Body Composition Changes With Long-Term Pegvisomant Therapy of Acromegaly

Adriana P. Kuker; Wei Shen; Zhezhen Jin; Simran Singh; Jun Chen; Jeffrey N. Bruce; Pamela U. Freda


J Endo Soc. 2021;5(3) 

In This Article

Materials and Methods

Subjects With Acromegaly

We prospectively studied 21 patients with acromegaly (13 males, 8 females), median age 48 years (range 19–62 years) who were beginning pegvisomant therapy. Acromegaly had been diagnosed biochemically based on elevated IGF-1 levels, nadir GH after oral glucose >1 μg/L, and characteristic clinical features. Maximal tumor diameter at diagnosis was 20 mm (median) (range 8–45 mm); 1 was a microadenoma and 20 were macroadenomas. All patients had prior therapy for acromegaly (Table 1). Twenty had noncurative transsphenoidal surgery from 0.75 to 13 years (median 3.05 years), 8 had radiotherapy from 1.15 years (range 0.4–10.5 years), and 19 had received other medical therapies that did not normalize their IGF-1 prior to starting pegvisomant (Table 1). Somatostatin analogs and dopamine agonists were last taken at least 3 months prior to baseline testing, except in 1 patient who continued cabergoline along with pegvisomant for treatment of hyperprolactinemia. The gonadal function of patients is shown in Table 1. Two patients had hypothyroidism on stable replacement therapy for the duration of the study. Six patients had type 2 diabetes mellitus, 4 were treated with oral hypoglycemic agents, and 2 were treated with insulin. All patients had active acromegaly as defined by a high serum IGF-1 level at the start of pegvisomant therapy (Table 2). None received medical therapy for acromegaly, radiotherapy, or additional surgery during the study period. All were ambulatory outpatients with normal renal function and no liver disease. The study was approved by the Institutional Review Board of Columbia University Medical Center and all subjects gave written informed consent before participation.

Nonacromegaly Comparison Groups

A group of 185 females and 130 males, aged 18–84 years, of different ethnicities were studied by total body MRI to develop models of predicted body composition as previously described.[8,9,20] A second group of 8 healthy subjects (7 males, 1 female) were studied by [1]HMRS of the liver and matched to the 8 subjects with acromegaly who underwent MRS of liver, for sex, age ± 5 years, and body mass index (BMI) ± 3 kg/m2. All were healthy without chronic medical problems or medications, nonsmoking, weight stable, and not heavy exercisers.

Study Design

Patients were studied before and up to 4 additional times at 1 to 2, 3 to 4, 5 to 6, and 8 or more years after starting pegvisomant. At each testing session, they had blood sampling, anthropometric measurements, and body composition testing by whole body MRI and/or DXA: MRI (n = 16), DXA (n = 19), and MRI and DXA (n = 14). Patients began pegvisomant therapy per standard clinical practice guidelines with a loading dose of 40 mg followed by 10 mg daily and the dose was escalated monthly in 5-mg increments until the treatment goal of IGF-1 level normalization was reached. Liver function tests were monitored per clinical guidelines and MRI of the pituitary was monitored yearly. Healthy subjects were studied once by whole body MRI body composition testing.

Study Procedures

Laboratory Testing. Blood sampling was done after an overnight fast for IGF-1, GH, insulin, glucose, leptin, and HbA1C. Serum and plasma were frozen at –80°C in multiple aliquots. IR was estimated by homeostasis model assessment (HOMA) scores[21] and by the quantitative insulin sensitivity check index (QUICKI)[22] (Table 2).

Anthropometrics. Body weight by a digital scale to the nearest 0.01 kg, height with a stadiometer to the nearest 0.5 cm and waist circumference to the nearest 0.1 cm were measured.

Total Body Magnetic Resonance Imaging and 1 HMRS. Total and regional body adipose tissue volumes were measured by whole body multislice MRI on a 1.5 T MR scanner (Achieva, Philips Healthcare) as previously described.[8,20] The intermuscular adipose tissue compartment (IMAT), defined as the AT located between muscle groups and beneath the muscle fascia,[23] is distinct from and does not include intramyocellular lipid (IMCL), namely the lipid within myocytes. Images were analyzed with SliceOmatic image analysis software (TomoVision, Inc., Montreal, Canada) in the Image Analysis Core Lab of the New York Obesity Nutrition Research Center. MRI volume estimates were converted to mass using the assumed density of 0.92 kg/L for AT and 1.04 kg/L for SM. The coefficient of variation (CV) for repeated measurements of the same scan by the same observer of MRI-derived AT volumes is 1.7% for subcutaneous adipose tissue (SAT), 2.3% for VAT, and 5.9% for IMAT.[23,24]

Water suppressed and nonwater suppressed single voxel 1HMRS spectra were acquired by applying point resolved spectroscopy technique to measure intrahepatic lipid (IHL) (n = 8; 7 M, 1 F) and tibialis anterior muscle for measurement of IMCL (n = 7; 6 M, 1 F) as previously described.[9]

Dual-energy x-ray Absorptiometry. Whole-body and regional lean tissue mass and fat mass were estimated in 19 patients (10 M, 8 F) by DXA (software version 11.4; GE Lunar Prodigy Advance, Madison WI) as previously described.[10] We calculated DXA-estimated IMAT-free SM mass (SMDXA) based on a prediction equation previously validated and found it to agree highly with total body SM mass by MRI in acromegaly as previously described.[20] Non-SM lean tissue (total lean tissue – SMDXA) was also calculated. The CV of repeated daily measurements was 1.7% for leg lean tissue, 2.0% for arm lean tissue, and 2.6% for appendicular lean tissue.

Hormone Assays

Growth hormone was measured by a chemiluminescent immunometric assay from IMMULITE® (Siemens) that is calibrated to World Health Organization (WHO) International Reference Standard 98/574 and had an intra-assay CV of 3.1% and interassay CV of 6%.[25,26] Functional sensitivity for GH was 0.05 μg/L.

IGF-1 was measured from 2002 to 2005 using the polyclonal radioimmunoassay (RIA) from the Nichols Institute (San Juan Capistrano, CA) calibrated to WHO 1st International Reference Reagent 1988 (IGF-1 87/518) that had an intra-assay CV of 4% and interassay CV of 11%,[27] from 2005 to 2016 by chemiluminescent immunoassay IMMULITE (Siemens) calibrated to WHO IRR NIBSC code 87/518 that has an intra-assay CV of 4% and interassay CV of 5.9%,[28] and from 2016 to 2020 by chemiluminescent immunoassay (IDS-iSYS) that is calibrated to the new recombinant standard 02/254[29,30] and has an intra-assay CV of 1.3% to 3.7% and interassay CV of 3.4% to 8.7%. IGF-1 levels were compared with the manufacturers' age- and gender-specific (for IDS-iSYS) normative ranges for each assay. IGF-1 levels were measured at both baseline and follow-up using the Nichols RIA in 5 patients, Immulite in 5, and IDS-iSYS in 1 patient, using the Nichols RIA then Immulite in 4, using the Nichols RIA then Immulite then IDS-iSYS in 2, and using the Immulite then IDS-iSYS in 4 patients.

Insulin was measured by IMMULITE (Siemens), glucose by the hexokinase method, and leptin using a sensitive sandwich enzyme-linked immunosorbet assay (R&D Systems), which has a sensitivity is 7 pg/mL.

Statistical Analysis

MRI AT depot and SM values for patients with acromegaly were compared with predicted values using the Wilcoxon signed rank test. Prediction equations were developed for mass of total adipose tissue, VAT, SAT, and SM compartments accounting for gender, age, height, weight, and race using generalized linear models from data in the body composition comparison group as previously described,[8,20] and IMAT as developed by Gallagher et al..[23] Fisher's exact test was used to compare the proportion of subjects with values above or below predicted before and after pegvisomant therapy. The Wilcoxon signed rank test was used to compare MRI and DXA values before pegvisomant therapy and Friedman test to compare values at different time points on pegvisomant. IHL in acromegaly was compared with that in controls using the Wilcoxon rank sum test. Spearman's correlation was used to assess the relationships between absolute and percent change in body composition measurements and those of IGF-1, GH, leptin, HOMA score, and QUICKI. Data are given as median and range unless stated otherwise. P < .05 was considered significant. Data were analyzed by Prism 8 for MAC and SAS 9.4 (SAS Institute, Cary, NC).