Treatment of acromegaly

INTRODUCTION — Acromegaly is nearly always caused by a somatotroph (growth hormone [GH]-secreting) adenoma of the pituitary gland and is associated with increased morbidity and mortality. As a result, almost all patients should be treated, even those who are asymptomatic and those in whom the disorder does not seem to be progressing. One exception is a patient with a short life expectancy who is not expected to live long enough to benefit from therapy.

GOALS OF THERAPY — The goals of therapy in acromegaly are to lower the serum insulin-like growth factor-I (IGF-I) concentration to within the reference range for the patient's age and gender and to lower the serum GH concentration to <1 ng/mL (1 mcg/L) as measured by immunoradiometric or chemiluminescent assay after a glucose load.

The IGF-1 criterion is probably better, since some patients who appear to have active disease clinically and by elevated IGF-1 concentration, have GH values that suppress to <1.0 ng/ml. Serum IGF-1 concentrations also correlate better than serum GH with insulin sensitivity in acromegalic patients. With normalization of serum IGF-1 concentrations, the life expectancy of acromegalic patients is similar to that of the general population. Therapy should also ameliorate symptoms, if any, due to the size of the somatotroph adenoma, but it should not cause hypopituitarism.

To achieve these goals, the adenoma secreting GH (or rarely growth hormone-releasing hormone) must be identified, and then treated. When effective control of GH hypersecretion is achieved, serum GH and insulin-like growth factor-I (IGF-I) concentrations decline to normal, the characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities, such as diabetes mellitus, improve. Unfortunately, restoration of completely normal GH secretion is not often achieved.

Even if the serum IGF-1 returns to normal, bony abnormalities generally do not regress, and joint symptoms persist. This was illustrated In a study of 118 acromegalic patients who were in long-term remission, as judged by serum normal IGF-1 concentration. However, 77 percent reported joint symptoms.

TRANSSPHENOIDAL SURGERY — Selective transsphenoidal surgical resection is the treatment of choice for patients with somatotroph adenomas that are small, large but still resectable, or large and cause visual impairment. Surgery may also be considered for large adenomas that are not entirely accessible surgically with the goal of removing a sufficient mass of tissue to increase the options for subsequent adjuvant therapy. In this setting, perioperative medical therapy is typically used.

When transsphenoidal surgery is performed by the most experienced pituitary neurosurgeons, GH secretion falls to normal in about 80 to 90 percent of patients with microadenomas (tumors less than 10 mm in diameter) and other pituitary hormonal secretion is preserved. The success rate is lower in patients with macroadenomas and/or higher preoperative serum GH concentrations.

Serum GH concentrations typically fall to normal within one to two hours, depending upon the degree of elevation, after transsphenoidal surgery. Serum IGF-I concentrations often fall to normal in 7 to 10 days, but can remain high for several months before declining to normal.There is a rapid diuresis, and soft tissue swelling and hyperglycemia can diminish remarkably in a few days. Vision, if impaired, and headaches can also improve in days, and cartilaginous overgrowth in some joints diminishes

Criteria for cure — Accurate interpretation and comparison of studies reporting surgical cure rates in patients with acromegaly is difficult, as both the duration of follow-up and the biochemical criteria for cure are variable. The biochemical criteria for surgical cure have been modified in recent years. Formerly, a postoperative baseline serum GH value of less than 5 ng/mL was considered an excellent response, but the current goal is a serum IGF-1 concentration normal for age and gender and a GH concentration less than 1 ng/mL or lower by immunoradiometric or chemiluminescent assay.

The cure rate using more stringent criteria is lower than older criteria. This was illustrated in a report of 57 patients followed for at least 12 months post-operatively. Surgical remission rates were 70.2, 66.7, and 61.1 percent, as assessed by normal serum IGF-1, random serum GH concentration <2.5 ng/mL, and glucose-suppressed GH concentration <1 ng/mL, respectively

Although using more stringent criteria lowers the reported cure rates, this may be counterbalanced by an improvement in surgical cure rates over time (presumably due to improved techniques and surgeon experience). In one report, the overall surgical cure rate improved from 45 percent before 1987 to 73 percent since 1991.

Although summarizing surgical cure rates across studies is difficult for the reasons noted above, the early cure rate in patients with acromegaly is in the range 40 to 60 percent overall, 80 to 90 percent for microadenomas, and less than 50 percent for macroadenomas

Recurrence — Studies with longer durations of follow-up provide information on recurrence rates. Approximately 3 to 10 percent of patients in whom the operation is initially successful, as determined by normal basal and normal post-glucose serum GH concentrations, have a recurrence several years or more after surgery, probably due to incomplete adenoma resection. One study of 59 acromegalic patients with 16 years of follow-up reported a higher recurrence rate (19 percent), with most recurrences occurring within the first five years after surgery

Even subtle abnormalities in nadir serum GH concentrations after a glucose load may be associated with a greater risk of recurrence. In a study of 77 patients with a biochemical remission after surgery (normal serum IGF-1 concentrations), subjects were stratified according to nadir GH concentration after an oral glucose load. Fifty patients (Group I) were considered to have a normal nadir GH (<0.14 ng/mL, based upon mean levels in normal healthy controls) and 26 had an abnormal nadir (>0.14 ng/mL, Group II). After a mean follow-up of 3.2 years, the following results were seen in Group II patients when compared with Group I patients:

  • Higher mean hourly GH concentrations (based upon hourly GH sampling for eight hours)
  • A higher recurrence rate in patients for whom longitudinal OGTT data was available (5 of 19 versus 0 of 49 patients developed an elevated serum IGF-1 concentration in Groups II and I, respectively).

Thus, patients with even subtle abnormalities in post-suppression GH levels may have additional evidence of enhanced GH secretion and possibly a greater risk of disease recurrence.

Complications — The mortality rate is less than 1 percent in patients with large invasive adenomas and negligible in patients with smaller ones. Deficiency of one or more pituitary hormones has been reported in 0 to 2 percent

Other major complications of surgery occur in about 8 percent of patients. These include central diabetes insipidus (2 percent), cerebrospinal fluid rhinorrhea (2 percent), and meningitis (2 percent). All of these problems are more common in patients with macroadenomas. These figures reflect results from neurosurgeons who have the most experience with transsphenoidal surgery. Less experienced surgeons are much more likely to cause all of the above complications

MEDICAL THERAPY — Several medications are now available for treating acromegaly, including some that inhibit GH secretion and one that inhibits its action.

Role of medical therapy — Pharmacologic treatment is used when surgery alone has not reduced GH and IGF-1 to normal, but its role as primary therapy has not yet been clearly established. Patients for whom a medication can be considered as primary therapy include those who have unacceptable surgical risk, refuse surgery, or have adenomas that are unlikely to be cured surgically

Somatostatin Analogs — Octreotide and lanreotide are analogs of somatostatin (growth hormone-inhibitory hormone) that inhibit GH secretion more effectively than native somatostatin because of their greater potency and longer plasma half-life (two hours versus two minutes). In large doses, they also inhibit the secretion of TSH, insulin, and glucagon. Somatostatin analog treatment is often effective in reducing elevated serum GH concentrations in acromegaly.

Mechanism of action — Octreotide inhibits GH secretion by binding to specific receptors for somatostatin and its analogs. Its effect is greater when the number of receptors is high; repetitive administration of octreotide does not result in desensitization or loss of efficacy

In a study of tissue samples from 32 surgically resected somatotroph macroadenomas, the mean growth fraction of tumors exposed to octreotide was suppressed by 83 percent in comparison with untreated surgical controls Another study of 39 patients confirmed that octreotide has an antiproliferative effect. However, octreotide had no effect on the apopototic index

Dosage and administration — Two somatostatin analogs are available commercially: octreotide and lanreotide. Octreotide is available in short- and long-acting forms in both Europe and the United States; lanreotide is available in two long-acting forms in Europe. The initial dose of the short-acting form of octreotide is 100 mcg subcutaneously every eight hours. If the serum IGF-1 concentration does not decrease to normal within a month or two, the dose can be increased gradually, to a maximum of 500 mcg every eight hours.

The long-acting form of octreotide, Sandostatin LARฎ, is given as an intramuscular injection once a month. The health care provider, or, in some cases, relative who gives the injection needs to be instructed in the technique for mixing the suspension prior to administration. The initial dose is 20 mg once a month. If the serum IGF-1 concentration does not decrease to normal within two months, the dose can be increased to 30 mg and then to 40 mg a month. Lanreotide is available in an intramuscular form, which is given as 30 mg every 7 to 14 days, and a deep subcutaneous form, called Autogelฎ, which is given as 60 to 120 mg every four weeks

Efficacy — Efficacy should be judged by normalization of the serum GH and IGF-1 concentrations, which should eventually be followed by regression of the soft tissue manifestations of acromegaly and by shrinkage of adenoma size.

  • Serum IGF-1 — Normalization of serum IGF-1 concentration with somatostatin analogs occurs in 40 to 75 percent of patients as illustrated by the following reports:

      - In a study of 27 patients who had not previously been treated and who were not preselected for responsiveness, 100 or 200 mcg of short-acting octreotide for 24 weeks decreased IGF-1 to normal in 38 percent. In 15 patients who then received long-acting octreotide for an additional 24 weeks, the reduction in IGF-I levels was maintained

      - In a review of several studies of the effect of somatostatin analogs in acromegaly, long-acting octreotide reduced IGF-1 to normal in 66 percent (range 41 to 75 percent), but patients in most of the studies reviewed had been preselected for responsiveness to the short-acting form. Efficacy with the every 10 to 14 day form of lanreotide was somewhat less, but most of those studies did not preselect for responsiveness.

Combined therapy with cabergoline and a somatostatin analog may be effective when either alone is not

  • Clinical manifestations of acromegaly — Somatostatin analog treatment is associated with an improvement in the clinical manifestations of acromegaly, including soft tissue swelling, carpal tunnel syndrome, and snoring A somewhat greater percentage of patients experience improvement in symptoms than experience normalization of serum IGF-1, presumably because even a partial decrease in GH results in some degree of symptomatic improvement.

Insulin sensitivity improves with somatostatin analog therapy; in diabetic patients treated with insulin, the insulin dose may need to be reduced substantially. Sleep apnea also may improve rapidly and, over 2 to 12 months, left ventricular mass decreases and left ventricular function improves concomitantly with the fall of serum GH and IGF-1 levels

  • Adenoma size — A review of the effect of short- and long-acting analogs on adenoma size reported that about 30 percent of patients had a decrease in adenoma size of 20 to 50 percent.

In a 2005 systematic review of patients with acromegaly receiving a somatostatin analog as primary medical therapy (before or as an alternative to surgery and radiotherapy), approximately 37 percent of patients experienced a significant reduction in tumor size; the mean percent reduction in size was 19 percent. In a subsequent study (published after the systematic review) of 99 patients with acromegaly receiving somatostatin analogs as primary therapy, 45 percent had normalization of serum IGF-1 concentrations, and 44 percent had a significant degree (>50 percent reduction in size) of tumor shrinkage

Octreotide and lanreotide also inhibit GHRH secretion by carcinoid tumors while concomitantly decreasing pituitary GH hypersecretion

Side effects — Somatostatin analogs have few side effects. About one-third of patients have nausea, abdominal discomfort, bloating, loose stools and fat malabsorption during the first several weeks of therapy, after which the symptoms subside spontaneously. Mild glucose intolerance occurs rarely, and is due to transient inhibition of insulin secretion. More important, octreotide reduces postprandial gallbladder contractility and delays gallbladder emptying, so that approximately 25 percent of patients develop asymptomatic cholesterol gallstones or sludge during the first 18 months of therapy. The incidence of gallstones as a consequence of somatostatin is geographically variable, with the highest rates occurring in China  Another disadvantage of somatostatin analogs is their high cost.

Dopamine agonists — Dopamine agonists, especially cabergoline(Dostinex)  may inhibit GH secretion in patients with acromegaly and have the advantage over other treatments that a few are taken orally.

Dosage and administration — The initial dose of cabergoline should be 0.5 mg once a week or 0.25 mg twice a week. The dose should be increased, if necessary, to 1.0 mg twice a week. Higher doses are not likely to decrease GH further.

Efficacy — In an uncontrolled study of 64 patients, cabergoline decreased serum GH concentrations to <2.0 ng/mL in 46 percent and serum IGF-I concentrations to <300 ng/mL in 39 percent. Reduction of IGF-1 to <300 ng/mL was more likely in those who had adenomas also secreting prolactin (50 percent) and those whose IGF-1 concentrations were <750 ng/mL (43 percent). Bromocriptine is less effective than cabergoline.

Growth hormone receptor antagonist — Pegvisomant is a growth hormone receptor antagonist that has been approved by the European Union and by the United States Food and Drug Administration (FDA) for treatment of acromegaly that has not responded to other treatments.

Structure and action — Pegvisomant is a mutated growth hormone molecule to which polyethylene glycol polymers have been attached at several sites . The mutation results in increased affinity to site one on the growth hormone receptor but decreased binding to site two. As a consequence, pegvisomant blocks native growth hormone from binding but does not activate the intracellular signaling that mediates growth hormone's action. The polyethylene glycol polymers prolong the half-life of the molecule.

Dosage and administration — Pegvisomant is administered as a daily subcutaneous injection. The initial daily dose is 10 mg. The serum IGF-1 concentration should be measured every four to six weeks and the dose adjusted, in 5 mg increments, to a maximum of 30 mg/day, to keep the serum IGF-1 within the normal range. Preliminary data suggest that alternate-day dosing may be effective in some patients .

Because pegvisomant does not inhibit GH secretion - in fact, GH concentration increases during treatment - GH cannot be used to monitor the effectiveness of treatment.

Efficacy — In a 12-week study of 112 patients, most of whom had received other treatment, pegvisomant doses of 10 mg, 15 mg, or 20 mg daily resulted in dose-dependent decreases in serum IGF-1 concentrations, as well as in fatigue, soft-tissue swelling, perspiration, and ring size, compared with no changes in the placebo group

In a study of combination therapy with monthly somatostatin analog and weekly pegvisomant (median weekly dose 60 mg; range 40-80 mg) serum IGF-1 concentrations were normalized. However, mild increases in liver enzymes were noted in 10 of 26 (38 percent) patients treated.

Side effects — About 20 percent of patients develop elevated serum aminotransferase concentrations, which return to normal after stopping treatment. Isolated cases of hepatitis have been reported. Pegvisomant should not be prescribed to patients who have clearly abnormal liver function, and patients who are treated should be monitored by liver function tests once a month during the first six months of treatment.

Adenoma size — Because pegvisomant does not inhibit growth hormone secretion, and its use is associated with an increase in growth hormone concentration, somatotroph adenoma size presumably will continue to grow at its previous rate, or possibly more, during its use. Adenoma growth and new visual field defects were described in one acromegalic patient receiving pegvisomant (10 to 40 mg/day for approximately two years) and in a second patient treated for three months. At this time, patients receiving pegvisomant should have adenoma size assessed by MRI at least once a year.

RADIOTHERAPY — External beam irradiation therapy can be used in patients whose disease is not controlled by surgery or medical therapy. The usual radiation dose is 4500 to 5000 reds (45 to 50 Gy) administered over five weeks in doses not exceeding 180 rad (1.8 Gy) per day, generated by conventional cobalt-60 sources or linear accelerators. Maximal tumor irradiation and minimal surrounding tissue damage has been achieved by MRI-directed tumor localization, beam direction, and field size simulation, head immobilization, and isocentral rotational techniques

Proton-beam therapy decreases GH secretion to normal more rapidly than conventional radiation therapy, but is not widely available. The frequency of neurologic side effects may be greater, and it is contraindicated in patients with suprasellar tumor extension, because the optic tracts may lie in the radiation field.

Efficacy — Adenoma growth is invariably arrested, but the decline in GH secretion — and the clinical improvement — is very slow, problems that seriously reduce the attractiveness of radiation therapy. Serum GH and IGF-I concentrations decline on average about 20 percent/year, so that serum GH concentrations may not reach 5 to 10 ng/mL until after as long as 5 or 10 or even more years, if the initial value is very high

By 20 years, 90 percent of patients have serum GH concentrations less than 5 ng/mL. However, few patients achieve the current goal of therapy, ie, a basal serum GH concentration less than 1 ng/mL. In one series, as an example, only 5 of 30 patients followed for 10 or more years reached this goal. Normalization of the serum IGF-1 concentration is about 50 percent in 10 years, but the results vary among studies

Results from a retrospective series of 884 patients with acromegaly who had received conventional pituitary irradiation  were slightly better than those in the studies noted above

  • 22 percent of patients achieved a serum GH concentration < 2.5 ng/mL by 2 years; 60 percent by 10 years; 77 percent by 20 years.
  • 63 percent of patients had a normal serum IGF-1 concentration by 10 years.

Side effects — Within 10 years, about 50 percent of patients treated with pituitary radiation develop deficiency of one or more pituitary hormones, and the incidence continues to increase thereafter. Gonadotropin deficiency is most common, followed by corticotropin and then TSH deficiency. In the large series noted above, the percentage of patients with new hormone deficiencies 10 years after irradiation were 18, 15, and 27 percent for LH/FSH, ACTH, and TSH, respectively

Other complications are cranial-nerve palsies, loss of vision, and memory deficits. All are rare, and usually occur only when the dose is high

Second intracranial tumors have been reported in up to 1.7 percent of patients within the first 10 years after pituitary radiation, a considerably higher frequency (relative risk 16) than in normal subjects. The reported tumors include astrocytoma, glioblastoma, meningioma, and sarcoma

Stereotactic radiotherapy — Stereotactic radiotherapy or "radiosurgery" is a technique performed in a limited number of specialized centers, with limited long-term outcomes data.

However, in one study of 82 patients with active acromegaly undergoing stereotactic ablation (of whom 63 had undergone previous transspenoidal surgery), the following results were seen after a mean follow-up of 49.5 months

  • Fourteen of the 82 patients (17 percent) were in remission after an average of 35.5 months (remission defined as GH concentrations <2 ng/mL and IGF-1 normal for age off somatostatin agonists for at least three months). Remission occurred in 4 of 19 (21 percent) and 10 of 63 (16 percent) patients who received gamma knife as primary treatment or after transsphenoidal surgery, respectively.
  • Nineteen patients who were previous uncontrolled on somatostatin agonists, were controlled on these medications after gamma knife.
  • Complications included complete (n=2) and partial (n=12) hypopituitarism diagnosed one to seven years after gamma knife.

This technique cannot be used for adenomas that extend above the sella because of potential damage to the optic chiasm and optic nerves.

LONG-TERM MONITORING — Several steps are required for the long-term management of patients with acromegaly.

Clinical and biochemical evaluation — Following initial treatment, patients should be evaluated every three to four months by both clinical examination and measurement of serum GH after a glucose load, and IGF-I levels. Patients who are being treated with a medication should have the dose adjusted, if necessaryIf normal values are not achieved, alternative therapy should be considered. Other pituitary hormones should be evaluated yearly.

Adenoma size — MRI should be repeated yearly for the first several years after initial treatment, less often thereafter. Visual field assessment is indicated for patients whose adenomas threaten their optic chiasm

Systemic evaluation — Colonoscopy should be done at three- to four-year intervals in patients over 50 years old and in those with more than three skin tags for early detection and treatment of premalignant colonic polyps  Comprehensive cardiovascular evaluation should be performed regularly and hypertension and cardiac failure treated aggressively

Patient support — Patients can get information about pituitary adenomas and their consequences from The Pituitary Society ( and The Pituitary Network Association, which publishes the Pituitary Patient Resource Guide (


  • For a patient who has a microadenoma, or a macroadenoma that appears to be fully resectable, or a macroadenoma causing impairment of vision, we recommend transsphenoidal surgery (performed by a neurosurgeon with considerable experience)
  • For patients whose adenoma does not appear to be fully resectable, and for patients whose risk of surgery is great or who choose not to have surgery, we suggest primary therapy with a long-acting somatostatin analog
  • For patients who have undergone transsphenoidal surgery with normalization of serum IGF-1 concentration, we suggest no further therapy
  • For patients who have undergone transsphenoidal surgery without normalization of serum IGF-1 concentration, we suggest secondary therapy with a long-acting somatostatin analog
  • If somatostatin analogs are ineffective, we suggest adding cabergoline or switching to cabergoline alone
  • If somatostatin analogs, cabergoline, or a combination of the two are ineffective, we suggest pegvisomant for controlling IGF-1 levels If pegvisomant alone is unsuccessful in controlling IGF-1, we recommend a combination of pegvisomant and a somatostatin analog
  • In patients who have a continued increase in adenoma size despite medical therapy (ie, cabergoline plus a somatostatin analog), we suggest RT