Treatment of acromegaly

INTRODUCTION — Acromegaly is almost 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.

The treatment of acromegaly will be reviewed here. The clinical manifestations and diagnosis of acromegaly are discussed separately. (See "Causes and clinical manifestations of acromegaly" and "Diagnosis of acromegaly".)

GOALS OF THERAPY — The goals of therapy in patients with acromegaly are to lower the serum insulin-like growth factor-1 (IGF-1) concentration to within the normal range for the patient's age and gender, control adenoma size and reduce mass effects, improve symptoms, and reverse metabolic abnormalities such as diabetes mellitus [1]. (See "Causes and clinical manifestations of acromegaly", section on 'Metabolic'.)

●In addition to lowering IGF-1, another biochemical goal is to lower the serum growth hormone (GH) concentration to <1 mcg/L as measured by immunoradiometric or chemiluminescent assay, as this also correlates with control of acromegaly. [2]. However, the IGF-1 criterion may be better since some patients who appear to have active disease clinically and by elevated IGF-1 concentration have serum GH values that suppress to <1 mcg/L [3,4]. Serum IGF-1 concentrations also correlate better than serum GH with insulin sensitivity in patients with acromegaly [5]. (See 'Biochemical outcomes' below.)

●When serum GH and IGF-1 concentrations decline to normal [6], the characteristic soft tissue overgrowth and related symptoms gradually recede and the metabolic abnormalities, such as diabetes mellitus, improve. In addition, life expectancy returns to that of the general population [7,8]. However, bony abnormalities generally do not regress and joint symptoms persist. (See 'Amelioration of symptoms' below.)

●Another goal of treatment is to alleviate symptoms due to the direct effects of the somatotroph adenoma (headaches, vision loss), without causing hypopituitarism.

OVERVIEW OF APPROACH — A summary of treatment effects is provided in the table (table 1). The choice of initial treatment depends upon the size and location of the adenoma, the presence of symptoms due to size (such as impairment of vision), and the patient's ability to undergo surgery (algorithm 1). The approach outlined here is similar to the Endocrine Society's 2014 Clinical Practice Guideline [2].

Transsphenoidal surgery — For the majority of patients with acromegaly, we recommend transsphenoidal surgery as the initial therapy (algorithm 1). This includes patients with a microadenoma, a macroadenoma that appears to be fully resectable, or a macroadenoma causing impairment of vision. We also recommend that transsphenoidal surgery be performed by a neurosurgeon with considerable experience in pituitary surgery [2]. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Somatotroph adenomas (acromegaly)'.)

We suggest surgical debulking for patients with macroadenomas abutting or adjacent to the chiasm (followed by medical therapy) (algorithm 1). Medical treatment may be more effective after surgical debulking. (See 'Somatostatin analogs' below.)

Potential complications — The perioperative mortality rate is less than 1 percent in patients with large, invasive adenomas and negligible in patients with smaller ones. Long-term deficiency of one or more pituitary hormones has been reported in up to 70 percent of patients [8,9]. Patients treated with both surgery and radiation are particularly prone to develop pituitary hormonal deficiencies, including growth hormone (GH) deficiency [10]. (See 'Should GH deficiency be treated?' below.)

Other major complications of surgery occur in approximately 8 percent of patients. These include arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) (2 percent), cerebrospinal fluid rhinorrhea (2 percent), and meningitis (2 percent) [8,11]. All are more common in patients with macroadenomas.

These complication rates reflect results from neurosurgeons with the most experience with transsphenoidal surgery. Rates with less experienced surgeons are much higher [12,13].

Postoperative evaluation — The early cure rate in patients with acromegaly is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas (see 'Surgical cure rate' below). We measure insulin-like growth factor-1 (IGF-1) levels and a random growth hormone (GH) approximately 12 weeks after surgery as it may take this long for IGF-1 to normalize; a decision can then be made whether adjuvant therapy should be initiated (algorithm 1). If a random GH is >1 mcg/L, we remeasure GH after a glucose load; a post-glucose serum GH less than 1 mcg/L is consistent with control of acromegaly [2].

The early cure rate in patients with acromegaly is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas. (See 'Biochemical outcomes' below and 'Surgical cure rate' below.)

We also suggest performing a pituitary magnetic resonance imaging (MRI) study at least 12 weeks after surgery to look for residual tumor and assess adjacent structures (algorithm 1). It is important to wait 12 weeks to allow for involution of gel foam and fat packing [2].

Normal IGF-1 and no residual tumor on MRI — If transsphenoidal surgery results in normalization of serum insulin-like growth factor-1 (IGF-1) concentration and no evidence of residual tumor on magnetic resonance imaging (MRI), we suggest no further therapy. Long-term biochemical monitoring and imaging follow-up for these patients is described below. (See 'Monitoring' below.)

The risk of recurrence is reviewed below. (See 'Recurrence' below.)

Patients with residual disease — Patients with residual disease (biochemically or on MRI) need additional treatment. This can include repeat surgery, medical therapy, and/or radiation therapy (algorithm 1).

Additional therapy for residual disease

Repeat surgery — We suggest repeat transsphenoidal surgery for patients with (algorithm 1):

●Residual intrasellar mass that compresses vital structures after initial surgery

●Significant residual tumor in the sella that is resectable

Medical therapy — For patients with an abnormal serum IGF-1 and moderate symptoms of GH excess after transsphenoidal surgery, but who do not need repeat surgery, we suggest medical therapy (algorithm 1).

For patients in whom transsphenoidal surgery does not result in normalization of serum IGF-1 concentration, particularly if they have moderate symptoms of GH excess, we suggest medical therapy with either a long-acting somatostatin analog or pegvisomant. We often use a somatostatin analog first because it tends to decrease the size of the adenoma, as well as its secretion of GH. Pegvisomant is another option for medical therapy in this setting. If a somatostatin analog is started first and treatment does not reduce IGF-1 levels to normal, we recommend adding pegvisomant, which blocks the action of GH. (See 'Somatostatin analogs' below and 'Pegvisomant' below.)

In patients with only modest biochemical abnormalities, eg, GH concentrations >1 mcg/L but <1.3 mcg/L and mild symptoms of GH excess, we suggest a trial of cabergoline. (See 'Dopamine agonists' below.)

Stereotactic radiation therapy — If medical therapy is ineffective or not tolerated, we suggest stereotactic radiation therapy (RT) (algorithm 1). Other indications for RT include (see 'Radiation therapy' below):

●An adenoma increasing in size despite medical therapy (ie, somatostatin analog plus pegvisomant)

●Aggressive or atypical adenomas

●Patient desire to avoid the cost and administration of long-term medical therapy

The use of RT for the management of acromegaly is reviewed in detail below. (See 'Radiation therapy' below.)

Role of primary medical therapy — Although we suggest transsphenoidal surgery as the initial step for most patients, we suggest medical therapy with a long-acting somatostatin analog as the initial step for patients who (algorithm 1) [2]:

●Have an adenoma that does not appear to be fully resectable (eg, because of extensive cavernous sinus invasion but have no chiasmal compression)

●Are poor surgical candidates or decline surgery

●Would benefit from preoperative medication to allow easier intubation by reducing severe laryngeal swelling and macroglossia and to improve obstructive apnea or cardiac dysfunction

Following initial treatment, patients should be evaluated every three to four months by both clinical examination and measurement of serum IGF-1 concentration for at least the first year. Medication dose is titrated upwards as needed; if IGF-1 is not normalized at the maximum dose of somatostatin analog, alternative therapy should be considered. (See 'Efficacy' below.)

Specifics about somatostatin analog therapy (dosing, impact on symptoms and adenoma size, and side effects) are reviewed below. (See 'Somatostatin analogs' below.)

●Pegvisomant – Daily pegvisomant monotherapy may also be used as first-line therapy; its efficacy is determined by measuring IGF-1 and not GH. (See 'Pegvisomant' below.)

●Combination therapy – Pegvisomant may be administered in combination with a somatostatin analog in patients in whom the IGF-1 response to the analog alone is suboptimal. If the combination is effective, it should be continued and monitored every six months. (See 'Combination therapy' below.)

If medical therapy is effective, it can be continued indefinitely.

Long-term management — Several steps are involved in the long-term management of patients with acromegaly.

Monitoring

●Clinical and biochemical – Following initial treatment, patients should be evaluated every three to four months by both clinical examination and measurement of serum IGF-1 levels.

Following initial treatment of acromegaly, whether surgery or medication, IGF-1 should be measured in two to three months. It should not be measured sooner, because of the long half-life of IGF-1. An elevated level suggests that the treatment has not been sufficient. If the IGF-1 level is normal after the initial treatment, it should be measured again in six months and then annually.

If IGF-1 levels are normal, measuring random GH or post-oral glucose tolerance test (OGTT) nadir GH levels may not add helpful information. Medical therapy dose adjustments should be made using the IGF-1 levels. The Endocrine Society guidelines suggest that an age-normalized serum IGF-1 and a random GH <1 mcg/L should both be therapeutic goals as they correlate with control of acromegaly [2].

Patients who are being treated with a medication should have the dose adjusted as needed [14]. If normal IGF-1 values are not achieved, alternative therapy should be considered. In patients well controlled on medical therapy, we suggest biochemical testing (serum GH, IGF-1) every six months.

●Imaging – MRI should be repeated 12 weeks after surgery and then yearly for the first several years after initial treatment and less often thereafter. Visual field assessment is indicated for patients whose adenomas threaten the optic chiasm [2].

●Systemic evaluation – Acromegaly appears to be associated with an excess risk of colonic polyps. Based upon these observations, we suggest that colonoscopy be performed at baseline and then every five years thereafter in patients in those found to have a polyp or those with persistently elevated IGF-1 levels and every 10 years in those without polyps and with normal IGF-1 levels [2]. (See "Causes and clinical manifestations of acromegaly", section on 'Other tumors'.)

Comprehensive cardiovascular evaluation should be performed regularly, and hypertension and heart failure should be treated [2]. (See "Causes and clinical manifestations of acromegaly", section on 'Cardiovascular disease'.)

Biochemical outcomes — When transsphenoidal surgery is performed by the most experienced pituitary neurosurgeons, GH secretion falls to normal in approximately 80 to 90 percent of patients with microadenomas (less than 10 mm in diameter) and pituitary secretion of other hormones is preserved [7,9,15]. The success rate is lower in patients with macroadenomas and/or higher preoperative serum GH concentrations [9,11,15,16].

●Time course – If surgery is successful, serum GH concentrations typically fall to normal within one to two hours, depending upon the degree of elevation. Serum IGF-1 concentrations fall more slowly, from 7 to 10 days to several months [17]. 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. Sleep apnea [18] and cartilaginous overgrowth also improve but often persist [19].

Amelioration of symptoms — When effective control of GH hypersecretion is achieved, serum GH and IGF-1 concentrations decline to normal [6], the characteristic soft tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities (such as diabetes mellitus) and quality-of-life measures improve [20].

Sleep apnea, tissue swelling, headache, and arthralgias resolve or improve in approximately 70 percent of patients controlled on medical therapy. Most patients recover from obstructive sleep apnea after surgical or medical control of the growth hormone excess [21]. Mortality outcomes appear to be more favorable with rigorous biochemical control.

Skeletal, jaw, and joint changes are not reversible. This was illustrated in a study of 118 patients with acromegaly who were in long-term remission, as judged by serum normal IGF-1 concentration; 77 percent reported joint symptoms [22]. (See "Causes and clinical manifestations of acromegaly", section on 'Bone and joints'.)

Should GH deficiency be treated? — We do not suggest the routine use of growth hormone (GH) therapy in patients with acromegaly who develop GH deficiency, as available data are conflicting.

It is estimated that 50 to 70 percent of patients with acromegaly treated with surgery alone or surgery combined with RT develop GH deficiency [10], a complication that is associated with a decreased quality of life [23]. However, the impact of GH therapy in those who develop GH deficiency is still unclear.

In one trial, patients with cured acromegaly who developed GH deficiency had improved body composition (decrease in total body fat mass and abdominal fat) with GH therapy compared with placebo [24]. In contrast, a second trial reported an increase in vascular events after two years of GH therapy in adults with GH deficiency previously treated for acromegaly [25].

Pregnancy — Most women with untreated acromegaly have menstrual dysfunction and infertility due to one or more of the following [26]:

●Decreased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) due to compression of gonadotroph cells by a macroadenoma

●Hyperprolactinemia due to pituitary stalk compression

●Hyperprolactinemia due to a mixed GH-prolactin secreting adenoma

We suggest the following approach to managing women planning pregnancy and pregnant/postpartum women with acromegaly:

Preconception

●The serum GH and IGF-1 concentrations should be as tightly controlled as possible in women with known acromegaly before attempting conception to minimize the risk of gestational diabetes mellitus (GDM) and gestation hypertension [2].

●Somatostatin analogs should be discontinued two months and pegvisomant one month prior to trying to conceive.

Short-acting octreotide may be used as necessary to control signs and symptoms of GH excess until conception [2].

During pregnancy/postpartum

●During pregnancy, medical therapy should be withheld. Short-acting octreotide can be used, but only for control of headache and adenoma size [2]. Most data suggest that somatostatin analog administration during pregnancy has not been associated with adverse events [27-29].

●We suggest against routine measurement of either serum GH or IGF-1 in pregnant patients. GH assays recognize both normal and placental variants of GH in gravid women. GH stimulates production of IGF-1 and may raise IGF-1 levels above the age-adjusted normal range [30,31].

●The majority of small pituitary adenomas do not grow during pregnancy [32]. For women who have macroadenomas, we suggest monitoring visual fields during each trimester of pregnancy. If visual fields show new defects, MRI should be performed. If vision is newly impaired and growth of the adenoma is the likely cause, surgery may be necessary.

●Breastfeeding is a reasonable option for women who do not require treatment hormone immediately after delivery.

Outcomes — When women with acromegaly do conceive, the majority appear to have uncomplicated pregnancies, although data are limited [28]. In one retrospective, multicenter study of 59 pregnancies in 46 women with GH-secreting pituitary macroadenomas or less often microadenomas, 43 of the 46 women had previously been treated with surgery or radiotherapy [32]. Prior to conception, GH and IGF-1 hypersecretion was controlled in 23 (40 percent) and uncontrolled in 34 (60 percent) patients. Medical therapy was discontinued in early pregnancy in all but four women. The following findings were noted:

●Pregnancy was uneventful for most women; the 59 pregnancies resulted in 64 healthy babies.

●No major neonatal malformations were encountered.

●Four women continued somatostatin analog therapy during pregnancy, all gave birth to a small for gestational age infant.

●GDM and gestational hypertension, which developed in 7 and 14 percent of pregnancies, respectively, was more common in women with active or uncontrolled acromegaly. Among those who had postpartum MRI imaging data available, only 2 of 22 (7 percent) showed an increase in pituitary tumor size.

●Seventeen women breastfed with no complications.

In a second report of 13 pregnancies in women with acromegaly, similar findings were seen; 10 of 13 received no medical therapy during the pregnancy. There were no pregnancy complications and no congenital malformations, but one of the three infants whose mother had received medical therapy (somatostatin analog) had low birth weight [28].

REVIEW OF TREATMENT OPTIONS

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 (algorithm 1) [11,15,33,34]. Surgery may also be considered for large adenomas that are not entirely accessible surgically (eg, those with cavernous sinus extension), with the goal of removing a sufficient mass of tissue to increase the likelihood that somatostatin analog treatment will be effective postoperatively. Some authorities recommend somatostatin analog treatment preoperatively, although the studies do not conclusively support this approach [35]. (See 'Role of primary medical therapy' above.)

Transsphenoidal surgery has been widely employed to treat pituitary adenomas, including somatotroph adenomas, since the 1970s. The approach during much of this time has been sublabial and transseptal using an operating microscope. During the past decade, an endoscopic approach has gained acceptance because it provides superior visualization of the suprasellar compartment and cavernous sinus walls. Studies describing patients treated for acromegaly by endoscopic surgery suggest that although this approach is promising, outcomes for acromegaly are not definitively superior to previously published microscopic series [36,37]. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses".)

Surgical cure rate — Accurate interpretation and comparison of studies reporting surgical cure rates in patients with acromegaly is difficult since both the duration of follow-up and the biochemical criteria for cure have varied. The current goal is a serum insulin-like growth factor-1 (IGF-1) concentration normal for age and gender and a serum growth hormone (GH) concentration less than 1 mcg/L or lower by immunoradiometric or chemiluminescent assay.

The cure rate using these criteria is illustrated in a report of 57 patients followed for at least 12 months postoperatively [38]. Surgical remission rates were 70, 67, and 61 percent, as assessed by normal serum IGF-1, random serum GH concentration <2.5 mcg/L, and glucose-suppressed GH concentration <1 mcg/L, respectively [38].

Although summarizing surgical cure rates across studies is difficult for the reasons noted above, the early cure rate in patients with acromegaly is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas [3,7-9,11,15,16,38,39].

Complications are reviewed above. (See 'Potential complications' above.)

Recurrence — Studies with several years 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-oral glucose tolerance test (OGTT) serum GH concentrations, have a recurrence several years or more after surgery, probably due to incomplete adenoma resection [7-9,11,38]. Higher rates of recurrence (eg, 19 percent) have been reported in series in which initial surgical cure rates were lower than those cited above [39].

Even if the nadir of the serum GH concentrations after an OGTT is only slightly above the target values, the risk of recurrence is greater, as illustrated by a study of 77 patients with apparent biochemical remission after surgery (normal serum IGF-1 concentrations) [40]. The patients were stratified according to the nadir serum GH concentration after an OGTT. Fifty patients (group 1) were considered to have a normal nadir GH (<0.14 mcg/L, based upon mean levels in normal, healthy controls) and 26 had an abnormal nadir (>0.14 mcg/L, group 2). At a mean follow-up of 3.2 years, the following results were seen in group 2 when compared with group 1 patients:

●Higher mean hourly GH concentrations (based upon hourly GH sampling for eight hours)

●Higher rate of recurrence, defined as an elevated serum IGF-1 concentration, in patients for whom data were available (5 of 19 versus 0 of 49)

Thus, patients with even subtle abnormalities in post-suppression GH levels may have a greater risk of recurrence.

Medical therapy — Several medications are available for treating acromegaly, including some that inhibit GH secretion and one that inhibits its action. Pharmacologic treatment is used when surgery alone has not reduced serum GH and IGF-1 to normal.

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 [1,41]. (See 'Role of primary medical therapy' above.)

Somatostatin analogs — Octreotide and lanreotide are analogs of somatostatin (GH-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). Somatostatin analogs inhibit GH secretion by binding to specific receptors for somatostatin and its analogs [42]. Their effect is greater when the number of receptors is high [43,44]; repetitive administration does not result in desensitization or loss of therapeutic efficacy [45].

Octreotide and lanreotide — Octreotide and lanreotide also cause pituitary adenoma shrinkage in some patients. The mechanism of the shrinkage remains unclear. In a study of tissue samples from 32 surgically resected somatotroph macroadenomas, the mean growth fraction of adenomas exposed to octreotide was 83 percent less than those not exposed [46]. However, in another report, octreotide exhibited an antiproliferative effect but no effect on the apoptotic index [47].

Dose and administration — Two somatostatin analogs, octreotide and lanreotide, are widely available. The long-acting form of octreotide is given as an intramuscular injection once a month. 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 different forms in different countries. A deep subcutaneous form (lanreotide autogel or depot) is given as 60 to 120 mg every four to six weeks [48].

In a study of 30 patients with a partial response to a somatostatin analog, use of high dose (180 mg/28 days) or high frequency (120 mg/21 days) both resulted in normalization of IGF-1 in approximately 30 percent of subjects [49]. These regimens were well tolerated, and adverse events were similar between the groups. In a prior study, use of a high-dose, long-acting octreotide preparation (60 mg/28 days) resulted in normalization of IGF-1 in 36 percent of partial responders [50]. Such regimen may be considered in such subjects.

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. The two once-monthly preparations, octreotide long-acting release (LAR) and lanreotide (autogel or depot) appear to be equivalent for control of biochemical markers and symptoms [51].

●Predictors of response – Tumor subtypes may be a predictor of response to somatostatin analog therapy. The densely granulated tumors are typically smaller and more active (produce more GH) and respond well to somatostatin analogs [52,53]. In contrast, the sparsely granulated subtype tumors tend to be larger, more common in females and in younger patients, more invasive, and are relatively less responsive to somatostatin analogs.

A hypointense T2 signal on magnetic resonance imaging (MRI) also appears to be associated with a better response to somatostatin analog therapy when given either pre- [54] or postoperatively [55].

●Biochemical improvement – Normalization of serum IGF-1 concentration with somatostatin analogs occurs in 40 to 75 percent of patients. The success rate varies markedly with study design, ranging in two reports from 38 percent in patients who were not preselected for responsiveness (figure 1) [56] to a mean of 66 percent in a review of several studies, most of which included patients who had been preselected for responsiveness to the short-acting form [57]. Combined therapy with cabergoline and a somatostatin analog may be effective when either alone is not [58].

●Improvement in symptoms – A somewhat greater percentage of patients appear to experience improvement in symptoms with somatostatin analogs than exhibit IGF-1 normalization, presumably because even a partial decrease in GH results in some degree of symptomatic improvement [59]. (See 'Amelioration of symptoms' above.)

Successful therapy is associated with an improvement in several signs and symptoms during the year following a decrease in biochemical parameters (see 'Amelioration of symptoms' above):

•Soft-tissue swelling, carpal tunnel syndrome, and snoring [57]

•Sleep apnea [60,61]

•Left ventricular mass and left ventricular function [62-64]

●Adenoma size – Somatostatin analog therapy leads to a reduction in adenoma size of approximately 20 to 50 percent in 30 percent of patients (figure 2 and image 1) [57]. 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 experienced a significant reduction in adenoma size (mean 19 percent) [65]. In a subsequent study of 99 patients who received somatostatin analogs as primary therapy, 45 percent had normalization of serum IGF-1 concentration, and 44 percent had a >50 percent reduction of adenoma size [66].

Side effects — Somatostatin analogs are usually well tolerated. Approximately 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 usually subside spontaneously with continued use [67].

Somatostatin analogs are associated with an increased risk of gallstone disease. Up to 56 percent of patients develop asymptomatic cholesterol gallstones or sludge during the first 18 months of therapy [57,68]. However, we do not suggest routine abdominal ultrasound monitoring. We suggest ultrasound only if the patient develops signs and symptoms suggestive of gallstone disease [2]. Less common side effects include hair loss, constipation, and bradycardia.

Octreotide and lanreotide transiently inhibit insulin secretion, but their clinical impact on glucose homeostasis is minimal. This was illustrated by a meta-analysis of 18 trials in patients receiving these analogs for acromegaly. Fasting insulin concentrations were significantly reduced and glucose levels were slightly higher on an OGTT, but there were no significant changes in fasting glucose or glycated hemoglobin (A1C) values [69].

Pasireotide — The somatostatin analog pasireotide is also effective in some patients with acromegaly and is approved for its treatment, but it frequently causes or worsens hyperglycemia.

In a 12-month trial of 358 patients with acromegaly (with no prior medical therapy) receiving pasireotide LAR (40 mg once/month by intramuscular injection) or octreotide LAR (20 mg/month intramuscular injection), biochemical control was achieved in more patients receiving pasireotide when compared with octreotide (31.3 versus 19.2 percent, respectively) [70]. Submaximal dosing of octreotide may have contributed to its lower rate of biochemical control. Similar to what has been observed in patients with Cushing's disease, hyperglycemia (often requiring insulin treatment) was more common with pasireotide LAR than octreotide LAR (57.3 versus 21.7 percent). (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Pasireotide'.)

Oral octreotide — An oral formulation of octreotide (delayed-release capsules) based on a transient permeability enhancer that enables bioactive gastrointestinal absorption has been approved for use for the management of acromegaly [71]. This agent is indicated for long-term maintenance therapy in patients with acromegaly who have responded to and tolerated treatment with either octreotide or lanreotide.

It appears to be effective in some patients with acromegaly, but perhaps less so than long-acting injectable preparations. In an open-label study of 155 patients previously controlled on injectable somatostatin analogs, patients were switched to oral octreotide capsules (40 mg/day in two divided doses, increased up to 80 mg/day as needed) [72]. Sixty-five percent (98 of 151) of the intent-to-treat population achieved the primary endpoint of GH/IGF-1 control, compared with 91 percent (138 of 151) while taking long-acting injectable somatostatin analogs; among the 91 patients who entered a subsequent fixed-dose phase (40 to 80 mg daily), 85 percent (77 of 91) sustained control for up to a total of 13 months. The adverse event profile was similar to that observed for injectable somatostatin analogs.

Pegvisomant — Pegvisomant is a GH receptor antagonist that is a mutated GH molecule to which polymers have been attached at several sites to prolong its half-life [73]. The mutation results in increased affinity to site 1 on the GH receptor but decreased binding to site 2. As a result, pegvisomant blocks native GH from binding but does not activate the intracellular signaling that mediates its action.

Patients receiving pegvisomant should be monitored by measuring IGF-1 levels (but not GH levels), as well as serial MRIs, to assure that there is no continued tumor growth. In addition, liver function tests (LFTs) should be measured every six months, and if more than threefold elevated, the drug should be discontinued.

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 [74].

A number of factors affect the dose required to normalize serum IGF-1 concentrations [75]. Higher doses are needed the higher the baseline IGF-1 concentration and the greater the patient's weight, and women need higher doses than men for the same weight. Lower doses are needed for patients who have had radiation therapy (RT) for comparable IGF-1 values.

Serum GH cannot be used to monitor the effectiveness of treatment, since pegvisomant inhibits the action of GH rather than its secretion.

Efficacy — Pegvisomant is an effective therapy for lowering serum IGF-1 concentrations. In a 12-week study of 112 patients, most of whom had received other treatment, pegvisomant doses of 10, 15, or 20 mg daily resulted in dose-dependent reductions 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 [76].

When the same patients and 48 others were treated with up to 40 mg/day for an average of 425 days, 97 percent of those treated for 12 months or more achieved normal IGF-1 concentrations (figure 3). This is a much higher response rate for IGF-1 levels than achieved by any other therapy. At the same time, the serum GH concentration increased by a mean 12.5 mcg/L [77].

The results in clinical practice may not be as good as in clinical trials. In an international surveillance registry of 1288 patients with acromegaly receiving pegvisomant for an average of 3.7 years [78], only 56.6 percent of subjects had normal IGF-1 concentrations one year after beginning pegvisomant.

Because pegvisomant does not inhibit GH secretion and its use is associated with an increase in the serum GH concentration, somatotroph adenoma size presumably could continue to grow during its use. However, this appears to be uncommon, as illustrated by the surveillance registry study cited above [78]. In 30 of 936 patients (3.2 percent) for whom MRI data were available, an increase in adenoma size was noted in an average 2.1 years of follow-up. Based upon such observations, patients receiving pegvisomant should have adenoma size assessed by MRI at least once a year [79].

Safety — In the registry study noted above [78], 30 subjects (2.5 percent) developed elevated liver enzymes greater than three times the upper limit of normal. In the 23 subjects for whom follow-up data were available, liver enzymes returned to normal after decrease or discontinuation of pegvisomant. There were no reports of liver failure [78].

Pegvisomant should therefore not be prescribed to patients who have clearly abnormal liver function, and patients who are treated should be monitored by LFTs once a month during the first six months of treatment and every four to six months thereafter. Pegvisomant has also been shown to be associated with lipohypertrophy both at the injection site and at distant sites [80,81].

Combination therapy — The combination of a long-acting somatostatin analog and pegvisomant, in a few reports [82-84], decreased serum IGF-1 concentrations to normal in a majority of patients, but the combination was not clearly better than pegvisomant alone. For example, in 27 patients who were suboptimally controlled while taking long-acting octreotide alone, randomization to either the combination of the analog combined with pegvisomant or pegvisomant alone led to normalization of IGF-1 in 62 and 56 percent, respectively [83]. The combination, however, seems to be associated with a greater incidence of transaminase elevations than either alone, as high as 38 percent [82-84].

Dopamine agonists — Dopamine agonists, especially cabergoline, may inhibit GH secretion in some patients with acromegaly but do not work as well as somatostatin analogs. However, their oral route of administration is an advantage over the other treatments, which are administered parenterally. Cabergoline is the most effective dopamine agonist for the adjuvant management of acromegaly and is therefore the drug of choice in this category [85].

We currently suggest a trial of cabergoline, rather than somatostatin analogs or pegvisomant, in patients with modest biochemical abnormalities, eg, GH concentrations >1 mcg/L but <1.3 mcg/L and only mild symptoms of GH excess.

We also suggest cabergoline in combination with a somatostatin analog in patients in whom somatostatin analog treatment alone has reduced serum IGF-1 concentrations almost to normal. This combination offers the possibility of reducing the IGF-1 further to mid-normal with the addition of a relatively inexpensive medication administered orally. (See 'Medical therapy' above.)

Cabergoline could also be tried as primary therapy in the occasional patient who has only a mild elevation of IGF-1 and a small adenoma, is not a good candidate for surgery, and refuses monthly injections of a somatostatin analog.

●Cabergoline dosing – 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 mg twice a week. Higher doses are not likely to decrease GH further [86]. The presence of hyperprolactinemia does not consistently predict GH and IGF-1 response.

In a meta-analysis of 15 studies of cabergoline therapy in 227 patients with acromegaly, cabergoline achieved normal serum IGF-1 levels in 51 of 149 patients (34 percent) [85]. In studies where cabergoline was added to a somatostatin analog, 40 of 77 (52 percent) achieved normal IGF-1 levels. However, these results should be interpreted with caution as some of the studies included in the meta-analysis included poorly defined patient groups and non-rigorous IGF-1 assays.

●Side effects – The most common side effects of cabergoline are nausea, light headedness, and mental fogginess. Less common are nasal stuffiness, depression, and constipation. The high doses of cabergoline used in Parkinson disease have been associated with valvular heart disease, but the lower doses used for lactotroph adenomas have not. (See "Management of hyperprolactinemia", section on 'Valvular heart disease'.)

Radiation therapy — RT is effective in reducing the size of somatotroph adenomas and decreasing GH and IGF-1 concentrations, often to normal, but because the decreases in GH and IGF-1 usually take years to occur, we suggest its use primarily for patients whose disease is not controlled by surgery or medical therapy (algorithm 1) [87].

Types of radiation — The types of radiation therapy for pituitary adenomas, radiation delivery systems, and their efficacy and side effects are reviewed in detail separately. (See "Radiation therapy of pituitary adenomas".)

●Stereotactic radiosurgery (SRS) – Radiation can be administered as a single dose (often called "stereotactic radiosurgery," or SRS, although there is no surgery), by linear accelerator, gamma radiation, or protons. It has the advantage of patient convenience and possibly faster control of hormonal hypersecretion [87]. Gamma radiation has been available more widely than the other forms of single-dose radiation (protons and x-radiation from a linear accelerator), so more data are available about it. The most commonly used stereotactic method used is the Gamma Knife.

A single dose of radiation cannot be used unless the adenoma is separated by several millimeters from the optic chiasm and optic nerves (to limit the exposure of the optic apparatus to less than 8 Gy), which would be severely damaged by such a high dose, resulting in blindness. In this situation, fractionated radiation must be used. (See "Radiation therapy of pituitary adenomas".)

●Fractionated radiation therapy – Fractionated radiation therapy is the delivery of radiation therapy in multiple, small, daily doses, usually five days a week for five to six weeks. This is the way RT is delivered for most other indications of radiation treatment.

●Delivery systems

•The linear accelerator is the most common device used for RT, ie, for conventional radiation. Modifications have been made to deliver the radiation to the desired location and dose. (See "Radiation therapy of pituitary adenomas", section on 'Radiation delivery systems'.)

•Gamma knife – Gamma Knife is an SRS treatment unit. Gamma radiation can be administered from a cobalt source but only as a single, large dose. Although this is called "Gamma Knife," there is no knife.

•Proton therapy – High-energy proton particles can be administered from a cyclotron in either a single, large dose or multiple fractions.

•Use of somatostatin agonists during RT – It was suggested in an earlier study that use of a somatostatin analog at the time of RT may limit its effectiveness, but this consideration has been refuted by subsequent studies [88-90]. However, most clinicians do hold somatostatin agonists therapy while patients undergo RT.

Efficacy — Few patients who undergo fractionated radiation achieve the current goal of therapy, ie, a basal serum GH concentration less than 1 mcg/L. Serum GH and IGF-1 concentrations decline on average approximately 20 percent per year, so that serum GH concentrations may not reach 5 to 10 mcg/L until 5 to 10 years or more after treatment if the initial value is very high [91].

By 20 years after treatment, up to 90 percent of patients have serum GH concentrations less than 5 mcg/L and 10 to 77 percent in different studies eventually achieved serum GH concentrations <2.5 mcg/L (table 1) [91-95]. In one series, as an example, only 5 of 30 patients (17 percent) followed for 10 or more years reached this goal [96]. (See "Radiation therapy of pituitary adenomas", section on 'Somatotroph adenomas (acromegaly)'.)

Normalization of the serum IGF-1 concentration occurs in approximately 55 to 70 percent of patients after 10 years, but the results vary among studies [92-95].

The efficacy of SRS appears to be similar to conventional RT. However, SRS may be more appealing because the treatment duration is shorter. In three studies of 35 to 96 acromegalic patients followed after gamma radiation [97-99], cure rates (defined as normal age- and gender-adjusted IGF-1 concentrations and basal GH of <2.5 mcg/L or post-glucose load values of <1 mcg/L) were 46 to 60 percent in 5 to 10 years.

As with fractionated radiation, cure rates due to single-dose radiation are higher the smaller the size of the adenoma and the lower the IGF-1 and GH.

Monitoring — Because the full therapeutic effect of the RT may take many years and some patients may have limited response, it is important to perform annual reassessment of radiation efficacy.

Once a normal serum IGF-1 level is achieved, medical therapy should be withdrawn annually for one to three months (depending on the specific drug) for reassessment of GH and IGF-1 levels.

For patients who have undergone RT, we suggest annual pituitary hormone testing to detect hypopituitarism, which is common post-RT. We also evaluate for other delayed radiation effects such as cerebrovascular disease and cranial nerve abnormalities.

Adverse effects

●Hypopituitarism – Within 10 years, approximately 40 percent of patients treated with pituitary radiation develop deficiency of one or more pituitary hormones [91,93], and the incidence continues to increase thereafter. Gonadotropin deficiency is most common, followed by corticotropin (ACTH) and then thyroid-stimulating hormone (TSH) deficiency. In the series of 884 patients, the percentage of patients with new hormone deficiencies 10 years after irradiation were 18, 15, and 27 percent for luteinizing hormone (LH)/follicle-stimulating hormone (FSH), ACTH, and TSH, respectively [91]. A second study reported higher rates of hormone deficiencies, but patients had more severe disease (higher baseline serum GH concentrations) and received higher radiation doses (mean dose 52 Gy [93] versus 45 Gy [91]).

Hypopituitarism occurs after single-dose radiation, as it does with fractionated, in approximately 40 percent of those treated by both gamma and proton radiation [97,98,100].

●Other complications – Other complications are cranial-nerve palsies, loss of vision, and memory deficits. All are rare and usually occur only when the dose is high [93].

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 [101,102]. The reported tumors include astrocytoma, glioblastoma, meningioma, and sarcoma [14].

Some evidence points to RT as being a significant independent determinant of overall mortality in acromegaly [103,104].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acromegaly (The Basics)")

●Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the Basics)")

Patients can also get information about pituitary adenomas and their consequences from The Pituitary Society and The Endocrine Society.

SUMMARY AND RECOMMENDATIONS — A summary of treatment effects is provided in the table (table 1).

●For patients with a microadenoma, a macroadenoma that appears to be fully resectable, or a macroadenoma threatening or impairing vision, we recommend transsphenoidal surgery performed by a neurosurgeon with considerable experience in pituitary surgery (algorithm 1) (Grade 1B). (See 'Transsphenoidal surgery' above.)

●For patients with an adenoma that 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 (algorithm 1) (Grade 2B). (See 'Somatostatin analogs' above.)

●If transsphenoidal surgery results in normalization of serum insulin-like growth factor-1 (IGF-1) concentration, we suggest no further therapy, but we do suggest continued monitoring to detect a recurrence (Grade 2B). (See 'Transsphenoidal surgery' above.)

●If transsphenoidal surgery does not normalize the serum IGF-1 concentration, we suggest medical therapy with a long-acting somatostatin analog or growth hormone (GH) receptor antagonist. We suggest the dopamine agonist cabergoline for mild disease (algorithm 1) (Grade 2B). (See 'Additional therapy for residual disease' above.)

●If a somatostatin analog, with or without cabergoline, is ineffective, we suggest pegvisomant alone or in combination with the somatostatin analog (Grade 2B). (See 'Combination therapy' above.)

●If adenoma size increases or GH/IGF-1 hypersecretion persists despite medical therapy (ie, somatostatin analog plus pegvisomant), we suggest radiation therapy (RT) or repeat surgery (algorithm 1) (Grade 2B). (See 'Radiation therapy' above.)

For women who desire pregnancy:

●Pregnancy should be postponed, if possible, until GH and IGF-1 levels are controlled and no residual tumor mass is seen. We suggest controlling the serum GH and IGF-1 concentrations as tightly as possible before attempting pregnancy to minimize the risk of gestational diabetes mellitus (GDM) and gestational hypertension (Grade 2C). (See 'Pregnancy' above.)

●We suggest stopping medical therapy when pregnancy is confirmed (Grade 2C). The majority of adenomas do not grow during pregnancy. Short-acting octreotide can be used during pregnancy, but only for control of headache and adenoma size. (See 'Pregnancy' above.)

●Visual fields should be monitored during pregnancy in women with macroadenomas starting at the end of the first trimester and every six weeks thereafter. Magnetic resonance imaging (MRI), without contrast, should be performed if visual field testing suggests a chiasmal lesion. If visual impairment due to a chiasmal lesion is confirmed, surgery may be necessary. (See 'Pregnancy' above.)