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Review Article
Pituitary-Tumor Endocrinopathies
Shlomo Melmed, M.D.
P
ituitary adenomas account for approximately 15% of intracra- From the Pituitary Center, Department
nial tumors.1 Management of these benign tumors requires diagnosis of the of Medicine, Cedars-Sinai Medical Center,
Los Angeles. Address reprint requests
specific intrasellar disease and comprehensive, multidisciplinary treatment to Dr. Melmed at Cedars-Sinai Medical
of local mass effects and peripheral endocrinopathies.2 Since tumors can produce Center, 8700 Beverly Blvd., Rm. 2015, Los
different hormones, their consequences and management vary widely. Angeles, CA 90048.
Cl a ssific at ion
Microadenomas are less than 10 mm in diameter. Regardless of the cell origin,
macroadenomas (≥10 mm) may impinge on critical parasellar vascular and neural
structures, with resultant visual-field defects, including bitemporal hemianopia
and decreased acuity, and headaches.5 Immunocytochemical evaluation of differ-
entiated, cell-specific pituitary transcription factors and hormones,11 as well as
clear biochemical, imaging, and clinical phenotypes, define tumor characteristics
Aneuploidy
Copy-number alterations
Germline or somatic mutations Paracrine stromal events
Unknown driver changes
Cell-cycle dysregulation Epigenetic changes
Optic
chiasm Cranial
nerves
V1
Cavernous sinus V2
Sphenoid sinus
Normal pituitary Microadenoma Macroadenoma Aggressive adenoma
Proliferative
Senescence
restraint
Secreted hormone Growth hormone Prolactin Corticotropin Thyrotropin Luteinizing hormone or None
follicle-stimulating hormone
or subunits
Adenoma subtypes Densely granulated Densely granulated Densely granulated Null cell
Sparsely granulated Sparsely granulated Sparsely granulated Silent gonadotroph
Mammosomatotroph Acidophil stem cell Crooke’s cell Silent corticotroph
Mixed somatolactotroph Silent somatotroph
Acidophil stem cell
Clinical phenotype Acromegaly Hypogonadism Cushing’s disease Hyperthyroidism Hypergonadism Pituitary failure
Gigantism Infertility Hypercortisolemia
Galactorrhea
and endocrine syndromes, allowing for indi- adenomas have persistent or progressive post-
vidualized treatment5,12 (Table 1). operative growth for up to four decades or even
Evaluation of a pituitary mass should include longer, with local invasion and an increased
magnetic resonance imaging (MRI) and visual- percentage of cells positive for Ki-67.11,15 In one
field examination for accurate tumor localiza- study, more than 40% of 50 aggressive pituitary
tion and assessment of local compressive mass adenomas showed cavernous sinus invasion.16
effects. Hormone hypersecretion should be as- Tumors particularly prone to invasive growth
sessed to distinguish nonsecretory from secretory and recurrence include those arising from
tumors13 (Table 2), and pituitary-reserve function sparsely granulated somatotrophs, silent corti-
should be tested.14 cotrophs, corticotroph Crooke’s cells (CK20-
Approximately 30% of surgically resected positive nonneoplastic cells with a prominent
* Hormones in parentheses are those secreted by the adenoma. CNS denotes central nervous system, CSF cerebrospinal
fluid, and SST2 and SST5 somatostatin receptor subtype 2 and subtype 5, respectively.
cytoplasmic hyaline ring that displaces the nor- accessible cavernous sinus tumor tissue, or dural
mal basophilic granules of corticotropic cells), nesting of hormone-secreting tumor cells.
and lactotrophs in middle-aged or older men.17 Radiation therapy, administered by means of
Pituitary carcinomas are exceedingly rare. They conventional external-beam or proton-beam tech-
account for less than 0.5% of pituitary tumors niques, or stereotactic radiosurgery requires local
and respond inconsistently to temozolomide.5 expertise and is generally reserved for tumors
that are resistant to medical treatment or are not
controlled by surgery. Tumor growth is usually
M a nagemen t
arrested over a period of several years, and ade-
Comprehensive management of a pituitary ade- noma-derived hormone hypersecretion may per-
noma includes transsphenoidal surgical resec- sist during the initial years.19 In most patients,
tion, irradiation, and medical therapy, each with pituitary failure develops within 10 years after
advantages and disadvantages that are specific radiation therapy, and lifelong hormone replace-
to the type of adenoma (Table 1). Serial or com- ment is required. Deterioration in vision and new
bined approaches may be required. cranial-nerve palsies are rarely observed.19 Mortal-
Surgery is generally indicated for masses that ity from cerebrovascular causes is increased by a
are 10 mm or more in diameter and those that factor of 4.42 (95% confidence interval [CI], 2.71 to
have extrasellar extension or central compressive 7.22) after conventional pituitary irradiation, with
features, as well as for persistent tumor growth, 16 observed deaths versus 3.6 expected deaths.20
especially if vision is compromised or threat-
ened.18 Resection may alleviate compression of Gene t ic S y ndrome s
vital structures and reverse compromised pitu-
itary hormone secretion. Predictors of remission Pituitary adenomas may occur in association
include experience of the surgeon, relatively low with several very rare genetic syndromes. Multi-
levels of secreted hormone (if the level is elevated ple endocrine neoplasia type 1 is associated with
at all), and small tumors. Postoperatively, hypo- pituitary adenomas as well as parathyroid and
pituitarism may develop, as may diabetes insipi- pancreatic-islet tumors and, less commonly, carci-
dus and cerebrospinal fluid leaks. Approximately noid, thyroid, and adrenal tumors. The McCune–
10% of patients have a recurrence over a period Albright syndrome is characterized by polyostotic
of 10 years after surgery. Persistent tumor post- fibrous dysplasia and cutaneous pigmentation,
operatively may reflect incomplete resection, in- with sexual precocity, hyperthyroidism, hypercor-
Features Pregnancy
Hyperprolactinemia Rule out secondary causes
Drugs
Amenorrhea,
Neuroleptics
oligomenorrhea,
D2 receptor blockers
infertility
Estrogens
Impotence,
Opiates
oligospermia,
Antidepressants
decreased libido Consider nonsecreting mass
Pituitary MRI Parasellar mass
Galactorrhea resulting in the stalk effect Hypothalamic irradiation
Osteoporosis
Chest-wall injury
Renal failure
Assess pituitary-
reserve function
Microprolactinoma Macroprolactinoma
Dose adjustment
Prolactin level not reduced Prolactin level normalized Prolactin level reduced
Unacceptable side effects
No tumor shrinkage Sexual function restored Sexual function restored
Tumor shrinkage Tumor persists with no local
compressive effects
Decrease dose
Maximize dose Continue medication Continue medication
Consider surgery if hyper-
prolactinemia or mass
persists
Reconsider diagnosis
Surgery or radiotherapy
of nonsecreting adenoma
required in rare cases
with stalk effect
Clinical Features and Diagnosis ing 385 consecutive patients with nonsecreting
Nonsecreting adenomas may be unrecognized adenomas, 289 had macroadenomas and 66 had
for years and are usually diagnosed because of giant adenomas (>4 cm in diameter), with most
local mass effects or hypogonadism or are de- of the patients presenting with headache or dis-
tected incidentally. Chiasmal compression causes turbances in vision.26 Approximately 10% of pa-
gradual, progressive deficits in vision, and about tients with nonsecreting adenomas present with
two thirds of patients have decreased gonadotro- pituitary apoplexy (characterized by the abrupt
pin levels and hypogonadism.25 In a study involv- onset of retroorbital pain, altered consciousness,
ized by aggressive growth and florid disease.12 incidence of cancer. Nevertheless, colonoscopy
In very rare cases, extrapituitary acromegaly is should be performed at diagnosis and subse-
caused by neuroendocrine tumor production of quently, according to published guidelines.59
growth hormone or growth hormone–releasing A 20-year study showed higher mortality rates
hormone.46,47 among 333 patients with acromegaly than among
4995 controls (113 deaths [34%] vs. 1334 deaths
Clinical Features [27%]; odds ratio 1.6; 95% CI, 1.2 to 2.2).60
Approximately 70% of patients with acromegaly Deaths associated with acromegaly are due to
have an invasive macroadenoma at diagnosis. cardiovascular, respiratory, and cerebrovascular
Coexisting conditions include headache and in- disorders, with cancer also reported as a cause
sidious acral and soft-tissue changes. The diag- of death in more recent years. Persistently elevat-
nosis of acromegaly can be delayed by a mean of ed growth hormone and IGF-1 levels, diabetes,
approximately 10 years after the onset of symp- hypertension, older age, pituitary irradiation,
toms.48 Patients may first seek dental, orthope- and inadequate treatment of adrenal insuffi-
dic, rheumatologic, or cardiac care. In one study, ciency all contribute significantly to mortality.61
approximately 20% of 324 patients sought care Gigantism, a rare condition, is due to exces-
because of an altered facial appearance, enlarged sive secretion of growth hormone before epiphy-
extremities, or both.49 Other features include seal closure. The disorder may be associated with
increased shoe or ring size, voice deepening, germline AIP mutations, the McCune–Albright
the carpal tunnel syndrome, hyperhidrosis, and syndrome, or acidophilic stem-cell adenomas;
frontal-skull bossing and coarse oily skin. Prog- X-linked gigantism is characterized by Xq26.3
nathism leads to incisor separation and jaw chromosomal microduplications, resulting in
malocclusion. Obstructive sleep apnea and ex- accelerated gigantism and overexpressed tumor
cessive snoring are hallmarks of uncontrolled GPR101 (a gene for a G-protein–coupled recep-
acromegaly. Arthropathy is reported in approxi- tor).62 Surgical resection with adjuvant growth
mately 70% of patients, with polyarticular arthri- hormone suppression is required to maintain
tis, osteophytosis, dorsal kyphosis, and vertebral remission and prevent long-term tissue exposure
fractures.48 Coexisting cardiovascular conditions to excess growth hormone and IGF-1.63
include hypertension, arrhythmias, and left ven-
tricular dysfunction, with an increased aortic- Diagnosis
root diameter.50 Despite biochemical control, IGF-1 levels that are elevated for the patient’s age
cardiovascular disorders may persist.51 Growth are highly specific for acromegaly and also cor-
hormone induces insulin resistance, with glu- relate with indexes of disease activity.64 The
cose intolerance,52 and patients with acromegaly pulsatile nature of adenoma growth hormone
have an increased risk of diabetes, as compared secretion precludes reliance on a random mea-
with a control cohort from the general popula- surement for diagnosis. Instead, the diagnosis is
tion (hazard ratio, 4.0 [95% CI, 2.7 to 5.8]; rate established by using an ultrasensitive assay to
per 1000 persons, 12.1 cases [95% CI, 9.0 to document nadir growth hormone levels of more
16.4] vs. 3.4 cases [95% CI, 2.9 to 4.1]).53 About than 0.4 μg per liter during a 75-g glucose
30% of patients have high prolactin levels, often load.65 Growth hormone levels are log-linearly
with galactorrhea. concordant with IGF-1 levels.66 Postoperatively,
Hypertrophic colonic mucosal folds and diver- IGF-1 levels may remain elevated for months
ticulae can occur in patients with acromegaly.54,55 despite control of growth hormone secretion.
In a case–control study, colonic polyps were
detected in 32% of 165 patients, with an esti- Treatment
mated relative risk of 6.21 (95% CI, 4.08 to Comprehensive treatment goals for acromegaly
9.48).56 Studies involving more than 2000 pa- include ablating or controlling the pituitary
tients showed an increased incidence of cancer, mass, suppressing growth hormone and IGF-1
with an overall standardized incidence ratio of hypersecretion, and preventing the development
1.5 (95% CI, 1.2 to 1.8), mostly accounted for by of associated disorders while maintaining ante-
colorectal, kidney, and thyroid cancers.57,58 How- rior pituitary function.59 In 13 studies involving
ever, other studies have shown no increase in the 1018 patients who underwent surgical resection,
control of growth hormone secretion and IGF-1 ferase levels, injection-site inflammation, and
levels was achieved in 73% of patients with micro- lipodystrophy. Growth hormone axis blockade
adenomas and 61% of patients with macroade- with growth hormone receptor–directed pegviso-
nomas.67-69 However, patients with macroadeno- mant combined with pituitary-directed somato
mas that invade the cavernous sinus invariably statin receptor ligand offers greater efficacy than
show persistent growth hormone hypersecretion either drug alone.81
after surgery. In a study involving 371 patients Treatment approaches have advantages and
treated with radiosurgery, biochemical remission disadvantages for individualizing patient care
was reported in 59% of the patients, with a and maximizing growth hormone and IGF-1
mean time to remission of 38 months and a control (Table 1).12 Patients should be monitored
mean time to recurrence of 17 months.70 for symptoms affecting the quality of life, in-
Dopamine agonists have been proposed for cluding anxiety. Management of coexisting con-
patients with mild disease, and the addition of ditions, especially high blood pressure, cardiac
cabergoline may normalize IGF-1 levels in some dysfunction, and sleep apnea, as well as elevated
patients with disease that is resistant to somato blood sugar levels, is important to reduce the
statin therapy.71 The somatostatin receptor ligands risk of death.
octreotide and lanreotide bind SST2 (somatosta-
tin receptor subtype 2), inhibiting growth hor- Cushing’s Dise a se
mone secretion.72 A meta-analysis of 90 studies
involving 4464 patients treated with somatosta- Corticotropin-secreting corticotroph adenomas,
tin receptor ligands showed overall control of which account for up to 15% of pituitary tu-
growth hormone secretion and of IGF-1 levels in mors, with an incidence of 1.6 cases per 1 mil-
56% and 55% of the patients, respectively.73 In a lion persons,82 are typically small (approximately
meta-analysis involving 1685 patients in 41 stud- 6 mm in diameter) and are 5 to 10 times as
ies, 53% of patients had a reduction in tumor common in women as in men. Excessive secre-
mass.74 Efficacy may be enhanced by increasing tion of corticotropin leads to adrenal hypercor-
the dose and injection frequency.75 Soft-tissue tisolemia. Corticotroph adenomas account for
swelling and headache usually resolve, sleep ap- approximately 70% of cases of Cushing’s syn-
nea abates, and left ventricular function im- drome, with iatrogenic hypercortisolism, ectopic
proves,48 but hypertension may persist. Tumor corticotropin or corticotropin-releasing hormone
SST2 expression, densely granulated tumor, and production, and cortisol-producing adrenal le-
hypointensity on T2-weighted MRI are important sions accounting for the rest.83
markers of treatment responsiveness.12,76 Tran-
sient gastrointestinal side effects, occurring in Clinical Features
approximately 30% of patients, include loose Typical cushingoid features include plethoric
stools and nausea. Gallbladder sludge occurs in moon facies with thin skin, purple striae, and
up to 25% of patients, although cholecystitis is easy bruising. Central obesity, hypertension, glu-
very rare. Asymptomatic sinus bradycardia also cose intolerance or diabetes, and, especially in
occurs. Octreotide and lanreotide do not gener- younger women, menstrual disturbances and
ally disrupt glucose homeostasis, but pasireotide, osteoporosis are observed, as are proximal mus-
a long-acting hexapeptide somatostatin multi- cle wasting and weakness, acne, hirsutism, depres-
receptor ligand, results in hyperglycemia and sion, psychoses, and susceptibility to infection.84
new-onset diabetes in about 60% of patients.77 The disorder may be indolent or clinically
Pegvisomant, a growth hormone receptor florid, with a high mortality rate if inadequately
antagonist that blocks peripheral growth hor- controlled. In a study involving 502 unselected
mone action and subsequent IGF-1 production,78 patients, the overall standardized mortality ratio
is useful for patients with disease that is resis- was 2.5 (95% CI, 2.1 to 2.9), with 133 observed
tant to somatostatin receptor ligands, as well as deaths versus 54 expected deaths; cardiovascular
patients with hyperglycemia, since the drug en- disease accounted for most of the excess deaths.85
hances insulin sensitivity.79 A surveillance study Mortality was also elevated among the patients
showed IGF-1 control in 63% of 1288 patients.80 with biochemical remission (standardized mor-
Side effects include elevated hepatic aminotrans- tality ratio, 1.9 [95% CI, 1.5 to 2.3]), with 89
observed deaths versus 47 expected deaths. efficacy of this treatment is delayed for several
Other causes of death include infections and years, and approximately 30% of patients have a
suicide. Rapid-onset hypercortisolism with skin relapse.
hyperpigmentation and severe myopathy sug- Adrenalectomy may immediately reverse hy-
gests an ectopic tumor source of corticotropin, percortisolism. However, lifelong replacement of
often associated with hypertension and hypo- adrenal hormones is challenging. Patients who
kalemic alkalosis.83 undergo adrenalectomy are also at risk for adre-
nal crisis and Nelson’s syndrome (pituitary en-
Diagnosis largement and development of corticotropin-
Accurate diagnosis of Cushing’s disease can be secreting pituitary adenomas, which often have
challenging.83 Approximately 40% of corticotro- an invasive growth pattern).
pin-secreting corticotroph tumors are not visible Adrenal-targeted medical therapy may offer
on imaging, and at least 10% of persons in the clinical and biochemical improvement, but most
general population have small, clinically silent studies of such treatment have not been rigor-
microadenomas. The disorder may therefore be ously controlled, and the results are often incon-
overdiagnosed, especially since clinical features sistent.89 Adrenal steroidogenesis inhibitors block
of hypercortisolemia overlap with other, much hypercortisolemia but do not target the pituitary
more common disorders, including obesity, hyper- tumor. Ketoconazole, an antifungal imidazole,
tension, glucose intolerance, and osteoporosis. normalizes urinary free cortisol levels in 50% of
The diagnosis of pathologic hypercortisolemia patients.90 Side effects include nausea, headache,
is established on the basis of clinical features of low testosterone levels, reversible elevated liver
hypercortisolism coupled with reproducible evi- enzyme levels, and in rare cases, hepatotoxicity.
dence of failure to suppress plasma cortisol at Metyrapone controls urinary free cortisol levels
8 a.m. to a level below 1.8 μg per deciliter after in about 50% of patients, and accumulated ste-
the administration of 1 mg of dexamethasone at roid precursors may cause acne, hirsutism, hyper-
11 p.m. or elevated 24-hour urinary free cortisol tension, and hypokalemia. Mitotane, an adreno-
levels and midnight salivary cortisol values.84 lytic agent, is used mainly for adrenal carcinoma.
Basal corticotropin levels are usually inappropri- Mifepristone, a glucocorticoid receptor antago-
ately high, and suppressibility of corticotropin nist, is approved for the treatment of hypergly-
by glucocorticoids may distinguish a pituitary cemia associated with Cushing’s syndrome in
tumor from an ectopic source. patients in whom surgery has failed or who are
Since the results of repeated urinary free cor- not surgical candidates. Since mifepristone blocks
tisol and midnight salivary cortisol measure- the action of cortisol, corticotropin and urinary
ments may vary, bilateral inferior petrosal sinus free cortisol levels are increased.91 Adrenal fail-
sampling of corticotropin levels may be required ure, hypokalemia, and excessive vaginal bleeding
to confirm the diagnosis. A central-to-peripheral may limit the use of this agent.
corticotropin gradient that exceeds 2 before and Pituitary-targeted drugs include high-dose
after the administration of corticotropin-stimu- cabergoline (up to 1 mg daily), which controls
lating hormone definitively localizes a cortico- hypercortisolism in up to 30% of patients, al-
troph tumor source with more than 95% sensi- though therapeutic efficacy is often not main-
tivity. tained in the long term. Pasireotide blocks ade-
noma-derived corticotropin secretion, normalizes
Treatment urinary free cortisol levels in approximately 40%
Selective transsphenoidal adenomectomy is rec- of patients with mild disease, and improves clini-
ommended as initial therapy for Cushing’s dis- cal features. Hyperglycemia develops in most
ease, with remission achieved in approximately patients.92,93
75% of patients and recurrence seen in approxi-
mately 10%.86 Although more radical surgery Th y ro t ropin-Secr e t ing T umor s
offers the potential for total adenoma resection,
complication rates are higher and pituitary dam- Accounting for approximately 1% of adenomas,
age is more likely with total resection.87 Radia- thyrotropin-secreting tumors lead to elevated or
tion therapy may control the disease,88 but the inappropriately suppressed thyrotropin levels
with normal or elevated thyroid hormone levels.94 tution, from Pfizer, consulting fees from Ionis, Midatech, and
Chiasma, grant support from Ono, advisory board fees from
Resection and adjuvant treatment are required Strongbridge, and advisory fees and travel support from Ipsen.
for adequate biochemical outcomes. No other potential conflict of interest relevant to this article
was reported.
Dr. Melmed reports receiving grant support, advisory board Disclosure forms provided by the author are available with the
fees, and fees for serving as a course mentor, paid to his insti- full text of this article at NEJM.org.
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