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The Growth Hormone (GH) Response to the Arginine Plus GH-Releasing Hormone Test Is Correlated to the Severity of Lipid Profile Abnormalities in Adult Patients with GH Deficiency

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples (A.C., G.C., R.P., C.D.S., A.F., G.L.), Naples; the Department of Endocrinology, University of Turin (G.A., G.C., E.G.), Turin; and the Department of Pediatric Endocrinology, Ospedale Regionale per le Microcitemie (S.L.), Cagliari, 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 Subjects and Methods Results Discussion References

 
The aim of the present study was to correlate the degree of the GH response to the combined arginine and GHRH (ARG+GHRH) test with clinical status in 157 adult hypopituitary patients and 35 healthy controls. On the basis of the GH response to ARG+GHRH, the 192 subjects were subdivided into 5 groups: group 1, very severe GH deficiency (GHD; 65 patients with GH peak <3 µg/L); group 2, severe GHD (37 patients with GH peak between 3.1–9 µg/L); group 3, partial GHD (25 patients with GH peak between 9.1–16.5 µg/L); group 4, non-GHD (30 patients with GH peak >16.5 µg/L); and group 5 (35 controls with GH peak >16.5 µg/L).

Plasma insulin-like growth factor I (IGF-I) concentrations were lower (P < 0.001) in patients of group 1 (74.4 ± 6.7 µg/L) and group 2 (81.4 ± 6.8 µg/L) than in those of group 3, 4, and 5 (163.6 ± 40.6, 185.9 ± 21, and 188.8 ± 11.1 µg/L, respectively). Plasma IGF-binding protein-3 concentrations were lower (P < 0.01) in group 1 (2.1 ± 0.2 mg/L) and group 2 (2.0 ± 0.2 mg/L) than in group 3 (3.4 ± 0.7 mg/L) and group 5 (3.8 ± 0.2 mg/L). In patients of group 1, total cholesterol (228.3 ± 5.7 mg/dL) and triglycerides levels (187.4 ± 15.3 mg/dL) were higher than those in group 3 (196.6 ± 9.6 and 115.8 ± 10.1 mg/dL, respectively), group 4 (176.8 ± 11.3 and 101.4 ± 12.5 mg/dL, respectively), and group 5 (160 ± 6.9 and 99.3 ± 5.4 mg/dL, respectively). High density lipoprotein cholesterol levels were lower in patients of group 1 (45.2 ± 2.4 mg/dL) than in those of group 4 (54.7 ± 3.5 mg/dL; P < 0.05) and group 5 (53.6 ± 2 mg/dL; P < 0.001), whereas low density lipoprotein cholesterol levels were higher in patients of group 1 (127.3 ± 7.9 mg/dL), group 2 (129.2 ± 9.5 mg/dL), and 3 (133 ± 9 mg/dL) than in those of group 5 (102.4 ± 7.4 mg/dL; P < 0.05). Patients of group 2 had total cholesterol, high density lipoprotein cholesterol, and triglycerides levels at an intermediate level with respect to those in groups 1, 3, and 4. Among the five groups, no difference was found in fasting glucose concentrations, heart rate, or systolic and diastolic blood pressures. A significant increase in fat body mass and a decrease in lean body mass and total body water were found in all patients compared to controls. Disease duration was significantly shorter in patients of group 4 than in those of the remaining three groups (P < 0.001).

A significant correlation was found between the GH peak after ARG+GHRH and disease duration (r = -0.401; P < 0.001), plasma IGF-I (r = 0.434; P < 0.001), total cholesterol (r = -0.324; P < 0.001), and triglycerides levels (r = -0.219; P < 0.05). A significant multiple linear regression coefficient was found between the GH peak after ARG+GHRH and plasma IGF-I levels (t = 2.947; P < 0.005), total cholesterol levels (t = -2.746; P < 0.01), and disease duration (t = -2.397; P < 0.05).

In conclusion, the results of the present study indicate that the degree of the GH response to ARG+GHRH is correlated with the severity of lipid profile abnormalities and substantiate the reliability of the ARG+GHRH test for the diagnosis of GHD in adults. Because at present GH treatment is recommended only in adult patients with severe GHD, patients with a GH response below 9 µg/L to the ARG+GHRH test should be treated with GH, as should patients with a peak GH response to an insulin tolerance test below 3 µg/L.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE SYNDROME of GH deficiency (GHD) in adults has been recently characterized as a specific clinical entity (1, 2). Adults with GHD present with increased fat and decreased lean body mass, osteopenia, disorders of glucose and lipid metabolism, increased prevalence of cardiovascular diseases, and reduced quality of life (1, 2). Short term studies showed that the biological changes associated with GHD can be reversed by GH treatment (3). As none of the symptoms of adult GHD is specific, the diagnosis is biochemical in patients with known pituitary disease (4). The insulin tolerance test (ITT) is considered the most reliable provocative test in the diagnosis of GHD in adulthood; GH responses less than 3 µg/L are considered diagnostic of severe GHD, with an accuracy of 100% (4, 5, 6, 7). However, the GH response to ITT was reported to have a great inter- and intraindividual variability in both patients and normal subjects (8, 9). Furthermore, ITT may induce harmful hypoglycemia in hypopituitary patients and may also be harmful in patients with electrocardiogram evidence and/or history of ischemic heart disease or in patients with seizure disorders (4, 7). This evidence has stimulated the search for other provocative tests for the diagnosis of adult GHD. In this regard, the combined administration of arginine and GHRH (ARG+GHRH) has been reported as a reliable, reproducible, and safe GH stimulation test in both adults and children (10, 11, 12). The ARG+GHRH test has been recently shown to be as sensitive as ITT in the diagnosis of GHD in adults, provided that appropriate cut-off limits are assumed (13). Furthermore, the GH response to ARG+GHRH, but not that to ITT, was positively correlated with insulin-like growth factor I (IGF-I) levels in GHD adults (13).

Reduced growth velocity for age and pubertal stage is the hallmark of GHD in children, and the impairment in the growth rate is correlated with the severity of GHD (4). Whether the severity of GHD, as evaluated by the peak GH response to a pharmacological stimulus, may be predictive of the clinical status in adults is not known. The aim of the present study was to correlate the degree of the GH response to ARG+GHRH with clinical status in a large series of adult hypopituitary patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

One hundred and fifty-seven hypopituitary patients (68 males and 89 females; age, 16–72 yr) suspected of having GHD and 35 healthy subjects (15 males and 20 females; age, 18–70 yr) entered this cross-sectional study after their informed consent had been obtained. All patients had been previously operated on via the transsphenoidal and/or transcranic route for nonfunctioning pituitary adenoma, meningioma, or craniopharyngioma, and 27 of them had also been irradiated. A variable degree of pituitary insufficiency was found in the 157 patients, as shown in Table 1. Hormone replacement therapy with L-T₄ (50–100 µg, orally, daily), cortisone acetate (25–37.5 mg/day), and DDAVP (5–20 µg/day) was given where appropriate. Males with hypogonadism were treated with testosterone enanthate (250 mg, im, monthly), whereas premenopausal females were given estro-progestinic replacement. The adequacy of hormone replacement therapy was periodically assessed by means of serum free thyroid hormones, testosterone, urinary free cortisol, and serum and urinary Na⁺ and K⁺ measurements. At study entry, these hormonal parameters were in the normal range for age in all patients. Thirty-five healthy subjects in the group of students, physicians, and parents who volunteered for this study were used as controls. For an optimal evaluation of lipid profile, all patients and controls were asked to maintain a low fat diet for 3 days.

At study entry, all 192 subjects underwent a careful clinical evaluation, including electrocardiogram; blood pressure and heart rate measurements; routine blood and urine analysis, including total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, and glucose; assay of IGF-I and IGF-binding protein-3 (IGFBP-3) levels; and assessment of body composition. All subjects were tested with ARG+GHRH. ARG (arginine hydrochloride, Damor, Naples, Italy) was administered at a dose of 0.5 g/kg, up to a maximal dose of 30 g slowly infused from 0–30 min; GHRH-(1–29) (Geref, Serono, Rome, Italy) was given at a dose of 1 µg/kg as an iv bolus at 0 min. Blood samples were taken every 15 min from -15 to 90 min. According to recent studies (10, 11, 13) showing that adult patients with a GH peak after an ITT of less than 3 µg/L had a GH response to ARG+GHRH below 9 µg/L, whereas normal subjects had a GH response after ARG+GHRH always greater than 16.5 µg/L, we classified the GH response after ARG+GHRH in our 192 subjects as follows: very severe GHD when below 3 µg/L, severe GHD when between 3.1–9 µg/L, partial GHD when between 9.1–16.5 µg/L, and normal when above 16.5 µg/L.

Assessment of body composition

Measurements of lean body mass (LBM), fat body mass (FBM), and total body water (TBW) were performed using BIA 101 (Bioimpedance; RJL Systems, Florence, Italy), which generates a 50-kHz, 800-microampere alternating current. Data are expressed as a percentage of body weight.

Assays

All hormone measurements were performed using the same reagents in two laboratories of the Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples, and the Department of Endocrinology, University of Turin. Assay performances were similar in the two laboratories. Serum GH levels were measured by immunoradiometric assay using commercially available kits (HGH-CTK-IRMA, Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/L. The intra- and interassay coefficients of variation (CVs) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction. The normal ranges in 20- to 30-, 31- to 40-, 41- to 50-, and over 50-yr-old subjects were 110–502, 100–494, 100–303, and 78–258 µg/L, respectively. The sensitivity of the assay was 0.8 µg/L. The intra-assay CVs were 3.4%, 3.0%, and 1.5% for the low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2%, 1.5%, and 3.7% for the low, medium, and high points of the standard curve. Plasma IGFBP-3 was measured by RIA after ethanol extraction. The normal ranges in 20- to 30-, 31- to 40-, 41- to 50-, and over 50-yr-old subjects were 2.1–7.6, 1.7–7.3, 2.1–4.3, and 2–4 mg/L, respectively. The sensitivity of the assay was 0.5 µg/L. The intraassay CVs were 3.9%, 3.2%, and 1.8% for the low, medium, and high points of the standard curve, respectively. The interassay CVs were 0.6%, 0.5%, and 1.6% for the low, medium, and high points of the standard curve. Serum testosterone, estradiol, free thyroid hormones, TSH, FSH, LH, PRL, and free urinary cortisol were measured by commercially available immunoassays.

Statistical analysis

ANOVA followed by the Newman-Keuls test for intergroup comparison and linear correlation by regression analysis were performed where appropriate. The multiple regression analysis was performed taking the GH peak after ARG+GHRH as the dependent variable vs. age, disease duration, total cholesterol, LDL, HDL, cholesterol, triglycerides, LBM, FBM, and TBW as the independent variables by calculating the coefficient for the variables related to the GH peak after ARG+GHRH at the linear correlation. Data are reported as the mean ± SEM. The limit of significance was set at 5%.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
On the basis of the GH response to ARG+GHRH, the 157 patients were subdivided into 4 groups: group 1, very severe GHD (65 patients with GH peak <3 µg/L; 0.9 ± 0.1 µg/L); group 2, severe GHD (37 patients with GH peak between 3.1–9 µg/L; 5 ± 0.3 µg/L); group 3, partial GHD (25 patients with GH peak between 9.1–16.5 µg/L; 11.4 ± 0.5 µg/L); and group 4, non-GHD (30 patients with GH peak >16.5 µg/L; 30.9 ± 4.6 µg/L). In all 35 controls (group 5), the GH response after ARG+GHRH was greater than 16.5 µg/L (40.7 ± 2.2 µg/L). The GH peaks after ARG+GHRH were similar in female and male subjects (Table 1). No significant difference was found in the mean age of the 5 groups of subjects, whereas the disease duration was significantly greater in patients of group 1 than in those of the remaining 3 groups (P < 0.001, Table 1).

IGF-I concentrations in patients of group 1 (74.4 ± 6.7 µg/L) and group 2 (81.4 ± 6.8 µg/L) were similar and lower (P < 0.001) than those in groups 3, 4, and 5, which were not different from each other (163.6 ± 40.6, 185.9 ± 21, and 188.8 ± 11.1 µg/L, respectively; Fig. 1). IGF-I concentrations were below the normal range for age in 46 patients of group 1 (70.8%), 22 of group 2 (59.4%), and 4 of group 3 (26.7%) and were normal in all subjects of groups 4 and 5. Plasma IGF-I levels were similar in female and male subjects (data not shown). IGFBP-3 concentrations in group 1 (2.1 ± 0.2 mg/L) and group 2 (2.0 ± 0.2 mg/L) were similar and lower than those in group 3 (3.4 ± 0.7 mg/L; P < 0.01) and group 5 (3.8 ± 0.2 mg/L; P < 0.01), but not in group 4 (2.9 ± 0.5 mg/L; Fig. 1).

View larger version (17K): [in this window] [in a new window]   Figure 1. Plasma IGF-I (top panel) and IGFBP-3 (bottom panel) levels in the five groups of patients grouped on the basis of the GH response to the ARG+GHRH test: very severe GHD, GH peak below 3 µg/L; severe GHD, GH peak between 3.1–9 µg/L; partial GHD, GH peak between 9.1–16.5 µg/L; and non-GHD, GH peak above 16.5 µg/L. *, P < 0.001 vs. groups 3–5; **, P < 0.01 vs. groups 3 and 5.

View larger version (30K): [in this window] [in a new window]   Figure 2. Total cholesterol, HDL cholesterol, and LDL cholesterol levels in the five groups of patients grouped on the basis of the GH response to the ARG+GHRH test: very severe GHD, GH peak below 3 µg/L; severe GHD, GH peak between 3.1–9 µg/L; partial GHD, GH peak between 9.1–16.5 µg/L; and non-GHD, GH peak above 16.5 µg/L. *, P < 0.001 vs. all other groups; **, P < 0.01 vs. groups 3–5; ***, P < 0.005 vs. groups 4 and 5; ****, P < 0.05 vs. group 4 and P < 0.001 vs. group 5; *****, P < 0.05 vs. group 5.

View larger version (11K): [in this window] [in a new window]   Figure 3. Triglycerides levels in the five groups of patients grouped on the basis of the GH response to the ARG+GHRH test: very severe GHD, GH peak below 3 µg/L; severe GHD, GH peak between 3.1–9 µg/L; partial GHD, GH peak between 9.1–16.5 µg/L; and non-GHD, GH peak above 16.5 µg/L. *, P < 0.005 vs. all other groups.

View larger version (30K): [in this window] [in a new window]   Figure 4. Body composition analysis assessed by BIA in the five groups of patients grouped on the basis of the GH response to ARG+GHRH test: very severe GHD, GH peak below 3 µg/L; severe GHD, GH peak between 3.1–9 µg/L; partial GHD, GH peak between 9.1–16.5 µg/L; and non-GHD = GH peak above 16.5 µg/L. *, P < 0.05 vs. all other groups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The results of this study demonstrated that the lower the GH response to ARG+GHRH, the lower the IGF-I levels and the higher the total cholesterol and triglycerides levels. Thus, the severity of GHD was correlated to the severity of lipid profile abnormalities.

GHD in adults is associated with increased fat mass, reduced lean mass, osteopenia, impaired fibrinolysis, altered cardiac structure and function, unfavorable glucose and lipid metabolism, reduced exercise capacity, and reduced quality of life (1, 2, 3). As none of the symptoms is specific for the adult GHD syndrome, the diagnosis must be established on a biochemical basis (4, 5, 6, 7). There is general consensus that the biochemical diagnosis of severe GHD in adults is established when peak GH levels after ITT fall below 3 µg/L. In patients with contraindications to the ITT, the ARG+GHRH test has been indicated as the most promising alternative (4, 7). In a recent study (13), adult patients with severe GHD, namely with a GH peak after ITT less than 3 µg/L, had a GH response to ARG+GHRH below 9 µg/L. In normal subjects, the GH response after ARG+GHRH was always greater than 16.5 µg/L in both adults and children (10, 11 and the present study). Thus, patients with a GH response after ARG+GHRH below 3 µg/L can be defined as having very severe GHD. Among the 157 hypopituitary patients included in this study, 102 patients could be diagnosed as very severe or severe GHD on the basis of a GH peak to ARG+GHRH below 3 or 9 µg/L, respectively. In line with a previous observation, the majority of patients with very severe (89.2%) or severe (70.2%) GHD had associated other pituitary hormone deficiencies (14). Conversely, only 36% of patients with partial GHD had associated other pituitary hormone deficiencies, as had 30% of patients with normal GH response after ARG+GHRH. Measurement of IGF-I in adults is only useful when its concentrations are below the normal range, and normal IGF-I concentrations in adults do not exclude the diagnosis of GHD (4, 5, 6, 7). Accordingly, in this study we have shown that IGF-I concentrations were subnormal in 70.8% of patients with very severe GHD and in 59.4% of patients with severe GHD.

Similar to previous findings, we observed no difference in fasting glucose concentrations (1), whereas a significant increase in total, LDL cholesterol, and triglycerides together with a decrease in HDL cholesterol were observed only in patients with very severe GHD (15, 16, 17). Total cholesterol and triglycerides concentrations were significantly correlated to the peak GH response to ARG+GHRH. The facts that hypercholesterolemia is only observed in patients with very severe/severe GHD (15–17, and this study), whereas triglycerides concentrations were reported as normal (18) or increased (16), demonstrate that the influence of GH on serum cholesterol is limited. It should also be considered that GH plays a complex effect on lipid metabolism; in fact, GH influences lipoprotein lipase activity, hepatic LDL receptor expression, and very low density lipoprotein turnover (15, 16, 19, 20). These contrasting results might be related to differences in the ages of the patients as well as to the effect of replacement therapy, particularly thyroid hormones (1). Only patients with very severe GHD presented abnormalities involving the whole lipid profile (total, HDL, and LDL cholesterol and triglycerides levels) whereas previous studies addressing the changes in lipid profile after GH replacement did not evaluate the results on the basis of the severity of GHD. Our findings suggest that the risk of premature atherosclerosis (18) might be limited to the patients with very severe/severe GHD. Long term studies are needed to ascertain whether GH treatment would normalize the lipid profile and reduce the risk of cardiovascular abnormalities in these patients.

Surprisingly, in our study we observed no difference in body composition between hypopituitary patients with GHD and those with non-GHD. However, slightly increased FBM and decreased LBM were observed in patients with very severe GHD, with a trend toward a decrease in FBM and an increase in LBM from very severe GHD to non-GHD patients. A notable difference in body composition was found between patients and controls, in keeping with previous reports (21, 22, 23). Increased FBM, decreased LBM, and reduced TBW have been previously observed in untreated GHD adults using BIA (21, 22, 23) as well as other techniques (21, 22).

Concerning the abnormalities of lipid profile and body composition, it should be considered that the patients included in this study had a variable degree of pituitary insufficiency and were receiving standard replacement therapies. As it is well known that thyroid hormones (24), gonadal steroids (25), and glucocorticoids (26) have profound effects on lipid metabolism as well as on body composition, the possibility that in some of our patients replacement treatment was not completely adequate can not be ruled out.

A hypokinetic syndrome has been described in GHD adults of childhood onset (27, 28). However, no significant difference in hemodynamic parameters was found in the patients of our study. It has been recently reported that some of the changes associated with GHD differ between adults with GHD of childhood onset and those with adult-onset disease (17). However, cardiac function, assessed by radionuclide angiography, was similar in patients with childhood- and adult-onset GHD, when GHD occurred before 40 yr of age (29). The present study, however, included only patients with adult-onset of hypopituitarism and/or GHD, which were subdivided in four groups matched for age. Individual patients’ ages were not considered for the analysis of hemodynamic parameters.

In conclusion, the unfavorable lipid profile described in patients with severe GHD, as diagnosed by the ITT test (1, 2, 3, 15, 16, 17, 18, 19), was only found in patients with a GH response to ARG+GHRH below 9 µg/L. Therefore, a GH response to ARG+GHRH below 9 µg/L diagnosed a status of severe GHD. Furthermore, the results of this study confirmed that the GH response to ARG+GHRH is correlated with plasma IGF-I concentrations (13). IGF-I is considered to be the best indicator of somatotroph function in children (30). Our results as well as those of Aimaretti et al. (13) and Shalet et al. (4) suggest that IGF-I may also be an useful indicator of somatotroph function in adult population. Taken together, these findings indicate that the degree of the GH response to ARG+GHRH is correlated with the clinical status and further substantiate the reliability of the ARG+GHRH test for the diagnosis of GHD in adults. To date, GH treatment is recommended only in adult patients with severe GHD (4, 5, 6, 7). Therefore, patients with a GH response below 9 µg/L to the ARG+GHRH test should be treated with GH, as should patients with a peak GH response to ITT below 3 µg/L (4, 5, 6, 7). Conversely, in patients with a GH peak above 9 µg/L, careful monitoring of clinical conditions is recommended before GH replacement therapy is considered.

Received July 31, 1998.

Revised September 30, 1998.

Revised November 9, 1998.

Accepted November 18, 1998.

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				R. D. Murray, M. Bidlingmaier, C. J. Strasburger, and S. M. Shalet The Diagnosis of Partial Growth Hormone Deficiency in Adults with a Putative Insult to the Hypothalamo-Pituitary Axis J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1705 - 1709. [Abstract] [Full Text] [PDF]

				J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [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]

				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]

				A. Faggiano, D. Melis, R. Alfieri, M. De Martino, M. Filippella, F. Milone, G. Lombardi, A. Colao, and R. Pivonello Sulfur Amino Acids in Cushing's Disease: Insight in Homocysteine and Taurine Levels in Patients with Active and Cured Disease J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6616 - 6622. [Abstract] [Full Text] [PDF]

				P. Marzullo, C. Marcassa, R. Campini, E. Eleuteri, A. Minocci, L. Priano, P. Temporelli, A. Sartorio, R. Vettor, A. Liuzzi, et al. The Impact of Growth Hormone/Insulin-Like Growth Factor-I Axis and Nocturnal Breathing Disorders on Cardiovascular Features of Adult Patients with Prader-Willi Syndrome J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5639 - 5646. [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, S. Di Maio, M. Salerno, A. Klain, S. Spiezia, and G. Lombardi Common Carotid Intima-Media Thickness in Growth Hormone (GH)-Deficient Adolescents: A Prospective Study after GH Withdrawal and Restarting GH Replacement J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2659 - 2665. [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]

				A. Colao, C. Di Somma, A. Cuocolo, M. Filippella, F. Rota, W. Acampa, S. Savastano, M. Salvatore, and G. Lombardi The Severity of Growth Hormone Deficiency Correlates with the Severity of Cardiac Impairment in 100 Adult Patients with Hypopituitarism: An Observational, Case-Control Study J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5998 - 6004. [Abstract] [Full Text] [PDF]

				K. Link, C. Moell, S. Garwicz, E. Cavallin-Stahl, J. Bjork, U. Thilen, B. Ahren, and E. M. Erfurth Growth Hormone Deficiency Predicts Cardiovascular Risk in Young Adults Treated for Acute Lymphoblastic Leukemia in Childhood J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5003 - 5012. [Abstract] [Full Text] [PDF]

				R. D. Murray, J. E. Adams, and S. M. Shalet Adults with Partial Growth Hormone Deficiency Have an Adverse Body Composition J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1586 - 1591. [Abstract] [Full Text] [PDF]

				A. Colao, G. Vitale, P. Cappabianca, F. Briganti, A. Ciccarelli, M. De Rosa, S. Zarrilli, and G. Lombardi Outcome of Cabergoline Treatment in Men with Prolactinoma: Effects of a 24-Month Treatment on Prolactin Levels, Tumor Mass, Recovery of Pituitary Function, and Semen Analysis J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1704 - 1711. [Abstract] [Full Text] [PDF]

				A. Colao, C. Di Somma, S. Spiezia, M. Filippella, R. Pivonello, and G. Lombardi Effect of Growth Hormone (GH) and/or Testosterone Replacement on the Prostate in GH-Deficient Adult Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 88 - 94. [Abstract] [Full Text] [PDF]

				A. Colao, C. Di Somma, M. Salerno, L. Spinelli, F. Orio, and G. Lombardi The Cardiovascular Risk of GH-Deficient Adolescents J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3650 - 3655. [Abstract] [Full Text] [PDF]

				B. M. K. Biller, M. H. Samuels, A. Zagar, D. M. Cook, B. M. Arafah, V. Bonert, S. Stavrou, D. L. Kleinberg, J. J. Chipman, and M. L. Hartman Sensitivity and Specificity of Six Tests for the Diagnosis of Adult GH Deficiency J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2067 - 2079. [Abstract] [Full Text] [PDF]

				A. Colao, C. di Somma, R. Pivonello, A. Cuocolo, L. Spinelli, D. Bonaduce, M. Salvatore, and G. Lombardi 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., March 1, 2002; 87(3): 1088 - 1093. [Abstract] [Full Text] [PDF]

				P. Marzullo, C. Di Somma, K. L. Pratt, J. Khosravi, A. Diamandis, G. Lombardi, A. Colao, and R. G. Rosenfeld Usefulness of Different Biochemical Markers of the Insulin-Like Growth Factor (IGF) Family in Diagnosing Growth Hormone Excess and Deficiency in Adults J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3001 - 3008. [Abstract] [Full Text] [PDF]

				A. Colao, C. di Somma, A. Cuocolo, L. Spinelli, N. Tedesco, R. Pivonello, D. Bonaduce, M. Salvatore, and G. Lombardi 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., May 1, 2001; 86(5): 1874 - 1881. [Abstract] [Full Text]

				A. Colao, A. Cuocolo, C. Di Somma, G. Cerbone, A. M. Della Morte, E. Nicolai, R. Lucci, M. Salvatore, and G. Lombardi Impaired Cardiac Performance in Elderly Patients with Growth Hormone Deficiency J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3950 - 3955. [Abstract] [Full Text]

				A. Colao, R. Pivonello, S. Spiezia, A. Faggiano, D. Ferone, M. Filippella, P. Marzullo, G. Cerbone, M. Siciliani, and G. Lombardi Persistence of Increased Cardiovascular Risk in Patients with Cushing's Disease after Five Years of Successful Cure J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2664 - 2672. [Abstract] [Full Text]

				A. Colao, C. Di Somma, R. Pivonello, S. Loche, G. Aimaretti, G. Cerbone, A. Faggiano, G. Corneli, E. Ghigo, and G. Lombardi Bone Loss Is Correlated to the Severity of Growth Hormone Deficiency in Adult Patients with Hypopituitarism J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1919 - 1924. [Abstract] [Full Text]

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