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Endocrine Care |
Research Centre for Endocrinology and Metabolism (G.G., J.S., J.K., B.-Å.B., G.J.), Department of Radiation Physics (M.A.), and Department of Clinical Nutrition (I.B.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Address all correspondence and requests for reprints to: Galina Götherström, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: galina.gotherstrom{at}medic.gu.se
Abstract
GH replacement therapy has proved its efficacy and safety in short-term trials and in a few long-term trials with limited number of subjects. In this 1-center study, including 118 consecutive adults (70 men and 48 women; mean age, 49.3 yr; range, 22–74 yr) with adult-onset GH deficiency, the effects of 5 yr of GH replacement on body composition, bone mass, and metabolic indices were determined.
The mean initial GH dose was 0.98 mg/d. The dose was gradually lowered, and after 5 yr the mean dose was 0.48 mg/d. The mean IGF-I SD score increased from -1.73 at baseline to 1.66 at study end. A sustained increase in lean body mass and a decrease in body fat were observed. The GH treatment increased total body bone mineral content as well as lumbar (L2–L4) and femur neck bone mineral contents. BMD in lumbar spine (L2–L4) and femur neck were increased and normalized at study end. Total cholesterol and low density lipoprotein cholesterol decreased, and high density lipoprotein cholesterol increased. At 5 yr, serum concentrations of triglycerides and hemoglobin A1c were reduced compared with baseline values. The treatment responses in IGF-I SD score, body fat as estimated by four- and five-compartment body composition models, total body protein and nitrogen, and lumbar bone mineral content and BMD were more marked in men than in women.
One patient died during the period, four patients discontinued the study due to adverse events, and one dropped out due to lack of compliance. Four patients were lost to follow-up. However, all patients were retained in the statistical analysis according to the intention to treat approach used.
In conclusion, 5 yr of GH substitution in GH-deficient adults is safe and well tolerated. The effects on body composition, bone mass, and metabolic indices were sustained. The effects on body composition and low density lipoprotein cholesterol were seen after 1 yr, whereas the effects on bone mass, triglycerides, and hemoglobin A1c were first observed after years of treatment.
THE INITIAL GH treatment trials in GH-deficient adults showed dramatic effects on body composition, with profound reductions of body fat and increases in lean mass (1, 2, 3, 4, 5). These first studies used high doses of GH and the effects on body composition were accompanied by fluid-related side-effects. Later studies using lower GH doses have also shown a maintained effect on body composition (6), although the magnitude of the reduction in body fat may be estimated differently by different methods (7).
GH treatment increases biochemical markers of both bone formation and bone resorption, suggesting an increased bone remodeling rate (8). In adults with GH deficiency of childhood origin, this increase in bone turnover resulted in a decreased or unaffected bone mineral content (BMC) during GH treatment for 6 months or less (3, 9, 10). However, prolonged treatment for 6–30 months increased BMC (11, 12, 13). In adults with adult-onset GH deficiency, the initial studies did not find increased BMC in response to treatment (4, 14), whereas more recent and prolonged treatment trials showed increased BMC and BMD (15, 16). Whether normalization of BMD can be achieved with long-term GH replacement has not yet been determined.
A number of studies have shown a reduction in low density lipoprotein cholesterol (LDL-C) during GH replacement for up to 10 yr (17, 18). GH treatment lowered or did not affect serum total cholesterol (TC) concentrations and increased or did not affect serum high density lipoprotein cholesterol (HDL-C) (17). The serum triglyceride (TG) concentration is generally unaffected by GH replacement therapy (17). Furthermore, adult GH deficiency without GH treatment is accompanied by insulin resistance (19). During the first weeks of treatment, there is an initial deterioration of insulin resistance by GH treatment that is restored to baseline values after 6 months of GH treatment (20). Insulin sensitivity then appears to be unchanged, compared with baseline, for up to 2 yr of GH treatment (21). However, a normalization of insulin sensitivity was reported in one study after 1 yr of GH treatment (22).
High doses of GH increased mortality in intensive care unit patients (23). There have been no reports of a similar effect of GH substitution in GH-deficient adults. Data from a large postmarketing surveillance program, the Pharmacia & Upjohn International Metabolic Database (KIMS), suggest that GH replacement may reduce the increased mortality found in hypopituitary patients not receiving GH treatment (24). However, the long-term effect on mortality in GH-deficient adults has not yet been fully evaluated.
The aim of this prospective study was to determine the efficacy as well as the safety of 5 yr of GH treatment in a large group of relatively unselected patients with adult-onset GH deficiency recruited at a single center.
Subjects and Methods
Patients
One hundred and eighteen adults with adult-onset pituitary
deficiency and with a mean (±SEM) age of 49.3 ± 1.0
yr (range, 22–74) years were included between 1990–1994. All patients
had known pituitary disease or other pituitary hormonal deficiency. The
pituitary deficiency was mainly caused by pituitary tumors or their
treatment (Table 1
). Ninety-two of the
patients had been treated surgically, and 56 of the patients had
received radiotherapy. Most patients had multiple anterior pituitary
deficiencies (Table 1). Possibly due to late effects of radiotherapy,
several patients had more anterior pituitary deficiencies at study end
than at baseline (Table 1). In 106 patients, the diagnosis of GH
deficiency was based on a maximum peak GH response of less than 3
µg/liter during insulin-induced hypoglycemia (blood glucose, 
2.2
mmol/liter). In the remaining 12 patients, all with serum IGF-I
concentrations below the age-adjusted normal range and multiple
anterior pituitary deficiencies, the diagnosis was based on
measurements of 24-h GH secretion (n = 5), a maximum GH response
less than 1.5 µg/liter during a glucagon stimulation test (n =
3), 3 consecutive morning GH concentrations below 0.33 µg/liter
(n = 3), and a low serum IGF-I concentration (n = 1). When
required, patients received replacement therapy with glucocorticoids,
thyroid hormone, gonadal steroids, and desmopressin throughout the
study period. At study start 60% (26 of 43), and at study end 70% (32
of 46), of the hypogonadal women received E replacement therapy. All
hypogonadal men received T replacement therapy at both study start and
study end. One patient was given oral glipizide for
diabetes after 2.5 yr of GH treatment. This patient was excluded from
analysis of blood glucose, serum insulin, and serum hemoglobin
A1c (HbA1c). Otherwise, the
patients were not receiving any medication that could affect the
measurements in this study.
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This is an ongoing, prospective, open label treatment trial of the administration of recombinant human GH in adult patients with GH deficiency. One hundred and eighteen consecutive adult patients with adult-onset GH deficiency were treated for 5 yr with GH. The initial target dose of GH in the first 80 patients was 11.9 µg/kg·d (0.25 IU/kg·wk). The dose was gradually lowered and individualized when the weight-based dose regimen was abandoned (25). In the remaining 38 patients, the GH dose was individualized from the beginning (25). Individualization of the dose of GH was performed with the aim of normalizing the serum IGF-I concentration, the IGF-I SD score, and body composition (estimated by the four-compartment model) in each patient (25).
At baseline and then after each year of GH treatment, physical and laboratory examinations were performed, including measurements of body composition and bone mass. In addition, dose titration and safety monitoring were performed by visits every third month during the first year and every sixth month thereafter. Body weight was measured in the morning to the nearest 0.1 kg, and body height was measured barefoot to the nearest 0.01 m. Systolic and diastolic blood pressures were measured after at least 5 min of supine rest using the sphygmomanometric cuff method. No effort was made to influence the patients’ physical activity levels during the study period.
Ethical considerations
Informed consent was obtained from all patients. The study was approved by the ethics committee at the University of Göteborg and the Swedish Medical Products Agency (Uppsala, Sweden).
Body composition
Dual energy x-ray absorptiometry (DEXA; software version 1.3, Lunar DPX-L, Lunar Corp., Madison, WI) was used to measure lean body mass and total body fat (BFDEXA) as described previously (26). The relative error for lean body mass was 1.5%.
The four-compartment body composition model used is based on total body potassium (TBK) and total body water (TBW) assessments as previously described by Bruce et al. (27). 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%). According to the four-compartment model, body weight is the sum of body cell mass, extracellular water, fat-free extracellular solids, and BF (27). Normative values for the four-compartment model were derived using regression equations from body composition studies of 476 healthy individuals (134 men and 342 women; aged 20–70 yr) (27). An individual observed/predicted values ratio could then be calculated for body cell mass (percentage), extracellular water (percentage), and BF (percentage).
Total body nitrogen (TBN) was measured by in vivo neutron activation as previously described (28, 29). The measurement error was approximately ±4% (28, 29).
The five-compartment model used included estimation of total body protein (TBN x 6.25), total body water, total body mineral (total BMC from DEXA x 1.235), and total body glycogen (total body protein x 0.044) (7, 30). Body fat is then body weight - fat-free mass.
BMC and BMD
DEXA (Lunar DPX-L, software version 1.3) was used to measure BMC and BMD in the total body, lumbar spine (L2–L4), and proximal femur as described previously (26). During the entire study period, a calibration phantom (COMAC-BME Quantitative Assessment of Osteoporosis Study Group) was used. The CVs between measurements were 0.4%, 0.5%, and 0.6% for total body BMD, lumbar (L2–L4) spine BMD, and femur neck BMD. The BMD z-score, which is the difference in SD of age- and sex-matched healthy subjects, and the BMD t-score, which is the difference in SD of sex-matched young (20- to 39-yr-old) healthy subjects, were determined using the Lunar DPX-L software program.
Biochemical assays
The serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter- and intraassay CVs 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 detection limit of the assay was 13.5 µg/liter. The individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a reference population of 197 men and 195 women (31). The individual IGF-I SD scores could then be calculated as described previously (32).
Serum osteocalcin was measured by a double antibody RIA (International CIS, Gif-sur-Yvette, France), with inter- and intraassay CVs 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 inter- and intraassay CVs of 7.8% and 7.4% 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.
TC and TG concentrations were determined using enzymatic methods (Roche Molecular Biochemicals). The interassay CVs for TC and TG determinations were 2.9% and 3.8%, respectively, and intraassay CVs were 0.9% and 1.1%, respectively. HDL-C levels were determined after the precipitation of apoB-containing lipoproteins with MgCl2 and heparin (33). LDL-C was calculated according to Friedewald’s formula adjusted to Systeme International units (34). Serum insulin was determined by RIA (Phadebas, Pharmacia Biotech, Uppsala, Sweden), and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Laboratory, Stockholm, Sweden). Serum HbA1c was determined by HPLC (Waters Corp., Milford, MA).
Statistical methods
All of the descriptive statistical results are presented as the mean (±SEM). For all variables, a one-way ANOVA was performed, with all data obtained from all time points, and with time as the independent variable. Post hoc analysis was performed using Student-Newman-Keuls test. Gender differences were calculated by a one-way ANOVA, with all data obtained from all time points and with gender as the independent variable. To eliminate baseline differences, data were transformed as the percent change or the change from baseline before analysis of gender differences. All analyses were performed using an intention to treat approach based on the last observation carried forward principle. A two-tailed P < 0.05 was considered significant.
Results
GH dose, IGF-I SD score, and blood pressure
The mean dose of GH was gradually lowered during the first 2–3 yr
of the study (Table 2). The mean IGF-I
SD score increased from -1.73 at baseline to 1.66 at study
end (Table 2). During the 5 yr period, height, weight, and BMI
increased, whereas systolic and diastolic blood pressures were
unaffected (Table 2).
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All methods for body composition showed a sustained increase in
lean mass (Table 3). After 5 yr, body fat
was reduced by an average of 1.2 kg as measured using DEXA, by 2.7 kg
as estimated by the four-compartment model, and by 1.9 kg as estimated
by the five-compartment model (Table 3). As estimated by the
four-compartment model, the percent BF was reduced to below 100% of
the predicted value (Table 3). The changes in BF and lean mass were
generally observed after 1 yr of treatment (Table 3). As assessed by
the five-compartment model, TBN, total body protein, and glycogen were
increased at 1–4 yr of GH treatment, but not at 5 yr (Table 3). The
TBN/TBK ratio was unaffected by GH treatment during the first 4 yr of
the study, whereas after 5 yr, the TBN/TBK ratio was decreased (Table 3).
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There were sustained increases in serum concentrations of
osteocalcin and calcium, whereas the serum intact PTH concentration was
unaffected by GH treatment (Table 4).
Total bone mineral, as estimated by the five-compartment model, was
increased by GH treatment (Table 4). Total BMC, lumbar (L2–L4) BMC,
and BMC in the femur neck were increased by averages of 2%, 7%, and
6%, respectively, at study end (Table 4). Total BMD was transiently
decreased by GH treatment, but was unchanged at study end (Table 5). Lumbar (L2–L4) and femur neck BMD as
well as lumbar and femur neck z-score and t-score were
increased by GH treatment (Table 5). The increases in lumbar (L2–L4)
and femur neck BMC, z-score, and t-score were progressive
throughout the 5 yr of GH treatment (Tables 4 and 5).
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Serum concentrations of TC and LDL-C were reduced, and the serum
HDL-C concentration was increased by GH treatment (Table 6). Serum LDL-C was excluded in five
patients due to serum TG values above 4.3 mmol/liter. The mean serum TG
concentration (with the five patients with serum TG values greater than
4.3 mmol/liter included) was reduced after 4 and 5 yr of GH replacement
therapy (Table 6). The blood glucose concentration was increased
throughout the study period, whereas the serum insulin concentration
was unaffected by GH treatment (Table 6). At 5 yr, the serum
HbA1c concentration was reduced compared with the
baseline value (Table 6).
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The dose of GH (milligrams per d) was similar in men and women
throughout the 5 yr of treatment, although the dose of GH tended
to be higher in men than in women at study start (Fig. 1A). Adjusted for body weight, the mean
dose of GH was higher in women than in men at all time during the 5-yr
period except at baseline (Fig. 1B). The increase in IGF-I
SD score was, however, more marked in men than in women
(Fig. 1C).
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) and the five-compartment models
(P < 0.05 men vs. women; data not shown).
However, the response in body fat was similar in men and women as
estimated by DEXA. At study end total body protein was increased by 4%
in men, whereas a 5% decrease was observed in women (P
< 0.05, men vs. women). In men, TBN was increased
throughout the study period, whereas in women, TBN was decreased at
study end (Fig. 3). No gender difference
was found in the responses of TBK and TBN/TBK ratio (Fig. 3). The
responses of other body composition measurements, including
measurements of TBW, were similar between men and women.
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). Although lumbar (L2–L4)
BMC increased in men, there was no significant change in women after 5
yr (Fig. 4). In addition, the mean lumbar (L2–L4) t-score
was increased by 0.73 (0.11) SD in men and by
0.31 (0.10) SD in women (P <
0.05 men vs. women). Other measurements of bone mass and
density, including BMC and BMD in femoral neck, were similar in both
sexes. No gender differences were found in the treatment response in
BH, BW, BMI, systolic and diastolic blood pressures, lipids, or the
variables reflecting glucose metabolism.
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One patient died of renal carcinoma after 3 yr of GH replacement. Four patients discontinued the study due to adverse events [prostatic cancer (n = 1), epileptic seizures (n = 2), angina pectoris (n = 1)], and one subject discontinued the study due to lack of compliance. Four patients were lost to follow-up because they moved to other parts of Sweden or abroad. However, all patients were retained in the statistical analysis, as the last observed value for each variable was carried forward according to the intention to treat approach used. One patient received oral medication with glipizide for diabetes mellitus after 2.5 yr of GH treatment. Four additional patients were given dietary restrictions due to a morning blood glucose concentration greater than 6.1 mmol/liter. After the dietary instructions, blood glucose was normalized (<6.1 mmol/liter) in two of these four patients.
Discussion
This is the largest single center study determining the effects of long-term GH replacement therapy in adult hypopituitary patients. The results show that GH replacement therapy is safe and well tolerated, and none of the patients was removed from the study due to GH related side-effects. The GH treatment elicited sustained effects on body composition, bone mass, and metabolic indices. Some effects were seen after 1 yr, whereas other effects were first observed after years of treatment.
The dose of GH was based on body weight in the first subjects included in this study. In men, this initial high dose resulted in overtreatment, seen as high IGF-I SD scores and excessive changes in body composition i.e. body fat levels below and extracellular fluid levels above the expected values based on age and sex. In women, the responses of IGF-I SD score and body fat were less marked. Gender differences should, however, be cautiously interpreted. There are large baseline variations between GH-deficient men and women (35). Different methodology may also estimate changes in body fat differently, which may be of clinical importance (7). In the present study the four- and five-compartment models showed a more pronounced reduction in body fat in the total study population than DEXA, and gender differences in the treatment response of body fat were only observed using the four- and five-compartment models. Furthermore, using weight-adjusted doses of GH, men were overtreated, whereas women tended to receive an inappropriately low dose of GH (36, 37). The most appropriate regimen for GH replacement is to individualize the GH dose that should be adjusted to serum IGF-I levels and the clinical response (25, 38). Such a regimen will have adequate efficacy with fewer short-term side-effects than weight-based doses of GH.
Serum concentrations of osteocalcin and calcium were increased
throughout the 5-yr period, suggesting a sustained increase in bone
turnover. In accordance with the biphasic model of GH action on bone
remodeling (8), this resulted in an initially negative
bone remodeling balance with a transient decrease in total BMD. After
prolonged GH treatment (2–5 yr), a positive remodeling balance was
observed with progressive increases in lumbar (L2–L4) and femur neck
BMC and BMD. After 5 yr, lumbar (L2–L4) and femur neck z-scores were
normalized (z-score, 
0), and the lumbar t-score reached
peak bone mass (t-score, 0). The BMD in spine and femur neck
is strongly related to the fracture risk in these regions (39, 40). Therefore, the present data suggest that GH substitution
may reduce the increased fracture risk previously found in
hypopituitary patients with untreated GH deficiency (41, 42).
In this study effects on total BMC and BMD were small, whereas there were prominent effects on lumbar (L2–L4) and femur neck BMC and BMD throughout the study. Similarly, in another study GH replacement for 2 yr exerted a regional effect on BMD, with an increase in BMD in several weight-bearing locations (16). In vitro studies show that human osteoblast-like cells express GH receptors and that GH exert anabolic actions on osteoblasts (43, 44). However, indirect effects of GH treatment, such an increased mechanical load on the skeleton, could explain the regional effects of GH on BMD in the present study. GH replacement has previously been shown to increase well-being and therefore is also likely to increase physical activity (5, 45), which could contribute to such an effect. Furthermore, the increase in muscle strength observed during GH replacement (46) could increase the mechanical load on the skeleton.
Gender differences were found, in addition to the previously discussed gender differences in IGF-I SD score and body fat, in the treatment responses of lumbar BMC, BMD, total body protein, and TBN. In men, there were sustained increases in lumbar (L2–L4) BMC and BMD, total body protein, and TBN during the 5 yr of GH replacement therapy. In women, the effects on lumbar (L2–L4) BMC and BMD were less marked than in men, and total body protein and TBN were even lower at study end than at baseline. Other studies have also shown a more marked increase in BMD during GH replacement therapy in men than in women (47, 48). The gender differences in the treatment responses in lumbar (L2–L4) BMC and BMD may be explained by suboptimal E replacement therapy. All male patients received T replacement therapy, whereas 60% and 70% of the female patients received E replacement therapy at study start and study end, respectively. However, E has previously been shown to antagonize the nitrogen-retaining effects of GH (49), and further studies are needed to investigate how E replacement therapy can be optimized in GHD adults. The TBN/TBK ratio was similar in women and men over the 5 yr of GH treatment; however, a decrease in the TBN/TBK ratio was observed in women at study end. TBN reflects total body protein (5, 30), whereas TBK reflects body cell mass (5, 27). Therefore, the decreased TBN/TBK ratio in women after 5 yr of GH replacement therapy may reflect a decreased formation of extracellular proteins at study end.
In this study, as in most others (17), GH treatment induced a sustained reduction in LDL-C. As in some, but not all, previous short-term studies (17), GH treatment reduced the serum TC concentration and increased the serum HDL-C concentration. Of interest, and unlike most previous short-term studies (17), a reduction in the serum TG concentration was found at study end. In addition, previous studies have shown that 2 yr of GH replacement therapy reduces visceral fat mass (50) and circulating plasminogen activator inhibitor-1 (51). Therefore, long-term GH treatment has beneficial effects on several cardiovascular risk factors.
The serum TG concentration is generally closely and inversely related to insulin sensitivity (52). Therefore, the reduction in TG may suggest that insulin sensitivity was increased after 5 yr of GH treatment. In support of this hypothesis, the serum HbA1c concentration, which relates to the mean blood glucose level during several weeks, was reduced at study end. Fasting blood glucose concentrations were increased throughout this study, which may reflect that the blood samples for glucose determinations were drawn in the morning after a GH injection before bedtime. It has been shown that the mean blood glucose concentration over 24 h is unaffected by short-term (3-month) GH replacement therapy (53). Furthermore, a lower morning blood glucose concentration can be expected in hypopituitary adults without GH substitution (54). Therefore, the present results suggest that the GH treatment increased morning blood glucose concentrations, whereas the mean 24-h blood glucose concentration could have been lowered at study end. It is plausible, although was not measured, that the reductions in HbA1c and TG between 2–5 yr could be an effect of increased physical activity. Data from a large postmarketing surveillance program in children, the Pharmacia & Upjohn International Growth Database (KIGS), suggest that GH treatment of short children increased the incidence of type 2 (noninsulin-dependent) diabetes mellitus (55). It is not known whether GH replacement affects the risk of developing type 2 diabetes mellitus in adults. The present study population was not large enough to enable a comparison with the normal population, but the long-term effect on glucose metabolism may suggest that the risk of developing type 2 diabetes mellitus was not increased.
The lowering of the dose of GH during this study could explain why some variables, such as total body protein and TBN, decreased during the last 2–3 yr of the study. Furthermore, the aging of the patients during this 5-yr trial could also have affected several of the end points studied. Aging is associated with decreased GH secretion (56, 57), and some features of aging, such as frailty and increased abdominal obesity, could be related to the decreased GH secretion (56, 57). However, although this is an uncontrolled study, most end points were changed in the opposite direction as that normally seen during aging. Further studies are needed to investigate whether long-term GH treatment in normal elderly subjects can prevent the decrease in physical performance as well as the accumulation of body fat that occur with increasing age.
One subject died during the study period (almost 600 patient yr). This finding is in line with a report from the KIMS database by Bengtsson et al. (24). In that study a mortality of 12 patients was observed during GH replacement therapy for 2334 patient years (1 death/195 patient yr). This mortality rate was significantly lower than that previously observed by Rosén et al. (24) in hypopituitary patients without GH substitution. Therefore, the results of the present study and that by Bengtsson et al. indicate that mortality in GH-deficient adults is not increased when hypopituitary adults are treated with adequate doses of GH. The increased mortality found by Takala et al. (23) during treatment with very high doses of GH in critically ill patients is therefore specific for that study population.
In conclusion, a treatment program of 5 yr of GH substitution in GH-deficient adults was safe and well tolerated. There were sustained effects on body composition, bone mass, and metabolic indices. Some effects were seen already after 1 yr, whereas other effects were first observed after years of treatment. Of major interest is the reductions in triglycerides and HbA1c, suggesting improved insulin sensitivity as well as the normalization of bone mass at study end. The responses in several variables reflecting body composition and bone mass and density were more marked in men than in women. Further studies are needed to evaluate whether GH replacement therapy can reduce the increased cardiovascular mortality as well as the increased fracture risk in GH-deficient adults.
Acknowledgments
We are indebted to Lena Wiren, Anne Rosen, Ingrid Hansson, and Sigrid Lindstrand at the Research Center for Endocrinology and Metabolism for their skillful technical support.
Footnotes
Presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, June 21–24, 2000.
This work was supported by a grant from the Swedish Medical Research Council (no. 11621) and the chair of Göteborg.
Abbreviations: BF, Body fat; BMC, bone mineral content; BMD, bone mineral density; CV, coefficient of variation; DEXA, dual energy x-ray absorptiometry; HbA1c, hemoglobin A1c; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TBK, total body potassium; TBN, Total body nitrogen; TBW, total body water; TC, total cholesterol; TG, triglycerides.
Received October 6, 2000.
Accepted June 25, 2001.
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G Gotherstrom, B-A Bengtsson, I Bosaeus, G Johannsson, and J Svensson Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency Eur. J. Endocrinol., January 1, 2007; 156(1): 55 - 64. [Abstract] [Full Text] [PDF]
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A A van der Klaauw, J A Romijn, N R Biermasz, J W A Smit, J van Doorn, O M Dekkers, F Roelfsema, and A M Pereira Sustained effects of recombinant GH replacement after 7 years of treatment in adults with GH deficiency. Eur. J. Endocrinol., November 1, 2006; 155(5): 701 - 708. [Abstract] [Full Text] [PDF]
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R. Abs, U. Feldt-Rasmussen, A. F Mattsson, J. P Monson, B.-A. Bengtsson, M. I Goth, P. Wilton, and M. Koltowska-Haggstrom Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis. Eur. J. Endocrinol., July 1, 2006; 155(1): 79 - 90. [Abstract] [Full Text] [PDF]
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B. Saller, A. F Mattsson, P. H Kann, H. P Koppeschaar, J. Svensson, M. Pompen, and M. Koltowska-Haggstrom Healthcare utilization, quality of life and patient-reported outcomes during two years of GH replacement therapy in GH-deficient adults - comparison between Sweden, The Netherlands and Germany. Eur. J. Endocrinol., June 1, 2006; 154(6): 843 - 850. [Abstract] [Full Text] [PDF]
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L. J. Woodhouse, A. Mukherjee, S. M. Shalet, and S. Ezzat The Influence of Growth Hormone Status on Physical Impairments, Functional Limitations, and Health-Related Quality of Life in Adults Endocr. Rev., May 1, 2006; 27(3): 287 - 317. [Abstract] [Full Text] [PDF]
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M. L. Healy, J. Gibney, C. Pentecost, P. Croos, D. L. Russell-Jones, P. H. Sonksen, and A. M. Umpleby Effects of High-Dose Growth Hormone on Glucose and Glycerol Metabolism at Rest and during Exercise in Endurance-Trained Athletes J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 320 - 327. [Abstract] [Full Text] [PDF]
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 M. Iruthayanathan, Y.-H. Zhou, and G. V. Childs Dehydroepiandrosterone Restoration of Growth Hormone Gene Expression in Aging Female Rats, in Vivo and in Vitro: Evidence for Actions via Estrogen Receptors Endocrinology, December 1, 2005; 146(12): 5176 - 5187. [Abstract] [Full Text] [PDF]
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J. D Veldhuis, J. M Patrie, K. Frick, J. Y Weltman, and A. L Weltman Administration of recombinant human GHRH-1,44-amide for 3 months reduces abdominal visceral fat mass and increases physical performance measures in postmenopausal women Eur. J. Endocrinol., November 1, 2005; 153(5): 669 - 677. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]
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A. F. Attanasio, E. Shavrikova, W. F. Blum, M. Cromer, C. J. Child, M. Paskova, J. Lebl, J. J. Chipman, the Hypopituitary Developmental Outcome Study Grou, and S. M. Shalet Continued Growth Hormone (GH) Treatment after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4857 - 4862. [Abstract] [Full Text] [PDF]
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K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho Estrogen Regulation of Growth Hormone Action Endocr. Rev., October 1, 2004; 25(5): 693 - 721. [Abstract] [Full Text] [PDF]
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 S. M. Harman and M. R. Blackman Hormones and Supplements: Do They Work?: Use of Growth Hormone for Prevention or Treatment of Effects of Aging J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2004; 59(7): B652 - B658. [Abstract] [Full Text] [PDF]
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J.-O. Jansson and J. Svensson Growth Hormone (GH) Replacement in Women in Relation to Their Endogenous GH Secretion J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3066 - 3066. [Full Text] [PDF]
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A. R. Hoffman, J. E. Kuntze, J. Baptista, H. B. A. Baum, G. P. Baumann, B. M. K. Biller, R. V. Clark, D. Cook, S. E. Inzucchi, D. Kleinberg, et al. Growth Hormone (GH) Replacement Therapy in Adult-Onset GH Deficiency: Effects on Body Composition in Men and Women in a Double-Blind, Randomized, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2048 - 2056. [Abstract] [Full Text] [PDF]
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S. Srinivasan, G. D. Ogle, S. P. Garnett, J. N. Briody, J. W. Lee, and C. T. Cowell Features of the Metabolic Syndrome after Childhood Craniopharyngioma J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 81 - 86. [Abstract] [Full Text] [PDF]
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 M. Misra, L. A Soyka, K. K Miller, S. Grinspoon, L. L Levitsky, and A. Klibanski Regional body composition in adolescents with anorexia nervosa and changes with weight recovery Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1361 - 1367. [Abstract] [Full Text] [PDF]
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J. Svensson and B.-A. Bengtsson Growth Hormone Replacement Therapy and Insulin Sensitivity J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1453 - 1454. [Full Text] [PDF]
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 W. L. Isley Growth Hormone Therapy for Adults: Not Ready for Prime Time? Ann Intern Med, August 6, 2002; 137(3): 190 - 196. [Abstract] [Full Text] [PDF]
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A. F. Attanasio, P. C. Bates, K. K. Y. Ho, S. M. Webb, R. J. Ross, C. J. Strasburger, R. Bouillon, B. Crowe, K. Selander, D. Valle, et al. Human Growth Hormone Replacement in Adult Hypopituitary Patients: Long-Term Effects on Body Composition and Lipid Status--3-Year Results from the HypoCCS Database J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1600 - 1606. [Abstract] [Full Text] [PDF]
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