| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Service d’Endocrinologie, Hopital de l’Antiquaille (F.B.-C., A.Se., S.B, F.L., Y.R., F.B), 69005 Lyon; Service de Médecine Interne (X.D.) et de Médecine du Sport (J.P.) Hopital Lyon-Sud, 69495 Pierre-Bénite; et Service de Médecine Nucléaire (Y.K., G.S.) et Laboratoire de biochimie des lipides (A.Sa.), Hopital Neurologique; 69003 Lyon, France
Address all correspondence and requests for reprints to: Dr F. Borson-Chazot, Service d’Endocrinologie, Hopital de l’Antiquaille, 69005 Lyon, France.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Twenty-two patients, included in a multicentric therapeutic
study, were asked to participate in an ancillary study. Their
characteristics are detailed in Table 1
.
GHD was defined by a GH peak below 3 µg/L during an insulin induced
hypoglycemia (glycemia < 2.2 mmol/L). The diagnosis was
confirmed, in each case, by a second GH stimulation test
(glucagon-propranolol or GHRH). The two GH tests had been performed
within the 5 yr preceding inclusion and controlled after the age of 20
yr in patients with childhood onset GHD. In most patients, the GH peak
was below 1 µg/L; and in 17 patients, insulin-like growth
factor 1 concentration was below the normal range for age (Table 1). All patients were on stable replacement therapy for at least 1 yr.
The only patient with blood hypertension was well controlled with ß
blockers. None of the patients had a history of diabetes or acromegaly
or had undergone previous treatment with GH.
|
The study was approved by the Ethical Committee of Lyon (France)
and was performed in accordance with the Helsinki guidelines. The goal
of the trial was explained to the patients, and their written consent
was obtained. The subjects were treated with GH (Genotonorm). The study
was designed as an open randomized study. After randomization, patients
were assigned to 0.5, 1, or 1.5 UI daily, self administered sc.
Compliance was checked by vial count and injection diary. Therapy was
adapted on an individual basis, to maintain insulin-like growth factor
(IGF)-1 concentration in the 95 percentile of the normal range using an
age-adjusted reference (Table 2 legend
and Ref. 13). Whatever the level of IGF-1, the dose of GH was reduced
by 0.5 UI/day in response to side effects, such as edema or arthralgia,
until disappearance of the symptoms. For patients included in this
study, the mean GH dose was 1 (range, 0.3–2.2) UI/day.
|
Body composition
Body composition was determined using a bioelectric impedancemeter (BIA 101, Eugedia, France). Results were expressed as percent fat mass.
Markers of cardiovascular risk
Blood pressure (systolic and diastolic) was measured, after 5-min supine rest, using the sphygmomanometric method. This measurement was repeated after 1 min, and the mean value was used.
Blood samples were drawn, in the morning, after an overnight fast. Plasma total cholesterol and triglycerides were measured by the enzymatic method [Roche Diagnostics, Basel, Switzerland; interassay coefficient of variation (CV): 1.8%]. High-density lipoprotein cholesterol was assessed after precipitation of apo B containing lipoproteins by phosphotungstic acid, and LDL was calculated according to the Friedwald formula. Lipoprotein a [Lp(a)] was measured by enzyme-linked immunosorbent assay [Biopool TintElize Lp(a), CV: 5.4%], plasma glucose by the enzymatic method (Biomerieux, CV: 1.6%), and insulin concentrations by immunoradiometry (Biosource, Fleurus, Belgium, CV: 3.2%).
Cardiovascular risk was estimated according to the multivariate equation of Framingham (14). This computed index takes into account sex, age, familial history of cardiovascular disease, smoking, diabetes, left ventricular hypertrophy, systolic blood pressure, and total cholesterol concentration. It is expressed as the probability of coronary events at 8 yr.
VO2 max
VO2 max was measured during continuous exercise on a cycloergometer. Sensitivity of the procedure was 0.01 L/min (15). Results are expressed in mL/min·kg.
IMT
Measurements of carotid IMT were performed at baseline and repeated after 1 yr (n = 22) and 2 yr (n = 11) of GH treatment using high-resolution mode B ultrasound (Hitachi EUB 415F) with an electrical linear transducer (midfrequency, 7.5 MHz). Each measure was the mean of 16 determinations performed in plaque-free areas on the last centimeter of both primitive carotid arteries, as previously described (16). All the measurements were performed by the same experienced physician (17). The intraindividual variation coefficient of lecture of this physician was tested in 2 control groups. In the first one, including 12 healthy subjects (mean age, 26 ± 5 yr), IMT (measured twice at 28 ± 6.2-day intervals) was 0.54 ± 0.07 mm, with a CV of 6.55 ± 1.8%. In the second group, comprising 10 diabetic patients (mean age, 62 ± 2 yr) with elevated IMT (0.89 ± 0.04 mm), the CV was 5.2 ± 0.7% for 2 IMT determinations performed at 3.6 ± 0.6-day intervals.In addition, a retrospective double reading of the GHD patients’ films was performed independently by 2 physicians, blinded to the subjects’ identity and the sequence of the films. The results were concordant, and the CV between these 2 readings was 7.8%.
Statistical analysis
The results are given as the mean ± SEM.
Intraindividual differences between basal values and values obtained at
various time points were calculated and tested using the nonparametric
Wilcoxon’s signed-rank test or 
-square test, as appropriate. The
nonparametric Spearman’s test was used for correlations. When multiple
comparisons were needed, the nonparametric Friedman’s test was used
for between-group comparisons. P < 0.05 was considered
significant.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
At baseline, mean IMT was measured at 0.78 ± 0.03 mm (0.59–1.09 mm) and was found to be greater in men than in women (P < 0.01). Baseline IMT was significantly related to age (P < 0.001), blood pressure (P < 0.02), body weight (P < 0.004), waist-to-hip ratio (P < 0.01), and score of cardiovascular risk (P < 0.001). No significant relation was detected with the known duration of hypopituitarism or with IGF-1 concentration.
Effect of GH replacement on IGF-1, body composition, VO2 max, and the parameters of the cardiovascular risk
After 1 yr of GH treatment, IGF-1 concentration and
VO2 max increased significantly. There was no change in
body weight but a significant decrease in waist circumference, as well
as in absolute and percent fat mass (Table 2
). Parameters of
cardiovascular risk were unaffected by treatment (Table 3), except for a moderate and transient
reduction in total and LDL cholesterol at 6 months, with a concomitant
decrease in the score of cardiovascular risk.
|
Effect of 1- and 2-yr GH replacement on IMT
After 1 yr of GH replacement, IMT decreased significantly, from
0.78 ± 0.03 mm to 0.70 ± 0.03 mm (P <
0.001). The mean change was 0.08 ± 0.01 mm. Individual data are
shown in Fig. 1. A decrement in IMT
was observed in 21 of the 22 patients. The changes in IMT were weakly
related to the changes in LDL cholesterol at 6 months (r = 0.42,
P < 0.05); there was no relation between decrease of
IMT and baseline IGF-1, age, body mass index, or duration of
hypopituitarism or between changes in IMT and changes in IGF-1,
VO2 max, fat mass, and waist circumference. No dose effect
of GH could be evidenced, perhaps because of the limited number of
patients and narrow range of doses. Changes in IMT were not different
in childhood and adulthood onset GHD. The only patient for whom IMT
increased slightly (from 0.59 mm to 0.62 mm) was a 27-yr-old woman with
a multiple pituitary deficit since 10 yr of age and a low score of
cardiovascular risk (<0.1% at 8 yr).
|
, minimal decrements in
IMT were observed between 1 and 2 yr in most patients; but in a
46-yr-old woman with multiple pituitary deficit secondary to Sheehan’s
syndrome, IMT, after an initial decrement from 0.81 mm to 0.62 mm
during the first year of treatment, increased again to 0.77 mm during
the course of the second year. In this particular patient, IGF-1
increased from 52 to 125 µg/L at 1 yr and returned to 67 µg/L at 2
yr, suggesting inadequate GH replacement during the second year of
treatment. |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Ultrasound measurement of IMT was carefully monitored, and our results at baseline were in agreement with previous reports. Basal IMT was strongly related to conventional risk factors, such as age, sex, blood pressure, and the score of cardiovascular risk, as commonly described in large epidemiological studies (4, 5, 6). Moreover, baseline IMT was 0.78 mm, close to that previously reported by Markussis et al. (7) in a comparable group of hypopituitary adult patients.
The main result of the present study is the 0.08-mm decrease in IMT after 1-yr GH replacement. This represents an 11% decrement from basal values and is highly significant, because it is twice the CV calculated for this series of measurements. Moreover, the decrease in IMT was observed in 21 of 22 patients. These results are in complete accordance with those recently presented in abstract form by Pfeifer et al. (18) in 12 GHD adults treated with a comparable dose of GH. Both studies showed the same rapid and deep effect of GH on IMT. Although a control group that could document the natural course of IMT in hypopituitary subjects is lacking, a spontaneous decrease in IMT is unlikely, especially because IMT increases regularly with age. Indeed, an annual increase of 0.01 mm and 0.03 mm, respectively, has been reported in middle-aged healthy subjects and in high-cardiovascular-risk patients (4, 5, 6); and we found a very similar progression, of 0.03 ± 0.01 mm, in a subgroup of 58 diabetic patients during a 3-yr follow-up (unpublished results).
Conventional substitution with other hormones remained unmodified throughout this study, which suggests that the changes in IMT were related to GH replacement. The mechanisms by which GH treatment might so deeply affect IMT is unclear and can only be hypothesized. The present study was based on B mode ultrasonography, which does not differentiate between intimal and medial layers and cannot detect the anatomical structures specifically involved in IMT changes. Despite this limitation, intima-media thickening is accepted as an early marker of atherosclerosis (5, 6). In interventional studies, it has been widely used as an intermediate surrogate, and a decrease in IMT has been associated with a reduction in the number of coronary events (19), suggesting regression of atherosclerosis. However, significant IMT changes were, in most cases, lower than in the present study. Moreover, they were only observed with aggressive lipid-lowering therapy, resulting in a 30–40% decrease in LDL cholesterol, and after long periods of treatment (2 or 3 yr) (19, 20, 21, 22). In our study, GH replacement resulted in a moderate reduction of body fat mass and waist circumference; but in agreement with a previous report (23), blood pressure and lipid profile were unmodified, except for a transient 10% decrease in LDL cholesterol. Thus, the score of cardiovascular risk, which is an expression of conventional risk factors, was unchanged at 1 and 2 yr. The presence of a relatively weak correlation between decrease in LDL concentration at 6 months and IMT changes at 1 yr is suggestive of some lipid-lowering effect. However, it does not seem to be determinant, because IMT remained stable at 2 yr despite return of LDL to basal values. In addition, during the study, there was no obvious regression of atherosclerotic plaques in the six patients exhibiting them at the beginning (results not shown). This suggests a direct effect of GH replacement on arterial wall trophicity, not involving atherogenesis and lipid deposition.
Adaptative thickening of IMT, unrelated to atherosclerosis, has been suggested as a compensatory response of the vessel to changes in blood flow or vascular tone (24). Conversely, because GH replacement is known to exert various effects on the vascular system, an adaptative reduction of IMT, in response to GH treatment, could be hypothesized. GH is known to increase volemia and decrease peripheral resistances (25). This latter effect is concordant with the decrease in arterial elasticity and distensibility reported in GHD adult patients (26). Most of the physiological effects of GH on the vascular system are mediated by IGF-1. Endothelial cells possess high-affinity binding sites for IGF-1 (27), and IGF-1 has been shown to increase endothelial nitric oxide formation (28). Decreased nitric oxide activity is associated with impaired arterial vasodilator capacity, increased platelet aggregability, and intimal thickening (29). The relationship between IGF-1 and IMT has been recently illustrated in vivo by the study of Lamberts et al. (30), who reported an inverse correlation between free IGF-1 and carotid IMT, in elderly non-GHD patients. Taken together, these data may suggest an effect of circulating and/or locally produced IGF-1 on IMT, through changes in endothelial reactivity.
In conclusion, the deep and rapid effect of GH replacement on IMT may be indicative of a beneficial effect of GH treatment on the vascular system. However, ultrasonographic data that we report cannot support speculation as to mechanisms, and their significance (in terms of cardiovascular risk) will be established only after the completion of randomized prospective trials.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received July 31, 1998.
Revised December 14, 1998.
Accepted December 28, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. Colao, C. Di Somma, S. Spiezia, S. Savastano, F. Rota, M. C. Savanelli, and G. Lombardi Growth Hormone Treatment on Atherosclerosis: Results of a 5-Year Open, Prospective, Controlled Study in Male Patients with Severe Growth Hormone Deficiency J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3416 - 3424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Utz, A. Yamamoto, L. Hemphill, and K. K. Miller Growth Hormone Deficiency by Growth Hormone Releasing Hormone-Arginine Testing Criteria Predicts Increased Cardiovascular Risk Markers in Normal Young Overweight and Obese Women J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2507 - 2514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Beauregard, A. L. Utz, A. E. Schaub, L. Nachtigall, B. M. K. Biller, K. K. Miller, and A. Klibanski Growth Hormone Decreases Visceral Fat and Improves Cardiovascular Risk Markers in Women with Hypopituitarism: A Randomized, Placebo-Controlled Study J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2063 - 2071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Colao, C. Di Somma, S. Spiezia, F. Rota, R. Pivonello, S. Savastano, and G. Lombardi The Natural History of Partial Growth Hormone Deficiency in Adults: A Prospective Study on the Cardiovascular Risk and Atherosclerosis J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2191 - 2200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Molitch, D. R. Clemmons, S. Malozowski, G. R. Merriam, S. M. Shalet, M. L. Vance, and for The Endocrine Society's Clinical Guidelines Su Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1621 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bollerslev, T. Ueland, A. P Jorgensen, K. J Fougner, R. Wergeland, T. Schreiner, and P. Burman Positive effects of a physiological dose of GH on markers of atherogenesis: a placebo-controlled study in patients with adult-onset GH deficiency. Eur. J. Endocrinol., April 1, 2006; 154(4): 537 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bollerslev, J. Hallen, K. J Fougner, A. P. Jorgensen, C. Kristo, H. Fagertun, O. Gudmundsen, P. Burman, and T. Schreiner Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial Eur. J. Endocrinol., September 1, 2005; 153(3): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Colao, C. Di Somma, A. Cuocolo, L. Spinelli, W. Acampa, S. Spiezia, F. Rota, M. C. Savanelli, and G. Lombardi Does a Gender-Related Effect of Growth Hormone (GH) Replacement Exist on Cardiovascular Risk Factors, Cardiac Morphology, and Performance and Atherosclerosis? Results of a Two-Year Open, Prospective Study in Young Adult Men and Women with Severe GH Deficiency J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5146 - 5155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Colao, C. Di Somma, F. Rota, R. Pivonello, M. C. Savanelli, S. Spiezia, and G. Lombardi Short-Term Effects of Growth Hormone (GH) Treatment or Deprivation on Cardiovascular Risk Parameters and Intima-Media Thickness at Carotid Arteries in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2056 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gola, S. Bonadonna, M. Doga, and A. Giustina Growth Hormone and Cardiovascular Risk Factors J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1864 - 1870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Miller, B. M. K. Biller, J. G. Lipman, G. Bradwin, N. Rifai, and A. Klibanski Truncal Adiposity, Relative Growth Hormone Deficiency, and Cardiovascular Risk J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 768 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Svensson, B.-A. Bengtsson, T. Rosen, A. Oden, and G. Johannsson Malignant Disease and Cardiovascular Morbidity in Hypopituitary Adults with or without Growth Hormone Replacement Therapy J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3306 - 3312. [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]
|
|
|
|
|
|
P. Maison, S. Griffin, M. Nicoue-Beglah, N. Haddad, B. Balkau, and P. Chanson Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults: A Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2192 - 2199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Serri, L. Li, F. Maingrette, N. Jaffry, and G. Renier Enhanced Lipoprotein Lipase Secretion and Foam Cell Formation by Macrophages of Patients with Growth Hormone Deficiency: Possible Contribution to Increased Risk of Atherogenesis? J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 979 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Underwood, K. M. Attie, and J. Baptista Growth Hormone (GH) Dose-Response in Young Adults with Childhood-Onset GH Deficiency: A Two-Year, Multicenter, Multiple-Dose, Placebo-Controlled Study J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5273 - 5280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Buijs, J. Burggraaf, J. G. Langendonk, R. C. Schoemaker, M. Frolich, J.-W. Arndt, A. F. Cohen, J. A. Romijn, M. T. Ackermans, H. P. Sauerwein, et al. Hyposomatotropism Blunts Lipolysis in Abdominally Obese Women J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3851 - 3858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Brevetti, P. Marzullo, A. Silvestro, R. Pivonello, G. Oliva, C. di Somma, G. Lombardi, and A. Colao Early Vascular Alterations in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3174 - 3179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ezzat, S. Fear, R.-C. Gaillard, C. Gayle, H. Landy, S. Marcovitz, T. Mattioni, S. Nussey, A. Rees, and E. Svanberg Gender-Specific Responses of Lean Body Composition and Non-Gender-Specific Cardiac Function Improvement after GH Replacement in GH-Deficient Adults J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2725 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Molitch Diagnosis of GH Deficiency in Adults--How Good Do the Criteria Need to Be? J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 473 - 476. [Full Text] [PDF]
|
|
|
|
|
|
G. Sesmilo, K. K. Miller, D. Hayden, and A. Klibanski Inflammatory Cardiovascular Risk Markers in Women with Hypopituitarism J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5774 - 5781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Sesmilo, B. M. K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone (GH) Administration on Homocyst(e)ine Levels in Men with GH Deficiency: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1518 - 1524. [Abstract] [Full Text]
|
|
|
|
|
|
R. Lanes, P. Gunczler, E. Lopez, S. Esaa, O. Villaroel, and R. Revel-Chion Cardiac Mass and Function, Carotid Artery Intima-Media Thickness, and Lipoprotein Levels in Growth Hormone-Deficient Adolescents J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1061 - 1065. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. Capaldo, V. Guardasole, F. Pardo, M. Matarazzo, F. Di Rella, F. Numis, B. Merola, S. Longobardi, and L. Sacca Abnormal Vascular Reactivity in Growth Hormone Deficiency Circulation, January 30, 2001; 103(4): 520 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Koshiyama, Y. Nakamura, S. Tanaka, and J. Minamikawa Decrease in Carotid Intima-Media Thickness after 1-Year Therapy with Etidronate for Osteopenia Associated with Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2793 - 2796. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Sesmilo, B. M.K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone Administration on Inflammatory and Other Cardiovascular Risk Markers in Men with Growth Hormone Deficiency: A Randomized, Controlled Clinical Trial Ann Intern Med, July 18, 2000; 133(2): 111 - 122. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS |
