In adults, GH replacement therapy will often be maintained for decades. Owing to the long duration of GH replacement in many adults, it is essential to establish the long-term safety aspects of the treatment. In this review, studies that have investigated the safety profile of long-term GH replacement will be reviewed with an emphasis on studies based on data from the Pfizer International Metabolic Database (KIMS). These studies show that long-term GH replacement in adults is safe and that long-term GH replacement may even improve cardiovascular mortality and morbidity in GH-deficient adults.
Johan Svensson and Bengt-Åke Bengtsson
Hans Herlitz, Olof Jonsson and Bengt-Åke Bengtsson
We investigated the relationship between mean plasma growth hormone (GH) concentration and cellular sodium transport in untreated and treated acromegaly. Seventeen patients (age 55±3 years) with active acromegaly were studied with respect to plasma GH (mean of 24 h GH profile) and erythrocyte electrolyte content as well as transmembrane sodium transport. The patients were reinvestigated two weeks after successful surgery (N=14) and again after one year (N=13). Erythrocyte electrolytes were analyzed by flame photometry and sodium influx and efflux rate constant determined by in vitro incubation using a modified Keyne's formula. In patients with active acromegaly there was a significant positive correlation between IGF-1 and cellular sodium transport, while GH tended to show a negative relationship to the same parameter. After successful treatment, both IGF-1 and GH disclosed a positive relationship to cellular sodium transport. After one year, a significant increase in erythrocyte sodium content was seen in the patients compared to the preoperative situation. In conclusion, if this is a generalized phenomenon the results are compatible with a sodium-retaining effect of GH via stimulation of transmembrane sodium transport. In active acromegaly this may be counteracted by a sodium transport inhibitor giving the reverse relationship between GH and cellular sodium transport.
Eva Bagge, Staffan Edén, Thord Rosén and Bengt-Åke Bengtsson
The prevalence of radiographic osteoarthritis in hand and knee joints was studied in elderly patients with acromegaly and growth hormone deficiency, respectively, and compared with a normal population of elderly people. There were no major differences in the prevalence of osteoarthritis between the acromegalics and the normal population, but the patients with growth hormone deficiency had significantly (p<0.001) less osteoarthritis than the normal population. The lack of differences between the acromegalics and the normal population could be an effect of the age interval studied in which the prevalence of osteoarthritis is high. The low prevalence of osteoarthritis in patients with growth hormone deficiency suggests that growth hormone is an important factor in the development of osteoarthritis.
Kerstin Landin, Björn Petruson, Karl-Erik Jakobsson and Bengt-Åke Bengtsson
The aim of this study was to investigate the skeletal muscle sodium/potassium (Na/K) ratio in acromegaly before and 1 year after trans-sphenoidal removal of a growth hormone (GH)-secreting pituitary adenoma. Muscle biopsies were taken and skeletal muscle electrolytes, body composition, glucose, insulin and blood pressure were studied. Fasting blood glucose and plasma insulin levels, but not blood pressure, were higher in acromegalic patients (N = 9) than in controls (N = 6). The skeletal muscle potassium content was higher (p <0.01) but the sodium content and the Na/K ratio were lower (p<0.05 and p<0.001, respectively) in untreated patients with acromegaly as compared to weight-matched healthy controls. Elevated GH, glucose and insulin levels normalized after surgery. Blood pressure remained unchanged. The total body potassium content, the lean body mass and the total body water content decreased and the body fat content increased while the body weight was unchanged. The skeletal muscle potassium content decreased from [median (range)] 9.8 (9.2–11.5) to 7.7 (5.7–9.5) mmol/100 g wet wt (p<0.001). The skeletal muscle sodium content increased from 2.8 (2.5–3.9) to 5.1 (4.3–6.7) mmol/100 g wet wt (p<0.001) and the Na/K ratio increased from 0.28 (0.26–0.38) to 0.56 (0.51–1.18) (p< 0.001) after surgery, which is a higher level than the controls with a Na/K ratio of 0.47 (0.39–0.84) (p<0.01). These changes seem to be mediated by a decreased GH effect on the Na/K pump after successful trans-sphenoidal surgery in acromegaly.
Mariam Elbornsson, Galina Götherström, Ingvar Bosæus, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Few studies have determined the effects of more than 5–10 years of GH replacement in adults on body composition and cardiovascular risk factors.
In this prospective, single-center, open-label study, the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults (93 men) with adult-onset GH deficiency (GHD). Mean age was 50.5 (range 22–74) years at study start. Body composition was measured using dual-energy X-ray absorptiometry.
The mean initial GH dose of 0.55 (s.e.m. 0.03) mg/day was gradually lowered to 0.40 (0.01) mg/day after 15 years. The mean serum IGF1 SDS increased from −1.53 (0.10) at baseline to 0.74 (0.13) at study end (P<0.001 vs baseline). Lean soft tissue (LST) increased to 3% above the baseline level at study end (P<0.001). After a 9% decrease during the first year of treatment (P<0.001 vs baseline), body fat (BF) started to increase and had returned to the baseline level after 15 years. Serum levels of total cholesterol and LDL-cholesterol decreased and serum HDL-cholesterol level increased. Fasting plasma glucose increased from 4.4 (0.1) at baseline to 4.8 (0.1) mmol/l at study end (P<0.001). However, blood HbA1c decreased from 5.0 (0.1) to 4.6 (0.1) % (P<0.001).
Fifteen-year GH replacement in GHD adults induced a transient decrease in BF and sustained improvements of LST and serum lipid profile. Fasting plasma glucose increased whereas blood HbA1c was reduced.
Josef Koranyi, Ingvar Bosaeus, Magne Alpsten, Bengt-Åke Bengtsson and Gudmundur Johannsson
Objective: Men with growth hormone deficiency (GHD) may be more sensitive to GH treatment than women in terms of changes in body composition. We have studied whether age, body-mass index (BMI) and the different types of methodology used to assess body composition may explain these differences.
Design: Forty-four men and forty-four women with GHD, closely matched for age and BMI, were studied before and after 6 months of GH replacement. The dose of GH was individually adjusted. Body composition was assessed by measurements of potassium-40, total body nitrogen (TBN), tritiated water dilution, dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA). Four- and five-compartment models for body composition were also calculated.
Results: The total daily dose of GH was similar in men and women at 6 months. Serum insulin-like growth factor-I (IGF-I) was higher in men than women at baseline and after 6 months of treatment (P = 0.01, paired t-test). The increment was, however, similar. In women, GH treatment reduced body weight and increased TBN. In both men and women, total body water and body cell mass increased, while total body fat (BF) mass decreased. At baseline, mean total BF varied considerably depending on the methodology used, with the highest value obtained from DXA. The changes in BF were, however, less dependent on the methodology, but DXA and BIA demonstrated the largest inconsistency between men and women.
Conclusions: These results suggest that gender differences in body composition in response to GH treatment are small, if adjustments are made for baseline factors such as age, BMI and dose of GH. Different methods of body composition measurements produce different results, but changes in response to GH administration are less inconsistent.
Cesar L Boguszewski, Lars Hynsjö, Gudmundur Johannsson, Bengt-Åke Bengtsson and Lena MS Carlsson
Boguszewski CL, Hynsjö L, Johansson G, Bengtsson B-Å, Carlsson LMS. 22-kD Growth hormone exclusion assay: a new approach to measurement of non-22-kD growth hormone isoforms in human blood. Eur J Endocrinol 1996;135:573–82. ISSN 0804–4643
Human growth hormone (GH) exists in a variety of isoforms. In the pituitary, the most abundant isoform is 22-kD GH (22 K GH), while other isoforms (non-22 K GH) are present in variable amounts. In human plasma, the GH heterogeneity contributes to the wide variability in GH levels measured by different immunoassays. The physiological role of the non-22 K GH isoforms is poorly understood, but they may represent a spectrum of agonists or antagonists of the GH receptor. It is possible that increased amounts of non-22 K GH isoforms in the circulation contribute to the growth failure observed in some short children and may be involved in the pathophysiology of acromegaly and other unrelated diseases. Currently, there is no method available to evaluate the ratio of non-22 K GH isoforms to total GH in large sets of serum samples. In this report, a novel assay procedure is described in which monomeric and dimeric isoforms of 22 K GH are removed from serum and non-22 K GH isoforms are quantitated. The 22 K GH exclusion assay (22 K GHEA) was established as a screening method to identify conditions in which the ratio of non-22 K GH isoforms to total GH in human blood is altered. A 22 K GH-speciflc monoclonal antibody (MCB) is used for binding to 22 K GH in serum. Magnetic beads coated with rat anti-mouse immunoglobulin G and a magnetic device are used to remove the 22 K GH-MCB complexes from serum. The non-22 K GH isoforms are measured by a polyclonal antibody-based immunoradiometric assay (GH-IRMA). The assay procedure was optimized systematically by statistical experimental designs. In serum spiked with monomeric or dimeric 22 K GH, the 22 K GH extraction was efficient at GH levels up to 100 μg/l (range 96.3–100%). The intra- and interassay precision for non-22 K GH levels of 3.9 μg/l were 2.6% and 8.7%, respectively, while for levels of 0.6 μg/l, which were very close to the detection limits of the assay, the coefficients were 17.0% and 21.6%, respectively. The percentage of non-22 K GH isoforms determined in serum samples from three different groups of subjects showed clearly distinctive values. The 22 K GHEA is a new method for evaluation of non-22 K GH isoforms in human blood under different physiological and pathophysiological conditions.
Cesar L Boguszewski, RCEM, Sahlgrenska University Hospital, Bruna Stråket, 16 S-413 45 Göteborg, Sweden
Thord Rosén, Tommy Hansson, Hans Granhed, Janos Szucs and Bengt-Åke Bengtsson
Bone mineral content was measured in a follow-up study of adult patients with hypopituitarism and growth hormone deficiency. There were 95 patients (59 males, mean age 54.0 years, range 21–74 years; 36 females, mean age 53.5 years, range 31–73 years). Routine replacement therapy with cortisone acetate and l-thyroxine was given. All males that were gonadal deficient were on proper testosterone therapy, except in four patients who were treated separately. Bone mineral content (g/cm) was measured using dual-photon absorptiometry in the third lumbar vertebra. Bone mineral content in the patients was compared with a control population (N=413, 25–74 years of age). Bone mineral content was significantly lower in males (N= 55, p<0.05) compared with controls. In females, bone mineral content was significantly lower both among the subjects with untreated gonadal deficiency (p<0.001) and among those with treated gonadal deficiency and normal premenopausal gonadal function (p<0.005) compared with controls. To summarize, patients with hypopituitarism on routine replacement therapy but not growth hormone have a lower bone mineral content than the controls. The reduced bone mineral content might be a result of untreated growth hormone deficiency.
Helga Á Sigurjónsdóttir, Josef Koranyi, Magnus Axelson, Bengt-Åke Bengtsson and Gudmundur Johannsson
Objective: In the past years the interaction of GH and 11βhydroxysteroid dehydrogenase (11βHSD) in the pathogenesis of central obesity has been suggested.
Design: We studied the effects of 9 months of GH treatment on 11βHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48–66 years, in a randomised, double-blind, placebo-controlled trial.
Methods: Urinary steroid profile was used to estimate 11βHSD type 1 and 2 (11βHSD1 and 11βHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic–hyperinsulinaemic glucose clamp was used to assess insulin sensitivity.
Results: In the GH-treated group the 11βHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11βHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11βHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11βHSD1 and 11βHSD 2 and changes in GDR.
Discussion: The study demonstrates that short- and long-term GH treatment has different effects on 11βHSD1 and 11βHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11βHSD.
Laila Füchtbauer, Daniel S Olsson, Bengt-Åke Bengtsson, Lise-Lott Norrman, Katharina S Sunnerhagen and Gudmundur Johannsson
Patients with acromegaly have decreased body fat (BF) and increased extracellular water (ECW) and muscle mass. Although there is a lack of systematic studies on muscle function, it is believed that patients with acromegaly may suffer from proximal muscle weakness despite their increased muscle mass. We studied body composition and muscle function in untreated acromegaly and after biochemical remission.
Prospective observational study.
Patients with acromegaly underwent measurements of muscle strength (dynamometers) and body composition (four-compartment model) at diagnosis (n = 48), 1 year after surgery (n = 29) and after long-term follow-up (median 11 years) (n = 24). Results were compared to healthy subjects.
Untreated patients had increased body cell mass (113 ± 9% of predicted) and ECW (110 ± 20%) and decreased BF (67 ± 7.6%). At one-year follow-up, serum concentration of IGF-I was reduced and body composition had normalized. At baseline, isometric muscle strength in knee flexors and extensors was normal and concentric strength was modestly increased whereas grip strength and endurance was reduced. After one year, muscle strength was normal in both patients with still active disease and patients in remission. At long-term follow-up, all patients were in remission. Most muscle function tests remained normal, but isometric flexion and the fatigue index were increased to 153 ± 42% and 139 ± 28% of predicted values, respectively.
Patients with untreated acromegaly had increased body cell mass and normal or modestly increased proximal muscle strength, whereas their grip strength was reduced. After biochemical improvement and remission, body composition was normalized, hand grip strength was increased, whereas proximal muscle fatigue increased.