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Original Studies |
Department of Molecular and Clinical Endocrinology and Oncology (A.Co., C.D.S., G.C., R.L., G.L.), Nuclear Medicine Center of the National Council of Research, Department of Biomorphological and Functional Sciences (A.Cu., A.M.D.M., E.N., M.S.), Federico II University of Naples, 80131 Naples; and INM 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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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Eleven patients with hypopituitarism (6 men and 5 women, aged 60–72 yr) and 11 sex- age- and body mass index-matched healthy subjects entered this study. None of the patients and controls presented with or had previously suffered from other concomitant diseases, such as diabetes mellitus, coronary artery diseases, long-standing hypertension, and hyperthyroidism, which could affect cardiac function. All patients had been previously operated on via the transsphenoidal and/or transcranic route for nonfunctioning pituitary adenoma, meningioma, or craniopharyngioma, and 6 of them had been irradiated. Eight patients had FSH/LH insufficiency, 5 had TSH insufficiency, and 6 had ACTH insufficiency, appropriately replaced. All subjects were tested with the combined arginine plus GHRH test showing a GH response below 9 µg/L.
No significant difference was found in plasma IGF-I levels (49.2
± 8.5 vs. 71.8 ± 7.5 µg/L) between patients and
controls. However, IGF-I levels were lower than the normal range in 8
patients and 3 controls. Interventricular septum thickness (9.1 ±
0.2 vs. 9.1 ± 0.2 mm), LV posterior wall thickness
(9.1 ± 0.2 vs. 9.0 ± 0.2 mm), and LVM after
correction for body surface area (97.6 ± 1.8 vs.
99.9 ± 1.5 g/m2) were similar in patients and
controls. Similarly, the LV ejection fraction at rest was similar in
patients and controls (57.1 ± 2% vs. 63.2 ±
2.5%; P = NS), and it was normal (
50%) in all
controls and in 10 of 11 patients. By contrast, the LV ejection
fraction at peak exercise was markedly depressed in elderly GHD
patients compared to age-matched controls (51 ± 2.5%
vs. 73.3 ± 3%; P < 0.001). A
normal response (5% increase compared to basal value) of LV ejection
fraction at peak exercise was found in 8 controls (72.7%) and in 2 of
11 patients (18.2%). No difference was found in the peak rate of LV
filling, whether peak filling rate was normalized to end-diastolic
volume (2.5 ± 0.2 vs. 2.6 ± 0.2
end-diastolic volume/s) or stroke volume (4.3 ± 0.3
vs. 4.0 ± 0.3 stroke volume/s), between patients
and controls. Finally, exercise duration was significantly shorter in
elderly GHD patients than in age-matched controls (7.2 ± 2.1
vs. 9.1 ± 0.2 min; P < 0.01).
In the patient group, the GH peak after arginine plus GHRH test was
significantly correlated with the LV ejection fraction at rest (r
= 0.822; P < 0.01), whereas IGF-I was
significantly correlated with the peak rate of LV filling whether the
peak filling rate was normalized to end-diastolic volume (r =
-0.863; P < 0.001) or stroke volume (r =
-0.616; P < 0.05) or expressed as the ratio of
peak filling rate to peak ejection fraction rate (r = -0.736;
P < 0.01). Disease duration was significantly
correlated with heart rate at peak exercise (r = 0.614;
P < 0.05) and with systolic and diastolic blood
pressures both at rest (r = 0.745; P < 0.01
and r = 0.650; P < 0.05) and at peak exercise
(r = 0.684; P < 0.05 and r = 0.617;
P < 0.05).
The results of the present study demonstrated that, as in young and adult GHD patients, cardiac performance was impaired in elderly GHD patients, whereas cardiac mass was normal. These findings further support the potential usefulness of GH replacement in elderly hypopituitary patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As GH secretion physiologically declines with age, and in aging GH and IGF-I levels are low, the existence of a GHD syndrome in elderly patients is still debated. Although impairment of GH dynamics has been reported in elderly patients with GHD (14, 15), controversial data have been reported on the impairment of bone mass or body composition (16, 17, 18). No study has been reported to date in elderly GHD patients to investigate cardiac function. In particular, it is unknown whether LV function is modified in accordance with patients’ age as a physiological response to aging, as in normal subjects a reduction of the rate and extent of LV filling has been reported (19, 20, 21).
This study was designed to evaluate heart morphology, by echocardiography, and function, by equilibrium radionuclide angiography, in a series of rigorously selected elderly patients with GHD but without evidence of other complications able to affect cardiac performance.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among 97 patients subjected to diagnostic screening for GHD
after pituitary surgery, 20 patients were more than 60 yr of age, and
11 of them (6 men and 5 women, aged 60–72 yr) entered this study after
their informed consent had been obtained. Eleven sex-, age-, and body
mass index (BMI)-matched healthy subjects served as controls. None of
the patients or controls presented with or had previously suffered from
other concomitant diseases, such as diabetes mellitus, coronary artery
diseases, long-standing hypertension, or hyperthyroidism, which could
affect cardiac function. All patients and controls had a similar
sedentary lifestyle; 2 patients and 2 controls were mild smokers (<10
cigarettes/day). None of the 22 subjects was obese (BMI, <30). Seven
patients and 5 controls were moderately overweight (BMI, 25–30). Table 1
shows the patients’ profile at study
entry. All patients had been previously operated on via a
transsphenoidal and/or transcranic route for nonfunctioning pituitary
adenoma, meningioma, or craniopharyngioma, and 6 of them had been
irradiated. Eight patients had FSH/LH insufficiency, 5 had TSH
insufficiency, and 6 had ACTH insufficiency. Hypothyroidism and
hypoadrenocorticism were treated with
L-T4 (50–100 µg, orally, daily)
and cortisone acetate (25–37.5 mg/day). All males with hypogonadism
were treated with testosterone depot (250 mg, im, monthly). Adequacy of
hormone replacement therapy was periodically assessed by 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 patients had ever
received GH treatment. Magnetic resonance imaging of the
hypothalamus-pituitary region documented empty sella in 5 and residual
tumor in 6. To avoid overestimation, the duration of the disease was
calculated from the time of diagnosis, and the retrospective evaluation
of symptoms presumably related to the pituitary disease was not
considered.
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At study entry, all subjects underwent a careful clinical evaluation, including electrocardiogram, blood pressure and heart rate measurements, routine blood and urine analysis, including total cholesterol and triglycerides levels, plasma IGF-I and IGF-binding protein-3 (IGFBP-3) assays, complete M-mode and two-dimensional echocardiographic evaluation, and equilibrium radionuclide angiography. All subjects were tested with the combined arginine (ARG) plus GHRH test (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-(1–44), (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 up to 90 min. According to recent studies (22, 23, 24, 25), a GH response to ARG+GHRH below 9 µg/L was considered diagnostic of GHD.
Assays
Serum GH levels were measured by immunoradiometric assay using commercially available kits. 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 range in over 60-yr-old subjects was 78–258 µg/L. The sensitivity of the assay was 0.8 µg/L. The intraassay CVs were 3.4%, 3.0%, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2%, 1.5%, and 3.7% for low, medium, and high points of the standard curve. Plasma IGFBP-3 was measured by RIA after ethanol extraction. The normal range in over 60-yr-old subjects was 2–4 mg/L. The sensitivity of the assay was 0.5 µg/L. The intraassay CVs were 3.9%, 3.2%, and 1.8% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 0.6%, 0.5%, and 1.6% for low, medium, and high points of the standard curve.
Gated blood pool cardiac scintigraphy
In vivo labeling of red blood cells was performed
with 555 megabecquerels (15 mCi) of 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 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 blood pressure (by cuff sphygmomanometer) were monitored
during exercise at each stage.
Radionuclide angiography studies were analyzed using a standard commercial software system (General Electric). 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 LV time-activity curve was generated. Indexes of LV function were derived by computer analysis of the background-corrected time-activity curve. Ejection fraction was computed on the basis of relative end-diastolic and end-systolic counts. Peak LV ejection and filling rates were also calculated after a Fourier expansion with four harmonics. Peak ejection rate was computed as the minimum negative peak before end-systole, and peak filling rate was the maximum positive peak after end-systole on the first derivative of the LV time-activity curve. Both peak ejection rate and peak filling rate were computed in the LV counts/s, normalized for the number of counts at end-diastole, and expressed as end-diastolic volume (EDV) per s. When normalized for EDV, both peak ejection rate and peak filling rate are influenced directly by the magnitude of the ejection fraction (26). To minimize this effect, we also analyzed peak filling rate using two additional normalization methods; the peak filling rate was expressed relative to LV stroke volume (SV) per s and as the ratio of peak filling rate to peak ejection rate (27, 28). These two latter methods have the additional advantage of being background independent. The time to peak ejection rate was measured from the R wave, and the time to peak filling rate was measured relative to end-systole (minimal volume on the time-activity curve).
Echocardiography evaluation
Complete M-mode and two-dimensional analyses were performed using an ultrasound mechanical system equipped with a 3.5-mHz transducer (Apogee CX, Interspec, Ambler, CA). M-Mode and two-dimensional recordings were made with subjects in a lateral recumbent position according to the standardization of the American Society of Echocardiography (29). Interventricular septum and LV posterior wall thickness and LV end-diastolic and end-systolic cavity dimensions were measured by averaging the values for four consecutive cycles. Individuals reading the studies were blind as to whether the exam they were interpreting was that of an adult GHD patient or a normal control subject. Calculation of the LVM was performed using the Penn convention with the following regression-corrected cube formula: Echo LVM = 1.04[(ISV + LVID + PWT)3 - (LVID)3] - 14 g (30). LV hypertrophy was considered when LVM values, corrected for body surface area (LVMi), were greater than or equal to 135 g/m2 in males and greater than or equal to 110 g/m2 in females.
Statistical analysis
Data are reported as the mean ± SEM. The statistical analysis was performed by means of the SPSS, Inc. (Cary, NC), package using ANOVA. Linear correlation analysis was carried out, calculating the Pearson’s coefficient, to assess the relationship among different parameters. Stepwise multiple linear regression was performed to evaluate the relative importance of disease duration and GH and IGF-I levels on structural (IST, LVPWT, and LVMi) and functional (PFR, PER, and resting and exercising EF) parameters. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), although the difference was
not statistically significant, and they were below the normal range in
eight patients and three controls. Similarly, total blood cholesterol
levels were significantly higher in patients than controls (231.7
± 8.9 vs. 184.3 ± 6 mg/dL; P <
0.001). Serum triglycerides (182.2 ± 20.1 vs.
161.2 ± 9.5 mg/dL) and low density lipoprotein cholesterol
(150.5 ± 21.6 vs. 117.2 ± 9.7 mg/dL) levels were
also slightly higher in GHD patients than in controls, but the
difference was not statistically significant.
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Interventricular septum thickness, LV posterior wall thickness,
and LVMi were similar in elderly GHD patients and controls (Table 2
).
Functional study
At rest, no significant difference was found in systolic
blood pressure between patients and controls, whereas systolic blood
pressure at peak exercise was significantly higher in patients than in
age-matched controls (P < 0.05). No significant
difference was found in diastolic blood pressure or heart rate either
at rest or at peak exercise between patients and controls (Table 2).
The LV ejection fraction at rest was similar in patients and controls.
In particular, the LV ejection fraction was normal (50%) in all
controls and in 10 of 11 patients. By contrast, at peak exercise it was
markedly depressed in elderly GHD patients compared to age-matched
controls (P < 0.001). A normal increase (5% of
basal value) in the LV ejection fraction at peak exercise was found in
eight controls (72.7%) and two elderly GHD patients (18.2%; Fig. 1). The peak rate of LV filling,
normalized to EDV or SV, was not different between patients and
controls. On the other hand, the ratio of LV peak filling rate to peak
ejection rate was significantly higher in GHD patients compared to
controls (P < 0.01). Finally, the exercise duration
was significantly shorter in elderly GHD patients than in age-matched
controls (P < 0.01).
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In the patient group, a significant relationship was observed between GH peak after the ARG+GHRH test and LV ejection fraction at rest (r = 0.822; P < 0.01). IGF-I was significantly correlated with the peak rate of LV filling, whether the peak filling rate was normalized to EDV (r = -0.863; P < 0.001) or SV (r = -0.616; P < 0.05) or expressed as the ratio of peak filling rate to peak ejection fraction rate (r = -0.736; P < 0.01). Disease duration was significantly correlated with heart rate at peak exercise (r = 0.614; P < 0.05) and with systolic and diastolic blood pressure both at rest (r = 0.745; P < 0.01 and r = 0.650; P < 0.05, respectively) and at peak exercise (r = 0.684; P < 0.05 and r = 0.617; P < 0.05, respectively).
The multiple regression analysis (Table 3) showed that IGF-I levels were the
strongest predictor of diastolic filling, whether the peak filling rate
was normalized to EDV or SV or expressed as the ratio of peak filling
rate to peak ejection fraction rate. The peak GH level after the
ARG+GHRH test was the strongest predictor of LV ejection fraction at
rest, and consequently, it was the second strongest predictor of the
peak filling rate normalized to SV.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The investigation of clinical symptoms in elderly patients with GHD is more difficult than in adults, as normal aging and GH deficiency share several clinical signs and symptoms, such as decreased muscle strength, increased osteoporosis and fracture risk, thinned skin, diminished psychosocial health, and sense of well-being. Because of these similarities, the relative GH insufficiency in the elderly has been postulated as one important factor contributing to their frailty (34). Aging is a process associated with a decline in the somatotroph axis function (35). Many of the catabolic sequelae found in normal aging have been attributed to decrease in circulating GH and IGF-I levels (36). At the age of 65 yr, spontaneous daily secretion of GH is reduced by 50–70%, and IGF-I levels decline progressively from the age of 40 yr. This hormonal pattern is distinct from the pathological decrease in GH and/or IGF-I levels associated with hypo-pituitarism. In the present study, the GH response to ARG+GHRH, a very potent GH stimulation test, was markedly decreased compared to that in healthy age-matched controls, in line with previous studies (14, 18). In addition, the median area under the curve of the GH profile, the median stimulated peak GH response to arginine, and the median serum IGF-I concentration, were reported to be lower in GHD elderly than in controls (35). However, in contrast with the clear-cut association between deficient/insufficient GH secretion and clinical symptoms reported in adult GHD patients, whether GHD could be responsible for clinical abnormalities in elderly patients is less clear. In a previous study we demonstrated that body composition was altered, and bone mass and turnover were impaired in elderly GHD patients compared to those in sex-, age-, and BMI-matched controls (18), in partial disagreement with the findings of Toogood et al. (16, 17). In the present study impaired cardiac performance was demonstrated at peak exercise, whereas both cardiac mass and diastolic function were normal. In the great majority of hypopituitary elderly (81.8%), at peak exercise the LV ejection fraction did not adequately increase, whereas systolic blood pressure increased significantly. Although aging is associated with a decrease in exercise capacity, hypopituitary patients had a significantly shortened exercise duration than age-matched healthy controls. Therefore, the results of cardiac function in elderly GHD patients cannot be interpreted as a physiological response of the heart less able to adapt to hemodynamic challenge in advancing age. In aging, a progressive loss of myocytes is observed, although myocyte volume per nucleus increases in both ventricles (37); additionally, although the overall size of the heart does not increase, LV wall thickness may increase slightly (37). Cardiac output tends to decrease with advancing age, both at rest and during exercise (38). These changes only partly reflect decreased demand and reduced skeletal mass. Heart rate, loading conditions, intrinsic muscle performance, and neurohormonal regulation are among the determinants of cardiac output that may be influenced by age, and with physical exercise, the maximal increase in the ejection fraction tends to be smaller in elderly than in younger people as an adaptive response. Despite the physiological decline in heart function in aging, the results of the present study demonstrated that elderly patients with GHD have a significantly reduced LV ejection fraction at peak exercise, suggesting that in these patients the heart is less able to adapt to hemodynamic challenge. The finding that IGF-I levels were the strongest predictor of diastolic filling and peak GH levels after the ARG+GHRH test was the strongest predictor of LV ejection fraction at rest confirmed the role played by the insufficient secretion of GH and IGF-I in determining the impaired cardiac performance in these patients. Thus, GH replacement therapy may be able to correct some abnormalities of cardiac function. Whether such correction results in a clinically significant improvement in well-being remains to be determined.
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Acknowledgments |
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Received May 14, 1999.
Revised July 7, 1999.
Accepted July 22, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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