Acromegaly

A 50-year-old male presents to the primary care physician with gradually progressive shortness of breath, headache, and visual disturbances over the past few months. He also reports fatigue, snoring at night, and daytime sleepiness. He has hypertension and type 2 diabetes mellitus, for which he takes amlodipine and metformin. On examination, he has coarse facial features, frontal bossing, prognathism, and enlarged hands and feet. Blood pressure is 150/90 mm Hg. Laboratory evaluation shows elevated IGF-1. Oral glucose tolerance testing demonstrates failure of growth hormone suppression. Echocardiography shows left ventricular hypertrophy with an ejection fraction of 55%. Pituitary MRI reveals a pituitary adenoma. Diagnosis?

Diagnosis is acromegaly.

1. Definition

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion after epiphyseal closure, resulting in elevated insulin-like growth factor 1 (IGF-1) and progressive soft tissue, skeletal, and visceral overgrowth.

The vast majority of cases are caused by a GH-secreting somatotroph pituitary adenoma.

2. Etiology

2.1 Most Common Cause

1.      GH-secreting somatotroph pituitary adenoma

2.      Some tumors may also secrete prolactin

2.2 Rare Causes

1.      Ectopic GHRH secretion

2.      Ectopic GH secretion, which is extremely rare

2.3 Genetic Associations

1.      Familial isolated pituitary adenoma, including AIP-associated disease

2.      MEN1

3.      Carney complex

4.      McCune-Albright syndrome

Genetic causes should be considered particularly in young-onset disease, gigantism, large or invasive tumors, or a positive family history.

3. Pathophysiology

3.1 Core Mechanism

1.      A somatotroph adenoma secretes excessive GH.

2.      GH stimulates production of IGF-1, mainly by the liver and peripheral tissues.

3.      IGF-1 causes:

o    Soft tissue overgrowth

o    Acral enlargement

o    Skeletal changes

o    Visceral enlargement

3.2 Metabolic and Systemic Effects

1.      GH causes insulin resistance, contributing to diabetes mellitus.

2.      Chronic GH and IGF-1 excess contribute to:

o    Hypertension

o    Left ventricular hypertrophy

o    Diastolic dysfunction

o    Cardiomyopathy

3.      Upper airway soft tissue enlargement contributes to obstructive sleep apnea.

4. Clinical Features

4.1 Acral and Facial Features

1.      Coarse facial features

2.      Frontal bossing

3.      Prognathism

4.      Enlarged hands and feet

5.      Increasing ring, glove, or shoe size

6.      Widely spaced teeth

7.      Macroglossia

4.2 Skin and Soft Tissue Features

1.      Thickened skin

2.      Hyperhidrosis

3.      Skin tags

4.      Deepened voice

4.3 Neurologic and Mass Effect Features

1.      Headache

2.      Visual impairment from optic pathway compression

3.      Bitemporal hemianopia may occur with optic chiasmal compression

4.      Carpal tunnel syndrome

4.4 Metabolic and Respiratory Features

1.      Hypertension

2.      Insulin resistance

3.      Type 2 diabetes mellitus

4.      Obstructive sleep apnea

5.      Snoring

6.      Daytime sleepiness

7.      Fatigue

4.5 Cardiovascular Features

1.      Left ventricular hypertrophy

2.      Diastolic dysfunction

3.      Cardiomyopathy

4.      Arrhythmias

5.      Valvular abnormalities

6.      Heart failure in advanced disease

In this patient, left ventricular hypertrophy may reflect acromegaly-related cardiac remodeling, with hypertension as an additional contributor. An ejection fraction of 55% indicates preserved resting left ventricular systolic function and does not, by itself, establish heart failure.

5. Diagnosis

5.1 IGF-1

1.      Measure serum IGF-1 using an age-adjusted reference range.

2.      IGF-1 is the principal biochemical test for suspected acromegaly.

3.      In a patient with typical clinical features, IGF-1 greater than 1.3 times the upper limit of normal for age confirms the diagnosis.

5.2 Oral Glucose Tolerance Test

1.      A 75-g oral glucose tolerance test is useful when biochemical results are equivocal.

2.      Normally, oral glucose suppresses GH secretion.

3.      In acromegaly, GH fails to suppress appropriately.

4.      In this patient, failure of GH suppression further supports the diagnosis.

5.3 Random Growth Hormone

1.      Random GH levels are variable because GH secretion is pulsatile.

2.      Random GH is not required to establish the diagnosis when the clinical features and IGF-1 level are diagnostic.

5.4 Pituitary MRI

After biochemical diagnosis, obtain contrast-enhanced pituitary MRI to assess:

1.      Tumor size

2.      Suprasellar extension

3.      Cavernous sinus invasion

4.      Relationship to the optic chiasm

5.5 Additional Pituitary Evaluation

Assess:

1.      Prolactin

2.      Adrenal axis

3.      Thyroid axis

4.      Gonadal axis

5.      Other evidence of hypopituitarism

5.6 Visual Field Testing

Formal visual field testing is indicated when:

1.      Visual symptoms are present

2.      The tumor approaches or compresses the optic chiasm

6. Evaluation of Comorbidities

6.1 Cardiovascular

At diagnosis assess:

1.      Blood pressure

2.      ECG

3.      Echocardiography

4.      24-hour ambulatory blood pressure monitoring for diagnosis and follow-up of hypertension

In this patient, left ventricular hypertrophy may reflect both acromegaly-related cardiac remodeling and coexisting hypertension.

6.2 Obstructive Sleep Apnea

1.      Obstructive sleep apnea is common in acromegaly.

2.      Systematic polysomnography or respiratory polygraphy is recommended at diagnosis, even in the absence of typical symptoms.

3.      This patient has strong clinical features of sleep apnea:

o    Snoring

o    Daytime sleepiness

o    Fatigue

6.3 Metabolic

Assess at diagnosis and during follow-up:

1.      Fasting plasma glucose

2.      HbA1c

3.      Diabetes mellitus

4.      Prediabetes

5.      Dyslipidemia

6.      Hypertension

6.4 Skeletal Assessment

1.      Acromegaly is associated with increased risk of vertebral fractures, even when bone mineral density is normal or increased.

2.      Vertebral morphometry should be considered at diagnosis to detect prevalent vertebral fractures.

6.5 Colonic Disease

1.      Colonoscopy is recommended at diagnosis according to applicable country-specific screening guidance.

2.      Subsequent screening should follow country-specific and individualized recommendations.

6.6 Thyroid Disease

1.      Thyroid enlargement and nodules are common.

2.      Cancer screening should follow general population recommendations.

3.      Thyroid ultrasound is indicated for a palpable thyroid nodule or other standard clinical indications, rather than routinely in every patient.

7. Complications

1.      Hypertension

2.      Diabetes mellitus

3.      Obstructive sleep apnea

4.      Left ventricular hypertrophy and cardiomyopathy

5.      Arrhythmias and valvular disease

6.      Arthropathy

7.      Vertebral fractures

8.      Carpal tunnel syndrome

9.      Colonic polyps and adenomas

10.  Thyroid nodules

11.  Hypopituitarism due to the pituitary tumor or its treatment

8. Management

8.1 Transsphenoidal Surgery

1.      Transsphenoidal surgery is the preferred primary treatment for most patients with a resectable pituitary adenoma, particularly when:

o    The tumor is potentially curable

o    There is optic chiasmal compression

o    There is significant tumor mass effect

2.      Surgery should ideally be performed by an experienced pituitary neurosurgeon.

8.2 Medical Therapy

Medical therapy is used for persistent disease after surgery, unresectable disease, or when surgery is inappropriate.

First-generation somatostatin receptor ligands

1.      Octreotide LAR

2.      Lanreotide

These suppress GH secretion and may reduce tumor size.

Pasireotide

1.      May be used in selected patients inadequately controlled with first-generation somatostatin receptor ligands.

2.      Has a significant risk of hyperglycemia, particularly in patients with pre-existing glucose intolerance or diabetes.

Growth hormone receptor antagonist

1.      Pegvisomant

2.      Blocks peripheral GH receptor signaling.

3.      Reduces IGF-1.

4.      Does not directly suppress GH secretion.

Dopamine agonist

1.      Cabergoline

2.      May be considered particularly in patients with mild biochemical disease, especially when IGF-1 is less than approximately 2.0 to 2.5 times the upper limit of normal.

3.      May also be useful in mixed GH-prolactin secreting tumors.

8.3 Radiotherapy

Radiotherapy may be considered for persistent or recurrent disease that remains inadequately controlled despite surgery and medical therapy.

1.      Stereotactic radiosurgery may be used when residual tumor anatomy is suitable.

2.      Other radiation techniques may be selected according to tumor size, location, and proximity to critical structures.

3.      Long-term monitoring for hypopituitarism is required.

8.4 Treatment of Comorbidities

1.      Treat hypertension according to standard guidelines.

2.      Optimize diabetes mellitus.

3.      Treat obstructive sleep apnea, including CPAP when indicated.

4.      Manage cardiac, skeletal, and other complications independently as required.

9. Follow-Up

9.1 Postoperative Biochemical Assessment

1.      Measure IGF-1 and GH approximately 3 months after surgery to assess biochemical response.

2.      Continue biochemical monitoring for at least 5 years, with subsequent follow-up individualized according to disease status and risk of recurrence.

9.2 Long-Term Follow-Up

1.      Monitor age-adjusted IGF-1 to assess biochemical control.

2.      GH measurements may provide additional information in selected patients.

3.      Repeat pituitary MRI according to tumor status and treatment.

4.      Monitor for:

o    Residual or recurrent tumor

o    Hypopituitarism

o    Hypertension

o    Diabetes

o    Sleep apnea

o    Cardiovascular disease

o    Skeletal complications

Long-term follow-up is required.

10. Prognosis

1.      Untreated or inadequately controlled acromegaly causes substantial cardiovascular, respiratory, metabolic, and musculoskeletal morbidity.

2.      Effective biochemical control improves morbidity and long-term outcomes.

3.      With modern treatment and appropriate management of comorbidities, mortality can approach that of the general population.

11. Key Clinical Insight

Coarse facial features + enlarged hands and feet + elevated age-adjusted IGF-1 + inappropriate GH nonsuppression + pituitary adenoma = acromegaly

The central pathophysiologic sequence is:

Somatotroph pituitary adenoma → excess GH → elevated IGF-1 → progressive somatic and systemic manifestations

In this patient:

1.      Coarse facial features, prognathism, and acral enlargement indicate chronic GH and IGF-1 excess.

2.      Hypertension, diabetes, and left ventricular hypertrophy represent important cardiometabolic manifestations.

3.      Left ventricular hypertrophy may reflect acromegaly-related remodeling, with hypertension as an additional contributor. An ejection fraction of 55% indicates preserved resting left ventricular systolic function and does not, by itself, establish heart failure.

4.      Snoring and daytime sleepiness strongly suggest obstructive sleep apnea.

5.      Headache and visual disturbances raise concern for pituitary tumor mass effect and warrant formal visual assessment.

6.      Transsphenoidal surgery is the preferred primary treatment if the pituitary adenoma is surgically resectable.

References

1.      Giustina A, Biermasz N, Casanueva FF, et al. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024;27(1):7-22. doi:10.1007/s11102-023-01360-1.

2.      Melmed S, di Filippo L, Fleseriu M, et al. Consensus on acromegaly therapeutic outcomes: an update. Nat Rev Endocrinol. 2025;21(11):718-737. doi:10.1038/s41574-025-01148-2.

3.      Giustina A, di Filippo L, Fleseriu M, et al. Consensus on acromegaly complications: an update. Pituitary. 2026;29(3):76. doi:10.1007/s11102-026-01639-z.