Endocrinology Metabolism

Acromegaly

Are You Sure the Patient has Acromegaly?

Acromegaly is a rare disease that is due to a growth hormone (GH)-secreting tumor of the pituitary gland. Acromegaly is very rare, with a reported incidence of up to 5 cases per million. It affects men and women equally and is not known to be more common in any race or population from a particular geographic region. The average age at presentation is 40-50 years, but acromegaly can present at all ages. When acromegaly develops before or during puberty, the disease can manifest as gigantism due to the rapid increase in height due to long-bone growth. Nearly all cases are sporadic, but rarely acromegaly is associated with other familial endocrine syndromes (see later).

The patient with acromegaly is transformed by the multisystem effects of longstanding exposure to excess growth hormone and IGF-I (insulin-like growth factor 1), a hormone whose production is increased by GH and that mediates most of the growth-promoting effects of GH.

The disease cannot be detected on routine laboratory work or by the presence of one of its common comorbidities alone. Rather, a clinical suspicion of the disease is necessary in almost all patients to trigger an investigation for acromegaly.

Most patients with acromegaly are recognized because they have enlargement of their hands and feet and classic changes in their facial features. These are present at diagnosis in nearly all patients. On examination, the characteristic facial changes appear as coarsening of the features (enlargement of the lips and nose, deepening of the creases), prominence of the brow, enlargement of the lower jaw and tongue, and increased spacing of the teeth. Patients may relay a history of having their rings enlarged and their shoe size increased, especially its width. These changes can be very marked, often indicating that the disease has been present, but undiagnosed, for many years. Most patients have had signs and symptoms for 8 to 10 years before diagnosis.

Other common signs and symptoms of acromegaly include hyperhidrosis, headache, joint pains and arthritis, visual disturbance, gonadal dysfunction, and carpal tunnel syndrome. Although the "classic patient" may have many of these findings, the constellation of signs at diagnosis varies, and in some patients, especially in the small number of patients whose disease is recognized early, the findings can be subtle.

At diagnosis most patients also have one or more of the major comorbidities associated with acromegaly including hypertension, diabetes mellitus, osteoarthritis, carpal tunnel syndrome, and sleep apnea.

Patients with acromegaly come to medical attention in many different ways.

Their multisystem complaints often lead them to visit a variety of physicians such as the internist for hypertension or diabetes, gynecologist for menstrual abnormalities, dentist for jaw/teeth problems, pulmonologist for sleep apnea, orthopedist for carpal tunnel surgery, rheumatologist for joint pain. and others. Occasionally, patients are diagnosed only incidentally when a head MRI is done for an unrelated reason. Often the disease is recognized by a physician, family member, or friend who has not seen him or her in some time and notices the patient's change in appearance.

The key to making the diagnosis is to think of it.

Other clinical manifestations

Not all patients with acromegaly have severe enough disease for it to be clinically obvious. Therefore, acromegaly should be considered in patients with subtle features because early diagnosis and treatment are clearly preferable. Early treatment can prevent the development of some of the disfiguring clinical features and small tumors are more likely to be cured surgically. On the other hand, not all patients with just one common comorbidity can be screened for the disease. Therefore, the history and exam should be thorough and attempt to elicit some of the more common (described earlier) as well as less common manifestations of acromegaly.

Less acromegaly-specific signs and symptoms include deepening of the voice, paresthesias, hirsutism, acne, sinus disease, kidney stones, skin tags, snoring, fatigue, and galactorrhea. Undertaking the biochemical evaluation should strongly be considered in the presence of a constellation of these characteristics. Rapid growth and tall stature in a child or teen should raise suspicion for acromegaly.

Pathophysiology

Acromegaly originates in almost all cases from a GH-secreting pituitary tumor. These benign tumors are composed of a monoclonal population of GH-secreting (somatotroph) pituitary cells. It is believed that a combination of dysregulated somatotroph cell growth and altered paracrine and endocrine factors regulating these cells growth and GH secretion contributes to the development of these tumors.

There are reports of central hypothalamic or peripheral GHRH-producing tumors such as carcinoids that result in pituitary GH cell hyperplasia and produce a clinical acromegaly syndrome. Exceedingly rare cases of ectopic GH producing tumors have been reported.

Acromegaly is rarely associated with a familial syndrome.

Pituitary hyperplasia is seen in McCune-Albright syndrome where activating mutations in GNAS (gene encoding alpha stimulating G protein) can lead to constitutively elevated cAMP levels and GH hypersecretion due to pituitary GH cell hyperplasia.

In the MEN 1 syndrome, an autosomal dominant disorder associated with germ-line mutations in MEN1, a tumor suppressor gene, GH-secreting pituitary tumors occur in about 20% of cases.

Recently, families with familial isolated pituitary adenomas (FIPAs) have been found to have mutations in the tumor suppressor aryl hydrocarbon receptor-interacting protein (AIP). In the families with isolated familial somatotropinomas, the affected patients tend to be younger, typically diagnosed in their teens through 20s, than most acromegaly patients.

What Else Could the Patient Have?

The classic clinical and biochemical syndrome of acromegaly is not mimicked by another etiology. However, many of its less specific manifestations, such as carpal tunnel syndrome or headache, occur commonly in the general population, and if these are evaluated individually, the underlying unifying diagnosis of acromegaly often goes unconsidered.

The comorbidities of acromegaly are also common in the general population, but acromegaly is rare. Therefore, all patients with these conditions, such as type 2 DM, cannot be screened for acromegaly. Rather, this screening should be done when they occur in conjunction with other possible features of acromegaly. In young women, acromegaly and the polycystic ovarian syndrome may need to be differentiated as they share some common features such as hirsutism and menstrual irregularity.

Any patient with hyperprolactinemia should have a serum IGF-I level measured. Some GH-secreting tumors co-secrete prolactin and others lead to hyperprolactinemia by compression of the hypothalamic-pituitary stalk. Acromegaly should be excluded by measurement of a serum IGF-1 level in any patient presenting with a pituitary tumor, even those without the clinical signs or symptoms.

Very rarely, ectopic GHRH or GH production may lead to acromegaly. Ectopic GHRH production might be considered in a patient with no visible discrete pituitary tumor, but who has the clinical and biochemical characteristics of acromegaly.

A number of conditions other than acromegaly can raise or lower GH and IGF-I levels resulting in misleading biochemical testing. These caveats to the interpretation of the laboratory diagnosis of acromegaly are discussed here.

Key Laboratory and Imaging Tests

After acromegaly is suspected, a biochemical workup needs to be performed to make the diagnosis. The biochemical hallmarks of the disease are documentation of hypersecretion of growth hormone and elevation of serum levels of IGF-I. In a patient with acromegaly, GH is secreted by the tumor at a higher than normal basal level but also still in a pulsatile fashion. Although GH is persistently very high in many patients, it is not in others so a random GH is not reliable for the diagnosis. In addition, many patients with milder acromegaly have GH levels that fall into the range of pulsatile GH secretion seen in healthy individuals.

GH excess should be assessed by a dynamic test, preferably its suppression after an oral glucose load in which GH levels are measured before and then at 60, 90, and 120 minutes after the ingestion of 75 or 100 g of oral glucose. In healthy individuals, GH levels suppress, typically near the lower limit of detection of current commercially available GH assays. However, in some healthy young woman, particularly those on estrogen therapy, which increases GH levels, GH may not suppress normally.

GH levels do not suppress after oral glucose in patients with acromegaly and often rise. Nearly all patients with newly diagnosed acromegaly will have GH levels >>1 µg/L after oral glucose. With highly sensitive and specific GH assays, a GH level of 0.4 µg/L best separates out acromegaly (above) and nonacromegaly (below) patients. It needs to be recognized, however, that these GH levels need to be interpreted in conjunction with the serum IGF-I level. GH suppression is not precise enough nor the cutoffs standardized enough to rely on this alone for the diagnosis of acromegaly.

GH assays remain heterogeneous in terms of their antibody specificity, sensitivity, and many other assay characteristics, so it is best to compare results to normative data specific for the assay being used.

IGF-I levels become persistently elevated in patients with acromegaly. The serum IGF-I level is a sensitive and specific measure of GH excess when it is measured in a reliable assay with a well-characterized and age-adjusted normative range (levels normally fall with advancing age). Serum IGF-I levels can provide an integrated measure of 24-hour GH secretion as its level remain fairly constant over the day.

In the appropriate clinical setting, persistent elevation of serum IGF-I level and documentation of GH excess confirm the biochemical diagnosis of acromegaly. There are caveats to the interpretation of GH and IGF-I levels. Abnormal GH suppression after oral glucose can occur in some settings other than acromegaly, including chronic renal insufficiency, liver disease, malnutrition, anorexia nervosa, hyperthyroidism, and diabetes mellitus.

Elevated IGF-I levels that are not due to acromegaly can occur in adolescents, during and early after pregnancy and in hyperthyroidism. Serum IGF-I levels can be lowered in the setting of malnutrition, liver disease, hypothyroidism, poorly controlled DM, and with oral estrogen use.

With the measurement of either GH or IGF-I, a variety of assay issues can also be the cause of false results.

When faced with discrepant GH and IGF-I results, the measurements should be repeated and those conditions that could alter one of the measurements need to be considered.

Following the biochemical confirmation of the disease, the pituitary region should be imaged with MRI. The MRI should be specific for the pituitary and sellar region and performed with and without gadolinium. Tumors are categorized into microadenomas (<1 mm in maximal diameter) and macroadenomas (≥1 cm). This cutoff was likely artificially generated but is used widely to guide statistics on surgical cure rates.

All patients also need to have the measurement of serum prolactin level to screen for a prolactin co-secreting tumor, which is present in up to 30% of patients. If the prolactin level is very high, the prolactin component may predominant and the patient may respond to dopamine agonist therapy.

Pituitary function (pituitary-adrenal, thyroid, and gonadal axes) needs to be fully investigated as many of these tumors are large at diagnosis and can produce hypopituitarism due to compression of the normal pituitary gland.

Additional lab studies

With the improvement in the sensitivity and specificity of assays for the measurement of GH and IGF-I, clinicians may be able to detect earlier disease, but also as a consequence of this, the diagnosis may not be as clear-cut in all patients. In such cases, it is often necessary to repeat the testing to confirm the diagnosis

Results of IGF-I assays may not always be reliable as the quality of assays varies. Delays in sample processing and other sample handling issues may be a factor. It may be necessary to repeat the IGF-I level with a different assay to verify the result. IGF-I levels need to be compared with well-characterized age-adjusted normative data. Caveats to the interpretation of IGF-I levels as discussed here earlier need to be considered.

Measurement of serum levels of IGFBP3 may be helpful in confusing cases. This protein, along with another, ALS (acid labile subunit), binds IGF-I in circulation in a ternary complex. Serum levels of IGFBP3 generally parallel those of IGF-I as they are also stimulated by GH. Documentation of an elevated IGFBP3 level along with that of IGF-I would help to confirm acromegaly. Conditions that lower IGF-1 such as liver disease and malnutrition also lower the levels of IGFBP3. Although ALS is also a very good marker of GH excess, its measurement is not available in commercial labs.

Management and Treatment of the Disease

The most urgent consideration when caring for a patient with newly diagnosed acromegaly, or any patient with a pituitary tumor, is whether the tumor exerts pressure on the optic nerve or chiasm and is producing visual or neurological abnormalities. All patients should be examined on presentation for these abnormalities and, if present and/or if MRI shows that the lesion is proximate to the optic structures, formal visual field testing should be performed. The presence of visual or neurological compromise due to tumor compression is an indication for urgent transsphenoidal surgery.

Another important consideration is whether secondary adrenal insufficiency or secondary hypothyroidism is present. These should be evaluated for and, if detected, replacement of the former and then the latter deficiency should be undertaken prior to surgery. The patient may also benefit from immediate treatment of certain comorbidities such as hypertension and diabetes mellitus. Some patients have such marked soft tissue hypertrophy of the pharynx and tongue that intubation can be problematic. A short course of preoperative somatostatin analog treatment may acutely lower GH levels and reduce this swelling, and potentially improve the perioperative course.

The goals of therapy of acromegaly are to control the biochemical excesses of the disease, to relieve the signs and symptoms including any due to mass effect on structures surrounding the pituitary gland, to treat coexistent hypopituitarism and comorbidities, and to achieve these goals with as few side effects as possible. Normalization of the serum IGF-1 level is the essential criterion for biochemical control.

Transsphenoidal Surgery

The initial therapy of acromegaly is transsphenoidal pituitary surgery for removal of the tumor. In the hands of an experienced pituitary surgeon, the success rate for remission after surgery alone is high. For microadenomas, the surgical cure rate approaches 90%. However, at diagnosis, about 75% of tumors are macroadenomas and the success of surgery falls progressively if the tumor is larger or is invasive, with the latter typically not being cured by surgery.

In addition to surgery being potentially curative, the use of surgery as initial therapy has some other clear advantages to other therapies because it can provide rapid relief of pressure to surrounding structures such as the optic nerve and a rapid decline in GH levels, which can quickly improve clinical symptoms. Decompression of the tumor, even if it cannot be completely removed, can provide these benefits. The resultant smaller tumor mass and lower GH levels from even partial tumor removal can increase the chance of success of some medical therapies.

Medical Therapy

In patients who do not achieve biochemical remission by surgery, options for adjunctive therapy include medical therapy and radiation therapy. There are three types of medical therapy that can be offered.

1. Somatostatin Analogs

The most commonly used class of medications used to treat acromegaly are somatostatin analogs. These long-acting analogs of the endogenous inhibitor of GH, somatostatin, will suppress GH and thereby lower circulating IGF-I levels. In most patients, they retard tumor growth, and some patients have significant tumor shrinkage. Complete biochemical remission occurs in 20% to 60% of patients. Somatostatin analogs work by activating somatostatin receptors on the tumor cells, but variability in the expression and density of the specific receptor subtypes activated by these analogs results in variable patient responses.

Three analogs are clinically available: octreotide LAR (long-acting release), lanreotide autogel, and pasireotide LAR. These are given as intramuscular (octreotide and pasireotide) and deep subcutaneous (lanreotide) injections. Dosages for octreotide LAR are 10, 20, and 30 mg/month with the initial recommended dose usually 20 mg/month; lanreotide doses are 60, 90, and 120 mg, with the starting dose being 90 mg; and pasireotide LAR doses are 20, 40, and 60 mg with the starting dose being 40 mg.

Although initially recommended to begin somatostatin analog therapy with two to three times daily injections of the short-acting subcutaneous form of octreotide to assess tolerability to the drug, this is no longer commonly done. Patients with underlying gastrointestinal (GI) disease who may be more susceptible to the side effects of the medication (see later) may be an exception to this. The doses are up- or down-titrated based on the biochemical response, in particular normalization of the serum IGF-I level. In patients who are very responsive, the interval between injections can be lengthened.

Pasireotide, because it activates a broader somatostatin receptor profile than octreotide or lanreotide, is effective in some patients in whom octreotide and lanreotide are not.

Somatostatin receptors are widely distributed, especially in the GI tract, and therefore side effects are not uncommon. Up to 50% of patients develop some initial GI complaints such as bloating and loose stools, but typically these wane with time. About 15% of patients develop gallstones. Somatostatin analog use can be associated with sinus bradycardia, rarely hair loss, and transient pain at the site of the injection. Hyperglycemia develops in up to 50% of pasireotide- and 20% of octreotide- and lanreotide-treated patients.

2. GH Receptor Antagonist

Another medical therapy option for acromegaly is the GH receptor antagonist pegvisomant. This drug works by attaching to GH receptors and blocking signal transduction through the GH receptor, thus blocking GH action and lowering serum IGF-I levels. The drug is highly effective, normalizing IGF-I levels in more than 90% of patients when given in sufficient doses. It is typically given as daily subcutaneous injections at doses of 10, 15, or 20 mg/day. Higher doses can be used. In addition, in patients with mild disease, the interval between injections can be lengthened.

As this medication blocks peripheral GH action, it does not retard pituitary tumor growth. In fact, pituitary tumors are likely to continue to grow at their natural rate while on this medication, so pituitary tumor size monitoring is especially important to perform in patients treated with the GH receptor antagonist. Overall, about 2% of tumors enlarge slowly on pegvisomant therapy. Rarely does rapid tumor growth occur.

Pegvisomant is generally well tolerated. Up to 5% of patients develop transient elevations of liver transaminases and rarely does this necessitate that the medication be discontinued. Periodic monitoring of the liver enzymes is recommended, especially over the first year of therapy. Patients may rarely experience transient mild flu-like symptoms and irritation and occasionally lipohypertrophy at the injection site.

3. Dopamine Agonists

Another class of medications, dopamine agonists, have been used for many years to treat acromegaly. These medications are not FDA approved for the treatment of acromegaly. Dopamine agonists, bromocriptine and cabergoline, can paradoxically suppress GH in some patients with acromegaly but only normalize serum IGF-I levels in 15% to 20% of patients. Patients with very mild disease and those whose tumor is a prolactin co-secreting tumor are more likely to respond. Recent data on the association of cardiac valvular abnormalities with the use of much higher doses of cabergoline in patients with Parkinson's disease have led to the reexamination of the use of this dopamine agonist for acromegaly. Although the acromegaly doses are much lower (usually 2-3 mg/week) than those associated with heart valve changes, acromegaly itself can be associated with heart valve abnormalities, so it should only be used if necessary and with caution for the treatment of acromegaly.

Radiation Therapy

Prior to the development of these effective medical therapies, radiation therapy was the most common second line therapy for patients not cured by surgery. Radiotherapy is still performed in many patients, but its use is more typical in patients who have already failed medical therapy. Patients may elect to have radiotherapy as first-line after noncurative surgery. Some patients choose this option because they desire to eventually be free from the use of acromegaly medications.

Radiotherapy (RT) can be given as focused, single-treatment stereotactic radiosurgery such as gamma knife or proton beam therapy in patients with a relatively discrete tumor and one that is not within a few millimeters of the optic nerve. Acromegaly can also be treated by conventional, fractionated stereotactic RT in which the radiation is administered in smaller divided doses over a 4- to 6-week period. The latter is necessary for patients with a more diffuse tumor remnant and/or tumor close to the optic apparatus.

Either form of RT takes years to take effect. With gamma knife, the time to remission seems to be shorter, with more than half of patients being in remission by 3 years after the treatment, whereas 6 to 10 years are required to reach this rate of remission after conventional fractionated RT. Medical therapy is withheld for 2 to 3 months before and after the administration of the RT because of data that suggest that this shortens the time to efficacy. Medical therapy is reinstituted until RT has resulted in biochemical remission.

Along with its tumoricidal effect, RT will eventually damage the normal pituitary gland and result in hypopituitarism in most patients. In studies where the durations of follow-up after each of the different forms of RT are comparable, the rates of new hypopituitarism are found to be similar. Therefore, pituitary function needs to be monitored periodically and indefinitely after RT and hormone replacements instituted as necessary.

In patients not cured by surgery or whose tumor visibly regrows over time (more common in younger patients), a second surgical resection can be done, but this is not typically curative. Therapy of acromegaly can require multiple modalities to achieve a biochemical remission.

Patients undergoing transsphenoidal surgery benefit from a team approach to their care. In addition to the neurosurgeon, an endocrinologist and a specialized nurse should be involved in the perioperative care. Management includes monitoring for diabetes insipidus and SIADH (which peaks in incidence at 7 days postoperatively) by monitoring of fluid status (including fluid intake, output, and urine specific gravity) and serum sodium levels.

New hypopituitarism occurs uncommonly after pituitary surgery. Therefore, early postoperative assessment of serum cortisol levels is necessary. One approach is to supplement with dexamethasone intraoperatively and on the first postoperative day and then to measure a morning cortisol on postoperative day 2. If the level is <10 µg/dl, discharge the patient on replacement hydrocortisone and the HPA axis is subsequently re-evaluated. The suspicion for secondary adrenal insufficiency should be heightened in patients with other pituitary deficiencies or who developed diabetes insipidus. Patients with secondary adrenal insufficiency preoperatively should be continued on therapy postoperatively.

Some data suggest that a course of preoperative somatostatin analog therapy may reduce pharyngeal swelling, potentially easing intubation and improving perioperative morbidity. Preoperative somatostatin analog therapy has not been definitively shown to improve the remission rate after surgery.

Prognosis

Acromegaly can be controlled in nearly all patients with the use of multimodality therapy. In the past, patients with active acromegaly had a life expectancy as many as 10 years less than expected. Mortality was increased because of cardiovascular, cerebrovascular, or respiratory comorbidities. However, as strict criteria for remission are now used and can be met with current treatments, life expectancy can be normalized. Normalization of serum IGF-I levels can return the excess mortality rate to that expected for the nonacromegaly population.

Effective treatment can markedly reduce hand and feet puffiness, sweating, fatigue, joint pain, snoring, and other symptoms of the disease. However, not all clinical manifestations reverse with therapy. In particular, the facial and bony changes will not completely reverse.

Effective biochemical control, specifically normalization of IGF-I level, does correlate with improvements in signs and symptoms and cardiovascular disease and with the reduction in insulin resistance. Diabetes mellitus may improve but does not often go away despite normalization of GH and IGF-I. Therefore, specific treatment for each comorbidity such as diabetes mellitus and hypertension should be continued as needed to improve patient outcome.

What-If Scenarios

How do you choose one medical therapy option over the other?

Although the chance of biochemical remission with somatostatin analogs is not as high as that with the GH receptor antagonist, most patients choose a long-acting somatostatin analog because of the relative ease of monthly injections and because it can retard further tumor growth. Thus, for patients who have a large amount of tumor remaining after surgery, a somatostatin analog is preferred. A 3- to 6-month trial of the long-acting somatostatin analog will be necessary to allow for adequate dose escalation and the determination of whether the patient is responsive to the drug. If the IGF-I level falls to near normal, further dose escalation to 40 mg/month may normalize it. However, this dose requires 2 injections monthly (2 doses of 20 mg each).

Patients who are only partially responsive or resistant to the somatostatin analog (IGF-I does not normalize) require additional therapy. Pegvisomant, potentially at a low dose, can be added to the somatostatin analog in patients who have a significant tumor residual or one that shrunk while on the somatostatin analog. It may be possible to increase the spacing between pegvisomant injections. Combination therapy does increase the change of liver enzyme abnormalities and these need to be monitored regularly. In addition, combination therapy is very expensive.

Patients whose tumor mass is not large or not visible can be treated with the GH receptor antagonist pegvisomant alone, either as initial adjuvant therapy after unsuccessful surgery or after failed somatostatin analog therapy.

Patients with diabetes mellitus are a special group for whom the GH receptor antagonist may be advantageous. Pegvisomant improves insulin sensitivity and glucose tolerance, and when acromegaly was the principal precipitant of diabetes, it can be markedly improved on pegvisomant therapy. Somatostatin analogs are generally not associated with glucose tolerance improvement.

Radiation therapy can also be considered as the next line of therapy for patients who fail somatostatin analog therapy.

In which patients should primary therapy with medication rather than surgery be considered?

Patient who are elderly, who have a medical contraindication to surgery, or whose tumor is not threatening vision, but is clearly not resectable (for example, within the cavernous sinus) can be considered candidates for primary medical therapy. In these cases, primary therapy with a long-acting somatostatin analog is preferred. Significant tumor shrinkage can occur. The rate of normalization of IGF-I, however, may still be as low as 25% in some recent series. If the long-acting somatostatin analog is effective, it can be continued without surgery.

What if the disease recurs after an apparent remission with surgery?

A small percentage of patients who achieve a complete biochemical remission after surgery will experience a recurrence. Rarely does the pituitary tumor grow back rapidly, but it can in some young patients. If there has been a clear regrowth of tumor and this is deemed potentially removable by surgery, then repeat transsphenoidal surgery can be considered. Typically, however, if the patient has been followed regularly, biochemical disease is detected before residual tumor is visible. In this case, medical therapy and/or radiotherapy will be undertaken.

It often arises that recurrence or residual disease will be very mild; for example, the IGF-I level may be within 50 ng/ml above the upper limit of the normal range. The result first needs to be verified (especially important given variability in IGF-I assays). In patients with recurrence of symptoms, the decision to treat is straightforward. Some patients who feel well, however, will question the need for treatment. Although, overall, elevated IGF-I levels are definitely associated with increased morbidity and mortality, the long-term outcome of mildly elevated levels is not known. One approach is to thoroughly investigate all potential comorbidities including cardiac structure by echocardiograph, exclude glucose intolerance, etc., and then weigh the potential adverse events, expense, and lifestyle issues associated with medical therapy against the potential risks of active disease. These decisions will need to be made on a patient-by-patient basis.

Follow-up

Testing of IGF-I and GH levels after surgery is needed to determine if the patient has gone into a remission. Although the patient may have marked improvement in signs and symptoms, residual biochemical evidence of acromegaly may remain. A pituitary MRI should be done 2 to 3 months postoperatively. Since this early MRI may demonstrate edema and other changes from surgery that may result, we also typically perform MRI 1 year postoperatively to establish a new baseline. Obvious tumor residual will be associated with laboratory evidence of active acromegaly, but many patients can have no visible postoperative remnant and have persistent acromegaly. For patients with a pure GH-secreting pituitary tumor who are in clear biochemical remission, repeated pituitary MRIs should not be necessary.

We typically measure a GH level early after surgery, at a 1-month postoperative visit, and then make a more definitive determination of disease status at the 3-month postoperative visit. At this visit, we measure IGF-I level and GH levels during an oral glucose test. The primary criterion for remission is normalization of age-adjusted IGF-I level. When GH levels are measured with modern highly sensitive and specific GH assays, most healthy people will have a GH of 0.05 µg/L or less after glucose. Some postoperative acromegaly patients have failure of normal GH suppression despite a normal IGF-I. Whether this represents persistent mild disease or GH dysregulation is not known. If the patient meets at least the normal IGF-I criterion, they can be followed without additional therapy. IGF-I and GH suppression after oral glucose are repeated yearly thereafter.

GH levels fall rapidly after surgery, and generally values obtained at 1 and 3 months will be the nadir. IGF-I levels fall more slowly, and although they generally have reached their lowest value by 3 months after surgery, levels can continue to fall somewhat.

If the patient has borderline IGF-I levels at 3 months but feels generally well, then he or she can be followed and the testing repeated. It is best to be sure that persistent disease is present before committing the patient to further therapy, which could mask a remission.

Acromegaly can recur and therefore long-term surveillance is necessary. In patients whose biochemical tests are conclusive for remission, the chance of recurrence is low.

What’s the Evidence?/References

Melmed, S. "Acromegaly pathogenesis and treatment". JCI. vol. 119. 2009. pp. 3189-3202.

(The author, an expert in the field of acromegaly and pituitary tumor pathogenesis, provides a comprehensive review. In particular, this article will be very useful for anyone who wants to know more about the pathogenesis of acromegaly.)

Nachtigall, L, Delgado, A, Swearingen, B. "Changing patterns in diagnosis and therapy of acromegaly over two decades". Journal of Clinical Endocrinology and Metabolism. vol. 93. 2008. pp. 2035-2041.

Reid, TJ, Post, KD, Bruce, JN, Kanibir, MN, Reyes-Vidal, CM, Freda, P. "Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006; Acromegaly remains under-recognized and under-diagnosed". Clinical Endocrinology. vol. 72. 2010. pp. 203-208.

(These two recent articles on the clinical presentations of acromegaly are useful for those wishing to learn more about ways in which acromegaly presents.)

Clemmons, DR. "Clinical laboratory indices in the treatment of acromegaly". Clin Chim Acta. vol. 412. 2011. pp. 403-409.

(The author, an expert in the field of acromegaly, provides a review of the laboratory evaluation of acromegaly and its potential pitfalls.)

Freda, PU. "Monitoring of acromegaly; what should be performed when GH and IGF-1 levels are discrepant". Clinical Endocrinology. vol. 71. 2009. pp. 166-170.

(This article provides a detailed discussion of how to approach the evaluation of a patient with acromegaly who has discrepant values of GH and IGF-I. The potential causes of abnormal GH suppression after oral glucose with a normal IGF-I and, the converse, an elevated IGF-I with apparently normal GH suppression are discussed.)

Ausiello, JC, Bruce, JN, Freda, PU. "Postoperative assessment of the patient after pituitary surgery". Pituitary. vol. 10. 2008. pp. 391-401.

(This article will be useful for those who wish to learn more about how to care for patients undergoing pituitary surgery.)

Katznelson, L. "Approach to the patient with persistent acromegaly after pituitary surgery". J Clin Endocrinol Metab. vol. 95. 2010. pp. 4114-4123.

(The author, an expert in the field of acromegaly, provides a very concise and clinically useful guideline to the management of patients with persistent disease after acromegaly. This article will be particularly useful for those who wish to know more about a practical clinical approach to management of these patients.)

Sherlock, M, Woods, C, Sheppard, MC. "Medical therapy in acromegaly". Nat Rev Endocrinol. vol. 7. 2011. pp. 291-300.

(A recent comprehensive review of the medical therapy of acromegaly from experts in the field.)

Dineen, R, Stewart, PM, Sherlock, M. "Acromegaly". 2016 Feb 12.

Melmed, S, Casanueva, FF, Klibanski, A, Bronstein, MD. "A consensus on the diagnosis and treatment of acromegaly complications". Pituitary. vol. 16. 2013 Sep. pp. 294-302.

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