Gender-Specific Responses of Lean Body Composition and Non-Gender-Specific Cardiac Function Improvement after GH Replacement in GH-Deficient Adults

GH deficiency (GHD) in adulthood is accompanied by physical and psychological impairments. One hundred fifteen patients (67 male, 48 female) with pronounced GHD were enrolled in a randomized, double-blind, placebo-controlled study with objectives that included effects on body composition, cardiac structure, and function and safety of replacement therapy with recombinant human GH (Saizen). Sixty patients (31 male, 29 female) received GH at a dose of 0.005–0.010 mg/kg·d, and 55 patients (36 male, 19 female) received placebo for 6 months. Assessment of body composition by dual-energy x-ray absorptiometry demonstrated a treatment difference in lean body mass increase of 2.1 kg (between-group comparison, P < 0.0001), which was significantly greater among males than females (P < 0.0001) [males: GH, +3.13 kg (2.42, 3.84); placebo, +0.11 kg (−0.60, 0.82); and females: GH, +0.64 kg (−0.15, 1.44); placebo: −0.90 kg (−2.20, 0.39)] [mean change 0–6 months (95% confidence limits)] and was associated with IGF-I changes. The decrease in fat mass of 2.8 kg (between-group comparison, P < 0.0001) noted by DEXA was also evident from bioelectric impedance and anthropometric measurements. Echocardiography showed comparable improvement in left ventricular systolic function after GH treatment in both genders. End-systolic volume decreased by 4.3 ± 10.5 ml (from 35.8 ± 17.6 ml; between-group comparison, P = 0.035) and ejection fraction increased by 5.1 ± 10.0% (from 55.0 ± 11.2%; between-group comparison, P = 0.048), approaching normalcy. Diastolic function did not change as assessed by isovolumic relaxation time, early diastolic flow, diastolic flow secondary to atrial contraction, or ratio of peak mitral early diastolic and atrial contraction velocity. GH treatment was well tolerated, with adverse events primarily related to effects on fluid balance. No apparent relationship between IGF-I levels and the occurrence or severity of adverse events was identified. In conclusion, GH replacement therapy in adults with GHD demonstrated beneficial effects on lean body mass composition that was more pronounced in males than females. In contrast, cardiac function improvement appears to benefit both genders equally.

ADULT HYPOPITUITARY PATIENTS, despite replacement therapy with T₄, corticosteroids, and sex hormones, suffer from both physical and psychological impairments. With the advent of recombinant human GH, it became possible to characterize GH deficiency (GHD) in adults and determine the effects of replacement therapy (1–4). In the 12 yr since the first placebo-controlled studies (1–3), the syndrome of GHD in adulthood has been described, and GH replacement has become an established therapy (5), but long-term consequences of GHD and long-term treatment effects remain to be defined (4).

Adults with GHD typically have abnormal body composition, reduced physical performance, poor muscle strength, cardiac dysfunction, and reduced well-being (4). Moreover, altered lipid metabolism and osteopenia are described, and morbidity and mortality are reported to be higher for hypopituitary patients than controls, primarily due to cardiovascular diseases (6–9). A 2-fold increase in cardiovascular mortality was found in one study (6), and a relative increase of 1.74 was found in another (8). Higher frequencies of sick leave and disability pension among patients with a history of pituitary adenoma have recently been reported (10). It is likely that a majority of the patients in these studies were GHD and that this GHD accounted for the observed morbidity and mortality. Beneficial effects of GH on body composition, psychological well-being, bone mineral density, and cardiac function have previously been described (4, 11), but end-point data in the form of fracture risk and/or cardiovascular mortality are not yet apparent (4, 11). Long-standing GHD is accompanied by structural cardiac changes and premature atherosclerosis (12–14), with contributing factors likely to include dyslipidemia, endothelial dysfunction, and abnormal coagulation (4, 15).

Numerous studies have reported on cardiac function in GHD, with variable results (15–21). Abnormalities in left ventricular diastolic function, both at rest and in response to exercise (15–17), have been determined either echocardiographically (16, 17) or through radionuclide angiography (15). Impairment in systolic function has similarly been reported, typically with increased end-systolic wall stress, reduced ventricular posterior wall thickness, reduced cardiac output (CO) and cardiac index, and lower ejection fraction and fractional shortening than controls (18–21). Abnormalities have been found regardless of the patients’ age and age of onset of their GHD (15, 17). A detailed analysis of 55 adulthood-onset GHD patients and 36 controls showed that 24% of the GHD patients but none of the controls had impaired ejection fraction at rest and that the ejection fraction response to exercise was abnormal in 65% of the GHD patients (15).

The effects of GH replacement have also been studied with evidence for improvement in ejection fraction, fractional shortening, stroke volume, and CO, but rarely with any structural changes of the heart (18, 20–26). Many of these studies, however, have been limited by small sample sizes, absence of a placebo-treated group, and use of GH doses significantly higher than those used today.

In this study, we investigated the effects of GH replacement on cardiac structure and functional indices measured by echocardiographic techniques in a large randomized double-blind placebo-controlled clinical trial using GH doses of 0.005–0.01 mg/kg·d. Effects of GH replacement on body composition and measures of safety were also recorded.

Materials and Methods

Experimental subjects

A total of 115 adult patients (67 male, 48 female) with GHD were recruited into a multicenter study; they were randomized, stratified by center, to receive either recombinant human GH or the corresponding placebo. Admission criteria were: age between 20 and 70 yr; acquired or idiopathic GHD present for at least 24 months; peak stimulated GH less than 5 ng/ml on insulin tolerance test or a combined GH-releasing hormone and arginine test; adequate replacement therapy for associated ACTH, TSH, or gonadotrophin deficits (glucocorticoids, thyroid and sex hormones) for at least 12 months; and no GH treatment for at least 2 yr. Patients with a history of Cushing’s disease were included only if their disease was in remission for at least 1 yr. All patients, including those with childhood-onset GHD, were subjected to GH testing before entry into the study. Exclusion criteria were: tumor recurrence or an enlarging tumor remnant on imaging of the sella turcica within 6 months of study entry and chronic severe kidney or liver disease, diabetes mellitus, malignancy, or unstable hypertension. Clinical and endocrine characteristics of the patients are summarized in Table 1. Of the 115 patients, 101 (88%) were receiving pituitary hormone replacement at baseline. Seventy-three percent of the female patients were receiving estrogen replacement, and 79% of the male patients were receiving T replacement.

Table 1.

Clinical and endocrine characteristics of patients at study entry

	GH (n = 60)	Placebo (n = 55)
Sex (male/female)	31 (52%)/29 (48%)	36 (66%)/19 (34%)
Age (yr) [mean ± sd (range)]	47.0 ± 11.5 (25–68)	45.9 ± 12.7 (20–70)
GHD etiology
Idiopathic	5 (8%)	4 (7%)
Pituitary adenoma	33 (60%)	34 (67%)
Craniopharyngioma	5 (9%)	7 (14%)
Other	17 (31%)	10 (20%)
All acquired	55 (92%)	51 (93%)
Treatment (surgery/irradiation/both)	24/0/21 (40/0/35%)	18/5/24 (33/9/44%)
Peak GH response (ng/ml) [mean ± sd (range)]	1.39 ± 1.3 (0.00–5.00)	1.33 ± 1.15 (0.10–4.10)
Duration of GHD (yr) [mean ± sd (range)]	9.7 ± 9.7 (0.7–47.0)	8.8 ± 8.4 (1.5–32.0)
Other pituitary hormone deficiencies
LH/FSH	45 (75%)	44 (80%)
TSH	38 (63%)	36 (66%)
ACTH	34 (57%)	30 (54%)
All of the above deficiencies	26 (43%)	24 (44%)
Other	13 (22%)	10 (18%)

Percentages are based on the total number of patients in the respective treatment group. n, Number of patients.

Experimental protocol

The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, with approval from individual human ethics review boards and patient informed consent. After prestudy and baseline assessments, patients were randomized in a double-blind manner, stratified by center, to receive sc either placebo or GH (Saizen and corresponding placebo, Serono International S.A.) 0.005 mg/kg·d for 1 month, followed by 0.010 mg/kg·d for 5 months.

Body composition methodologies

Body composition was assessed by whole-body dual-energy x-ray absorptiometry (DEXA), bioelectric impedance analysis (BIA), and anthropometry (skinfold thickness, circumference, and waist to hip ratio measurements). DEXA was performed on a whole-body dual energy x-ray absorptiometer (Hologic model QDR-2000, Hologic, Inc., Bedford, MA, or Lunar Corp. International, Madison, WI), calibrated using a calibration standard each day. DEXA determinations provided data on lean body mass and fat mass according to the manufacturers’ protocol. Phantoms were used to monitor accuracy, precision, and trending variations for DEXA measurements and were standardized between centers. Total body water and extracellular water determinations were made with BIA (HYDRA ECF/ICF Model 4200 scanner, Xitron Technologies, Inc., San Diego, CA), and estimates for fat-free mass, fat mass, and intracellular water were calculated. Anthropometric measurements included sum of skinfold thicknesses (biceps, triceps, subscapular, and suprailiac) and sum of circumferences (waist, hip, mid-arm, and mid-leg) in accordance with the Anthropometric Standardization Reference Manual (27).

Echocardiography

Cardiovascular function was assessed by two-dimensional (2-D), M-mode and Doppler echocardiography at baseline and after 6 months, by a cardiologist blinded to study treatment. Cardiac measures were performed after an overnight 12-h fast, usually 30 min after the recumbent position. Subjects were instructed to avoid alcohol- or caffeine-containing products. The echocardiographic analysis was performed with ultrasound systems equipped with 2.5, 3.5, or 5 mHz transducers, and the M-mode and 2-D tracings were obtained with the subjects in the left lateral recumbent position according to the standardization of the American Society of Echocardiography (28).

Evaluation of left ventricular systolic function was made by determinations of ejection fraction and fractional shortening. Ejection fraction is calculated from 2-D echocardiography measurements and is the ratio (expressed as a percentage) of the difference between the end-diastolic and end-systolic volumes (stroke volume) and the left ventricle end-diastolic volume. Fractional shortening is a rough measure of ventricular systolic function and is calculated from the determinations of the left ventricle internal dimensions, measured by M-mode echocardiography. Fractional shortening is the ratio (in percent) of the difference between the left ventricle’s end-diastolic and end-systolic diameters and the end-diastolic diameter. M-mode determinations also allowed calculations of left ventricle mass by the formula of Devereux and Reichek (29).

Evaluation of the ventricular diastolic filling and function was made from Doppler echocardiography assessments. The isovolumic relaxation time (IVRT), which represents the time interval between aortic valve closure and mitral valve opening, was determined, together with the peak filling rates during diastole E max (the early filling rate) and A max (the atrial filling rate). E/A ratio and E/F slope were also determined. Doppler echocardiography measurements were also used to calculate CO and systemic vascular resistance (SVR). CO was calculated as the product of heart rate, aortic flow velocity, and aortic cross-sectional area. SVR was calculated from mean arterial pressure (MAP) and CO as SVR = MAP × 80/CO, where MAP was calculated as the diastolic blood pressure plus one third of the pulse pressure.

Growth factors

Serum levels of IGF-I, IGF-II, and IGF binding protein (IGFBP)-1 and -3 were followed during the study. Samples were assayed centrally for all study centers at the Serono Clinical Laboratories (Cambridge, UK). IGF-I and IGFBP-3 were measured using Mediagnost RIAs (Mediagnost GmbH, Tübingen, Germany), and IGF-II and IGFBP-1 were measured using assays from Diagnostics Systems Laboratories, Inc. (Webster, TX) and Biogenesis (Kingston, NH), respectively.

Laboratory analyses

Routine laboratory tests for hematology, blood chemistry, thyroid function, and urinalysis were assessed throughout the study. Serum bone biochemistry [intact PTH, bone-specific alkaline phosphatase, C-terminal propeptide of type I collagen (RIA by Farmos Inc.), osteocalcin, 1,25-dihydroxyvitamin D3], and urinary deoxypyridoline were assayed centrally for all study centers at the Serono Clinical Laboratories (Cambridge, UK).

Statistical methods

Analysis of covariance with the baseline value, gender, and center as covariates was made for each endpoint; P values quoted are for between-group comparisons of change from baseline. All statistical tests were two-sided with α = 0.05. All efficacy analyses are based on complete cases, i.e. all patients with available data for each analysis. All patients who received a minimum of one injection of study drug were included in the safety summaries.

Results

Biochemical changes

The patients included in the study had peak GH concentrations of 1.39 ± 1.30 and 1.33 ± 1.15 ng/ml in the GH and placebo groups, respectively, after provocative testing. Serum levels of IGF-I increased from 93.5 ± 47.8 ng/ml (mean ± sd) at baseline to 249.4 ± 119.3 ng/ml at 6 months in GH group (P < 0.001) and was unaltered in the placebo group (baseline, 95.9 ± 46.7 ng/ml; 6 months, 105.8 ± 66.7 ng/ml). Normal ranges for the IGF-I measurement in the assay used decrease with age; the 5th centile for age 20 is 115 ng/ml, whereas that for 70–80 yr is 47 ng/ml. At the upper end, the 95th centile is 340 ng/ml for a 20 yr old, but 207 ng/ml for a 70 yr old. The changes in IGF-I were significantly greater in males than in females (207 ± 97.1 ng/ml in males vs. 110 ± 87.2 ng/ml in females; P = 0.003) (Fig. 1).

Figure 1.

Six-month changes in growth factor levels. The changes in IGF-I were significantly greater in males than in females (P = 0.003), but there was no gender effect for IGFBP-3 (P = 0.76). The graphs suggest possible gender effects in IGF-II and IGFBP-1, but these are not significant (P = 0.71 and 0.58, respectively). The height of the solid bars shows the mean change; the error bars give 95% confidence intervals for these mean changes. r-hGH, Recombinant human GH.

An increase in IGF-II was also observed during GH treatment from 698 ± 294 ng/ml at baseline to 843 ± 268 ng/ml at 6 months (P < 0.001) but not with placebo treatment (baseline, 688 ± 273 ng/ml; 6 months, 713 ± 269 ng/ml). IGFBP-3 levels were also significantly increased from 2687 ± 1178 ng/ml at baseline to 4038 ± 1267 ng/ml at 6 months during GH treatment (P < 0.001) and from 2748 ± 1173 ng/ml at baseline to 2927 ± 1351 ng/ml at 6 months during placebo treatment. A slight but not significant decrease in IGFBP-1 was noted in the GH group, from 37.2 ± 30.4 to 31.9 ± 28.1 ng/ml, whereas IGFBP-1 was unchanged in the placebo group (baseline, 37.1 ± 34.6 ng/ml; 6 months, 37.1 ± 32.6 ng/ml). Unlike the IGF-I responses, there were no gender differences in the IGF-II (P = 0.76), IGFBP-3 (P = 0.76), or IGFBP-1 (P = 0.58) responses.

Serum levels of the marker of bone formation, osteocalcin (Nichols Institute Diagnostics, San Juan Capistrano, CA; immunoradiometric assay), increased significantly after treatment in the GH group compared with the placebo-treated group. The response was significantly greater in males compared with females (data not shown). Similarly, C-terminal propeptide of collagen type I increased significantly during GH treatment, but there was no significant gender effect (data not shown). There were no significant changes of bone mineral density at the femoral neck, Ward’s triangle, trochanter major, or L2-L4 vertebrae during the 6 months of treatment (data not shown).

Body composition changes

Assessment of body composition by DEXA demonstrated an increase in lean body mass and a decrease in fat mass (Table 2). The observed treatment difference in lean body mass increase between GH and placebo was 2.1 kg (P < 0.0001). The effect was significantly larger in males (P < 0.0001) [GH, +3.13 kg (2.42, 3.84); placebo, +0.11 kg (−0.60, 0.82)] [mean change 0–6 months (95% confidence limits)] than in females [GH, +0.64 kg (−0.15, 1.44); placebo, −0.90 kg (−2.20, 0.39)] (Fig. 2). There was a strong, positive association (P < 0.0001) between IGF-I changes and lean body mass increases over the 6 months of treatment among the entire cohort of patients. The treatment difference in fat mass decrease was 2.8 kg (P < 0.0001), and the decrease was not significantly greater in males [GH, −2.78 kg (−4.05, −1.51); placebo, +0.38 kg (−0.39, 1.14)] than in females [GH, −1.81 kg (−2.66, −0.97); placebo, +0.63 kg (−0.16, 1.42)] (Fig. 1). Determinations by BIA showed similar changes as those derived from the DEXA measurements; fat-free mass increased for the entire group [GH, 1.46 kg (0.79, 2.13); placebo, −0.32 kg (−1.98, 1.34)]. Again a distinct gender difference was noted in lean body mass increases, with a gain of only 0.80 kg (−0.09, 1.70) among females compared with 2.12 kg (1.12, 3.12) in males. There was no gender difference among the placebo-treated group, with modest reductions of −0.42 kg (−1.53, 0.70) for females and −0.27 kg (−2.77, 2.22) for males. The corresponding fat mass reduction revealed similar changes with loss of fat mass among the GH-treated group [GH, −1.92 kg (−2.67, −1.17) for both sexes; −1.90 kg (−2.72, −1.08) females; and −1.93 kg (−3.24, −0.63) males], with no effect among the placebo-treated group [+0.44 kg (−1.14, 2.01) both sexes; 0.38 kg (−0.79, 1.55) females; and 0.46 kg (−1.90. 2.83) males]. Extracellular water increased during GH treatment [change 0–6 months: GH, 1.07 ± 1.20 liters (0.74 ± 1.11 liters for females, 1.40 ± 1.22 liters for males); placebo, 0.32 ± 2.11 liters] but not significantly (between-group comparison, P = 0.33 after adjustment for significant between-center differences). Total body water also did not change significantly (change 0–6 months: GH, 0.94 ± 1.97 liters; placebo, 0.31 ± 4.43 liters). As with the fat mass reduction, anthropometric measurements showed a decrease in the sum of circumferences (mid-arm, mid-leg, waist, and hip) [change 0–6 months: GH, −2.02 ± 8.59 cm (−3.42 ± 9.98 cm for females, −0.62 ± 6.83 cm for males); placebo, 1.42 ± 8.55 cm; between-group comparison, P = 0.017). The waist to hip ratio did not change (Table 2). There was no significant change in total body weight, body mass index, or sum of skinfold thicknesses (biceps, triceps, subscapular, and suprailiac) (data not shown).

Table 2.

Changes in body composition and cardiac function

	GH		Placebo
	Baseline	Change, 0–6 months	Baseline	Change, 0–6 months
DEXA
Lean body mass (kg)	49.1 ± 11.7 (n = 59)	1.89 ± 2.23 (n = 52)1	53.7 ± 11.9 (n = 54)	−0.25 ± 2.26 (n = 51)
Fat mass (kg)	27.7 ± 10.7 (n = 59)	−2.30 ± 2.69 (n = 52)2	28.9 ± 14.8 (n = 54)	0.47 ± 1.96 (n = 51)
BIA
Fat free mass (kg)	49.1 ± 13.6 (n = 60)	1.46 ± 2.46 (n = 54)	53.0 ± 14.1 (n = 54)	−0.32 ± 6.03 (n = 53)
Fat mass (kg)	31.0 ± 12.1 (n = 60)	−1.92 ± 2.73 (n = 54)	31.7 ± 15.2 (n = 54)	0.43 ± 5.73 (n = 53)
Anthropometry
Sum of circumferences (mm)	285 ± 39.4 (n = 59)	−2.0 ± 8.59 (n = 52)	289 ± 40.3 (n = 55)	1.4 ± 8.55 (n = 54)
Waist/hip ratio	0.90 ± 0.09 (n = 60)	−0.004 ± 0.049 (n = 52)	0.90 ± 0.08 (n = 55)	−0.01 ± 0.036 (n = 54)
2-D Echocardiography
LV end-systolic volume (ml)	−4.29 ± 10.53 (n = 44)3	39.04 ± 16.0 (n = 48)	−1.14 ± 11.84 (n = 51)
Ejection fraction (%)	54.90 ± 11.21 (n = 52)	5.05 ± 9.99 (n = 43)4	54.41 ± 12.91 (n = 50)	3.01 ± 12.80 (n = 47)
M-mode echocardiography
LV posterior wall thickness (cm)	0.87 ± 0.18 (n = 56)	0.05 ± 0.17 (n = 49)5	0.94 ± 0.21 (n = 51)	−0.04 ± 0.14 (n = 46)

Values are expressed as mean ± sd. LV, Left ventricular; n, number of patients.

Comparison of changes between treatment groups,

¹

P < 0.0001;

²

P < 0.0001;

³

P = 0.035;

⁴

P = 0.048;

⁵

P = 0.03.

Figure 2.

Changes in body composition (lean body mass and fat mass) and cardiac function [left ventricular end-systolic volume (LVESV) and ejection fraction (EF)] in males and females after 6 months of treatment with GH or placebo. The changes in lean body mass were significantly greater in males than in females (P < 0.0001), and a similar trend was seen in fat mass. There was a significant improvement in cardiac function in left ventricular function after GH treatment, compared to placebo, and this improvement was similar in males and females. The height of the solid bars shows the mean change; the error bars give 95% confidence intervals for these mean changes. r-hGH, Recombinant human GH.

Cardiac changes

Echocardiographic determinations demonstrated a significant decrease in left ventricular end-systolic volume, from 35.8 ± 17.6 ml (mean ± sd; normal, <25–40 ml) at baseline to 30.4 ± 15.4 ml after 6 months of GH treatment (between-group P value, 0.035) and a corresponding increase in ejection fraction, from 54.9 ± 11.2% (normal, > 60%) at baseline to 60.9 ± 9.5% after 6 months (between-group P value, 0.048) (Table 2). The effect was similar in males and females for both left ventricular end-systolic volume [males: GH, −5.53 ml (−11.38, 0.31); placebo, −2.12 ml (−7.17, 2.93); females: GH, −2.92 ml (−5.55, −0.28); placebo, 0.81 ml (−3.32, 4.94)] [mean change 0–6 months (95% confidence limits)] and for ejection fraction [males: GH, 6.13% (1.48, 10.78); placebo, 3.12% (−1.52, 7.76); females: GH, 3.81% (−0.47, 8.09); placebo, 2.80% (−4.40, 10.00)] (Fig. 1). The internal dimensions of the left atrium and ventricle did not change except for the left ventricular posterior wall thickness, which increased significantly during GH treatment (between-group P value, 0.036) (Table 2). Again, there were no significant gender differences. No change in fractional shortening occurred during GH treatment (data not shown). Indices of left ventricle diastolic filling and function, IVRT, E max, A max, E/A ratio and E/F slope, were not altered in any of the treatment groups. There was a small but not statistically significant decrease in CO during GH treatment. Also, there was a trend for a reduction in SVR after GH treatment, but this difference did not reach statistical significance vs. the change in the placebo group. There were no overall changes in heart rate or resting systolic or diastolic blood pressure in either treatment group. Moreover, the changes in cardiac parameters did not correlate with the changes in body composition.

Adverse events

Study drug compliance was excellent, as evidenced by significant increases in IGF-I levels. Treatment was also well tolerated as shown by an overall dropout rate of only 9.6% (GH, 11.7%; placebo, 7.3%). Thus, 53 GH-treated and 51 placebo-treated patients completed the 6-month study period. Of these completers, 18 and 8, respectively, had some period of dose reduction (mean duration, 11 d) on an individual patient basis, due to presumed drug-related adverse reactions. Doses for males and females were similar.

As seen in Table 3, adverse events were primarily those related to the effects of GH on fluid balance: peripheral edema, stiffness in the hands and fingers, paraesthesia, hypoesthesia, arthralgia, and myalgia. The majority were of mild or moderate severity. The proportions of mild, moderate, and severe adverse events were similar in patients with low, normal, and high IGF-I levels, respectively (data not shown). Four patients withdrew from GH treatment due to adverse events. The reasons were carpal tunnel syndrome, recurrence of a pituitary adenoma, cerebral hemorrhage, and arthralgia. One patient withdrew during placebo treatment due to hypertension and paraesthesia. An abnormal glucose tolerance test was found for one patient after 3 months of GH treatment. This patient had already before the study demonstrated abnormal glucose tolerance, and no change in GH treatment was considered necessary. No apparent trends were seen in any biochemical parameters during treatment.

Table 3.

Adverse events with incidences of 5% or greater

Preferred term	GH (n = 60)	Placebo (n = 55)
Arthralgia	14 (23.3%)	7 (12.7%)
Headache	11 (18.3%)	8 (14.5%)
Influenza-like symptoms	9 (15.0%)	3 (5.5%)
Oedema peripheral	9 (15.0%)	2 (3.6%)
Back pain	6 (10.0%)	5 (9.1%)
Myalgia	5 (8.3%)	2 (3.6%)
Rhinitis	5 (8.3%)	2 (3.6%)
Dizziness	4 (6.7%)	3 (5.5%)
Upper respiratory tract infection	4 (6.7%)	2 (3.6%)
Paraesthesia	4 (6.7%)	1 (1.8%)
Hypoaesthesia	4 (6.7%)	0
Bronchitis	3 (5.0%)	5 (9.1%)
Oedema dependent	3 (5.0%)	2 (3.6%)
Nausea	3 (5.0%)	2 (3.6%)
Skeletal pain	3 (5.0%)	1 (1.8%)
Carpal tunnel syndrome	3 (5.0%)	1 (1.8%)
Edema	3 (5.0%)	0
Chest pain	3 (5.0%)	0
Depression	3 (5.0%)	0
Hypothyroidism	3 (5.0%)	0
Insomnia	3 (5.0%)	0
Pain	2 (3.3%)	3 (5.5%)
Injection site bruising	1 (1.7%)	3 (5.5%)
Hypertension	1 (1.7%)	4 (7.3%)
Pharyngitis	0	3 (5.5%)

n, Number of patients.

Discussion

This study was designed to evaluate the efficacy and safety of GH replacement therapy in a large patient cohort of adults with GHD. The study design with a 6-month double-blind, placebo-controlled phase has been shown to be adequate to demonstrate the metabolic effects of GH, particularly on body composition (reviewed in Ref. 4). One hundred fifteen patients were enrolled, which to our knowledge makes this one of the largest studies of its kind. The starting dosage of 0.005 mg/kg·d and the maintenance dosage of 0.01 mg/kg·/d used in the study are in agreement with current clinical practice and the recommendations by the Growth Hormone Research Society (5) (starting dose interval, 0.15–0.30 mg/d). The participants were representative of adult patients with acquired GHD. The majority of our patients (92%) had adulthood-onset GHD, most typically secondary to a pituitary tumor, and were already receiving other pituitary regulated hormones.

As expected, serum levels of the GH-dependent IGF-I and IGFBP-3 were generally low at baseline in both study groups, increased rapidly and significantly during GH treatment, but remained low in the placebo group. A small decrease in IGFBP-1 was noted during GH treatment, presumably related to increased plasma insulin levels and/or a direct inhibitory effect of GH on this IGFBP (30).

The measurements of lean body mass by DEXA clearly demonstrated a significant increase after 6 months of treatment with GH compared with placebo. This change in lean body mass was accompanied by a decrease in fat mass. The response in lean body mass was significantly greater among males than females, and a similar trend between gender was seen for the reduction in fat mass. On average, treated males added 2.52 kg of lean body mass more than treated females. There are several methodologies for assessment of body composition, but no single technique can be defined as the “gold standard” and none has been absolutely validated for adult GHD patients. Nevertheless, remarkably similar results have been obtained in a large number of published studies despite methodological differences (reviewed in Ref. 4).

Our current findings on changes in body composition are consistent with the published data that showed increases in lean body mass of between 1.4 and 4.6 kg during 6–12 months of treatment and between 2.2 and 2.4 kg after 18–24 months (1–4, 31–36). Lean tissue increases in the trunk, legs, and arms (34), and this effect is maintained during long-term treatment (37). After 10 yr of GH treatment, lean body mass was still significantly greater than at baseline. However, the reduction in fat mass did not appear to be sustained (37). This is consistent with findings from several studies in which an initial decrease in fat mass was followed by stabilization (37, 38). Five-year data have shown an initial decrease in sc and intra-abdominal fat mass of 31 and 46%, respectively, during the first year and then a partial regain (38). The changes in lean and fat tissue were also evident from anthropometric measures in the present study, as shown by decrease of the sum of waist, hip, mid-arm, and mid-leg circumferences during GH treatment. Most of our study participants had adulthood-onset GHD with multiple hormone deficiencies, but similar changes in body composition have been reported for patients with isolated GHD, patients with multiple pituitary hormone deficiencies (33), and in both childhood-onset and adulthood-onset GHD (31). The changes in body composition have been more pronounced in men than in women both in this and several other studies involving fewer patients (33, 39, 40).

Several studies have been published examining the cardiac and vascular structure and function in adults with GHD compared with healthy controls and the effects during GH replacement therapy (15–26, 41). The present study demonstrates an increase in ejection fraction after 6 months of GH treatment associated with a decrease in left ventricular end-systolic volume but without any significant change in end-diastolic volume. Our study provides convincing evidence that GHD adults have significant cardiac dysfunction as evidenced by a depressed ejection fraction (55 ± 11%; normal, >60%). Similar low values, between 53 and 59%, which are considerably lower than ejection fraction in normal controls, 62 to 69%, have been reported in GHD adults (15, 19, 20). Treatment with GH for 6 months in the present study normalized ejection fraction (61 ± 9%). Unlike changes in body composition, this improvement in cardiac function was noted similarly among male and female patients.

Cardiac structure parameters such as left atrial and ventricular inner diameters, septal and posterior wall thickness, and left ventricular mass have been found to be lower in GHD patients than normal controls (21, 24, 41). Fractional shortening was reduced in GHD patients compared with controls in one study (19), but was similar to controls in another study (24). In the present study, there was an increase in posterior wall thickness during GH treatment, but no changes were seen for the atrial or ventricular diameters or the ventricular septal wall thickness. Consequently, fractional shortening and left ventricular mass did not change. Similarly, other studies showed few structural changes (21, 26). Increases in left ventricular mass or left ventricular mass index have been observed in studies with higher GH doses or longer treatment duration than the present study (21, 23, 25, 26). Increases in stroke volume, CO, and cardiac index have also been shown in several studies (20, 22, 23–25). In one of them, the increase in stroke volume became apparent after 42 months of treatment at a GH dose of 0.5 IU/kg·wk (corresponding to ∼0.024 mg/kg·d) (22). At such a high dose, GH might exert hypertrophic effects on the myocardium, mimicking what is seen in patients with acromegaly (15). Moreover, increase in heart rate has been observed with relatively high GH doses (23, 24), and together with the increased stroke volume this could explain increased CO. Alternatively, the increase in stroke volume might be compensatory to the fluid overload induced by GH. This explanation seems unlikely because poor diastolic filling and reduced total peripheral resistance decreases have been observed with high dose GH treatment (23, 42). The use of lower doses intended to physiologically replace GH, however, may be associated with fewer side effects from fluid retention. A slight, but not statistically significant, decrease in systemic peripheral resistance was observed in the present study.

Diastolic dysfunction has been found in several studies (15–17), showing abnormal left ventricular filling with concomitantly low E/A ratios, i.e. the ratio between the maximum early rapid filling (E-wave) after the mitral valve opens and the maximum filling (A-wave) from the left atrium to the ventricle before the mitral valve closes during diastole. Left ventricular end-diastolic volume has also been found to be reduced regardless of age and duration of GHD (15). Another study found reduced left ventricular end-diastolic diameter compared with controls but no difference in left ventricular filling (E/A ratio) (24). The present study does not support the contention that GHD adults suffer from significant diastolic dysfunction. At baseline, indices of diastolic function (E max, A max, E/A ratio and IVRT) were relatively preserved as compared with published normal controls (43). Such a comparison, however, needs to be made with caution, because direct comparison with sex, age, and body-mass-matched controls would have been ideal. Moreover, more sensitive radionuclide angiographic techniques may be required to demonstrate early diastolic dysfunction in GHD adults (15). Nevertheless, GH treatment in our study did not result in significant improvement in diastolic function as has been noted in several smaller studies (18, 22, 23).

The changes in cardiac parameters did not correlate with the changes in body composition. This distinct difference between the effects of GH on body composition and cardiac function parameters raises the question of possibly different mechanisms of action for GH on these tissues. The role of GH in the regulation of cardiac function needs to be clarified, but present data suggest both direct GH effects and indirect effects through IGF-I, and possibly also other mediators (reviewed in Ref. 15).

The treatment was generally well tolerated, with few adverse events requiring dose adjustments or treatment interruptions. Arthralgia, peripheral edema, other types of edema, myalgia, paraesthesia, and hypoesthesia were more common in the GH group than in the placebo group. There were three cases of carpal tunnel syndrome in the GH group and one in the placebo group. These types of events are consistent with previous findings (4, 31, 44) and are thought to be related to the effects of GH on fluid homeostasis. More importantly, using the larger power of this multicenter design, we were able to examine the ability of IGF-I monitoring to predict the occurrence and/or severity of adverse events. The overall incidence of adverse events was similar in patients with low or high IGF-I levels but higher in patients with normal IGF-I levels, and there was no clear relationship between the severity of an adverse event and the IGF-I level achieved. Thus, a high IGF-I level does not appear to be highly predictive of the occurrence or severity of adverse events.

There was one case of a recurrence of a pituitary adenoma, reported as a serious adverse event and deemed by the investigator to be possibly drug-related. Follow-up during 3 yr did not show any progression of the adenoma, and the patient receives treatment with GH today. Reports from other large series of adult GHD patients suggest that there is no increased risk of tumor recurrence from GH treatment and that the frequency is not higher than expected in the absence of GH treatment (44). Regular follow-up examinations of a patient with a history of pituitary adenoma or central nervous system tumor is warranted, but the current experience with GH replacement therapy does not suggest a need for intensifying such follow-up examinations (5).

One patient in the present study developed impaired glucose tolerance after 3 months of treatment. Both GHD and long-term GH replacement therapy have been associated with changes in glucose tolerance (45–47). However, a recently published study showed no significant effects on glucose tolerance and insulin concentrations after 7 yr of GH replacement therapy (48).

In conclusion, this study has shown that replacement therapy with GH in adults with GHD at a dosage of 0.005–0.010 mg/kg·d induced beneficial effects on body composition, particularly by increasing lean body mass and reducing fat mass, and improved left ventricular systolic function. Although the effects on lean body composition were more pronounced in males, female subjects experienced equally beneficial effects on cardiac function. The mechanisms for these contrasting gender-related differences are unclear. Moreover, the long-term beneficial effects on cardiac function, physical performance, and cardiovascular-related morbidity and mortality remain to be defined.

Acknowledgments

The support of study center coordinators Nadine Clifford, Anita Furlong, Diane Gagnon, Lori Kingdon, and Yvonne McKensie is deeply appreciated. Dr. James Alexander Stewart (Montréal, Canada) and Dr. Zion Sasson (Toronto, Canada) are acknowledged for the cardiac performance measurements.

This work was presented in part at the 83rd Annual Meeting of The Endocrine Society, Denver, Colorado, 2001, and at the Sixth Joint Meeting of the Lawson Wilkins Pediatric Endocrine Society and European Society for Pediatric Endocrinology, Montréal, Canada, 2001.

Abbreviations:

• A max,

  Diastolic flow secondary to atrial contraction;

• BIA,

  bioelectric impedance analysis;

• CO,

  cardiac output;

• 2-D,

  two-dimensional;

• DEXA,

  dual-energy x-ray absorptiometry;

• E/A ratio,

  ratio of peak mitral early diastolic and atrial contraction velocity;

• E/F slope,

  early diastolic deceleration slope;

• E max,

  early diastolic flow;

• GHD,

  GH deficiency or GH-deficient;

• IVRT,

  isovolumic relaxation time;

• MAP,

  mean arterial pressure;

• SVR,

  systemic vascular resistance.