Acromegaly

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Acromegaly
Acromegaly. Image courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California
ICD-10	E22.0
ICD-9	253.0
OMIM	102200
DiseasesDB	114
MeSH	D000172

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

Synonyms and keywords: Somatotroph adenoma; Growth hormone excess; Pituitary giant; Somatotroph pituitary neuroendocrine tumor (PitNET); GH-secreting pituitary adenoma; Somatotropinoma.

Overview

Acromegaly is a rare, chronic, multisystem disorder caused by sustained hypersecretion of growth hormone (GH) and the resulting excess of insulin-like growth factor 1 (IGF-I). In more than 95% of patients the source is a GH-secreting pituitary somatotroph tumor, which the 2022 World Health Organization classification names a PIT1-lineage pituitary neuroendocrine tumor (PitNET, formerly pituitary adenoma). Rare causes include ectopic secretion of growth hormone-releasing hormone (GHRH) by neuroendocrine tumors and hereditary syndromes such as familial isolated pituitary adenoma related to germline AIP variants, multiple endocrine neoplasia type 1, Carney complex, McCune-Albright syndrome and X-linked acrogigantism. When GH excess begins before closure of the epiphyseal growth plates, it causes gigantism. The disease develops insidiously, with acral enlargement, coarse facial features, prognathism, headache, hyperhidrosis, arthralgia and carpal tunnel syndrome, and diagnosis is commonly delayed by 5 to 10 years or more. Uncontrolled disease causes hypertension, cardiomyopathy, obstructive sleep apnea, diabetes mellitus, vertebral fractures, arthropathy and impaired quality of life, and is associated with excess mortality that is largely reversed by biochemical control. The diagnosis is established by an elevated age-adjusted serum IGF-I (a value greater than 1.3 times the upper limit of normal confirms the diagnosis in a patient with typical clinical features), with an oral glucose tolerance test reserved for equivocal results, followed by gadolinium-enhanced magnetic resonance imaging of the pituitary. Transsphenoidal surgery performed by an experienced pituitary surgeon is the first-line treatment for most patients. Persistent disease is treated with medical therapy, including first-generation somatostatin receptor ligands (octreotide and lanreotide, including oral octreotide capsules and a monthly subcutaneous octreotide depot), the oral SST2 agonist paltusotine, pasireotide, the GH receptor antagonist pegvisomant, cabergoline, or combinations of these agents, while stereotactic radiosurgery or fractionated radiotherapy is generally reserved for disease that is not controlled by surgery and medical therapy. Management is lifelong and is best delivered by a multidisciplinary team in a Pituitary Tumor Center of Excellence.

Historical Perspective

• In 1886, Pierre Marie used the term "acromegaly" for the first time and gave a full description of its clinical picture, although several physicians had described cases earlier, sometimes under other names.
• After 1886, it gradually became clear that pituitary enlargement caused by a pituitary adenoma was the cause, and not the consequence, of acromegaly, and that acromegaly and gigantism are the same disease occurring at different stages of life.
• In 1989, somatic mutations that inhibit the GTPase activity of the alpha chain of the stimulatory G protein (the "gsp" oncogene, encoded by GNAS) and stimulate adenylyl cyclase were identified in human GH-secreting pituitary tumors.
• In 2000, a randomized, placebo-controlled trial of the GH receptor antagonist pegvisomant reported normalization of IGF-I in 10%, 54%, 81% and 89% of patients receiving placebo, 10 mg/day, 15 mg/day and 20 mg/day, respectively.
• In 2006, germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were identified as a cause of pituitary adenoma predisposition.
• In 2014, Xq26.3 microduplications involving the orphan G protein-coupled receptor gene GPR101 were identified as the cause of X-linked acrogigantism (X-LAG).
• Biochemical criteria evolved through successive Acromegaly Consensus Conferences and guidelines:
  • The first Acromegaly Consensus Conference (Cortina, Italy, 1999) excluded acromegaly if random GH was less than 0.4 µg/L or the GH nadir during a 75-g oral glucose tolerance test (OGTT) was less than 1 µg/L, with a normal age- and sex-matched IGF-I.
  • The 2010 consensus no longer required an OGTT when IGF-I and GH were clearly elevated and proposed a nadir GH of less than 0.4 µg/L as a criterion of control when ultrasensitive assays are used.
  • The 2011 American Association of Clinical Endocrinologists guideline and the 2014 Endocrine Society guideline followed; the latter recommended confirming the diagnosis by lack of GH suppression to less than 1 µg/L after documented hyperglycemia during an oral glucose load.
  • The 14th Acromegaly Consensus Conference (published in 2024) concluded that an IGF-I greater than 1.3 times the upper limit of normal for age confirms the diagnosis in a patient with typical features, and that normalization of age-adjusted IGF-I is the primary biochemical remission target.
• In 2017, the International Pituitary Pathology Club proposed replacing the term "pituitary adenoma" with "pituitary neuroendocrine tumor" (PitNET), a terminology adopted by the 2022 World Health Organization classification; a 2021 nomenclature workshop recommended that the term "adenoma" be retained.
• Acromegaly Consensus Group recommendations on the diagnosis and treatment of disease complications were first published in 2003 and updated in 2013, 2020 and 2026.
• Oral octreotide capsules received United States Food and Drug Administration (FDA) approval in June 2020 for long-term maintenance treatment of patients who have responded to and tolerated octreotide or lanreotide.
• A subcutaneous octreotide depot (CAM2029, Oczyesa) received European Union marketing authorisation on 30 June 2025 for maintenance treatment, and the oral nonpeptide SST2 agonist paltusotine (Palsonify) received FDA approval in September 2025.

Classification

Acromegaly can be classified according to its cause, the size and invasiveness of the underlying tumor, the histopathologic (cell lineage) subtype of the tumor, and the age at onset of GH excess.

Classification by Etiology

More than 95% of patients with acromegaly have a somatotroph pituitary tumor, and approximately 70% of somatotroph tumors are macroadenomas at diagnosis. A minority of patients have an inherited or postzygotic genetic cause, including germline variants in AIP, MEN1, CDKN1B, MAX and PRKAR1A, Xq26.3 microduplications causing X-linked acrogigantism, and postzygotic gain-of-function GNAS variants in McCune-Albright syndrome. Very rarely, acromegaly results from ectopic GHRH secretion by a neuroendocrine tumor; in a French nationwide series of 21 patients, the primary tumor was identified in 20 patients (12 pancreatic, 7 bronchial and 1 appendicular), and 47.6% had metastasized at the time acromegaly was diagnosed.

Etiologic category	Examples	Comments
Sporadic pituitary somatotroph tumor (PIT1-lineage PitNET)	Densely or sparsely granulated somatotroph tumor; mammosomatotroph tumor; mixed somatotroph-lactotroph tumor; other PIT1-lineage tumors	More than 95% of cases; approximately 70% are macroadenomas
Hereditary or syndromic pituitary disease	Familial isolated pituitary adenoma (germline AIP variants); X-linked acrogigantism (Xq26.3 microduplication including GPR101); multiple endocrine neoplasia type 1 (MEN1); MEN4 (CDKN1B); Carney complex (PRKAR1A); MAX-related disease; McCune-Albright syndrome (postzygotic GNAS)	Enriched in familial acromegaly and in patients with childhood or adolescent onset of GH excess (pituitary gigantism)
Extrapituitary GHRH excess	Ectopic GHRH secretion by pancreatic, bronchial or other well-differentiated neuroendocrine tumors	Very rare; suspected when no pituitary tumor is identified; plasma GHRH and cross-sectional imaging identify the source

Classification by Tumor Size and Cavernous Sinus Invasion

Somatotroph tumors are classified as microadenomas (smaller than 10 mm) or macroadenomas (10 mm or larger), and macroadenomas account for approximately 70% of somatotroph tumors. Invasion of the cavernous sinus is graded on magnetic resonance imaging (MRI) with the Knosp classification, which was validated against surgical findings and later modified by dividing grade 3 into grade 3A (extension into the superior cavernous sinus compartment) and grade 3B (extension into the inferior compartment). In an endoscopic series of 137 pituitary macroadenomas, true cavernous sinus invasion was found in 9.9% of grade 2, 26.5% of grade 3A and 70.6% of grade 3B tumors, and all grade 4 tumors were invasive. Tumor size and invasiveness, particularly invasion of the cavernous sinus, are the main predictors of surgical remission, and Knosp grade correlates with surgical outcome.

Knosp grade	MRI definition (relative to the intracavernous and supracavernous internal carotid artery)	True invasion at endoscopic surgery
Grade 0	Tumor does not extend beyond the medial tangent of the carotid arteries	Not reported
Grade 1	Tumor extends beyond the medial tangent but not beyond the intercarotid line	Not reported
Grade 2	Tumor extends beyond the intercarotid line but not beyond the lateral tangent	9.9%
Grade 3A	Tumor extends beyond the lateral tangent into the superior cavernous sinus compartment	26.5%
Grade 3B	Tumor extends beyond the lateral tangent into the inferior cavernous sinus compartment	70.6%
Grade 4	Total encasement of the intracavernous internal carotid artery	All grade 4 tumors invasive

Histopathologic Classification

The 2022 WHO classification refers to well-differentiated adenohypophyseal tumors as pituitary neuroendocrine tumors (PitNETs; formerly pituitary adenomas) and subtypes them by cell lineage, endorsing routine immunohistochemistry for the transcription factors PIT1, TPIT, SF1, GATA3 and ERα. GH-secreting tumors belong to the PIT1 lineage. In the 2022 classification, mammosomatotroph and acidophil stem cell tumors are distinct PIT1-lineage PitNETs, and the former PIT1-positive plurihormonal category was replaced by the immature PIT1-lineage tumor (formerly silent subtype 3 tumor) and the mature plurihormonal PIT1-lineage tumor. Somatotroph tumors are further divided into densely granulated (DG) and sparsely granulated (SG) tumors, with a transitional group; in a series of 78 patients, acute and long-term responses to somatostatin analogues were lower in SG tumors (P = 0.001 and P = 0.043, respectively), whereas the transitional group behaved clinically like DG tumors. DG somatotroph tumors respond more favorably to the SST2-selective ligands octreotide and lanreotide, whereas SG tumors may respond more favorably to pasireotide, which has a higher affinity for somatostatin receptor subtype 5 (SST5). In a 2026 single-center series of 128 patients treated with surgery alone, 39% of tumors were DG, 22% SG and 39% GH- and prolactin-secreting (GH-PRL); SG tumors were diagnosed at a younger age, were larger, and expressed more SST5 and less SST2 than DG tumors, and remission at last follow-up was 80% for DG, 74% for GH-PRL and 57% for SG tumors (P = .091).

PIT1-lineage tumor type	Defining features	Clinical implications
Densely granulated somatotroph tumor	GH-expressing tumor with dense secretory granules	More responsive to first-generation somatostatin receptor ligands (SRLs)
Sparsely granulated somatotroph tumor	GH-expressing tumor with sparse secretory granules and fibrous bodies	Younger age at diagnosis, larger tumors, lower SST2 and higher SST5 expression; less responsive to first-generation SRLs and may respond better to pasireotide
Mammosomatotroph and mixed somatotroph-lactotroph tumors	Tumors expressing both GH and prolactin	GH-PRL tumors were more often p53-positive and had a higher mitotic count than DG tumors in one series
Mature plurihormonal PIT1-lineage tumor	Expresses multiple PIT1-lineage hormones	Replaces part of the former PIT1-positive plurihormonal category
Immature PIT1-lineage tumor	Formerly silent subtype 3 tumor	Replaces part of the former PIT1-positive plurihormonal category
Acidophil stem cell tumor	Distinct PIT1-lineage PitNET	Recognized as a separate entity in the 2022 classification

Classification by Age at Onset

• Acromegaly and gigantism are the same disease occurring at different stages of life.
• GH excess that begins before closure of the epiphyseal growth plates produces accelerated linear growth and tall stature (gigantism); in an international study of 208 patients with pituitary gigantism, 163 (78.4%) were male.
• GH excess that begins after epiphyseal closure produces the classical acral and soft-tissue features of acromegaly.

Pathophysiology

Physiology of the GH/IGF-I Axis

• Growth hormone is secreted by pituitary somatotrophs under stimulation by hypothalamic growth hormone-releasing hormone (GHRH) and inhibition by somatostatin; GH acts through hepatic and peripheral GH receptors to stimulate production of insulin-like growth factor 1 (IGF-I), which mediates most of its growth-promoting effects and inhibits GH secretion by negative feedback.
• Serum IGF-I reflects GH action on peripheral tissues, primarily the liver, whereas serum GH reflects the secretory activity of the somatotroph tumor.
• GH also exerts direct metabolic effects; GH-induced insulin resistance is the main mechanism of the impaired glucose tolerance and diabetes mellitus seen in acromegaly.

Pathogenesis of Somatotroph Tumors

• Somatotroph tumors are monoclonal expansions of differentiated somatotrophs and are usually sporadic. Pituitary adenomas are found in about 10% of the population, but fewer than one in a thousand cause clinically significant disease.
• Somatic activating mutations of the stimulatory G protein alpha subunit gene (GNAS, the "gsp" oncogene) inhibit its GTPase activity and stimulate adenylyl cyclase, increasing intracellular cyclic AMP; gsp mutations are found in approximately 40% of somatotroph adenomas.
• Transcriptomic profiling of 58 somatotropinomas identified subtypes with different sensitivity to somatostatin analogues: sensitive tumors clustered in subgroups characterized by somatic GNAS mutation, PIT1 and SF1 co-expression, or expression of the stem-cell marker SOX2, whereas resistant tumors were enriched in genes related to the cell cycle and mesenchymal differentiation.
• Germline AIP variants cause familial isolated pituitary adenoma: in a population-based series from Northern Finland, two AIP mutations accounted for 16% of all patients with GH-secreting adenomas and 40% of those diagnosed before 35 years of age, and AIP behaves as a low-penetrance susceptibility gene. In an international study of 96 patients with AIP mutations and 232 controls, somatotropinomas in AIP mutation carriers presented about two decades earlier and showed less tumor shrinkage during somatostatin analogue therapy.
• X-linked acrogigantism is caused by Xq26.3 microduplications that include GPR101, which were found in 13 of 43 patients with gigantism, all with onset in early childhood; a GPR101 p.E308D variant was found in 11 of 248 patients with acromegaly. The duplications disrupt a topologically associating domain around GPR101 and create a new domain in which ectopic enhancers drive GPR101 overexpression; GPR101 is a constitutively active receptor that signals through multiple G proteins and protein kinases A and C to promote GH and prolactin hypersecretion.
• In Carney complex, inactivating heterozygous mutations of PRKAR1A, which encodes the regulatory subunit 1α of protein kinase A, are identified in more than 70% of index cases, making the syndrome a model of dysregulated cyclic AMP and protein kinase A signaling.
• Multiple endocrine neoplasia type 1 is an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, which encodes the 610-amino acid protein menin; first-degree relatives of affected patients have a 50% risk of developing the disease.
• McCune-Albright syndrome is caused by postzygotic gain-of-function GNAS variants.

Somatostatin Receptor Expression and Treatment Response

• Somatotroph tumors express somatostatin receptor subtypes 2 (SST2) and 5 (SST5). Octreotide and lanreotide are SST2-selective, whereas pasireotide has a higher affinity for SST5; SST2 expression is associated with response to octreotide and lanreotide, and higher SST5 expression with response to pasireotide.
• In 36 patients, an SST2A immunoreactivity score of 5 or higher predicted IGF-I normalization during adjuvant octreotide therapy with a sensitivity of 86% and a specificity of 91%.
• In tumors resistant to first-generation somatostatin analogues, higher SST5 immunostaining was associated with response to pasireotide.
• Paltusotine is a nonpeptide selective SST2 agonist taken orally once daily.
• Pegvisomant is a GH receptor antagonist; serum GH rises during pegvisomant therapy and falls back to baseline within 30 days of withdrawal, so treatment efficacy is assessed by IGF-I alone.

Mechanisms of Clinical Manifestations

• Excess GH and IGF-I cause overgrowth of soft tissue, cartilage and bone, producing acral enlargement, coarse facial features, prognathism and arthropathy.
• Swelling of the upper airway soft tissues causes snoring and obstructive sleep apnea, which improve after treatment.
• Hypertension is related to insulin resistance, expansion of the extracellular water compartment, increased peripheral vascular resistance and sleep apnea, and these effects may not be fully reversible.
• GH excess increases bone turnover; in a meta-analysis of 41 studies (1935 patients), bone formation (standardized mean difference [SMD] 1.49; 95% CI 0.97-2.01) and resorption (SMD 1.57; 95% CI 1.03-2.10) markers were higher than in controls, lumbar spine bone mineral density (BMD) did not differ, and vertebral fractures were more frequent (odds ratio 8.26; 95% CI 2.91-23.39). Vertebral fractures may occur despite normal or increased BMD because bone quality deteriorates.
• Erythrocyte counts are increased and correlate with IGF-I values.
• Expansion of the pituitary tumor may cause headache, visual field defects and hypopituitarism, and associated prolactin hypersecretion may cause erectile dysfunction in men or menstrual disturbances in women.

Causes

• Pituitary somatotroph tumor: A GH-secreting somatotroph tumor is the cause in more than 95% of patients. Tumors that secrete both GH and prolactin also occur.
• Hereditary and syndromic causes: Germline variants in AIP, MEN1, CDKN1B, MAX and PRKAR1A, Xq26.3 microduplications (X-linked acrogigantism) and postzygotic GNAS variants (McCune-Albright syndrome) cause familial acromegaly and pituitary gigantism; emerging candidate genes include NF1, PRKACB, PAM and CHEK2. Nearly half of patients with pituitary gigantism have an identifiable genetic cause, and X-linked acrogigantism accounts for about 10% of pituitary gigantism.
• Ectopic GHRH secretion: Well-differentiated neuroendocrine tumors of the pancreas, bronchus or appendix may secrete GHRH and cause acromegaly; in the French nationwide series, median plasma GHRH was 548 (range 270-9779) ng/L.

Differentiating Acromegaly from other Diseases

Pseudoacromegaly describes conditions in which patients have acromegaloid physical features or tall stature but no excess of GH or IGF-I; because many of these conditions have a genetic origin, such as pachydermoperiostosis, Sotos syndrome, Weaver syndrome or Cantú syndrome, collaboration with clinical geneticists is often required. Elevated IGF-I must also be interpreted in context: results can be affected by pregnancy, estrogen use, starvation and metabolic changes, reference intervals change with age, and reference ranges and patient classification differ between commercial assays.

Condition	Clinical features	GH and IGF-I axis	Distinguishing evaluation
Acromegaly due to a pituitary somatotroph tumor	Acral and facial enlargement, prognathism, hyperhidrosis, headache, sleep apnea, diabetes mellitus	IGF-I elevated for age (greater than 1.3 times the upper limit of normal confirms the diagnosis with typical features); GH not suppressed during an OGTT when performed	Pituitary MRI shows a somatotroph tumor, a macroadenoma in about 70%
Acromegaly due to ectopic GHRH secretion	Acromegaly phenotype with features of the underlying neuroendocrine tumor	IGF-I elevated; plasma GHRH elevated	No discrete pituitary adenoma; computed tomography or somatostatin receptor scintigraphy identifies a pancreatic, bronchial or appendicular tumor
Pituitary gigantism, including X-linked acrogigantism and AIP-related disease	Accelerated linear growth and tall stature beginning before epiphyseal closure; X-linked acrogigantism typically begins in infancy	GH and IGF-I elevated; prolactin frequently elevated in X-linked acrogigantism	Pituitary MRI; genetic testing for AIP variants and Xq26.3 microduplication
Insulin-mediated pseudoacromegaly and lipodystrophy syndromes	Acromegaloid features with severe insulin resistance	Normal GH suppression and normal IGF-I	Marked hyperinsulinemia; normal pituitary imaging
Pachydermoperiostosis (primary hypertrophic osteoarthropathy)	Digital clubbing, thickened facial and scalp skin, periostosis	Normal	Radiographic periostosis; genetic testing
Hypothyroidism	Coarse facial features, macroglossia, myxedema, carpal tunnel syndrome	Normal GH axis	Elevated thyroid-stimulating hormone with low free thyroxine in primary hypothyroidism
Sotos syndrome, Weaver syndrome and other overgrowth syndromes	Childhood overgrowth with characteristic facial features	Normal	Clinical genetic evaluation
Cantú syndrome	Hypertrichosis with coarse facial features	Normal	Clinical genetic evaluation
Marfan syndrome and constitutional tall stature	Tall stature without acral soft-tissue overgrowth	Normal for age	Clinical and genetic evaluation
Physiologic or assay-related IGF-I elevation	Pregnancy, adolescence; no acromegaly features	IGF-I interpreted against age-specific reference intervals; results differ between assays	Repeat IGF-I with the same validated assay; interpret in clinical context

Epidemiology and Demographics

Prevalence

• In a 2021 systematic review and meta-analysis of 32 studies, 22 of which were pooled, the global prevalence of acromegaly was 5.9 (95% CI 4.4-7.9) per 100,000 persons, with considerable between-study heterogeneity (I² = 99.3%).
• In a Danish nationwide cohort, the prevalence in 2010 was 85 cases per 1,000,000 persons.
• In a large United States commercial health plan database (2008-2012), the annual prevalence was approximately 78 cases per 1,000,000, increasing with age from 29-37 per 1,000,000 among children aged 0-17 years to 148-182 per 1,000,000 among adults aged 65 years and older.
• The prevalence in France is estimated at approximately 60 cases per 1,000,000.
• Acromegaly is underdiagnosed: in the DETECT study, screening of 6773 unselected adult primary care patients for elevated IGF-I identified biochemical acromegaly at a rate corresponding to 1034 per 1,000,000 patients.

Incidence

• The pooled global incidence rate was 0.38 (95% CI 0.32-0.44) cases per 100,000 person-years (I² = 86.0%).
• In Denmark (1991-2010), the annual incidence was 3.8 cases per 1,000,000 persons (95% CI 3.6-4.1) and remained stable over two decades.
• In the Swedish Pituitary Register (1991-2011), the annual incidence was 3.7 per 1,000,000, and 71% of patients had a macroadenoma.
• In the United States health plan analysis, the annual incidence was approximately 11 cases per 1,000,000 person-years and increased with age.

Age

• Onset peaks in the fourth decade of life.
• The mean age at diagnosis was 48.7 years (95% CI 47.2-50.1) in the Danish cohort.
• In the Liège Acromegaly Survey of 3173 patients from 10 countries, men were diagnosed at a younger age than women (43.5 vs 46.4 years; P < 0.001), the ages at diagnosis and at first symptoms increased over time, and tumor size and invasion were inversely related to age.

Sex

• Women made up 54.5% of the Liège Acromegaly Survey, and the median delay from first symptoms to diagnosis was 2 years longer in women.
• A Korean population-based study of 718 patients found a slightly higher incidence in women, and most studies agree that men are diagnosed younger, by a median of 4.5 years.
• In the United States health plan analysis, prevalence was similar in men and women (approximately 77 per 1,000,000 each), while incidence averaged 12 cases per 1,000,000 person-years in women and 10 in men.
• Pituitary gigantism shows a marked male predominance (78.4% of 208 patients).

Geographic Distribution

• In the United States, incidence ranged from 7 cases per 1,000,000 person-years in the Midwest to 14 in the Northeast, and prevalence from 57 per 1,000,000 in the Midwest to 92 in the Northeast.
• Data source and geographic area explained about 50% of the between-study variability in the global meta-analysis.

Risk Factors

• Most cases of acromegaly are sporadic.
• Genetic predisposition: germline variants in AIP, MEN1, CDKN1B, MAX and PRKAR1A, Xq26.3 microduplications (X-linked acrogigantism) and postzygotic GNAS variants (McCune-Albright syndrome).
• Young age at onset: in Northern Finland, AIP mutations accounted for 40% of patients with GH-secreting adenomas diagnosed before 35 years of age. In 208 patients with pituitary gigantism, AIP mutations were found in 29%, while more than 50% had no identified genetic cause.
• Family history: a family history of pituitary tumors, or a personal or family history of multiple endocrine neoplasia type 1 or Carney complex, indicates a hereditary cause.

Screening

• Case finding: The Endocrine Society recommends measuring serum IGF-I in patients with typical clinical manifestations of acromegaly, especially acral and facial features; suggests considering acromegaly in patients without typical manifestations who have several associated conditions (sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis and hypertension); and recommends measuring IGF-I in all patients with a pituitary mass. The Endocrine Society pituitary incidentaloma guideline likewise recommends laboratory screening for hormone hypersecretion in patients with a pituitary incidentaloma.
• Underdiagnosis: Screening of primary care patients for elevated IGF-I suggests a high prevalence of undiagnosed acromegaly.
• Targeted biochemical screening: Among 2270 adults aged 20 to 70 years with diabetes mellitus or glucose intolerance in whom acromegaly had not been suspected, IGF-I screening followed by an OGTT identified 6 patients with persistently elevated IGF-I and inadequate GH suppression, 3 of whom had a pituitary adenoma on MRI, corresponding to an estimated prevalence of 480 cases per 1,000,000 adults; the cost-effectiveness of biochemical screening in such groups requires further study.
• Reducing diagnostic delay: The 2024 Acromegaly Consensus Conference recommended implementing strategies to reduce diagnostic delay worldwide, because prolonged exposure to GH excess increases comorbidity and mortality and impairs quality of life. Artificial intelligence applied to facial recognition may shorten diagnostic delay, but ethical issues, privacy and performance in diverse populations remain challenges. In a study of 57 patients and 60 matched controls, face classification software correctly classified 71.9% of patients, compared with 63.2% by acromegaly experts and 42.1% by general internists, with the largest differences in patients with mild facial features.
• Genetic screening: In a 12-year prospective study of familial isolated and young-onset pituitary tumors, AIP mutation carriers identified by screening (n = 22) had smaller lesions than those who presented clinically (n = 145). In multiple endocrine neoplasia type 1, presymptomatic tumor detection may improve prognosis, and mutation carriers should be followed by multidisciplinary teams; the 2025 best-practice guideline provides 55 recommendations for adults and children. Genetic testing for familial acromegaly and pituitary gigantism should be multimodal (next-generation sequencing, chromosomal microarray and droplet digital PCR), arranged by pituitary specialists and performed in accredited laboratories.

Natural History, Complications and Prognosis

Natural History

• Signs and symptoms of acromegaly are nonspecific and develop insidiously, and there may be a delay of 5 to 10 years or more between the first symptom and the diagnosis.
• In a Swedish nationwide cohort of 603 patients, the mean diagnostic delay (time from the first registered acromegaly-associated comorbidity) was 5.5 years (SD 6.2; median 3.3 years); the delay was 1 to less than 5 years in 23% of patients, 5 to less than 10 years in 17%, and 10 years or longer in 24%, and the number of comorbidities increased with longer delay.
• The risk of complications is already increased before diagnosis; the risk of diabetes mellitus is most pronounced in the 3 years preceding diagnosis.
• Delayed diagnosis allows continued tumor growth and invasion of the cavernous sinus, which limit the success of surgery regardless of surgical expertise.
• At diagnosis in the Liège Acromegaly Survey, diabetes mellitus was present in 27.5% of patients, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%; stroke, heart failure and myocardial infarction were present in less than 5%, thyroid nodules in 34.0%, colonic polyps in 13% of the 820 patients who underwent colonoscopy, and osteoporosis in 12.3%.
• In a systematic review of 124 studies, cardiovascular comorbidity at diagnosis was lower in more recent studies.

Complications

• Cardiovascular: Hypertension affects approximately 40% of patients and up to 60% in some series, occurs at a younger age than in the general population, and is more frequent with active disease; 24-hour ambulatory blood pressure monitoring is recommended for diagnosis and follow-up. Left ventricular hypertrophy has been reported in 11% to 78% of patients and diastolic dysfunction in 11% to 58%, although cardiac MRI found left ventricular hypertrophy in only 5%, suggesting overestimation by echocardiography; heart failure now occurs in 1% to 4% of patients, and valvular dysfunction, reported in up to 86%, is rarely clinically significant. In the Danish cohort, patients had an increased risk of heart failure (hazard ratio [HR] 2.5; 95% CI 1.4-4.5) and venous thromboembolism (HR 2.3; 95% CI 1.1-5.0). In a Finnish nationwide cohort of 565 patients and 5629 controls followed for a median of 17.2 years, cardiovascular morbidity increased years before diagnosis and remained elevated thereafter (HR 1.59; 95% CI 1.42-1.78), most markedly for diseases of the pulmonary arteries (HR 2.74), valvular diseases and cardiomyopathies (HR 2.68) and hypertension (HR 2.11); radiotherapy, hypopituitarism and post-treatment IGF-I above or below the reference range were associated with greater morbidity, which persisted even in patients in remission with normal pituitary function after surgery.
• Respiratory: Obstructive sleep apnea is present in up to 80% of newly diagnosed patients. The Danish cohort found an HR of 11.7 (95% CI 7.0-19.4) for sleep apnea. In a meta-analysis of 24 studies (734 patients), the apnea-hypopnea index improved significantly after treatment (effect size -0.36; 95% CI -0.49 to -0.23).
• Metabolic: Diabetes mellitus affects about 30% of patients and dyslipidemia about 30%; acromegaly increases the risk of diabetes mellitus (HR 4.0; 95% CI 2.7-5.8), and diabetes increases overall mortality by 60% and doubles cardiovascular mortality.
• Skeletal and joints: Morphometric vertebral fractures have a median prevalence of 40%; incident vertebral fractures occurred in 34.3% of patients, and fracture progression occurred in 35% over a 9-year follow-up. Arthropathy risk is increased (HR 2.1; 95% CI 1.6-2.6), and joint space narrowing affects 10% to 15% of patients with controlled acromegaly.
• Neoplastic: In a Swedish matched cohort of 1035 patients and 10,261 controls, acromegaly was associated with higher adjusted hazards of all cancer (HR 1.28; 95% CI 1.11-1.49), colorectal cancer (HR 1.84; 95% CI 1.28-2.64), lung cancer (HR 1.95; 95% CI 1.22-3.11), hematologic cancer (HR 1.68; 95% CI 1.03-2.73) and breast cancer in women (HR 1.46; 95% CI 1.02-2.11), starting 5 years before diagnosis. In a Danish cohort of 529 patients, the overall cancer standardized incidence ratio (SIR) was 1.1 (95% CI 0.9-1.4), while a meta-analysis of 23 studies yielded an overall SIR of 1.5 (95% CI 1.2-1.8), with elevated SIRs for colorectal (2.6), thyroid (9.2), breast (1.6), gastric (2.0) and urinary tract (1.5) cancers; SIRs were higher in single-center studies and in small studies, suggesting selection bias. In a Danish nationwide cohort of 809 biochemically validated patients followed for up to 44 years and 80,900 matched controls, overall cancer risk was not clearly increased (incidence rate ratio [IRR] 1.10 [0.93-1.30]), whereas the risks of colorectal cancer (IRR 1.78 [1.22-2.60]), thyroid cancer (IRR 3.68 [1.16-11.66]) and benign colorectal lesions (IRR 2.32 [1.96-2.76]) were increased, and cancer-specific mortality was not increased (IRR 0.95 [0.72-1.25]). The Pituitary Society concluded that the rate of thyroid malignancy is not greater than in the general population and that, after a screening colonoscopy at diagnosis, further colon surveillance should follow general population recommendations.
• Endocrine: Tumor mass effect or treatment may cause hypopituitarism, which should be assessed and treated.
• Renal and psychological: Kidney function should be assessed at diagnosis, and anxiety and depression should be assessed and monitored.
• Quality of life: Fatigue, musculoskeletal pain, arthropathy, sleep disturbance and body-image concerns are highly prevalent and frequently persist despite biochemical remission, and health-related quality of life remains impaired in physical, psychological and social domains. In a meta-analysis of 46 studies (3301 patients), symptoms and health-related quality of life improved during treatment: the AcroQoL score increased by 2.9 points (95% CI 0.5-5.3), and the Patient-Assessed Acromegaly Symptom Questionnaire score changed by -2.3 points (95% CI -1.3 to -3.3).

The 2026 Acromegaly Consensus Conference statement on complications (16th conference, 43 experts) summarized the following evaluations.

Complication	Reported frequency	Recommended evaluation
Hypertension	About 40% (up to 60% in some series)	24-hour ambulatory blood pressure monitoring at diagnosis and during follow-up
Cardiomyopathy and valvular disease	Left ventricular hypertrophy 11% to 78% on echocardiography (5% on cardiac MRI); heart failure 1% to 4%	Baseline assessment of cardiac function and morphology at diagnosis, individualized thereafter
Obstructive sleep apnea	Up to 80% at diagnosis	Sleep questionnaire plus polysomnography or respiratory polygraphy at baseline, with regular monitoring
Diabetes mellitus and dyslipidemia	About 30% each	Fasting plasma glucose, hemoglobin A1c and lipids at diagnosis and during follow-up
Vertebral fractures and bone disease	Median prevalence of morphometric vertebral fractures 40%	Vitamin D status; vertebral morphometry on spine radiograph, lateral DXA scan or chest radiograph; DXA bone mineral density and trabecular bone score
Colonic neoplasia	Polyps in 13% of patients undergoing colonoscopy at diagnosis	Colonoscopy at diagnosis according to country-specific general guidelines
Thyroid nodules	34.0% at diagnosis	Thyroid ultrasound if the thyroid is palpably nodular
Arthropathy	Joint space narrowing in 10% to 15% of controlled patients	Early clinical joint assessment, with radiologic evaluation as needed
Kidney function	Not stated	Glomerular filtration rate at diagnosis
Quality of life, anxiety and depression	Impaired quality of life is common	Disease-specific questionnaires; screening for anxiety and depression

Prognosis

• Untreated acromegaly is associated with a 30% decrease in life span.
• In a meta-analysis, patients with a final random GH less than 2.5 µg/L had a standardized mortality ratio (SMR) of 1.1 (95% CI 0.9-1.4), compared with 1.9 (95% CI 1.5-2.4) when GH remained above 2.5 µg/L; a normal IGF-I at last follow-up was associated with an SMR of 1.1 (95% CI 0.9-1.4), compared with 2.5 (95% CI 1.6-4.0) when IGF-I remained elevated.
• In a meta-analysis of 26 studies, mortality was increased in 17 studies published before 2008 (SMR 1.76; 95% CI 1.52-2.4) but was not different from the general population in 9 studies published after 2008 (SMR 1.35; 95% CI 0.99-1.85); mortality was not increased when somatostatin analogues were used as adjuvant therapy (SMR 0.98; 95% CI 0.83-1.15) but was higher in series treated only with surgery and/or radiotherapy (SMR 2.11; 95% CI 1.54-2.91), and mortality was normalized in patients who achieved biochemical control.
• In a Swedish nationwide cohort of 1089 patients, the overall SMR was 2.79 (95% CI 2.43-3.15), driven mainly by circulatory diseases (SMR 2.95; 95% CI 2.35-3.55), including ischemic heart disease (SMR 2.00; 95% CI 1.35-2.66) and cerebrovascular disease (SMR 3.99; 95% CI 2.42-5.55), and by malignancy (SMR 1.76; 95% CI 1.27-2.26); mortality decreased from an SMR of 3.45 (95% CI 2.87-4.02) for patients diagnosed in 1987-1995 to 1.86 (95% CI 1.04-2.67) for those diagnosed in 2005-2013, as the use of pituitary surgery increased from 58% to 72% and the prevalence of hypopituitarism decreased from 41% to 23%.
• In the Swedish Pituitary Register (698 patients diagnosed in 1991-2011), the overall SMR was 1.29 (95% CI 1.11-1.49); mortality was not increased in patients with biochemical control at the latest follow-up (SMR 1.06 [95% CI 0.85-1.33] for patients diagnosed in 1991-2000 and 0.87 [95% CI 0.61-1.24] for those diagnosed in 2001-2011) but remained elevated in noncontrolled patients (SMR 1.90 [95% CI 1.33-2.72] and 1.98 [95% CI 1.24-3.14], respectively). In contrast, in an Italian nationwide survey of 811 patients with a mean observation period of 15 years, mortality was increased overall (SMR 1.7; 95% CI 1.4-2.0) and remained elevated in patients with disease control (SMR 1.3; 95% CI 1.1-1.6), and oncological causes of death outweighed cardiovascular causes.
• Prolonged diagnostic delay is associated with higher mortality: the SMR was 1.45 (95% CI 1.11-1.86) overall, 1.76 (95% CI 1.12-2.65) in patients with the longest delay, and 1.18 (95% CI 0.68-1.92) in patients without delay.
• In the Danish cohort, overall mortality was elevated (HR 1.3; 95% CI 1.0-1.7) but was not influenced by treatment modality.
• Persistently elevated IGF-I was associated with higher overall mortality (HR 1.50; 95% CI 1.10-2.01) but not with higher cancer incidence or cancer mortality compared with biochemically controlled patients.
• Cancer has become a leading cause of death in acromegaly as life expectancy has improved.
• Structural cardiac and joint changes are unlikely to resolve after biochemical control, whereas glucose metabolism, obstructive sleep apnea and cardiovascular outcomes improve.

Diagnosis

History and Symptoms | Physical Examination | Laboratory findings | x ray | CT | MRI | Ultrasound | Other imaging findings | Other diagnostic studies

Diagnostic Study of Choice

• Serum IGF-I, measured with a validated assay and interpreted against age-specific reference ranges, is the initial biochemical test.
• In a patient with typical clinical features, an IGF-I greater than 1.3 times the upper limit of normal (ULN) for age confirms the diagnosis; random GH measured after an overnight fast may inform prognosis and complications but is not required for diagnosis.
• For equivocal results, IGF-I can be repeated using the same validated assay, and an OGTT may be useful. The 2014 Endocrine Society guideline recommends against relying on random GH to diagnose acromegaly and recommends confirming an elevated or equivocal IGF-I by lack of GH suppression to less than 1 µg/L following documented hyperglycemia during an oral glucose load.
• After biochemical confirmation, gadolinium-enhanced pituitary MRI is performed; computed tomography is used when MRI is contraindicated or unavailable.
• Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology or imaging findings at diagnosis.

Diagnostic Algorithm

Clinical suspicion of acromegaly (typical acral and facial features, several associated conditions, or a pituitary mass)

Measure serum IGF-I (validated assay, age-specific reference range)

IGF-I normal for age: acromegaly unlikely

IGF-I equivocal or mildly elevated: repeat IGF-I with the same assay

IGF-I above 1.3 times ULN with typical features: diagnosis confirmed

OGTT with 75 g glucose (GH at 30, 60, 90 and 120 min): absent GH suppression supports the diagnosis

Gadolinium-enhanced pituitary MRI (T1 and T2 sequences, 2-3 mm slices)

Somatotroph tumor identified: visual fields if the chiasm is involved, pituitary function and prolactin

No adenoma identified: expert neuroradiology review; plasma GHRH and cross-sectional imaging; consider 11C-methionine PET

Comorbidity assessment and referral to a multidisciplinary pituitary center

Ectopic GHRH-secreting neuroendocrine tumor or MRI-occult pituitary tumor

History and Symptoms

A systematic review of 124 studies reported the following weighted mean prevalence of clinical signs and symptoms at diagnosis: acral enlargement 90%, facial changes 65%, oral changes 62%, headache 59%, fatigue or tiredness 53% (including daytime sleepiness 48%), hyperhidrosis 47%, snoring 46%, oily skin 37%, thicker skin 35%, weight gain 36% and arthralgia 34%. The features that most often led to the diagnosis were typical physical changes (acral enlargement, facial changes and prognathism), local tumor effects (headache and visual defects), diabetes mellitus, thyroid cancer and menstrual disorders. Patients may also report symptoms of associated prolactin hypersecretion (erectile dysfunction in men or menstrual cycle disorders in women) or of mass-induced hypopituitarism, such as fatigue.

Symptom or sign at diagnosis	Weighted mean prevalence
Acral enlargement	90%
Facial features	65%
Oral changes	62%
Headache	59%
Fatigue or tiredness (daytime sleepiness)	53% (48%)
Hyperhidrosis	47%
Snoring	46%
Oily skin	37%
Weight gain	36%
Thicker skin	35%
Arthralgia	34%

Physical Examination

• Acral and facial changes: enlargement of the hands and feet, coarsening of the facial features, frontal bossing, prognathism, macroglossia and dental malocclusion.
• Skin: thickened and oily skin and hyperhidrosis.
• Musculoskeletal: arthropathy, carpal tunnel syndrome and kyphosis.
• Cardiovascular: elevated blood pressure.
• Neck: thyroid nodularity; thyroid nodules were present in 34.0% of patients at diagnosis.
• Eyes: visual field defects, typically bitemporal hemianopia, when the tumor compresses the optic chiasm; formal visual field testing is suggested when the tumor abuts the chiasm.
• Children and adolescents: accelerated linear growth and tall stature (gigantism).

Laboratory Findings

IGF-I

• IGF-I should be measured with a well-validated assay, and the same assay should be used throughout follow-up of each patient. An international consensus recommended a commutable standard for each GH and IGF assay for worldwide use.
• Age-specific reference intervals are required; a multicenter study established IGF-I reference intervals from birth to senescence in 15,014 subjects using an automated chemiluminescence assay.
• Results differ between commercial assays: in 911 healthy adults measured with six immunoassays, the lower limits of the reference intervals were similar but the upper limits varied markedly, with pairwise concordance of 0.38 to 0.70; in 102 patients with GH disorders, agreement in classification between assays (weighted kappa) ranged from 0.50 to 0.81.
• IGF-I shows substantial intra-individual week-to-week variation, and reference upper limits in middle-aged and older adults are lower than historical ranges.
• New or persistent IGF-I elevations should be interpreted in the context of factors such as pregnancy, estrogen use, starvation and metabolic changes.

Growth Hormone and the Oral Glucose Tolerance Test

• Random GH is not recommended for the diagnosis of acromegaly.
• If an OGTT is performed, 75 g of glucose is given after an overnight fast and GH is measured at 30, 60, 90 and 120 minutes; glucose measured at baseline and 120 minutes also detects disturbances in glucose homeostasis.
• No glucose-suppressed GH cutoff definitively excludes acromegaly. Body mass index (BMI)-based nadir cutoffs of less than 0.4 µg/L for BMI below 25 kg/m² and less than 0.2 µg/L for BMI of 25 kg/m² or higher can be considered, although they may be assay-dependent; up to one-third of patients may show a paradoxical rise in GH after glucose.
• In 525 healthy adults (IDS-iSYS assay), mean GH nadirs in normal-weight vs overweight individuals were 0.124 vs 0.065 µg/L in men, 0.173 vs 0.078 µg/L in postmenopausal women, and 0.624 vs 0.274 µg/L in premenopausal women taking estradiol-containing oral contraceptives. Oral estrogen therapy may be stopped 4 weeks before an OGTT to avoid its effects on the GH axis.
• The OGTT can be performed safely in patients with impaired glucose tolerance or type 2 diabetes mellitus, but random and post-glucose GH levels should be interpreted with caution in uncontrolled diabetes.

Other Laboratory Tests

• Prolactin, because some tumors co-secrete GH and prolactin.
• Assessment of the other pituitary axes for hypopituitarism, with hormone replacement as indicated.
• Plasma GHRH when no pituitary tumor is found; in ectopic GHRH secretion, median GHRH was 548 (range 270-9779) ng/L, and rising GHRH during follow-up accurately indicated recurrence.
• Fasting plasma glucose, hemoglobin A1c and lipid profile.

Test	Role	Interpretation
Serum IGF-I	Initial test and primary marker of disease activity	Greater than 1.3 times ULN for age confirms the diagnosis with typical features; use the same validated assay during follow-up
Random (fasting) GH	Prognosis and complications	Not required and not relied upon for diagnosis
OGTT with GH measurement	Equivocal or mildly elevated IGF-I	Endocrine Society: GH not suppressed to less than 1 µg/L confirms; consensus: BMI-based nadir cutoffs of less than 0.4 µg/L (BMI below 25 kg/m²) or less than 0.2 µg/L (BMI 25 kg/m² or higher) can be considered
Prolactin and other pituitary hormones	Co-secretion and hypopituitarism	Treat deficiencies according to hypopituitarism guidelines
Plasma GHRH	No pituitary tumor identified	Elevated in ectopic GHRH secretion

Imaging Findings

MRI

• Gadolinium-enhanced pituitary MRI should be performed in all patients at diagnosis using high-quality equipment, such as 1.5 T or 3 T scanners, with T1- and T2-weighted fast spin echo sequences in coronal and sagittal planes and 2-3 mm slice thickness.
• Tumor dimensions, suprasellar and infrasellar extension, cystic components, and T2 signal intensity relative to the temporal lobe help predict treatment response. In 120 patients receiving primary somatostatin analogue therapy, 84 tumors were T2-hypointense, 17 isointense and 19 hyperintense; hypointense tumors had median decreases in GH and IGF-I of 88% and 59%, significantly greater than in isointense and hyperintense tumors (P < 0.001), and tumor shrinkage of 38%, compared with 8% and 3% in isointense and hyperintense tumors (P < 0.0001). In 45 newly diagnosed patients, 27% of adenomas were hypointense, 33% isointense and 40% hyperintense; in the 25 patients treated first with long-acting somatostatin analogues, median IGF-I reductions were 51%, 36% and 13%, respectively (P = 0.03), and T2 hyperintensity was associated with a sparsely granulated pattern.
• Cavernous sinus invasion is graded with the Knosp classification (see Classification).
• An equivocal diagnosis associated with a pituitary microadenoma should be reviewed by an experienced neuroradiologist before further imaging is considered.
• A standardized, tiered approach to pituitary imaging, guided by patient features and the anticipated treatment, has been proposed.

CT

• Pituitary computed tomography is used when MRI is contraindicated or unavailable.
• Cross-sectional imaging of the chest and abdomen is used to locate an ectopic GHRH-secreting tumor; in the French series, tumors measured 10-80 mm and were identified by computed tomography in 18 of 20 cases.

X-ray

• Vertebral fractures are often silent and should be screened for at diagnosis by vertebral morphometry on a spine radiograph, a lateral DXA scan, or a chest radiograph obtained for another indication.

Ultrasound

• Thyroid ultrasound is suggested when the thyroid is palpably nodular.
• Routine abdominal ultrasound to screen for gallstones in patients receiving somatostatin receptor ligands is not suggested; imaging is reserved for symptoms.
• Echocardiography is used for baseline assessment of cardiac function and morphology, although it may overestimate left ventricular hypertrophy compared with cardiac MRI.

Other Imaging Findings

• 11C-methionine positron emission tomography may help localize a tumor when MRI cannot identify an adenoma at diagnosis or, more often, residual tumor in patients with persistent GH hypersecretion; its availability is limited.
• Somatostatin receptor scintigraphy had a sensitivity similar to computed tomography (81% vs 86%) for locating ectopic GHRH-secreting tumors.
• Dual-energy X-ray absorptiometry (DXA) measures bone mineral density and trabecular bone score; in patients with low bone mineral density, DXA is repeated every 18 to 24 months.

Other Diagnostic Studies

• Histopathology: Somatotroph tumors are defined by GH immunohistochemistry, and standard pathology reports should include immunohistochemistry for pituitary hormones. Transcription factor staining assigns the tumor lineage. A clinicopathologic classification that combines Knosp grade, sphenoid sinus invasion, Ki-67 and mitotic count identifies tumors with potentially more aggressive behavior, and somatostatin receptor immunostaining, granulation pattern and mutation status may identify tumors less likely to respond to somatostatin receptor ligands.
• Visual field testing when the tumor abuts the optic chiasm.
• Sleep studies: polysomnography or respiratory polygraphy at baseline.
• Colonoscopy at diagnosis according to country-specific general guidelines.
• Genetic testing in young-onset, familial or syndromic disease, using next-generation sequencing, chromosomal microarray and droplet digital PCR.
• Clinical activity and patient-reported outcome tools: clinician-reported instruments such as SAGIT and ACRODAT and patient-reported measures can be considered when making treatment decisions. The 22-item Acromegaly Quality of Life Questionnaire (AcroQoL) contains physical and psychological scales.

Treatment

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

Goals of Treatment

• Biochemical control: normalization of age-adjusted serum IGF-I is the primary biochemical treatment target; the Endocrine Society also suggests a random GH less than 1.0 µg/L as a therapeutic goal. The 2020 multidisciplinary consensus considered that IGF-I values slightly above the upper limit of normal (for example, 1.2 to 1.3 times ULN) could be acceptable depending on the clinical scenario, and recommended relying on IGF-I when GH and IGF-I are discordant.
• Tumor control: control of tumor growth and, ideally, reduction of tumor size.
• Clinical control: relief of symptoms and active management of comorbidities, because symptoms and clinical manifestations can be dissociated from biochemical values.
• Survival and quality of life: biochemical control restores mortality toward that of the general population, and patient-centered outcomes, including quality of life and treatment burden, should be assessed.

Treatment Algorithm

Acromegaly confirmed: multidisciplinary evaluation at a Pituitary Tumor Center of Excellence

Surgical candidate: transsphenoidal surgery by an experienced pituitary surgeon

Surgery not feasible, declined or unlikely to cure: primary medical therapy; consider debulking surgery

IGF-I and random GH at 12 weeks; MRI at 3-6 months

Remission: normal age-adjusted IGF-I; long-term surveillance

Persistent disease

Medical therapy guided by response predictors: first-generation SRL (injectable or oral), paltusotine, pasireotide, pegvisomant, cabergoline or combinations

Controlled: continue therapy; IGF-I every 6-12 months

Uncontrolled or tumor growth: switch or combine drugs; consider repeat surgery or radiotherapy

Initial Management

• Referral to an expert center: Treatment is best determined by a multidisciplinary team in a Pituitary Tumor Center of Excellence (PTCOE) that includes pituitary neurosurgeons, endocrinologists, neuroradiologists, neuropathologists, radiation oncologists and specialized nurses. An audit of nine leading international centers proposed numerical PTCOE criteria, including 100 pituitary operations per center per year as preferred and 50 as acceptable; in these centers, the reported postsurgical remission rate for acromegaly macroadenomas was 49%, and the median control rate in medically treated acromegaly was 83% (range 64%-93%).
• Baseline evaluation: All patients should be evaluated for associated comorbidities, including hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis and sleep apnea, and for hypopituitarism, with replacement of deficient hormones.
• First-line therapy: Transsphenoidal surgery is the primary therapy in most patients. The 2025 Congress of Neurological Surgeons guideline found Class III evidence of benefit for surgery over medical management of GH-secreting adenomas.
• Preoperative somatostatin receptor ligands:
  • In randomized trials, preoperative octreotide increased short-term cure in macroadenomas from 4 of 25 (16%) to 13 of 26 (50%) (P = 0.017), with a nonsignificant overall difference of 45% vs 23% (P = 0.11), and preoperative lanreotide increased short-term cure from 18.4% to 49.0% (P = 0.001).
  • A meta-analysis of 4 randomized trials (261 patients) found higher IGF-I normalization 3 months after surgery with preoperative somatostatin analogues (relative risk 2.47; 95% CI 1.66-3.77), but the evidence did not extend beyond short-term outcomes.
  • Because results are conflicting and often not sustained during long-term follow-up, the 2020 multidisciplinary consensus did not support a general recommendation for preoperative treatment, the Endocrine Society suggests against its routine use to improve postoperative biochemical control, and the 2025 Congress of Neurological Surgeons guideline does not recommend perioperative somatostatin analogue treatment to improve surgical or medical outcomes.
  • Preoperative SRL therapy may be considered to reduce surgical risk in patients with severe pharyngeal thickness and sleep apnea or with high-output heart failure. Because preoperative SRL therapy may have carryover effects on IGF-I, postoperative remission should be confirmed at 3 to 6 months.
• Primary medical therapy: Medical therapy, usually with a first-generation SRL, is used as primary treatment when surgery is contraindicated or declined, when surgery is unlikely to be curative (for example, with extensive cavernous sinus invasion and no chiasmal compression), or in poor surgical candidates. Advanced age, severe cardiomyopathy and poorly controlled diabetes mellitus are relative contraindications to surgery.

Medical Therapy

Medical therapy is recommended for patients with persistent disease after surgery and is used as primary therapy in selected patients. Available options have expanded to include oral octreotide capsules, the oral SST2 agonist paltusotine and a monthly self-administered subcutaneous octreotide depot, in addition to injectable first-generation SRLs, pasireotide long-acting release (LAR) and pegvisomant.

First-Generation Somatostatin Receptor Ligands

• Long-acting octreotide and lanreotide are first-line medical therapy because of their favorable risk-benefit profile; 30% to 55% of patients achieve a normal IGF-I during long-term treatment, and more than half have a tumor size reduction of more than 20%.
• A meta-analysis of octreotide and lanreotide trials (4464 enrolled patients) found overall control rates of 56% for mean GH and 55% for IGF-I normalization; treatment duration was related to both GH and IGF-I control, whereas switch designs, preselection for SRL responsiveness and retrospective design had no significant effect on reported efficacy.
• In the PRIMARYS study of primary lanreotide 120 mg in treatment-naive patients with macroadenomas, a tumor volume reduction of at least 20% occurred in 62.9% (95% CI 52.0-72.9) of 89 patients in the intention-to-treat population. Older age, female sex, lower baseline IGF-I and T2-hypointense tumors predict a better response.
• Increasing the dose or frequency can improve control in patients who are sensitive to but inadequately controlled on standard doses, and extended dosing intervals may be effective in well-controlled patients; 88.7% of patients controlled on octreotide LAR 10 or 20 mg every 4 weeks maintained a normal IGF-I after switching to lanreotide 120 mg every 6 weeks.
• Labeled dosing (United States): Octreotide LAR is given at 20 mg intragluteally every 4 weeks for 3 months (after at least 2 weeks of subcutaneous octreotide to establish tolerance and response in patients not already receiving it), then adjusted to 10, 20 or 30 mg every 4 weeks according to GH, IGF-I and symptoms, and increased to 40 mg every 4 weeks if control remains inadequate on 30 mg; doses higher than 40 mg are not recommended. Lanreotide is started at 90 mg by deep subcutaneous injection every 4 weeks for 3 months and then adjusted to 60, 90 or 120 mg every 4 weeks according to GH, IGF-I and symptoms; patients controlled on 60 or 90 mg may be considered for 120 mg every 6 or 8 weeks, with GH and IGF-I measured 6 weeks after the change.
• Adverse effects are mainly gastrointestinal symptoms and gallstones. Overall effects on glucose metabolism are neutral; in a meta-analysis, SRLs had no significant effect on fasting glucose (effect size +0.04; P = 0.52) or hemoglobin A1c (effect size +0.11; P = 0.09). Routine ultrasound screening for gallstones is not suggested.

Oral Octreotide Capsules

• Oral octreotide capsules were approved by the FDA in June 2020 for long-term maintenance treatment of patients who have responded to and tolerated octreotide or lanreotide. Treatment starts at 40 mg/day (20 mg twice daily) and is titrated in increments of 20 mg/day, based on IGF-I and symptoms, to a maximum of 80 mg/day; capsules are taken with water on an empty stomach at least 1 hour before or at least 2 hours after a meal, because food reduces bioavailability by about 90%. IGF-I and symptoms are monitored every 2 weeks during titration and monthly once the maintenance dose is reached, and switching to another somatostatin analogue should be considered if IGF-I remains above the ULN at 80 mg/day or the drug is not tolerated.
• In an open-label phase 3 trial of 155 patients switched from injectable SRLs, 65% maintained the primary biochemical response.
• In the randomized, placebo-controlled OPTIMAL trial (56 patients), IGF-I normalization was maintained in 58.2% of patients on oral octreotide vs 19.4% on placebo (P = .008).
• In the randomized MPOWERED trial (92 patients), biochemical response was maintained in 50 of 55 (91%) patients on oral octreotide and 37 of 37 (100%) patients on injectable SRLs, meeting the prespecified non-inferiority criterion (95% CI -19.9 to 0.5).

Octreotide Subcutaneous Depot (CAM2029)

• In the randomized, double-blind ACROINNOVA 1 trial, 72 patients controlled on standard SRLs were randomized 2:1 to once-monthly subcutaneous octreotide depot or placebo; at weeks 22-24, IGF-I was at or below the ULN in 72.2% vs 37.5% (risk difference 34.6; 95% CI 11.3-57.9; P = .0018), and the combined IGF-I and GH response was 70.0% vs 37.5% (P = .0035). The formulation allows self-administration and room-temperature storage.
• The European Union authorized the formulation (Oczyesa) on 30 June 2025 for maintenance treatment of adults with acromegaly who have responded to and tolerated somatostatin analogue treatment, given once every 4 weeks. In the United States, a resubmitted new drug application was accepted for FDA review in July 2026, with a target action date of 18 December 2026.

Paltusotine

• Paltusotine is a nonpeptide, selective SST2 agonist taken orally once daily.
• In PATHFNDR-1, patients controlled on injectable octreotide or lanreotide were randomized to paltusotine or placebo for 36 weeks; IGF-I at or below 1.0 times ULN was maintained in 83.3% (25 of 30) of patients on paltusotine vs 3.6% (1 of 28) on placebo (odds ratio 126.53; 95% CI 13.73 to more than 999.99; P < .0001), and mean GH remained below 1.0 ng/mL in 87.0% vs 27.8%.
• In PATHFNDR-2, a randomized, placebo-controlled trial in medically untreated patients with biochemically uncontrolled acromegaly, IGF-I normalized at 24 weeks in 55.6% of patients on paltusotine vs 5.3% on placebo (odds ratio 42.81; 95% CI 8.44-455.82; P < .0001).
• Paltusotine (Palsonify) was approved by the FDA in September 2025 for adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. The recommended starting dose is 40 mg once daily (temporarily reducible to 20 mg for tolerability), titrated to 60 mg once daily after 2 to 4 weeks based on IGF-I, taken on an empty stomach at least 6 hours after a meal and at least 1 hour before the next meal. Labeled warnings include cholelithiasis, hyperglycemia and hypoglycemia, cardiovascular abnormalities, thyroid function abnormalities, steatorrhea and malabsorption of dietary fats, and vitamin B12 deficiency.

Pasireotide LAR

• Pasireotide is a multireceptor SRL with higher affinity for SST5 than first-generation SRLs.
• In medically naive patients, pasireotide LAR achieved biochemical control more often than octreotide LAR (31.3% vs 19.2%; P = .007) in a randomized trial of 358 patients, with more hyperglycemia-related adverse events (57.3% vs 21.7%).
• In the PAOLA trial of 198 patients inadequately controlled on octreotide or lanreotide, biochemical control at 24 weeks was achieved in 15% of patients on pasireotide 40 mg and 20% on pasireotide 60 mg, and in none of those continuing their previous SRL. In the extension study, 37% achieved control at some point, and diabetes mellitus was reported in 32% of patients on 40 mg and 40% on 60 mg.
• Pasireotide may cause hyperglycemia in up to 70% of patients and secondary diabetes in 25% to 40%, through suppression of insulin and incretin secretion; candidates should be screened and monitored carefully, and pasireotide is not recommended in patients with poor glycemic control, particularly if they are not treated with insulin.
• The United States labeled dose is 40 mg by intramuscular gluteal injection every 4 weeks, increased to a maximum of 60 mg if GH and/or IGF-I have not normalized after 3 months at 40 mg and the dose is tolerated, and decreased in 20 mg decrements for adverse reactions or over-response; blood glucose should be monitored weekly for the first 3 months of treatment and for the first 4 to 6 weeks after dose increases.
• In a randomized phase IV study of pasireotide-associated hyperglycemia, incretin-based therapy produced a difference in hemoglobin A1c of -0.28% (95% CI -0.63 to 0.08) compared with insulin.
• Among patients unresponsive to octreotide or lanreotide, those with T2-hyperintense tumors are more likely to show IGF-I improvement on pasireotide, and those with lower SST2 and higher SST5 expression are more likely to show tumor shrinkage.

Pegvisomant

• Pegvisomant blocks GH action at the GH receptor; its efficacy does not depend on tumor characteristics.
• In the pivotal 12-week randomized trial (112 patients), IGF-I normalized in 10%, 54%, 81% and 89% of patients receiving placebo or pegvisomant 10, 15 or 20 mg/day. In long-term treatment, 87 of 90 patients (97%) treated for 12 months or more achieved a normal IGF-I; antibodies to GH were detected in 16.9% without tachyphylaxis.
• In the real-world ACROSTUDY registry (2221 patients), the proportion with normal IGF-I increased from 53.7% at year 1 to 75.4% at year 10. Tumor size increased in 6.8% of patients, and 3% of patients with normal baseline liver tests had at least one transaminase elevation above 3 times ULN, without liver failure.
• Pegvisomant is generally used as second-line therapy after maximal SRL doses, started at a low dose and up-titrated; it is preferred for patients with diabetes mellitus or hyperglycemia that does not respond to octreotide or lanreotide and for patients without clinically relevant residual tumor. Patients with diabetes or obesity require higher doses (mean 18.2 vs 15.3 mg/day in diabetic vs nondiabetic patients).
• The United States labeled regimen is a 40 mg subcutaneous loading dose under medical supervision, followed by 10 mg once daily, adjusted in 5 mg steps every 4 to 6 weeks according to IGF-I (measured every 4 to 6 weeks) within a range of 10 to 30 mg/day; the dose should not be based on GH concentrations or on signs and symptoms of acromegaly.
• Liver tests should be monitored monthly for 6 months and then every 6 months, with consideration of discontinuation if transaminases exceed 3 times ULN, and tumor size should be monitored with MRI.

Combination Therapy

• In a randomized trial of 56 patients suboptimally controlled on octreotide LAR, pegvisomant alone and pegvisomant plus octreotide LAR showed no differences in adverse events, and IGF-I normalized in 56% and 62% of patients, respectively. In a long-term cohort of 141 patients, pegvisomant combined with long-acting SRLs was effective in 97%. Low-dose octreotide LAR or lanreotide combined with weekly pegvisomant achieved biochemical control in 96% of 51 patients at considerably lower cost.
• The Endocrine Society suggests adding pegvisomant or cabergoline when the response to an SRL is inadequate. Combination of pegvisomant with an SRL may be preferred over switching to pasireotide when residual tumor and impaired glucose tolerance coexist.
• In the PAPE study (61 patients controlled on first-generation SRL plus pegvisomant), switching to pasireotide with or without reduced-dose pegvisomant normalized IGF-I in 73.8% of patients at 24 weeks, but the prevalence of diabetes mellitus increased from 32.8% to 68.9%.

Cabergoline

• Cabergoline is an oral, inexpensive dopamine agonist whose effect is mostly limited to patients with mild postoperative GH and IGF-I elevation (IGF-I less than 2.5 times ULN), and escape from response can occur. The Endocrine Society suggests a trial of cabergoline for modest IGF-I elevation with mild symptoms.
• In a meta-analysis without randomized trials, cabergoline alone normalized IGF-I in 51 of 149 patients (34%), and its addition to a somatostatin analogue normalized IGF-I in 40 patients (52%).

Other Agents

• Estrogens and selective estrogen receptor modulators inhibit hepatic IGF-I production but have a limited role in acromegaly; for therapies that target the GH receptor or estrogen receptor, efficacy is assessed by IGF-I normalization only.
• Temozolomide and other chemotherapeutic agents should be limited to highly aggressive or malignant pituitary tumors and administered under the supervision of a neuro-oncologist.

Personalized Treatment Selection

• Clinical, imaging and pathology markers (T2-weighted MRI signal, the acute octreotide test and tumor immunohistochemistry, including granulation pattern and SST2 and SST5 expression) can identify patients unlikely to respond to first-generation SRLs; a biomarker-guided strategy validated in the ACROFAST study allows earlier use of pegvisomant, pasireotide or combination therapy and achieves hormonal control in nearly 80% of patients.
• Predictive algorithms have been validated in investigational settings, but their implementation, accuracy and standardization in routine practice remain to be established.
• A 2025 network meta-analysis (27 studies, 4131 patients, 11 treatments) ranked pegvisomant and then pasireotide LAR highest for IGF-I normalization; both outperformed first-generation SRLs combined with dopamine agonists (odds ratio 1.83; 95% CI 1.37-2.46 and odds ratio 1.46; 95% CI 1.02-2.08, respectively), octreotide LAR was superior to oral octreotide capsules (odds ratio 5.41; 95% CI 1.89-15.52), and pasireotide LAR was most effective for tumor shrinkage compared with SRLs (odds ratio 11.47; 95% CI 1.5-87.64), although methodological heterogeneity limited comparability.

Agent	Mechanism and administration	Key efficacy data	Main adverse effects and monitoring
Octreotide LAR and lanreotide	SST2-selective SRLs; octreotide LAR 10 to 40 mg intramuscularly every 4 weeks (starting dose 20 mg); lanreotide 60 to 120 mg by deep subcutaneous injection every 4 weeks (starting dose 90 mg), or 120 mg every 6 or 8 weeks in selected controlled patients	Normal IGF-I in 30% to 55% during long-term treatment; at least 20% tumor shrinkage in 62.9% with primary lanreotide 120 mg	Gastrointestinal symptoms, gallstones; neutral overall effect on glucose
Oral octreotide capsules	Oral SST2-selective SRL; 40 mg/day (20 mg twice daily), titrated by 20 mg/day to a maximum of 80 mg/day, on an empty stomach	Maintained response in 58.2% vs 19.4% with placebo; non-inferior to injectable SRLs (91% vs 100%)	Gastrointestinal adverse events; food markedly reduces absorption
Octreotide subcutaneous depot (CAM2029)	Once-monthly self-administered subcutaneous octreotide	IGF-I at or below ULN in 72.2% vs 37.5% with placebo	Safety consistent with standard SRLs; EU approval 2025
Paltusotine	Oral nonpeptide selective SST2 agonist; 40 mg once daily titrated to 60 mg, fasting	Maintained IGF-I control in 83.3% vs 3.6%; IGF-I normalization in 55.6% vs 5.3% of uncontrolled patients	Cholelithiasis, glycemic changes, bradycardia and conduction abnormalities, thyroid function changes, steatorrhea, vitamin B12 deficiency
Pasireotide LAR	Multireceptor SRL with higher SST5 affinity; 40 mg intramuscularly every 4 weeks, increased to a maximum of 60 mg	Control 31.3% vs 19.2% with octreotide LAR in naive patients; 15% to 20% in patients uncontrolled on first-generation SRLs	Hyperglycemia in up to 70% and diabetes in 25% to 40%; glucose monitoring
Pegvisomant	GH receptor antagonist; 40 mg subcutaneous loading dose, then 10 to 30 mg once daily (weekly regimens used in combination with SRLs)	Normal IGF-I in 53.7% at year 1 and 75.4% at year 10 in ACROSTUDY	Transaminase elevation; possible tumor growth; liver tests and MRI monitoring
Cabergoline	Oral dopamine agonist	IGF-I normalization in 34% alone and 52% when added to a somatostatin analogue	Useful mainly for mild IGF-I elevation; escape phenomenon

Procedural / Surgical Therapy

Transsphenoidal Surgery

• Transsphenoidal tumor resection is the optimal primary treatment in most patients; craniotomy is very rarely indicated, and intraoperative MRI and other techniques for visualizing tumor remnants remain investigational.
• Endoscopic vs microscopic approach: Comparative data are incomplete, and the choice of technique depends on the expertise and preference of the neurosurgeon. A systematic review of 4375 patients found initial remission rates of 58.2% (microsurgical) vs 57.4% (endoscopic) and long-term remission rates of 69.2% vs 70.2%. The 2025 Congress of Neurological Surgeons guideline found insufficient data to support either approach overall for extent of resection, hormonal remission, length of stay or complications, with a suggestion that the endoscopic technique may be superior for operative time, extent of resection and remission in noninvasive macroadenomas.
• Outcomes: In specialized referral centers, remission is achieved in 80% to 90% of microadenomas and in about 50% to 75% of macroadenomas, with much lower rates for invasive or very large (for example, larger than 4 cm) tumors. In a series of 506 patients undergoing primary surgery, 57.3% were cured according to contemporary biochemical criteria. Tumor size, invasiveness (particularly of the cavernous sinus), Knosp grade and preoperative GH level predict surgical remission, and surgical expertise has a major impact on remission rates.
• Sex and age: In a single-center series of 463 patients, men had higher rates of total resection (92.6% vs 85.5%) and remission (89.7% vs 76.5%) than women, who had larger and more invasive tumors; in 57 patients aged 65 years or older, surgical remission was 73.7%, and age does not appear to predict surgical outcome.
• Complications: Postsurgical hypopituitarism occurs in 5% to 10% of patients and persistent cerebrospinal fluid leak in 2% to 3%; diabetes insipidus occurs in 10% to 15% and is usually transient, and the syndrome of inappropriate antidiuretic hormone secretion may occur 5 to 14 days after surgery and requires monitoring of serum sodium. Visual deterioration, carotid artery injury, oculomotor palsy and meningitis are rare.
• Metabolic benefit: After surgery, glucose tolerance improved in 87.3% of patients with impaired glucose tolerance and 66.7% of those with diabetes mellitus. In one study, surgical remission reduced the prevalence of diabetes mellitus from 28% to 8%.
• Postoperative assessment: IGF-I should be measured 12 weeks after surgery to determine biochemical remission; early random GH on postoperative days 1 to 14, compared with preoperative GH, indicates the degree of tumor removal, and a fasting GH below 1 µg/L on postoperative day 1 or 2 has the best sensitivity for predicting outcome. Delayed IGF-I normalization has been reported as late as 24 to 57 months after surgery. MRI should be performed 3 to 6 months postoperatively and used as the baseline for further assessment.

Debulking Surgery

• When complete resection is unlikely, debulking surgery can improve the response to subsequent medical therapy. In 86 patients, a normal IGF-I during somatostatin analogue therapy was achieved by 9 patients (10%) before partial tumor removal and by 48 patients (55%) afterwards. Debulking may also reduce the target volume before radiotherapy.

Repeat Surgery

• Repeat surgery may be considered for significant, potentially resectable residual tumor, and should be performed in a specialized center after multidisciplinary evaluation.
• Repeat surgery cured 21.3% of patients in a large surgical series. In a meta-analysis (161 reoperations and 2189 first-time operations), disease control was achieved in 46.8% (95% CI 20%-74%) of patients after reoperation and in 56.4% (95% CI 49%-63%) after first surgery; control rates were similar for microadenomas (73.6% vs 77.6%) but lower after reoperation for macroadenomas (27.5% vs 54.3%) and for tumors invading the cavernous sinus (14.7% vs 38.5%). The 2025 Congress of Neurological Surgeons guideline found insufficient data to support reoperation over radiation or medical treatment for recurrent tumor.

Radiotherapy

• Radiotherapy is typically a third-line option, reserved for patients whose disease is not controlled by surgery and medical therapy or who are unfit for or decline them; it is used to control tumor growth and to lower GH secretion. The Endocrine Society suggests radiation for residual tumor after surgery when medical therapy is unavailable, unsuccessful or not tolerated, and prefers stereotactic radiotherapy over conventional radiotherapy unless it is technically unavailable, the residual tumor is large, or the optic chiasm would receive more than 8 Gy.
• Radiotherapy controls biochemical parameters in more than 60% of patients and tumor growth in more than 90%, but the full response may take 10 to 15 years, so medical therapy is required in the interval. Single-fraction stereotactic radiosurgery appears to be associated with fewer side effects than fractionated radiotherapy, although comparative data are limited.
• In 136 patients treated with stereotactic radiosurgery and followed for a median of 61.5 months, 65.4% achieved remission (actuarial remission 31.7%, 64.5%, 73.4% and 82.6% at 2, 4, 6 and 8 years), and new pituitary hormone deficiency developed in 31.6%. In an international multicenter cohort of 371 patients, actuarial initial and durable remission rates at 10 years were 69% and 59%, new endocrinopathy occurred in 26%, and stopping IGF-I-lowering medication before radiosurgery was the only independent predictor of durable remission.
• A systematic review and meta-analysis for the International Stereotactic Radiosurgery Society estimated, for acromegaly, a tumor control rate of 97.0% (95% CI 96.0%-98.0%), an endocrine remission rate of 44.0% (95% CI 35.0%-53.0%) and a rate of new hypopituitarism of 17.0% (95% CI 13.0%-23.0%).
• The 2025 Congress of Neurological Surgeons guideline concluded that radiosurgery, hypofractionated radiosurgery, fractionated radiotherapy and conventional radiotherapy provide excellent radiographic control with variable hormonal reduction, which may continue for up to 10 years, and that endocrine suppressive medication may be continued before radiosurgery. A 2026 Pituitary Society Delphi consensus of 29 international experts reached consensus on 24 of 27 statements (88.9%) on the role of radiotherapy for pituitary adenomas and emphasized that follow-up longer than 10 years is required.
• Hypopituitarism is the most frequent complication regardless of technique, with rates approaching 25% to 50% after 5 years, and endocrine function should be monitored lifelong; the Endocrine Society recommends annual testing for hypopituitarism and annual GH and IGF-I reassessment after withdrawal of medical therapy.

Study	Design and population	Biochemical remission	New hypopituitarism
Lee et al., 2014	Single-center radiosurgery cohort, 136 patients	65.4% at a median of 61.5 months	31.6%
Ding et al., 2019	International multicenter radiosurgery cohort, 371 patients	69% initial and 59% durable at 10 years	26% (new endocrinopathy)
Mathieu et al., 2022	Systematic review and meta-analysis (45 studies of secretory adenomas)	44.0% (95% CI 35.0%-53.0%) in acromegaly	17.0% (95% CI 13.0%-23.0%) in acromegaly
German Acromegaly Registry (summarized by the Pituitary Society)	Fractionated radiotherapy (233 patients) and radiosurgery (119 patients)	48% (fractionated) and 52% (radiosurgery) at 10 years	29% after radiosurgery at a median of 29.5 months

Long-Term Management

• Biochemical monitoring: Within the first postoperative year, IGF-I may be measured every 3 to 6 months to confirm remission and then every 6 to 12 months to detect recurrence. In patients receiving adjuvant SRL therapy, IGF-I should be assessed 3 months after starting or changing the dose of an injectable SRL and 2 to 4 weeks after starting or changing an oral SRL, and then every 6 to 12 months once control is achieved. After radiotherapy, treatment can be paused at least once a year to test for radiation-induced remission.
• Assay considerations: The same validated IGF-I assay should be used throughout follow-up. In a meta-analysis of 39 studies (7071 patients), GH and IGF-I results were discordant in 25.7% (95% CI 22.3-29.4) of treated patients, more often with ultrasensitive GH assays (30.7% vs 19.8%; P = 0.04). In 229 noncured patients in the Belgian registry, 35% had discordant GH and IGF-I results. When results are discordant, IGF-I should be relied upon.
• GH nadir and recurrence: In surgically treated patients with normal IGF-I, 63 of 68 (93%) with normal GH suppression during an OGTT remained in remission, whereas 9 of 29 (31%) with abnormal suppression had a recurrence. In 285 patients, those with a postoperative nadir GH below 0.4 µg/L had a significantly higher 5-year control rate than those with a nadir of 0.4 to 1.0 µg/L. Recurrence is very uncommon after postoperative remission, even after 10 years of follow-up.
• Imaging: Regular MRI follow-up is not indicated for all patients. After the 3- to 6-month postoperative baseline MRI, imaging should be repeated when there are signs of biochemical or clinical progression or before a change in treatment, such as repeat surgery or radiotherapy; an individualized approach is appropriate for patients receiving pegvisomant, those with genetic syndromes, and those with aggressive disease.
• Comorbidities: Hypertension, cardiac function, sleep apnea, glucose and lipid metabolism, vertebral fractures, bone mineral density, kidney function, joints, mood and quality of life should be monitored as summarized in the complications table above.
• Hypopituitarism: Pituitary function should be reassessed after surgery and radiotherapy, and deficiencies replaced according to the Endocrine Society hypopituitarism guideline.
• Symptoms and patient-reported outcomes: Symptoms may fluctuate during long-acting SRL therapy even when biochemical control is achieved, and discordance between biochemical and clinical response requires consideration of signs and symptoms in addition to IGF-I. Fatigue, pain, arthropathy and impaired quality of life frequently persist despite biochemical control, and injection burden, gastrointestinal effects and financial demands add to the treatment burden; patient-reported outcome tools include the AcroQoL, the Patient-Assessed Acromegaly Symptom Questionnaire, the Acromegaly Treatment Satisfaction Questionnaire and the Acromegaly Symptom Diary.

Parameter	Suggested timing
IGF-I after surgery	At 12 weeks; every 3 to 6 months during the first year; then every 6 to 12 months
IGF-I during SRL therapy	3 months after starting or changing an injectable SRL; 2 to 4 weeks after starting or changing an oral SRL; then every 6 to 12 months
IGF-I during paltusotine titration	After 2 to 4 weeks at 40 mg daily, before titration to 60 mg
IGF-I during oral octreotide titration	Every 2 weeks during titration; monthly once the maintenance dose is reached
Blood glucose during pasireotide therapy	Weekly for the first 3 months and for the first 4 to 6 weeks after dose increases
IGF-I during pegvisomant titration	Every 4 to 6 weeks, with dose changes in 5 mg steps
Liver tests during pegvisomant therapy	Monthly for 6 months, then every 6 months
Pituitary MRI	3 to 6 months after surgery; thereafter if there is biochemical or clinical progression or before a change in treatment
After radiotherapy	Annual GH and IGF-I after withdrawal of medical therapy; annual testing for hypopituitarism
Bone mineral density	Every 18 to 24 months in patients with low bone mineral density

Special Populations

Pregnancy

• Premenopausal women with uncontrolled acromegaly are at risk of increased complications during pregnancy; data on fertility, pregnancy and fetal effects of acromegaly drugs are limited to case reports and series, and pregnancies, including spontaneous conceptions, typically have good maternal and fetal outcomes.
• Pregnancy in women with acromegaly is generally safe, with tumoral and hormonal stability in most patients; controlling tumor size and hormonal activity before pregnancy is recommended, interruption of treatment once pregnancy is confirmed has proven safe, and exposure to somatostatin analogues during pregnancy might increase the chance of lower birth weight.
• The Endocrine Society suggests stopping long-acting SRLs and pegvisomant about 2 months before attempts to conceive (short-acting octreotide may be used until conception), withholding medical therapy during pregnancy except for tumor and headache control, considering serial visual field testing in women with macroadenomas, and not monitoring GH or IGF-I during pregnancy. The European Society of Endocrinology has published a guideline on the management of functioning and nonfunctioning pituitary adenomas in pregnancy.

Children and Adolescents (Pituitary Gigantism)

• In an international study of 208 patients with pituitary gigantism, 78.4% were male, AIP mutations were found in 29%, more than 50% had no identified genetic cause, and GH and IGF-I control was achieved in 39%.
• X-linked acrogigantism typically begins in infancy and can lead to the tallest individuals described; patients usually have mixed GH- and prolactin-secreting macroadenomas, occasionally with hyperplasia, and resistance to somatostatin analogues, while pegvisomant is often effective. Hormone hypersecretion and overgrowth can be controlled before adult gigantism develops, often at the cost of permanent hypopituitarism.
• The Endocrine Society recommends using the standard approaches to normalize GH and IGF-I in patients with gigantism. Genetic testing is indicated in young-onset disease.

Older Adults

• Older patients tend to have smaller, less invasive tumors and lower GH levels. Surgical remission was 73.7% in 57 patients aged 65 years or older, and remission allowed about one-third of patients older than 65 years to stop medications for hypertension and diabetes mellitus.
• In 118 patients diagnosed at age 65 years or older in Spain, the overall standardized mortality ratio was 1.02 (95% CI 0.57-1.54), 0.60 (95% CI 0.35-1.06) in men and 1.80 (95% CI 1.07-2.94) in women.

Women

• Women may have larger and more invasive tumors and lower surgical remission rates than men, and a Korean nationwide study found higher mortality in women (HR 1.75; 95% CI 1.07-2.84) but not in men compared with matched controls. In a later Korean nationwide cohort of 1884 patients and 94,200 matched controls, all-cause mortality was higher than in controls (HR 1.74; 95% CI 1.38-2.19), with a greater excess in women than in men (HR 2.17 vs 1.36); malignancy was the most common cause of death, and the risks of obstructive sleep apnea and diabetes mellitus were also higher in women.

Hereditary Syndromes

• AIP-related disease: AIP mutation carriers present about two decades earlier and respond less to somatostatin analogues. Screening of carriers detects smaller tumors.
• Multiple endocrine neoplasia type 1: MEN1-associated tumors may be larger, more aggressive and more resistant to treatment than sporadic tumors, and patients and their families should be managed by multidisciplinary teams.
• Carney complex: Acromegaly is one of the endocrine manifestations; patients require multidisciplinary management, long-term follow-up and genetic counseling.
• McCune-Albright syndrome: Management of GH excess and other endocrinopathies follows the fibrous dysplasia/McCune-Albright syndrome international consortium guidelines.

Ectopic GHRH Secretion

• Complete resection of the GHRH-secreting tumor led to remission in 91% of patients in the French series; the remaining patients achieved IGF-I normalization with somatostatin analogues (one patient required pegvisomant), although plasma GHRH remained elevated, and 85% of patients were alive after a median follow-up of 5 years. Rising plasma GHRH accurately identified recurrence.

Patients with Diabetes Mellitus

• Achieving biochemical remission is the first step in improving glycemic control. Pasireotide is not recommended in patients with poor glycemic control, whereas pegvisomant is preferred for patients with diabetes mellitus or hyperglycemia that does not respond to octreotide or lanreotide. Dual GIP and GLP-1 receptor agonists should be used with caution because GIP has been implicated in the paradoxical GH response to glucose.

Case Studies

Case #1

Related chapters

• Gigantism
• Pituitary adenoma
• Hypopituitarism
• Multiple endocrine neoplasia type 1
• McCune-Albright syndrome
• Carney complex