help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1844
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/5/2659    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Colao, A.
Right arrow Articles by Lombardi, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Colao, A.
Right arrow Articles by Lombardi, G.
Related Collections
Right arrow Cardiovascular Endocrinology
Right arrow Neuroendocrinology and Pituitary
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2659-2665
Copyright © 2005 by The Endocrine Society

Common Carotid Intima-Media Thickness in Growth Hormone (GH)-Deficient Adolescents: A Prospective Study after GH Withdrawal and Restarting GH Replacement

Annamaria Colao, Carolina Di Somma, Francesca Rota, Salvatore Di Maio, Mariacarolina Salerno, Antonella Klain, Stefano Spiezia and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology (A.C., C.D.S., F.R., G.L.), Department of Pediatrics (M.S.), "Federico II" University of Naples, 80131 Naples, Italy; Division of Pediatric Endocrinology (S.D.M., A.K.), Santobono Hospital of Naples, 80123 Naples, Italy; and Emergency Unit, "S. Maria degli Incurabili" Hospital of Naples (S.S.), 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II," University of Naples, Via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
We prospectively investigated the risk of early atherosclerosis, by classical cardiovascular risk factors and intima-media thickness (IMT) at the common carotid arteries, in 23 adolescents diagnosed as GH deficient (GHD) during childhood and in 23 healthy sex-, age-, and BMI-matched controls. Measurements were performed in all subjects before stopping GH replacement. Because the diagnosis of GHD had been confirmed in 15 of the 23 adolescents, the protocol changed according to the diagnosis as follows: measurements were repeated after 6 months of GH withdrawal and 6 months of GH reinstitution in the 15 with GHD, and after 6 and 12 months of GH withdrawal, measurements were also taken in the eight non-GHD subjects.

Serum IGF-I levels were in the normal range for age in all patients before GH withdrawal. When compared with controls, before GH withdrawal, GHD adolescents had reduced high-density lipoprotein cholesterol levels and increased total/high-density lipoprotein cholesterol ratio, fibrinogen, low-density lipoprotein cholesterol, and glucose levels; non-GHD adolescents had increased glucose, insulin, and homeostasis model assessment score. IMT at the common carotid arteries was similar in GHD and controls (0.52 ± 0.03 vs. 0.55 ± 0.06 mm; P = 0.23) and was higher in non-GHD than in controls (0.62 ± 0.03 vs. 0.54 ± 0.06 mm; P = 0.01). In GHD adolescents, 6 months of GH treatment withdrawal and 6 months of GH treatment reinstitution modified IGF-I levels, lipid profile, and insulin resistance but not IMT or systolic and diastolic peak velocities at the common carotid arteries. In non-GHD subjects, 12 months of GH treatment withdrawal significantly decreased IGF-I levels, IMT (to 0.54 ± 0.06 mm; P < 0.001 vs. baseline), systolic and diastolic peak velocities, and improved insulin resistance.

In conclusion, the discontinuation of GH in confirmed GHD adolescents is not followed by significant alterations of the common carotid arteries, despite the profound negative alterations of the lipid profile. In adolescents who were not confirmed to have GHD, IMT was increased while on GH therapy and normalized when they were taken off of GH.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE MORTALITY FOR cardiovascular and cerebrovascular diseases is increased in hypopituitary patients (1, 2, 3, 4, 5). Increased cardiovascular risk factors such as body fat, peripheral insulin resistance, the frequency of impaired glucose tolerance, and an abnormal cardiac structure and performance are all typical features of adults who are GH deficient (GHD) (6, 7, 8, 9, 10). GHD adults have also been shown to have vascular disease demonstrated by an increased number of atheromatous plaques in the carotid and the femoral arteries, increased intima-media thickness (IMT) and stiffness of the carotid arteries, and impaired flow-mediated endothelium-dependent dilation of the brachial artery (11, 12, 13, 14, 15, 16). Increased IMT is a sign of premature atherosclerosis directly related to mortality from coronary artery disease (17). More recently, low IGF-I levels were shown to be independently related to an increased risk of death for ischemic heart diseases in a healthy elderly population free of cardiovascular events (18, 19). Low IGF-I levels were also associated with increased IMT and prevalence of atherosclerotic plaques at the common carotid arteries in adult GHD patients (20). To reinforce the role of GH on the negative cardiovascular profile of GHD patients, GH replacement has been shown to induce beneficial effects on lipid profile, cardiac performance, and atherosclerosis (6, 7, 8, 9, 13, 14).

The current practice for childhood GHD patients is to stop GH replacement at final height (21). The persistence of GHD is then reevaluated by appropriate GH testing because one third to one half of the patients with GHD during childhood do not have persistent severe GHD later on in adulthood (22, 23). The discontinuation of GH therapy in adolescents with severe GHD for 1 yr causes the accumulation of cardiovascular risk factors such as increase of total body and abdominal fat mass, a decrease of lean body mass, and an increase of total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B, with a decrease of high-density lipoprotein (HDL)-cholesterol (24). Lipid alterations in these young patients are particularly relevant, because increased total and LDL-cholesterol levels during adolescence have been shown to predict IMT later on in life in non-hypopituitary subjects (25). We had previously shown that GH discontinuation is inappropriate in adolescents with severe GHD because it induces impairment of lipid profile and cardiac morphology and performance (26). In a cross-sectional study by Lanes et al. (27), however, no difference in cardiac mass and function and in the atherosclerotic profile was found in GHD adolescents during GH replacement, in those studied at the diagnosis of GHD (and thus not receiving GH) or in healthy adolescents.

This prospective study was designed to investigate the risk of early atherosclerosis in GHD adolescents during GH replacement and withdrawal. The classical cardiovascular risk factors such as IMT and systolic and diastolic peak velocities at the common carotid arteries, were measured in adolescent GHD patients reaching their final height within 6 months of stopping GH replacement and 6 months after GH treatment was restarted. The results were compared with sex- and age-matched healthy adolescents who served as a control group and to patients who were not confirmed to have GHD at retesting.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Twenty-three adolescent patients with GHD during childhood (10 boys and 13 girls, aged 15–20 yr) with adult bone age and completed puberty (Tanner stages IV–V) and a mean height SD score of –0.27 ± 0.31 were studied. GHD had been diagnosed 4.5–12.3 yr before entering the study by two classical stimulation tests [insulin tolerance test, clonidine or arginine with peak GH concentrations < 10 µg/liter and arginine plus GHRH (ARG+GHRH) with peak GH concentrations < 20 µg/liter]. Fourteen patients had idiopathic, isolated GHD, whereas the remaining nine had organic GHD within a context of hypopituitarism (Table 1Go). All of the patients from the latter group had been treated by surgery alone (n = 6) or associated with radiotherapy (n = 3, nos. 15, 21, and 22; Table 1Go), for pituitary lesions. All of the patients had received GH in the past for a period of 8.9 ± 1.9 yr. Hormone replacement therapy with L-T4 (50–100 µg by mouth daily), cortisone acetate (25–37.5 mg/d), and 1-disamino-ß-D-arginine vasopressin (5–20 µg/d) was given where appropriate. Hypogonadism was treated in boys with testosterone enanthate (250 mg im monthly) and in girls with standard oral estrogen/progestin association. An adequacy of hormone replacement therapy was periodically assessed by serum free thyroid hormones and testosterone and urinary free cortisol together with serum and urinary Na+ and K+ measurements.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Individual patient profiles at study entry and at the end of the 12-month study

 
At study entry, all of the patients had normal blood pressure and pulse as well as normal adrenal and thyroid function tests; circulating levels of gonadal steroids were appropriate for their age. Ten of the 23 patients had been included in a previous study (26). Informed consent was obtained by the patients or their parents (if the patient was under 18 yr of age), and the study was approved by the local Ethical Committee.

Controls

Twenty-three healthy adolescents (10 boys and 13 girls, aged 15–20 yr) comparable for age (±), sex, pubertal status, BMI (±1) participated in the study as controls. Informed consent was obtained by the patients or their parents (if the patient was aged <18 yr). The patients’ and controls’ profile at study entry is shown in Table 2Go.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Anthropometrical, endocrine, metabolic, and vascular parameters in 15 adolescent patients with confirmed GHD after retesting (peak GH to ARG+GHRH test, 3.1 ± 1.9 µg/liter) and in eight adolescent patients with no confirmed GHD after retesting (peak GH to ARG+GHRH test, 20.5 ± 1.1 µg/liter) and their age- and gender-matched controls at study entry

 
Treatment protocol

At study entry, the patients received GH replacement at a median dose of 35 µg/kg·d, following the recommendations for the pediatric age. At the restart of the treatment, according to the Consensus Conference that was recently reported (28), all GHD patients received recombinant GH at the starting dose of 8–10 µg/kg·d as suggested for the young adult population. After 3 months, the dose was adjusted, aiming at reaching the 50th percentile of normal serum IGF-I concentrations for sex and age, as previously reported (29, 30). At the end of the study, the median GH dose was 10 µg/kg·d in boys and 12 µg/kg·d in girls; the maximal dose was 11 µg/kg·d in boys and 15 µg/kg·d in girls.

Study protocol

At study entry, all 46 subjects underwent electrocardiogram, systolic and diastolic blood pressure and heart rate measurement, assay of serum IGF-I, total, LDL-, and HDL-cholesterol, triglycerides, glucose, and fibrinogen level, and ultrasonography of the common carotid arteries. The conversion factors (mg/dl to mmol/liter) for lipids and glucose were as follows: cholesterol, 0.02586; triglycerides, 0.01129; and glucose, 0.5551. We also calculated the total/HDL-cholesterol ratio, considered as an index of severe cardiovascular risk (31), and the estimate of insulin resistance by the homeostasis model assessment (HOMA) score, by applying the formula of Matthews et al. (32): fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/liter)/22.5. After 1–3 months of GH withdrawal, retesting of the GH secretory status was performed using the ARG+GHRH test as previously reported (26). According to Aimaretti et al. (23) and our previous studies (33, 34), severe GHD was defined on the basis of a GH peak less than or equal to 9 µg/liter. In GHD patients, IGF-I, total, LDL-, and HDL-cholesterol, triglycerides, and fibrinogen levels and ultrasonography of the common carotid arteries were repeated after 6 months of GH withdrawal and 6 months of restarting GH. In non-GHD patients, IGF-I, total, LDL-, and HDL-cholesterol, triglycerides, and fibrinogen levels and common carotid arteries ultrasonography were repeated after 6 and 12 months of GH withdrawal. A magnetic resonance of the sellar region was performed at study entry and then after 12 months at the end of the study in all GHD patients; no change was observed in the pituitary size.

Carotid ultrasonography

Common carotid arteries ultrasound imaging was carried out with Vingmed Sound CMF 725 equipment (Horten, Norway) by means of a 7.5-MHz annular phased array transducer; the details on the technique were reported elsewhere (20). Right and left carotid arteries were scanned longitudinally, 2.5 cm proximal and 1 cm distal to the bifurcation. When satisfactory B-mode imaging of the common carotid artery wall was achieved, M-mode images were taken for several cardiac cycles to obtain the best quality measurements of IMT. Quantitative and semiquantitative indices were evaluated by echo-Doppler ultrasonography placing the sample volume (set at 75% of lumen caliber) in the middle of the vessel lumen. The variability in the IMT measurement for our instrument was 0.03 mm. Our intra-observer variability for repeated measurements of carotid artery diameter is 0.01 ± 0.02 mm. Flow indices of both carotids were investigated by measuring blood systolic and diastolic peak velocities. The epidemiological data currently available indicate that a value of IMT at or above 1 mm at any age is associated with a significantly increased risk of myocardial infarction and/or cerebrovascular disease (35). The presence, location, and size of plaques were also evaluated at the level of the common carotid arteries. A type IV plaque featured by a thickening of the vascular wall and an increased density of all ultrasonography-detectable layers without any hemodynamic alteration was defined as a well-defined plaque (36).

Assays

Serum GH levels were measured by immunoradiometric assay (IRMA) using commercially available kits (HGH-CTK-IRMA Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intra- and interassay coefficients of variation (CV) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction. The sensitivity of the assay was 0.8 µg/liter. The normal IGF-I range in adolescent subjects (16–20 yr) is 141 (3rd percentile) to 625 (97th percentile) µg/liter. The 50th percentile of IGF-I levels in our laboratory is 350 µg/liter, calculated in samples taken from 60 healthy adolescents. The intraassay CV was 3.4, 3.0, and 1.5% for the low, medium, and high points on the standard curve, respectively. The interassay CV was 8.2, 1.5, and 3.7% for the low, medium, and high points on the standard curve.

Statistical analysis

Results are expressed as mean ± SD unless otherwise specified. The statistical analysis was performed by SPSS Inc. (Cary, NC) package using nonparametric tests. The comparison between patients and controls was performed by the Wilcoxon matched-pairs test; the comparison between GHD and non-GHD controls was performed by the Mann-Whitney test. The significance was set at 5%. The comparison among baseline and 6 and 12 months in the two groups of adolescents was performed by the Kruskal-Wallis test followed by the Dunn’s test for paired data. The significance was set at 1%.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Before GH withdrawal (Table 2Go)

Patients were classified as GHD (n = 13) or non-GHD (n = 8) based on the ARG+GHRH test performed 1–3 months after stopping GH replacement (Table 1Go). Non-GHD did not restart GH replacement therapy. Before GH withdrawal, serum IGF-I levels were in the normal range for age in all patients (Table 1Go). They were similar in non-GHD and controls (325.6 ± 33.1 µg/liter vs. 301.6 ± 35.5 µg/liter), lower in both isolated GHD and multiple GHD patients than in controls (198.4 ± 15.7 and 189.2 ± 51.3 vs. 291.0 ± 30.7 µg/liter; P < 0.001) but similar in the two GHD groups (P = 0.33). Compared with controls, before GH withdrawal, GHD adolescents had reduced HDL-cholesterol levels, and increased total/HDL-cholesterol ratio, fibrinogen, LDL-cholesterol, and glucose levels, and non-GHD adolescents had increased glucose, insulin, and HOMA. IMT at the common carotid arteries was similar in GHD and controls and was higher in non-GHD than in controls. Systolic and/or diastolic peak velocities at the common carotid arteries were higher in both GHD and non-GHD patients than in controls.

Six months after GH treatment withdrawal (Table 3Go)

Serum IGF-I levels significantly decreased both in GHD (Fig. 1Go) and in non-GHD adolescents (Fig. 2Go). Only in GHD patients did BMI increase, and lipid profile and insulin resistance were significantly impaired. IMT at the common carotid arteries did not change in GHD patients (Figs. 1Go and 3Go) and significantly decreased in non-GHD patients (Fig. 2Go) and became similar to controls (Fig. 3Go). Systolic and diastolic peak velocities at the common carotid arteries slightly increased in GHD patients, whereas they decreased in non-GHD.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Endocrine, metabolic, and ultrasonographic parameters in 15 GHD adolescents after retesting (peak GH to ARG+GHRH test, 3.1 ± 1.9 µg/liter) at study entry, after 6 months of GH withdrawal, and 6 months after restarting of GH replacement and in eight adolescent patients with no confirmed GHD after retesting (peak GH to ARG+GHRH test, 20.5 ± 1.1 µg/liter) at study entry and after 6 and 12 months of GH withdrawal

 


View larger version (23K):
[in this window]
[in a new window]
  		FIG. 1. Individual values of serum IGF-I levels (top) and measured mean IMT of right and left common carotid arteries, by ultrasonography (bottom), in the 15 GHD adolescents ({circ}) at study entry, after 6 months of GH withdrawal, and after 6 months of reinstitution of GH replacement and their sex-, age-, and BMI-matched controls (•). Patients with isolated GHD are shown as solid lines; patients with multiple GHD are shown as dashed lines.

 


View larger version (16K):
[in this window]
[in a new window]
  		FIG. 2. Individual values of serum IGF-I levels (top) and measured mean IMT of the right and left common carotid arteries by ultrasonography (bottom), in the eight non-GHD adolescents ({square}) at study entry after 6 and 12 months of GH withdrawal and their sex-, age-, and BMI-matched controls ({blacksquare}).

 


View larger version (13K):
[in this window]
[in a new window]
  		FIG. 3. Measured mean IMT of the right and left common carotid arteries by ultrasonography (bottom) in GHD ({circ}) and non-GHD adolescents ({square}) during the study and their sex-, age-, and BMI-matched controls (•, {blacksquare}) shown as mean ± SD. A, P < 0.01 vs. GHD patients; and B, P < 0.01 vs. controls.

 
Six months after restarting GH treatment in GHD or 12 months after GH withdrawal in non-GHD (Table 3Go)

GH replacement was restarted in the 15 patients who were confirmed to have GHD. The final dose of GH replacement was similar in boys and girls (11.4 ± 2.5 vs. 13.5 ± 3.2 µg/kg·d; P = 0.28); in only one girl with hypopituitarism and receiving oral estro-progestin replacement, the maximal dose was 20 µg/kg·d, higher than that used in boys (Table 1Go). Serum IGF-I levels promptly increased after GH was restarted in GHD patients (Fig. 1Go). However, 6 months after GH was restarted, IGF-I levels were still subnormal in one patient with multiple GHD (no.18, Table 2Go). In non-GHD adolescents, IGF-I levels did not significantly change after 6 months off of GH (Fig. 2Go). Lipid profile and glucose tolerance returned to those measured at study entry in GHD patients and remained unmodified in non-GHD adolescents. However, serum IGF-I and HDL-cholesterol remained lower whereas LDL-cholesterol and total/HDL-cholesterol remained higher than in controls. In non-GHD adolescents, IMT (Fig. 3Go) and systolic and diastolic peak velocities at the common carotid arteries decreased significantly when compared with baseline observations during GH treatment and approximated those of control subjects. In the GHD patients, ultrasonographic parameters did not change, except for a mild decrease in systolic peak velocity that returned to baseline values.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results of the current prospective study show that the discontinuation of GH replacement in confirmed GHD adolescents impaired lipid profile and insulin resistance without any apparent change of morphological parameters at the common carotid arteries. Six months after restarting GH replacement, the lipid profile and insulin resistance improved, and IGF-I levels normalized in the low-normal range; however, the total/HDL-cholesterol ratio, which is a relevant predictive parameter for cardiovascular risk, still remained slightly higher than in controls. Ultrasonographic parameters of vascular morphology at the common carotid arteries remained unchanged. Interestingly, before GH withdrawal in the adolescents that were not confirmed to have GHD, lipid profile and glucose metabolism were normal, but IMT at both common carotid arteries was increased compared with healthy controls. Twelve months of GH withdrawal in this latter group normalized IMT and systolic and diastolic peak velocities. The results of this short-term study indicate that GH replacement therapy should be continued into adulthood only in severe childhood onset of GHD, to prevent an impairment of cardiovascular risk factors and insulin resistance. Furthermore, special attention should be paid to the patients with partial or isolated GHD, who may not be confirmed to have GHD in adulthood because of potential detrimental effects of GH therapy on major vessels.

An unfavorable lipid profile, increased body fat with decrease of lean body mass, increased peripheral insulin resistance, decreased plasma fibrinolytic activity, abnormal cardiac structure with impaired cardiac performance, and premature atherosclerosis with increased arterial IMT are associated with cardiovascular morbidity and mortality in adult GHD patients (6, 7). GH replacement improves left ventricular morphology and function (7), reduces IMT, and improves endothelial dysfunction (6). GH deprivation for 6 months in severe GHD adolescents (26) and 12 months in severe GHD adults further aggravates cardiac performance (30).

During childhood, reduced growth velocity is an evident clinical end-point of GHD and guides GH replacement, even if it is necessary to confirm the diagnosis by using biochemical testing. Because clear-cut clinical endpoints are lacking in adulthood, the current practice is to stop GH replacement at the final height and to reevaluate the diagnosis of GHD by appropriate GH testing: one third to one half of patients with GHD during childhood do not have persistent severe GHD in adulthood (21, 22, 23). However, discontinuation of GH therapy in adolescents with severe GHD for 6–12 months causes the accumulation of cardiovascular risk factors, such as the increase of total body and abdominal fat mass, decrease of lean body mass, increase of total cholesterol, LDL-cholesterol, lipoprotein-a, and apolipoprotein B, and decrease of HDL-cholesterol, (24, 27) and the impairment of cardiac morphology and performance (26). An impairment of the lipid profile is an early and constant finding of GHD and has been suggested as playing the main role on the coronary risk of GHD patients (37).

To give further insight on the risk of early atherosclerosis in GHD adolescents during GH replacement and withdrawal, we analyzed the classical cardiovascular risk factors and some parameters of the vascular structure and dynamics before and after GH withdrawal and after restarting GH in GHD adolescents. We also compared the results with those obtained in non-GHD adolescents undergoing the same protocol and with the results of sex-, age-, and BMI-matched healthy adolescents. Although we confirmed previous data on the worsening of the lipid profile and insulin sensitivity after GH withdrawal and its improvement after GH reinstitution, we also added some new findings in GHD adolescents. In particular, at the common carotid arteries, we found a normal vascular structure and slightly decreased systolic peak velocity after GH reinstitution. The absence of any alteration of IMT at the common carotid arteries is in agreement with previous findings by Lanes et al. (27) in another cohort of adolescents. However, it is worth noting that non-GHD adolescents showed an increased IMT and systolic and diastolic peak velocities at study entry that returned to normal after 12 months of GH withdrawal. Circulating IGF-I levels play a relevant role on endothelial properties possessing high-affinity binding sites on endothelial cells (38) and increasing nitric oxide (NO) production (39, 40). Decreased NO activity is associated with impaired arterial vasodilator capacity, increased platelet aggregability, and intimal thickening (41), linking GH and IGF-I deficiency with atherosclerosis. GHD patients had decreased NO production that improved after GH replacement (42). Excess GH and IGF-I in acromegaly is also accompanied by a slight increase of IMT (43, 44) and endothelial dysfunction (45, 46) but not, interestingly, by increase of atherosclerotic plaques (43, 47). The evidence that IMT at the common carotid arteries is significantly higher in non-GHD adolescents than in healthy sex-, age-, and BMI-matched controls, in the absence of alterations of the lipid profile, could be explained by a direct effect of a constant but slightly higher IGF-I level during GH treatment in this cohort. It should be mentioned, however, that serum IGF-I levels at study entry and during GH replacement were not different in non-GHD adolescents from those measured in controls. However, IGF-I levels decreased significantly after GH withdrawal, suggesting that they were slightly elevated during GH treatment, even in the accepted normal range for age. Whether these findings could be an expression of a future risk of atherosclerosis in the adolescents diagnosed as GHD and treated with GH during childhood, but not confirmed to maintain GHD in adulthood, cannot be ruled out by our present data.

In conclusion, GH discontinuation in severe GHD adolescents is not followed by significant alterations of the structural parameters at the common carotid arteries and by only a slight decrease of systolic peak velocity, despite alterations of the lipid profile and insulin resistance. These results suggest that increased IMT in the adult GHD population begins later in life or after a longer period of GH deprivation. Interestingly, in the adolescents not confirmed to maintain GHD, IMT at the common carotid arteries was increased during GH treatment and reversed to normal 12 months after GH withdrawal. These results strengthen the recommendation that adolescents with idiopathic GHD be retested for GHD after completion of growth as continued GH replacement in non-GHD subjects could negatively affect endothelial properties, even when IGF-I levels are maintained in the accepted normal range for sex and age. More data are required to understand whether the study of IMT at the common carotid arteries could be an additional parameter to monitor during GH replacement in GHD patients, because it seems to reflect IGF-I activity more than the simple biochemical measurement.


   Acknowledgments
 
We thank Dr. Alfonso Gruosso for the editing of the manuscript.


   Footnotes
 
This study was partially supported by a grant from Regione Campania L. R. (41/94, 1999, no.7492) and by a grant of the Italian Minister of Research and University in Rome (no. 2003069821, 2003).

First Published Online February 15, 2005

Abbreviations: ARG+GHRH, Arginine plus GHRH; BMI, body mass index; CV, coefficient of variation; GHD, GH deficient; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IMT, intima-media thickness; IRMA, immunoradiometric assay; LDL, low-density lipoprotein.

Received September 17, 2004.

Accepted January 28, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
  2. Bates AS, Vant’Hoff W, Jones PJ, Clayton RN 1996 The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 81:1169–1172[Abstract]
  3. Bulöw B, Hagmar L, Mikoczy Z, Nordström CH, Erfurth EM 1997 Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol 46:75–81[CrossRef][Medline]
  4. Bulöw B, Hagmar L, Eskilsson J, Erfurth EM 2000 Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab 85:574–584[Abstract/Free Full Text]
  5. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands prospective study Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]
  6. Beshyah SA, Johnston DG 1999 Cardiovascular disease and risk factors in adults with hypopituitarism. Clin Endocrinol 50:1–15[CrossRef][Medline]
  7. Colao A, Di Somma C, Marzullo P, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol 54:137–154[CrossRef][Medline]
  8. Vance ML, Mauras N 1999 Growth hormone therapy in adults and children. N Engl J Med 341:1206–1216[Free Full Text]
  9. Carroll PV, Christ ER, Sonksen PH 2000 Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge. Trends Endocrinol Metab 11:231–238[CrossRef][Medline]
  10. Bengtsson BA, Johannsson G, Shalet SM, Simpson H, Sonken PH 2000 Treatment of growth hormone deficiency in adults. J Clin Endocrinol Metab 85:933–942[Free Full Text]
  11. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicholaides AN, Johnston D 1992 Detection of premature atherosclerosis by high resolution ultrasonography in symptom free hypopituitary adults. Lancet 340:1188–1192[CrossRef][Medline]
  12. Capaldo B, Patti L, Oliviero U, Longobardi S, Pardo F, Vitale F, Fazio S, Di Rella F, Biondi B, Lombardi G, Saccà L 1997 Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J Clin Endocrinol Metab 82:1378–1381[Abstract/Free Full Text]
  13. Borson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, Labrousse F, Pastene J, Sassolas A, Roux Y, Berthezéne F1999 Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 84:1329–1333
  14. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN 1999 Growth hormone treatment (GH) reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 84:453–457[Abstract/Free Full Text]
  15. Murata M, Kaji H, Mizuno I, Sakurai T, Iida K, Okimura Y, Chihara K 2003 A study of carotid intima-media thickness in GH-deficient Japanese adults during onset among adults and children. Eur J Endocrinol 148:333–338[Abstract]
  16. Leonsson M, Hulthe J, Oscarsson J, Johannsson G, Wendelhag I, Wikstrand J, Bengtsson BA 2002 Intima-media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors. Clin Endocrinol (Oxf) 57:751–759[CrossRef][Medline]
  17. Bonithon-Kopp C, Touboul P-J, Berr C, Berr C, Leroux C, Mainard F, Bourbon D, Ducimetiere P 1996 Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The vascular aging (EVA) study. Arterioscler Thromb Vasc Biol 16:310–316[Abstract/Free Full Text]
  18. Vasan RS, Sullivan LM, D’Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW 2003 Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med 139:642–648[Abstract/Free Full Text]
  19. Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D 2004 The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho-Bernardo study. J Clin Endocrinol Metab 8:114–120
  20. Colao A, Di Somma C, Filippella M, Rota F, Pivonello R, Orio Jr F, Vitale G, Lombardi G 2004 Insulin-like growth factor-I deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf) 61:360–366[CrossRef][Medline]
  21. Shalet SM, Rosenfeld RG 1998 Growth hormone replacement therapy during transition of patients with childhood-onset growth hormone deficiency into adulthood: what are the issues? Growth Horm IGF Res 8(Suppl B):177–184
  22. Longobardi S, Merola B, Pivonello R, Di Rella F, Di Somma C, Colao A, Ghigo E, Camanni F, Lombardi G 1996 Reevaluation of GH secretion in sixty-nine adults diagnosed as GH deficient patients during childhood. J Clin Endocrinol Metab 81:1244–1247[Abstract]
  23. Aimaretti G, Baffoni C, Bellone S, Di Vito L, Corneli G, Arvat E, Benso L, Camanni F, Ghigo E 2000 Retesting young adults with childhood-onset growth hormone (GH) deficiency with GH-releasing-hormone-plus-arginine test. J Clin Endocrinol Metab 85:3693–3699[Abstract/Free Full Text]
  24. Johannsson G, Albertsson-Wikland K Bengtsson BA 1999 Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. J Clin Endocrinol Metab 84:4516–4524[Abstract/Free Full Text]
  25. Davis PH, Dawson JD, Riley WA, Lauer RM 2001 Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle-age. The Muscatine Study. Circulation 104:2815–2819[Abstract/Free Full Text]
  26. Colao A, Di Somma C, Salerno M, Spinelli L, Orio F, Lombardi G 2002 The cardiovascular risk of GH-deficient adolescents. J Clin Endocrinol Metab 87:3650–3655[Abstract/Free Full Text]
  27. Lanes R, Gunczler P, Lopez E, Esaa S, Villaroel O, Revel-Chion R 2001 Cardiac mass and function, carotid artery intima-media thickness, and lipoprotein levels in growth hormone-deficient adolescents. J Clin Endocrinol Metab 86:1061–1065[Abstract/Free Full Text]
  28. 1998 Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 83:379–381
  29. Colao A, Di Somma C, Cuocolo A, Spinelli L, Tedesco N, Pivonello R, Bonaduce D, Salvatore M, Lombardi G 2001 Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab 86:1874–1881[Abstract/Free Full Text]
  30. Colao A, di Somma C, Pivonello R, Cuocolo A, Spinelli L, Bonaduce D, Salvatore M, Lombardi G 2002 The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective study. J Clin Endocrinol Metab 87:1088–1093[Abstract/Free Full Text]
  31. Castelli WP 1996 Lipids, risk factors and ischaemic heart disease. Atherosclerosis 124(Suppl):S1–S9
  32. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
  33. Colao A, Cerbone G, Pivonello R, Aimaretti G, Loche S, Di Somma C, Faggiano A, Corneli G, Ghigo E, Lombardi G 1999 The growth hormone (GH) response to arginine plus GH releasing hormone test is correlated to the severity of lipid profile abnormalities in adult patients with GH deficiency. J Clin Endocrinol Metab 84:1277–1282[Abstract/Free Full Text]
  34. Colao A, Di Somma C, Pivonello R, Loche S, Aimaretti G, Cerbone G, Faggiano A Corneli G, Ghigo E, Lombardi G 1999 Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 84:1919–1924[Abstract/Free Full Text]
  35. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J 2002 Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 20:159–169[CrossRef][Medline]
  36. Belcaro G, Laurora G, Cesarone MR 1993 Noninvasive ultrasonic biopsy: evaluation of early arteriosclerotic lesions progression in normal asymptomatic, hyperlipidemic and diabetic subjects. Angiology 44:93–99
  37. Abdu TA, Neary R, Elhadd TA, Akber M, Clayton RN 2001 Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities. Clin Endocrinol 55:209–216[CrossRef][Medline]
  38. Delafontaine P, Lou, H, Alexander RW 1991 Regulation of insulin-like growth factor 1 messenger RNA levels in vascular smooth muscle cells. Hypertension 18:742–747[Abstract/Free Full Text]
  39. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS 1994 Direct demonstration of insulin-like growth factor I induced nitric oxide production by endothelial cells. Kidney Int 45:598–604[Medline]
  40. Walsh F, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR 1996 Insulin-like growth factor-I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology 137:1798–1803[Abstract]
  41. Bayes-Genis A, Conover CA, Schwartz RS 2000 The insulin-like growth factor axis: a review of atherosclerosis and restenosis. Circ Res 86:125–130.[Abstract/Free Full Text]
  42. Böger RH, Skamira C, Bode-Böger SM, Brabant C, Von Zur Muhlen A, Frolich JC 1996 Nitric oxide mediates the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. J Clin Invest 98:2706–2713[Medline]
  43. Colao A, Spiezia S, Cerbone G, Pivonello R, Marzullo P, Ferone D, Di Somma C, Assanti AP, Lombardi G 2001 Increased arterial intima-media thickness by B-M mode echodoppler ultrasonography in acromegaly. Clin Endocrinol (Oxf) 54:515–524[CrossRef][Medline]
  44. Colao A, Spinelli L, Cuocolo A, Spiezia S, Bonaduce D, Salvatore M, Lombardi G 2002 Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab 87:3097–3104[Abstract/Free Full Text]
  45. Chanson P, Megnien JL, del Pino M, Coirault C, Merli I, Houdouin L, Harris AG, Levenson J, Lecarpentier Y, Simon A, Chemla D 1998 Decreased regional blood flow in patients with acromegaly. Clin Endocrinol (Oxf) 49:725–731[CrossRef][Medline]
  46. Brevetti G, Marzullo P, Silvestro A, Pivonello R, Oliva G, Di Somma C, Lombardi G, Colao A 2002 Early vascular alterations in acromegaly. J Clin Endocrinol Metab 87:3174–3179[Abstract/Free Full Text]
  47. Kasayama S, Otsuki M, Takagi M, Saito H, Sumitani S, Kouhara H, Koga M, Saitoh Y, Ohnishi T, Arita N 2001 Characterization of premature atherosclerosis of carotid arteries in acromegalic patients. Clin Endocrinol (Oxf) 54:791–796[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Salerno, V. Esposito, V. Farina, G. Radetti, A. Umbaldo, D. Capalbo, L. Spinelli, S. Muzzica, G. Lombardi, and A. Colao
Improvement of Cardiac Performance and Cardiovascular Risk Factors in Children with GH Deficiency after Two Years of GH Replacement Therapy: An Observational, Open, Prospective, Case-Control Study
J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1288 - 1295.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/5/2659    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Colao, A.
Right arrow Articles by Lombardi, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Colao, A.
Right arrow Articles by Lombardi, G.
Related Collections
Right arrow Cardiovascular Endocrinology
Right arrow Neuroendocrinology and Pituitary

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