| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Endocrinology (Y.J., N.H., F.R.) and Clinical Chemistry (M.F.), Leiden University Medical Center, The Netherlands
Address all correspondence and requests for reprints to: F. Roelfsema, Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 AA Leiden, The Netherlands. E-mail: Roelfsema{at}rullf2.medfac.leidenuniv.nl
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our data suggest that a low physiological dose of rhGH, individually adjusted to maintain serum insulin-like growth factor I levels within the normal laboratory reference range, increased bone turnover in favor of bone formation, as suggested by the significant, albeit small increase in BMD observed after 2 yr of treatment. Further studies are required to establish whether in patients with adult-onset GHD the preservation and/or increase in bone mass observed with the use of physiological doses of rhGH could be maintained with longer-term treatment.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In earlier studies, doses of rhGH used were based on doses used in children. The high incidence of side effects (mainly related to fluid retention) and supranormal serum IGF-I levels, suggest that the dose used in adult patients with GHD may have been too large. Reduced doses were used in subsequent studies, resulting in a lesser increase in serum levels of IGF-I (although supranormal levels were still reported), and a decrease in the incidence of side-effects. Data recently published by our group on the effect of a low physiological dose of rhGH, based on secretion data in healthy normal subjects, indicated that a dose of 0.6 IU/day was able to increase the low serum IGF-I levels, while a dose of 1.2 IU/day resulted in a normalization of these levels (15). The aim of this study was to investigate the long-term effects of a low (physiological) dose of rhGH on biochemical parameters of bone turnover and on BMD in patients with adult-onset GHD treated for 2 yr as part of a study examining the optimal GH dose required for replacement therapy.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Sixty patients with GHD, as evidenced by a peak serum GH response of less than 7 mU/L during insulin-induced hypoglycemia (IIH), were studied. There were 30 males and 30 females and all were Caucasian. None of the patients had a body mass index (BMI) >32 kg/m2. Thirteen of the patients were excluded from the study on the basis of confounding factors such as childhood-onset GHD, potentially associated with a low peak bone mass (n = 9); temporary immobilization as a result of disc prolapse (n = 2); untreated gonadal deficiency, which may result in an increase in bone turnover (n = 1); and one patient who was still growing and had not reached his definitive height yet.
Forty-seven patients fulfilled the entry criteria for the study. These included 27 women (mean age 47 yr, range 26–68 yr) and 20 men (mean age 49 yr, range 33–70 yr). The estimated age of onset of GHD was 37 yr (range 20–64 yr), with an estimated duration of GHD state of 10.8 yr (median 6 yr; range 1–37 yr). Only two (male) patients had isolated GHD, whereas all others had additional pituitary hormone deficiencies: LH/FSH deficiency (n = 3), LH/FSH and TSH deficiency (n = 3), LH/FSH and ACTH deficiency (n = 3), total anterior pituitary gland failure (n = 26), and total pituitary gland failure (anterior and posterior) (n = 10). All women were LH/FSH deficient and 19 received estrogen replacement therapy, except for 8 of the older women who did not (mean age 61.3, range 50–68 yr). All other patients received conventional substitution therapy as indicated. Substitution therapy was monitored during rhGH therapy and doses adjusted as required.
The etiology of GHD was a pituitary adenoma in 33 patients: nonfunctioning adenoma (n = 16), ACTH producing adenoma (n = 9), prolactinoma (n = 7), and GH producing adenoma (n = 1). In the other 14 patients, the etiology was trauma (n = 3), Sheehan’s syndrome (n = 3), or a tumor in the pituitary region (n = 8).
Informed consent was obtained from all subjects, and the study was approved by the ethics committee of the Leiden University Medical Center.
Study design
Before the start of rhGH therapy, fasting blood samples were drawn for the measurement of serum calcium, albumin, alkaline phosphatase activity, osteocalcin, and IGF-I. A 24-h urine sample, collected on a hydroxyproline-free diet, was measured for creatinine, calcium, hydroxyproline, and N-telopeptide excretion. Urinary results are expressed as the ratio of the various parameters to creatinine. BMD of the lumbar spine was measured in all patients at the start of the study.
After initial assessment, all patients were treated with daily sc
injections of rhGH (Genotropin, Pharmacia & Upjohn AB, Peptide
Hormones, Uppsula, Sweden) given in the evening. To evaluate the effect
of GH dose on biochemical bone parameters, patients were randomized to
three groups to receive one of three dose regimens: 0.6 IU/day (
0.2
mg/day) for 24 weeks (group 1); 0.6 IU/day for 4 weeks followed by 1.2
IU/day (0.4 mg/day) for 20 weeks (group 2); and 0.6 IU/day for 4
weeks, followed by 1.2 IU/day for a further 4 weeks and 1.8 IU/day
(0.6 mg/day) for the rest of the study (group 3). Between 24 and 52
weeks of treatment, the dose of rhGH was individually adjusted, using a
dose range of 0.6–1.8 IU/day, to maintain the concentration of serum
IGF-I within the normal (age-dependent) laboratory reference range.
After 52 weeks of treatment, doses greater than 1.8 IU/day were allowed
when serum IGF-I was still below the normal range. The occurrence of
side effects was also taken in consideration in tailoring the dose.
Biochemical evaluation was repeated at 24 and 52 weeks and after 2 yr of rhGH treatment. Measurement of BMD was repeated at 52 weeks and 2 yr from the start of treatment with rhGH.
BMD
BMD of the lumbar spine (L1-L4) was measured using dual-photon X-ray absorptiometry (DXA; Hologic QDR 1000, Waltham, MA). Results are expressed as absolute values (BMD) or Z-scores (SD above or below that of age- and sex-matched controls). Traditional T-scores (SD above or below that of healthy young adults) are used to define osteopenia (T-scores between -2.5 and -1) and osteoporosis (T-scores < -2.5) (16).
Assays
Total serum IGF-I concentration was determined by RIA (Incstar, Stillwater, MN) after extraction and purification on octadecasilyl-silica columns. The interassay coefficient of variation was less than 11%. IGF-I was expressed as a SD score from age-related normal levels (SD score), as determined in the same laboratory. GH was measured with a time-resolved immunofluorescent assay (Wallac, Turku, Finland), specific for the 22-kDa GH protein. Serum calcium, albumin, phosphate, alkaline phosphatase activity, and urinary calcium and creatinine were measured by automated techniques. Serum calcium concentrations were adjusted to an albumin concentration of 42 g/L. Serum osteocalcin was measured by a commercial RIA (Incstar). The detection limit was 0.2 ng/mL. Hydroxyproline was measured by the method of Prockop and Udenfriend (17). An enzyme-linked immunosorbent assay was used for the measurement of cross-linked N-telopeptide of type I collagen (Ntx) in urine (Osteomark: Ostex International, Seattle, WA).
Statistical analysis
Statistical analysis was performed using SPSS for Windows (Chicago, Illinois, Release 7.0). Results are expressed as mean ± SEM, unless otherwise specified. Z-scores and IGF-I SD scores were tested vs. zero at baseline using a two-tailed t test. Differences between males and estrogen-replete and estrogen-deplete women were tested with ANOVA. Post hoc analysis was performed with Bonferroni. A two-tailed paired t test was used to test for significant differences between different time points. Pearson’s correlation coefficient was used to calculate correlations. Partial correlations, corrected for baseline values, were used to determine GH dose dependency. Differences were considered significant when P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patients’ characteristics. Baseline characteristics of
patients at entry in the study, subdivided into men and
estrogen-replete and estrogen-deplete women, are shown in Table 1
.
|
. IGF-I SD scores were lower
in estrogen-replete women than in estrogen-deplete women or men
(P = 0.017 and P < 0.0005,
respectively). Biochemical parameters of bone turnover generally fell
within the low-normal range, being relatively highest in
estrogen-deplete women and lowest in estrogen-replete women.
|
.
Mean Z-score in patients with adult-onset GHD was -0.20 ± 0.16,
which was not significantly different from zero (P =
0.217). There was no significant difference in Z-scores between men and
estrogen-replete or -deplete women (P = 0.599).
Five patients had osteoporosis of the lumbar spine, 14 patients were
osteopenic, and the remaining 27 patients had normal T-scores.
|
Effects of rhGH treatment
Seven patients stopped treatment within 2 yr of starting the study. One subject stopped at 24 weeks of treatment, because she expressed the wish to become pregnant. Three patients chose to discontinue treatment, because they experienced no clinical improvement after 52 weeks. Three other patients were lost to follow-up after 52 weeks of treatment.
GH dose and serum IGF-I. After 24 weeks of treatment, all
patients randomized to groups 1 and 2 were receiving rhGH at a dose of
0.6 IU and 1.2 IU/day, respectively. Two patients in group 3 were
receiving only 0.9 and 1.2 IU/day rather than 1.8 IU/day, because they
experienced side effects related to fluid retention on the planned
highest doses. Mean rhGH dose after 52 weeks and 2 yr of treatment were
1.4 ± 0.1 and 1.6 ± 0.1 IU/day, respectively. Mean IGF-I
SD score increased significantly during treatment compared
with baseline (Fig. 2; P
values < 0.0005 at all time points). After 2 yr of treatment,
IGF-I SD scores were still significantly lower in
estrogen-replete than -deplete women (P = 0.042) or men
(P = 0.011), although the mean GH dose was
significantly higher in estrogen-replete women compared with
estrogen-deplete women and men (P = 0.027 and
P = 0.004, respectively).
|
). The increases in serum osteocalcin concentration and urinary
hydroxyproline/creatinine ratio, corrected for baseline values, were
rhGH dose-dependent (P < 0.0005 for both parameters).
A further increase in mean serum osteocalcin and alkaline phosphatase
activity was observed between 24 and 52 weeks of treatment
(P = 0.021 and P = 0.006,
respectively). Urinary hydroxyproline/creatinine and urinary
N-telopeptide/creatinine excretion did not change between 24 and 52
weeks of treatment. Mean serum osteocalcin levels and urinary
N-telopeptide concentrations remained stable between 52 weeks and 2 yr
of treatment. At 2 yr of treatment, there was a small but significant
decrease in serum alkaline phosphatase activity and urinary
hydroxyproline excretion (P = 0.003 and
P = 0.018, respectively), although both parameters
remained significantly increased compared to baseline. After 2 yr of treatment, levels of bone formation remained significantly lower in estrogen-replete than in estrogen-deplete women (P = 0.011, P = 0.003 for serum alkaline phosphatase activity and serum osteocalcin, respectively) or men (P = 0.001 for both parameters). Urinary N-telopeptide/creatinine levels also remained significantly higher in estrogen-deplete than in estrogen-replete women (P = 0.042), but were not significantly different from levels in men. Urinary hydroxyproline/creatinine excretion was not significantly different between the three groups.
Serum calcium concentration was significantly increased after 24 and 52 weeks of treatment (mean 2.29 ± 0.02 mmol/L and 2.31 ± 0.01, respectively), but returned to baseline values after 2 yr of rhGH treatment. Serum phosphate levels increased during treatment (1.21 ± 0.03, 1.18 ± 0.03, and 1.13 mmol/L after 24, 52 weeks, and 2 yr, respectively; P values at all time points compared with baseline <0.001). The urinary calcium/creatinine excretion significantly increased after 24 weeks of treatment compared with baseline values (0.34 ± 0.03 to 0.41 ± 0.03 mmol/mmol; P = 0.002) but demonstrated no significant change thereafter.
BMD. A significant increase in Z-scores was documented after
52 weeks of treatment (P < 0.05) with a further
increase after 2 yr of treatment (P < 0.005). Absolute
values of BMD were significantly increased after 2 yr of treatment
compared with baseline (P = 0.009) with a mean increase
of 0.020 ± 0.005 g/cm2, which represents a percentage
increase of 2.07 ± 0.54% (P = 0.001; Fig. 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Bone histomorphometric data are not available in patients with adult-onset GHD. Our findings, and those of others, show, however, that GH treatment significantly increases bone turnover, as judged by changes in biochemical parameters of bone resorption and formation (11, 12, 13, 20). BMD of the lumbar spine was normal at baseline and increased statistically significantly, albeit probably not clinically significantly (2%) during treatment, suggesting a relatively greater increase in bone formation than bone resorption. Concern that the increase in bone turnover may have adverse effects on the skeleton was thus not justified.
Despite an increment in the mean dose of rhGH, serum IGF-I levels were lower at 2 yr of treatment compared with those after 52 weeks of treatment, but were still greater than baseline values. There are at least two possible explanations for this observation. First, most of the patients changed injecting device between 52 weeks and 2 yr of treatment, with a switch to a (Genotropin) pen with a 16 IU/mL vial instead of a syringe with a 4 IU/mL vial (Kabi Mixer). Changing to a more concentrated solution may decrease the availability of rhGH and thus result in a decrease in serum IGF-I (21). In addition, changing from syringe to pen may also decrease GH availability as reported by Jørgensen et al. (22), although not confirmed by Blok et al. (21), when both injection volumes and needle length were controlled. A second possibility, although as yet speculative, is that patients became less sensitive to circulating GH concentrations. Actually, one report even mentions an increase in sensitivity to rhGH during treatment (23). It was of note that BMD continued to rise between 52 weeks and 2 yr of treatment despite the observed decrease in serum IGF-I levels, suggesting that these lower levels still had positive skeletal effects.
BMD at the femoral neck, which contains, in contrast to the lumbar spine, relatively more cortical than trabecular bone, was unfortunately not measured in this study. Data on femoral and lumbar BMD were available in 19 of the 47 patients 1–3 yr before the start of the study. No significant difference could be found between T-scores at the lumbar spine and femoral neck sites (data not shown). This confirms previously published data (11, 13), which also showed that there was no significant difference in basal measurements or in response to GH treatment between the two sites (11, 12, 13).
It is notable that almost all our patients with adult-onset GHD had multiple pituitary deficiencies, for which conventional substitution was given. A number of patients had a history of hormone excess syndromes such as ACTH excess or hyperprolactinemia. Both hypo- and hyperfunction of the pituitary can influence bone mass and metabolism adding further complexity to the evaluation of these parameters in the deficient patients (24, 25, 26, 27). In our study, all hormonal deficiencies were substituted except for estrogen in eight older women (age range 50–68 yr). Excessive bone loss caused by estrogen deficiency is the most important risk factor for osteoporosis in postmenopausal women (28). As expected in the postmenopausal state in patients with no pituitary pathology (29) and in agreement with the results of Holloway et al. (30), the eight older women with GHD and estrogen deficiency had a significantly greater bone turnover than their counterparts who were estrogen replete, both at baseline and during rhGH therapy. Although we did not have a GH-untreated control group, a significant increase in BMD after 2 yr of rhGH treatment was also found in patients with stable sex hormone status and with no cortisol excess for the 5 yr preceding the study.
In conclusion, our data demonstrate that bone and mineral metabolism appear to be largely undisturbed, and that BMD at the lumbar spine is not reduced in patients with adult-onset GHD. A physiological replacement dose of rhGH, individually adjusted to maintain serum IGF-I levels within the normal laboratory reference range, increases bone turnover, as measured by biochemical parameters of bone resorption and formation, in favor of bone formation as suggested by the overall positive influence on bone mass. Longer-term studies are required to establish whether these beneficial skeletal effects to preserve and/or increase bone mass would be further maintained beyond 2 yr of treatment in patients with adult-onset GHD.
|
Footnotes |
|---|
Received October 29, 1997.
Revised December 19, 1997.
Revised February 11, 1998.
Accepted February 18, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. Giustina, G. Mazziotti, and E. Canalis Growth Hormone, Insulin-Like Growth Factors, and the Skeleton Endocr. Rev., August 1, 2008; 29(5): 535 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. van der Klaauw, T. van der Straaten, R. Baak-Pablo, N. R. Biermasz, H.-J. Guchelaar, A. M. Pereira, J. W. A. Smit, and J. A. Romijn Influence of the d3-Growth Hormone (GH) Receptor Isoform on Short-Term and Long-Term Treatment Response to GH Replacement in GH-Deficient Adults J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2828 - 2834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Murray, J. E. Adams, and S. M. Shalet A Densitometric and Morphometric Analysis of the Skeleton in Adults with Varying Degrees of Growth Hormone Deficiency J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 432 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mauras, O. H. Pescovitz, V. Allada, M. Messig, M. P. Wajnrajch, B. Lippe, and on behalf of the Transition Study Group Limited Efficacy of Growth Hormone (GH) during Transition of GH-Deficient Patients from Adolescence to Adulthood: A Phase III Multicenter, Double-Blind, Randomized Two-Year Trial J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3946 - 3955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. D. Murray, B. Columb, J. E. Adams, and S. M. Shalet Low Bone Mass Is an Infrequent Feature of the Adult Growth Hormone Deficiency Syndrome in Middle-Age Adults and the Elderly J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1124 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gillberg, H. Mallmin, M. Petren-Mallmin, S. Ljunghall, and A. G. Nilsson Two Years of Treatment with Recombinant Human Growth Hormone Increases Bone Mineral Density in Men with Idiopathic Osteoporosis J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4900 - 4906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yuen, K. Ong, S. Husbands, P. Chatelain, L. Fryklund, P. Gluckman, M. Ranke, D. Cook, R. Rosenfeld, J. Wass, et al. The Effects of Short-Term Administration of Two Low Doses Versus the Standard GH Replacement Dose on Insulin Sensitivity and Fasting Glucose Levels in Young Healthy Adults J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1989 - 1995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Mericq, H. Gajardo, M. Eggers, A. Avila, and F. Cassorla Effects of Treatment with GH Alone or in Combination with LHRH Analog on Bone Mineral Density in Pubertal GH-Deficient Patients J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 84 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Biermasz, N. A. T. Hamdy, Y. J. H. Janssen, and F. Roelfsema Additional Beneficial Effects of Alendronate in Growth Hormone (GH)-Deficient Adults with Osteoporosis Receiving Long-Term Recombinant Human GH Replacement Therapy: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3079 - 3085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Rosen and J. P. Bilezikian Anabolic Therapy for Osteoporosis J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 957 - 964. [Abstract] [Full Text]
|
|
|
|
|
|
S. Longobardi, N. Keay, C. Ehrnborg, A. Cittadini, T. Rosén, R. Dall, M. A. Boroujerdi, E. E. Bassett, M. L. Healy, C. Pentecost, et al. Growth Hormone (GH) Effects on Bone and Collagen Turnover in Healthy Adults and Its Potential as a Marker of GH Abuse in Sports: A Double Blind, Placebo-Controlled Study J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1505 - 1512. [Abstract] [Full Text]
|
|
|
|
|
|
B. M. K. Biller, G. Sesmilo, H. B. A. Baum, D. Hayden, D. Schoenfeld, and A. Klibanski Withdrawal of Long-Term Physiological Growth Hormone (GH) Administration: Differential Effects on Bone Density and Body Composition in Men with Adult-Onset GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 970 - 976. [Abstract] [Full Text]
|
|
|
|
|
|
Y. J. H. Janssen, F. Helmerhorst, M. Frölich, and F. Roelfsema A Switch from Oral (2 mg/Day) to Transdermal (50 {micro}g/Day) 17{beta}-Estradiol Therapy Increases Serum Insulin-Like Growth Factor-I Levels in Recombinant Human Growth Hormone (GH)-Substituted Women with GH Deficiency J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 464 - 467. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
), all
others (•) had additional pituitary deficiencies and received
conventional substitution therapy when indicated. All female patients
had additional pituitary deficiencies and received conventional
substitution therapy (•), except for eight older women (
) who did
not receive estrogen replacement therapy.
