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Research Centre for Endocrinology and Metabolism (L.-L.N., G.J., J.S.), Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden; and Research Group for Rehabilitation Medicine (K.S.S.), Institute of Neuroscience and Physiology, Göteborg University, SE-40530 Göteborg, Sweden
Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Department of Internal Medicine, Gröna Stråket 8, Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden. E-mail: johan.svensson{at}medic.gu.se.
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Abstract |
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Objective, Design, and Patients: In this single-center, open-labeled, prospective study, 10 consecutive GHD adults with cured acromegaly (A group) and 10 matched GHD adults with previous nonfunctioning hypopituitary disease (NF group) were included. Comparisons were made at baseline and in the responses in body composition, muscle strength, bone mass, and metabolic indices during 2 yr of GH replacement.
Results: At baseline, upper leg local muscle endurance and serum low-density lipoprotein-cholesterol concentration were more impaired in the A group. The A group contained three patients with hypertension, one with diabetes mellitus type 2, and one with hyperlipidemia. The NF group had only one patient with hypertension. There were no significant between-group differences in the responses to the GH therapy. Body composition and serum lipid pattern improved in both groups without any deterioration of glucose homeostasis. At study end, no difference remained between the two groups in any variable. During the 2-yr treatment, one patient had a myocardial infarction and two had cerebral infarctions in the A group, whereas no vascular event occurred in the NF group.
Conclusions: GHD patients with previous acromegaly have an impaired cardiovascular risk profile and decreased local muscle endurance as compared with other GHD patients. Two-year GH replacement eliminated these differences, but vascular events occurred more frequently in the A group. Therefore, GHD patients with cured acromegaly will benefit from GH replacement, but careful monitoring of cardiovascular status is needed.
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Introduction |
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GHD in hypopituitary adults is associated with increased body fat, decreased lean and bone mass, disturbed lipoprotein pattern, impaired insulin sensitivity, decreased muscle strength, and increased cardiovascular mortality (13, 14, 15). GH replacement normalizes most of these abnormalities in adult populations mainly consisting of patients with previous nonfunctioning pituitary disease (13, 14, 15). Little is known of the baseline status and the effects of GH replacement in adult GHD as a result of pituitary surgery or irradiation due to previous acromegaly. One study based on Pfizer International Metabolic Database (KIMS), a large postmarketing surveillance program, suggested that patients with previous functioning pituitary disease (acromegaly or Cushing’s disease) as the cause of GHD had similar baseline characteristics and response to GH therapy as adults with GHD of other etiologies (16). However, the GHD patients with previous acromegaly had more history of cerebral infarctions at baseline than other GHD patients (16).
In this single-center, prospective study, 10 consecutive GHD adults previously treated for acromegaly (A group) and 10 patients with previous nonfunctioning hypopituitary disease (NF group) were included. All patients had adult-onset GHD, and the two groups were matched groupwise in terms of age, gender, body height, body weight, body mass index (BMI), waist to hip ratio, and number of anterior pituitary hormonal deficiencies. Baseline characteristics and the effects of 2-yr GH replacement on body composition, muscle strength, bone mass, and metabolic indices were determined in the A group and compared with that in the NF group.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Ten consecutive GHD adults with previous acromegaly (A group), and 10 GHD adults with previous nonfunctioning hypopituitary disease (NF group) were selected contemporaneously from the endocrinological outpatient ward at Sahlgrenska University Hospital. The patients were included from 1991–1997, and all had adult-onset disease. In the NF group, all patients had known pituitary disease or other pituitary hormonal deficiency [nonfunctioning pituitary adenoma (n = 7), pituitary apoplexy (n = 1), empty sella (n = 1), and trauma (n = 1)]. In the A and NF groups, five and eight patients had been treated surgically and 10 and eight patients had received radiotherapy, respectively. In the A group, the diagnosis of GHD was based on peak serum GH of less than or equal to 6.0 mIU/liter (
2.0 µg/liter) during an insulin tolerance test (ITT, n = 8), peak GH of 2.3 mIU/liter (
0.8 µg/liter) during an arginine stimulation test (n = 1), or three additional pituitary deficiencies combined with peak GH of 0.46 mIU/liter (0.15 µg/liter) during a 24-h GH profile (n = 1). Twenty-four-hour GH profiles (sampling every 30 min) had been performed in nine patients in the A group with a peak GH value less than or equal to 2.5 mIU/liter (0.8 µg/liter), whereas in one patient with two additional pituitary deficiencies, a GH profile was not performed because all GH values during ITT were less than 1 mIU/liter (<0.33 µg/liter). In the NF group, the diagnosis was based on peak GH less than or equal to 6.3 mIU/liter (2.1 µg/liter) during ITT. When required, patients received adequate and stable therapy with glucocorticoids, T4, gonadal steroids, and desmopressin. However, five of nine (56%) and four of nine (44%) of the estrogen-deficient women in the A and NF groups, respectively, did not receive estrogen therapy.
Study protocol
This was a prospective, open-label treatment trial. In one patient in both the A and the NF group, respectively, the initial target dose of GH was 11.9 µg/kg·d (0.25 IU/kg·wk). The dose in these two patients was gradually lowered and individualized when the weight-based dose regimen was abandoned (17). In the remaining patients, the GH dose was individualized from the beginning with the aim of normalizing serum IGF-I concentration and body composition in each patient (17).
At baseline and after 1 and 2 yr, physical examinations including measurements of body composition, muscle strength, bone mass, and metabolic indices were performed. In addition, dose titration was performed by visits every third month during the first year and every sixth month thereafter. Body weight, body height, BMI, waist circumference, hip girth, and systolic and diastolic blood pressure were measured using standard methods described previously (18).
Ethical considerations
Informed consent was obtained from all patients. The study was approved by the Ethics Committee at Göteborg University and the Swedish Medical Products Agency (Uppsala, Sweden).
Body composition
Dual-energy x-ray absorptiometry (DEXA) (Lunar DPX-L; Lunar Corp., Madison, WI; software version 1.3) was used to measure lean body mass (LBM) and body fat (BF) (19). The relative error for LBM was 1.5%.
Body cell mass (BCM), extracellular water (ECW), and BF were estimated using a four-compartment model based on total body potassium (TBK), and total body water (TBW) assessments (20). TBK was assessed using a whole-body counter [coefficient of variation (CV) =2.2%], and TBW was determined by the isotope dilution of tritiated water (CV= 3.2%).
Total body nitrogen (TBN) was measured by in vivo neutron activation with a measurement error of approximately ±4% (21, 22).
Measurements of muscle function
Isometric knee extensor and flexor strength at knee angles of 60° (
/3 rad) and isokinetic concentric muscle action at angular velocities of 60°/sec (/3 rad/sec) and 180°/sec ( rad/sec), were measured using a Kin-Com dynamometer (Chattecx Co., Chattanooga, TN) (23). The methodological errors in duplicate measurements were between 8 and 9% (23). Right and left handgrip strength was measured using an electronic grip force instrument (Grip-It) (24). The methodological error was between 4.4 and 9.1% (24).
Local muscle endurance in the quadriceps muscle was measured as the percentage reduction (fatigue index) in peak torque between the first and the last three knee extensions in a series of 50 maximal voluntary concentric contractions with an angle of velocity of 180°/sec. The methodological error was 1.4% (25).
Bone mineral content (BMC) and bone mineral density (BMD)
DEXA (Lunar DPX-L, software version 1.3) was used to measure BMC and BMD, as described previously (19). During the entire study period, a calibration phantom (COMAC-BME Quantitative Assessment of Osteoporosis Study Group) was used. The CV between measurements were 0.4, 0.5, and 0.6% for total body BMD, lumbar (L2–L4) spine BMD, and femur neck BMD.
Biochemical assays
Serum IGF-I concentration was determined by RIA after HCl/ethanol precipitation of binding proteins (Nichols Institute Diagnostics, San Juan Capistrano, CA). Interassay and intraassay CV were 5.4 and 6.9%, respectively, at a mean serum IGF-I concentration of 126 µg/liter and 4.6 and 4.7%, respectively, at a mean serum IGF-I concentration of 327 µg/liter. The individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a reference population (26). The individual IGF-I SD scores could then be calculated (27).
Serum osteocalcin was measured by a double-antibody RIA (International CIS, Gif-sur Yvette, France) with interassay and intraassay CV of 2.4 and 2.9%, respectively, at a serum concentration of 10.4 µg/liter, and 3.3 and 2.9%, respectively, at a mean serum concentration of 22.3 µg/liter. Serum calcium was measured by absorption spectrophotometry (Roche Molecular Biochemicals, Mannheim, Germany) with an interassay CV of 2.5% and an intraassay CV of 1.7%. Intact PTH was measured by immunoradiometric assay (Nichols Institute Diagnostics) with interassay and intraassay CV of 7.8 and 7.4%, respectively, at a mean serum concentration of 23.4 ng/liter and 6.0 and 4.5%, respectively, at serum concentration of 43.1 ng/liter.
Total cholesterol (TC) and triglyceride (TG) concentrations were determined using enzymatic methods (Roche Molecular Biochemicals) with inteassay CVs of 2.9 and 3.8%, respectively, and intraassay CV of 0.9 and 1.1%, respectively. High-density lipoprotein-cholesterol (HDL-C) levels were determined after the precipitation of apolipoprotein B-containing lipoproteins with MgCl2 and heparin (28). Low-density lipoprotein (LDL)-C was calculated according to Friedewald’s formula (29). Serum insulin was determined by RIA (Phadebas, Pharmacia, Sweden), and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Blood glycosylated hemoglobin (HbA1c) was determined by HPLC (Waters, Millipore AB, Sweden).
Statistical methods
The descriptive statistical results are shown as the mean (SEM). Between-group differences at baseline and 1 and 2 yr were calculated using the Mann-Whitney U test. A two-stage method was used to calculate differences for the 2-yr treatment period (30). This means that the repeated measurements from each patient were reduced to one summary variable, reflecting the within-individual change with time. The coefficient of the slope (β) for the estimated individual regression line was chosen as the summary variable, using each effect variable as a dependent and time as an independent variable. A Wilcoxon signed rank test was used to test the within-group effect of treatment, and the Mann-Whitney U test was used to calculate the between-group effect. Correlations were sought using the Spearman rank order correlation test. Significance was obtained if the two-tailed P-value was 0.05.
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Results |
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The A and NF groups were matched groupwise in terms of gender, age, body height, body weight, BMI, waist to hip ratio, and number of anterior pituitary deficiencies (Table 1
). In the A group, the mean duration from the onset of acromegaly to GH start was 15.4 (3.3) yr and the mean time from a confirmatory diagnostic test of GHD to GH start was 2.6 (0.9) yr. In the NF group, the time from the first pituitary deficiency was detected to GH start was 13.1 (4.0) yr.
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The dose of GH as well as serum IGF-I concentration, IGF-I SD score, BMI, and waist to hip ratio were similar in both groups (Table 2). Three patients in the A group had treated hypertension vs. one patient in the NF group. These patients were excluded from the analyses of blood pressure. In the remaining patients, there was a nonsignificant tendency to higher diastolic blood pressure in the A group (Table 2).
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Lean mass and total BF were similar in both study groups at all time points of the study (Table 3). Total BF reduced and ECW increased significantly only within the NF group, whereas BCM increased significantly only within the A group. There were, however, no significant between-group differences in the response in body composition (Table 3). TBN was unchanged in both study groups (Table 3).
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The fatigue index [the reduction in peak torque between the first and the last three knee extensions (180°/sec) in a series of 50 maximal contractions] was higher in the A group at baseline, indicating decreased local muscle endurance in the A group as compared with the NF group (Fig. 1A). Although there was no between-group difference in the treatment response, the fatigue index was similar in both groups at study end (Fig. 1A). In isometric knee flexor strength (60°), there was a significant within-group increase in the A group that tended to be significant vs. that in the NF group (Fig. 1B). Other measurements of muscle performance were similar in both groups [isokinetic knee flexor strength (60°/sec) is shown in Fig. 1C, whereas other measures of upper leg strength and handgrip strength are not shown].
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There was no between-group difference at any time point of the study in circulating markers of bone turnover (osteocalcin, PTH, and calcium; data not shown). All the serum markers of bone turnover increased to a similar extent in response to the 2-yr GH replacement in both groups (data not shown). Total body, lumbar (L2–L4) spine, and femur neck BMC and BMD were similar in both groups throughout the study, and there was no within- or between-group difference in the treatment response (data not shown).
Lipid and glucose metabolism
At baseline, serum LDL-C concentration was higher in the A group than in the NF group (Fig. 2). There was no between-group difference in the response to 2-yr GH replacement in terms of serum lipid levels. Within both study groups, serum concentrations of TC and LDL-C tended to be reduced, serum HDL-C level increased significantly, and serum TG level was unaffected (Fig. 2).
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At baseline in the A group, three patients had treated hypertension, one patient had diabetes mellitus (DM) type 2, and one had treated hyperlipidemia vs. only one patient with treated hypertension in the NF group. The onset of the DM type 2 in the patient in the A group occurred during active acromegaly with no major change in glucose homeostasis after being cured using radiotherapy. No other patient had previously in life had DM type 2. During the 2-yr GH replacement, three patients had vascular events in the A group, whereas no vascular event occurred in the NF group. One 68-yr-old woman in the A group died after 5 months of a myocardial infarction. This patient was retained in the statistical analyses according to the intention-to-treat approach used. One woman and one man in the A group had cerebral infarctions after 2 and 6 wk of GH replacement, respectively. Both had left side body weakness that almost fully recovered in the 64-yr-old man, whereas a mild to moderate left side weakness persisted in the 65-yr-old woman. Both patients had previously received radiotherapy, and both continued the GH replacement throughout the study period. No serious adverse events occurred in the NF group.
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Discussion |
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Although all GHD patients with previous acromegaly at our center from 1991–1997 were included, the present study population was relatively small. This, combined with the dominance of women (nine of 10 in both study groups), can explain the small within-group treatment effects as compared with previous trials (13, 14, 15). The strength on the other hand is the careful matching of the patients, the homogeneous GH replacement regimen, and the homogeneous methodology used for body composition and muscle strength as compared with a previous trial based on the KIMS database (16). Of interest is that also in the previous trial (16), the majority of the GHD patients with previous acromegaly were women (16). In contrast, there is no major gender difference in the prevalence of active acromegaly (31, 32). One possible explanation for the dominance of women in this study and the previous KIMS study (16) may be that women could have more severe clinical consequences of GHD after the cure of acromegaly and, therefore, to a higher degree be selected for testing and treatment of GHD.
There was no between-group difference at baseline or in the treatment response in BF, lean mass, and TBN, suggesting similar responsiveness to GH in both study groups. In ECW, there was a nonsignificant tendency to higher values in the A group at baseline. In active acromegaly, ECW is increased (1, 2, 3), and studies larger than the present one are needed to evaluate whether there could be small differences in baseline ECW values between GHD patients with previous acromegaly as compared with adults with GHD of other etiologies. However, ECW increased only within the NF group, and at study end, there was no longer any tendency to a between-group difference in ECW. GH replacement in GHD patients with previous acromegaly does therefore not result in excess ECW.
Patients with active acromegaly display weight-bearing joint discomfort (32), excessive fatigue (7), and unchanged or even decreased muscle strength after correction for the increased lean mass (8). The decreased local muscle endurance (increased fatigue index) in the A group at baseline is probably not caused by differences in muscle size because lean mass was similar in both groups. Longstanding effects of the previous acromegaly on weight-bearing joint discomfort or intrinsic muscle morphology or metabolism could be of importance, although the long mean duration since cure of acromegaly in the A group argues against this. Although not measured, the reduced local muscle endurance could be due to low physical activity caused by the impaired baseline status in the A group with more treated hypertension, hyperlipidemia, and diabetes mellitus. The 2-yr GH replacement eliminated the baseline difference in the local muscle endurance and also tended (P = 0.06 vs. NF group) to increase isometric (60°) knee flexor strength more in the A group. Therefore, GHD patients with previous acromegaly have a small decrease in muscle performance as compared with other GHD adults that can be reversed by GH replacement.
The effect of active acromegaly on bone mass is controversial, but the results of most studies suggest increased cortical bone mass in acromegalic patients adequately substituted with other anterior pituitary hormones (9, 10, 11, 12). In this study, there was no between-group difference at baseline or in the treatment response in any variable reflecting bone mass and density. Therefore, previous acromegaly as the cause of adult GHD does not affect the clinical characteristics in terms of bone mass and density.
In this study, one patient in the A group had treated hyperlipidemia and the remaining patients had increased baseline serum LDL-C concentration. In active acromegaly, serum LDL-C level is reduced (33). It is unclear why previous acromegaly causes increased serum LDL-C level in GHD patients. However, after 2 yr of GH replacement, the serum lipid profile had improved in both study groups and the baseline difference in serum LDL-C level had been eliminated.
One patient in the A group had treated DM type 2. In the remaining patients, baseline circulating levels of glucose, insulin, and HbA1c were similar to that in the NF group. Patients with active acromegaly are insulin resistant (4), but it does not seem that this results in more disturbed baseline glucose homeostasis in GHD adults with previous acromegaly as compared with other GHD patients if DM type 2 had not already developed. The response to 2-yr GH replacement was similar in both study groups in terms of glucose metabolism. Therefore, GH replacement is a safe procedure in terms of glucose homeostasis in GHD patients with previous acromegaly.
Quality of life (QoL) is decreased in active acromegaly (7). Treatment of the GH excess improves, but does not fully normalize, QoL (7, 34). In the previous KIMS study (16), female GHD patients with previous acromegaly had lower baseline QoL than female GHD patients with previous nonfunctioning hypopituitary disease, whereas there was no difference in males (16). The improvement in QoL in response to GH replacement was approximately similar in the GHD patients with previous acromegaly as compared with those without previous acromegaly (16). In the present study, which included mainly female patients, QoL was not assessed, but the clinical impression was that the GHD patients with previous acromegaly had lower baseline QoL, whereas the response to GH replacement was of a similar magnitude in both study groups.
In this study, there were three vascular events in the A group. One woman (68 yr of age at study start) died after 5 months of a myocardial infarction, and two patients experienced cerebral infarctions but continued the GH replacement (altogether one vascular event per approximately 7 patient-years). In a previous study performed at our center, including 289 GHD adults with previous nonsecreting hypopituitary disease (patients with previous acromegaly or Cushing’s disease were excluded), there were nine vascular events (two myocardial infarctions and seven cerebrovascular events) during the 1443 patient-years (approximately one vascular event per 160 patient-years) (35). The present study is too small to statistically evaluate vascular morbidity and mortality, but it seems that during GH replacement, GHD patients with previous acromegaly have an increased rate of vascular events as compared with other GHD patients.
The two patients in the A group that experienced cerebral infarctions had both received radiotherapy, which could be of importance because radiation-induced angiopathy is a risk factor for stroke (36, 37), and previous radiotherapy is a predictor of increased cerebrovascular mortality in hypopituitary patients with (38) or without (39, 40) previous acromegaly. Furthermore, in active acromegaly, the prevalence of hypertension as well as cardiovascular morbidity and mortality are increased (5, 6). In line with this, three patients in the A group had treated hypertension as compared with one patient in the NF group. In the previous KIMS study, the number of serious adverse events was similar during GH replacement in GHD patients with previous acromegaly as compared with other GHD patients, although the diagnoses of the serious adverse events were not specified (16). In the present study, the increased rate of vascular events during GH therapy in the GHD patients with previous acromegaly is a clear safety concern. However, the extent to which this increased rate of vascular events is due to the impaired cardiovascular risk profile at baseline or to the GH replacement in itself must be evaluated in studies with larger study populations and longer duration than the present one.
In conclusion, GHD patients with previous acromegaly have an impaired cardiovascular risk profile and decreased upper leg local muscle endurance at baseline as compared with GHD patients with previous nonfunctioning hypopituitary disease. Two-year GH replacement improved body composition and serum lipid pattern in both groups without any deterioration of glucose homeostasis. At study end, the baseline differences in muscle performance and serum LDL-C concentration were eliminated. GHD patients with cured acromegaly will therefore benefit from GH replacement and should be considered for GH replacement. However, the increased frequency of vascular events in the GHD patients with previous acromegaly observed in this study is a safety concern, and careful evaluation and monitoring of cardiovascular risk status is therefore needed if GH replacement is commenced.
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Acknowledgments |
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Footnotes |
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Disclosure statement: The authors have nothing to disclose.
First Published Online April 8, 2008
Abbreviations: BCM, Body cell mass; BF, body fat; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; C, cholesterol; CV, coefficients of variation; DEXA, dual-energy x-ray absorptiometry; DM, diabetes mellitus; ECW, extracellular water; GHD, GH deficiency; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; ITT, insulin tolerance test; LBM, lean body mass; LDL, low-density lipoprotein; QoL, quality of life; TBK, total body potassium; TBN, total body nitrogen; TBW, total body water; TC, total cholesterol; TG, triglyceride.
Received December 3, 2007.
Accepted April 2, 2008.
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References |
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-ray analysis. J Nucl Med 20:1158–1165
-Lipoprotein cholesterol in relation to acute myocardial infarction and its risk factors. Scand J Clin Lab Invest 40:239–247[Medline]This article has been cited by other articles:
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  O. Klefter and U. Feldt-Rasmussen Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis Eur. J. Endocrinol., August 1, 2009; 161(2): 213 - 221. [Abstract] [Full Text] [PDF]
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C L Ronchi, C Giavoli, E Ferrante, E Verrua, S Bergamaschi, D I Ferrari, S Corbetta, L Montefusco, M Arosio, B Ambrosi, et al. Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments Eur. J. Endocrinol., July 1, 2009; 161(1): 37 - 42. [Abstract] [Full Text] [PDF]
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