This Article Abstract Full Text (PDF) All Versions of this Article: 91/11/4408    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Franco, C. Articles by Svensson, J. Search for Related Content PubMed PubMed Citation Articles by Franco, C. Articles by Svensson, J. Related Collections Metabolism Neuroendocrinology and Pituitary

Baseline Characteristics and Effects of Growth Hormone Therapy over Two Years in Younger and Elderly Adults with Adult Onset GH Deficiency

Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: Johan.Svensson{at}medic.gu.se.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: The effects of GH replacement in elderly GH-deficient (GHD) adults are not well known.

Objective/Design/Patients: In this prospective, single-center, open-label study, baseline characteristics and the effects of 2-yr GH replacement were determined in 24 GHD adults above 65 yr of age and in 24 younger GHD patients (mean age, 37 yr; range, 27–46 yr). All patients had adult onset disease, and both groups were comparable in terms of the number of pituitary hormonal deficiencies, gender, body mass index, and waist/hip ratio. Duration of hypopituitarism was, however, longer in the elderly patients.

Results: The mean maintenance dose of GH was 0.31 (SEM, 0.03) mg/d in the elderly GHD patients and 0.44 (0.04) mg/d in the younger patients. The less marked response in IGF-I SD score, total body fat, and extracellular water in the elderly patients lost significance when the dose of GH was accounted for in the statistical analyses. Despite the lower dose in the elderly GHD group, these patients had a more marked reduction in waist/hip ratio and serum low-density lipoprotein-cholesterol level, and these differences remained also after correction for duration of hypopituitarism. There was no difference at baseline or in responsiveness in lean mass, bone mineral density, and glucose homeostasis.

Conclusions: This study identifies elderly GHD adults as a GH-sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism. GH replacement should therefore be considered in elderly GHD adults.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
GH SECRETION DECLINES with increasing age (1, 2). This may be important for the metabolic changes seen in normal aging, such as an increased relative amount of total and visceral fat and increased low-density lipoprotein-cholesterol (LDL-C) (1, 2). There are, however, distinct differences between normal elderly subjects and elderly GH-deficient (GHD) adults with structural hypothalamic-pituitary disease. The elderly GHD adults have lower GH secretion (3) and increased total body fat (BF) (4) as compared with age-matched healthy subjects, whereas there is little difference in lean mass (4) and bone mass (5, 6).

GH replacement can normalize most features of adult GHD (7, 8, 9). The response to GH replacement may, however, vary in different subgroups of patients depending on the cause and severity of disease (10), as well as on whether the disease was acquired in childhood or adulthood (11). Little is known of the responsiveness to GH replacement in elderly GHD adults. Several studies suggest that GH replacement in elderly GHD patients has similar efficacy as in younger GHD adults in terms of body composition and serum lipid pattern (12, 13), but it is unknown whether the magnitude of the changes differs. It has been suggested in some studies that the elderly GHD patients may need a lower dose of GH than younger patients (14), whereas in other studies, it has been suggested that the main effect of GH replacement in elderly patients may be to prevent further age-related decline in variables such as muscle strength (15).

In this single-center, prospective study, baseline characteristics were determined in 24 consecutive GHD patients more than 65 yr of age at study start and compared with those in 24 GHD adults aged 27–46 yr. The two groups were matched with regard to gender, body mass index (BMI), waist circumference, waist/hip ratio, and number of anterior pituitary hormonal deficiencies, and all patients had adult onset GHD. The main purpose was to study between-group differences in the response to 2-yr GH replacement therapy in body composition, bone mass, and metabolic indices.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Twenty-four consecutive GHD adults more than 65 yr of age (mean age, 68; range, 65–75 yr) and 24 younger GHD adults (mean age, 37; range, 27–46 yr) were included from 1992–1997. All patients had adult onset pituitary disease (Table 1). No patient had previously received GH treatment. In both study groups, 20 patients had been treated surgically. Nine elderly and six younger patients had received radiotherapy. In 45 of the patients, the diagnosis of GHD was based on a peak GH less than 3 µg/liter during a stimulation test [insulin (n = 41), GHRH (n = 3), glucagon (n = 1)]. In one elderly patient and in two younger patients, all with multiple pituitary hormonal deficiencies, the diagnosis was based on measurements of 24-h spontaneous GH secretion (n = 2) or on a serum IGF-I concentration below –2 SD (n = 1). When required, patients received adequate and stable therapy with glucocorticoids, thyroid hormone, gonadal steroids, and desmopressin. However, at entry to the study, two of nine (22%) and five of nine (56%) of the estrogen-deficient women in the elderly and younger GHD groups, respectively, received estrogen therapy.

Study protocol

This is an ongoing, prospective, open-label treatment trial in adult GHD patients. Various brands of recombinant human GH are used in this trial. In two patients (one elderly and one younger), 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 already during the first year of treatment. In the remaining 46 patients, the dose of GH was individualized from the beginning (16).

The individualization of the dose of GH was performed with the aim of normalizing IGF-I SD score (target range, 0 to + 2 SD of predicted values) and body composition (to approximately 100% of predicted values as estimated by the four-compartment model) in each patient (16). The use of IGF-I SD scores may result in lower absolute serum IGF-I values in the elderly than in the younger GHD patients during the GH replacement because serum IGF-I concentration declines with increasing age in the normal population (17). In most patients, the titration of the dose of GH was based on the IGF-I SD score. However, in some patients, mainly patients with an IGF-I SD score in the low normal range at baseline, the normalization of body composition was of increasing importance. The initial dose of GH was 0.5–1.0 IU (0.17–0.33 mg) per day in the patients that received individualized dose titration. Dose adjustments were made by 0.1–0.17 mg/d, depending on the injection device being used.

According to the study protocol, the dose of GH was to be reduced by half in the event of side effects that became a burden for the patients. Therefore, the dose of GH was reduced by half due to fluid-related side effects in the two patients (one elderly and one young GHD patient) that received their initial dose of GH based on body weight. Smaller reductions (0.1–0.17 mg/d) of the dose of GH were made in 14 additional (five elderly and nine young) patients due to IGF-I SD score values above +2 SD or due to mild fluid-related side effects.

At baseline and then after each year of GH treatment, physical and laboratory examinations were performed including measurements of body composition, bone mass, and metabolic indices. Dose titration and safety monitoring were performed 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. BMI was calculated as the weight in kilograms divided by the height in meters squared. Waist circumference was measured in the standing position with a flexible plastic tape placed midway between the lower rib margin and the iliac crest, and hip girth was measured at the widest part of the hip. Systolic and diastolic blood pressure was measured after at least 5 min of supine rest using the sphygmomanometric cuff method. No effort was made to influence the patients’ physical activity level 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) (Lunar DPX-L, Lunar Corporation, Madison, WI; software version 1.3) was used to measure lean body mass (LBM) and BF (18). 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 and total body water assessments (19). Total body potassium was assessed using a whole body counter [coefficient of variation (CV), 2.2%], and total body water was determined by the isotope dilution of tritiated water (CV, 3.2%). Normative values were derived from studies of 476 healthy subjects (19). Individual observed/predicted values ratios could then be calculated for BCM (BCM%), ECW (ECW%), and BF (BF%).

BMC and bone mineral density (BMD)

DEXA (Lunar DPX-L, software version 1.3) was used to measure BMC and BMD (18). 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, lumbar (L2–L4) spine, and femur neck BMD, respectively. BMD z-score, which is the difference in SD of age- and sex-matched healthy subjects, and 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

Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Interassay and intraassay CVs were 5.4 and 6.9%, respectively, at a mean serum IGF-I level of 126 µg/liter, and 4.6 and 4.7%, respectively, at a mean serum IGF-I level of 327 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 (17). The individual IGF-I SD scores could then be calculated (20).

Serum osteocalcin was measured by a double-antibody RIA (International CIS, GiF-sur Yvette, France) with interassay 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 interassay 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 a serum concentration of 43.1 ng/liter.

Total cholesterol (TC) and triglyceride (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. High-density lipoprotein (HDL-C) levels were determined after the precipitation of apolipoprotein B-containing lipoproteins with MgCl₂ and heparin (21). LDL-C was calculated according to Friedewald’s formula adjusted to SI units (22). 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 high-pressure liquid chromatography (Waters, Millipore AB, Sweden).

Statistical methods

All the descriptive statistical results are presented as the mean and SEM. Between-group differences during the 2-yr treatment period were determined using a one-way ANOVA of the percent change from baseline at all time points and with onset category as the independent variable. Between-group P values at baseline and at study end were determined using one-way ANOVA. Within-group P values were determined using a one-way ANOVA followed by Student-Newman-Keuls post hoc test. All analyses were performed according to the intention-to-treat principle (using the carry forward principle). A two-tailed P < 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Baseline characteristics (Table 1)

Both study groups consisted of 15 men and nine women (Table 1). The two groups were comparable in terms of gender, body length, body weight, BMI, waist circumference, waist/hip ratio, and number of anterior pituitary hormonal deficiencies (Table 1). There was, however, a nonsignificant tendency for the younger GHD patients to be taller and heavier and for the elderly patients to have larger waist/hip ratios. Furthermore, duration of hypopituitarism was longer in the elderly GHD group (Table 1).

GH dose and serum IGF-I (Fig. 1)

The daily dose of GH was lower in the elderly GHD patients throughout the 2-yr follow-up (Fig. 1A). Serum IGF-I level was lower in the elderly patients throughout treatment (Fig. 1B). The serum IGF-I SD score (adjustment for age and gender) tended, however, to be higher in the elderly GHD adults (P = 0.16) at baseline (Fig. 1C). There was no significant between-group difference in the percent change in absolute serum IGF-I level, whereas the change in IGF-I SD score was smaller in the elderly than in the younger GHD adults (Fig. 1).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Dose of GH (A), serum IGF-I concentration (B), and IGF-I SD score (C) in 24 elderly GHD patients above 65 yr of age and 24 younger GHD patients (mean age, 37; range, 27–46 yr). The vertical bars indicate the SE for the mean values shown. Between-group P values (0–2 yr) are based on an analysis of the percent change or change from baseline (for the dose of GH the analysis was based on the percent change from the dose prescribed at the baseline visit), whereas other P values are based on an analysis of the absolute values. C, The shaded area represents ±2 SD. a P < 0.01; b P < 0.001 [vs. young GHD adults at the same time point (baseline or study end)]. c P < 0.05; d P < 0.01; e P < 0.001 (vs. baseline).

BMI, waist/hip ratio, and blood pressure (Table 2)

There was no change during the study period in either group in body weight. Waist circumference and waist/hip ratio reduced more markedly in the elderly GHD group. Systolic and diastolic blood pressure was higher in the elderly GHD group throughout treatment. Although transient reductions in systolic and diastolic blood pressure were observed in the elderly GHD patients after 1 yr of treatment, there was no significant between-group difference.

Body composition (Table 3 and Fig. 2)

At baseline, there was no difference in absolute values of measures of body composition except for a lower BCM, as measured using the four-compartment model, in the elderly GHD patients (Table 3). If body composition values were expressed as a percentage of body weight, however, baseline fat and lean mass (including BCM) were similar in the two study groups (data not shown). After correction for age and gender using observed/predicted values ratios (four-compartment model), the elderly GHD patients had lower baseline BF (% of predicted) than the younger GHD patients (Fig. 2).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Observed/predicted (pred) values ratios for total BF (A), BCM (B), and ECW (C), as estimated using the four-compartment model, in 24 elderly GHD patients above 65 yr of age and 24 younger GHD patients (mean age, 37; range, 27–46 yr). The vertical bars indicate the SE for the mean values shown. Between-group P values (0–2 yr) are based on an analysis of the percent change from baseline, whereas other P values are based on an analysis of the absolute values. a P < 0.05 [vs. young GHD patients at the same time point (baseline or study end)]. b P < 0.05; c P < 0.01 (vs. baseline).

Bone markers, BMC, and BMD (data not shown)

There was no baseline difference in circulating markers of bone turnover (osteocalcin, calcium, and intact PTH). Within both study groups, circulating osteocalcin and calcium levels were increased by the GH replacement, whereas serum intact PTH level was unaffected within both groups. There was, however, no between-group difference in the response to treatment (data not shown).

Baseline total body or lumbar (L2–L4) spine BMC, BMD, t-score, and z-score were not statistically different between the two groups (data not shown). There were, however, nonsignificant tendencies to lower total body BMD [1.15 (0.03) vs. 1.20 (0.02) g/cm²], lumbar (L2–L4) spine BMD [1.08 (0.07) vs. 1.18 (0.03) g/cm²], and total body and lumbar (L2–L4) spine t-scores (data not shown) in the elderly than in the younger patients. Total body and lumbar (L2–L4) spine z-scores, however, tended to be higher in the elderly GHD patients and were approximately that predicted in the background population (z-score 0) in this group [mean (SEM) total body and lumbar (L2–L4) spine z-scores in the elderly GHD group were –0.02 (0.24) and 0.06 (0.26), respectively; both P = not significant vs. the young group]. At the femur neck, BMC [4.46 (0.33) vs. 5.31 (0.18) g; P < 0.05], BMD [0.84 (0.05) vs. 1.02 (0.02) g/cm²; P < 0.001], and t-score (data not shown, P < 0.001) were lower in the elderly than in the younger patients, whereas there was a weak tendency to higher femur neck z-score in the elderly than in the younger GHD group [–0.07 (0.22) vs. –0.21 (0.16); P = not significant].

There was no within- or between-group difference in the response to 2-yr GH replacement in any variable reflecting bone mass and density.

Metabolic analyses (Table 4)

At baseline, serum LDL-C concentrations were higher in the elderly GHD adults, whereas circulating levels of TC, HDL-C, TG, glucose, insulin, and HbA1c were similar in both groups. A reduction in serum LDL-C level and a tendency to a reduction in serum TC level were only found in the elderly GHD adults (P < 0.05 and P = 0.05, respectively, vs. younger GHD group). There were no within- or between-group changes in the other measured metabolic indices.

When the higher dose of GH in the younger GHD patients was accounted for using analysis of covariance, the between-group differences in responsiveness in terms of IGF-I SD score, BF%, ECW, and ECW% lost statistical significance.

The more marked reductions in the elderly GHD group in waist/hip ratio, waist circumference, and serum LDL-C level all remained also after correction for the longer duration of hypopituitarism in the elderly patients (P < 0.05, P < 0.01, and P < 0.05, respectively).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this single-center, prospective study, a low mean dose of GH normalized serum IGF-I concentration and improved body composition in elderly GHD patients without any significant deterioration in glucose homeostasis. The reductions in waist/hip ratio and serum LDL-C concentration were even more marked in the elderly GHD patients than in the younger GHD patients. Therefore, low-dose GH replacement therapy also produces beneficial effects in elderly GHD adults.

In this study, only one patient in each group started GH replacement with a fixed dose of GH based on body weight and already within the first year of treatment, the dose was gradually individualized in these two patients. In all other patients, the GH therapy was individualized from study start. Therefore, the results of this study show, in line with some previous observations (14), that individualized GH replacement results in a lower dose of GH in elderly than in younger GHD patients. Furthermore, the elderly GHD patients had lower absolute values of serum IGF-I at baseline than the younger GHD patients, whereas after correction for the age-related decline in serum IGF-I concentration using IGF SD score, there was a nonsignificant tendency to higher IGF-I SD score in the elderly patients. This confirms previous observations of a greater overlap in serum IGF-I level between GHD adults and normal individuals with increasing age (23). The change in IGF-I SD score in response to GH was less marked in the elderly GHD adults. Although IGF-I SD score was statistically similar in the two study groups after 1 and 2 yr, the IGF-I SD score values at these time points were approximately +2 SD in the young GHD patients. This, combined with the supranormalization of ECW in the younger patients, could suggest that the dose of GH was a little too high in this group.

The between-group differences at baseline were not due to differences in gender distribution, BMI, or severity of disease (as estimated by number of anterior pituitary hormonal deficiencies), because the two study groups were comparable with regard to these factors. However, although they had similar BMI, the elderly patients tended to have higher waist circumference and waist/hip ratios. Baseline total BF (observed/predicted values ratio), was, however, lower in the elderly than in the younger patients. These results demonstrate that the younger subjects had more excess BF than the elderly, whereas the elderly patients had a more marked abdominal/visceral fat distribution. This is not surprising because visceral obesity increases with aging in the normal population, and therefore, increasing age possibly increases the relative amount of abdominal/visceral obesity also in GHD adults. In the elderly GHD patients, BCM was approximately that predicted in the background population, which supports previous observations that there is no major abnormality in lean mass in elderly GHD adults (4).

As measured using the four-compartment model, the reduction of BF (observed/predicted values ratio) and the increase in ECW were less marked in the elderly GHD patients after 2-yr GH replacement. After correction for the lower dose of GH in the elderly patients using an analysis of covariance, the difference in responsiveness in total BF and ECW lost statistical significance. This suggests that GH dose-dependently decreased BF and increased ECW in GHD adults independent of age, thereby eliminating the baseline difference in BF between the two study groups. ECW, was, however, increased to supraphysiological levels in the younger patients, which is in line with a previous report of more marked fluid retention in younger GHD adults in response to GH replacement (14).

At baseline, serum LDL-C level was, as in the normal population, higher in the elderly than in the younger GHD patients. This suggests, as previously discussed for abdominal adipose tissue distribution, that serum LDL-C level increases with increasing age both in the normal population and in GHD adults. The reduction of waist circumference, waist/hip ratio, and serum LDL-C level after 2 yr was seen only in the elderly GHD patients, and these changes were significantly larger than in the younger group. These differences remained after correction for the longer duration of hypopituitarism in the elderly patients. These findings therefore suggest that the elderly GHD patients had the greatest improvement of abdominal fat mass and serum lipid pattern, which eliminated the baseline differences in these variables.

Femur neck t-score was, as expected based on their increased age, lower in the elderly GHD patients. After correction for age and gender by using z-score, there was instead a nonsignificant tendency to a higher mean value in the elderly patients. Mean z-score values at all the skeletal sites measured were approximately zero in the elderly GHD patients. This finding is in line with previous studies showing that age- and gender-corrected BMD in elderly GHD patients is not, or is only marginally, affected by the hypopituitary disease (5, 6). BMC at the femur neck was, however, lower in the elderly GHD group at baseline. The biological relevance of this finding is not clear, but the possibility cannot be excluded that a lower femur neck BMC is of importance for the mechanical strength at this skeletal site, which consists mainly of GH-sensitive cortical bone (24). The incidence of fractures is increased in GHD adults of various ages (25, 26, 27), but fracture frequency has not been studied specifically in elderly GHD patients. Prospective studies are therefore needed to explore whether fracture incidence is increased in elderly GHD patients as compared with an age-matched reference population.

There was no significant deterioration of glucose homeostasis in the study groups, and no patient developed diabetes mellitus. Insulin sensitivity could be a concern in elderly GHD adults because they may be expected to have lower insulin sensitivity at baseline. This study clearly demonstrates that individualized, low-dose GH therapy in elderly GHD adults can produce beneficial results in body composition and serum lipid profile without any significant impairment of glucose metabolism.

The effects of GH replacement on body composition and metabolism were beneficial in the elderly GHD patients, and the reductions in central fat and serum LDL-C level were larger than in the younger patients, thereby eliminating the baseline difference in these variables between the two study groups. There is a possibility that the changes seen in elderly hypopituitary patients were due to regression to the mean, and our findings may also be consistent with the tendency for most treatments [like statins (28)] to be more effective in terms of absolute response when administered to patients with more severe metabolic deviations at baseline. The changes observed in the elderly GHD patients in this study are, however, opposite of the changes seen during normal aging. Therefore, it appears that GH replacement in hypopituitary patients can at least partly reverse age-related changes in some variables.

In this study, the titration of the dose of GH was performed with the aim of normalizing IGF-I SD score. Therefore, in the elderly GHD patients, the GH replacement increased serum IGF-I concentration to that expected in normal elderly subjects. In previous short-term studies in normal elderly subjects, the dose of GH has most often been relatively high, aiming at increasing serum IGF-I concentration to that seen in normal young adults (29, 30). In the study by Blackman et al. (29), the mean dose of GH was approximately 9–10 µg/kg·d and in the study by Lange et al. (30), the final dose of GH was 7.2 µg/kg·d. Although the GH treatment affected body composition and serum lipid pattern also in the normal elderly subjects, there was a relatively high frequency of fluid-related side effects (29, 30). In the present study, the final dose in the elderly GHD patients was considerably lower (0.31 mg/d; approximately 3.8 µg/kg·d). Although the aim of the GH dose titration differed between the present study in elderly GHD patients and the previous studies in normal elderly subjects, there is a need for further studies to determine whether long-term, low-dose GH treatment can produce similarly beneficial effects in normal elderly subjects as in hypopituitary patients with few side effects.

In conclusion, this study shows that elderly patients with GHD, in similarity with the normal aging, have increased central adiposity and increased serum LDL-C level. Lean and bone mass were, however, not different from that in the normal population. The younger GHD patients had, due to the higher dose of GH in this study group, a larger change in IGF-I SD score, total BF, and ECW, whereas the improvement of waist/hip ratio and serum lipid pattern was only observed in the elderly GHD patients. These effects were achieved with a small dose of GH that did not significantly affect glucose homeostasis. GH replacement therapy should therefore be considered also in elderly GHD patients.

	Acknowledgments

 
We are indebted to Lena Wirén, Ingrid Hansson, and Sigrid Lindstrand at the Research Centre for Endocrinology and Metabolism for their skillful technical support.

	Footnotes

 
The study received support from the Sahlgrenska Academy at the University of Göteborg, and NovoNordisk Scandinavia.

Disclosure statement: The authors have nothing to disclose.

First Published Online August 29, 2006

Abbreviations: BCM, Body cell mass; BF, body fat; BMD, bone mineral density; BMI, body mass index; CV, coefficient of variation; DEXA, dual-energy x-ray absorptiometry; ECW, extracellular water; GHD, GH-deficient or GH deficiency; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LBM, lean body mass; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.

Received April 25, 2006.

Accepted August 18, 2006.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Corpas E, Harman S, Blackman M 1993 Human growth hormone and human aging. Endocr Rev 14:20–38[Abstract]
2. Lamberts S, Van ben Beld A, Van der Lely A-J 1997 The endocrinology of aging. Science 278:419–424[Abstract/Free Full Text]
3. Toogood A, O'Neill P, Shalet S 1996 Beyond the somatopause: growth hormone deficiency in adults over the age of 60 years. J Clin Endocrinol Metab 81:460–465[Abstract]
4. Toogood A, Adams J, O’Neill P, Shalet S 1996 Body composition in growth hormone deficient adults over the age of 60 years. Clin Endocrinol (Oxf) 45:399–405[CrossRef][Medline]
5. Toogood A, Adams J, O’Neill P, Shalet S 1997 Elderly patients with adult-onset growth hormone deficiency are not osteopenic. J Clin Endocrinol Metab 82:1462–1466[Abstract/Free Full Text]
6. Fernholm R, Bramnert M, Hagg E, Hilding A, Baylink D, Mohan S, Thoren M 2000 Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease. J Clin Endocrinol Metab 85:4104–4112[Abstract/Free Full Text]
7. De Boer H, Blok G-J, Van Der Veen E 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16:63–86[CrossRef][Medline]
8. Carroll P, Christ E, Bengtsson B-Å, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sönksen P, Tanaka T, Thorner M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
9. Drake W, Howell S, Monson J, Shalet S 2001 Optimizing GH therapy in adults and children. Endocr Rev 22:425–450[Abstract/Free Full Text]
10. Johannsson G, Sunnerhagen K, Svensson J 2004 Baseline characteristics and the effects of two years of growth hormone (GH) replacement therapy in adults with GH deficiency previously treated for Cushing's disease. Clin Endocrinol (Oxf) 60:550–559[CrossRef][Medline]
11. Koranyi J, Svensson J, Götherström G, Sunnerhagen K, Bengtsson B-Å, Johannsson G 2001 Baseline characteristics and the effects of five years of growth hormone (GH) replacement therapy in adults with GH deficiency of childhood or adulthood onset; a comparative, prospective study. J Clin Endocrinol Metab 86:4693–4699[Abstract/Free Full Text]
12. Monson JP, Abs R, Bengtsson B-Å, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl E, Thoren M, Westberg B, Wilton P, Wüster C 2000 Growth hormone deficiency and replacement in elderly hypopituitary adults. KIMS Study Group and the KIMS International Board. Pharmacia and Upjohn International Metabolic Database. Clin Endocrinol (Oxf) 53:281–289[CrossRef][Medline]
13. Elgzyri T, Castenfors J, Hagg E, Backman C, Thorén M, Bramnert M 2004 The effects of GH replacement therapy on cardiac morphology and function, exercise capacity and serum lipids in elderly patients with GH deficiency. Clin Endocrinol (Oxf) 61:113–122[CrossRef][Medline]
14. Feldt-Rasmussen U, Wilton P, Jonsson P 2004 Aspects of growth hormone deficiency and replacement in elderly hypopituitary adults. Growth Horm IGF Res 14 (Suppl A):S51–S58
15. Götherström G, Bengtsson B-Å, Sunnerhagen K, Johannsson G, Svensson J 2005 The effects of five-year growth hormone replacement therapy on muscle strength in elderly hypopituitary adults. Clin Endocrinol (Oxf) 62:105–113[CrossRef][Medline]
16. Johannsson G, Rosén T, Bengtsson B-Å 1997 Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clin Endocrinol (Oxf) 47:571–581[CrossRef][Medline]
17. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosén T, Lindstedt G, Lundberg P, Bengtsson B-Å 1994 Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol (Oxf) 41:351–357[Medline]
18. Mazess R, Barden H, Bisek J, Hanson J 1990 Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition. Am J Clin Nutr 51:1106–1112[Abstract/Free Full Text]
19. Bruce Å, Andersson M, Arvidsson B, Isaksson B 1980 Body composition. Prediction of normal body potassium, body water and body fat in adults on the basis of body height, body weight and age. Scand J Clin Lab Invest 40:461–473[Medline]
20. Svensson J, Johannsson G, Bengtsson B-Å 1997 Insulin-like growth factor-I in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test. Clin Endocrinol (Oxf) 46:579–586[CrossRef][Medline]
21. Wiklund O, Fager G, Craigh I, Wilhelmsson C, Vedin A, Olofsson S, Bondjers G, Wilhelmsen L 1980 -Lipoprotein cholesterol in relation to acute myocardial infarction and its risk factors. Scand J Clin Lab Invest 40:239–247[Medline]
22. Friedewald W, Levy R, Fredrickson D 1972 Estimation of low-density lipoprotein in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502[Abstract]
23. Shalet S, Toogood A, Rahim A, Brennan B 1998 The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 19:203–223[Abstract/Free Full Text]
24. Ohlsson C, Bengtsson B-Å, Isaksson O, Andreassen T, Slootweg M 1998 Growth hormone and bone. Endocr Rev 19:55–79[Abstract/Free Full Text]
25. Wüster C, Slenczka E, Ziegler R 1991 Increased prevalence of osteoporosis and arteriosclerosis in conventionally substituted anterior pituitary insufficiency: need for additional growth hormone substitution? Klinische Wochenschrift 69:769–773[CrossRef][Medline]
26. Rosén T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson B-Å 1997 Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 137:240–245[Abstract]
27. Wüster C, Abs R, Bengtsson B-Å, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl E, Monson JP, Westberg B, Wilton P 2001 The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. J Bone Miner Res 16:398–405[CrossRef][Medline]
28. Heart Protection Study Collaborative Group 2002 MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22[CrossRef][Medline]
29. Blackman M, Sorkin JD, Munzer T, Bellantoni M, Busby-Whitehead J, Stevens T, Jayme J, O’Connor K, Christmas C, Tobin J, Stewart K, Cottrell E, St Clair C, Pabst K, Harman S 2002 Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288:2282–2292[Abstract/Free Full Text]
30. Lange K, Andersen J, Beyer N, Isaksson F, Larsson B, Rasmussen M, Juul A, Bulow J, Kjaer M 2002 GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab 87:513–523[Abstract/Free Full Text]

This article has been cited by other articles:

				L.-L. Norrman, G. Johannsson, K. S. Sunnerhagen, and J. Svensson Baseline Characteristics and the Effects of Two Years of Growth Hormone (GH) Replacement Therapy in Adults with GH Deficiency Previously Treated for Acromegaly J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2531 - 2538. [Abstract] [Full Text] [PDF]

				J. L. M. Oliveira, M. H. Aguiar-Oliveira, A. D'Oliveira Jr, R. M. C. Pereira, C. R. P. Oliveira, C. T. Farias, J. A. Barreto-Filho, F. D. Anjos-Andrade, C. Marques-Santos, A. C. Nascimento-Junior, et al. Congenital Growth Hormone (GH) Deficiency and Atherosclerosis: Effects of GH Replacement in GH-Naive Adults J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4664 - 4670. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 91/11/4408    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Franco, C. Articles by Svensson, J. Search for Related Content PubMed PubMed Citation Articles by Franco, C. Articles by Svensson, J. Related Collections Metabolism Neuroendocrinology and Pituitary