Peri-operative Dynamics of the Growth Hormone Axis in Subjects With Acromegaly

Acromegaly Overview

Acromegaly is a rare, insidious disorder characterized by excessive secretion of growth hormone (GH) almost always from a pituitary adenoma. (Melmed NEJM 1990) Excess GH secretion in turn leads to increased levels of insulin-like growth factor-I (IGF-I), which is primarily responsible for the clinical manifestations of the disease. Features of acromegaly are numerous and include acral and soft tissue growth, arthropathy, excessive sweating, glucose intolerance, and carpal tunnel syndrome. Many patients have cardiomyopathy and hypertension and the diagnosis of acromegaly carries with it an excessive morbidity and mortality related to cardiovascular disease.

Therapy

The goals of therapy include management of the pituitary mass, control of symptoms of GH excess, improvement in long term morbidity and mortality associated with GH excess, and biochemical normalization of IGF-I and GH secretion without disruption of normal anterior pituitary function. Treatment for acromegaly has generally included one or a combination of three modalities, surgery, radiation and medication.

Classically, surgery has been the primary treatment modality with surgical cure being dependent upon pituitary tumor size and the surgical expertise of the surgeon. In experienced hands, transsphenoidal surgical resection of pituitary adenomas is a low risk procedure with few peri-operative or long term complications. Published cure rates for microadenomas and macroadenomas range from 39-91% and 12-71%, respectively. (Melmed S, Kleinberg DL, Williams Textbook of Endocrinology.) Subjects who are not controlled with surgery alone require additional therapy in the form of radiation or medication.

Medical therapy is the preferred choice of second line therapies and is available in multiple forms including short and long acting somatostatin analog therapy aimed at reducing GH secretion via the SSTR2 receptor, dopamine agonist therapy (effective in only about 10% of patients) and pegvisomant, a GH receptor antagonist which lowers IGF-I levels but does not decrease GH secretion or control tumor size.

Radiation therapy is available in multiple modalities and is an effective form of controlling excessive GH secretion and tumor size. One drawback to radiation therapy is the length of time needed for the therapy to take effect. GH secretion gradually declines over several years and medical therapy is often needed to control GH secretion until radiation therapy has taken effect. The major side effect of all forms of radiation therapy is hypopituitarism, with approximately 50% of all subjects experiencing some form of hypopituitarism at 10 years.

Assessing Control

Since there is no well-defined clinical outcome to help establish if a patient is cured, the assessment of disease activity has generally relied on arbitrary biochemical parameters. These parameters include normalization of IGF-I when compared to age and gender matched normal values and reducing the GH response to glucose suppression to less than 1mcg/L. The level of GH suppression has evolved to the current level due to advances in the sensitivity of the growth hormone assay. Previous values of greater than 1mcg/L were based on the use of a less sensitive polyclonal radio-immunoassay (RIA) and have become obsolete with the widespread use of far more sensitive monoclonal assays (chemiluminescent, immunoradiometric, or immunoflourometric). Future improvements in GH assay sensitivity may alter the currently held cutoff point of 1mcg/L to even lower levels, but the clinical significance of these lower levels has yet to be established.

The amount of glucose used for the suppression of GH during an oral glucose tolerance test (OGTT) has been either 75g or 100g, and there has been no data establishing the superiority of one dose compared to the other. Recent consensus guidelines suggest the use of 75g of oral glucose for the purposes of standardization (Giustina et al, 2000, JCEM, Vol 85: p526-9).

Long-Term Management

Long-term follow-up of subjects treated for their acromegaly has shown an improvement in morbidity and mortality. Swearingen et al. (JCEM 1998 Vol. 83: p 3419-3426) showed that patient-years with persistence of disease, as defined by normalization of IGF-I, carried with it a 3.5 fold relative mortality risk compared to patient-years in remission using a Cox proportional hazards model. They were also able to demonstrate that subjects who had achieved control of their acromegaly showed similar survival rates to those in the general U.S. population. These data underscore the benefits of achieving control of acromegaly and draws attention to the need for accurate criteria for defining control and standardized methodology of observation following treatment of acromegaly.

GH-IGF-I Discordance and the Risk For Recurrence

Other investigators (Freda et al, 2004, JCEM 89: 495-500) have found that some post-operative subjects with acromegaly with normal IGF-I levels (age and gender matched) have persistently abnormal nadir GH responses to OGTT (100g dextrose; nadir GH >0.14 mcg/L). These subjects had an increased rate of disease recurrence when followed longitudinally as compared to post-operative subjects with normal IGF-I and normal nadir GH responses to OGTT (GH < 0.14 mcg/L).

Abnormal GH responses to OGTT in the setting of normal IGF-I levels may not be reflective of a "lack of cure" in subjects status-post surgical treatment for acromegaly. These subjects may be secreting elevated amounts of GH due to a lack of inhibition by lower levels of IGF-I. IGF-I levels may be considered normal in comparison to control data for the age and gender matched populations; but may be either low for that particular individual, or lower than IGF-I levels seen prior to treatment for acromegaly. In this setting, the IGF-I level is considered low and the normal pituitary tissue responds by secreting excessive amounts of GH in the absence of IGF-I suppression.

Recent data regarding the feedback mechanism responsible for GH release from pituitary somatotroph cells supports what has long been theorized: that circulating levels of free IGF-I, and not IGF-I bound to the IGF binding protein complex, suppress secretion of GH (Chen JW et al., 2005, JCEM 90: 366-371.) Generally, measuring levels of free IGF-I has not added any significant clinical data to the assessment of GH secretion in the diagnosis or management of acromegaly. However, it has been suggested that in situations where there is discordant information regarding the GH suppression in response to oral glucose and the measurement of total IGF-I, that free IGF-I levels may be a better indicator of GH secretion and bioactivity (Frystyk J, 2004, GH and IGF-I Research, 14: 337-75 and Feelders RA, 2005, JCEM 90: 6480-6489.)

Hypothesis: Assessment of post-operative subjects with low-normal IGF-I but non-suppressed nadir GH levels will show normalization over time with lower, normal nadir levels of GH in response to OGTT. IGF-I levels could increase over time, but would still be considered normal as compared to age and gender matched normal levels in subjects who are considered "controlled." Rather than consider subjects with abnormal responses to OGTT in the setting of low-normal IGF-I as "not cured" and at a higher risk for recurrence, these subjects may be exhibiting compensatory elevation of GH in the absence of IGF-I suppression. Over time, subjects with non-suppressed GH responses to OGTT and low-normal IGF-I would have lower GH nadirs in response to OGTT and persistently normal (although possibly higher than the post-operative initial assessment) IGF-I levels. This setting would be contrary to the expected elevation of IGF-I above normal limits in the setting of excess GH secretion.

Objectives: The primary objective of this study will be to determine the natural course of acromegaly treated with surgery in subjects with non-suppressed GH nadir values and normal total IGF-I values. A second objective of the study will be to determine the reliability of GH nadir to OGTT, free IGF-I, total IGF-I, and IGF binding proteins on post-operative day 1 in predicting long-term cure outcomes in acromegaly. A third objective will be to determine inter-assay variability in the measurement of GH and IGF-I levels.