Introduction
Background
Increased and unregulated growth hormone (GH) production, usually caused by a GH-secreting pituitary tumor (somatotroph tumor), characterizes acromegaly. Other causes of increased and unregulated GH production, all very rare, include increased growth hormone–releasing hormone (GHRH) from hypothalamic tumors, ectopic GHRH from nonendocrine tumors, and ectopic GH secretion by nonendocrine tumors.
Symptoms develop insidiously, taking years to decades to become apparent, with a mean duration of symptom onset to diagnosis of 12 years. Excess GH produces a myriad of signs and symptoms and significantly increases morbidity and mortality rates. Additionally, the mass effect of the pituitary tumor itself can cause symptoms. Annual new patient incidence is estimated to be 3-4 cases per million population per year. The mean age at diagnosis is 40-45 years.
Pathophysiology
GH secreted from the anterior pituitary somatotrophs is normally controlled by 2 hypothalamic factors.
- GHRH stimulates GH secretion and synthesis and is synthesized in the hypothalamus and transported via the hypothalamic pituitary portal system to the somatotrophs of the anterior pituitary.
- Several tissues, including the endocrine pancreas, produce somatostatin in response to GH. Somatostatin inhibits GHRH secretion in a negative feedback pathway.
Once released into circulation, GH stimulates the production of insulinlike growth factor-I (IGF-I), also known as somatomedin C (SM-C). The main source of circulating IGF-I is the liver, though it is produced in many other tissues. IGF-I is the primary mediator of the growth-promoting effects of GH.
More than 95% of acromegaly cases are caused by a pituitary adenoma that secretes excess amounts of GH. Ectopic production of GH and GHRH by malignant tumors accounts for other causes.
Of these tumors, up to 40% have a mutation involving the alpha subunit of the stimulatory guanosine triphosphate (GTP)–binding protein. In the presence of a mutation, persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs results in excessive GH secretion.
The pathologic effects of GH excess include acral overgrowth (ie, macrognathia; enlargement of the facial bone structure; enlarged hands and feet; visceral overgrowth, including macroglossia and enlarged heart muscle, thyroid, liver, kidney), insulin antagonism, nitrogen retention, and increased risk of colon polyps/tumors.
Frequency
United States
Acromegaly is unusual, with a new case incidence of 3-4 per million subjects per year and a mean age of 40-45 years.
Mortality/Morbidity
Studies estimate an all-cause mortality rate at least twice that of the normal population. The major sequelae of acromegaly include cardiorespiratory and cerebrovascular diseases, diabetes, and neoplasia, particularly colon cancer.
The increase in mortality is attributed to excess GH and IGF-I. Because IGF-I is a general growth factor, somatic hypertrophy occurs across all organ systems, including but not limited to, acromegalic heart, increased muscle and soft tissue mass, and increased kidney size. Articular overgrowth of synovial tissue and hypertrophic arthropathy occur. Joint symptoms, back pain, and kyphosis are common presenting features. Other symptoms of soft tissue overgrowth include thick skin, hyperhidrosis (often malodorous), carpal tunnel syndrome, and other entrapment syndromes. Macroglossia may result in sleep apnea.
Visceral hypersomia includes heart, liver, and kidneys. Multinodular goiter is often present. With heart hypersomia comes hypertension, left ventricular hypertrophy, and, frequently, acromegalic cardiomyopathy with dysfunction and arrhythmias.
There also appears to be a relationship between GH/SM-C excess and premalignant colon polyposis, though this is not as clear as the other effects. In studies, the polyps were generally multiple and proximal to the splenic flexure, making them less likely to be discovered during sigmoidoscopy.
In a study by Bates et al, patients with GH concentration greater than 10 ng/mL had double the expected mortality rate, whereas patients with GH concentration less than 5 ng/mL approached normal mortality. The differential mortality underscores the necessity to reduce GH and IGF-I concentration.
Race
No clear relationship exists between incidence and race.
Sex
Acromegaly occurs with equal frequency in males and females. No clear sex predilection is apparent.
Age
Median age at diagnosis is 40 years in males and 45 years in females.
Clinical
History
Acromegaly can be an insidious disease. Symptoms might precede diagnosis by several years. Symptoms can be divided into 2 groups.
- Symptoms due to local mass effects of the tumor
- Symptoms depend on the size of the intracranial tumor.
- Headaches and visual field defects are the most common symptoms. Visual field defects depend on which part of the optic nerve pathway is compressed.
- The most common manifestation is a bitemporal hemianopsia due to pressure on the optic chiasm.
- Tumor damage to the pituitary stalk might cause hyperprolactinemia due to loss of inhibitory regulation of prolactin secretion by the hypothalamus. Damage to normal pituitary tissue can cause deficiencies of glucocorticoids, sex steroids, and thyroid hormone.
- Loss of end organ hormones is due to diminished anterior pituitary secretion of corticotropin (ie, adrenocorticotropic hormone [ACTH]), gonadotropins (eg, luteinizing hormone [LH], follicle-stimulating hormone [FSH]), and thyrotropin (ie, thyroid-stimulating hormone [TSH]).
- Symptoms due to excess of GH/IGF-I
- Soft tissue swelling and enlargement of extremities
- Increase in ring and/or shoe size
- Hyperhidrosis
- Coarsening of facial features
- Prognathism
- Macroglossia
- Arthritis
- Increased incidence of obstructive sleep apnea
- Increased incidence of glucose intolerance or frank diabetes mellitus, hypertension, and cardiovascular disease
- Hyperphosphatemia, hypercalcuria, and hypertriglyceridemia possible
- Increased incidence of congestive heart failure, which might be due to uncontrolled hypertension or to an intrinsic form of cardiomyopathy attributable to excess GH/IGF-I
- Increased incidence of colonic polyps and adenocarcinoma of the colon
Physical
- Typical facies of acromegaly
- Frontal bossing
- Thickening of the nose
- Macroglossia
- Prognathism
- Women can have mild hirsutism.
- The thyroid gland might be enlarged and typically manifests as multinodular goiter.
- Enlarged extremities with sausage-shaped fingers are signs of acromegaly.
- Skin is oily and has skin tags. Skin tags are possible markers for colonic polyps.
Causes
- Acromegaly can be either GHRH independent or GHRH dependent. Both forms cause identical clinical syndromes.
- Most cases are GHRH independent. Elevated GH concentration suppresses GHRH production by the hypothalamus.
- More than 95% of the GHRH-independent cases are due to a GH-secreting pituitary tumor. The pituitary adenoma might be a macroadenoma (>1 cm) or a microadenoma (<1 cm). Macroadenomas account for 80% of tumors; microadenomas account for the remaining 20%. Histopathologically, tumors include acidophil adenomas, densely granulated GH adenomas, sparsely granulated GH adenomas, somatomammotropic adenomas, and plurihormonal adenomas.
- In rare cases, GHRH-independent acromegaly may result from an ectopic pituitary tumor or ectopic production of GH by other tumors (eg, cancers of the pancreas or lung).
- In GHRH-dependent cases, GHRH stimulates the somatotrophs of the anterior pituitary, leading to hyperplasia and increased GH secretion. GHRH-dependent acromegaly can be caused by eutopic production of GHRH by a hypothalamic tumor or by ectopic production of GHRH by tumors such as those of the pancreas, kidneys, or lungs.
More on Acromegaly |
 Overview: Acromegaly |
| Differential Diagnoses & Workup: Acromegaly |
| Treatment & Medication: Acromegaly |
| Follow-up: Acromegaly |
| References |
| Next Page » |
References
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Further Reading
Keywords
growth hormone, GH, somatotroph tumor, growth hormone-releasing hormone, GHRH, insulinlike growth factor-I, IGF-I, somatomedin C, SM-C, guanosine triphosphate, GTP, glycogen synthetase phosphatase, GSP, acral overgrowth, macrognathia, visceral overgrowth, macroglossia, panhypopituitarism, somatic hypertrophy, hypertrophic arthropathy, kyphosis, hyperhidrosis, visceral hypersomia, multinodular goiter, colon polyposis, pseudoacromegaly, transsphenoidal hypophysectomy, somatostatin analogues, dopamine agonists, immunoradiometric assay, IRMA
