Definition and epidemiology
Acromegaly is a clinical syndrome resulting from chronic excessive secretion of growth hormone (GH) in adults after closure of the epiphyseal growth plates. When GH excess occurs before epiphyseal closure in childhood or adolescence, the condition manifests as gigantism with excessive linear growth.
The prevalence is approximately 40-70 cases per million population, with an incidence of 3-4 new cases per million per year. The disease affects both sexes equally and is typically diagnosed in the fourth to fifth decade of life, though symptoms often begin years earlier. The delay in diagnosis averages 4-10 years from symptom onset due to the insidious progression of physical changes.
Acromegaly is associated with increased mortality, primarily from cardiovascular and respiratory complications. Early diagnosis and effective treatment can normalize life expectancy.
- Elevated IGF-1 is the best screening test; lack of GH suppression below 1 microgram per liter on OGTT confirms diagnosis
- Over 95% of cases result from a GH-secreting pituitary adenoma
- Transsphenoidal surgery is first-line treatment for most patients
- Cardiovascular disease is the leading cause of death; untreated acromegaly doubles mortality risk
- Octreotide and lanreotide are somatostatin analogs used as first-line medical therapy
- Patients have 2-3 fold increased risk of colorectal cancer requiring regular colonoscopy
- Bitemporal hemianopsia results from suprasellar extension compressing the optic chiasm
- Pegvisomant is a GH receptor antagonist that normalizes IGF-1 in over 90% but does not shrink tumors
Etiology and risk factors
Over 95% of acromegaly cases result from a GH-secreting pituitary adenoma (somatotroph adenoma). These are typically macroadenomas (greater than 10 mm) at diagnosis in approximately 75% of cases.
Primary causes
- Pituitary adenoma: Accounts for more than 95% of cases; usually sporadic, occasionally part of MEN1 syndrome
- Ectopic GH secretion: Rare; from pancreatic islet cell tumors or lymphoma
- Ectopic GHRH secretion: Rare; from carcinoid tumors, pancreatic tumors, or small cell lung cancer leading to pituitary hyperplasia
- Familial acromegaly: Occurs in less than 5% of cases
Genetic syndromes associated with acromegaly
- Multiple endocrine neoplasia type 1 (MEN1): Mutations in MEN1 gene
- Carney complex: Associated with cardiac myxomas and pigmented skin lesions
- McCune-Albright syndrome: Polyostotic fibrous dysplasia and café-au-lait spots
- Familial isolated pituitary adenoma (FIPA): AIP gene mutations
Most pituitary adenomas in acromegaly are monoclonal and arise from somatic mutations, particularly in the GNAS gene (found in approximately 40% of somatotroph adenomas), leading to constitutive activation of the cAMP pathway and autonomous GH secretion.
Pathophysiology
Growth hormone is secreted by somatotroph cells of the anterior pituitary under the regulation of hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin. GH acts directly on tissues and stimulates hepatic production of insulin-like growth factor 1 (IGF-1), which mediates most of GH's growth-promoting effects.
In acromegaly, autonomous GH secretion from a pituitary adenoma leads to persistently elevated GH and IGF-1 levels. These hormones exert multiple pathological effects:
Skeletal and soft tissue effects
IGF-1 stimulates chondrocyte proliferation and periosteal bone growth. Since epiphyseal plates are closed in adults, linear growth does not occur. Instead, there is acral enlargement (hands and feet), mandibular overgrowth with prognathism, frontal bossing, and cartilage proliferation causing arthropathy.
Metabolic effects
GH is a counter-regulatory hormone that antagonizes insulin action, leading to insulin resistance, impaired glucose tolerance, and diabetes mellitus in approximately 25-50% of patients. GH also promotes lipolysis and protein synthesis.
Cardiovascular effects
Chronic GH excess causes concentric biventricular hypertrophy independent of hypertension. Hypertension occurs in approximately 30-40% of patients due to sodium retention and increased cardiac output. Valvular abnormalities and arrhythmias may develop.
Other systemic effects
Soft tissue overgrowth causes organomegaly (thyroid, liver, spleen, kidneys). Colonic polyps and increased risk of colorectal cancer occur. Sleep apnea results from macroglossia and upper airway soft tissue proliferation. Visceromegaly and nerve entrapment (especially carpal tunnel syndrome) are common.
Clinical features
The clinical presentation of acromegaly is insidious, with gradual progression over years. Patients often do not recognize changes in their appearance, though comparing old photographs reveals striking differences.
Acral and facial features
- Hand and foot enlargement: Increased ring and shoe size; broad, spade-like hands with thick fingers
- Facial changes: Coarse facial features, frontal bossing, prominent supraorbital ridges, enlarged nose, thick lips
- Mandibular changes: Prognathism (protruding jaw), widened interdental spaces, malocclusion
- Skin changes: Thick, oily, sweaty skin; skin tags; acanthosis nigricans
Mass effect symptoms (from pituitary tumor)
- Headache: Present in 40-60% of patients
- Visual disturbances: Bitemporal hemianopsia from optic chiasm compression
- Hypopituitarism: From compression of normal pituitary tissue; may present with hypogonadism, hypothyroidism, or adrenal insufficiency
Systemic manifestations
- Arthropathy: Joint pain in 70% of patients; affects knees, hips, shoulders, spine
- Carpal tunnel syndrome: Median nerve entrapment in up to 50% of patients
- Macroglossia: Enlarged tongue
- Voice deepening: From laryngeal soft tissue hypertrophy
- Sleep apnea: Obstructive and central types; present in 60-80%
- Hyperhidrosis: Excessive sweating
- Fatigue and weakness: Common presenting complaints
- Organomegaly: Goiter, hepatomegaly, splenomegaly
Metabolic and cardiovascular complications
- Glucose intolerance or diabetes mellitus: 25-50% of patients
- Hypertension: 30-40% of patients
- Cardiomyopathy: Biventricular hypertrophy, heart failure
- Arrhythmias: Increased risk of atrial fibrillation
Malignancy risk
Increased incidence of colonic polyps and colorectal cancer; routine colonoscopic screening is recommended.
Diagnosis
Diagnosis of acromegaly requires biochemical confirmation of GH excess in a patient with compatible clinical features. Imaging is then performed to localize the source.
Biochemical testing
Serum IGF-1 measurement: The initial screening test. IGF-1 is elevated in acromegaly and reflects integrated GH secretion over 24 hours. Results must be compared to age- and sex-adjusted reference ranges. A normal IGF-1 essentially excludes acromegaly.
Oral glucose tolerance test (OGTT): The gold standard confirmatory test. After oral glucose load, GH should suppress to less than 1 microgram per liter (using modern assays) or less than 0.4 microgram per liter (using ultrasensitive assays). In acromegaly, GH fails to suppress and may paradoxically rise. A single random GH level is not diagnostic due to pulsatile secretion.
Random GH levels: Not reliable for diagnosis due to pulsatile secretion and overlap with normal individuals, but markedly elevated levels (greater than 10 microgram per liter) in the presence of elevated IGF-1 strongly suggest acromegaly.
Imaging
Pituitary MRI with gadolinium contrast: Performed after biochemical confirmation to identify and characterize the pituitary adenoma. MRI detects over 90% of adenomas and defines tumor size, extension, and relationship to optic chiasm and cavernous sinuses.
Visual field testing: Formal perimetry if tumor approaches or compresses the optic chiasm.
Evaluation for ectopic sources
If no pituitary adenoma is identified on MRI, measure plasma GHRH levels and perform imaging of chest and abdomen to search for ectopic GHRH or GH-secreting tumors.
Pituitary function testing
Assess other pituitary axes (thyroid, adrenal, gonadal, prolactin) as macroadenomas may cause hypopituitarism. Approximately 30% of GH-secreting adenomas co-secrete prolactin.
Differential diagnosis
The clinical diagnosis is usually straightforward once acromegaly is considered, but the following conditions should be distinguished:
Physiological GH elevation
- Adolescence and puberty: Normal GH and IGF-1 elevation; clinical context differentiates
- Pregnancy: GH and IGF-1 may be elevated; placental GH variant production
- Malnutrition or anorexia nervosa: Elevated GH with low IGF-1
Other causes of coarse features
- Hypothyroidism: Coarse facies, macroglossia, but no acral growth; low TSH in primary cases
- Pachydermoperiostosis: Hereditary disorder with thickened skin and clubbing, but normal GH/IGF-1
- Familial resemblance: Family members may share prominent features; biochemistry is normal
Gigantism
Occurs when GH excess develops before epiphyseal closure, leading to excessive linear growth. The underlying pathophysiology is identical to acromegaly, but the clinical presentation differs due to timing.
Pseudoacromegaly
Severe insulin resistance syndromes may cause acanthosis nigricans and coarse features, but acral growth and elevated IGF-1 are absent.
Other pituitary masses
Non-functioning pituitary adenomas, craniopharyngiomas, and other sellar masses cause mass effect symptoms without biochemical evidence of GH excess.
Management
Treatment goals are to normalize GH and IGF-1 levels, relieve mass effect symptoms, preserve pituitary function, and prevent complications. A multidisciplinary approach involving endocrinologists, neurosurgeons, and radiation oncologists is optimal.
Surgical treatment
Transsphenoidal surgery is the first-line treatment for most patients. An experienced neurosurgeon can achieve biochemical remission in 70-90% of microadenomas and 40-60% of macroadenomas. Surgery provides rapid symptom relief and tumor debulking. Complications include cerebrospinal fluid leak, hypopituitarism, diabetes insipidus (usually transient), and rarely meningitis or vascular injury.
Medical therapy
Indications include persistent disease after surgery, surgical contraindications, patient refusal of surgery, or while awaiting the effect of radiation therapy.
Somatostatin receptor ligands (SRLs): First-line medical therapy. Octreotide and lanreotide bind somatostatin receptors on the adenoma, suppressing GH secretion and often causing tumor shrinkage. Given as monthly depot injections. Normalize IGF-1 in approximately 60% of patients. Side effects include gastrointestinal symptoms, cholelithiasis, and bradycardia.
Dopamine agonists: Cabergoline is effective in approximately 30% of patients, particularly those with GH-prolactin co-secreting tumors. Less effective as monotherapy but may be used adjunctively. Side effects include nausea, orthostatic hypotension, and rarely cardiac valvulopathy at high doses.
GH receptor antagonist: Pegvisomant blocks GH action at its receptor, normalizing IGF-1 in over 90% of patients. Does not reduce GH levels or tumor size, so requires ongoing tumor monitoring. Given as daily subcutaneous injection. May cause hepatotoxicity requiring monitoring. Expensive; typically reserved for patients failing other therapies.
Radiation therapy
Indicated for residual or recurrent disease not controlled by surgery and medical therapy. Options include conventional fractionated radiotherapy and stereotactic radiosurgery (e.g., Gamma Knife). Biochemical control is achieved slowly over 5-15 years. High risk of progressive hypopituitarism requiring long-term hormone replacement. Risk of secondary malignancy and cerebrovascular disease.
Treatment algorithm
Most guidelines recommend transsphenoidal surgery as initial therapy for resectable tumors. Medical therapy is initiated if surgery is unsuccessful or contraindicated. Combination medical therapy may be required in refractory cases. Radiation is reserved for patients not controlled by surgery and medical management.
Monitoring and follow-up
Biochemical control is defined as normal age-adjusted IGF-1 and random GH less than 1 microgram per liter. Patients require lifelong monitoring with periodic IGF-1 measurements and pituitary MRI. Assess for treatment complications, including hypopituitarism. Screen for cardiovascular disease, diabetes, sleep apnea, and colonoscopy for polyp surveillance.
Complications and prognosis
Untreated or inadequately controlled acromegaly is associated with significant morbidity and a 2-3 fold increase in mortality compared to the general population.
Major complications
Cardiovascular disease: The leading cause of death in acromegaly. Includes cardiomyopathy, heart failure, arrhythmias, valvular disease, coronary artery disease, and hypertension. Risk improves with biochemical control but may not normalize completely.
Respiratory complications: Obstructive sleep apnea affects 60-80% of patients and contributes to cardiovascular risk. Upper airway obstruction from soft tissue overgrowth may occur.
Metabolic disorders: Diabetes mellitus occurs in 25-50% and impaired glucose tolerance in another 15-25%. Insulin resistance often improves with treatment but may not fully resolve.
Arthropathy: Progressive and often irreversible joint damage. Pain may improve with treatment, but structural changes persist.
Malignancy: Increased risk of colorectal polyps and cancer (2-3 fold increased risk). Guidelines recommend colonoscopy at diagnosis and every 3-5 years. Possible increased risk of thyroid cancer.
Neurological complications: Carpal tunnel syndrome, headache, visual field defects from tumor compression.
Hypopituitarism: From tumor mass effect or as a complication of surgery or radiation therapy.
Prognosis
With early diagnosis and effective treatment achieving biochemical control (normal IGF-1), life expectancy can normalize. Postoperative GH less than 2.5 microgram per liter and normal IGF-1 are associated with normal mortality rates.
Soft tissue changes (hand and foot swelling, skin thickness) improve with treatment, but skeletal changes (prognathism, frontal bossing) are irreversible. Cardiovascular hypertrophy may partially regress. Quality of life improves significantly with treatment, though some symptoms (arthropathy, sleep apnea) may persist.
Prognostic factors for surgical cure include smaller tumor size, no cavernous sinus invasion, lower preoperative GH levels, and surgeon experience. Macroadenomas with cavernous sinus invasion have low surgical cure rates and often require multimodal therapy.
Long-term follow-up is essential as approximately 10% of patients experience tumor recurrence after initial surgical remission.
GROWTH for features of acromegaly: Glucose intolerance, Ring/shoe size increase, Organomegaly, Widened interdental spaces, Thick skin, Hypertension and Heart disease
Practice questions
1. A 48-year-old man presents with progressive enlargement of his hands and feet over 5 years. He has difficulty wearing his wedding ring and has changed shoe size twice. He reports excessive sweating, fatigue, and joint pain. Examination reveals coarse facial features, frontal bossing, and prognathism. Fasting glucose is 148 mg/dL. Which of the following is the most appropriate initial diagnostic test?
2. A 52-year-old woman with newly diagnosed acromegaly undergoes transsphenoidal resection of a pituitary macroadenoma. Six weeks postoperatively, her serum IGF-1 remains elevated at twice the upper limit of normal, and growth hormone does not suppress below 3 microgram per liter during oral glucose tolerance testing. Visual fields are normal. Which of the following is the most appropriate next step in management?
3. A 45-year-old man with a 10-year history of untreated acromegaly presents with progressive dyspnea on exertion. Echocardiography shows concentric left ventricular hypertrophy with preserved ejection fraction, mild mitral regurgitation, and diastolic dysfunction. ECG shows left ventricular hypertrophy. Blood pressure is 155/92 mmHg. Which of the following best explains his cardiac findings?
Frequently asked questions
What causes acromegaly?
Acromegaly is caused by excessive growth hormone secretion, most commonly from a pituitary adenoma (over 95% of cases). A benign tumor in the pituitary gland autonomously produces growth hormone, which stimulates the liver to produce insulin-like growth factor 1. These hormones cause progressive enlargement of hands, feet, and facial features. Rare causes include ectopic growth hormone or growth hormone-releasing hormone production from tumors elsewhere in the body.
What are the first symptoms of acromegaly?
Early symptoms are often subtle and develop gradually over years. Patients typically first notice their rings or shoes becoming tight as hands and feet enlarge. Excessive sweating, fatigue, joint pain, and headaches are common early complaints. Facial changes like coarse features, enlarged nose, and jaw protrusion develop slowly, so patients often do not notice until comparing old photographs. Family members may notice the changes before the patient does.
How is acromegaly diagnosed?
Diagnosis requires both biochemical testing and imaging. First, a serum IGF-1 level is measured and compared to age-adjusted normal ranges; elevated IGF-1 suggests acromegaly. Diagnosis is confirmed with an oral glucose tolerance test, where growth hormone fails to suppress below 1 microgram per liter despite glucose administration. Once biochemically confirmed, pituitary MRI with contrast is performed to identify and characterize the adenoma causing the hormone excess.
Is acromegaly curable?
Acromegaly is potentially curable with transsphenoidal surgical removal of the pituitary adenoma. Surgery achieves cure in 70-90% of small tumors but only 40-60% of large tumors. If surgery is unsuccessful or incomplete, medical therapy with drugs like octreotide or lanreotide can control hormone levels in most patients. While skeletal changes are permanent, soft tissue swelling improves with treatment, and with good biochemical control, life expectancy can normalize.
Acromegaly vs gigantism — what is the difference?
Acromegaly and gigantism are caused by the same problem—excessive growth hormone—but differ in timing of onset. Gigantism occurs when growth hormone excess begins before the growth plates close in childhood or adolescence, causing excessive height. Acromegaly develops after growth plates have closed in adulthood, so instead of growing taller, patients experience enlargement of hands, feet, and facial bones. Both conditions are usually caused by pituitary adenomas.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: E22.0
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.