Excess secretion of growth hormone (GH) induces gigantism in prepubertal children and acromegaly in adults. Acromegaly arises from GH-secreting pituitary adenomas. GH is necessary for normal linear growth. GH is not the principal stimulator of growth, but it acts indirectly by stimulating the formation of other hormones. These hormones are termed somatomedins (SMs, ie, somatotropin-mediating hormones) or insulinlike growth factors (IGFs).
Somatomedin C (SM-C; insulinlike growth factor I [IGF-I]), the most important SM in postnatal growth, is produced in the liver, chondrocytes, kidney, muscle, pituitary, and gastrointestinal tract.
Pathophysiology
GH secretion from the pituitary gland is controlled by a combined hypothalamic regulation. Secretion is stimulated by growth hormone–releasing hormone (GHRH) and inhibited by GH release–inhibitory hormone or somatostatin (also termed somatotropin release–inhibitory factor or SRIF).
Syndromes of excessive secretion of GH or acromegaly are caused 95% of the time by a pituitary adenoma of the somatotrophs. A few cases of ectopic GHRH-producing tumors, usually seen in the lung or pancreas, also have been described.
Isolated familial somatotropinoma is a rare disease; at least 2 cases of acromegaly or gigantism has been reported in a family that does not exhibit features of Carney complex or multiple endocrine neoplasia type 1.1 It appears to be inherited as an autosomal dominant disease with incomplete penetrance. Although an association exists between the disease and loss of heterozygosity on 11q13, the responsible gene remains unknown.
Approximately 40% of somatotroph tumors have a mutation in the alpha subunit of a stimulatory G protein. Activation of this G protein is associated with binding of guanosine triphosphate (GTP) to the alpha subunit, which allows the alpha subunit to stimulate cyclic adenosine monophosphate (AMP) production. The normal free subunit has intrinsic GTPase activity, which inactivates GTP, preventing continued cyclic AMP stimulation. The mutant alpha subunit in acromegalic patients does not possess GTPase activity; therefore, continued cyclic AMP stimulation results.
GHRH-induced acromegaly is rare but is clinically indistinguishable from acromegaly caused by pituitary adenomas.
High levels of IGF-I are found in acromegaly, and low levels are found in children with GH deficiency. Insulin and IGF-I are similar peptides, and either can bind to IGF-I receptors.
Activation of this receptor leads to the growth and differentiation of many different cell lines, including keratinocytes, fibroblast, and the pilar unit of the skin.
Epidermal growth factor (EGF) and its homologs, transforming growth factor-alpha and amphiregulin, play a pivotal role in the regulation of keratinocyte growth and differentiation. All 3 growth factors stimulate cell growth by activating the epidermal growth factor receptor (EGF-R) that is expressed on keratinocytes in culture and in situ. Active proliferation of keratinocytes is associated with increased expression of the EGF-R and of its ligands (ie, transforming growth factor-alpha and amphiregulin) in the epidermis.
IGF-I and insulin, both of which stimulate keratinocyte growth through the IGF-I receptor, have been identified as primary keratinocyte mitogens. Proliferation induced by insulin and IGF-I requires the presence of other growth factors (notably EGF), and IGF-I stimulates keratinocyte proliferation in the absence of any other polypeptide growth factor at physiologic concentrations, through the IGF-I receptor. Thus, IGF-I is 1 of the factors inducing the growth factor component of the EGF-R–dependent autocrine loop in keratinocytes.
Frequency
United States
Acromegaly is uncommon, with an incidence of 3-4 cases per million per year. This figure easily may be an underestimation because of the insidiousness of this disease.
Mortality/Morbidity
Acromegaly is a severe disease often diagnosed late. Morbidity and mortality rates are high, in particular, because of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.
- Acromegaly is associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathologic studies on acromegalic hearts have shown extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy.
- Alveolar hypertrophy or hyperplasia is the mechanism for lung growth in this condition.
- Increased colon and breast cancers have been associated with acromegaly.
Sex
Male-to-female ratio is equal.
Age
Acromegaly occurs most frequently in middle age. The mean age of diagnosis is 40 years in men and 45 years in women.
Treatment
Medical Care
No single treatment modality consistently achieves control of the disease. A multimodality approach usually requires surgery as the first line of treatment, followed by medical therapy for residual disease. Radiation treatment usually is reserved for recalcitrant cases. The most effective and practical drugs currently in use include somatostatin analogs and dopamine agonists such as bromocriptine.
This chronic debilitating disorder caused by a GH-producing pituitary adenomas is usually treated with transsphenoidal surgery as the treatment of choice; however, radiotherapy and medical treatment are important because surgery cures only approximately 60% in long-term studies.Slow-release formulations of somatostatin are now widely used, also as primary treatment, and appear to be safe and effective in 50-60% of the patients. A GH-receptor blocking agent, pegvisomant, appears to normalize IGF-1 levels in almost all patients
- Somatostatin is a natural inhibitor of GH secretion. Octreotide is used most extensively.
- Octreotide 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 less than 2 ng/mL in 40%.
- Octreotide normalizes the IGF-I concentration in 60% of patients.
- Tumor shrinkage is seen in 20-50% of patients.
- Bromocriptine lowers serum GH in as many as 75% of patients, but in only 20% are the levels reduced to normal.
- Patients in whom prolactin is elevated are more likely to have a favorable response.
- GH-secreting tumors usually do not decrease in size with bromocriptine.
- Bromocriptine has an adjunctive role in patients who fail to achieve a cure by surgical treatment or who are to be treated with radiation.
- Periodic reassessment of GH production is advisable after treatment.
- Criteria for cure include a normal basal GH level and normal GH dynamic responses.
- SM-C levels appear to correlate better with clinical activity than do GH levels; therefore, SM-C levels should be monitored.
- Radiotherapy takes years to become effective. Approximately 60% of patients have GH concentration of less than 5 ng/mL 10 years after radiotherapy. A similar number develop panhypopituitarism as a result of treatment. Because of the disappointing results and adverse effects, radiotherapy is used as an adjunct treatment for large invasive tumors and when surgery is contraindicated. Some studies suggest that radiation is associated with the development of secondary tumors.
Surgical Care
Surgery is performed as first-line therapy.
- 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 rates of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.
- Carefully monitor patients for enlargement or recurrence of a pituitary mass lesion.
- The biochemical activity of disease after pituitary surgery in persons with acromegaly has been evaluated. By definition, biochemical cure in acromegaly involves both the normalization of IGF-1 levels and a glucose-suppressed GH level of less than 1 ng/mL. A significant proportion of acromegalic patients were found have a change in biochemical status upon long-term follow-up after surgery. Most of these changes occurred within the first postoperative year and were more likely to occur if the initial GH postglucose and IGF-1 levels were discordant.
The goal of pharmacotherapy is to reduce morbidity and to prevent complications.
Drug Category: Somatostatin analogs
Reduce blood levels of GH and IGF-I in patients with an inadequate response to surgery, radiation, and bromocriptine.
| Drug Name | Octreotide (Sandostatin) |
|---|---|
| Description | Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion. Also has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides. |
| Adult Dose | Initial: 50 mcg SC tid; may increase to 500 mcg tid Doses of 300-600 mcg/d or higher seldom result in additional benefit |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May reduce cyclosporine effects; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dose adjustments |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Adverse effects primarily are related to effect on GI motility and include nausea, abdominal pain, diarrhea, increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia may be seen because of alteration in counter-regulatory hormones, insulin, glucagon, and GH; bradycardia, cardiac conduction abnormalities, and arrhythmias reported; hypothyroidism also may occur because of inhibition of TSH secretion; caution in renal impairment |
| Drug Name | Octreotide LAR (Sandostatin LAR) |
|---|---|
| Description | Long-acting somatostatin analog given q4wk. Similar improvements in GH/IGF-I concentration compared to octreotide, but associated with fewer adverse effects. A trial of short-acting somatostatin analog is necessary to confirm patient's ability to tolerate the compound. Do not administer in deltoid area because of significant discomfort at injection site. Gluteal injection sites should be alternated. |
| Adult Dose | 10-30 mg IM q28d |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May reduce cyclosporine effects; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dose adjustments |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Adverse effects primarily are related to effect on GI motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia may be seen because of alteration in counter-regulatory hormones, insulin, glucagon, and GH; bradycardia, cardiac conduction abnormalities, and arrhythmias reported; hypothyroidism may occur because of inhibition of TSH secretion; caution in renal impairment; cholelithiasis may occur |
Drug Category: Dopamine agonists
Usually added to somatostatin analogs if complete remission is not achieved. Have modest effects if used as single agent.
| Drug Name | Bromocriptine (Parlodel) |
|---|---|
| Description | Acts on central dopamine receptors. More effective in tumors that co-secrete prolactin. Dose used to treat acromegaly usually is much higher than for hyperprolactinemia. |
| Adult Dose | 1.25 mg PO hs qd initial; increase gradually to 20-30 mg PO qd in divided doses Safety not demonstrated with dosages >100 mg/d |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; uncontrolled hypertension; ischemic heart disease; peripheral vascular disorders |
| Interactions | Other ergot alkaloids increase toxicity of bromocriptine; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Adverse effects include nausea, vomiting, headaches, nasal congestion, orthostatic hypotension, and digital vasospasm; patients tend to develop tolerance to adverse effects; caution in renal or hepatic disease |
Drug Category: Growth hormone antagonists
The newest class of drugs used to decrease excessive GH effect. Blocks GH binding to receptors, thus, decreases IGF-I, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS).
| Drug Name | Pegvisomant (Somavert) |
|---|---|
| Description | Recombinant DNA analog of human GH structurally altered to act as GH receptor antagonist. Selectively binds to GH receptors on cell surfaces, thereby blocking endogenous GH binding. This action interferes with GH signal transduction, resulting in decreased levels of IGF-I, IGFBP-3, and ALS. |
| Adult Dose | Loading dose: 40 mg SC Maintenance dose: 10 mg SC qd initially; may increase or decrease q4-6wk by 5-mg increments as determined by IGF-I levels; not to exceed 30 mg/d |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease insulin or oral hypoglycemic effects; patients receiving opioid analgesics may require higher doses to suppress IGF-I production to recommended levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Vial stopper contains latex; may cause GH-secreting tumors to grow; may increase insulin sensitivity; may induce GH deficiency; may increase liver enzyme levels |
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