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.
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.
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.
Mariam Elbornsson, Galina Götherström, Celina Franco, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH-deficient (GHD) adults.
In this prospective, single-center, open-label study, the effects of 3-year GH replacement were determined in 45 GHD patients >65 years and in 45 younger control GHD patients with a mean age of 39.5 (s.e.m. 1.1) years. All patients had adult-onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index, and waist:hip ratio.
The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (P<0.01). The 3 years of GH replacement induced a marginal effect on total body BMC and BMD, whereas femur neck and lumbar (L2–L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (P<0.05 vs younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations.
This study shows that GH replacement increases lumbar (L2–L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports the notion that long-term GH replacement is also useful in elderly GHD patients.
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.
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.
Galina Götherström, Mariam Elbornsson, Katharina Stibrant-Sunnerhagen, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Only few studies have investigated the effects of GH replacement on muscle strength in elderly patients with GH deficiency (GHD).
Objective, design, and patients
In this prospective open-labeled study, the effects of 10 years of GH replacement on muscle strength and neuromuscular function were followed in 24 elderly GHD adults (mean age of 65.2 years; range 61–74 years). Muscle strength was compared with reference values obtained from the background population.
The mean initial GH dose of 0.72 mg/day was lowered to 0.37 mg/day. The mean IGF1 SDS increased from −1.10 at baseline to 1.17 at study end. GH replacement induced a sustained increase in lean body mass and a transient increase in isometric knee flexor strength. Isometric knee extensor strength was reduced after 10 years. However, after correction for age and gender, using observed/predicted value ratios, there was sustained and even progressive increase in most variables reflecting muscle strength. Measurements of neuromuscular function showed unchanged voluntary motor unit activation after 10 years.
Ten years of GH replacement therapy in elderly GHD adults resulted in a transient increase in isometric knee flexor strength, and provided protection from most of the normal age-related decline in muscle performance and neuromuscular function.
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.