Endocrinology · PANCE / PANRE

Acromegaly

Growth hormone excess from a pituitary somatotroph adenoma; insidious enlargement of soft tissues, hands, feet, and jaw.

Also known as: acromegaly, gigantism, growth hormone-secreting adenoma, GH excess, IGF-1 excess

Overview

Chronic disease caused by sustained hypersecretion of growth hormone (GH) and consequent elevation of insulin-like growth factor 1 (IGF-1), almost always from a pituitary somatotroph adenoma. When onset is before epiphyseal closure (children), it produces gigantism; after closure, it produces acromegaly.

Epidemiology

Prevalence ~60 per million; incidence 3-4 per million per year. Equal sex distribution. Mean age at diagnosis 40-50 — typically presenting after 7-10 years of symptoms. Mortality 2-3× background if untreated, primarily from cardiovascular disease.

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Question 1EndocrineMedium
A 48-year-old man presents to his primary care provider complaining that his wedding ring no longer fits and his shoe size has increased two sizes over the past 3 years. He also reports headaches, excessive sweating, and new snoring. On examination he has prominent supraorbital ridges, an enlarged jaw with widely spaced teeth, and large fleshy hands. Random serum insulin-like growth factor-1 (IGF-1) is markedly elevated, and growth hormone fails to suppress after a 75-gram oral glucose load. Which of the following is the most likely diagnosis?
  • APituitary somatotroph adenoma
  • BPituitary corticotroph adenoma
  • CPrimary hypothyroidism
  • DSevere insulin resistance syndrome
Reveal answer & full explanation
Correct answer: A — Pituitary somatotroph adenoma
  • APituitary somatotroph adenoma
  • BPituitary corticotroph adenoma
  • CPrimary hypothyroidism
  • DSevere insulin resistance syndrome

Why pituitary somatotroph adenoma is correct

  • This patient demonstrates the classic adult presentation of acromegaly: enlargement of acral parts (hands, feet, jaw), frontal bossing, macroglossia, and soft tissue overgrowth occurring after epiphyseal closure — almost always due to a growth hormone-secreting pituitary somatotroph adenoma
  • Diagnostic gold standard is failure of growth hormone to suppress below 1 ng/mL after a 75-gram oral glucose tolerance test, combined with an elevated age-adjusted IGF-1 — both present in this patient
  • Pituitary MRI is then obtained to localize the adenoma; first-line therapy is transsphenoidal resection
  • If growth hormone excess occurs before epiphyseal closure, the result is gigantism rather than acromegaly

Why the others are wrong

  • Pituitary corticotroph adenoma — (Cushing disease) produces central obesity, moon facies, purple striae, and proximal weakness from cortisol excess, not acral enlargement
  • Primary hypothyroidism — can cause a puffy, coarse appearance but does not enlarge the jaw or hands or elevate IGF-1; TSH would be high and free T4 low
  • Severe insulin resistance syndrome — can produce some acromegaloid soft-tissue features (pseudoacromegaly) but with normal GH and IGF-1 levels and a normal glucose suppression test
Question 2EndocrineMedium
A 48-year-old man reports that his hands and feet have enlarged over the past several years, requiring larger gloves and shoes. He has coarsened facial features, jaw prognathism, and a prominent brow. He was recently diagnosed with type 2 diabetes mellitus and hypertension. A serum IGF-1 level is elevated for his age and sex. Which test should be ordered to confirm the diagnosis?
  • AOral glucose tolerance test with serial growth hormone measurement
  • BRandom serum growth hormone level
  • C24-hour urinary free cortisol
  • DHigh-dose dexamethasone suppression test
Reveal answer & full explanation
Correct answer: A — Oral glucose tolerance test with serial growth hormone measurement
  • AOral glucose tolerance test with serial growth hormone measurement
  • BRandom serum growth hormone level
  • C24-hour urinary free cortisol
  • DHigh-dose dexamethasone suppression test

Why Oral glucose tolerance test with serial growth hormone measurement is correct

  • Acromegaly is caused in nearly all cases by a growth hormone (GH)-secreting pituitary adenoma
  • GH stimulates hepatic production of IGF-1, which mediates the somatic effects: acral enlargement, frontal bossing, prognathism, soft-tissue thickening, plus insulin resistance (diabetes) and hypertension
  • Because GH is secreted in pulses and is influenced by sleep, stress, and food, an isolated GH value is unreliable; IGF-1, which integrates GH activity over time, is the best screening test
  • Confirmation requires demonstrating that GH fails to suppress: an oral glucose tolerance test is administered and GH is measured serially; in normal individuals the glucose load suppresses GH to a low nadir, whereas in acromegaly GH remains inappropriately elevated
  • The oral glucose tolerance test with serial GH measurement is the confirmatory test, performed after a screening IGF-1 and before pituitary MRI to localize the adenoma

Why the others are wrong

  • B) Random serum growth hormone level — pulsatile secretion makes a single value uninterpretable for confirmation
  • C) 24-hour urinary free cortisol — this is the screening test for Cushing syndrome, a different cause of weight change and hypertension, not acromegaly
  • D) High-dose dexamethasone suppression test — used to localize the source of cortisol excess in Cushing syndrome and has no role in evaluating GH disorders
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Risk factors

  • Sporadic GH-secreting pituitary adenoma (>95%)
  • MEN1 — pituitary + parathyroid + pancreatic NET (menin mutation)
  • McCune-Albright syndrome — fibrous dysplasia, café-au-lait, precocious puberty (GNAS mutation)
  • Carney complex (PRKAR1A) — myxomas, lentigines
  • Familial isolated pituitary adenoma (AIP mutation)
  • Rare: ectopic GHRH from carcinoid or pancreatic NET, ectopic GH

Pathophysiology

Excess GH directly affects metabolism (insulin resistance, lipolysis) and stimulates hepatic IGF-1 production. IGF-1 drives growth of bone, cartilage, soft tissues, viscera, and vascular smooth muscle. Slow, progressive structural changes account for the delayed diagnosis. Pituitary mass effect may produce headache and bitemporal visual field defects.

Clinical presentation

Symptoms

  • Insidious change in hand/shoe/ring/hat size (often a key historical clue)
  • Coarsened facial features, prognathism, dental spacing, malocclusion
  • Frontal bossing, enlarged tongue, deepened voice, snoring/OSA
  • Hyperhidrosis, oily skin, skin tags, acanthosis nigricans
  • Carpal tunnel syndrome, paresthesias
  • Headache, bitemporal hemianopia (mass effect)
  • Polyuria/polydipsia (diabetes), arthralgia, fatigue, decreased libido

Signs / physical exam

  • Coarse facial features with frontal bossing, prognathism, widely spaced teeth
  • Enlarged hands and feet (spade-like)
  • Macroglossia, deepened voice, prominent supraorbital ridges
  • Skin tags, hyperhidrosis, oily skin, acanthosis nigricans
  • Hypertension, evidence of cardiomyopathy (S3, displaced PMI)
  • Visual field testing — bitemporal hemianopia if optic chiasm compressed

Classic findings

Patient who states the ring or shoes stopped fitting; old photographs show progressive facial coarsening over years.

Differential diagnosis

  • Familial tall stature — Childhood onset, no biochemical excess, normal IGF-1
  • Pseudoacromegaly — Coarse features without biochemical excess; some insulin-resistance syndromes
  • Hypothyroidism with myxedema — Coarse features, fatigue, weight gain; TSH and free T4 abnormal
  • Chronic phenytoin or minoxidil use — Drug-induced coarse features; reversible
  • Marfan syndrome — Tall stature, arachnodactyly, aortic root dilation; no biochemical GH/IGF-1 excess
  • Prognathism / dental malocclusion isolated — Skeletal variant without acral changes or biochemical confirmation

Diagnostic workup

Diagnostic criteria

Elevated age/sex-adjusted IGF-1 + failure of GH to suppress below 1 ng/mL on OGTT + pituitary lesion on MRI.

Labs

  • Serum IGF-1 (age- and sex-adjusted) — first-line screen; elevated above reference range supports diagnosis
  • Oral glucose tolerance test (OGTT) with GH suppression — confirmatory; GH should suppress to <1 ng/mL (or <0.4 with ultrasensitive assay) after 75 g oral glucose; failure to suppress confirms acromegaly
  • Random GH alone is not reliable (pulsatile)
  • Prolactin (~25% of GH adenomas also secrete prolactin)
  • Full anterior pituitary panel: TSH, free T4, ACTH/cortisol, FSH/LH, testosterone/estradiol
  • Fasting glucose and A1c (insulin resistance, diabetes)
  • Lipid panel, BMP, calcium (MEN1 screen)

Imaging

  • Pituitary MRI with gadolinium — almost always shows macroadenoma (>1 cm)
  • Formal Humphrey visual field testing if optic chiasm compressed
  • Echocardiogram — concentric LVH, biventricular hypertrophy, valvular regurgitation
  • Sleep study for OSA
  • Colonoscopy at diagnosis and routinely after (increased risk of adenomatous polyps and colon cancer)

Diagnostic algorithm

TestResult in acromegalyNotes
Serum IGF-1 (age/sex-matched)ElevatedBest screening test
OGTT GH suppressionGH fails to suppress <1 ng/mLConfirmatory; gold standard
Random GHVariable, often elevatedUnreliable due to pulsatile release
Pituitary MRIMacroadenoma in majorityDefines anatomy for surgery
ProlactinElevated in ~25%Mixed somato-mammotroph tumors
ColonoscopyAdenomatous polyps in manyBaseline at diagnosis
Acromegaly diagnostic testing — IGF-1 screens, OGTT confirms, MRI localizes.

Complications

  • Cardiovascular: hypertension, biventricular hypertrophy, cardiomyopathy, valvular disease, arrhythmia
  • Metabolic: diabetes mellitus, dyslipidemia
  • OSA (very common; often unrecognized)
  • Arthropathy (large joints), carpal tunnel syndrome
  • Colon polyps and increased colon cancer risk
  • Thyroid nodules and modest increase in thyroid cancer
  • Hypopituitarism after surgery or radiation
  • Visual loss from optic chiasm compression

PANCE pearls

  • IGF-1 is the screening test; oral glucose suppression of GH is confirmatory. Random GH alone is unreliable due to pulsatile secretion.
  • Old photographs are diagnostic — coarsening of features over years.
  • Suspect MEN1 in acromegaly + hypercalcemia/hyperparathyroidism or pancreatic NET.
  • Macroglossia, sweating, headache, and OSA are early clues. Carpal tunnel may be the first complaint.
  • Pegvisomant normalizes IGF-1 without shrinking tumor — always monitor MRI for adenoma growth.
  • Colon cancer screening is more aggressive in acromegaly — colonoscopy at diagnosis and every 5-10 years (or per individual risk).

References

  • Endocrine Society 2014 — Acromegaly: An Endocrine Society Clinical Practice Guideline (Katznelson et al., J Clin Endocrinol Metab 2014)
  • Pituitary Society 2020 — Multidisciplinary Management of Acromegaly: A Consensus (Melmed et al., Rev Endocr Metab Disord 2018; updated Pituitary 2020)
  • AACE 2011 — AACE Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly (Katznelson et al., Endocr Pract 2011)

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