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Original Article |
Departments of Molecular and Clinical Endocrinology and Oncology (A.C., C.D.S., F.O., G.L.), Pediatrics (M.S.), and Internal Medicine I (L.S.), University Federico II of Naples, 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
To investigate the onset of the cardiovascular impairment in patients with GH deficiency (GHD), we prospectively studied cardiovascular risk parameters, cardiac mass and performance (by echocardiography) in 10 adolescent patients (5 with isolated GHD and 5 with multiple GHD) who reached their final height before GH replacement withdrawal, 6 months after GH replacement withdrawal, and 6 months after GH treatment was restarted, and in 10 sex- and age-matched controls.
At study entry, when compared with controls, GHD adolescents had lower IGF-I levels (although still in the normal age range) and high-density lipoprotein (HDL)-cholesterol levels, higher total/HDL-cholesterol ratio, lower triglyceride levels, higher fibrinogen levels, and lower heart rate, systolic blood pressure, and early-to-late mitral flow velocity ratio (E/A). Left ventricular (LV) mass index and ejection fraction were normal. Six months after GH withdrawal, IGF-I levels decreased remarkably in all cases (from 176.6 ± 8.3 to 77.5 ± 8.9 µg/liter; P < 0.001), whereas low-density lipoprotein-cholesterol and triglyceride levels significantly increased. The total/HDL-cholesterol ratio (from 3.89 ± 0.1 to 4.74 ± 0.2; P < 0.05) and fibrinogen levels (from 261 ± 7.1 to 287.5 ± 6.4 mg/dl; P < 0.05) also significantly increased compared with study entry, without any change in the other parameters. In contrast, both LV mass index (from 94.2 ± 1.6 to 87.8 ± 1.7 g/m2; P = 0.05) and E/A (from 1.32 ± 0.05 to 1.12 ± 0.03; P < 0.01) decreased, although remaining in the normal range. Six months after restarting GH replacement (at a median dose of 10 µg/kg·d), lipid and cardiac parameters were brought back to the levels measured at study entry, but in no patient did IGF-I levels reach the 50th centile for age. HDL-cholesterol levels (P < 0.0001), heart rate (P < 0.05), systolic blood pressure (P < 0.01), LV ejection fraction (P < 0.005), and E/A (P < 0.0001) remained lower, whereas total/HDL-cholesterol ratio (P < 0.01), triglycerides, and fibrinogen levels (P < 0.05) remained higher than controls.
In conclusion, GH discontinuation is inappropriate in adolescents with severe GHD, inducing impairment of lipid profile and cardiac morphology and performance. Because the results on the cardiovascular system and on the lipid profile were suboptimal, it is likely that the GH dose in severe GHD adolescents should be higher.
HYPOPITUITARY PATIENTS HAVE an increased risk of mortality for cardiovascular disease (1, 2, 3, 4, 5). This is likely due to increased cardiovascular risk factors, increased body fat, premature atherosclerosis, decreased fibrinolytic activity, increased peripheral insulin resistance, increased frequency of impaired glucose tolerance, abnormal cardiac structure, and impaired cardiac performance, all typical features of adults with GH deficiency (GHD; Refs. 6 , 7). As specific cardiac signs, both young childhood-onset and adulthood-onset GHD adults have reduced left ventricular (LV) mass, inadequacy of ejection fraction (EF) overall on effort, and abnormalities of LV diastolic filling (7). However, they also have a vascular disease, demonstrated by an increased number of atheromatous plaques in the carotid and femoral arteries, increased intima-media thickness and stiffness of the carotid arteries, and impaired flow-mediated endothelium-dependent dilation of the brachial artery (6).
The reason to consider GHD one of the most important causes for the increased mortality from cardiovascular diseases of hypopituitary patients is that GH replacement improves abdominal fat distribution, low-density lipoprotein (LDL) cholesterol, and cardiac function; increases cardiac mass; reverses diastolic abnormalities; and decreases the carotid intima-media thickness in adults (8, 9, 10, 11). However, except for a recent study coming from a Europe register (12), its final effect on increased cardiovascular mortality is still questioned.
Current practice in childhood GHD patients is to stop GH replacement at final height (13). The persistence of GHD is then reevaluated by appropriate GH testing because one third to one half of patients with GHD during childhood do not have persistence of the disease in adulthood (14, 15). 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, decrease of lean body mass, and increase of total cholesterol, LDL-cholesterol, and apolipoprotein B, with decrease of high-density lipoprotein (HDL) cholesterol (16). In contrast, Lanes et al. (17) in a cross-sectional study did not find any difference in cardiac mass and function or in early atherosclerotic changes in GHD adolescents during GH replacement, those studied at the diagnosis of GHD (and thus not receiving GH), or healthy adolescents.
To further investigate the onset of the cardiovascular impairment in GHD patients, we designed this prospective study. The cardiovascular profile, cardiac mass and performance by echocardiography, were investigated in adolescent GHD patients who reached their final height before stopping GH replacement, 6 months after stopping GH replacement, and 6 months after restarting GH treatment. The results were compared with a sex- and age-matched control group.
Patients and Methods
Patients
Ten adolescent patients with GHD (five boys and five girls, aged 17–20 yr) with adult bone age and completed puberty (Tanner stage IV) and a mean height SD score of -0.71 ± 0.3 were studied. GHD had been diagnosed 6.6–12.3 yr before entering the study by two classical stimulation tests [insulin tolerance test, clonidine or arginine (ARG) with peak GH concentrations <10 µg/liter]. Five patients had idiopathic, isolated GHD, whereas the remaining five had organic GHD within a context of hypopituitarism. All patients of the latter group had been treated by surgery, either alone (n = 2) or associated with radiotherapy (n = 3), for pituitary lesions. All patients had received GH in the past for a period of 9.6 ± 0.5 yr. Hormone replacement therapy with L-T4 (50–100 µg/d p.o.), cortisone acetate (25–37.5 mg/d), and DDAVP (5–20 µg/d) was given where appropriate. Hypogonadism was treated in boys with testosterone enanthate (250 mg/month im) and in girls with standard oral estrogen/progestinic association. Adequacy of hormone replacement therapy was periodically assessed by serum free thyroid hormones, testosterone, urinary free cortisol together with serum and urinary Na+ and K+ measurements. At study entry, all patients had normal blood pressure and pulse, as well as normal adrenal and thyroid function tests; circulating levels of gonadal steroids were appropriate for age. Ten healthy adolescents (five boys and five girls, aged 17–20 yr), who were comparable for age, pubertal status, body height, body weight, blood pressure, and pulse, participated in the study as controls. Profiles of patients and controls at study entry are shown in Table 1
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At study entry, all subjects underwent electrocardiogram; systolic and diastolic blood pressure (SBP, DBP) and heart rate measurement; serum IGF-I; total-, LDL-, and HDL-cholesterol; triglyceride, glucose, and fibrinogen level assay; and echocardiography. Then, in GHD patients, IGF-I, total-, LDL- and HDL-cholesterol, triglyceride and fibrinogen levels, and echocardiography were repeated 6 months after GH withdrawal and 6 months after GH restarting. The total/HDL-cholesterol ratio, which is considered an index of severe cardiovascular risk (18), was also calculated. Three months after GH withdrawal, retesting of the GH secretory status was performed using the ARG + GHRH test as previously reported (19, 20). According to Aimaretti et al. (15), severe GHD was defined on the basis of a GH peak no greater than 9 µg/liter. A magnetic resonance of the sellar region was performed at study entry and 12 months later at the end of the study. No change in the pituitary size was observed.
Treatment protocol
At study entry, patients received GH replacement at the median dose of 35 µg/kg·d. According to the Consensus Conference (21), all 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 centile of normal serum IGF-I concentrations for sex and age, as previously reported (22, 23). 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.
Echocardiography
M-mode, two-dimensional, and pulsed Doppler echocardiographic studies were performed with ultrasound systems (Apogee CX, Interspec, Inc., Ambler, PA) using a 3.5-mHz transducer during at least three consecutive cardiac cycles. The records were made by one investigator (L.S.) blind in respect to the patients’ status. All patients were studied in the left lateral recumbent position after a 10-min resting period according to the recommendations of the American Society of Echocardiography (24). The following measurements were recorded on M-mode tracing; interventricular septum thickness (IST) and posterior wall thickness (PWT), the frequency normalized mean velocity of circumferential fiber shortening end-diastolic volume (EDV), end-systolic volume (ESV), and EF (EF = EDV - ESV/EDV%); they were estimated according to the Quinones method (25). LVEF is normal when above 50%. The LV mass (LVM) was calculated by using Devereux’s formula according to Penn’s convention with the following regression-corrected cube formula: LVM = 1.04 [(IST + LVID + PWT)3 - (LVID)3] - 14 g. (LVID is LV internal diameter.) Doppler studies provided indexes of ventricular filling that were derived from the mitral flow velocity curves, i.e. maximal early diastolic flow velocity (E in centimeters per second), maximal late diastolic flow velocity (A in centimeters per second), and the ratio between E and A curves (E/A; normal value >1).
Assays
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/liter. The intra- and interassay coefficients of variation (CV) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction. The sensitivity of the assay was 0.8 µg/liter. The normal IGF-I range in adolescent subjects (age, 16–20 yr) is 141 (3rd centile) to 625 (97th centile) µg/liter. The 50th centile of IGF-I levels in our laboratory is 350 µg/liter, calculated in samples taken from 60 healthy adolescents. The intra-assay CV was 3.4, 3.0, and 1.5% for low, medium, and high points on the standard curve, respectively. The interassay CV was 8.2, 1.5, and 3.7% for low, medium, and high points on the standard curve, respectively.
Statistical analysis
Data are reported as mean ± SEM. The statistical analysis was performed by means of an SPSS, Inc. (Cary, NC) package using Mann-Whitney U test to analyze the difference between controls and patients; Kruskal-Wallis test followed by the Mann-Whitney U test was used to analyze the difference in GHD patients before and after GH withdrawal and restarting. Significance was set at 5%.
Results
At study entry, compared with controls, GHD adolescents under GH replacement had lower IGF-I levels and HDL-cholesterol levels, accounting for a higher total/HDL-cholesterol ratio; lower triglyceride levels; higher fibrinogen levels; slightly but significantly lower heart rate and SBP; and lower E/A ratio (Table 1
). The LVMi and LVEF were normal. Serum IGF-I levels were normalized in all patients (Fig. 1), without any difference between isolated and multiple GHD (data not shown). None achieved the 50th centile (350 µg/liter), but all were above the 10th centile (160 µg/liter). One month after GH withdrawal, the ARG + GHRH test confirmed the persistence of GHD in all patients (Table 1).
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), total and HDL-cholesterol were unmodified, and LDL-cholesterol and triglyceride levels significantly increased (Table 2). The total/HDL-cholesterol ratio (from 3.89 ± 0.1 to 4.74 ± 0.2; P < 0.05) and fibrinogen levels (from 261 ± 7.1 to 287.5 ± 6.4 mg/dl; P < 0.05) also significantly increased compared with study entry, whereas glucose levels did not change (from 85 ± 1.7 to 82.9 ± 1.8 mg/dl). Also, no change was observed in heart rate [from 86.4 ± 1.1 to 84.1 ± 2.1 beats per minute (bpm)], SBP (from 106 ± 3 to 99 ± 3 mm Hg), DBP (from 74.5 ± 1.7 to 73.5 ± 1.9 mm Hg), and LVEF (from 54.4 ± 0.9 to 53.0 ± 0.8%; P = 0.06; Fig. 2). In contrast, both LVMi (from 94.2 ± 1.6 to 87.8 ± 1.7 g/m2; P = 0.05; Fig. 2) and E/A (from 1.32 ± 0.05 to 1.12 ± 0.03; P < 0.01; Fig. 2) significantly decreased after GH withdrawal, although remaining in the normal range.
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, lipid and cardiac parameters were brought back to the levels measured at study entry. However, 6 months after GH restarting, IGF-I levels were still subnormal in one patient with multiple GHD (Fig. 1); among the remaining patients, none achieved the 50th centile (350 µg/liter), four were on the 10th centile (160 µg/liter), and five were between the 3rd and the 10th centiles. Additionally, HDL-cholesterol levels (P < 0.0001), heart rate (P < 0.05), SBP (P < 0.01), EF (P < 0.005), and E/A (P < 0.0001) remained lower, whereas total/HDL-cholesterol ratio (P < 0.01), triglyceride and fibrinogen levels (P < 0.05) remained higher than controls. The dose of GH replacement was similar in boys and girls (10 ± 0.3 vs. 12 ± 0.9 µg/kg·d; P = 0.15), although in two girls with hypopituitarism and receiving oral estroprogestinic replacement, the maximal dose was 13 and 15 µg/kg·d, slightly higher than that used in boys. After GH withdrawal, IGF-I levels (59.8 ± 9 vs. 101.2 ± 2.2 µg/liter; P < 0.01) and LVEF (50.8 ± 0.4 vs. 55.2 ± 0.4%; P < 0.01) were lower, whereas triglyceride levels were higher (114 ± 4.1 vs. 88 ± 4.6 mg/dl; P < 0.01) in patients with multiple GHD than in those with isolated GHD. The other parameters were similar in the two groups (data not shown).
Discussion
The results of the current prospective study show that discontinuation of GH replacement in severe GHD adolescents impairs lipid profile and modifies heart morphology by inducing decrease in size and function by reducing cardiac filling. Six months after restarting GH treatment, improvement of the parameters above is observed; however, IGF-I levels were still not completely normalized and the total/HDL-cholesterol ratio, as a relevant predictive parameter for the cardiovascular risk, was still higher than controls. Similarly, both systolic and diastolic function remained slightly lower than controls. Altogether the results suggest that in severe childhood-onset GHD, GH replacement should be continued into adulthood.
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 intima-media thickness can all lead to an increased incidence of cardiovascular morbidity and mortality in GHD patients (6, 7). In particular, young GHD patients who acquired the disease in adulthood have a remarkable decrease of cardiac performance, exercise performance, and capacity on effort (26). In these patients, GH replacement has been widely reported to affect positively the LV morphology and function (7), whereas persistence of untreated GHD for 12 months further aggravates cardiac performance (27).
In GHD adolescents, Johannsson et al. (16) have recently reported that the discontinuation of GH treatment results in the accumulation of relevant cardiovascular risk factors and increase of body and abdominal fat and total and LDL-cholesterol concentrations. Lanes et al. (17) in a cross-sectional study including GH-treated and untreated GHD adolescents and controls reported similar results in terms of abnormal lipid and lipoprotein-a concentrations, whereas they did not find any abnormality in cardiac mass, LVEF at rest, and pulmonary venous flow velocities.
To better understand the risk of GH discontinuation in severe GHD adolescents reaching their final height, we designed this prospective study. In analogy with data obtained in young adults with GHD, GH withdrawal in GHD adolescents remarkably reduced IGF-I levels, unfavorably modified lipid profile, and, even if slightly, decreased cardiac size and impaired the diastolic filling. Heart rate and SBP were also slightly reduced. In particular, the abnormalities in lipid profile can be clinically relevant because they severely increase the coronary risk of GHD patients (28). Our results confirm that the total/HDL-cholesterol ratio is already increased in GHD patients during GH replacement and further increases after withdrawal. Increase in the total/HDL cholesterol ratio, an important parameter in the Framingham equation, is related to GHD both directly (LDL) and indirectly through increased central obesity (HDL) (28). In fact, the existence of a strong association between the serum cholesterol level measured early in adult life in men and cardiovascular disease in midlife has been suggested (29). This indicates the need to lower cholesterol (total/LDL) levels in young GHD patients. Moreover, our results in GHD adolescents off GH therapy are very similar to those recently reported by Johannsson et al. (16), except for triglyceride levels that were reduced in the Swedish study and increased in our study. A difference in the dietary intake of lipids between the two patient groups can be taken as partial explanation for this discrepancy. In agreement with Johannsson et al. (16), we also found in our patients an improvement of IGF-I secretion and metabolic parameters after restarting GH replacement. Hemodynamic parameters were not significantly modified, although a trend toward increase in heart rate and SBP was observed, similar to the results obtained in other cohorts of adult GHD patients (22, 26). Additionally, cardiac mass was significantly increased, being similar to controls, and the diastolic filling improved, although the latter was still significantly lower than controls. The systolic function, measured as LVEF, was not significantly modified by GH withdrawal, and restarting, although a trend toward an impairment before and an improvement after, was noted. It is likely that the small number of patients enrolled in this study prevented the achievement of statistical significance. Lastly, even if in a very small series, the EF, IGF-I, and triglyceride levels appear to be worse in patients with multiple GHD after GH withdrawal than in those with isolated GHD, suggesting that in a context of hypopituitarism GH replacement should never been withdrawn.
In conclusion, GH discontinuation seems to be inappropriate in adolescents with severe GHD because it causes impairment of lipid profile and cardiac morphology and performance. The dose of GH used in this study was calculated as suggested by the recent Consensus Conference for the young adult population of GHD subjects (21). On the basis of our results demonstrating a suboptimal effect on IGF-I levels, cardiovascular system, and lipid profile, the GH dose in adolescents and very young adults with GHD should be higher, likely doubled compared with the dose that we used. It should be mentioned, however, that our series is still small and the treatment period is short; other data are thus helpful in confirming the requirement of higher GH doses in the transitional period.
Acknowledgments
Footnotes
This work has been partially supported by Grant 7492 from Regione Campania L.R. 41/94 1999.
Abbreviations: ARG, Arginine; bpm, beats per minute; CV, coefficient(s) of variation; DBP, diastolic blood pressure; E/A, early-to-late mitral flow velocity ratio; EF, ejection fraction; GHD, GH deficiency or deficient; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LV, left ventricular; LVMi, LV mass index; PWT, posterior wall thickness; SBP, systolic blood pressure.
Received December 12, 2001.
Accepted May 7, 2002.
References
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