Prognostic value of nadir GH levels for long-term biochemical remission or recurrence in surgically treated acromegaly.

CONTEXT: Outcome of acromegaly surgery is assessed by IGF-1 and glucose-suppressed GH, but whether the latter provides additional clinically relevant information when IGF-1 is normal is unclear. The role of GH suppression testing after surgery requires clarification. METHODS: We studied 97 acromegaly patients with normal IGF-1 after surgery by measuring GH after oral glucose longitudinally, initially at ≥ 3 months after surgery and repeated one or more times ≥ 1 year later. Nadir GH was categorized as normal or abnormal relative to the 97.5th percentile of nadir GH in 100 healthy subjects, which were ≤ 0.14 µg/L (DSL IRMA) or ≤ 0.15 µg/L(IDS iSYS). Signs and symptoms scores and insulin resistance were followed longitudinally. RESULTS: Of 68 patients with initial normal GH suppression 63 (93%) remained in remission and of 29 with initial abnormal GH suppression, 9 (31%) recurred. Recurrence was more common in patients with abnormal suppression (P < 0.001). A total of 14 patients recurred, including 5 with normal GH suppression progressing to abnormal and then recurrence. Overall, serial signs and symptoms and insulin resistance assessments did not identify patients with abnormal suppression or recurrence. CONCLUSION: Risk of recurrence after surgery is increased for patients with a normal IGF-1 level, but abnormal GH suppression. We newly find, using both our and others' cut-offs, that while normal suppression predicts long-term remission in most patients, some can progress from normal to abnormal suppression and then recurrence after many years of follow up. Nadir GH levels are of prognostic value in acromegaly patients with normal IGF-1 levels after surgery.

Presenting Features in 269 Patients With Clinically Nonfunctioning Pituitary Adenomas Enrolled in a Prospective Study.

CONTEXT: Clinically nonfunctioning pituitary adenomas (CNFPAs) typically remain undetected until mass effect symptoms develop. However, currently, head imaging is performed commonly for many other indications, which may increase incidental discovery of CNFPAs. Since current presentation and outcome data are based on older, retrospective series, a prospective characterization of a contemporary CNFPA cohort was needed. OBJECTIVE: To determine the prevalence of incidental presentation and hypopituitarism and its predictors in a CNFPA cohort that spanned 6 to 9 mm micro- to macroadenoma included observational and surgical therapy. METHODS: At enrollment in a prospective, observational study, 269 patients with CNFPAs were studied by history, examination, blood sampling, and pituitary imaging analysis and categorized into incidental or symptoms presentation groups that were compared. RESULTS: Presentation was incidental in 48.7% of patients and due to tumor symptoms in 51.3%. In the symptoms and incidental groups, 58.7% and 27.4% of patients had hypopituitarism, respectively, and 25% of patients with microadenomas had hypopituitarism. Many had unappreciated signs and symptoms of pituitary disease. Most tumors were macroadenomas (87%) and were larger in the symptoms than incidental and hypopituitary groups than in the eupituitary groups. The patients in the incidental group were older, and males were older and had larger tumors in both the incidental and symptoms groups. CONCLUSIONS: Patients with CNFPAs commonly present incidentally and with previously unrecognized hypopituitarism and symptoms that could have prompted earlier diagnosis. Our data support screening all large micro and macro-CNFPAs for hypopituitarism. Most patients with CNFPAs still have mass effect signs at presentation, suggesting the need for more awareness of pituitary disease. Our ongoing, prospective observation of this cohort will assess outcomes of these CNFPA groups.

Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Adipose Tissue Redistribution and Ectopic Lipid Deposition in Active Acromegaly and Effects of Surgical Treatment.

CONTEXT: GH and IGF-I have important roles in the maintenance of substrate metabolism and body composition. However, when in excess in acromegaly, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) deposition. OBJECTIVES: The purpose of this study was to examine the effect of surgery for acromegaly on AT distribution and ectopic lipid deposition in liver and muscle. DESIGN: This was a prospective study before and up to 2 years after pituitary surgery. SETTING: The setting was an academic pituitary center. PATIENTS: Participants were 23 patients with newly diagnosed, untreated acromegaly. MAIN OUTCOME MEASURES: We determined visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue (IMAT), and skeletal muscle compartments by total-body magnetic resonance imaging, intrahepatic and intramyocellular lipid by proton magnetic resonance spectroscopy, and serum endocrine, metabolic, and cardiovascular risk markers. RESULTS: VAT and SAT masses were lower than predicted in active acromegaly, but increased after surgery in male and female subjects along with lowering of GH, IGF-I, and insulin resistance. VAT and SAT increased to a greater extent in men than in women. Skeletal muscle mass decreased in men. IMAT was higher in active acromegaly and decreased in women after surgery. Intrahepatic lipid increased, but intramyocellular lipid did not change after surgery. CONCLUSIONS: Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

IGF-1 levels across the spectrum of normal to elevated in acromegaly: relationship to insulin sensitivity, markers of cardiovascular risk and body composition.

PURPOSE: Activity of acromegaly is gauged by levels of GH and IGF-1 and epidemiological studies demonstrate that their normalization reduces acromegaly's excess mortality rate. However, few data are available linking IGF-1 levels to features of the disease that may relate to cardiovascular (CV) risk. Therefore, we tested the hypothesis that serum IGF-1 levels relative to the upper normal limit relate to insulin sensitivity, serum CV risk markers and body composition in acromegaly. METHODS: In this prospective, cross-sectional study conducted at a pituitary tumor referral center we studied 138 adult acromegaly patients, newly diagnosed and previously treated surgically, with fasting and post-oral glucose levels of endocrine and CV risk markers and body composition assessed by DXA. RESULTS: Active acromegaly is associated with lower insulin sensitivity, body fat and CRP levels than acromegaly in remission. %ULN IGF-1 strongly predicts insulin sensitivity, better than GH and this persists after adjustment for body fat and lean tissue mass. %ULN IGF-1 also relates inversely to CRP levels and fat mass, positively to lean tissue and skeletal muscle estimated (SM(E)) by DXA, but not to blood pressure, lipids, BMI or waist circumference. Gender interacts with the IGF-1-lean tissue mass relationship. CONCLUSIONS: Active acromegaly presents a unique combination of features associated with CV risk, reduced insulin sensitivity yet lower body fat and lower levels of some serum CV risk markers, a pattern that is reversed in remission. %ULN IGF-1 levels strongly predict these features. Given the known increased CV risk of active acromegaly, these findings suggest that of these factors insulin resistance is most strongly related to disease activity and potentially to the increased CV risk of active acromegaly.

Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk.

CONTEXT: Although epidemiological studies have found that GH and IGF-1 normalization reduce the excess mortality of active acromegaly to expected rates, cross-sectional data report some cardiovascular (CV) risk markers to be less favorable in remission than active acromegaly. OBJECTIVE: The objective of the study was to test the hypothesis that remission of acromegaly after surgical therapy increases weight and adiposity and some CV risk markers and these changes are paralleled by a rise in ghrelin. DESIGN: Forty-two adults with untreated, active acromegaly were studied prospectively. Changes in outcome measures from before to after surgery were assessed in 26 subjects achieving remission (normal IGF-1) and 16 with persistent active acromegaly (elevated IGF-1) after surgery. SETTING: The study was conducted at tertiary referral centers for pituitary tumors. MAIN OUTCOME MEASURES: Endocrine, metabolic, and CV risk parameters, anthropometrics, and body composition by dual-energy X-ray absorptiometry were measured. RESULTS: Remission increased total ghrelin, body weight, waist circumference, C-reactive protein, homocysteine, high-density lipoprotein, and leptin and reduced systolic blood pressure, homeostasis model assessment score, triglycerides, and lipoprotein (a) by 6 months and for 32 ± 4 months after surgery. The ghrelin rise correlated with the fall in the levels of GH, IGF-1, and insulin and insulin resistance. Weight, waist circumference, and ghrelin did not increase significantly in the persistent active acromegaly group. Total body fat, trunk fat, and perentage total body fat increased by 1 year after surgery in 15 remission subjects: the increase in body fat correlated with the rise in total ghrelin. CONCLUSIONS: Although most markers of CV risk improve with acromegaly remission after surgery, some markers and adiposity increase and are paralleled by a rise in total ghrelin, suggesting that these changes may be related. Understanding the mechanisms and long-term implications of the changes that accompany treatment of acromegaly is important to optimizing management because some aspects of the postoperative profile associate with the increased metabolic and CV risk in other populations.

Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed.

BACKGROUND: Traditionally, acromegaly evaded diagnosis until in its clinically obvious later stages when treatment is more difficult. Over the last 25 years diagnostic tests have improved, but whether clinical disease detection also improved was unknown, so we tested if disease severity at diagnosis had changed from 1981 to 2006. METHODS: Data on 324 consecutive acromegaly patients presenting from 1981 to 2006 at two New York City hospitals were collected by retrospective review (n = 324) and by interview (n = 200). The main complaint, acromegaly associated comorbidities, signs, symptoms, healthcare providers visited, preoperative GH and IGF-I levels and pituitary tumour size at diagnosis were compared in patients presenting in the earlier vs. later halves of the time period. RESULTS: Times from symptom onset to diagnosis were 5.9 year (early) vs. 5.2 year (late; P = NS). At diagnosis, 96% of early and late groups had facial feature changes and/or hand/foot enlargement. Comorbidities included hypertension 37% (early) vs. 36% (late), carpal tunnel syndrome (24%vs. 24%), sleep apnoea (13%vs. 29%; P < 0.01), osteoarthritis (25%vs. 23%) and diabetes mellitus (18%vs. 15%); each patient had 1.2 (early) vs. 1.3 (late; P = 0.53) comorbidities. Groups were similar in signs, symptoms, tumour size, GH and IGF-I. CONCLUSIONS: Clinical, biochemical and tumour size characteristics at diagnosis of acromegaly patients were unchanged from 1981 to 2006. Most patients still have marked manifestations of acromegaly at diagnosis, suggesting that acromegaly remains clinically under-recognized. Healthcare professionals should more commonly consider acromegaly, which can lead to earlier diagnosis and better treatment outcome.

Skeletal muscle mass in acromegaly assessed by magnetic resonance imaging and dual-photon x-ray absorptiometry.

CONTEXT: GH and IGF-I are nitrogen retaining and anabolic, but the impact of long-term exposure to supraphysiological GH and IGF-I, either from endogenous overproduction in acromegaly or exogenous sources, on skeletal muscle (SM) mass is not clear. OBJECTIVES: The objectives of the study were to assess SM mass by whole-body magnetic resonance imaging (MRI) in acromegaly and test the hypothesis that dual-energy x-ray absorptiometry (DXA) lean tissue mass-derived estimates of SM accurately estimate true SM mass. DESIGN, SETTING, AND PATIENTS: The design was a cross-sectional study in 27 acromegaly patients compared with predicted models developed in 315 nonacromegaly subjects and to matched controls. OUTCOME MEASURES: Mass of SM from whole-body MRI and lean tissue from DXA were measured. RESULTS: SM mass did not differ from predicted or control values in active acromegaly: 31.75 +/- 8.6 kg (acromegaly) vs. 33.06 +/- 8.9 kg (predicted); SM was 95.6 +/- 12.8% of predicted (range 66.7-122%) (P = 0.088). Lean tissue mass (DXA) was higher in acromegaly than controls: 65.91 +/- 15.2 vs. 58.73 +/- 13.5 kg (P < 0.0001). The difference between lean tissue mass (DXA) and SM in acromegaly patients was higher than that in controls (P < 0.0001) consistent with an enlarged non-SM lean compartment in acromegaly. SM mass predicted by DXA correlated highly with SM mass by MRI (r = 0.97, P < 0.0001). SM (MRI) to SM (DXA predicted) ratio was 1.018 (range 0.896-1.159), indicating high agreement of these measures of SM. CONCLUSIONS: SM mass in active acromegaly patients did not differ from predicted values. SM mass estimated from DXA agreed highly with SM by MRI, supporting the validity of the DXA model in assessing SM in acromegaly and other disorders of GH/IGF-I secretion.

Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly.

CONTEXT: GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. OBJECTIVES: Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. OUTCOME MEASURES: Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. RESULTS: VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. CONCLUSIONS: VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.