Epidemiology and Etiology
Epidemiology
- The median age of diagnosis is 40 years old with a lag time of 10 years from onset to diagnosis.
- Life expectancy is shortened by approximately 10 years.
- Children treated early can have a normal life expectancy.
Etiology
- Benign pituitary adenoma in > 95% of cases
- Growth hormone (GH)- and growth hormone-releasing hormone (GHRH)-secreting tumors of the pancreas, lungs, and adrenal glands (rare)
Pathophysiology
Pathophysiology
- Acromegaly and gigantism result from excessive GH.
- GH, also known as somatotropin, is secreted by the anterior pituitary.
- GH mediates growth and metabolic functions.
- GH interacts with insulin to control fat, glucose, and protein metabolism during fasting and feeding states.
- Main effects:
- Lipolysis in adipose tissue
- Promotes gluconeogenesis (in the liver) and stimulates insulin-like growth factor-1 (IGF-1) secretion, resulting in increased glucose levels
- Muscle increases amino acid uptake and protein synthesis.
- Bones promote linear growth by the proliferation of epiphyseal cartilage in children (gigantism).
Regulation
Regulation is a step-wise process:
- The hypothalamus secretes GHRH and somatostatin (growth hormone-inhibiting hormone).
- Adenohypophysis secretes GH.
- The liver produces IGF-1.
- Proliferative effects on bone, cartilage, skeletal muscle, skin, soft tissue, organs, and glucose tolerance:
- Stimulation: hypoglycemia, stress, physical strain, deep sleep, puberty
- Inhibition: glucose, somatostatin, somatomedin (from the liver)
Schematic diagram of the direct and indirect effects of growth hormone (GH)
Image by Lecturio. License: CC BY-NC-SA 4.0Clinical Presentation
Clinical findings
- In children, growth plates have not yet fused, leading to gigantism:
- Characterized by the symmetrical enlargement of body tissues, which leads to an overgrowth of long bones
- Patients are commonly over 6’6” tall.
- In adults, growth plates have fused, leading to acromegaly with an overgrowth of characteristic areas:
- Nose
- Supraorbital bulges
- Jaw
- Hands
- Cranium
- Visceromegaly:
- Goiter
- Cardiomyopathy
- Colon polyps
- Deep voice
- Thickening of the dermis (pachydermia)
- Hypoesthesia or paresthesia
- Macroglossia
- Separation of the teeth and broadened interdental grooves
- Prognathism
- Headache
- Fatigue
- Perspiration
- Bone pain
- Vision loss
The hand of a healthy subject (left) next to the hand of a patient with acromegaly (right)
Image: “Acromegaly hands” by Philippe Chanson and Sylvie Salenave. License: CC BY 2.0
A patient with the typical facial features of acromegaly: enlarged nose, supraorbital bulges, prognathism, and a large head
Image: “Acromegaly facial features” by Philippe Chanson and Sylvie Salenave. License: CC BY 2.0
Complications
- Disturbances in the visual field
- Cranial nerve palsies
- Disturbances of the menstrual cycle
- Galactorrhea
- Erectile dysfunction
- Decreased libido
- Osteoarthritis
- Carpal tunnel syndrome
- Sleep apnea
- Diabetes mellitus
- Hypertension
- Cardiomyopathy and heart failure
- Secondary hypogonadism
- Increased incidence of colorectal cancer
Diagnosis
Clinical presentation is typically the most important aspect of diagnosis.
- Labs: GH low point greater than 0.4 µg/L or 1 µg/L (depending on GH standards) during the oral glucose tolerance test, and elevated, age-adjusted IGF-1 level
- Imaging:
- MRI:
- Can show a pituitary mass
- If a pituitary adenoma is absent, search the chest and abdomen for other tumors.
- CT scan:
- Abdomen and pelvis: Evaluate for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH.
- Chest: Evaluate for bronchogenic carcinoma secreting GH/GHRH.
- MRI:
MRI of a patient with a pituitary adenoma (green circle) that is exerting mass effect on the surrounding structures
Image: “Before pasireotide therapy. MRI scan of pituitary – coronal view” by Rajesh Rajendran et al. License: CC BY 3.0, edited by Lecturio.
Magnetic resonance imaging (MRI) of a patient with a large pituitary adenoma, resulting in acromegaly
Image: “Acromegaly” by Elgee. License: CC BY 3.0
Management
- Surgical option: transsphenoidal adenomectomy via endonasal access (pituitary adenomas)
- Nonsurgical options:
- Nonpharmacological:
- Stereotactic radiosurgery
- Proton therapy
- Conventional radiation therapy
- Pharmacological:
- Dopamine-D2-agonists (bromocriptine) inhibit GH production by the pituitary adenoma.
- GH-receptor-antagonists (pegvisomant) normalize the elevated IGF-1 level.
- Somatostatin-analogs (octreotide) decrease the size of the adenoma and normalize the GH level.
- Nonpharmacological:
Differential Diagnosis
- McCune-Albright syndrome: a rare, hypersecretory syndrome consisting of polyostotic fibrous dysplasia, cutaneous pigmentation, precocious puberty, hyperthyroidism, hypercortisolism, hyperprolactinemia, and acromegaly due to somatotroph hyperplasia. Patients are differentiated by additional constellations of signs and symptoms.
- Multiple endocrine neoplasia: GH-cell pituitary adenoma is a component of the autosomal-dominant, multiple endocrine neoplasia (MEN) type 1 syndrome, which also includes parathyroid and pancreatic tumors. In addition to the finding of excess GH, the patient demonstrates other endocrine anomalies.
- Acromegaloidism: soft tissue and skin changes usually associated with acromegaly, a normal baseline, dynamic GH/IGF-1, and no demonstrable pituitary or extrapituitary tumor. Acromegaloidism is rare.
- Pachydermoperiostosis: Patients present with enlargement of the fingers and toes, swelling or pain of the large joints, coarsening of facial features, and grooves/depressions in the scalp. Pachydermoperiostosis is caused by mutations in HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase, the key enzyme of prostaglandin degradation. The grooves/depressions of the scalp help to differentiate pachydermoperiostosis from acromegaly.
References
- Melmed, S. (2020). Treatment of acromegaly. In Snyder, P.J. (Ed.), UpToDate. Retrieved June 2, 2021, from https://www.uptodate.com/contents/treatment-of-acromegaly
- Melmed, S. et al. (2018). Primary Immune Deficiency Diseases. In Jameson J., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Chapter 373). McGraw-Hill.
