Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

Clinical Endocrinology (1994) 41, 615-620

Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

Leif Thuesen', Jens 0. L. Jergensent, Jern R. YJliiefl, Bent 0. Kristensen*, Nieis E. Skakkebmu, Nina Vahit and Jens S. Christiansent *Department of Cardiology, Skejby Hospital; tMedical Department M (Diabetes and Endocrinology), Aarhus University, Aarhus, and $Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark

(Received 18 February 1994; returned lor revision 7 April 1994; finally revised 31 May 1994; accepted 13 July 1994)

Summary

OBJECTIVE Since OH substitution therapy is now avaii- able for adult OH deficient patients, information on the cardiovascular effects of OH substitution has assumed malor clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients.

graphy was performed in 21 GH deficient patients after 4months placebo and 4months GH therapy, In a double blind cross-over study. in an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of OH therapy. Twenty-one age and sex-matched normal control subJects were also investlgated. RESULTS Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further Increase (lo%, WO.01) and seemed to remain elevated after 16 months of OH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patlents than in controls, and dld not change significantfy after OH treatment. The left ventricular diastolic diameter was reduced in patlents as compared to controls, but increased after 4 months GH therapy (P>0.05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following OH therapy and remained elevated after 16 and 38 months (P < 0.05) of OH substitution. CONCLUSION Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions

Correspondence: Leif Thuesen, Department of Cardiology, Skejby Hospital, DK-8200 Aarhus N, Denmark.

PATIENTS AND MEASUREMENTS Doppler echocardio-

increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supranormal levels.

The production of biosynthetic growth hormone (GH) has opened a possibility for treatment of adult GH deficient patients, and GH substitution has been shown to improve muscle strength, exercise capacity and psychosocial well- being in these patients (Jergensen et al., 1989; Mcauley et al., 1990). Premature atherosclerosis has been detected by ultrasonography in symptom-free hypopituitary adults (Markussis et af., 1992) and both GH deficiency (Rosen & Bengtsson, 1990) and GH excess (Wright et al., 1970) seem to be associated with increased cardiovascular morbidity and mortality. Cardiovascular effects of GH administration for 6 months in GH deficient adults have been assessed in two studies, and increases in the left ventricular end- diastolic dimensions and wall thickness and fractional shortening, were demonstrated (Cuneo et al., 1991; Amato et al., 1993).

Information of the cardiovascular effects of long-term GH substitution therapy is of major clinical interest in relation to possible adverse effects of long-term GH substitution. Therefore, the present study has assessed cardiovascular effects of GH substitution therapy for 4, 16 and 38 months.

Methods

Patients

The study population consisted of 22 GH deficient adults, who had previously been treated with GH. Twenty-one patients (8 females, 13 males, mean age 23.8 f 5.5years) completed a double blind cross-over study (4 months GH or placebo treatment, separated by a 4 months wash-out period). Eleven of these patients had isolated GH deficiency and 10 had multiple pituitary deficiency. In the group of multiple pituitary deficient patients, 9 received thyroxine; 8, testosterone; 6, cortisol; 2, oestradiol; and 2, desmopressin. Data on height, weight and body mass index are given in Table 1. Further details on patients and methods have been reported earlier (Jsrgensen et af., 1989).

After the initial double blind randomized phase, 13 patients (4 females and 9 males, mean age 26.4 f 6.1 years)

61 5

010 L. Thuesen et a / . Clinical Endocrinology (1994) 41

agreed to continue GH therapy in an open study. Six of these patients had isolated GH deficiency and 7 had multiple pituitary deficiency. In the group of multiple pituitary deficient patients, 6 received thyroxine; 5, testosterone; 4, cortisol; 2, oestradiol; and 1, desmopressin. These 13 patients were restudied after 16 months of GH therapy. Further clinical information has been provided in a previous publication (Jsrgensen ef al., 1991). Eight patients did not participate in the open study for the following reasons: inconvenience of injections and of frequent in and out- patient control visits (n = 6), planning pregnancy (n = l), emigration (n = 1).

Nine of the 13 patients who participated in the open GH substitution study (3 females and 6 males, mean age 26.7 f 4.2 years) continued further GH substitution therapy and were examined again after 38 months of GH therapy. Five of these patients had isolated GH deficiency and 4 had multiple pituitary deficiency. In the group of multiple pituitary deficient patients, 3 received thyroxine; 2, testosterone; 1, cortisol; and 2, oestradiol. Three patients did not want to continue because of inconvenience of frequent in and out- patient visits, and in one patient the echocardiographic examination was inadequate because of technical problems.

The patients treated themselves with daily subcutaneous injections of GH (Norditropin, Novo-Nordisk, Gentofte, Denmark). GH was administered in a dose of 2 IU/m2, during the placebo controlled four-month period. During the initial 16 months of the open GH therapy the daily GH dosage was 2.91U/m2, but this dose was subsequently reduced in all patients to 2 IU/m2 for the rest of the study period.

Twenty-one age and sex-matched normal control subjects were investigated for control prrposes (Table 1).

Informed consent was obtained fiom all the participants of the study, which was approved by the locally appointed ethics committee in accordance with the declaration of Helsinki.

Heart rate, blood pressure and Doppler echocardiography

Haemodynamic evaluation was performed by Doppler echocardiography and by heart rate and blood pressure measurements after the initial placebo/GH treatment period, and after 16 and 38 months of GH replacement therapy.

After 15 minutes in a supine position heart rate was measured by palpation of the radial pulse over 1 minute, blood pressure was measured by a sphygmomanometer, and M-mode, two-dimensional and pulsed Doppler echocardiography were performed by means of a Toshiba 40A or a Toshiba 270 ultrasound machine. A 3-5-MHz transducer was used for 2-D and M-mode echocardiography, and a 2.5- MHz transducer for the pulsed Doppler measurements.

During the echocardiographic measurements the subjects were placed in the left lateral decubitus position, and the head of the bed was slightly elevated. The parasternal short- axis view and the apical 4-chamber view were used for the M-mode and the mitral flow velocity recordings, respectively. The measurements were based upon means of 5 consecutive cardiac cycles. The paper speed was lOOmm/s for measurement of transmitral flow velocities and 50 mm/s for M-mode measurements.

All echocardiograms were recorded and assessed by a single operator (LT). During the placebo controlled part of the study the echocardiograms were recorded and analysed blind. During the open part of the study the echocardiograms were also analysed blind.

The left ventricular internal end-systolic diameter (LVIDs), the internal end-diastolic diameter (LVIDd), the septa1 diastolic thickness (SPT) and the posterior wall diastolic (PWT) and systolic thickness were measured just below the tip of the mitral valve (Sahn et al., 1978; Feigenbaum, 1981).

Fractional shortening of the left ventricle (FS%) was calculated as

{(LVIDd-LVIDS) x lOO}/LVIDd (%)

and used as an index of the left ventricular systolic function (Feigenbaum, 1981). Afterload was calculated as the end- systolic meridional wall stress, using the end-systolic diameter, posterior wall end-systolic thickness (PWTs) and the cuff systolic blood pressure (SBP) in the following formula:

0.334 x LVIDs x SBP/PWTs x (1 + PWTs/LVIDs) (lo3 dyn/cm2)

(Reichek et al., 1982). The stroke volume index (SVI) and the cardiac index (CI)

were calculated from the systolic and the diastolic left ventricular short-axis diameters and the heart rate as described by Teichholz et al. (1976).

SVI: (diastolic volume-systolic volume)/ body surface area (ml/m2)

body surface area (l/min m2)

The left ventricular wall mass was calculated by means of

CI: {(diastolic volume-systolic volume) x heart rate}/

the following formula:

1.04 x { (IVT + LVIDd + PWTp -LVIDd}

(Devereux BE Reicheck, 1977). Left ventricular filling (the diastolic function of the left

ventricle) was assessed by pulsed Doppler measurements of the mitral inflow velocities. The ratio of peak velocity of

Clinical Endocrinology (1994) 41 Cardiovascular effects of growth hormone therapy 617

early and atrial mitral flow (E/A ratio) was calculated and used as an index of the left ventricular diastolic function (Rokey et al., 1985; Spirit0 et al., 1986).

Under such conditions the coefficient of variation in 11 young, healthy men based upon two echocardiographic examinations at an interval of 3 weeks were LVIDd 3-1 %, LVIDs 3*3%, FS 3-7%, SPT 7.0%, PWT 6.8%, wall mass 12.6%, end-systolic meridional wall stress 12.1%, and

Table 1 shows results from normal controls and from patients after the placebo period and following 4 months of GH therapy. Data from 13 patients treated with GH for 16 months and from 9 patients treated for 38 months are given in Table 2 and Table 3, respectively. No systematic difference between patients with isolated GH deficiency and patients with multiple pituitary deficiency was seen.

cardiac output 17.4% (Thuesen et al., 1988,).

Statistical analysis

Data are given as mean f 1 SD. Data from the initial double blind, placebo-controlled part of the study were evaluated statistically by the paired and the non-paired two-tailed Student’s t-test. The data obtained from the open part of the study (16 and 38 months of GH therapy) were compared to the placebo values from the initial part of the study by means of two-way analysis of variance

Heart rate and blood pressure

Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further increase (lo%, P<O-Ol) and seemed to remain elevated after 16 months GH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls. Neither the systolic nor the diastolic blood pressures changed significantly after GH treatment.

Doppler echocardiographic parameters (ANOVA). If this test yielded a P-value cO.1, the paired Student’s 1-test was used for post hoc analysis. Level of significance 0.05. The left ventricular diastolic diameter was reduced in

patients compared to controls. It showed a slight but significant increase after 4 months GH therapy (P < 0.05) and seemed to increase further during the longer study period. The systolic diameter was the same in patients and controls and did not change significantly during the study.

Results

Data on heart rate, blood pressure and the Doppler echocardiographic parameters are given in three tables.

Table 1 Height, weight, body mass index, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), left ventricular internal short axis systolic diameter (LVIDs), left ventricular internal short axis diastolic diameter (LVIDd), left ventricular fractional shortening (FS%), left ventricular end-systolic meridional wall stress (ESMWS), left ventricular stroke volume index (SVI), cardiac index (CI), left ventricular septa1 thickness (SPT), left ventricular posterior wall thickness (PWT), left ventricular wall mass (wall mass) and the ratio of left ventricular early and atrial filling (E/A ratio) in 21 GH deficient adult patients before and after 4 months GH substitution therapy and in 21 age and sex-matched control subjects

GH deficient patients

Controls placebo GH treatment (n = 21) (n = 21) (n = 21)

Height (cm) Weight (kg) Body mass index (kg/m2) Heart rate (lJeats/min) Systolic BP (mmHg) Diastolic BP (mmHg) LIVDd (mm) LVIDs (mm) FS (%) ESMWS (lo’ dyn/cm2) SVI (mI/m2) CI (I/min m2) SPT (mm) PWT (-1 Wall mass (g/mZ) E/A ratio

177 f 8 69f 10

21.8 f 1.4 63 f 9

116f 1 1 72 f 12 50 f 4 32 f 4 3 5 f 4 70f 13 41 f 7 2.5 f 0.5

10.0 f 2.0 10.9 f 1.8 120 f 22 1.7 f 0.3

163 f 12* 59 f 15*

22.0 f 4.1 69f 11*

101 f 8** 69 f 9** 46 f 6* 30 f 5 34 k 6 61 f 18 36 f 10

2.5 f 0.8 9.8 f 1-5

10.1 * 1.5 119 f 31 1.9 f 0.5

6 0 k 15*

76 f Is**? 105 f 1152

70 f lo** 47 f 6*t 30 f 6 35 f 6 65f 19 40f 10 3.0 f l.O**t

10.0 f 1.7 10.1 f 1.6 122 f 33 1.8 f 0.5

P< 0.05, ** P<O.Ol as compared to normal control subjects. t P < 0.05 as compared to placebo treatment.

618 L. Thuesen eta / . Clinical Endocrinology (1994) 41

Table 2 Clinical and haemodynamic parameters in 13 GH deficient adult patients before and following GH therapy for 4 and 12 months. See Table 1 for legend

GH substitution therapy

16 months Placebo 4 months (n = 13) (n = 13) (n = 13)

Height (cm) Weight (kg) Body mass index (kg/m2) Heart rate (beatslmin) Systolic BP (mmHg) Diastolic BP (mmHg) LIVDd (mm) LVIDs (mm) FS (%) ESMWS (lo' dyn/cm2) Stroke index (rnl/m2) CI Q/min mZ) SPT (mm) PWT (mm) Wall mass (g/m2) E/A ratio

165 f 14 59f 12

21.6 f 3.2 69 f 10 102 f 7 72 f 9 46 f I 31 f6 32 f 6 62 f 16 36 f 12 2.5 f 0.9 9.9 f 1.7 10.1 f 1.5 124 f 36 1.9 f 0.4

165 f 13 58 f 12

21.3 f 3.2 80 f 13' 105 f 12 69 f 10 47 f I 30 f 6 36 f 7. 59f 14 41 f 12* 3.2 f 1.2' 9.5 f 1.5 9.8 f 1-3 123 f 38 1.8 f 0.5

167 f 14' 61 f 12

22.1 f 2.9 14f 10

108 f 11 71 f 8 48 f 5 29 f 5 40 f 6' 50 f 12 44f9* 3.1 f 0.8 9.6 f 0.9 9.7 f 09 122 f 20 1.8 f 0.4

* P < 0.05 as compared to placebo treatment.

The left ventricular fractional shortening showed similar values in controls and patients during placebo treatment and during 4 months GH therapy but was found to be increased by prolonged therapy (P < 0.05). Cardiac index was the same in controls and in placebo treated patients, but increased by 20% following GH therapy and remained elevated after 16 and 38 months (P < 0-05) of GH treatment.

The left ventricular diastolic function, as assessed by the E/A ratio, showed no significant differences between controls and patients or between the placebo and the GH treatment periods.

Left ventricular septa1 thickness, posterior wall thickness and wall mass were the same in patients and in controls and did not change significantly during the study.

None of the Doppler echocardiographic parameters were related to the changes in the height, weight or body mass index, which were Seen after 16 and 38 months of GH therapy.

Dlrcuuion

This is the first study in which the cardiovascular function of GH substituted adults had been monitored for a long time. The major findings were an increase in heart rate, left ventricular diastolic diameter and cardiac index,

Cuneo et al. (1991) investigated 24 GH deficient adults, who were randomized to GH substitution therapy or placebo for 6 months. They observed a slight (4%), but

significant, increase in the left ventricular diastolic diameter and suggested GH induced activation of the renin- aldosterone system with sodium retention and increased plasma volume (preload) might be responsible for the left ventricular enlargement. Similar results were obtained in a recent non-randomized study of 7 GH deficient adults before and after GH replacement therapy for 6 months (Amato et af., 1993). The present study confirms the finding of left ventricular dilatation following GH therapy. In addition, our study showed that the left ventricular dilatation continues longer and that the increase in diastolic diameter probably indicates normalization, since the mean diastolic diameter during GH therapy approached the value found in age and sex-matched healthy control subjects.

The increase in the diastolic diameter was associated with an unchanged or slightly reduced systolic diameter. Thus, according to the Starling effect, an increase in cardiac output might be anticipated. Calculation of cardiac index from M- mode echocardiographic systolic and diastolic diameters is justified in the present patients who had a normal left ventricular contraction pattern (Teichholz et al., 1976). Accordingly, we found a 20-24% increase of cardiac index following GH substitution, and cardiac index was increased significantly following GH substitution compared both to placebo treatment and to normal control subjects. Our finding of increased cardiac index is compatible with previous studies showing increased cardiac output in

Clinical Endocrinology (1994) 41 Cardiovascular effects of growth hormone therapy 819

Table 3 Clinical and haemodynamic parameters in 9 growth hormone (GH) deficient adult patients before and following GH therapy for 4, 12 and 38 months. See Placebo 4 months 16 months 38 months Table 1 for legend

GH substitution therapy

(n = 9) (n = 9) (n = 9) (n = 9)

Height (cm) Weight (kg) Body mass index (kg/min2) Heart rate (beatslmin) Systolic BP (mmHg) Diastolic BP (mmHg) LVIDd (mm) LVIDs (mm) FS (%) ESMWS (lo3 dyn/cm2) Stroke index (ml/m2) CI O/min m2) SPT (-1 PWT (-1 Wall mass (g/m2) E/A ratio

165 f 11 60f 12

22.0 f 3.5 69f 11

101 1 7 71 f 10 45 f 6 3 1 f 5 32 f 6 57f 13 34 f 9

2.3 f 0.6 10.0 f 1.8 10.2 f 1.5 120 f 32 1.9 f 0.4

166 f 11 59 f 12

21.5 f 3.4 78 f 14

105 f 13 69 f 12 45 f 6 29 f 5 35 f 7* 55 f I 1 37f 11 2.9f 1.1 9.3 f 1.5 9.8 f 1.3 112 f 28 1.8 f 0.5

167 f 12* 63 f 12

22.4 f 2.8 74 f 10

108 f 13 69 f 7 47 f 5 29 f 4 39 f 4+ 50 f 13 42 f 8 2.9 f 0.6 9.6 f 0.9 9.9 f 0.9 119 f 18 1.8 f 0.5

167 f 12* 68 f l l *

24.1 f 2.9’ 74 f 10

107 f 12 72 _+ 6 48 f 5 30 f 3 38 * 4* 52 * 13 42 f 8 3.1 f 0*4* 9.4 f 0.9 9.9 f 0.9 117 f 19 1.9 f 0.5

* P < 0.05 as compared to placebo treatment.

acromegalic patients (Thuesen et al., 1988~) and in normal subjects treated with GH for 2 weeks (Thuesen et ul., 1988b). Furthermore, one study showed a dramatic increase in cardiac output in female rats implanted with a G H secreting tumour (Penney et af., 1985). The increase in cardiac output resulted from a combination of increased stroke volume and heart rate, as both heart rate and stroke volume were found to be increased by about 10% following GH administration.

Fractional shortening was also found to be increased after GH administration, but to a significant degree only after 16 and 38 months of GH therapy. An enhanced fractional shortening indicates an increased ventricular contractility only if the loading conditions of the heart remain constant (Braunwald, 1988). Here, afterload (end-systolic wall stress) was found to be unchanged, while the preload (diastolic diameter) was increased. Thereafter, the increase of fractional shortening is due at least in part to altered loading conditions, possibly due to increased peripheral blood flow. However, a positive inotropic effect of GH cannot be excluded (Thuesen et af., 1988b). Our data on the fractional shortening is consistent with the findings of Amato et af. (1993).

In the study by Cuneo er ul. (199 I), hypertrophy of the left ventricle was suggested on the basis of their finding of an increased left ventricular wall mass following GH substitution therapy. The wall mass in our study did not change significantly, since the left ventricular wall thickness was unchanged. Cuneo et ul. (1991) also found the wall thickness was unchanged. Thus, the augmented left ventricular wall

mass was a consequence of increased left ventricular diastolic diameter (dilatation of the left ventricle), and not due to left ventricular hypertrophy. In contrast, Amato et af. (1993) found a significant increase in the left ventricular septum, posterior wall and diastolic diameter, and conse- quently also a 35% increase of the left ventricular wall mass.

Blood pressure was significantly lower in the G H deficient patients than in controls. There was an insignificant increase of blood pressure after GH therapy. Such a change in blood pressure would be compatible with the activation of the renin-aldosterone system following GH substitution therapy (Cuneo et al., 1991; Jnrrgensen, 1987).

Both GH excess and GH deficiency are associated with increased cardiovascular morbidity and mortality (Roskn & Bengtsson, 1990; Wright et uf., 1970). It is likely that GH exerts significant cardiovascular effects by increasing plasma volume and peripheral blood flow and by enhancing left ventricular stroke volume, heart rate and cardiac output. At present, the long-term cardiovascular consequences of these changes is unknown. Therefore, as a consequence of our demonstration of heart rate and cardiac output at a supranormal level, we would recommend regular assessment of cardiovascular function in GH substituted patients.

Acknowledgement

The GH and placebo preparations were generously supplied by Novo Nordisk, Gentofte, Denmark.

620 L. Thuesen et al. Clinical Endocrinology (1994) 41

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Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults