Overview
Acromegaly
1. Clinical Overview
Summary
Acromegaly is a rare hormonal disorder caused by excessive growth hormone (GH) secretion, usually from a pituitary adenoma (greater than 95% of cases). GH stimulates hepatic IGF-1 production, which mediates most clinical effects. The disease is insidious, with typical diagnostic delay of 7-10 years. Characteristic features include acral enlargement (hands, feet), coarsening of facial features, and systemic complications including cardiovascular disease, diabetes mellitus, and obstructive sleep apnoea. Untreated acromegaly doubles mortality, primarily from cardiovascular disease. Treatment is primarily surgical (transsphenoidal adenomectomy), with medical therapy and radiotherapy for residual disease.
Key Facts
- Definition: Excessive GH secretion in adults causing tissue overgrowth and metabolic dysfunction
- Prevalence: 40-125 per million
- Incidence: 3-4 per million per year
- Cause: Pituitary GH-secreting adenoma (greater than 95%)
- Diagnostic delay: 7-10 years on average
- Key investigation: IGF-1 (screening); OGTT with GH (diagnostic)
- Treatment of choice: Transsphenoidal surgery
- Mortality: 2x increased if untreated; normalises with biochemical control
Clinical Pearls
Compare Old Photos: Acromegaly is insidious. Compare current photos to photos from 10-20 years ago to appreciate the progressive facial coarsening. Family members often do not notice the gradual changes.
GH Does Not Suppress: In acromegaly, GH fails to suppress below 1 μg/L during OGTT (normal response is suppression to less than 0.4 μg/L).
The "Sick-Looking" Pituitary Patient: Acromegaly patients look unwell — coarse features, sweating, fatigue. Hyperprolactinaemia from stalk compression can cause galactorrhoea in women.
Why This Matters Clinically
Acromegaly causes significant morbidity and mortality if untreated. Early recognition prevents cardiovascular complications (cardiomegaly, heart failure, arrhythmias), metabolic sequelae (diabetes), and local mass effects (vision loss). Biochemical cure normalises life expectancy. Recognition requires awareness of the characteristic phenotype.
2. Epidemiology
Incidence & Prevalence
- Prevalence: 40-125 per million
- Incidence: 3-4 new cases per million per year
- Trend: Stable (or increasing detection)
Demographics
| Factor | Details |
|---|---|
| Age at diagnosis | 40-50 years (peak); due to diagnostic delay |
| Age at symptom onset | 30-40 years |
| Sex | Equal Male:Female |
| Ethnicity | No significant variation |
| Geography | Worldwide |
Risk Factors
Non-Modifiable:
- Genetic syndromes (rare): MEN1, Carney complex, McCune-Albright syndrome, Familial Isolated Pituitary Adenoma (FIPA)
- AIP mutations (younger onset, aggressive)
Modifiable:
| Risk Factor | Relative Risk |
|---|---|
| No modifiable risk factors known | — |
3. Pathophysiology
Mechanism
Step 1: GH Hypersecretion
- Pituitary somatotroph adenoma develops (usually sporadic; 40% have GNAS mutation)
- Adenoma secretes GH autonomously, independent of normal feedback
- GH secretion is pulsatile and loses normal diurnal variation
Step 2: IGF-1 Overproduction
- GH stimulates liver to produce Insulin-like Growth Factor 1 (IGF-1)
- IGF-1 mediates most of the growth-promoting effects of GH
- IGF-1 has a long half-life (18-20 hours) making it stable for measurement
Step 3: Tissue Effects
- IGF-1 stimulates growth of bone, cartilage, soft tissue, and organs
- Acral tissues (hands, feet, jaw) enlarge
- Visceral organs enlarge (cardiomegaly, hepatomegaly)
- Metabolic effects: insulin resistance, diabetes mellitus
Step 4: Local Mass Effects
- Macroadenoma (greater than 10mm) causes local compression
- Optic chiasm compression → bitemporal hemianopia
- Stalk compression → hyperprolactinaemia
- Lateral invasion → cavernous sinus, cranial nerve palsies
Classification
| Type | Definition | Clinical Features |
|---|---|---|
| Microadenoma | Tumour less than 10mm | Better surgical cure rate; fewer mass effects |
| Macroadenoma | Tumour greater than or equal to 10mm | Lower cure rate; may have mass effects |
| Giant adenoma | Tumour greater than 40mm | Often invasive; poor cure rate |
| Ectopic GH/GHRH secretion | Non-pituitary source (rare, less than 1%) | Carcinoid, pancreatic tumours; normal pituitary |
Anatomical/Physiological Considerations
- Pituitary gland sits in sella turcica, below optic chiasm
- Somatotrophs comprise 50% of anterior pituitary cells
- Normal GH is regulated by GHRH (stimulatory) and somatostatin (inhibitory) from hypothalamus
- Cavernous sinuses lie lateral to pituitary and contain cranial nerves III, IV, V1, V2, VI
4. Clinical Presentation
Symptoms
Typical Presentation:
Atypical Presentations:
Signs
Red Flags
[!CAUTION] Red Flags — Urgent assessment if:
- Bitemporal hemianopia or visual deterioration (urgent MRI, ophthalmology)
- Sudden severe headache, nausea/vomiting (pituitary apoplexy — emergency)
- Diplopia (cranial nerve palsy)
- Signs of hypopituitarism (hypotension, hypoglycaemia, hyponatraemia)
- New heart failure symptoms
Enlargement of hands and feet (rings, shoes no longer fit) (90%)
Common presentation.
Coarsening of facial features (thickened lips, enlarged nose)
Common presentation.
Excessive sweating and oily skin (70%)
Common presentation.
Fatigue and weakness
Common presentation.
Headaches (50-60%)
Common presentation.
Joint pain (osteoarthritis)
Common presentation.
Visual disturbance (if macroadenoma with chiasmal compression)
Common presentation.
Menstrual irregularity / decreased libido
Common presentation.
5. Clinical Examination
Structured Approach
General:
- Compare to old photographs (request patient bring them)
- Overall body habitus (tall stature if onset before epiphyseal closure = gigantism)
- Observe for sweating, oily skin
Head and Face:
- Frontal bossing
- Prognathism (prominent jaw)
- Increased interdental spacing
- Macroglossia (tongue impressions on teeth)
- Enlarged nose, thickened lips
- Deep voice (laryngeal hypertrophy)
Hands and Feet:
- Spade-like appearance; enlarged, doughy
- Carpal tunnel (Tinel's sign, Phalen's test)
- Ask about ring size, shoe size changes
Systemic:
- Cardiovascular: blood pressure, heart sounds (cardiomegaly, murmurs)
- Thyroid: goitre
- Neurological: visual fields to confrontation
Special Tests
| Test | Technique | Positive Finding | Sensitivity/Specificity |
|---|---|---|---|
| Visual field confrontation | Compare to examiner's field | Bitemporal hemianopia | Low sens / High spec |
| Tinel's sign | Tap over carpal tunnel | Tingling in median nerve distribution | Suggests carpal tunnel syndrome |
| Heel pad thickness | Measure on lateral foot X-ray | Greater than 23mm (men), greater than 21.5mm (women) | Marker of soft tissue overgrowth |
6. Investigations
First-Line (Bedside)
- Clinical assessment — Characteristic phenotype
- Old photographs — Document progression
Laboratory Tests
| Test | Expected Finding | Purpose |
|---|---|---|
| Serum IGF-1 | Elevated (age/sex adjusted) | Screening test; stable marker |
| GH during OGTT | Fails to suppress below 1 μg/L (or < 0.4 μg/L modern assays) | Confirmatory test |
| Random GH | Elevated (but pulsatile, less reliable) | Supportive if markedly elevated |
| Prolactin | May be elevated (co-secretion or stalk effect) | Check for co-secretion |
| Full pituitary profile | Check ACTH, cortisol, TSH, fT4, LH, FSH, testosterone/oestradiol | Assess for hypopituitarism |
| Fasting glucose, HbA1c | Often impaired/diabetic | Screen for diabetes mellitus |
| Lipid profile | May be dyslipidaemic | Cardiovascular risk assessment |
Imaging
| Modality | Findings | Indication |
|---|---|---|
| MRI Pituitary (with gadolinium) | Adenoma visualisation; size, invasion, chiasmal compression | All patients with confirmed biochemistry |
| Visual field perimetry | Bitemporal hemianopia | Macroadenoma, visual symptoms |
| Echocardiogram | Cardiomegaly, LVH, valvular abnormalities | Cardiovascular assessment |
| Sleep study (polysomnography) | Obstructive or central sleep apnoea | If snoring, daytime somnolence |
| Colonoscopy | Colonic polyps (higher incidence) | Screening recommended |
Diagnostic Criteria
- Screening: Elevated IGF-1 for age and sex
- Confirmatory (Endocrine Society): Failure of GH to suppress to less than 1 μg/L (less than 0.4 μg/L with ultrasensitive assay) during 75g OGTT
- Imaging: MRI confirmation of pituitary adenoma
7. Management
Management Algorithm
Acute/Emergency Management
Pituitary Apoplexy (Haemorrhage/Infarction into Adenoma):
- ABC, IV access
- Hydrocortisone 100mg IV stat (assume ACTH deficiency)
- Urgent MRI pituitary
- Ophthalmology assessment
- Neurosurgical consultation for possible urgent decompression
Conservative Management
- Cardiovascular risk optimisation
- Diabetes management
- OSA treatment (CPAP)
- Dental/orthodontic care
- Psychological support
Medical Management
| Drug Class | Drug | Dose | Duration/Notes |
|---|---|---|---|
| Somatostatin analogue (SSA) | Octreotide LAR | 20-30mg IM monthly | First-line medical; normalises IGF-1 in 50-70% |
| Somatostatin analogue (SSA) | Lanreotide Autogel | 60-120mg SC monthly | Similar efficacy to octreotide |
| GH receptor antagonist | Pegvisomant | 10-30mg SC daily | Highly effective; use if SSA fails; doesn't shrink tumour |
| Dopamine agonist | Cabergoline | 0.5-2mg weekly | Useful if co-secreting prolactin; 30% response rate |
Surgical Management
Transsphenoidal Adenomectomy:
- First-line treatment for most patients
- Approach via nasal/sphenoid route to sella
- Cure rates: 80-90% for microadenomas; 40-60% for macroadenomas
- Post-operative assessment at 12 weeks: IGF-1 and OGTT with GH
Indications for Surgery:
- First-line in most cases
- Compressive symptoms (vision loss)
- Debulking before medical therapy if giant adenoma
Radiotherapy (Third-Line):
- Stereotactic radiosurgery (Gamma Knife) or fractionated radiotherapy
- Reserved for residual disease after surgery and medical therapy
- Delayed effect (GH normalisation takes years)
- Risk of hypopituitarism (50-80% at 10 years)
Disposition
- Refer to tertiary centre: All patients with biochemically confirmed acromegaly
- Multidisciplinary care: Endocrinology, neurosurgery, ophthalmology, cardiology
- Lifelong follow-up: Required; monitor IGF-1, pituitary function, tumour recurrence, comorbidities
8. Complications
Immediate (Minutes-Hours)
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Pituitary apoplexy | Rare (5%) | Sudden headache, visual loss, hypopituitarism | IV hydrocortisone, urgent surgery if visual compromise |
Early (Days-Weeks)
- Post-operative CSF leak: Clear rhinorrhoea; may need lumbar drain or repair
- Post-operative hypopituitarism: May need hormone replacement (hydrocortisone, levothyroxine)
- Transient diabetes insipidus: Polyuria, polydipsia; usually self-limiting
Late (Months-Years)
- Cardiovascular disease: Cardiomegaly, heart failure (leading cause of death), arrhythmias
- Hypertension: 40-50%
- Diabetes mellitus: 20-40%
- Obstructive sleep apnoea: 60-80%
- Osteoarthritis: Joint pain, reduced mobility
- Colorectal polyps/cancer: Increased risk; screening colonoscopy recommended
- Hypopituitarism: From tumour or treatment (especially post-radiotherapy)
- Carpal tunnel syndrome: 20-40%
- Recurrence of disease: Lifelong monitoring required
9. Prognosis & Outcomes
Natural History
- Untreated acromegaly reduces life expectancy by 10 years
- Mortality 2x increased, primarily from cardiovascular disease
- Progressive disfigurement and disability
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Surgical cure (microadenoma) | 80-90% |
| Surgical cure (macroadenoma) | 40-60% |
| Biochemical control (any therapy) | 70-80% achieve target IGF-1 |
| Mortality with biochemical control | Normalised (SMR = 1) |
| Mortality without control | 2x increased |
Prognostic Factors
Good Prognosis:
- Microadenoma (less than 10mm)
- No cavernous sinus invasion
- Pre-operative GH less than 10 μg/L
- Early diagnosis and treatment
- Achievement of biochemical control (normal IGF-1)
Poor Prognosis:
- Macroadenoma with invasion
- Delay in diagnosis
- Failure to achieve biochemical control
- Cardiovascular complications established
- Significant comorbidities (diabetes, cardiomyopathy)
10. Evidence & Guidelines
Key Guidelines
- Endocrine Society Clinical Practice Guideline (2014, updated) — Diagnosis and treatment of acromegaly. Endocrine Society
- Pituitary Society Consensus (2018) — Criteria for defining disease control in acromegaly.
- NICE Guidance — Octreotide and lanreotide for acromegaly (TA64).
Landmark Trials
Colao et al. Meta-analysis (2009) — Somatostatin analogues efficacy
- Meta-analysis of SSA trials
- Key finding: SSAs normalise IGF-1 in 50-55% of treatment-naive patients
- Clinical Impact: Established SSAs as standard first-line medical therapy
Trainer et al. (Pegvisomant) (2000) — GH receptor antagonist efficacy
- Key finding: Pegvisomant normalised IGF-1 in greater than 90% of patients
- Clinical Impact: Introduced pegvisomant as highly effective rescue therapy
Holdaway et al. (2004) — Mortality meta-analysis
- Meta-analysis of acromegaly mortality studies
- Key finding: Mortality 2x increased if GH/IGF-1 elevated; normalised if controlled
- Clinical Impact: Emphasised importance of achieving biochemical control
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Transsphenoidal surgery (first-line) | 2a | Large surgical series |
| Somatostatin analogues | 1a | Meta-analyses |
| Pegvisomant (SSA-resistant) | 1b | RCTs |
| OGTT for diagnosis | 1a | Consensus guidelines |
11. Patient/Layperson Explanation
What is acromegaly?
Acromegaly is a rare condition caused by a small growth (usually non-cancerous) in your pituitary gland — a pea-sized gland at the base of your brain. This growth produces too much growth hormone. Because adults have stopped growing in height, the extra growth hormone instead causes enlargement of the hands, feet, and face, and affects other parts of your body.
Why does it matter?
If untreated, acromegaly can lead to serious health problems including heart disease, diabetes, high blood pressure, and joint problems. It can also affect your vision if the growth presses on the nerves to your eyes. The good news is that treatment is effective and can prevent these complications.
How is it treated?
- Surgery: The main treatment is an operation to remove the growth through your nose (transsphenoidal surgery). This cures most smaller growths.
- Injections (medication): If surgery does not fully cure the condition, monthly injections (somatostatin analogues like octreotide) can control the hormone levels.
- Daily injections: If injections do not work, a daily injection (pegvisomant) can block the effects of growth hormone very effectively.
- Radiotherapy: Rarely needed, but can be used if other treatments fail.
What to expect
- After successful treatment, many symptoms improve (sweating, headaches, joint pain)
- Changes to hands, face, and feet do not reverse but stop progressing
- You will need lifelong follow-up with blood tests and scans
- You may need treatment for related conditions (diabetes, sleep apnoea)
When to seek help
Contact your doctor urgently if:
- You develop sudden severe headache with nausea/vomiting (pituitary apoplexy)
- Your vision changes or you notice loss of peripheral vision
- You feel very unwell, fatigued, or faint (possible adrenal insufficiency)
- You have new symptoms of sleep apnoea (snoring, stopping breathing at night, extreme tiredness)
12. References
Primary Guidelines
- Katznelson L, et al. Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. PMID: 25356808
- Melmed S, et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552-561. PMID: 30050156
Key Trials
- Colao A, et al. Efficacy of somatostatin analogues in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2009;94(2):400-409. PMID: 19033370
- Trainer PJ, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342(16):1171-1177. PMID: 10770982
- Holdaway IM, et al. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol. 2008;159(2):89-95. PMID: 18524797
Further Resources
- Pituitary Foundation (UK): pituitary.org.uk
- Acromegaly Community: acromegalycommunity.com
- Endocrine Society Patient Resources: endocrine.org/patient-engagement
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Consult an endocrinologist for pituitary disorders.