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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0597
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5146-5155
Copyright © 2005 by The Endocrine Society

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

Annamaria Colao, Carolina Di Somma, Alberto Cuocolo, Letizia Spinelli, Wanda Acampa, Stefano Spiezia, Francesca Rota, Maria Cristina Savanelli and Gaetano Lombardi

Departments of Molecular and Clinical Endocrinology and Oncology (A.Co., C.D.S., F.R., M.C.S., G.L.), Biomorphological and Functional Sciences, Nuclear Medicine Centre of the National Council of Research (A.Cu., W.A.), Internal Medicine I (L.S.), "Federico II" University of Naples, 80131 Naples, Italy; and Emergency Unit (S.S.), "S. Maria degli Incurabili" Hospital of Naples, Naples 80138, Italy

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


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: GH secretion and response to GH replacement are gender-related.

Objective: The objective of this study was to investigate the effects of GH deficiency (GHD) and replacement on the cardiovascular system according to gender.

Design: The design was open and prospective.

Setting: The study was conducted at a university hospital.

Subjects: Subjects included 36 severe adult-onset GHD patients (18 men, 20 women, aged < 45 yr); 36 gender-, age-, and body mass index-matched healthy subjects served as controls.

Interventions: Subjects received GH replacement at a median dose of 6.5 µg/kg·d in men and 7.7 µg/kg·d in women for 2 yr.

Main Outcome Measures: Homeostasis model assessment index, total to HDL cholesterol ratio, fibrinogen and C-reactive protein levels, left ventricular mass index, blood pressure, heart rate, diastolic filling, and systolic function at rest and at peak exercise and intima-media thickness (IMT) at common carotid arteries were measured.

Results: Basal prevalence and/or degree of insulin resistance, lipid alterations, compromised cardiac function, and IMT were similar in women and men. Diastolic dysfunction was more prevalent in men (61 vs. 25%, P = 0.036). After GH replacement, IGF-I levels normalized in all patients. Lipid profile, fibrinogen, and C-reactive protein levels normalized in all cases. The total to HDL ratio (P = 0.04) was higher in women than men. The homeostasis model assessment index persisted higher in GHD patients than controls and decreased only in GHD men (P = 0.017). Left ventricular mass index normalized during treatment in both women and men, abnormal diastolic function persisted in three women (P = 0.031), and abnormal systolic performance persisted in six women and one man (P = 0.13). IMT decreased similarly in women and men, persisting higher than in controls. Exercise performance normalized in all.

Conclusions: Two-year GH replacement has similar beneficial effects on cardiac and exercise performance and atherosclerosis in women and men with severe GHD.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ADULT PATIENTS WITH hypopituitarism under adequate conventional hormone replacement therapy were reported to have reduced life expectancy due to excess vascular events (1, 2, 3, 4). GH deficiency (GHD) is considered to play a major role in determining the excess mortality because it is associated with lipid abnormalities, visceral adiposity, glucose intolerance, insulin resistance, hypertension, and cardiac abnormalities (5, 6, 7). GH replacement improves body composition (5, 6, 8), lipid profile (5, 6, 8, 9), cardiovascular markers (5, 6, 8, 9), cardiac size (7, 10), and performance (7). Additionally, in some studies adult patients with GHD have been reported to have increased intima-media thickness (IMT) at major arteries (11, 12, 13, 14), particularly when GHD was associated with low IGF-I levels (14). In a few GHD adult patients, GH replacement for 6–24 months was associated with reduced IMT at common carotid arteries (15, 16, 17). In contrast, 6 months of GH deprivation are associated with an impairment of the cardiovascular risk profile in severe GHD adults (17) and 12 months of GH withdrawal are followed by reduction of carotid IMT in GH sufficient adolescents (18).

Sexual dimorphism exists in GH secretion (19): women in fertile age have higher GH levels and lower IGF-I levels than males. After GH replacement in GHD patients, improvements of body composition, lipid profile, and bone mass are more evident in men than women, who require higher GH doses than men to achieve normal IGF-I levels (20, 21, 22). In a placebo-controlled study enrolling a large series of adult GHD patients, GH replacement was shown to have beneficial effects on lean body mass that were more pronounced in males than females, whereas the effects on cardiac function, measured by echocardiography, were also beneficial but appeared to benefit both genders equally (23). Moreover, in an epidemiological study conducted in Sweden (24), hypopituitary women exhibited an increased incidence of cardiovascular disease, high cardioactive drug consumption, and an increased prevalence of cardiovascular risk factors. This is in contrast with the results of the nonhypopituitary population that show a lower prevalence of ischemic heart disease and less severity of the alteration of cardiovascular risk factors in women than men (25).

To further explore the existence of gender-related effects of GHD and GH replacement on common cardiovascular risk factors, cardiac size and performance, exercise performance, and early atherosclerosis measured as carotid IMT, we designed this 2-yr open, prospective study in young adult men and women with severe GHD.


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

Of 160 adult patients diagnosed as severe GHD in our department from January 1996 to December 2002, 38 patients (20 women aged 18–45 and 18 men aged 19–45 yr) with partial or complete hypopituitarism were included in this study. Exclusion criteria were: 1) age greater than 45 yr (n = 34) to exclude the effect of aging and menopause; 2) body mass index (BMI) 30 or greater to exclude the effect of obesity (n = 13); 3) personal history of cardiovascular diseases (n = 11); 4) GHD of childhood onset (n = 17); 5) GHD in patients previously affected with Cushing’s disease (n = 5). Twenty-seven patients were subsequently excluded due to the requirement of treatments with drugs known to interfere with glucose or lipid metabolism and/or to influence blood pressure after starting GH replacement. Another 12 patients were excluded because they were part of a study requiring GH treatment withdrawal after 6 months (17). All the 38 patients had been previously operated on via transsphenoidal and/or transcranic route for prolactinomas, nonfunctioning pituitary adenoma, or craniopharyngioma, and none of them had been irradiated.

At study entry, GHD was diagnosed by a GH peak less than 9 µg/liter after arginine plus GHRH test in all patients (26, 27): GH peak was 3.8 ± 3.2 µg/liter in women (mean ± SD) and 3.0 ± 3.1 µg/liter in men [vs. 63.2 ± 26.9 µg/liter in control women (P < 0.0001) and 46.5 ± 19.2 µg/liter in control men (P < 0.001)]. GHD was associated with panhypopituitarism in 23 patients [60.5% (11 females and 12 males)]; FSH/LH and TSH deficiency in six patients (four females and two males); TSH and ACTH deficiency in five patients (two females and three males); TSH deficiency alone in three patients (one female and two males); and FSH, LH, and ACTH deficiency in one male patient; four female and six male patients with hypopituitarism also had diabetes insipidus. Hormone replacement therapy with L-thyroxin (75–125 µg orally daily), cortisone acetate (25–37.5 mg/d), and DDAVP (5–20 µg/d) was given where appropriate. Hypogonadism was treated in men with testosterone enanthate (250 mg im monthly); 12 women received standard oral estrogen/progestin association, the other four agreed to receive transdermal estradiol (25–50 µg twice a week) for 4 wk and progesterone 10 mg/d starting 2 wk after estradiol. Adequacy of hormone replacement therapy was periodically assessed by serum-free thyroid hormones, testosterone, serum Na+ and K+ measurements, and blood pressure. At study entry, these hormonal parameters were in the normal range for age in all patients. According to previous studies (14, 25, 26), the estimated duration of GHD was calculated from the time of diagnosis of the pituitary tumor and was 6.6 ± 4.0 yr in women (median 7 yr) and 7.1 ± 3.9 yr in men (median 7.5 yr).

Controls

Thirty-eight healthy subjects, among clerks, guardians, and medical and paramedical personnel of the Department of Molecular and Clinical Endocrinology and Oncology of the University "Federico II" of Naples, selected from a large series of controls (28), matched for sex, age (± 1 yr), and BMI (± 1) with the patients agreed to participate in this study and were used as controls. As for the patients, familial or personal history of cardiovascular diseases and previous treatments with drugs known to interfere with glucose or lipid metabolism or to influence blood pressure were exclusion criteria for controls. The characteristics of patients and controls at study entry, according to gender, are shown in Table 1Go. All patients and controls gave their informed consent to participate in this study that was designed in accordance with the Helsinki II Declaration on human experimentation and was approved by the Ethical Committee of the University "Federico II" of Naples. Twenty patients (52.6%) and 21 controls were nonsmokers (55.3%), three (7.8%) and four were ex-smokers (10.5%), and 15 (38.5%) and 13 (34.2%) were mild smokers [<15 cigarettes/d ({chi}2 , P = 0.86)]. All had a sedentary lifestyle.


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  		TABLE 1. Patients’ and controls’ profile at study entry

 
Study protocol

At study entry, all 76 subjects underwent serum assay of IGF-I, glucose, insulin, total-, and high-density lipoprotein (HDL)-cholesterol, triglycerides, fibrinogen, C-reactive protein (CRP) levels after an overnight fasting, left ventricular mass index by echocardiography, systolic and diastolic blood pressure (SBP, DBP) and heart rate measurement at rest and at peak exercise, peak filling rate, left ventricular ejection fraction at rest and at peak exercise by equilibrium radionuclide angiography, and common carotid artery ultrasonography. The total to HDL-cholesterol ratio, index of cardiovascular risk, was calculated (29). Blood pressure was measured at the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was used for analysis. The fourth Korotkoff phase was considered as DBP. Hypertension was diagnosed in the presence of DBP above 90 mm Hg (30). The oral glucose tolerance test (oGTT) was performed by measuring blood glucose every 30 min for 2 h after the oral administration of 75 g glucose diluted in 250 ml saline solution. Diabetes mellitus was diagnosed when fasting glucose was above 7 mmol/liter (126 mg/dl) at two consecutive measurements or when 2 h after the oGTT glucose was 11.1 mmol/liter or more (200 mg/dl). Impaired glucose tolerance was diagnosed when fasting glucose was less than 7 at baseline and was between 7.7 mmol/liter or more and less than 11.1 mg/dl 2 h after the oGTT (31). The estimate of insulin resistance by the homeostasis model assessment (HOMA) score, by applying the formula of Matthews et al. (32) [fasting serum insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5]. Hypertriglyceridemia was diagnosed when triglycerides levels were greater than 1.7 mmol/liter (150 mg/dl) (33), whereas hypercholesterolemia was diagnosed when total cholesterol levels were greater than 5.2 mmol/liter (200 mg/dl) (34). The conversion factors (milligrams per deciliter to millimoles per liter) for lipids and glucose were as follows: cholesterol, 0.02586; triglycerides, 0.01129; and glucose, 0.05551. Only in the patients, biochemical markers, echocardiography, equilibrium radionuclide angiography, and carotid ultrasonography were reevaluated after 12 and 24 months.

Treatment protocol

According to previous studies (35, 36), all of the patients received recombinant GH at the adult starting dose of 4–5 µg/kg·d. Subsequently the dose was adjusted to reach the 50th percentile [0 SD score (SDS)] of normal serum IGF-I concentrations for sex and age. At the end of the study the median GH dose was 6.5 µg/kg·d in men and 7.7 µg/kg·d in women, the maximal dose was 8 µg/kg·d in men and 10 µg/kg·d in women. This latter dose was employed in only two of the 12 women requiring oral estrogen replacement.

Carotid ultrasonography

Common carotid artery ultrasound imaging was carried out with Sound CMF 725 equipment (Vingmed, Horten, Norway) by means of a 7.5-MHz annular phased array transducer. Details on the technique were reported elsewhere (14). Right and left carotid arteries were scanned longitudinally, 2.5 cm proximal and 1 cm distal to the bifurcation. When satisfactory B-mode imaging of the common carotid artery wall was achieved, M-mode images were taken for several cardiac cycles to obtain the best quality measurements of IMT. Quantitative and semiquantitative indices were evaluated by echo-Doppler ultrasonography placing the sample volume (set at 75% of lumen caliber) in the middle of the vessel lumen. The variability in the IMT measurement for our instrument was 0.03 mm. Our intraobserver variability for repeated measurements of carotid artery diameter was 0.01 ± 0.02 mm. Because epidemiological data currently available indicate IMT 1 mm or greater at any age as associated with a significantly increased risk of myocardial infarction and/or cerebrovascular disease (37), we considered this threshold value as marker of atherosclerosis in our hypopituitary population. Presence, location, and size of plaques were also evaluated at the level of common carotid arteries. A type IV plaque featured by thickening of vascular wall and increased density of all ultrasound-detectable layers without any hemodynamic alteration was defined as a well-defined plaque (38). The records were made by one investigator (S.S.) blind in respect to controls or patient examination and individual patient response to treatment.

Echocardiography

M-mode, two-dimensional, and pulsed Doppler echocardiography was 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 (39). The following measurements were recorded on M-mode tracing: interventricular septum thickness and left ventricular (LV) posterior wall thickness, LV mass (LVM) calculation by the formula of Devereux (40), according to the Penn convention with the following regression-corrected cube formula: LVM = 1.04 [(interventricular septum thickness + left ventricular internal diameter + posterior wall thickness) 3 – (left ventricular internal diameter)3] – 14 g. LV hypertrophy was considered when LVM indexed for body surface area (LVMi) was 135 g/m2 or greater in men and 110 g/m2 or greater in women. The records were made by one investigator (L.S.) blind in respect to controls or patients examination and individual patient response to treatment.

Equilibrium radionuclide angiography

The angiography study was performed as already reported (27, 35, 36). Briefly, radionuclide angiography was performed at rest and during dynamic physical exercise in the 45-degree left anterior projection with a 15-degree craniocaudal tilt with the patient in supine position. 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 W every 2 min until angina, limiting dyspnea, or fatigue developed. No patient developed high-grade ventricular arrhythmias necessitating termination of exercise, but four patients (10.5%, two women and two men) could not perform exercise at study entry due to early muscular exhaustion. LV ejection fraction (LVEF) 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 on the first derivative of the LV time-activity curve, normalized for the number of counts at end-diastole and expressed as end-diastolic volume (EDV)/sec. Normal parameters were: peak filling rate (PFR) at rest = 2.5 EDV or greater per second; LVEF at rest = 50% or greater; changes of LVEF at peak exercise, compared with baseline ({Delta} LVEF)equals an increase of 5% or more. The records were made by two investigators (A.Cu., W.A.) blind in respect to controls or patients examination and individual patient response to treatment.

Assays

Serum GH levels were measured by immunoradiometric assay (IRMA) using commercially available kits (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intra- and interassay coefficients of variation (CVs) were 4.5 and 7.9%, respectively. The sensitivity of the assay was 0.2 µg/liter. The intra- and interassay CVs were 4.5 and 7.9%, respectively. Serum IGF-I was measured by IRMA after ethanol extraction (Diagnostic System Laboratories, Inc., Webster, TX). In our laboratory (28), the normal range in 20 or less, 21–30, 31–40, and 41–50; in old men it was 180–500, 118–415, 102–400, and 100–306 µg/liter, respectively, whereas in women it was 151–430, 118–390, 100–370, and 96–288 µg/liter, respectively. The sensitivity of the assay was 0.8 µg/liter. The intraassay CVs were 3.4, 3.0, and 1.5% for low, medium, and high points of the standard curve, respectively. CRP was measured by a sensitive ELISA (DSL-10–42100 active ELISA kit; Diagnostics Systems Laboratories). The interassay CVs were 8.2, 1.5, and 3.7% for low, medium, and high points of the standard curve, respectively. Fasting total-, low-density lipoprotein-, and HDL-cholesterol, triglycerides and fibrinogen levels were measured by standard procedures.

Statistical analysis

Results were expressed as mean ± SD unless otherwise specified. The statistical analysis was performed by a package from SPSS Inc. (Chicago, IL) using nonparametric tests. The comparison of the results of patients and their matched controls at baseline and the patients at study end and controls at baseline was performed by the Wilcoxon matched paired test. Changes of all variables were calculated as percentage difference with baseline results. The comparison between female and male patients at any point of the study was performed by the Mann-Whitney U test. Categorical variables were compared using the Pearson’s {chi}2 test. The significance was set at 5%.


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

Both female and male GHD patients had insulin resistance, impairment of lipid profile, increased fibrinogen and CRP levels and IMT at both common carotid arteries, reduced cardiac size although in the normal range, and reduced cardiac performance, compared with controls (Table 1Go). Exercise performance, namely duration and capacity, was profoundly decreased: in particular, duration was lower in both GHD women (6.2 ± 1.7 min) and men (6.1 ± 2.1 min) than in controls (10.1 ± 1.3 and 9.2 ± 1.4 min, P < 0.0001). Exercise capacity was also significantly lower in GHD women and men (72.4 ± 24.8 and 71.0 ± 29.7 W) than controls (107.5 ± 14.3 and 98.6 ± 20.1 W, P < 0.001). There were some differences between female and male patients when compared with controls: female patients had increased BMI and DBP at peak exercise; male patients had reduced DBP at peak exercise and heart rate at rest. Female GHD patients had significantly lower cardiac size (as expected) and significantly higher PFR at rest than male GHD patients. Individual mean values of IMT, LVMi, and {Delta}LVEF in controls and GHD patients according to gender are shown in Figs. 1–3GoGoGo. Hypercholesterolemia was found in 18 women (90%) and 12 men (66.7%, P = 0.17) and hypertriglyceridemia in eight women (40%) and three men (16.7%, P = 0.22). Low diastolic filling was found in five women (25%) and 11 men (61.1%, P = 0.036), low systolic performance at rest in nine women (45%) and six men (33.3%, P = 0.69) and at peak exercise in 15 women (83.3%) and 12 men (75%, P = 0.16). High IMT (≥1 mm on one or both common carotid arteries) was found in five women (25%) and two men (11.1%, P = 0.49).



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  		FIG. 1. Individual data of mean value of IMT measured at right and left common carotid arteries in female (top) and male (bottom) controls (left) and GHD patients (right). Columns refer to mean ± SEM. The interrupted line indicates the threshold of 1 mm that is considered the cut-off value at any age for an increased risk of cerebrovascular disease (37 ). *, P < 0.001 vs. patients at baseline; **, P < 0.01 vs. patients at study end.

 


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  		FIG. 2. Individual data of LVMi in female (top) and male (bottom) controls (left) and GHD patients (right). *, P < 0.001 vs. patients at baseline.

 


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  		FIG. 3. Individual data of percentage changes ({Delta}) of the LVEF at peak exercise in female (top) and male (bottom) controls (left) and GHD patients (right). *, P < 0.001 vs. patients at baseline; **, P < 0.05 vs. patients at study end.

 
Two-year GH replacement in GHD women and men on anthropometry, IGF-I levels, and cardiovascular risk factors (Table 2Go)

The final dose of GH was significantly higher in women than men (7.5 ± 1.5 vs. 6.5 ± 0.9 µg/kg·d, P = 0.019). BMI significantly decreased only in men. Serum IGF-I levels were normalized in both groups after 1 yr of therapy (Fig. 4Go). The IGF-I z-SDS score was similar in women and in men after 1 yr of therapy, whereas it was lower in the women after 2 yr [P = 0.05 (Fig. 4Go)]. Two of the four women received transdermal 17-ß-estradiol during the 2 yr of GH replacement: the GH dose was not changed in these two patients even if IGF-I levels decreased, compared with the first year of follow-up because they were still between 0 and 0.5 SDS IGF-I score. After 2 yr of GH replacement, the lipid profile was normalized; however, the total to HDL ratio (P = 0.04) was higher in women than men. Some degree of insulin resistance remained in both women and men, compared with controls (Table 1Go). The HOMA index did not change in women, whereas in men it significantly decreased, although percentage changes did not differ according to gender (Table 2Go). None of the patients developed diabetes, but three women impaired their glucose tolerance during treatment. Fibrinogen and CRP levels normalized at study end in both groups.


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  		TABLE 2. BMI, IGF-I levels (shown as SDS by age), cardiovascular risk parameters, LVM, and performance, exercise performance, and common carotid artery ultrasonography according to gender in GHD females (n = 20) and males (n = 18), before and after 24 months of GH replacement

 


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  		FIG. 4. IGF-I z-score in the patients before and during GH replacement and in controls, according to gender.

 
Two-year GH replacement in GHD women and men on common carotid ultrasonography (Table 2Go)

IMT at right and left common carotids decreased at a similar extent in women and in men after 1 and 2 yr of GH replacement but was still higher than in controls at study end (Fig. 1Go). None of the seven patients with well-defined atherosclerotic plaques at study entry had disappearance of plaques during the study: in these patients mean IMT (mean between right and left common carotid arteries) decreased by 10.3 ± 5.7%, from 1.19 ± 0.16 to 1.07 ± 0.19 mm. In the remaining 31 patients not showing atherosclerotic plaques, mean IMT decreased by 10.3 ± 6.6%, from 0.76 ± 0.13 to 0.68 ± 0.09 mm, being similar to controls. No difference was found between female and male patients in the percentage decrease of IMT after GH replacement.

Two-year GH replacement in GHD women and men on cardiac size and performance and exercise performance (Table 2Go)

In this series, baseline LVMi was lower in both female and male patients, compared with controls, significantly increased during treatment, without any difference according to gender, and were similar to controls at study end (Fig. 2Go). In none of the patients, LV hypertrophy did occur. SBP and DBP and heart rate did not change significantly during the study: the only exception was a lower level of SBP at rest in women than men after 2 yr of treatment (117.0 ± 6.6 vs. 121.7 ± 7.1 mm Hg, P = 0.042). On equilibrium radionuclide angiography in both female and male patients, there was a significant increase of PFR at rest, higher in men than women, and at peak exercise (only in males). Of the five women and 11 men with low PFR on baseline, three women still presented low PFR at study end (P = 0.031). There was a sustained increase of LVEF at rest (only in males) and at peak exercise (in both) without any difference according to gender. At study end, however, {Delta}LVEF was still lower than in controls in both female and male patients (P < 0.01; Fig. 3Go). LVEF response at peak exercise remained abnormal in six women (30%) and one man (5.5%, P = 0.13).

Exercise performance on equilibrium radionuclide angiography was still lower than normal after 1 yr of GH replacement but was normalized after 2 yr in both female and male patients.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results of this open, 2-yr, prospective study demonstrate that GH replacement in women and men with severe GHD normalizes lipid profile, fibrinogen, and CRP levels; reduces IMT at common carotid arteries, up to the values of controls in most cases; increases cardiac size, without inducing hypertrophy; and improves cardiac performance and exercise performance by inducing an increase of LVEF at peak exercise, exercise duration, and potency. Blood pressure and heart rate also improved during treatment, whereas insulin levels remained elevated so that the HOMA index persisted higher than in controls, particularly in the women. We did not observe significant gender-related differences in the long-term effects of GH replacement but confirmed the requirement of a higher GH dose to normalize IGF-I levels in women taking oral estrogens. Nevertheless, we found that female GHD patients achieved a significant lower IGF-I z-score than male patients. Additionally, female patients did not reduce their BMI, whereas male patients did, and women maintained a higher total to HDL-cholesterol ratio than males.

Hypopituitarism is associated with increased cardiovascular mortality (1, 2, 3, 4). Long-standing GHD is likely one of the most important factors in determining altered cardiovascular conditions because it causes unfavorable lipid profile, increased abdominal fat, endothelial dysfunction, reduced arterial stiffness, decreased systolic performance at peak exercise, and increased IMT at major arteries (5, 6, 7, 8, 9, 10). A number of clinical studies, by us and others (5, 6, 7, 8, 9, 10, 35, 36, 41, 42), have reported beneficial effects of GH replacement on cardiovascular risk and cardiac performance in adult GHD patients. However, although long-term GH replacement to GHD adults was reported to be able to recover body composition, bone mineral density, exercise capacity, and strength as well as to improve the lipid profile and coagulation (41, 42), the ultimate clinical efficacy of GH treatment on the reversibility of the cardiovascular risk is still unknown, as was also remarked in a recent metaanalysis of a number of studies on this topic (10).

Consensus exists on the beneficial effects of GH replacement on lipid profile (8). In our series, we found that besides both women and men with GHD had improved their lipid profile, men improved more remarkably and achieved lower total to HDL cholesterol ratio than women at the end of 2 yr of GH replacement. This effect is likely to be mediated by a higher IGF-I level, based on z-IGF score, achieved in men than women despite women received higher GH doses than men. Additionally, men had some improvement of insulin resistance, whereas women did not have any significant improvement of insulin resistance. In our series, however, women had at baseline glucose levels similar to controls and lower than men; the HOMA index did not change during GH treatment in women, whereas it significantly decreased in men. In both groups, however, the HOMA index persisted higher than in controls. The effects on lipid profile and insulin resistance indirectly indicate an improvement of cardiovascular disease. However, blood vessel IMT is considered as one of the earliest morphological changes in the arterial wall in the process of atherogenesis (43). Deposit of lipids occurs in the intima of systemic arteries with subsequent leukocytes adhesion, smooth muscle proliferation, and thrombosis that may eventually lead to clinically detectable disease (44). Patients with GHD, either developed during childhood or adulthood, were shown to have early atherosclerosis, increased prevalence of plaques, and increased risk of cardiovascular disease (5, 6).

Carotid IMT is considered an independent predictor of acute myocardial infarction (38) and cerebrovascular disease (45) and was found to be increased at common carotid arteries in some (11, 12, 13, 14, 16, 17, 46) but not all (15, 46, 47) studies. In our population of GHD adult patients (14) and nonhypopituitary subjects considered healthy on strict inclusion criteria (28), we found that increased IMT at common carotid arteries and presence of atherosclerotic plaques were characteristics of subjects with IGF-I levels less than 2 SD from the mean or lower. GH replacement has beneficial effects in reversing such alterations (5, 6, 9). Improvement of endothelial dysfunction, fall in the serum concentrations of adhesion molecules and inflammatory markers, and decrease of IMT have been reported after 12–24 months of GH replacement (6). Interestingly, Abdu et al. (46) reported that the coronary risk calculated by the Framingham’s equation decreased in severe GHD patients 12 months after GH replacement and found that this effect was mainly due to reduction in SBP and DBP and increase in HDL-cholesterol. However, both Pfeifer et al. (15) and Borson-Chazot et al. (16) reported substantial reduction of IMT after GH replacement in their populations. In the current study including a larger cohort of severe GHD patients, we found a significant decrease of IMT, by 10% in average, in all cases, even in those with well-defined atherosclerotic plaques. Whereas in the patients showing moderately increased carotid IMT at baseline IMT returned similar to controls after 2 yr of GH replacement; in the cases showing atherosclerotic plaques, carotid IMT, although decreased, remained significantly higher than controls: if the time of observation is too short when plaques are developed or if GH replacement alone is not sufficient to completely reverse atherosclerosis cannot be ruled out by the present study. We can, however, exclude any gender-related effect of GH replacement of IMT. Because we also found persistence of some degree of insulin resistance in our patients, this could be responsible (at least partly) in maintaining an increased IMT in GHD patients.

Another clear effect of GH replacement is to increase cardiac size (10), as was also found in our current study. We did not find any patient showing cardiac hypertrophy, in contrast with a previous study (47), but our patients were replaced with a substantially lower GH dose. Two long-term GH replacement studies in GH-deficient adults (48, 49) confirmed the absence of cardiac hypertrophy. No gender difference was found in the increase of cardiac size, and men maintained higher cardiac size than women as it has to be physiologically. As far as cardiac performance is concerned, by echocardiography no change was reported by some authors, whereas increase in stroke volume was reported by others (7, 10). However, the evaluation of cardiac function by echocardiography is affected by two major limitations: the intra- and interobserver variability and the poor sensitivity because of the assumptions necessary to calculate the LVEF (39). In previous studies we reported that LVEF at peak exercise is impaired in the majority of adult GHD patients independently from age (50) but dependently on the severity of GH deficiency (27), increases after 12 months of GH replacement (35, 36), and further decreases after 12 months of GH deprivation (36). The only study investigating the effects of GH replacement therapy in adults with GHD according to gender showed no gender difference in the beneficial effects on cardiac function (22). Besides, Ezzat et al. (23) confirmed that the GH effect on lean body mass was more pronounced in male than female patients (21). In the current study, we could confirm the absence of any gender difference in terms of improvement of systolic performance at peak exercise or exercise performance. In our series systolic performance, measured as LVEF at peak exercise, normalized in 14 of 15 women and 11 of 12 men. Partial gender difference was observed in the relatively more evident improvement of diastolic function in men. In fact, PFR at rest normalized in all 11 men and in only two of the five women. It should be noted, however, that PFR was higher in women than men at baseline, indicating a more preserved diastolic function in women. Longer follow-up studies are required to rule out possible gender-related effects on diastolic performance after GH replacement.

In conclusion, the results of this observational, open, prospective study enrolling a large series of patients with severe GHD replaced with GH at current doses for 2 yr confirms that GH replacement has several beneficial effects on cardiovascular risk factors and atherosclerosis. Additionally, we did not observe any gender-related effect on cardiovascular risk factors, atherosclerotic profile, cardiac size, and performance and exercise performance with the exception of a lower effect on lipid profile in women and a slightly better effect on insulin resistance in men. Interestingly, improvement of systolic performance on peak exercise improved at the same extent in women and men and normalized in the vast majority of cases and so did carotid IMT. At the end of the 2 yr of the study follow-up, GHD patients did not show a complete normalization of insulin resistance, diastolic and systolic performance, and IMT (in the patients showing plaques before GH replacement). This could indicate the need of a longer period of observation. The requirement of additional treatments aiming at reducing insulin resistance also could be helpful.


   Footnotes
 
This work was partially supported by a grant from the Italian Minister of Research and University in Rome (2004062974 of 2004).

First Published Online June 28, 2005

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CV, coefficient of variation; DBP, diastolic blood pressure; EDV, end-diastolic volume; GHD, GH deficiency; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IMT, intima-media thickness; IRMA, immunoradiometric assay; LV, left ventricular; LVEF, LV ejection fraction; LVM, LV mass; LVMi, LVM indexed for body surface area; oGTT, oral glucose tolerance test; PFR, peak filling rate; SBP, systolic blood pressure; SDS, SD score.

Received March 17, 2005.

Accepted June 17, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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