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Original Studies |
Departments of Medicine (E.R.C., M.H.C., P.H.S., D.L.R.-J.) and Hematology (N.B.W., B.M.S., T.C.P.), St. Thomas’ Hospital, London, United Kingdom
Address all correspondence and requests for reprints to: Dr. E. Christ, Department of Medicine, United Medical and Dental School, 4th Floor, North Wing, St. Thomas’ Hospital, Lambeth Palace Road, London, United Kingdom SE1 7EH. E-mail e.christ{at}umds.ac.uk
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Abstract |
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We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg·day).
TBW and lean body mass significantly increased by 2.5 ± 0.53 kg (mean ± SEM; P < 0.004) and 3.4 ± 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 ± 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 ± 108 vs. 1850 ± 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 ± 43 (P < 0.006), 350 ± 117 (P < 0.03), and 515 ± 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 ± 0.116 x 1012/L (P < 0.03) with a decrease in ferritin levels by 39.1 ± 4.84 µg/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 ± 0.43 (P < 0.001) and 1.3 ± 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02).
We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.
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Introduction |
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Adult patients with GHD are generally not anemic, and treatment with GH does not influence the peripheral blood hemoglobin concentration (Hb) or packed cell volume (PCV) (11). GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis under various conditions in vitro (12, 13), in animal studies (14), and in children with short stature (15). Whether the GH-IGF axis affects erythropoiesis and, therefore, RCM in adults is unknown.
A 3-month, double blind, placebo-controlled trial of GH treatment in adult GHD was performed to determine, firstly, whether TBV contributes to the changes in ECW and, secondly, whether GH and its dependent proteins have a regulatory effect on erythropoiesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thirteen patients with adult GHD (seven women and six men)
volunteered for the study. The clinical characteristics of these
patients are summarized in Table 1
. All
had multiple pituitary deficiencies, had suffered from GHD for at least
1 yr, and were receiving stable conventional replacement therapy. GHD
was defined as a peak GH of less than 3 mU/L during an insulin
provocation test with nadir plasma glucose less than 2.2 mmol/L. None
of the patients included had a primary hematological disorder. All
patients provided informed written consent, and the study was approved
by St. Thomas’ Hospital ethics committee.
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The study was randomized, double blind, and placebo controlled. Patients were instructed in self-administration of GH using a pen device (Genotropin-pen, Pharmacia-Upjohn, Milton-Keynes, UK) and injected GH (Genotropin, Pharmacia-Upjohn; 0.018 U/kg·day for the first week, followed by 0.036 U/kg·day for the remainder of the study) or placebo sc at bedtime. The dose was reduced in the event of side-effects. Identical investigations were performed at baseline and after 3 months GH or placebo.
All subjects were admitted to the metabolic ward at 0830 h after a 12-h fast. An indwelling cannula was placed in a superficial vein of each antecubital fossa. Blood samples were taken for Hb, PCV, red blood cell count (RBC), ferritin, vitamin B12, red cell folate (RBC-folate), IGF-I, insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3), and erythropoietin (EPO). Twenty milliliters of heparinized blood were collected for blood volume assay. Serum samples were immediately analyzed or stored at -70 C until further processing.
Body composition
Body weight was measured on an electronic balance with subjects wearing light clothes and without shoes. Height was assessed by a stadiometer. Bioelectrical impedance analysis was performed in the erect position after voiding using a body fat analyzer TBF-105 (Tanita Corp., IL). TBW, FM, and lean body mass (LBM) were calculated using equations supplied by the manufacturer of the equipment that were based upon a comparison of densitometric data in a healthy population.
Blood volume assays
RCM and PV were measured by radionuclide dilution (16).
Briefly, autologous red cells from 20 mL blood were labeled with 700
kBq 51Cr (Amersham International, Aylesbury, UK) and
reinjected together with autologous plasma containing 1.85
kilobequerels/kg BW 125I-labeled human albumin (Amersham
International). Blood samples were taken 10, 20, and 30 min after
injection; appropriate standards were hemolyzed; and 5-mL aliquots were
counted for 10 min using a 
-counter (LKB Wallac, Bromma, Sweden)
with channel settings of 260–400 and 20–83 keV for 51Cr
and 125I counting, respectively. RCM was calculated using
the mean 51Cr counts of the three postinjection samples and
their corresponding microhematocrits (measured in triplicate and
corrected by 1.5% for trapped plasma). PV was determined by
extrapolating the 125I counts (corrected for cross-counting
of 51Cr) to zero time by linear regression. TBV was
calculated as the sum of RCM and PV.
RCM, PV, and TBV were compared with the age, sex, and surface area match of predicted normal values that were determined using radionuclide dilution techniques in normal volunteers (17).
Blood counts, hematinics, and biochemical measurements
Hb, PCV, and RBC were measured by an automated analyzer (STKS, Coulter Electronics, Luton, UK). Serum ferritin, serum vitamin B12, and RBC-folate were measured by enzyme immunoassay (IMX kits, Abbott Laboratories, North Chicago, IL), and serum EPO was determined by RIA [intraassay coefficient of variation (CV), 6%] (18). Serum IGF-I concentrations were measured by a double antibody RIA after an ethanol-hydrochloric acid extraction as previously described (19). The intraassay CVs were 10%, 5%, and 9% at 15, 50, and 400 nmol/L, respectively. The interassay CVs were 10%, 9%, and 8% at 13, 35, and 173 nmol/L, respectively. The cross-reactivities with IGF-II and proinsulin were 1% and 1.4%, respectively. Serum IGFBP-3 was determined by a two-site immunoradiometric assay (Diagnostics Systems Laboratories, Webster, TX). The intraassay CVs were 1.8%, 3.2%, and 3.9% at IGFBP-3 concentrations of 82.72, 27.53, and 7.35 ng/mL, respectively. The interassay CVs were assessed as 1.9%, 0.5%, and 0.6% for IGFBP-3 concentrations of 76.9, 21.5, and 8.03 ng/mL, respectively.
Data presentation and statistics
As the ages of the patients ranged from 24–72 yr, the age-dependent values (IGF-I and IGFBP-3) were transformed into SD units by the following formula: observed IGF value minus mean value of the age-matched healthy population divided by the SD of the age-matched healthy population. Results were expressed as the mean ± SEM. Unpaired t testing was used for between-group comparisons, and Student’s t test was used for within-group comparisons. Linear associations were tested using Pearson’s correlation coefficient. P < 0.05 was considered significant.
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Results |
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Subject details are shown in Table 1
. The mean age of the
GH-treated group was 47.7 ± 6.8 yr (range, 24–66), and the mean
age of the placebo-treated group was 56.8 ± 5.6 yr (range,
27–72; P = NS). The mean body mass index (kilograms
per meters squared) in the GH- and placebo-treated groups were
29.4 ± 2.7 and 31.4 ± 2.1 (P = NS),
respectively. There was not a difference in the response between men
and women in any of the measured parameters. Treatment was generally
well tolerated. Only one patient in the GH-treated group (subject 9)
complained of symptoms of fluid retention, and the dose of GH was
reduced by 50%.
Body composition
Total body weight remained stable in both groups. TBW, LBM, and FM did not change significantly in the placebo group [TBW, 42.9 ± 4.92 to 42.5 ± 4.81 kg (mean ± SEM); LBM, 58.7 ± 6.71 to 58.1 ± 6.58 kg; FM, 28.0 ± 4.88 to 29 ± 4.5 kg]. All seven patients with GH treatment exhibited an increase in TBW and LBM [TBW, 37 ± 3.26 to 39.5 ± 3.61 kg (mean ± SEM; P < 0.004); LBM, 50.7 ± 4.38 to 54.1 ± 4.84 kg (P < 0.001)]. FM decreased in all treated patients (30.1 ± 6.3 to 27.7 ± 6.13 kg; P < 0.004).
RCM, PV, and TBV
The mean RCM of all patients with GHD was significantly decreased
compared with the predicted normal values (1635 ± 108
vs. 1850 ± 104 mL; P < 0.002). PV and
TBV were not statistically different from predicted normal values;
however, there was a tendency to a reduced TBV in patients with GHD
(4545 ± 224 vs. 4708 ± 225 mL; P
< 0.08). There was no significant change in RCM, PV, and TBV after 3
month of treatment with placebo (Fig. 1).
GH-treated patients showed significant increases in RCM, PV, and TBV
[Fig. 1; RCM, 1542 ± 119 to 1725 ± 118 mL
(P < 0.006); PV, 2805 ± 190 to 3155 ± 235
mL (P < 0.03); TBV, 4365 ± 273 to 4880 ±
343 mL (P < 0.004)]. After 3 months of treatment with
GH, all variables (RCM, PV, and TBV) were not significantly different
from predicted normal values.
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)RBC, Hb, and PCV in all patients were within the normal range at baseline and did not change significantly in the placebo group after 3 months. However, GH treatment significantly increased RBC at 3 months. Hb and PCV increased with treatment, but these differences did not reach statistical significance.
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) Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and RBC-folate were statistically different in the GH- and placebo-treated groups at baseline. There were no obvious underlying conditions that may result in these findings, and it is likely that the differences are a feature of the randomization. However, throughout the study all patients had values within the normal range. These values did not change significantly in the placebo group after 3 months. In contrast, there were statistically significant decreases in MCV, MCH, and mean corpuscular hemoglobin concentration (MCHC) together with a marked decrease in ferritin levels in the GH-treated group, whereas vitamin B12 and RBC-folate did not change.
IGF-I, IGFBP-3, and EPO (Table 2)
IGF-I and IGFBP-3 concentrations did not change in the placebo group. However, GH treatment significantly increased IGF-I and IGFBP-3 concentrations, whereas EPO levels were not affected in either group.
Correlations
Within the GH-treated group, changes in TBV positively correlated with changes in TBW and LBM (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively) and negatively with changes in FM (r = 0.95; P < 0.02). In the GH-treated group, changes in RCM were not significantly related to changes in IGF-I, IGFBP-3, or EPO.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A decreased RCM compared to the predicted normal values at baseline and an increase in RCM after GH treatment demonstrate the importance of the GH-IGF-I axis in the regulation of erythropoiesis in adults with GHD. These findings are consistent with the results of in vitro studies using human erythroid progenitors (13, 20) and rat models (14) that have shown GH and IGF-I to be erythropoietic. In children with short stature treated with GH, a close correlation between hemoglobin concentrations and body height, IGF-I, and IGFBP-3 has been previously reported (15). This suggests that the GH-IGF-I axis plays an important role in the production of erythrocytes throughout life and may contribute to the observed gradual increase in RCM during childhood. In normal adults, a steady state is reached, and RCM is constant, as the rates of production and degradation of erythrocytes are equal. The role of the GH-IGF-I axis is, therefore, less obvious. RCM is a determinant of oxygen transport capacity and influences exercise performance. Adult patients with GHD have a lower exercise capacity than age-, sex-, and height-matched controls, but this improves with GH treatment (11). This improvement has been attributed to the increase in muscle mass (11) and to the increased myocardial contractility leading to improved cardiac performance (21, 22). In these studies, oxygen transport capacity was assessed by Hb and PCV, which did not change significantly and were not thought to contribute to the increased exercise performance. However, Hb and PCV are influenced by the actual blood volume and depend, therefore, on RCM and PV. In the present study, GH simultaneously increased RCM and PV in the treated patients, leading to a net increase in oxygen transport capacity not reflected by changes in Hb and PCV. This may have contributed to the improved exercise performance and may also help to explain why GH is frequently abused by top athletes and body builders (23).
GH treatment significantly raised RBC and significantly decreased all red cell indexes (MCV, MCH, and MCH concentration) and serum ferritin concentrations. This is in keeping with a GH-induced increase in the erythrocyte production rate, leading to an increased demand for iron. These findings are similar to the observations in children with short stature, in whom serum ferritin decreased after treatment with GH (24). Anttila et al. (25) reported that in normal early male puberty, serum ferritin levels fell at a time when GH secretion was increased. Thus, the markers of iron consumption during GH replacement in this study probably reflect a physiological role of GH in reactivating erythropoiesis in adults with GHD.
The role of EPO as a regulator of erythropoiesis is well documented (26). In anemic patients, EPO secretion is stimulated by hypoxemia and is, therefore, negatively correlated to hemoglobin concentrations (26, 27). No such correlation has been reported in subjects with normal Hb levels (28). In keeping with previous studies (15, 28), the patients in the present study were not anemic, and a correlation between EPO and Hb could not be established. However, Vihervuori et al. (15) demonstrated that Hb concentrations fell during the first week of GH treatment and was accompanied by an increase in EPO in GH-treated children. They suggested that initial hemodilution due to the fluid-retaining effect of GH may have lead to a relative reduction of Hb that consequently stimulated EPO secretion.
Although there are GH receptors in the bone marrow, in vitro experiments using human erythroid progenitors (13, 20) and studies with rats (14) have shown that the effects of GH on erythropoiesis are probably mediated by IGF-I. IGF-I plays a key role in proliferation (29) and maturation (30) of erythroid progenitors. Unlike the findings of Vihervuori et al. in children (15), the changes in RCM in the GH-treated patients in the present study did not significantly correlate with changes in IGF-I or IGFBP-3. This finding may reflect the small sample size in the current study rather than the lack of a relationship between IGF-I and erythropoiesis.
The observation that GH increases PV is in contrast to the findings of previous studies in patients with GHD (8) and healthy adults (7). Using radionuclide dilution methods, both research groups found an increase in ECW, but failed to detect a rise in PV after 1 or 2 weeks of treatment, respectively. They concluded that the fluid-retaining effects of short term treatment with GH were primarily due to increased water in the interstitial space. Our results, however, have recently been confirmed by Moller et al. (31), who reported an increase in PV after a GH exposure of at least 3 weeks in adult GHD. A possible mechanism for increased PV is an enhanced synthesis of extracellular proteins that require hydration (1), which takes longer to occur. This is supported by the observations of Rosen et al. (32), who reported a larger increase in total body nitrogen (TBN) than in total body potassium in adults with GHD given GH. As TBN reflects total extra- and intracellular proteins, and total body potassium represents intracellular lean body cell mass the more pronounced increase in TBN may well have been due to an increase in extracellular proteins (32).
Whether the renin-angiotensin system (RAS) or atrial natriuretic peptide is involved in the fluid-retaining effect of GH remains controversial (1). Hoffman et al. (8) found in a short term study in adult GHD that a physiological dose of GH increased the early components of the RAS (angiotensinogen and PRA), but failed to detect an increase in aldosterone levels or a decrease in atrial natriuretic peptide. Cuneo at al. (22) had similar results in a long term trial in adult GHD. Changes in PV observed in our trial could be related to the RAS system; a direct effect of GH on the regulation of PV, however, cannot be excluded.
Taking account of all the evidence, we hypothesize that GH induces an early increase in ECW largely within the interstitial space followed by a shift of the interstitial water into the intravascular compartment after 2–3 months of treatment due to increased circulating protein. This hypothesis would support the clinical observation that early signs of fluid retention resolves spontaneously after approximately 2–3 months of treatment without dose adjustment (2).
Body composition was assessed by bioelectrical impedance analysis. The directly measured bioimpedance is inversely related to TBW and has been shown to yield results similar to those obtained with the isotope dilution method (33). Assuming a constant ratio of 2:1 between intracellular water and ECW (34), the mean increase in TBV in the present study accounts for approximately 20% of the increase in TBW and for about 60% of the increase in ECW.
TBV depends on TBW as well as on body composition (35). In this respect the significant correlations between changes in TBV and changes in TBW, LBM, and FM found here were to be expected.
In conclusion, the present study has shown that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.
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Acknowledgments |
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Footnotes |
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Received February 21, 1997.
Revised May 20, 1997.
Accepted May 30, 1997.
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References |
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