, tests of ACTH reserve in asymptomatic patients are

more efficiently deferred until after surgery.

TREATMENT

Acromegaly

The goal of treatment is to control GH and IGF-1 hypersecretion,

ablate or arrest tumor growth, ameliorate comorbidities, restore

mortality rates to normal, and preserve pituitary function.

Surgical resection of GH-secreting adenomas is the initial treatment for most patients (Fig. 380-8). SRLs are used as adjuvant

treatment for preoperative shrinkage of large invasive macroadenomas, immediate relief of debilitating symptoms, and reduction of

GH hypersecretion; in frail patients experiencing morbidity; and in

patients who decline surgery or when surgery fails to achieve biochemical control. Irradiation or repeat surgery may be required for

patients who cannot tolerate or do not respond to adjunctive medical therapy. The high rate of late hypopituitarism and the slow rate

(5–15 years) of biochemical response are the main disadvantages of

TABLE 380-6 Causes of Acromegaly

PREVALENCE, %

Excess Growth Hormone Secretion

Pituitary

 Densely or sparsely granulated GH cell adenoma

Mixed GH cell and PRL cell adenoma

Mammosomatotrope cell adenoma

Plurihormonal adenoma

GH cell carcinoma or metastases

 Multiple endocrine neoplasia 1 (GH cell adenoma)

McCune-Albright syndrome

 Ectopic sphenoid or parapharyngeal sinus pituitary

adenoma

Extrapituitary tumor

Pancreatic islet cell tumor

Lymphoma

98

60

25

10

<1

Excess Growth Hormone–Releasing Hormone Secretion

Central

 Hypothalamic hamartoma, choristoma, ganglioneuroma

Peripheral

 Bronchial carcinoid, pancreatic islet cell tumor, smallcell lung cancer, adrenal adenoma, medullary thyroid

carcinoma, pheochromocytoma

<1

<1

Abbreviations: GH, growth hormone; PRL, prolactin.

Source: Data from S Melmed: Medical progress: Acromegaly. N Engl J Med

355:2558, 2006.

2913Pituitary Tumor Syndromes CHAPTER 380

radiotherapy. Irradiation is also relatively ineffective in normalizing

IGF-1 levels. Stereotactic ablation of GH-secreting adenomas by

Gamma Knife radiotherapy is promising, but long-term results

and side effects appear similar to those observed with conventional

radiation. SRLs may be required while awaiting the full benefits of

radiotherapy. Systemic comorbid sequelae of acromegaly, including

cardiovascular disease, diabetes, and arthritis, should be managed

aggressively. Mandibular surgical repair may be indicated.

SURGERY

Transsphenoidal surgical resection by an experienced surgeon is the

preferred primary treatment for both microadenomas (remission

rate ~70%) and macroadenomas (<50% in remission). Soft tissue

swelling improves immediately after tumor resection. GH levels

return to normal within an hour, and IGF-1 levels are normalized

within 3–4 days. In ~10% of patients, acromegaly may recur several

years after apparently successful surgery; hypopituitarism develops

in up to 15% of patients after surgery.

SOMATOSTATIN RECEPTOR LIGANDS

SRLs exert their therapeutic effects through SST2 and SST5 receptor subtypes, both expressed by GH-secreting tumors.

The preferred medical treatments for patients with acromegaly

include long-acting injectable SRL depot formulations of octreotide and lanreotide as well as oral octreotide capsules. Although

responses vary widely in individual patients, meta-analyses indicate that GH and IGF-1 levels are normalized in ~50% of patients.

Octreotide acetate is an eight-amino-acid synthetic somatostatin

analogue. In contrast to native somatostatin, the analogue is relatively resistant to plasma degradation. It has a 2-h serum half-life

and possesses 40-fold greater potency than native somatostatin

to suppress GH. Octreotide LAR is a sustained-release, longacting formulation of octreotide incorporated into microspheres

that sustain drug levels for several weeks after intramuscular injection. GH suppression occurs for as long as 6 weeks after a 30-mg

intramuscular injection; long-term monthly treatment sustains GH

and IGF-1 suppression and also reduces pituitary tumor size in

~50% of patients. Lanreotide, in a slow-release depot SRL preparation, is a cyclic somatostatin octapeptide analogue that suppresses

GH and IGF-1 hypersecretion after a 60-mg subcutaneous injection. Long-term (every 4–6 weeks) administration controls GH

hypersecretion in about two-thirds of treated patients and improves

patient compliance because of the long interval required between

drug injections. Oral octreotide capsules (40–80 mg daily) maintain

biochemical control in patients previously maintained on injectable

formulations. Rapid relief of headache and soft tissue swelling

occurs in ~75% of patients within days to weeks of SRL initiation.

Most patients report symptomatic improvement, including amelioration of headache, perspiration, obstructive apnea, and cardiac

failure. Pasireotide LAR, a multireceptor ligand with preferential

SST5 binding (see below), has been shown to exhibit efficacy in

achieving biochemical control in patients resistant to octreotide or

lanreotide preparations.

Side Effects SRLs are well tolerated in most patients. Adverse

effects are similar for injectable octreotide and lanreotide as well

as for oral octreotide formulation. They are short-lived and mostly

relate to drug-induced suppression of gastrointestinal motility and

secretion. Transient nausea, abdominal discomfort, fat malabsorption, diarrhea, and flatulence occur in one-third of patients, and

these symptoms usually remit within 2 weeks. Gallbladder contractility and emptying are attenuated; up to 30% of patients develop

long-term echogenic sludge or asymptomatic cholesterol gallstones.

Other side effects include mild glucose intolerance due to transient

insulin suppression, asymptomatic bradycardia, hypothyroxinemia,

and local injection site discomfort. Pasireotide is associated with

similar gastrointestinal side effects but with a higher prevalence of

glucose intolerance and new-onset diabetes mellitus.

GH RECEPTOR ANTAGONIST

Pegvisomant antagonizes endogenous GH action by blocking peripheral GH binding to its receptor. Consequently, serum

IGF-1 levels are suppressed, reducing the deleterious effects of

excess endogenous GH. Pegvisomant is administered by daily

A

B

C

FIGURE 380-7 Features of acromegaly/gigantism. A 22-year-old man with gigantism due to excess growth hormone is shown to the left of his identical twin. The increased

height and prognathism (A) and enlarged hand (B) and foot (C) of the affected twin are apparent. Their clinical features began to diverge at the age of ~13 years. (Reproduced

with permission from RF Gagel, IE McCutcheon. Images in clinical medicine. Pituitary gigantism. N Engl J Med 340:524, 1999.)

2914 PART 12 Endocrinology and Metabolism

subcutaneous injection (10–30 mg) and normalizes IGF-1 in ~70%

of patients. GH levels, however, remain elevated as the drug does

not target the pituitary adenoma. Side effects include reversible liver

enzyme elevation, lipodystrophy, and injection site pain. Tumor size

should be monitored by MRI.

Combined treatment with monthly SRLs and weekly or biweekly

pegvisomant injections has been used effectively in resistant

patients.

DOPAMINE AGONISTS

Very high doses of cabergoline (0.5 mg/d) may achieve short-lived

and modest GH therapeutic efficacy. Combined treatment with octreotide and cabergoline may induce additive biochemical control

compared with either drug alone.

RADIATION THERAPY

External radiation therapy or high-energy stereotactic techniques

are used as adjuvant therapy for acromegaly. An advantage of

radiation is that patient compliance with long-term treatment is

not required. Tumor mass is reduced, and GH levels are attenuated

over time. However, 50% of patients require at least 8 years for GH

levels to be suppressed to <5 μg/L; this level of GH reduction is

achieved in ~90% of patients after 18 years but represents suboptimal GH suppression. Patients may require interim medical therapy

for several years before attaining maximal radiation benefits. Most

patients also experience hypothalamic-pituitary damage, leading

to gonadotropin, ACTH, and/or TSH deficiency within 10 years

of therapy.

SUMMARY

Surgery is the preferred primary treatment for GH-secreting

microadenomas (Fig. 380-8). The high frequency of residual GH

hypersecretion after macroadenoma resection usually necessitates

adjuvant or primary medical therapy for these larger tumors.

Patients unable to receive or respond to unimodal medical treatment may benefit from combined treatments, or they can be offered

radiation. Very rarely, repeat surgery may be required.

■ CUSHING’S DISEASE (ACTH-PRODUCING ADENOMA)

(See also Chap. 386)

Etiology and Prevalence Pituitary corticotrope adenomas (Cushing’s disease) account for 70% of patients with endogenous causes of

Cushing’s syndrome. However, it should be emphasized that iatrogenic

hypercortisolism is the most common cause of cushingoid features.

Ectopic tumor ACTH production, cortisol-producing adrenal adenomas, adrenal carcinoma, and adrenal hyperplasia account for the

other causes; rarely, ectopic tumor CRH production is encountered.

ACTH-producing adenomas account for ~10–15% of all pituitary

tumors. Because the clinical features of Cushing’s syndrome often

lead to early diagnosis, most ACTH-producing pituitary tumors

are relatively small microadenomas. However, macroadenomas also

are seen and some ACTH-expressing adenomas are clinically silent.

Cushing’s disease is 5–10 times more common in women than in men.

These pituitary adenomas exhibit unrestrained ACTH secretion, with

GH-secreting pituitary tumor

Well controlled Surgery

Well controlled

Monitor IGF-1 Well controlled

Well controlled

Well controlled

Pegvisomant Reoperation

Primary SRLa

Cabergolineb

Increase SRL dose

Monitor IGF-1

Monitor IGF-1

Monitor IGF-1

Monitor IGF-1

Not controlled

Not controlled

Not controlled

Not controlled

Not controlled

SRL

Radiotherapy Pasireotide +

pegvisomant

SRL +

pegvisomant Pasireotide

FIGURE 380-8 Management of acromegaly. a

If curative surgery is not feasible. b

Consider in cases of mild postoperative GH/IGF-1 elevations. GH, growth hormone; IGF,

insulin-like growth factor; SRL, somatostatin receptor ligand (octreotide or lanreotide).

2915Pituitary Tumor Syndromes CHAPTER 380

resultant hypercortisolemia. However, they retain partial suppressibility in the presence of high doses of administered glucocorticoids,

providing the basis for dynamic testing to distinguish pituitary from

nonpituitary causes of Cushing’s syndrome.

Presentation and Diagnosis The diagnosis of Cushing’s syndrome presents two great challenges: (1) to distinguish patients with

pathologic cortisol excess from those with physiologic or other disturbances of cortisol production and (2) to determine the etiology of

pathologic cortisol excess.

Typical features of chronic cortisol excess include thin skin, central

obesity, hypertension, plethoric moon facies, purple striae and easy

bruisability, glucose intolerance or diabetes mellitus, gonadal dysfunction, osteoporosis, proximal muscle weakness, signs of hyperandrogenism (acne, hirsutism), and psychological disturbances (depression,

mania, and psychoses) (Table 380-7). Hematopoietic features of

hypercortisolism include leukocytosis, lymphopenia, and eosinopenia.

Immune suppression includes delayed hypersensitivity and infection

propensity. These protean yet commonly encountered manifestations

of hypercortisolism make it challenging to decide which patients mandate formal laboratory evaluation. Certain features make pathologic

causes of hypercortisolism more likely; they include characteristic

central redistribution of fat, thin skin with striae and bruising, and

proximal muscle weakness. In children and young females, early osteoporosis may be particularly prominent. The primary cause of death

is cardiovascular disease, but life-threatening infections and risk of

suicide are also increased.

Rapid development of features of hypercortisolism associated with

skin hyperpigmentation and severe myopathy suggests an ectopic

tumor source of ACTH. Hypertension, hypokalemic alkalosis, glucose

intolerance, and edema are also more pronounced in these patients.

Serum potassium levels <3.3 mmol/L are evident in ~70% of patients

with ectopic ACTH secretion but are seen in <10% of patients with

pituitary-dependent Cushing’s syndrome.

Laboratory Investigation The diagnosis of Cushing’s disease is

based on laboratory documentation of endogenous hypercortisolism.

Measurement of 24-h UFC is a precise and cost-effective screening

test. Alternatively, the failure to suppress plasma cortisol after an

overnight 1-mg dexamethasone suppression test can be used to identify patients with hypercortisolism. As nadir levels of cortisol occur

at night, elevated midnight serum or salivary samples of cortisol

are suggestive of Cushing’s disease. Basal plasma ACTH levels often

distinguish patients with ACTH-independent (adrenal or exogenous

glucocorticoid) from those with ACTH-dependent (pituitary, ectopic ACTH) Cushing’s syndrome. Mean basal ACTH levels are about

eightfold higher in patients with ectopic ACTH secretion than in

those with pituitary ACTH-secreting adenomas. However, extensive overlap of ACTH levels in these two disorders precludes using

ACTH measurements to make the distinction. Preferably, dynamic

testing based on differential sensitivity to glucocorticoid feedback

or ACTH stimulation in response to CRH or cortisol reduction is

used to distinguish ectopic from pituitary sources of excess ACTH

(Table 380-8). Very rarely, circulating CRH levels are elevated, reflecting ectopic tumor-derived secretion of CRH and often ACTH. For

further discussion of dynamic testing for Cushing’s syndrome, see

Chap. 386.

Most ACTH-secreting pituitary tumors are <5 mm in diameter, and

about half are undetectable by sensitive MRI. The high prevalence of

incidental pituitary microadenomas diminishes the ability to distinguish ACTH-secreting pituitary tumors accurately from nonsecreting

incidentalomas.

Inferior Petrosal Venous Sampling Because pituitary MRI with

gadolinium enhancement is insufficiently sensitive to detect small

(<2 mm) pituitary ACTH-secreting adenomas, bilateral inferior petrosal sinus ACTH sampling before and after CRH administration may

be required to distinguish these lesions from ectopic ACTH-secreting

tumors that may have similar clinical and biochemical characteristics.

Simultaneous assessment of ACTH in each inferior petrosal vein and in

the peripheral circulation provides a strategy for confirming and localizing pituitary ACTH production. Sampling is performed at baseline

and 2, 5, and 10 min after intravenous bovine CRH (1 μg/kg) injection.

TABLE 380-7 Clinical Features of Cushing’s Syndrome (All Ages)

SYMPTOMS/SIGNS FREQUENCY, %

Obesity or weight gain (>115% ideal body weight) 80

Thin skin 80

Moon facies 75

Hypertension 75

Purple skin striae 65

Hirsutism 65

Menstrual disorders (usually amenorrhea) 60

Plethora 60

Abnormal glucose tolerance 55

Impotence 55

Proximal muscle weakness 50

Truncal obesity 50

Acne 45

Bruising 45

Mental changes 45

Osteoporosis 40

Edema of lower extremities 30

Hyperpigmentation 20

Hypokalemic alkalosis 15

Diabetes mellitus 15

Source: Adapted with permission from MA Magiokou et al, in Wierman ME:

Diseases of the Pituitary. Totowa, NJ: Humana; 1997.

TABLE 380-8 Differential Diagnosis of ACTH-Dependent

Cushing’s Syndromea

ACTH-SECRETING

PITUITARY TUMOR

ECTOPIC ACTH

SECRETION

Etiology Pituitary corticotrope

adenoma

Plurihormonal adenoma

Bronchial, abdominal

carcinoid

Small-cell lung cancer

Thymoma, other sources

Sex F > M M > F

Clinical features Slow onset Rapid onset

Pigmentation

Severe myopathy

Serum potassium

<3.3 μg/L

<10% 75%

24-h UFC High High

Basal ACTH level Inappropriately high Very high

Dexamethasone

suppression

1 mg overnight

Low-dose (0.5 mg q6h) Cortisol >5 μg/dL Cortisol >5 μg/dL

High-dose (2 mg q6h) Cortisol <5 μg/dL Cortisol >5 μg/dL

UFC >80% suppressed Microadenomas: 90%

Macroadenomas: 50%

10%

Inferior petrosal sinus

sampling (IPSS)

Basal

 IPSS: peripheral >2 <2

CRH-induced

 IPSS: peripheral >3 <3

a

ACTH-independent causes of Cushing’s syndrome are diagnosed by suppressed

ACTH levels and an adrenal mass in the setting of hypercortisolism. Iatrogenic

Cushing’s syndrome is excluded by history.

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing

hormone; F, female; M, male; UFC, urinary free cortisol.

2916 PART 12 Endocrinology and Metabolism

Pituitary

 irradiation

ACTH-dependent

hypercortisolism

Biochemical

 cure

Persistent

 hypercortisolism

Consider chest/abdomen

imaging

Ectopic ACTH excluded

Glucocorticoid

 replacement,

 if needed

Follow-up:

Steroidogenic

 inhibitors

Glucocorticoid

 receptor

 antagonist

and/or

and/or

and/or

Pituitary MRI

Petrosal sinus

 ACTH sampling*

ACTH-secreting

 pituitary adenoma

Transsphenoidal surgical

 resection

Adrenalectomy

Pasireotide

Serial biochemical

 and MRI

 evaluation

?Irradiation

Risk of Nelson’s

syndrome

FIGURE 380-9 Management of Cushing’s disease. ACTH, adrenocorticotropin

hormone; MRI, magnetic resonance imaging; *

, Not usually required.

An increased ratio (>2) of inferior petrosal:peripheral vein ACTH

confirms pituitary Cushing’s syndrome. After CRH injection, peak

petrosal:peripheral ACTH ratios ≥3 confirm the presence of a pituitary

ACTH-secreting tumor. The sensitivity of this test is >95%, with very

rare false-positive results. False-negative results may be encountered in

patients with aberrant venous drainage. Petrosal sinus catheterizations

are technically difficult, and ~0.05% of patients develop neurovascular

complications. The procedure should not be performed in patients

with hypertension, in patients with known cerebrovascular disease, or

in the presence of a well-visualized pituitary adenoma on MRI.

TREATMENT

Cushing’s Disease

Selective transsphenoidal resection is the treatment of choice for

Cushing’s disease (Fig. 380-9). The remission rate for this procedure is ~80% for microadenomas but <50% for macroadenomas.

However, surgery is rarely successful when the adenoma is not visible on MRI. After successful tumor resection, most patients experience a postoperative period of symptomatic ACTH deficiency that

may last up to 12 months. This usually requires low-dose cortisol

replacement, as patients experience steroid withdrawal symptoms

and have a suppressed hypothalamic-pituitary-adrenal axis. Biochemical recurrence occurs in ~5% of patients in whom surgery

was initially successful. As persistent hypercortisolemia may cause

blood clotting defects, prophylactic postoperative thromboembolic

management has been advocated for vulnerable patients.

When initial surgery is unsuccessful, repeat surgery is sometimes indicated, particularly when a pituitary source for ACTH is

well documented. In older patients, in whom issues of growth and

fertility are less important, hemi- or total hypophysectomy may be

necessary if a discrete pituitary adenoma is not recognized. Pituitary irradiation may be used after unsuccessful surgery, but it cures

only ~15% of patients. Because the effects of radiation are slow and

only partially effective in adults, adrenal-targeted steroidogenic

inhibitors are used in combination with pituitary irradiation to

block adrenal responses to persistently high ACTH levels.

Pasireotide LAR 10–40 mg intramuscularly, an SRL with high

affinity for SST5 > SST2 receptor subtypes, may control hypercortisolemia in a subset of patients with ACTH-secreting pituitary

tumors when surgery is not an option or has not been successful.

The drug lowers plasma ACTH levels and normalizes 24-h UFC

levels in ~20% of patients, and up to 40% of patients may experience

pituitary tumor shrinkage. Side effects are similar to those encountered for other SRLs and include transient abdominal discomfort,

diarrhea, nausea, and gallstones (20% of patients). Notably, hyperglycemia and new-onset diabetes develop in up to 70% of patients,

likely due to suppressed pancreatic secretion of insulin and incretins. Because patients with hypercortisolism are insulin-resistant,

hyperglycemia should be rigorously managed. The drug requires

consistent long-term administration.

Osilodrostat (2 mg twice daily titrated up to 30 mg twice daily),

an oral 11β-hydroxylase inhibitor that blocks adrenal gland cortisol

biosynthesis, normalized 24-h UFC in 86% of patients. Mild, mostly

transient gastrointestinal symptoms are common. Patients should

be closely monitored for development of hypocortisolism and adrenal insufficiency. Elevated adrenal hormone precursors may lead

to hypokalemia and hypertension. QTc prolongation and possibly

increased tumor volume are also reported.

Ketoconazole, an imidazole derivative antimycotic agent, inhibits several P450 enzymes and effectively lowers cortisol in most

patients with Cushing’s disease when administered twice daily

(600–1200 mg/d). Elevated hepatic transaminases, gynecomastia,

impotence, gastrointestinal upset, and edema are common side

effects.

Mifepristone (300–1200 mg/d), a glucocorticoid receptor antagonist, blocks peripheral cortisol action and is approved to treat

hyperglycemia in Cushing’s disease. Because the drug does not

target the pituitary tumor, both ACTH and cortisol levels remain

elevated, thus obviating a reliable circulating biomarker. Side effects

are largely due to general antagonism of other steroid hormones

and include hypokalemia, endometrial hyperplasia, hypoadrenalism, and hypertension.

Metyrapone (2–4 g/d) inhibits 11β-hydroxylase activity and normalizes plasma cortisol in up to 75% of patients. Side effects include

nausea and vomiting, rash, and exacerbation of acne or hirsutism.

Mitotane (3–6 g/d orally in four divided doses) suppresses cortisol

hypersecretion by inhibiting 11β-hydroxylase and cholesterol sidechain cleavage enzymes and by destroying adrenocortical cells. Side

effects of mitotane include gastrointestinal symptoms, dizziness,

gynecomastia, hyperlipidemia, skin rash, and hepatic enzyme elevation. It also may lead to hypoaldosteronism. Other agents include

aminoglutethimide (250 mg tid), trilostane (200–1000 mg/d), cyproheptadine (24 mg/d), and IV etomidate (0.3 mg/kg per h). Glucocorticoid insufficiency is a potential side effect of agents used to block

steroidogenesis.

The use of steroidogenic inhibitors has decreased the need for

bilateral adrenalectomy. Surgical removal of both adrenal glands

corrects hypercortisolism but may be associated with significant

morbidity rates and necessitates permanent glucocorticoid and

mineralocorticoid replacement. Adrenalectomy in the setting of

residual corticotrope adenoma tissue predisposes to the development of Nelson’s syndrome, a disorder characterized by rapid

pituitary tumor enlargement and increased pigmentation secondary to high ACTH levels. Prophylactic radiation therapy may be

indicated to prevent the development of Nelson’s syndrome after

adrenalectomy.

■ NONFUNCTIONING AND GONADOTROPINPRODUCING PITUITARY ADENOMAS

Etiology and Prevalence Nonfunctioning pituitary adenomas

include those that secrete little or no pituitary hormones into the systemic circulation, as well as tumors that produce too little hormone

to result in recognizable clinical features. They are the most common

type of pituitary adenoma and are usually macroadenomas at the time

of diagnosis because clinical features are not apparent until tumor mass

effects occur. Based on immunohistochemistry, most clinically nonfunctioning adenomas can be shown to originate from gonadotrope

cells or from pituitary null cells. These tumors typically produce small