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Departments of Molecular and Clinical Endocrinology and Oncology, Nuclear Medicine Center of the National Council of Research (A.Co., C.D.S., R.P., G.L.); Departments of Biomorphological and Functional Sciences (A.Cu., N.T., M.S.) and Internal Medicine I (L.S., D.B.), Federico II University of Naples, 80131 Naples; and Scientific Institute for Research and Cure Neuromed (A.Cu.), Pozzilli, 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
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Abstract |
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In conclusion, GH replacement for 12 months significantly improved lipid profile, decreased fibrinogen levels, and increased LVMi and LVEF in young adults with co- or ao-GHD. However, lipid profile, fibrinogen levels, and systolic function remained abnormal compared with those in age- and sex-matched controls, suggesting that a longer period of GH replacement is necessary to normalize cardiovascular parameters and reverse the cardiovascular risk of these patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From a clinical perspective, clear-cut evidence for the existence of specific acromegalic cardiomyopathy is now recognized (9, 10, 11), whereas in patients with GHD a decrease in left ventricular posterior wall and interventricular septum thickness leading to decreased left ventricular (LV) mass (LVM) was described by some researchers (12, 13, 14), although this was not a constant finding (15, 16, 17). Besides alterations of cardiac geometry, GHD patients present varying degrees of diastolic dysfunction, whereas systolic function at rest is reported to be normal (12, 13, 14, 15, 16, 17). However, using equilibrium radionuclide angiography, a technique more sensitive than echocardiography to evaluate systolic function, we recently demonstrated that the prevalence of impaired response of the LV ejection fraction (EF) during exercise was relevant, occurring in 65.4–81.8% of adult (18) and elderly (19) GHD patients. However, the described hypokinetic syndrome of GHD patients (20) was evident only in young subjects who had heart rate and LVEF, both at rest and at peak exercise, significantly lower than age-matched controls (18). These findings confirmed previous data collected in a smaller series of patients with childhood-onset (co-) or adulthood-onset (ao-) disease (21, 22, 23).
A large number of short-term studies have reported beneficial effects of GH replacement on lipid profile, body composition and metabolism, physical performance, cognitive function, and general well-being (24, 25, 26). Cardiac function did not change after 6 months of treatment in one study (15), whereas in another study a 26% increase in the LVM index (LVMi) and a 12% increase in systolic function were observed (14). In a small series of adult co-GHD patients we reported an increase in cardiac performance (21, 22) after 6 months of GH replacement. However, data concerning long-term GH replacement on the reversibility of cardiovascular risk in these patients are still lacking.
The aim of this prospective controlled cohort study was to investigate the effect of GH replacement for 12 months on cardiovascular risk factors, such as lipid profile and fibrinogen levels (27) and cardiac mass and performance in adult patients with GHD. As GHD is likely to display different effects in young, adult, and elderly patients, and patients with disease onset during childhood were shown to present more severe symptoms than those with adult onset of disease (28), only young patients were enrolled in the current study. The results were analyzed both in the entire population and separately in co- and ao-GHD patients and were compared with those from an appropriate sex- and age-matched control group.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty patients (11 men and 9 women; age range, 19–40 yr;
median age, 26.5 yr) with diagnosis of GHD (see below) during childhood
(in 10) or as adults (in 10) entered this open prospective study. As a
control group we studied 20 healthy volunteers sex- and age-matched
with the patients (11 men and 9 women; age range, 18–40 yr; median
age, 31 yr). All patients and controls gave informed consent to
participate in this study, and the study protocol was approved by the
ethics committee of the Medical School of the University Federico II
(Naples, Italy). None of the patients and controls presented with or
had previously suffered from other concomitant diseases affecting
cardiac function, such as diabetes mellitus, coronary artery diseases,
long-standing hypertension, or hyperthyroidism. None of the 40 subjects
was obese (body mass index, <30). Table 1
shows anthropometrical, endocrine, and
metabolic data, and Table 2 shows cardiac
data in patients and controls. All patients, except 3 with idiopathic
co-GHD, had been previously operated on via the transsphenoidal and/or
transcranic route for PRL-secreting adenomas, nonfunctioning pituitary
adenoma, or craniopharyngioma, and 8 of them had been irradiated. Five
patients had panhypopituitarism, 4 patients had FSH/LH and TSH
deficiencies, 2 patients had FSH/LH and ACTH insufficiency, 4 patients
had FSH/LH deficiencies, and 5 patients had GHD alone. 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.
Hypogonadism was treated in men with testosterone enanthate (250 mg,
im, monthly) and in women with standard estroprogestinic association.
The adequacy of hormone replacement therapy was periodically assessed
by measurements 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. None of
the ao-GHD patients had ever received GH treatment. Patients with
co-GHD had received GH replacement with extractive and/or recombinant
GH for 3–13 yr and withdrew from treatment at least 2 yr before
entering the study. At study entry, the diagnosis of GHD was performed
by insulin tolerance test (GH peak, <3 µg/L) and/or arginine plus
GHRH test (GH peak, <9 µg/L) (29, 30, 31). The equivalent
ratio of milliunits per L to micrograms per L is 2 (2 mU/L equals 1
µg/L) before January 1997 or 2.5/3 after that (32). The
duration of GHD was calculated from the time of diagnosis of the
pituitary tumor in ao-GHD patients and from the time of GH withdrawal
in co-GHD patients; in this group estimated GHD duration was 8.6
± 1.2 yr.
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At study entry all 40 subjects underwent electrocardiogram; systolic and diastolic blood pressure (SBP and DBP) and heart rate measurements; serum IGF-I; total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, triglycerides, and fibrinogen level assays; echocardiography; and equilibrium radionuclide angiography. In GHD patients, IGF-I measurements were repeated after 1, 2, 3, 6, and 12 months; total, LDL, and HDL cholesterol; triglycerides; and fibrinogen measurements were repeated after 3, 6, and 12 months; and echocardiography and equilibrium radionuclide angiography were repeated after 12 months of GH replacement. Before and after 12 months of GH replacement all patients were subjected to magnetic resonance of the sellar region, which showed no evidence of intrasellar or parasellar residual tumor at study entry.
Treatment protocol
All patients received recombinant GH at a starting dose of 10 µg/kg·day. Subsequently, the dose was adjusted on the basis of serum IGF-I concentrations up to the normal range for sex and age. The maximal dose used in this study was 15 µg/kg·day in men and 20 µg/kg·day in women.
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/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 using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX). The normal range in 20- to 40-yr-old subjects is 110–450 µg/L. The sensitivity of the assay was 0.8 µg/L. The intraassay coefficients of variation were 3.4%, 3.0%, and 1.5% for the low, medium, and high points of the standard curve, respectively. The interassay coefficients of variation were 8.2%, 1.5%, and 3.7% for the low, medium, and high points of the standard curve. Fasting total, LDL, and HDL cholesterol, triglycerides, and fibrinogen levels were measured by standard procedures. The total/HDL cholesterol ratio, considered the index of severe cardiovascular risk (33), was also calculated.
Echocardiography
M-mode, two-dimensional, and pulsed Doppler echocardiographies were performed with commercially available ultrasound systems (Sonos 2500, Hewlett-Packard Co., Andover, MA) using a 2.5-mHz transducer during three to five consecutive cardiac cycles. 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 (34). The following measurements were recorded on M-mode tracing: interventricular septum thickness (IVST) and posterior wall thickness (LVPWT), and LVM calculation by Devereux’s formula according to the Penn convention with the following regression-corrected cube formula: LVM = 1.04[(IVST + LVID + PWT)3 - (LVID)3] - 14 g. LV hypertrophy was considered when LVMi was 135 g/m2 or more in men and 110 g/m2 or more in women. The echocardiography operator was blinded to control or patient examination.
Equilibrium radionuclide angiography
The angiography study was performed as previously reported
(10, 18, 21, 22, 23). In vivo labeling of red blood
cells was performed with 555 megabecquerels (15 mCi)
99mTc. Radionuclide angiography was performed at
rest and during dynamic physical exercise in the 45° left anterior
projection with a 15° craniocaudal tilt with the patient in a supine
position. A small field of view 
-camera (Starcam 300 A/M, General
Electric, Milwaukee, WI) equipped with a low energy, all purpose
collimator was used. Data were recorded at a rate of 30 frames/cardiac
cycle for the resting study and 16 frames/cardiac cycle for the
exercise study on a dedicated computer system (General Electric). At
least 200,000 counts/frame were acquired. Exercise studies were
performed using a bicycle ergometer with a restraining harness to
minimize patient motion under the camera. Exercise loads were increased
by 25 watts every 2 min until angina, limiting dyspnea, or fatigue
developed. No patient developed high grade ventricular arrhythmias
necessitating termination of exercise. Heart rate and SBP and DBP,
determined by cuff sphygmomanometer, were monitored during exercise at
each stage. Radionuclide angiography studies were analyzed using a
standard commercial software system (General Electric). The LV regions
of interest were automatically drawn for each frame, and a background
region of interest was also computer delineated on the end-systolic
frame. After background correction, a time-activity curve was
generated. Indexes of LV function were derived by computer analysis of
the background-corrected time-activity curve. LVEF was computed on the
basis of relative on end-diastolic and end-systolic counts. Peak
LV ejection and filling rates were also calculated after Fourier
expansion with four harmonics. Peak ejection rate (PER) was computed as
the minimum negative peak before end-systole, and peak filling rate
(PFR) was calculated as the maximum positive peak after end-systole on
the first derivative of the LV time-activity curve. Both PER and PFR
were computed in LV counts per s, normalized for the number of counts
at end-diastole and expressed as end-diastolic volume per s (EDV/s).
When normalized for end-diastolic volume, both PER and PFR are
influenced directly by the magnitude of LVEF (35). To
minimize this effect, we also analyzed PFR as the PFR to PER ratio
(36), a method that is background independent.
Statistical analysis
Data are reported as the mean ± SEM. Statistical analysis was performed by means of an SPSS, Inc. (Cary, NC), package using two-tailed ANOVA to analyze differences between controls and patients and between co- and ao-GHD patients before and after GH replacement. Student’s t test for paired data was used to analyze the effect of GH replacement in GHD patients. The linear regression analysis was used to correlate patients’ age, duration of GHD, and exercise-induced changes in LVEF with GH peak after testing; IGF-I; total, LDL, and HDL cholesterol, triglycerides, and fibrinogen levels; LVMi; LVEF at rest and at peak exercise; PFR; PER; and the percent increase in IGF-I levels and LVMi after GH replacement. Significance was set at 5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
Conversely, IGF-I and HDL cholesterol levels were lower, and total
cholesterol, LDL cholesterol, triglycerides, and fibrinogen levels and
total/HDL cholesterol ratio were higher in patients than in controls
(Table 1). IST, LVPWT, LVMi, and exercise capacity and duration were
lower in GHD patients than in controls (Table 2). Similarly, GHD
patients had decreased SBP at rest (P = 0.03), PER
(P = 0.005), and LVEF at rest (P =
0.001) and at peak exercise (P < 0.0001). Among the 20
patients and 20 controls, high total cholesterol levels were found in 8
(40%) and 1 (0.5%; 
2 = 5.2;
P = 0.02), low HDL cholesterol levels were found in 3
(15%) and none, high triglycerides levels were found in 2 (10%) and
none, mild hypertension was found in 2 (10%) and none, impaired LVEF
at rest was found in 7 (35%) and none (2 =
6.2; P = 0.01), and inadequate response of LVEF at peak
exercise was found in 16 (80%) and none (2 =
23.4; P < 0.0001), respectively. One patient could not
perform the physical effort due to deep muscular asthenia. The LV
diastolic filling, measured either as PFR or as the PFR/PER ratio, was
similar in patients and controls (Table 2). Effect of 12-month GH replacement
After 12 months, a significant increase in IGF-I and HDL
cholesterol levels and a significant decrease in total and LDL
cholesterol, triglycerides, and fibrinogen levels and the total to HDL
cholesterol ratio (from 4.9 ± 0.3 to 3.6 ± 0.2;
P < 0.0001) was observed in GHD patients (Fig. 1). Total cholesterol levels normalized
in 6 of 8 patients (75%), whereas IGF-I, HDL cholesterol, and
triglycerides levels normalized in all patients. Significant increases
in IST, LVPWT, and LVMi; LVEF at peak exercise; and exercise-induced
changes in LVEF (Fig. 2), exercise
capacity (from 82.9 ± 3.3 to 100.0 ± 4.2 watts;
P = 0.0009), and duration (from 7.3 ± 0.4 to
8.9 ± 0.4 min; P = 0.003) were also obtained
after GH replacement. LVEF at rest normalized in 4 of 7 patients
(57.1%), whereas its response at peak exercise normalized in 6 of 16
(37.5%). Resting SBP decreased (from 111.0 ± 2.9 to 104.0
± 2.1 mm Hg; P = 0.01), whereas no change in heart
rate and DBP either at rest or at peak exercise, PFR,or PER was found.
None of the patients developed hypertension during GH treatment, and
the 2 patients with mild hypertension regained a normal DBP. However,
at the end of treatment, total cholesterol levels, the ratio between
total and HDL cholesterol levels (3.6 ± 0.2 vs.
3.0 ± 0.2; P = 0.04), fibrinogen levels, and LVMi
were higher, whereas IGF-I levels, HDL cholesterol levels,
triglycerides levels, and LVEF both at rest and at peak exercise were
lower than control values (Figs. 1 and 2).
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At baseline, co- and ao-GHD patients had similar IGF-I levels,
hemodynamic parameters, and exercise capacity and duration (data not
shown). Conversely, ao-GHD patients had greater age (32.6 ± 1.6
vs. 23.4 ± 1.7 yr; P < 0.0001) and
disease duration (11.6 ± 1.6 vs. 5.6 ± 1.0 yr;
P = 0.01) and lower PER (2.5 ± 0.2 vs.
3.4 ± 0.2 EDV/s; P = 0.01) and LVEF at rest
(47.5 ± 2.2% vs. 55.7 ± 3.0%;
P = 0.01) and at peak exercise (42.4 ± 1.7%
vs. 51.9 ± 1.7%; P < 0.0001) than
co-GHD patients. After GH replacement, IGF-I levels, LVPWT, IST, LVMi,
LVEF at peak exercise, and exercise-induced changes in LVEF increased
similarly in both groups (Figs. 3 and 4).
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Neither age nor disease duration was correlated with baseline IGF-I, LVPWT, IST, and LVMi or with the percent increase in IGF-I levels and LVMi after GH replacement. The age of the patients was significantly correlated with PFR (r2 = 0.4; P = 0.001), PFR/PER (r2 = 0.2; P = 0.03), heart rate at rest (r2 = 0.2; P = 0.02), and SBP at peak exercise (r2 = 0.3; P = 0.02), whereas GHD duration was significantly correlated with the exercise-induced changes in LVEF (r2 = 0.6; P = 0.0002) and SBP and DBP at peak exercise (r2 = 0.4; P = 0.004 and r2 = 0.2; P = 0.04, respectively). Exercise-induced changes in LVEF were significantly correlated with LVEF at rest (r2 = 0.3; P = 0.02) and the total/HDL cholesterol ratio (r2 = 0.2; P = 0.0002).
Side-effects
Mild arthralgia was reported during the first week of treatment by three patients (15%), whereas two other patients experienced mild fluid retention that resolved at the end of the second month of therapy without changing the GH dose. Pain at the joint sites, peculiarly hands, knees, and feet, was reported by one patient after increasing the dose to 20 µg/kg·day; dose reduction induced the disappearance of symptoms. No patient withdrew from treatment because of side-effects, and magnetic resonance imaging did not show any tumor recurrence after 12 months.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The main cause of death in patients with long-standing GHD is cardiovascular disease (1, 2, 3). In our cohort, GHD was significantly associated with increased total cholesterol levels and impaired LVEF at rest and at peak exercise, confirming previous data (21, 22, 23, 24, 25, 26, 29). A large number of clinical studies have reported beneficial effects of GH replacement in adult GHD patients (24, 25, 26). However, although long-term GH replacement to GHD adults was reported to be able to improve body composition, bone mineral density, exercise capacity, strength, lipid profile, and coagulation (24, 25, 26), the ultimate clinical efficacy of GH treatment on the reversibility of the cardiovascular risk is still unknown. Furthermore, the dose of GH employed during the last decade was progressively reduced and largely varied in different studies, ranging from 6–26 µg/kg BW. GH replacement was shown to increase cardiac mass in some studies of short duration (14, 16, 37, 38), but not in others (15, 39, 40). In particular, Amato et al. (14) reported a sustained increase in LVMi up to about 26% of the baseline together with an improvement in resting LVEF after GH replacement patients at a dose of 10 µg/kg BW for 6 months; these effects were reversed by 6 months of GH discontinuation. A significant increase in cardiac mass was found during sustained (41) and low doses (16) of GH. A similar increase in LVMi by 17.5 ± 1.3% was observed in our patients treated with low GH doses. Although after GH replacement, LVMi was significantly higher in GHD patients than in controls, none of the patients developed clear-cut LV hypertrophy. Interestingly, a significant increase in cardiac mass was also reported by Ter Maaten et al. (41) during the first year of a 10-yr follow-up GH replacement study at elevated doses. However, the hypertrophic effect of GH replacement subsided during treatment, and after the 2–10 yr of follow-up cardiac mass was similar to pretreatment values (41). Similarly, no change in cardiac size was reported by Gibney et al. (42) in another 10-yr follow-up study.
By echocardiography, no change in cardiac performance at rest was reported by some researches (15, 38), an increase in stroke volume was reported by others (16, 37, 39, 43, 44), but improvement of cardiac performance with exercise has been investigated in only a few studies. It should be considered that the evaluation of cardiac function by echocardiography is affected by two major limitations: the intra- and interobserver variabilities and the poor sensitivity because of the assumptions necessary to calculate the LVEF (34). In fact, in a large cohort of 55 patients with ao-GHD, an impaired LVEF response at peak exercise was found by radionuclide angiography in as many as 65.4% of patients regardless of age of onset of the disease, whereas LVEF at rest was impaired in only 23.6% of them (18). As the diastolic filling reduces with aging (35), to minimize the variability in the negative effect of GHD during the life span only young patients were investigated in the current study. A second end point was to disclose potential differences of the beneficial effect of GH replacement on cardiac performance between co- and ao-GHD, who were shown to bear different clinical and laboratory characteristics (28).
In the entire series of patients, LVEF at peak exercise as well as the exercise-induced changes in LVEF and exercise duration and capacity increased significantly. In particular, normalization of LVEF at rest and at peak exercise was obtained in 57.1% and 37.5% of patients, respectively. It should be noted that ao-GHD had lower LVEF both at rest and at peak exercise, PER, and PFR and higher SBP at peak exercise than co-GHD patients at study entry. These results were probably due to a longer exposure to GHD of ao-GHD patients than co-GHD patients, who were treated with GH during part of their developmental period before entering the study. In fact, the 2 patients who withdrew from GH replacement for 2 yr still had normal cardiac performance even in the presence of low IGF-I levels, whereas all ao-GHD patients had inadequate LVEF responses at peak exercise. Therefore, 57.1% of co-GHD patients regained a normal LVEF response at peak exercise compared with 22.2% of ao-GHD patients. Hemodynamic parameters are also known to be modified during GH replacement, contributing to the improvement in cardiac performance. In particular, heart rate has been reported to increase after GH replacement (16, 17, 22, 41), although in the current series heart rate at rest or at peak exercise was not significantly modified by GH treatment. In contrast, a significant decrease in SBP was found in the GHD population as a whole, probably via the endothelial action of IGF-I (45). However, the improved cardiac performance was sustained by a remarkable increase in exercise performance. In line with previous reports (24, 25, 26), we found a notable increase in exercise capacity and duration.
In conclusion, 12 months of GH replacement significantly reduced total and LDL cholesterol and fibrinogen levels, increased LVMi, and improved cardiac performance in young adult patients with co- or ao-GHD to a similar extent. However, systolic function remained depressed compared with that in age- and sex-matched controls. In particular, 42.8% and 62.5% of GHD patients had inadequate LVEF at rest and during exercise, respectively. These findings indicate that in young patients with long GHD duration, a more than 12-month period of GH replacement may be necessary to restore a normal lipid and coagulation profile and normal cardiac performance, probably reversing the poor prognosis for cardiovascular accidents.
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Footnotes |
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Received November 17, 2000.
Revised January 26, 2001.
Accepted January 29, 2001.
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L. E. Underwood, K. M. Attie, and J. Baptista Growth Hormone (GH) Dose-Response in Young Adults with Childhood-Onset GH Deficiency: A Two-Year, Multicenter, Multiple-Dose, Placebo-Controlled Study J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5273 - 5280. [Abstract] [Full Text] [PDF]
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J. C. Smith, H. A. Lane, J. Lewis, S. Dann, J. Goodfellow, P. Collins, L. M. Evans, M. F. Scanlon, and J. S. Davies Endothelial Function and Coagulant Factors in Growth Hormone-Treated Hypopituitary Adults Receiving Desmopressin J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2152 - 2156. [Abstract] [Full Text] [PDF]
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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]
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 W. L. Isley Growth Hormone Therapy for Adults: Not Ready for Prime Time? Ann Intern Med, August 6, 2002; 137(3): 190 - 196. [Abstract] [Full Text] [PDF]
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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]
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) in LVEF (bottom right)
before and after 12 months of GH replacement in young patients with GHD
compared with sex- and age-matched controls.
)
and ao-GHD (•) patients before and after GH replacement.