Pituitary adenoma

For patient information click here

Pituitary adenoma Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Pituitary adenoma from other Diseases
Epidemiology and Demographics
Risk Factors
Natural history, Complications and Prognosis
Diagnosis
Staging
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Pituitary adenoma On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Pituitary adenoma All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Pituitary adenoma
CDC on Pituitary adenoma
Pituitary adenoma in the news
Blogs on Pituitary adenoma
Directions to Hospitals Treating Pituitary adenoma
Risk calculators and risk factors for Pituitary adenoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omar Elshafei, MD[2] Ahmad Al Maradni, M.D. [3]

Synonyms and keywords:: Pituitary macroadenoma; Pituitary microadenoma; Pituitary adenomas, Adenoma of the pituitary gland; Pituitary non-functioning adenoma; Gonadotropic adenoma; Thyrotropic adenoma; TSH-oma; Plurihormonal pituitary adenoma; Null cell adenomas; Pituitary neuroendocrine tumor; PitNET

Overview

Pituitary adenomas are neoplasms arising from the hormone-producing cells of the anterior pituitary gland. The 2022 World Health Organization classification renames them pituitary neuroendocrine tumors (PitNETs) and subtypes them by transcription factor lineage (PIT1, TPIT and SF1), whereas clinical societies continue to use the term adenoma because the vast majority are benign and do not shorten life expectancy. Tumors are classified by size as microadenomas (smaller than 10 mm) or macroadenomas (10 mm or larger), and by secretory status as functioning tumors, which cause hyperprolactinemia, acromegaly or gigantism, Cushing's disease or, rarely, central hyperthyroidism, or as clinically nonfunctioning tumors, which present with mass effect or are discovered incidentally.

Pituitary adenomas are common. A systematic review estimated a pooled prevalence of 16.7% in autopsy and imaging studies, and clinically evident adenomas affect approximately 1 in 1100 people. Prolactinomas are the most frequent clinically apparent subtype, followed by nonfunctioning adenomas, somatotroph tumors and corticotroph tumors. Most tumors are sporadic, but germline predisposition, including multiple endocrine neoplasia type 1, familial isolated pituitary adenoma and AIP mutations, is more frequent in young and familial cases. Macroadenomas may compress the optic chiasm and cause visual field defects, headache and hypopituitarism, and hemorrhage or infarction of an adenoma causes pituitary apoplexy, a medical emergency.

Evaluation requires dedicated pituitary magnetic resonance imaging, biochemical testing for hormone excess and deficiency, and formal visual field assessment when the tumor approaches the optic apparatus. Dopamine agonist therapy, preferably with cabergoline, is first-line treatment for most prolactinomas, and transsphenoidal surgery is an accepted alternative for selected microprolactinomas. Transsphenoidal surgery is first-line for somatotroph, corticotroph and thyrotroph tumors and for nonfunctioning adenomas causing mass effect, whereas asymptomatic nonfunctioning adenomas can be followed with surveillance imaging. Medical options include somatostatin receptor ligands (including oral formulations), pegvisomant, steroidogenesis inhibitors and glucocorticoid receptor antagonists; radiotherapy is a second- or third-line option, and temozolomide is the first-line chemotherapy for aggressive tumors. Lifelong follow-up is required because hypopituitarism, active acromegaly and Cushing's disease are associated with excess mortality.

Historical Perspective

• In 1993, Knosp and colleagues proposed a magnetic resonance imaging classification of cavernous sinus invasion based on the position of the tumor relative to the intracavernous and supracavernous internal carotid artery, which remains the standard grading system for parasellar extension.
• In 1994, a randomized comparison in 459 women with hyperprolactinemic amenorrhea showed that cabergoline was more effective and better tolerated than bromocriptine.
• In 2000, a 12-week randomized, double-blind, placebo-controlled trial in 112 patients established the growth hormone receptor antagonist pegvisomant as a treatment for acromegaly.
• In 2006, germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) were identified as a cause of low-penetrance pituitary adenoma predisposition.
• In 2013, a five-tier clinicopathological classification based on invasion and proliferation was validated in 410 patients followed for 8 years after surgery.
• In 2014, X-linked acrogigantism (X-LAG), caused by Xq26.3 microduplications involving GPR101, was described as a cause of early childhood gigantism, and somatic mutations in the deubiquitinase gene USP8 were subsequently identified in corticotroph adenomas causing Cushing's disease.
• In 2017, the International Pituitary Pathology Club proposed replacing the term pituitary adenoma with pituitary neuroendocrine tumor (PitNET). The fifth edition of the WHO classification of endocrine and neuroendocrine tumors (2022) adopted the PitNET terminology, whereas the Pituitary Society-coordinated Pituitary Neoplasm Nomenclature (PANOMEN) workshop concluded in 2021 that there was not yet a case for adopting it.
• In 2022, an international working group proposed renaming central diabetes insipidus arginine vasopressin deficiency (AVP-D) and nephrogenic diabetes insipidus arginine vasopressin resistance (AVP-R).
• Since 2020, phase 3 randomized trials have established oral somatostatin receptor ligand therapy for acromegaly, first with oral octreotide capsules and then with the once-daily nonpeptide somatostatin receptor type 2 agonist paltusotine.

Classification

Pituitary adenomas are classified by size, by clinical secretory status, by histopathological lineage according to the 2022 WHO classification, and by invasiveness and proliferation.

Classification by Size

Category	Maximum diameter	Clinical relevance
Microadenoma	Smaller than 10 mm	Usually present with hormone excess or are found incidentally; nonfunctioning microadenomas have a low probability of growth
Macroadenoma	10 mm or larger	Account for 48% of pituitary adenomas; may cause visual field defects, headache and hypopituitarism
Giant adenoma	Conventionally 40 mm or larger	Recognized as a separate size category in prognostic clinicopathological classification

Classification by Secretory Status

Tumor type	Hormone in excess	Clinical syndrome	Approximate proportion of pituitary adenomas
Lactotroph tumor (prolactinoma)	Prolactin	Hypogonadism, infertility and galactorrhea	53%
Somatotroph tumor	Growth hormone	Acromegaly in adults; gigantism in children	12%
Corticotroph tumor	Adrenocorticotropic hormone	Cushing's disease	4%
Thyrotroph tumor (TSH-secreting adenoma)	Thyroid-stimulating hormone	Central hyperthyroidism with elevated free thyroid hormones and a nonsuppressed TSH	Very rare
Clinically nonfunctioning tumor (mostly gonadotroph tumors; also null cell and clinically silent tumors)	None clinically evident	Mass effect, hypopituitarism or incidental discovery	30%

2022 WHO Classification of Pituitary Neuroendocrine Tumors

The fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors distinguishes anterior lobe (adenohypophyseal) tumors, namely PitNETs, pituitary blastoma and the two types of craniopharyngioma, from posterior lobe tumors (the pituicyte tumor family) and hypothalamic neuronal tumors. PitNETs are subtyped by tumor cell lineage, cell type and related characteristics, and routine immunohistochemistry for the pituitary transcription factors PIT1, TPIT and SF1, together with GATA3 and estrogen receptor alpha (ERα), is endorsed.

Lineage (transcription factor)	PitNET types and subtypes	Usual clinical presentation
PIT1	Somatotroph (densely and sparsely granulated); lactotroph (densely and sparsely granulated); mammosomatotroph; mixed somatotroph and lactotroph; thyrotroph; mature plurihormonal PIT1-lineage tumor; immature PIT1-lineage tumor (formerly silent subtype 3); acidophil stem cell tumor	Acromegaly or gigantism; hyperprolactinemia; central hyperthyroidism; some tumors are clinically silent
TPIT	Corticotroph (densely granulated, sparsely granulated and Crooke cell)	Cushing's disease, or a clinically silent corticotroph tumor
SF1	Gonadotroph	Usually clinically nonfunctioning
No distinct lineage	Null cell tumor (a diagnosis of exclusion); plurihormonal tumors with multilineage differentiation	Usually clinically nonfunctioning

• Mammosomatotroph and acidophil stem cell tumors are distinct PIT1-lineage PitNETs, and the 2017 category of PIT1-positive plurihormonal tumor has been replaced by the immature PIT1-lineage tumor and the mature plurihormonal PIT1-lineage tumor.
• The null cell tumor is reserved for PitNETs with no evidence of adenohypophyseal lineage differentiation, and recognition of multiple synchronous PitNETs is emphasized to avoid misclassification.
• Subtypes associated with a high risk of adverse biology, including sparsely granulated somatotroph tumors, immature PIT1-lineage tumors, Crooke cell tumors and silent corticotroph tumors, are emphasized within their lineage.
• The term metastatic PitNET replaces "pituitary carcinoma" to avoid confusion with poorly differentiated neuroendocrine carcinoma.

Classification by Cavernous Sinus Invasion (Knosp Grade)

The Knosp classification grades parasellar extension on coronal magnetic resonance imaging relative to three lines drawn on the intracavernous and supracavernous internal carotid artery: a medial tangent, the intercarotid line through the cross-sectional centers, and a lateral tangent. The modified classification divides grade 3 into superior (3A) and inferior (3B) compartment extension.

Knosp grade	Radiological definition	Invasion confirmed at endoscopic surgery	Gross-total resection	Endocrine remission (functioning tumors)
0	Does not extend beyond the medial tangent (normal condition)	No invasion in the original series	Not assessed
1	Extends beyond the medial tangent but not beyond the intercarotid line	1.5%	83%	88%
2	Extends beyond the intercarotid line but not beyond the lateral tangent	9.9%	71%	60%
3A	Extends beyond the lateral tangent into the superior cavernous sinus compartment	26.5%	85%	67%
3B	Extends beyond the lateral tangent into the inferior cavernous sinus compartment	70.6%	64%	0%
4	Total encasement of the intracavernous internal carotid artery	100%	0%	0%

In the original microscopic series, surgically proven invasion was present in all grade 3 and grade 4 tumors and in all but one grade 2 tumor. Direct endoscopic inspection found invasion in 9.9% of grade 2 adenomas compared with 88% on microscopic evaluation, and in 37.9% of grade 3 adenomas compared with 86%.

Clinicopathological Grading

A five-tier prognostic classification combines magnetic resonance imaging evidence of cavernous or sphenoid sinus invasion with proliferation markers (Ki-67, mitotic count and p53).

Grade	Definition
1a	Noninvasive
1b	Noninvasive and proliferative
2a	Invasive
2b	Invasive and proliferative
3	Metastatic

In a multicentric case-control study of 410 patients with 8 years of postoperative follow-up, invasive and proliferative (grade 2b) tumors carried a 25-fold increase in the probability of tumor persistence and a 12-fold increase in the probability of progression compared with noninvasive (grade 1a) tumors.

Aggressive and Metastatic PitNETs

• Aggressive pituitary tumors are a small subset that does not respond to standard medical treatment and shows multiple local recurrences; tumors with metastases were previously termed pituitary carcinomas and are now designated metastatic PitNETs.
• In a European Society of Endocrinology survey of 166 patients with aggressive tumors or carcinomas, 69% of tumors were clinically functioning, corticotroph tumors were the most frequent immunohistochemical subtype (45%), and the Ki-67 index did not distinguish aggressive tumors from carcinomas (median 7% and 10%, respectively).
• In a subsequent survey of 171 patients (121 aggressive tumors and 50 carcinomas), 96% initially presented as macroadenomas or giant tumors, 97 tumors initially considered clinically benign demonstrated aggressive behavior after 5.5 years (IQR 2.8 to 12), and metastases were observed a median of 6.3 years (IQR 3.7 to 12.1) after diagnosis. At first surgery, the Ki-67 index was 3% or higher in 74 of 93 tumors (80%) and 10% or higher in 38 of 93 (41%).

Nomenclature

The terms pituitary adenoma and pituitary neuroendocrine tumor are both in current use. The WHO classification adopted the PitNET terminology, whereas a multidisciplinary workshop including representatives nominated by the Endocrine Society, the European Society of Endocrinology, the European Neuroendocrine Association, the Growth Hormone Research Society and the International Society of Pituitary Surgeons recommended retaining the term adenoma, because the vast majority of pituitary adenomas are benign and do not adversely affect life expectancy and because the PitNET designation does not address the main challenge of prognostic prediction.

Pathophysiology

Tumor Biology

• Pituitary adenomas occur in 10% of the population, yet the overwhelming majority remain harmless during life, and fewer than one-thousandth of all pituitary adenomas are estimated to cause clinically significant disease.
• Disease-causing adenomas are triggered by somatic or germline mutations that disrupt intrapituitary signaling and promote benign cell proliferation associated with chromosomal instability; cellular senescence acts as a buffer against malignant transformation, which is an extremely rare event.
• Growth hormone-secreting adenomas arise as monoclonal expansions of differentiated somatotroph cells and are usually sporadic; they are almost invariably benign but can be locally invasive and may grow progressively despite treatment.
• Tumor phenotype follows the lineage-restricted pituitary transcription factors that govern normal adenohypophyseal differentiation: PIT1 for somatotroph, lactotroph and thyrotroph cells, TPIT for corticotroph cells and SF1 for gonadotroph cells.

Molecular Genetics

• Somatic USP8 mutations: exome sequencing identified somatic mutations in the deubiquitinase gene USP8 in 4 of 10 corticotroph adenomas. The mutations cluster in the 14-3-3 protein binding motif, enhance proteolytic cleavage and catalytic activity of USP8, increase deubiquitination of the epidermal growth factor receptor and sustain EGF signaling, which enhances proopiomelanocortin promoter activity.
• Germline AIP mutations: two AIP mutations accounted for 16% of all patients with growth hormone-secreting adenomas in a population-based series from Northern Finland and for 40% of those diagnosed before 35 years of age; carriers typically lack a strong family history, consistent with low penetrance. Germline AIP mutations are associated with large adenomas presenting in children, adolescents and young adults, usually somatotropinomas, and gigantism occurs in more than one third of affected somatotropinoma patients. Patients with truncating AIP mutations have a younger age at disease onset and diagnosis than those with nontruncating mutations, and somatic GNAS1 mutations are absent from AIP-mutated tumors.
• X-linked acrogigantism: Xq26.3 microduplications were found in 13 of 43 patients with gigantism, all with disease onset in early childhood. GPR101 was the only duplicated protein-coding gene overexpressed in pituitary lesions, and a recurrent GPR101 mutation (p.E308D) was found in 11 of 248 patients with acromegaly, mostly in tumor tissue.
• Multiple endocrine neoplasia type 1: an autosomal dominant disorder caused by mutations in the tumor-suppressor gene MEN1, which encodes the scaffold protein menin, and characterized by the combined occurrence of parathyroid tumors, duodenopancreatic neuroendocrine tumors and anterior pituitary adenomas.

Mechanisms of Clinical Manifestations

Mechanism	Pathophysiology	Clinical consequences
Prolactin excess	Autonomous prolactin secretion by lactotroph tumors, or loss of dopaminergic inhibition of normal lactotrophs when a sellar mass compresses the pituitary stalk	Hypogonadism, infertility and galactorrhea
Growth hormone and IGF-I excess	Persistent excess of growth hormone and its target hormone insulin-like growth factor 1	Cardiovascular, respiratory, metabolic, musculoskeletal, neurological and neoplastic comorbidities that might not be reversible with disease control
ACTH excess	Corticotroph tumor-driven adrenocorticotropic hormone secretion with adrenal cortisol excess	Cushing's disease, with comorbidities that may persist after remission and impair quality of life
TSH excess	Autonomous thyroid-stimulating hormone secretion	Elevated free T4 and T3 with a nonsuppressed TSH; inappropriate thyroid ablation results in a significant increase in tumor mass
Compression of the optic apparatus	Suprasellar extension compresses the optic chiasm	Visual field defects in 18% to 78% of patients with macroadenomas
Compression of the normal gland	Loss of anterior pituitary hormone production	Hypopituitarism in 34% to 89% of patients with macroadenomas
Sellar mass effect	Local expansion of the sellar contents	Headache in 17% to 75% of patients with macroadenomas
Parasellar invasion	Extension into the cavernous sinus	Lower likelihood of gross-total resection and endocrine remission; palsies of the third, fourth and sixth cranial nerves occur particularly with apoplexy
Hemorrhage or infarction	Abrupt hemorrhagic or ischemic necrosis of the adenoma	Pituitary apoplexy

Causes

Category	Cause	Key features
Sporadic	Somatic genetic alterations, such as USP8 mutations in corticotroph tumors	Account for the large majority of pituitary adenomas
Syndromic hereditary	Multiple endocrine neoplasia type 1 (MEN1)	Autosomal dominant; parathyroid tumors, duodenopancreatic neuroendocrine tumors and anterior pituitary adenomas
Nonsyndromic hereditary	Familial isolated pituitary adenoma (FIPA), including germline AIP mutations	FIPA comprises approximately 2% of pituitary adenomas and AIP mutations account for 20% of FIPA families; large, early-onset tumors, usually somatotroph
Nonsyndromic hereditary	X-linked acrogigantism (Xq26.3 microduplication involving GPR101)	Gigantism with onset in early childhood
Other rare hereditary syndromes	Multiple endocrine neoplasia type 4 (CDKN1B), Carney complex (PRKAR1A) and succinate dehydrogenase-related syndromes	Pituitary tumors occur as part of a broader syndromic phenotype

Differentiating Pituitary adenoma from other Diseases

Pituitary adenomas are the most frequently encountered sellar masses, but other lesions must be considered. In a 10-year series of 2598 patients undergoing pituitary magnetic resonance imaging, a normal gland was reported in 47% of patients; nonadenomatous sellar masses accounted for 18% of visible lesions, of which the most common were Rathke cleft cyst (19%), craniopharyngioma (15%) and meningioma (15%), and metastases accounted for 5% of nonpituitary lesions, with breast cancer the most common primary source.

Differentiating Pituitary Adenoma from Other Sellar and Parasellar Lesions

Condition	Clinical features	Imaging features	Endocrine features	Distinguishing points
Pituitary adenoma (PitNET)	Hormone excess syndrome, hypogonadism, visual field defects, headache or incidental finding	Sellar mass that may extend into the suprasellar cistern or cavernous sinus; may be cystic or hemorrhagic	Hormone excess (prolactin, growth hormone, ACTH or TSH) or hypopituitarism	Most frequent sellar mass; lineage confirmed by transcription factor immunohistochemistry
Rathke's cleft cyst	Often incidental; headache	Intrasellar or suprasellar cyst	Usually normal	Most common nonadenomatous sellar lesion; cystic lesions rarely enlarge (0.05 per 100 person-years)
Craniopharyngioma	Visual loss and headache; growth failure in children	Cystic and solid suprasellar mass, frequently calcified	Hypopituitarism and arginine vasopressin deficiency	Two types are recognized by the WHO classification
Meningioma	Visual loss	Dural-based enhancing mass	Pituitary function usually preserved	15% of nonadenomatous sellar lesions
Hypophysitis (autoimmune, IgG4-related, immune checkpoint inhibitor-induced or secondary to systemic disease)	Headache with anterior and/or posterior pituitary dysfunction	Pituitary stalk thickening and homogeneous enlargement of the gland; imaging is not always specific	Hypopituitarism, often with arginine vasopressin deficiency	A response to glucocorticoids is not diagnostic; only biopsy confirms the type and excludes other etiologies
Pituitary metastasis	Known or occult malignancy	Sellar or parasellar mass	Variable	5% of nonpituitary sellar lesions; breast cancer is the most common primary source
Posterior lobe and hypothalamic tumors (pituicyte tumor family, gangliocytoma, neurocytoma)	Mass effect	Sellar or suprasellar mass	Variable	Rare; classified separately from PitNETs by the WHO
Physiological pituitary enlargement in pregnancy	Pregnancy	Diffuse enlargement of the gland	Physiological changes of pregnancy	Pituitary gland size increases during normal pregnancy

Differentiating Causes of Hyperprolactinemia

Category	Causes	Diagnostic approach
Physiological	Pregnancy, lactation and venipuncture stress	Pregnancy test; repeat measurement on a sample obtained without excessive venipuncture stress
Pharmacological	Antipsychotics and other dopamine antagonists, among other drugs	If safe, discontinue the drug for 3 days or substitute an alternative and remeasure prolactin; if this is not possible and the onset of hyperprolactinemia did not coincide with therapy, obtain pituitary MRI
Pituitary and sellar disease	Prolactinoma; stalk compression by a nonfunctioning adenoma or another sellar mass	Pituitary MRI; serial dilution of the sample when a large adenoma is accompanied by a normal or mildly elevated prolactin, to exclude the hook effect
Systemic disease	Primary hypothyroidism; chronic kidney disease	TSH and free T4; renal function
Analytical	Macroprolactinemia	Assessment for macroprolactin in asymptomatic hyperprolactinemia

Differentiating TSH-Secreting Adenoma from Resistance to Thyroid Hormone

Feature	TSH-secreting adenoma	Resistance to thyroid hormone
Free T4 and free T3	Elevated	Elevated
TSH	Nonsuppressed	Nonsuppressed
TSH response to TRH stimulation	Absent or blunted in most patients	Normal or exaggerated
TSH after T3 suppression	Never completely suppressed	Suppressed, although suppression may be incomplete
Sex hormone-binding globulin	Elevated	Normal
Alpha-subunit and alpha-subunit/TSH molar ratio	Often elevated	Normal
Pituitary MRI	Adenoma usually visible	Usually no adenoma; incidental pituitary lesions may coexist
Genetic testing and family history	Negative	THRB variant usually identified; affected relatives

Epidemiology and Demographics

Prevalence

• A systematic review of autopsy and imaging studies estimated an overall prevalence of pituitary adenomas of 16.7% (14.4% in autopsy studies and 22.5% in radiological studies).
• Pituitary adenomas are estimated to occur in 10% of the population, although fewer than one-thousandth cause clinically significant disease.
• Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons; approximately 53% are prolactinomas, 30% are nonfunctioning adenomas, 12% are somatotropinomas and 4% are corticotropinomas.

Population-based prevalence of clinically relevant pituitary adenomas
Study	Population	Prevalence	Subtype distribution
Liège, Belgium (cross-sectional case finding, 2005)	68 patients among 71,972 residents	94 ± 19.3 per 100,000 (95% CI 72.2 to 115.8); one case per 1064 individuals	Prolactinoma 66%; nonsecreting 14.7%; somatotropinoma 13.2%; Cushing's disease 5.9%
Banbury, United Kingdom (community-based, 2006)	63 patients identified through general practice records	77.6 per 100,000	Prolactinoma 57%; nonfunctioning 28%; acromegaly 11%; corticotroph 2%; unknown functional status 2%
Iceland (nationwide, 1955 to 2012)	471 individuals	115.57 per 100,000 in 2012	Across the whole period: nonfunctioning 43.0%; prolactinoma 39.9%; acromegaly 11.3%; Cushing's disease 5.7%

• Among adenomas initially identified on pituitary MRI at a tertiary referral center, prolactinomas accounted for 40%, nonfunctioning adenomas for 37% and growth hormone-secreting adenomas for 13%.

Incidence

• In Iceland, the total standardized incidence rate of pituitary adenomas increased significantly over six decades to 5.8 per 100,000 per year; prevalence in 2012 was highest for prolactinomas (54.37 per 100,000), followed by nonfunctioning adenomas (42.32 per 100,000).
• In a Swedish nationwide registry study of 2795 patients, the annual incidence of nonfunctioning pituitary adenoma was 20.3 (95% CI 18.8 to 21.9) cases per 1 million inhabitants.

Age

• In the Liège cohort, the mean age at diagnosis was 40.3 years.
• In the Banbury cohort, the median age at diagnosis was 32.0 years for prolactinomas, 51.5 years for nonfunctioning adenomas, 47 years for acromegaly and 57 years for corticotroph adenomas. Prolactinomas were the most frequent adenomas up to the age of 60 years (75% of adenomas at 0 to 20 years and 61% at 20 to 60 years), whereas nonfunctioning adenomas predominated after the age of 60 years (60% of adenomas).
• In Sweden, the mean age at diagnosis of nonfunctioning adenoma was 58 years (60 years in men and 56 years in women).

Sex

• In the Liège cohort, 67.6% of patients were female.
• Nonfunctioning adenomas accounted for 57% of adenomas in men, whereas prolactinomas accounted for 76% of adenomas in women.
• Women are diagnosed at a younger age and with smaller adenomas than men.

Clinical Characteristics at Diagnosis

• In the Liège cohort, 42.6% of patients had macroadenomas, 55.9% underwent surgery and 20.6% had hypopituitarism.
• The median duration of symptoms before diagnosis was 1.5 years for prolactinomas, 0.8 years for nonfunctioning adenomas, 4.5 years for acromegaly and 7 years for corticotroph adenomas.
• Although the rising incidence is related to the introduction of modern imaging, the vast majority of patients are symptomatic at diagnosis.

Risk Factors

Most pituitary adenomas are sporadic. Recognized risk factors include:

• Germline predisposition: multiple endocrine neoplasia type 1, familial isolated pituitary adenoma and germline AIP mutations, and X-linked acrogigantism.
• Young age at onset: AIP mutations accounted for 40% of patients with growth hormone-secreting adenomas diagnosed before 35 years of age in Northern Finland.
• Family history of pituitary adenoma: familial isolated pituitary adenoma families comprise approximately 2% of pituitary adenomas, although AIP mutation carriers frequently lack a strong family history.
• Sex and age by subtype: prolactinomas predominate in women and before the age of 60 years, whereas nonfunctioning adenomas predominate in men and after the age of 60 years.

Risk Factors for Pituitary Apoplexy

• Macroadenoma and nonfunctioning status were the only factors consistently associated with apoplexy in a systematic review of 7 studies including 4937 patients.
• Precipitating factors include increased intracranial pressure, arterial hypertension, major surgery, anticoagulant therapy and dynamic endocrine testing.
• Pregnancy is a recognized risk factor.

Risk Factors for Aggressive Behavior

• A Ki-67 index of 10% or higher and ACTH secretion are associated with a worse prognosis in aggressive tumors and metastatic PitNETs.
• Invasive and proliferative tumors carry the highest risk of persistence and progression after surgery.

Screening

Screening for pituitary adenomas is targeted to individuals with an inherited predisposition, patients with clinical features suggestive of pituitary hormone excess, and patients with an incidentally discovered pituitary lesion.

Inherited Predisposition

• Multiple endocrine neoplasia type 1: identification of individuals at high risk is facilitated by genetic testing of patients and their first-degree relatives, followed by periodic clinical, biochemical and radiological screening of patients and MEN1 mutation carriers. Without treatment, MEN1 carries high morbidity and premature mortality, which can be mitigated by early tumor detection and intervention.
• AIP mutation carriers: among 164 apparently unaffected AIP mutation-positive family members, pituitary disease was detected in 18 of those who underwent clinical screening, a quarter of the carriers screened, which justifies screening.
• X-linked acrogigantism: testing for Xq26.3 microduplication is relevant in early childhood gigantism; in the original series, none of the patients with gigantism who lacked the microduplication presented before 5 years of age.

Clinical Suspicion of Hormone Excess

• Acromegaly: measurement of serum insulin-like growth factor 1 is recommended in patients with typical clinical manifestations, especially acral and facial features, and acromegaly should be considered in patients without typical manifestations who have several associated conditions, such as obstructive sleep apnea, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis and hypertension; random growth hormone levels should not be relied upon for diagnosis.
• Cushing's syndrome: after exclusion of exogenous glucocorticoid use, testing is recommended in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and in patients with an adrenal incidentaloma.
• Hyperprolactinemia: a single measurement of serum prolactin is used for diagnosis, provided that the sample was obtained without excessive venipuncture stress.

Incidentally Discovered Pituitary Lesions

• Patients with a pituitary incidentaloma should undergo a complete history and physical examination, laboratory screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm.
• Biochemical screening for hyperprolactinemia and acromegaly is needed in all patients with a pituitary incidentaloma, whereas testing for hyposecretion is recommended for lesions larger than 6.0 mm.

Natural History, Complications and Prognosis

Natural History

Nonfunctioning Adenomas and Incidentalomas

Lesion	Source	Growth
Macroadenoma	Meta-analysis of 11 cohort studies	12.5 per 100 person-years (95% CI 7.9 to 17.2)
Solid lesion	Meta-analysis of 11 cohort studies	5.7 per 100 person-years (95% CI 2.3 to 9.2)
Microadenoma	Meta-analysis of 11 cohort studies	3.3 per 100 person-years (95% CI 2.1 to 4.5)
Cystic lesion	Meta-analysis of 11 cohort studies	0.05 per 100 person-years (95% CI 0.0 to 0.2)
Nonfunctioning microadenoma	UK NFPA consortium, 459 patients	Cumulative probability 7.8% (95% CI 4.9% to 8.1%) at 3 years and 14.5% (95% CI 10.2% to 18.8%) at 5 years
Conservatively managed nonfunctioning macroadenoma	UK NFPA consortium, 949 patients	9.8 per 100 patient-years (95% CI 8.8 to 10.8); cumulative probability 1.6%, 8.1%, 18.4%, 29.2% and 43.6% at 6 months, 1, 2, 3 and 5 years

• In the meta-analysis, follow-up ranged from 3 to 15 years, the overall incidence of new endocrine dysfunction was 2.4 per 100 person-years (95% CI 0.0 to 6.4), pituitary apoplexy and worsening of visual field defects were rare, and the quality of the evidence was very low.
• Nonfunctioning microadenomas may also regress, with a cumulative probability of reduction of 14.1% (95% CI 10.4% to 17.8%) at 3 years and 21.3% (95% CI 16.4% to 26.2%) at 5 years. Median enlargement was 2 mm (IQR 1 to 3), 49% of the microadenomas that grew became macroadenomas (nearly all were larger than 5 mm at detection), 8 patients (1.9%) underwent surgery, and 2 patients (0.6%) developed new hypopituitarism, both after progression to a macroadenoma.
• In conservatively managed macroadenomas, enlargement was more frequent in tumors abutting or displacing the optic chiasm, and none of the tumors not in contact with the chiasm that enlarged within 6 months affected the visual fields. After a first enlargement with continued monitoring (median 2.6 years), further growth occurred in 60.5%, stability in 35.5% and shrinkage in 4.0%; new pituitary hormone deficits developed in 4.0% to 4.9%, mainly driven by tumor enlargement.

Aggressive Behavior

• Aggressive behavior may emerge late: in a series of 171 aggressive tumors and metastatic PitNETs, 97 tumors initially considered clinically benign became aggressive after 5.5 years (IQR 2.8 to 12), and 5 of 13 silent corticotroph tumors and 2 of 6 silent somatotroph tumors became secreting.

Complications

• Mass effect: visual field defects, headache and hypopituitarism occur in approximately 18% to 78%, 17% to 75% and 34% to 89% of patients with macroadenomas, respectively.
• Pituitary apoplexy: abrupt hemorrhage or infarction complicates 2% to 12% of pituitary adenomas, especially nonfunctioning tumors. Sudden severe headache is the main symptom, sometimes with visual disturbance or ocular palsy, meningeal irritation or altered consciousness, and corticotropic deficiency with adrenal insufficiency may be life-threatening if left untreated. In the Banbury population, 5 patients (7.9%) presented with classical apoplexy, a prevalence of 6.2 cases per 100,000 inhabitants. Across 7 studies including 4937 patients with adenomas, 490 (9.92%) had apoplexy, including subclinical events.
• Complications of growth hormone excess: cardiovascular, respiratory, metabolic, musculoskeletal, neurological and neoplastic comorbidities, which might not be reversible with disease control and require multidisciplinary management.
• Complications of hypercortisolism: causes of death in endogenous Cushing's syndrome include atherosclerotic disease and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%) and suicide (2.2%). The elevated risk of venous thromboembolism associated with hypercortisolism underlies recommendations for thromboprophylaxis.
• Complications of treatment:
  • New hormone deficiency at 6 months after transsphenoidal surgery for nonfunctioning adenomas occurred in 28.4% of patients after microscopic surgery and 9.7% after endoscopic surgery.
  • After transsphenoidal surgery for prolactinoma, permanent diabetes insipidus occurred in 2% (95% CI 0 to 5) and cerebrospinal fluid leakage in 3% (95% CI 2 to 5).
  • After surgery for nonfunctioning macroadenoma, hypopituitarism reversed in 12% to 17%, additional anterior pituitary hormone deficits developed in 12% to 15%, and permanent vasopressin deficiency occurred in 3.5%.
  • After Gamma Knife radiosurgery for nonfunctioning adenomas, new or worsened hypopituitarism occurred in 21% and new or progressive cranial nerve deficits in 9%.
  • Hyperglycemia-related adverse events occurred in 57.3% of patients receiving pasireotide LAR, compared with 21.7% receiving octreotide LAR.
  • Dopamine agonists may cause impulse control disorders, depression, mania and psychosis regardless of prior psychiatric history, and low-dose cabergoline is associated with an increased prevalence of tricuspid regurgitation of uncertain clinical significance.

Prognosis

Mortality associated with pituitary adenomas and their complications
Population	Study design	Standardized mortality ratio (SMR)
Hypopituitarism (1014 patients; 57% with nonfunctioning adenomas)	Prospective cohort, West Midlands, United Kingdom	1.87 (99% CI 1.62 to 2.16); women 2.29 (1.86 to 2.82) and men 1.57 (1.28 to 1.93); untreated gonadotropin deficiency 2.97 (2.13 to 4.13) versus treated 1.42 (0.97 to 2.07)
Nonfunctioning pituitary adenoma (2795 patients)	Swedish nationwide registry study	1.10 (95% CI 1.00 to 1.20); diagnosis before 40 years 2.68 (1.23 to 5.09); women 1.29 (1.11 to 1.48); men 1.00 (0.88 to 1.12)
Acromegaly	Meta-analysis of 26 studies	Studies published after 2008: 1.35 (95% CI 0.99 to 1.85); series using somatostatin analogs as adjuvant treatment: 0.98 (0.83 to 1.15); series treated only with surgery and/or radiotherapy: 2.11 (1.54 to 2.91)
Endogenous Cushing's syndrome	Meta-analysis of 14 articles (3691 patients)	All Cushing's syndrome 3.0 (95% CI 2.3 to 3.9); Cushing's disease 2.8 (2.1 to 3.7)
Cushing's disease (502 patients)	Swedish nationwide study	2.5 (95% CI 2.1 to 2.9); patients in remission 1.9 (1.5 to 2.3)

• In hypopituitarism, excess mortality was attributed to cardiovascular (SMR 1.82, 1.30 to 2.54), respiratory (2.66, 1.72 to 4.11) and cerebrovascular (2.44, 1.58 to 4.18) causes, and was higher with an underlying diagnosis of craniopharyngioma (9.28, 5.84 to 14.75) and in patients treated with radiotherapy (2.32, 1.71 to 3.14). Age at diagnosis, female sex, craniopharyngioma and untreated gonadotropin deficiency were independent risk factors.
• In nonfunctioning adenomas, mortality was increased from cerebrovascular (SMR 1.73, 1.34 to 2.19) and infectious diseases (2.08, 1.17 to 3.44) and in patients with diabetes insipidus (1.71, 1.07 to 2.58), whereas mortality from malignant tumors was decreased (0.76, 0.61 to 0.94).
• In acromegaly, mortality is not increased in patients who achieve biochemical control but remains higher in those with active disease, and cancer has become a leading cause of death as life expectancy has improved.
• In Cushing's disease, cardiovascular disease was the commonest cause of death (SMR 3.3, 95% CI 2.6 to 4.3), with excess mortality also from infections and suicide. Among patients in remission, bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas growth hormone replacement was associated with improved outcome. The proportion of deaths in Cushing's syndrome fell from 10% in articles published before 2000 to 3% thereafter.
• Median survival in aggressive pituitary tumors and metastatic PitNETs was 17.2 and 11.3 years, respectively.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Diagnostic Approach

• All patients with a pituitary tumor require endocrine evaluation for hormone hypersecretion; patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing.
• Dedicated pituitary magnetic resonance imaging is the imaging study of choice for characterizing sellar lesions.
• In acromegaly, referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology or imaging findings at diagnosis.

Diagnostic Algorithm

Suspected pituitary adenoma Sellar mass on imaging, clinical features of hormone excess, hypogonadism or mass effect

Dedicated pituitary MRI with gadolinium Focused history and physical examination Formal visual field testing if the lesion abuts the optic nerves or chiasm

Hormonal evaluation for hypersecretion and hypopituitarism Prolactin, with serial dilution if a large adenoma has a normal or mildly elevated level IGF-I; testing for hypercortisolism if clinically suspected TSH and free T4; LH, FSH and testosterone or estradiol; morning cortisol

Hyperprolactinemia

Excess growth hormone, ACTH or TSH

No hormone excess

Exclude pregnancy, medications, primary hypothyroidism, renal failure and macroprolactin Prolactin disproportionately low for a macroadenoma suggests stalk compression Concordant findings indicate a prolactinoma

Acromegaly: IGF-I more than 1.3 times the upper limit of normal with typical features; OGTT if equivocal Cushing disease: two concordant first-line tests and ACTH-dependent hypercortisolism; IPSS if MRI is negative or equivocal TSH-secreting adenoma: elevated free T4 and T3 with nonsuppressed TSH; exclude resistance to thyroid hormone

Clinically nonfunctioning adenoma or nonadenomatous sellar lesion Evaluate for hypopituitarism, particularly in macroadenomas Consider Rathke cleft cyst, craniopharyngioma, meningioma, hypophysitis and metastasis

History and Symptoms

• Mass effect: headache (17% to 75% of patients with macroadenomas), visual field loss (18% to 78%), classically bitemporal hemianopia from chiasmal compression, and symptoms of hypopituitarism (34% to 89%).
• Prolactin excess: hypogonadism, infertility, galactorrhea and, in women, menstrual irregularity or amenorrhea.
• Growth hormone excess: acral and facial changes and associated conditions such as sleep apnea, diabetes, arthritis, carpal tunnel syndrome, hyperhidrosis and hypertension; the median duration of symptoms before diagnosis of acromegaly was 4.5 years in a community-based study.
• Cortisol excess: multiple and progressive features of Cushing's syndrome; the median duration of symptoms before diagnosis of a corticotroph adenoma was 7 years.
• TSH excess: symptoms of hyperthyroidism in the presence of a nonsuppressed TSH.
• Pituitary apoplexy: sudden onset of headache, vomiting, visual impairment and decreased consciousness, with or without involvement of the second, third, fourth and sixth cranial nerves.
• Family history: pituitary tumors in relatives, or features of multiple endocrine neoplasia type 1 such as primary hyperparathyroidism or pancreatic neuroendocrine tumors.

Physical Examination

• Visual assessment: visual acuity, confrontation visual fields followed by formal perimetry when the lesion abuts the optic apparatus, and ocular motility to detect cranial nerve palsies.
• Acromegaly: acral enlargement and coarse facial features.
• Cushing's syndrome: features with a high discriminatory value, such as easy bruising, facial plethora, proximal myopathy and reddish-purple striae.
• Hyperprolactinemia: galactorrhea and signs of hypogonadism.
• TSH-secreting adenoma: signs of hyperthyroidism and goiter.

Laboratory Findings

Clinical question	Initial testing	Confirmation and interpretation
Hyperprolactinemia	Single serum prolactin measurement on a sample obtained without excessive venipuncture stress	Exclude pregnancy, medications, primary hypothyroidism and renal failure; assess for macroprolactin in asymptomatic patients; perform serial dilution when a large adenoma is accompanied by a normal or mildly elevated prolactin (hook effect)
Acromegaly	Age-adjusted serum insulin-like growth factor 1 (IGF-I)	In a patient with typical features, IGF-I more than 1.3 times the upper limit of normal for age confirms the diagnosis; random growth hormone is not required for diagnosis but may inform prognosis; for equivocal results, repeat IGF-I with the same validated assay and consider an oral glucose tolerance test, in which lack of suppression of growth hormone to less than 1 μg/L confirms the diagnosis
Cushing's disease	After excluding exogenous glucocorticoids, one test with high diagnostic accuracy: 24-hour urinary free cortisol, late-night salivary cortisol, or the 1 mg overnight or 2 mg 48-hour dexamethasone suppression test (abnormal if serum cortisol exceeds 1.8 μg/dL, 50 nmol/L)	An abnormal result requires a second test, and concordant abnormal results establish Cushing's syndrome; plasma adrenocorticotropic hormone identifies ACTH-dependent disease, followed by pituitary MRI and, when indicated, inferior petrosal sinus sampling
TSH-secreting adenoma	Free T4, free T3 and TSH	Elevated free thyroid hormones with a nonsuppressed TSH; TSH after T3 suppression and TRH stimulation, pituitary imaging and genetic testing distinguish TSH-secreting adenoma from resistance to thyroid hormone
Hypopituitarism	Morning serum cortisol; free T4 with TSH; LH and FSH with testosterone in men, or estradiol and menstrual history in women; IGF-I; serum sodium	A morning cortisol below 3 μg/dL indicates adrenal insufficiency and a value above 15 μg/dL likely excludes it; a low free T4 with a low, normal or mildly elevated TSH indicates central hypothyroidism, and free T4 rather than TSH is used to monitor replacement; dynamic testing is used when results are indeterminate

• In a Pituitary Society modified Delphi panel of 41 participants, with consensus defined as at least 70% agreement, 45% (14/31) and 44% (11/25) of statements reached consensus in the two rounds; most panelists reported using late-night salivary cortisol to diagnose mild Cushing's syndrome and to monitor patients after pituitary surgery or medical or radiation therapy.
• In acromegaly, random growth hormone measured after an overnight fast may be useful for informing prognosis, and diagnostic delay has adverse consequences.

Imaging Findings

Magnetic Resonance Imaging

• Dedicated pituitary magnetic resonance imaging with gadolinium enhancement is the modality of choice for detecting and characterizing pituitary adenomas and for follow-up.
• Coronal imaging allows grading of cavernous sinus invasion with the Knosp classification, which predicts surgically confirmed invasion and the likelihood of gross-total resection and endocrine remission.
• Half of all pituitary MRI scans performed in a large referral population showed no visible lesion, so imaging must be interpreted together with biochemical findings.

Computed Tomography

• Computed tomography or MRI confirms the diagnosis of pituitary apoplexy by revealing a pituitary tumor with hemorrhagic and/or necrotic components.
• In suspected pituitary apoplexy, MRI is preferred, and CT is used when MRI is contraindicated or unavailable.

Echocardiography

• In patients treated with cabergoline for hyperprolactinemia for at least 6 months, a meta-analysis of 13 case-control studies found more tricuspid regurgitation than in controls (OR 3.74, 95% CI 1.79 to 7.8); no tricuspid valve dysfunction was diagnosed on the basis of clinical symptoms, and no other valvulopathy was increased.
• Cardiovascular complications of acromegaly require assessment and management as part of comorbidity care.

Other Diagnostic Studies

• Formal visual field testing: recommended when the lesion abuts or compresses the optic nerves or chiasm, at baseline and during follow-up.
• Inferior petrosal sinus sampling: used to distinguish pituitary from ectopic ACTH secretion in ACTH-dependent Cushing's syndrome when pituitary imaging is negative or equivocal or noninvasive tests are discordant.
• Genetic testing: AIP testing in familial isolated pituitary adenoma and young-onset adenomas, MEN1 testing in patients with features of MEN1 and their first-degree relatives, and Xq26.3 microduplication testing in early childhood gigantism.
• Histopathology: classification requires immunohistochemistry for pituitary hormones and transcription factors, and proliferative markers such as Ki-67 and mitotic count help identify tumors at risk of aggressive behavior.

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Initial Management

General Principles

• Patients should be managed by a multidisciplinary team; the Pituitary Society has defined criteria for Pituitary Tumor Centers of Excellence to guide improvements in care delivery.
• Treatment aims to control hormone hypersecretion and tumor growth, relieve mass effect, preserve or restore pituitary and visual function, and manage comorbidities; in acromegaly, normalization of IGF-I and growth hormone are the primary therapeutic aims, with tumor shrinkage, symptom relief, management of complications and improved quality of life as additional goals.
• For adenomas requiring treatment, first-line therapy is usually transsphenoidal surgery, except for prolactinomas, for which medical therapy with bromocriptine or cabergoline is usually first-line.
• Surgery is recommended for pituitary incidentalomas with a visual field deficit, other visual abnormalities such as ophthalmoplegia, or neurological compromise due to compression; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or hypersecretion other than prolactin.

Treatment Selection Algorithm

Pituitary adenoma confirmed Define subtype, size, Knosp grade, visual status and pituitary function Review by a multidisciplinary pituitary team

Prolactinoma

Somatotroph, corticotroph or thyrotroph tumor

Nonfunctioning adenoma with visual deficit, chiasmal contact or neurological compromise

Nonfunctioning adenoma without mass effect

Cabergoline as first-line therapy, including macroadenomas Transsphenoidal surgery as an alternative first-line option for selected microprolactinomas Surgery or radiotherapy for resistance or intolerance

Transsphenoidal surgery by an experienced pituitary surgeon Medical therapy, repeat surgery or radiotherapy for persistent disease Primary medical therapy if surgery is not possible

Transsphenoidal surgery Observation or radiotherapy for residual tumor Radiotherapy or radiosurgery for progression or recurrence

Surveillance MRI and visual assessment Repeat pituitary function testing for macroadenomas or tumor growth Surgery if growth threatens the optic apparatus

Pituitary Apoplexy

• Classical pituitary apoplexy is a medical emergency in which rapid replacement with hydrocortisone may be life-saving, and patients should be referred to a multidisciplinary team that includes a neurosurgeon and an endocrinologist. Surgery is indicated in patients with worsening neurological symptoms; for the majority of patients, it is unclear whether conservative or surgical management carries the best outcome.
• Conservative management is increasingly used in selected patients without important visual acuity or field defects and with normal consciousness, because a wait-and-see approach may also provide excellent outcomes for oculomotor palsy, pituitary function and subsequent tumor growth; studies comparing the two approaches were retrospective and uncontrolled.
• In a meta-analysis of 15 cohort studies comprising 908 patients, there was no statistically significant difference between conservative and surgical management in recovery of ophthalmoplegia (RR 1.09, 95% CI 1.00 to 1.18), visual field (RR 1.09, 0.91 to 1.3), visual acuity (RR 1.05, 0.87 to 1.26), hypopituitarism (RR 1.37, 0.81 to 2.32) or tumor recurrence (RR 0.74, 0.34 to 1.61), although more severe cases typically underwent surgery.
• After apoplexy, careful monitoring for recurrence of tumor growth is required.

Suspected pituitary apoplexy Sudden severe headache, vomiting, visual impairment, ophthalmoplegia or decreased consciousness

Immediate management Draw blood for cortisol and other pituitary hormones Hydrocortisone without delay for hemodynamic instability, altered consciousness, reduced visual acuity or a severe visual field defect; otherwise guided by the cortisol level Correct fluid and electrolyte disturbances Urgent MRI, or CT if MRI is unavailable Joint neurosurgical, endocrine and ophthalmological assessment

Severe or deteriorating visual acuity, visual field defect or level of consciousness

Stable or improving neuro-ophthalmic signs with normal consciousness

Transsphenoidal decompression by an experienced pituitary surgeon Continue glucocorticoid replacement and monitor fluid balance and sodium

Conservative management with close neuro-ophthalmic and endocrine monitoring Proceed to surgery if signs deteriorate

Perioperative Management

• A Pituitary Society Delphi process among 55 invited pituitary endocrinologists reached strong consensus on 68.6% (24/35) of statements on perioperative endocrine evaluation and management, and on 88% (31/35) with less strict criteria; consensus was not reached on assessment of immediate postoperative remission in acromegaly or Cushing's disease.
• In a randomized trial of patients with an intact hypothalamic-pituitary-adrenal axis undergoing transsphenoidal surgery, withholding perioperative glucocorticoids (n = 20) was compared with intravenous hydrocortisone 100 mg followed by dexamethasone (n = 23). Mean postoperative 8 am cortisol was higher without steroids (745 ± 359 versus 386 ± 193 nmol/L, P = .001), fewer patients were discharged on glucocorticoids (12% versus 42%, P = .07), postoperative complications did not differ, and permanent adrenal insufficiency occurred in 8%. Perioperative steroids can be safely withheld when the axis is intact, and their administration may interfere with postoperative assessment of the axis.
• Management of hypopituitarism during pituitary surgery and other surgery is addressed by the Endocrine Society hormone replacement guideline.
• In endogenous Cushing's syndrome, an international Delphi panel of 18 experts recommended considering thromboprophylaxis at diagnosis and continuing it for 3 months after biochemical remission, with standard weight-based prophylactic low-molecular-weight heparin as the preferred agent, and reconsidering prophylaxis perioperatively and around inferior petrosal sinus sampling.
• In newly diagnosed acromegaly, 6 months of preoperative octreotide increased the postoperative cure rate in macroadenomas (13 of 26, 50%, versus 4 of 25, 16%, P = 0.017), although the overall difference (45% versus 23%) was not significant (P = 0.11). The Endocrine Society suggests against routine preoperative medical therapy to improve biochemical outcome, but suggests preoperative somatostatin receptor ligands to reduce surgical risk in patients with severe pharyngeal thickness and sleep apnea or high-output heart failure.

Medical Therapy

Prolactinoma

• Dopamine agonists are the treatment of choice. In a randomized trial of 459 women with hyperprolactinemic amenorrhea, stable normoprolactinemia was achieved in 83% with cabergoline (0.5 to 1.0 mg twice weekly) versus 59% with bromocriptine (2.5 to 5.0 mg twice daily) (P < 0.001); ovulatory cycles or pregnancy occurred in 72% versus 52%, adverse effects in 68% versus 78% (P = 0.03), and discontinuation for intolerance in 3% versus 12% (P < 0.001).
• The Endocrine Society recommends dopamine agonist therapy to lower prolactin, decrease tumor size and restore gonadal function in symptomatic microprolactinomas and in macroprolactinomas, preferring cabergoline because of its higher efficacy in normalizing prolactin and higher frequency of tumor shrinkage, and suggests that asymptomatic microprolactinomas need not be treated with dopamine agonists.
• In a meta-analysis, biochemical control was achieved in 81% (95% CI 75 to 87) of patients during dopamine agonist treatment, with side effects in 26% (95% CI 13 to 41).
• Withdrawal: tapering and discontinuation may be considered after at least 2 years of therapy in patients with a normal prolactin level and no visible tumor remnant. In a meta-analysis of 19 studies with 743 patients, normoprolactinemia persisted after withdrawal in 21% (95% CI 14 to 30), in 32% with idiopathic hyperprolactinemia, 21% with microprolactinomas and 16% with macroprolactinomas; success was most likely when cabergoline had been used for at least 2 years. A later meta-analysis estimated long-term remission after withdrawal at 34% (95% CI 26 to 46).
• Adverse effects: impulse control disorders (with hypersexuality mostly in men), depression, mania and psychosis may occur regardless of prior psychiatric history, and sex, type of dopamine agonist, dose and duration of therapy did not correlate with psychiatric pathology. In hyperprolactinemia treated with cabergoline for at least 6 months, tricuspid regurgitation was more prevalent than in controls (OR 3.74, 95% CI 1.79 to 7.8), but no tricuspid valve dysfunction was diagnosed as a result of clinical symptoms.
• Resistance or intolerance: options include transsphenoidal surgery and radiotherapy and, for aggressive tumors, temozolomide.

Acromegaly

• Medical therapy is used for persistent disease after surgery, as primary therapy when surgery is not possible, and while awaiting the effect of radiotherapy; the Pituitary Society updated the treatment algorithm to incorporate oral octreotide and combination therapy.

Agent	Mechanism	Pivotal evidence	Key outcomes	Notable adverse effects
Octreotide LAR and lanreotide (first-generation somatostatin receptor ligands)	Somatostatin receptor type 2 agonism reducing growth hormone secretion	Active comparator in a randomized trial of 358 medically naive patients	Biochemical control (growth hormone below 2.5 μg/L and normal IGF-1) at 12 months in 19.2% with octreotide LAR	Gastrointestinal effects characteristic of somatostatin receptor ligands
Pasireotide LAR	Multireceptor somatostatin receptor ligand	Randomized trial versus octreotide LAR in 358 medically naive patients; PAOLA trial in 198 patients inadequately controlled on first-generation ligands	Biochemical control 31.3% versus 19.2% (P = .007); in PAOLA, 15% with 40 mg and 20% with 60 mg versus 0% with continued first-generation ligands	Hyperglycemia-related adverse events in 57.3% versus 21.7%; diabetes in 21% and 26% versus 8% in PAOLA
Oral octreotide capsules	Oral formulation of octreotide	CHIASMA OPTIMAL (placebo-controlled, 56 patients) and MPOWERED (versus injectable ligands, 92 randomized patients)	IGF-1 normalization maintained in 58.2% versus 19.4% with placebo; biochemical response maintained in 91% versus 100% with injectable ligands, meeting non-inferiority	Gastrointestinal effects
Paltusotine	Once-daily oral nonpeptide selective somatostatin receptor type 2 agonist	PATHFNDR-1 (switch from injected ligands, 58 patients) and PATHFNDR-2 (medically untreated, 111 patients)	IGF-I maintained at or below the upper limit of normal in 83.3% versus 3.6%; IGF-I normalization in 55.6% versus 5.3% at 24 weeks	Mild, transitory gastrointestinal effects
Octreotide subcutaneous depot (CAM2029)	Once-monthly subcutaneous octreotide depot allowing self-administration	ACROINNOVA 1 (72 patients controlled on standard care)	IGF-1 at or below the upper limit of normal in 72.2% versus 37.5% with placebo	Safety consistent with standard somatostatin receptor ligands
Pegvisomant	Growth hormone receptor antagonist	12-week randomized trial in 112 patients	IGF-I normalized in 10% (placebo), 54% (10 mg/day), 81% (15 mg/day) and 89% (20 mg/day)	Adverse effect incidence similar to placebo in the pivotal trial
Cabergoline	Dopamine agonist	Individual-patient meta-analysis of 15 nonrandomized studies (227 patients)	IGF-I normalized in 34% as monotherapy and in 52% when added to a somatostatin analog, even with normoprolactinemia	See dopamine agonist adverse effects

• In PATHFNDR-1, mean growth hormone was maintained below 1.0 ng/mL in 87.0% of patients receiving paltusotine versus 27.8% receiving placebo. In PATHFNDR-2, IGF-I decreased in 92.6% of paltusotine-treated patients within the first 4 weeks, IGF-I below 1.3 times the upper limit of normal was achieved in 66.7% versus 14.0%, and pituitary tumor volume was stable or reduced.
• In CHIASMA OPTIMAL, growth hormone below 2.5 ng/mL was maintained in 77.7% with oral octreotide versus 30.4% with placebo, and 75% of patients receiving oral octreotide completed the trial on oral therapy.
• Management of acromegaly comorbidities, including diabetes, hypertension and arthritis, was updated by the 16th Acromegaly Consensus Conference.

Cushing's Disease

• Surgical resection is generally the first-line approach; the choice of second-line treatment, including medication, bilateral adrenalectomy and radiation therapy, must be individualized, and comorbidities require adjunctive treatment.
• Metyrapone is an additional steroidogenesis inhibitor, and cabergoline may be used in selected patients, as outlined in consensus management algorithms.

Agent	Class	Pivotal evidence	Key outcomes	Notable adverse effects
Osilodrostat	11-beta-hydroxylase inhibitor	LINC 3 (137 patients, randomized withdrawal) and LINC 4 (73 patients, placebo-controlled)	Complete response maintained in 86% versus 29% after randomized withdrawal (OR 13.7, 95% CI 3.7 to 53.4); mean urinary free cortisol at or below the upper limit of normal in 77% versus 8% at week 12 and in 81% at week 36	Nausea (42%), headache (34%), fatigue (28%) and adrenal insufficiency (28%) in LINC 3; hypocortisolism in 51% and adrenal hormone precursor-related events in 42%
Levoketoconazole	Steroidogenesis inhibitor	SONICS (94 patients, single-arm) and LOGICS (44 patients randomized to withdrawal)	31% (29 of 94) responders after 6 months of maintenance; loss of response in 95.5% with placebo versus 40.9% with continued treatment	Alanine aminotransferase above 3 times the upper limit of normal in 11%; QT interval prolongation; adrenal insufficiency
Ketoconazole	Steroidogenesis inhibitor	French retrospective multicenter study (200 patients)	Normal urinary free cortisol in 49.3% at last follow-up and at least a 50% decrease in 25.6%	Discontinuation for poor tolerance in 20.5%; liver enzyme elevation below 5 times normal in 13.5% and above 5 times normal in 2.5%, without fatal hepatitis
Pasireotide	Pituitary-directed somatostatin receptor ligand with high affinity for somatostatin receptor subtype 5	Twice-daily subcutaneous phase 3 trial (162 patients) and once-monthly LAR phase 3 trial (150 patients)	Primary end point met by 12 of 82 patients (600 μg) and 21 of 80 (900 μg); with LAR, mean urinary free cortisol normalized at month 7 in 41.9% (10 mg) and 40.8% (30 mg)	Hyperglycemia-related adverse events in 118 of 162 with the subcutaneous formulation; with LAR, hyperglycemia in 49% and 47% and cholelithiasis in 20% and 45%
Mifepristone	Glucocorticoid receptor antagonist	SEISMIC (50 patients, open-label)	Glucose area-under-the-curve response in 60% of patients with diabetes or impaired glucose tolerance; diastolic blood pressure response in 38% of patients with hypertension; clinical improvement in 87%	Fatigue, nausea, headache, hypokalemia, arthralgia, vomiting, edema and endometrial thickening
Relacorilant	Investigational selective glucocorticoid receptor modulator	GRACE (152 enrolled; 62 randomized to withdrawal)	Loss of hypertension control more frequent after withdrawal to placebo (proportion difference 34%; OR 0.17, 95% CI 0.04 to 0.77; P = 0.022)	No cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, drug-induced hypokalemia or drug-induced QT prolongation

• With subcutaneous pasireotide, glucose and glycated hemoglobin rose soon after treatment initiation and then stabilized, and glucose-lowering medication was started in 74 of 162 patients.
• With mifepristone, mean glycated hemoglobin decreased from 7.43 ± 1.52% to 6.29 ± 0.99% in patients with diabetes or impaired glucose tolerance.
• Most members of a Pituitary Society Delphi panel considered that block-and-replace regimens can be used in patients with cyclical or severe Cushing's syndrome, and the panel agreed that restoration of circadian rhythm is a treatment goal.

TSH-Secreting Adenomas

• Surgery is the treatment of choice. In cases of surgical failure, somatostatin analogs normalize TSH secretion in more than 90% of patients. Failure to recognize a TSH-secreting adenoma may result in inappropriate thyroid ablation, which results in a significant increase in tumor mass.

Clinically Nonfunctioning Adenomas

• The Congress of Neurological Surgeons evidence-based guideline addresses medical therapy, radiation therapy and observation alongside surgery for nonfunctioning adenomas.
• In a single-center, open-label, 2-year randomized trial in residual nonfunctioning adenoma after transsphenoidal surgery, cabergoline (n = 59) compared with nonintervention (n = 57) resulted in tumor shrinkage in 28.8% versus 10.5%, stabilization in 66.1% versus 73.7% and enlargement in 5.1% versus 15.8% (P = 0.01); tumor dopamine D2 receptor expression was not associated with response, and no major side effects occurred.

Aggressive Pituitary Tumors and Metastatic PitNETs

• Patients should be managed by a multidisciplinary expert team. Temozolomide monotherapy is the first-line chemotherapy after failure of standard therapies; response should be evaluated after 3 cycles, and responders should continue treatment for at least 6 months in total. In the guideline's systematic review, a positive treatment effect was seen in 47% (95% CI 36 to 58) of temozolomide-treated patients.
• In the 2016 ESE survey, temozolomide was the first-line chemotherapy in 157 patients and resulted in complete response in 6%, partial response in 31%, stable disease in 33% and progressive disease in 30% at the end of treatment (median 9 cycles). Responses were more frequent with concomitant radiotherapy, complete responses occurred only with low MGMT expression, and clinically functioning tumors were more likely to respond; 25%, 40% and 48% of patients with complete response, partial response and stable disease, respectively, progressed after a median follow-up of 12 months, and other oncological drugs produced partial response in 20%.
• In a subsequent survey of 171 patients, temozolomide in 156 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1% and progressive disease in 32.2%; partial regression was achieved with bevacizumab in 1 of 10, immune checkpoint inhibitors in 1 of 6 and peptide receptor radionuclide therapy in 3 of 11 patients.

Procedural / Surgical Therapy

Transsphenoidal Surgery

• Transsphenoidal surgery is first-line therapy for somatotroph, corticotroph and thyrotroph tumors and for nonfunctioning adenomas that cause mass effect or approach the optic chiasm.
• In the prospective multicenter TRANSSPHER study of nonfunctioning adenomas, gross-total resection was achieved in 80.0% (60/75) of microscopic and 83.7% (139/166) of endoscopic procedures (P = 0.47), although the microscopic surgeons were more experienced. Volumetric extent of resection, length of stay and unplanned readmissions were similar; new hormone deficiency at 6 months was more frequent after microscopic surgery (28.4% versus 9.7%, OR 3.7, 95% CI 1.7 to 7.7), and microscopic procedures were shorter.
• Increasing Knosp grade predicts surgically confirmed cavernous sinus invasion and lower rates of gross-total resection and endocrine remission; in grade 4 adenomas, both rates were 0%.
• Prolactinoma: in a meta-analysis, long-term remission was 67% (95% CI 60 to 74) after transsphenoidal surgery and 83% (95% CI 76 to 90) in microprolactinomas, compared with 34% and 36%, respectively, after dopamine agonist withdrawal, with 0% surgical mortality. Refinement of endoscopic neurosurgery allows definitive cure of some patients with permanent discontinuation of medical therapy.
• Acromegaly: repeat surgery is suggested for residual intrasellar disease, and surgical debulking of tumors unlikely to be fully resected may improve the response to subsequent medical therapy.
• Cushing's disease: initial resection of the corticotroph tumor is recommended unless surgery is not possible or is unlikely to reduce glucocorticoid excess significantly.
• Surgery should be performed by experienced pituitary surgeons in specialized centers.

Radiotherapy and Stereotactic Radiosurgery

• Radiotherapy is a second- or third-line treatment after transsphenoidal surgery for functioning and nonfunctioning adenomas; its use has declined with improvements in surgical technique and medical therapy and with a shift from fractionated radiotherapy to stereotactic radiosurgery in appropriately selected patients.
• A Pituitary Society Delphi panel of 29 international experts reached consensus on 24 of 27 statements (88.9%): radiotherapy indication and timing should be assessed by multidisciplinary tumor boards that include a radiation oncologist, the technique should be determined by patient and adenoma characteristics, hormone secretion in functioning adenomas should be controlled while awaiting the maximal effect of radiotherapy, and follow-up beyond 10 years is required to assess delayed efficacy, recurrence and side effects.
• In a multicenter study of 512 patients with nonfunctioning adenomas (93.6% with prior resection) treated with Gamma Knife radiosurgery at a median tumor margin dose of 16 Gy, actuarial tumor control was 98%, 95%, 91% and 85% at 3, 5, 8 and 10 years. Smaller adenoma volume was associated with progression-free survival; new or worsened hypopituitarism occurred in 21%, new or progressive cranial nerve deficits in 9%, and new or worsening optic nerve dysfunction in 6.6%.
• In aggressive tumors, responses to temozolomide were more frequent with concomitant radiotherapy.

Bilateral Adrenalectomy

• Bilateral adrenalectomy is a second-line option in Cushing's disease that must be individualized. In a Swedish nationwide cohort, bilateral adrenalectomy was independently associated with increased mortality among patients in remission.

Long-Term Management

Hormone Replacement

• Replacement of pituitary hormone deficiencies should avoid both over-replacement and under-replacement to decrease the risk of comorbidities.
• Free T4 rather than TSH is used to monitor replacement in central hypothyroidism, and glucocorticoid replacement is usually given as hydrocortisone 15 to 20 mg daily in single or divided doses, with education on stress dosing.
• Untreated gonadotropin deficiency was associated with excess mortality (SMR 2.97, 2.13 to 4.13, compared with 1.42, 0.97 to 2.07, when treated).
• The term arginine vasopressin deficiency is recommended in place of central diabetes insipidus.

Surveillance of Nonfunctioning Adenomas and Incidentalomas

• The Endocrine Society recommends MRI at 6 months for macroincidentalomas and at 1 year for microincidentalomas, thereafter progressively less frequently if unchanged; visual field examination at 6 months and yearly for lesions abutting or compressing the optic apparatus; and endocrine testing at 6 months and yearly for macroincidentalomas.
• UK cohort data support less intensive protocols. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of growth or clinical manifestations is a safe approach for nonfunctioning microadenomas, and in macroadenomas not in contact with the optic chiasm the first follow-up scan can be delayed to 1 year, while new hypopituitarism in stable tumors is rare.
• After radiotherapy, follow-up for more than 10 years is required.

Acromegaly

• Biochemical remission is the primary measure of treatment outcome but should be interpreted within the clinical context; follow-up should combine biochemical evaluation, imaging for residual or recurrent adenoma, and assessment of clinical signs, complications and comorbidities, with referral to a multidisciplinary pituitary center for patients insufficiently responsive to standard treatment.
• The Endocrine Society suggests an age-normalized IGF-I and a random growth hormone below 1.0 μg/L as therapeutic goals.
• Mortality is normalized with biochemical control.

Cushing's Disease

• Late-night salivary cortisol is widely used for monitoring after pituitary surgery and after medical or radiation therapy.
• Several comorbidities persist even after remission and can affect quality of life, so they require continued management.
• Excess mortality persists in remission, highlighting the importance of continued active surveillance, adequate hormone replacement and evaluation of cardiovascular risk and mental health.

Prolactinoma

• Hyperprolactinemia recurs in a considerable proportion of patients after dopamine agonist withdrawal, so prolactin should be monitored after discontinuation.

Special Populations

Pregnancy

• Counseling of premenopausal women about their chance of conceiving and about the optimal preconception treatment should start at diagnosis. The normal physiological changes of pregnancy must be considered when interpreting endocrine tests, and hormone replacement doses may need adjustment across the trimesters.
• Pituitary gland size increases in healthy pregnancy and some adenomas enlarge, so women with macroadenomas or tumors near the optic chiasm are at risk of visual impairment; pituitary apoplexy is a rare acute complication that may require surgery. Most pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a specialized center.
• In women with prolactinomas, dopamine agonist therapy is generally discontinued once pregnancy is confirmed.
• In acromegaly, discontinuation of long-acting somatostatin receptor ligands and pegvisomant approximately 2 months before attempts to conceive is suggested.

Children and Adolescents

• Prolactinomas accounted for 75% of pituitary adenomas diagnosed between 0 and 20 years of age.
• Genetic causes should be considered: X-linked acrogigantism presents with gigantism in early childhood, germline AIP mutations cause large adenomas in children, adolescents and young adults, with gigantism in more than one third of affected somatotropinoma patients, and MEN1 recommendations address both adults and children.
• Prolactinoma management in children is addressed in the AME/ICCE position statement.

Hereditary Syndromes

• MEN1 mutation carriers require periodic clinical, biochemical and radiological screening.
• AIP-mutated adenomas raise clinical challenges to successful treatment.

Older Adults

• Nonfunctioning adenomas predominate after the age of 60 years. In conservatively managed nonfunctioning macroadenomas, new hypopituitarism was rare in stable tumors, supporting surveillance in selected patients.

Patients Receiving Dopamine Agonists

• All physicians who prescribe dopamine agonists need increased awareness of impulse control disorders, depression, mania and other psychoses, which can occur regardless of prior psychiatric history.

Case Studies

Case #1

Related Chapters

• Adult brain tumors
• Prolactinoma
• Acromegaly
• Cushing's disease
• Hypopituitarism
• Pituitary apoplexy
• Craniopharyngioma
• Multiple endocrine neoplasia type 1

External links

• Cancer.gov: pituitary tumors