Acromegaly is a rare, insidious, and potentially life-threatening condition for which there is good, albeit incomplete, treatment that can add years of high-quality life for the patient.[1] 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.
GH secreted from the anterior pituitary somatotrophs is normally controlled by 2 hypothalamic factors.
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.
The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism.[2]
Acromegaly is unusual, with a new case incidence of 3-4 per million subjects per year and a mean age of 40-45 years.
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.
A study by Berg et al found an increased prevalence of cardiovascular risk factors in patients with acromegaly compared with controls. The retrospective, comparative study used a Framingham risk score calculation compared with age- and gender-matched controls of the general population and an evaluation of effect of IGF-I normalization.[3] This study documents the importance of aggressive management as early as possible in the disease process; however, it should be remembered that this study looks at risk factors only and not the cardiac disease process itself. Although treating a disease is a basic tenet, treatment of acromegaly is difficult, expensive, and apart from the biochemical evidence, hard to show responsiveness in a way that is satisfying to the patient.
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.[4] The differential mortality underscores the necessity to reduce GH and IGF-I concentration.
No clear relationship exists between incidence and race.
Acromegaly occurs with equal frequency in males and females. No clear sex predilection is apparent.
Median age at diagnosis is 40 years in males and 45 years in females.
Acromegaly can be an insidious disease. Symptoms might precede diagnosis by several years. Symptoms can be divided into 2 groups.
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]).
Typical facies of acromegaly include the following:
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.
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.
Random GH measurements are often not diagnostic because of the episodic secretion of GH, its short half-life, and the overlap between GH concentration in acromegalic patients and healthy subjects.
Because GH secretion is inhibited by glucose, measurement of glucose nonsuppressibility might be useful. Two baseline GH levels are obtained prior to ingestion of 75 or 100 g of oral glucose, and additional GH measurements are made at 30, 60, 90, and 120 minutes following the oral glucose load.
Patients with active acromegaly are unable to suppress GH concentration below 2 ng/mL after a 75-g oral glucose load. With newer assays for GH using the immunoradiometric assay (IRMA), a criterion of less than 1 mcg/L is used following oral glucose ingestion.
A paradoxical rise in GH concentration is observed in 15-20% of patients with acromegaly following oral glucose ingestion.
Because IGF-I has a long half-life, its measurement is useful to gauge integrated GH secretion, to screen for acromegaly, and to monitor the efficacy of therapy. IGF-I concentrations vary with age. An assay in which reference ranges have been stratified in such a manner is required. Starvation, obesity, and diabetes mellitus decrease IGF-I concentration. Pregnancy increases IGF-I concentration.
Measurement of IGF-binding protein-3 (IGFBP-3), the main binding protein for circulating IGF, is increased in acromegaly and might be useful in the diagnosis of acromegaly. Measurement may also be helpful in following the activity of the disease during treatment.
GHRH concentration can be obtained if clinically indicated. Levels of less than 300 pg/mL usually indicate an ectopic source of GHRH. In pituitary disease (GHRH independent), GHRH concentration is within reference ranges or suppressed.
Because up to 20% of GH-secreting pituitary adenomas cosecrete prolactin, the prolactin level may also be elevated. However, as indicated above, a rise in prolactin can be due to stalk compression as well as co-secretion from a pituitary adenoma.
Pituitary adenomas can be associated with deficiencies of other pituitary hormones. Consider evaluation of the adrenal, thyroid, and gonadal axes.
Because of the relatively high incidence of nonfunctioning, incidentally discovered pituitary adenomas, obtain imaging studies only after a firm biochemical diagnosis of acromegaly.
Because GH-secreting pituitary adenoma is the most common cause, perform imaging of the sella turcica first. MRI is more sensitive than CT scan. MRI provides detailed information about surrounding structures such as the optic chiasm and cavernous sinuses.
If the MRI findings of the sella are negative, appropriate studies to localize tumors causing ectopic secretion of GH or GHRH can be obtained. CT scan of the abdomen/pelvis evaluates for pancreatic, adrenal, or ovarian tumors secreting GH/GHRH. Chest CT scanning evaluates for bronchogenic carcinoma secreting GH/GHRH.
The goal of treatment is amelioration of symptoms caused by the local effects of the tumor, excess GH/IGF-I production, or both.
Because elevated GH/IGF-I concentration is associated with increased mortality rates, try to decrease/normalize their concentration. Most experts define cure, or adequate control, as a glucose-suppressed GH concentration of less than 2 ng/mL by radioimmunoassay (RIA) (1 mcg/L by IRMA) and normalization of the serum IGF-I concentration.
No single modality of treatment consistently achieves the above levels.[5] A multimodality approach usually requires surgery as the first line of treatment, followed by medical therapy for residual disease. Radiation treatment is generally reserved for refractory cases.
Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment and are generally used after failure of primary surgery to induce complete remission.
Bromocriptine is a dopamine agonist with limited effectiveness in the treatment of acromegaly. It can reduce the circulating GH level to less than 5 ng/mL in only 20% of patients and can normalize the IGF-I concentration in 10% of patients. Shrinkage in tumor size is also observed in fewer than 20% of patients. Cabergoline, another dopamine agonist, fares somewhat better with response rates of 46%.
A meta-analysis found that cabergoline used as single-agent therapy in patients with acromegaly normalized IGF-I levels in one third of patients.[6] In cases where a somatostatin analog failed to control acromegaly, cabergoline adjunction normalized IGF-I levels in about 50% of gases.
Tumors that cosecrete prolactin have a better response rate to dopamine agonists. The response to these agents is often detected by a trial of the drug in suitable patients.
Somatostatin is a natural inhibitor of GH secretion. Because of its very short half-life, long-acting analogues have been developed. The long-acting analogue can be administered once per month but is extremely expensive (>$12,000/y in 1999).
Octreotide is the most extensively studied and used somatostatin analogue. It primarily binds to the somatostatin receptor subtypes II and V and inhibits GH secretion. Treatment with octreotide reduces GH concentration to less than 5 ng/mL in 65% of patients and to less than 2 ng/mL in 40% of patients; it normalizes concentration IGF-I in 60% of patients. Tumor shrinkage is observed in 20-50% of patients.
Pegvisomant, a GH receptor antagonist normalizes IGF-I levels in 90-100% of patients. As expected from its mechanism of action, GH levels increase during treatment and no decrease in tumor size is seen. A minority of patients may experience an increase in tumor size; whether this is due to natural history of the disease or an effect of treatment is unclear. Periodic imaging studies are advised in patients on this medication.
Radiation treatment takes to reduce/normalize GH/IGF-I levels. About 60% of patients have a GH concentration of less than 5 ng/mL 10 years after radiotherapy. A similar percentage of patients develop panhypopituitarism as a result of treatment. Because of the disappointing results and adverse effects, radiotherapy is used as an adjuvant for large invasive tumors and when surgery is contraindicated. Some studies suggest that radiation is associated with the development of secondary tumors.
Even though surgery might not cure a significant number of patients, it is employed as first-line therapy. Patients with residual disease can then be offered adjuvant treatment.
Transsphenoidal hypophysectomy has the dual advantage of rapidly improving symptoms caused by mass effect of the tumor and significantly reducing or normalizing GH/IGF-I concentrations. Remission depends on the initial size of the tumor, the GH level, and the skill of the neurosurgeon. A remission rate of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.
The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with postoperative GH concentration greater than 5 ng/dL.
After transsphenoidal surgery, somatostatin analogues are generally the first line of treatment, followed by GH receptor antagonist or dopamine agonists.
Clinical Context: Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides. Periodically monitor GH/IGF-I concentrations to assess response.
Clinical Context: Long-acting somatostatin analogue is administered every 4 wk. Similar improvements occur in GH/IGF-I concentration compared to octreotide but are associated with fewer adverse effects. A trial of short-acting somatostatin analogue is necessary to confirm the patient's ability to tolerate the compound.
Clinical Context: Indicated for long-term treatment of acromegaly in patients who experience inadequate response to other therapies. Octapeptide analogue of natural somatostatin. Inhibits a variety of endocrine, neuroendocrine, exocrine, and paracrine functions. Elicits high affinity for human somatostatin receptors 2, 3, and 5. Inhibits basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide. Markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Also significantly decreases prostaglandin E1 – stimulated jejunal secretion of water, sodium, potassium, and chloride. Reduces prolactin levels in acromegalic patients when treated long term.
Used to reduce blood levels of GH and IGF-I in patients who have an inadequate response to surgery. Their role as the primary treatment modality is being evaluated.
Clinical Context: Acts on central dopamine receptors. More effective in tumors that co-secrete prolactin. Dose used to treat acromegaly is usually much higher than that used for hyperprolactinemia.
Usually added to somatostatin analogues if complete remission has not been achieved. Have modest effects if used as a single agent.
Clinical Context: Recombinant DNA analog of human growth hormone (GH) that is structurally altered to act as a GH receptor antagonist. Selectively binds to growth hormone (GH) receptors on cell surfaces, thereby blocking endogenous GH binding. This action interferes with GH signal transduction, resulting in decreased insulinlike growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS).
Blocks GH binding to receptors, resulting in decreased IGF-1, IGFBP-3, and acid-labile subunit.
Remission depends on the initial size of the tumor, the GH level, and the skill of the neurosurgeon. Remission rates of 80-85% and 50-65% can be expected for microadenomas and macroadenomas, respectively. The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration greater than 5 ng/dL.