Download Cardiovascular effects of growth hormone

587
Clinical Science (1991)81,587-592
Cardiovascular effects of growth hormone treatment in
growth-hormone-deficient adults: stimulation of the
renin-aldosterone system
ROSS C. CUNEO', FRANC0 SALOMON', PETER WILMSHURST2, CHRIS BYRNE2,
C. MARK WILES3, RICHARD HEW4 AND PETER H. SONKSEN'
Divisions of 'Medicine, *Cardiologyand 3Neurology,United Medical and Dental Schools of Guy's and St Thomas' Hospitals,
St Thomas' Hospital, London, and 4Divisionof Radio-Isotopes, Medical Research Council, Northwick Park Hospital, Harrow,
Middlesex. U.K.
(Received 22 January/l3 May 1991; accepted 3 June 1991)
SUMMARY
1. In adult humans with growth hormone deficiency,
treatment with growth hormone has recently been shown
to have major anabolic effects and to improve exercise
performance. The cardiovascular effects of growth
hormone in adults with growth hormone deficiency were
examined in 24 patients treated with recombinant human
growth hormone (0.07 units/kg at night) in a doubleblind, placebo-controlled trial lasting 6 months.
2. Compared with placebo, resting M-mode echocardiography showed increases in left ventricular enddiastolic dimension and stroke volume in the group
treated with recombinant human growth hormone. No
differences were noted between the groups with respect to
left ventricular end-systolic dimension, fractional shortening, wall thicknesses or mean arterial blood pressure. Left
ventricular myocardial mass increased in the group given
recombinant human growth hormone.
3. The supine plasma renin activity was increased and
remained elevated over the 6 months, whereas the plasma
aldosterone concentration was unchanged, after treatment with recombinant human growth hormone. Clinical
signs of sodium retention were evident during the first 3
months of treatment with recombinant human growth
hormone.
4. We conclude that treatment with recombinant
human growth hormone in adults with growth hormone
deficiency resulted in small increases in left ventricular
pre-load, due to the sodium-retaining action of growth
hormone. Activation of the re&-aldosterone system was
involved in such changes. Myocardial hypertrophy was
observed without changes in mean arterial pressure, reflectingthe anabolic action of growth hormone.
Correspondence: Professor Peter H. Sonksen, Division of
Medicine, St Thomas' Hospital, London SE1 7EH.
Key words: aldosterone, echocardiography, insulin-like
growth factor-1, lean body mass, plasma renin activity,
somatotropin.
Abbreviations: ANG I, angiotensin I; GH, growth
hormone; IGF-1, insulin-like growth factor-1; IVS,interventricular septa1 thickness; LVED, left ventricular enddiastolic dimension; LVES, left ventricular end-systolic
dimension; LVPW, left ventricular posterior wall thickness; PRA, plasma renin activity; rhGH, recombinant
human growth hormone; V O ~ , , maximal
, ~ ~ , , oxygen uptake.
INTRODUCTION
Growth hormone (GH) is a potent anabolic agent, with
multiple effects on lipid and carbohydrate metabolism.
Recently, the effects of recombinant human GH (rhGH)
in adult man with GH deficiency have been examined in
two controlled treatment trials. Major increases in lean
body mass [l]and skeletal muscle mass [2, 31 have been
demonstrated, reflecting the anabolic action of GH.
Similar anabolic responses have been seen when GH has
been given to adult patients with burns [4],
after gastrointestinal surgery [5], with malnutrition [6] and with
chronic obstructive airways disease [7], and when given
to elderly male subjects [8].
GH treatment in adults with GH deficiency has
resulted in major improvements in exercise performance
[3,9]. Since cardiac output is generally considered to be a
major determinant of exercise performance and GH has
antinatriuretic effects, we report resting cardiac function,
determined by M-mode echocardiography, and plasma
levels of hormones regulating blood volume in a group of
adults with GH deficiency before and after rhGH treatment, and we relate these to changes in exercise performance.
588
R. C. Cuneo et al.
METHODS
Patients
The study reported here involves the same patients as
previously reported [ l , 3, 91. Briefly, patients were
selected if (a) G H deficiency (defined as a peak plasma
G H concentration of < 3 m-units/l during an adequate
insulin hypoglycaemia test) had been present for 12
months, (b)their age was between 18 and 52 years, and (c)
if required, stable and optimal conventional pituitary
hormone replacement was given for 12 months before
entry into the trial. Doses of these hormone replacements
remained unchanged during the trial, except in three
patients in the rhGH group, where thyroxine doses were
reduced at 1 month to maintain free tri-iodothyronine
levels within the reference range [ 11. Patients with
Cushing’s disease were all cured more than 12 months
before entry to the trial. Patients with other illnesses or
ingesting drugs or alcohol sufficient to affect myocardial
function or sodium balance were excluded.
Trial design
The protocol was approved by the hospitals’ ethics
committees and all patients gave written, informed
consent. Patients were randomly assigned to receive
either rhGH (Genotropin; 4 i.u./ml, 2.7 i.u./mg; KabiVitrum, Stockholm, Sweden) or identically presented
placebo, for 6 months, given as a daily subcutaneous dose
of 0.07 unit/kg body weight at 20.00 hours. Women were
studied in the first half of their menstrual cycle where
appropriate.
Echocardiography
Patients requiring pituitary hormone treatment took
their usual medications on the morning of the study.
Parasternal long-axis images were recorded just below the
mitral valve using a Hewlett-Packard machine (model
77020 AC) with the patient in the left lateral position. A
single observer, blinded to the treatment code and patient
details, performed all measurements. Left ventricular
end-diastolic wall thicknesses [interventricular septa1
(IVS) and posterior wall (LVPW)], and internal dimensions [end-diastolic (LVED) and end-systolic (LVES)]
were recorded to the nearest 0.1 cm.
Blood was collected via a plastic venous catheter after
an overnight fast, at least 30 min after the subject had
assumed the recumbent position. Plasma was separated
and was stored at -20°C until assayed. Brachial blood
pressure was then recorded, as the average of three
sphygmomanometric recordings in the non-dominant arm
at baseline and after 1, 3 and 6 months of treatment.
Plasma renin activity (PRA) was measured by established
methods [lo]. Plasma aldosterone concentration was
measured by r.i.a. [ 111 after solvent extraction using the
DPL Aldosterone Kit [DPL (U.K.) Ltd, Abingdon, Oxon,
U.K.]. Intra- and inter-assay coefficients of variation for
PRA were less than 5.2% and 7.0%, and for plasma
aldosterone concentration were less than 6.9% and 7.8%,
respectively. Maximal oxygen uptake ( V O ~ , , , ~
was
~,)
measured on a cycle ergometer on the day preceding
echocardiography, as previously reported [9].
Calculations
Mean arterial blood pressure was calculated as:
diastolic pressure + 1/3 X (systolic -diastolic pressure).
Diastolic and systolic volumes were determined as:
(7 x D3)/(2.4+ D), where D is the internal short diameter
in cm [12]. Fractional shortening ( O h ) was calculated as:
(LVED - LVES) X 100/LVED. Left ventricular wall mass
was determined as: 1.04 X [(LVED+ 3 MMT)2- LVED3]
- 13.6 g, where MMT represents mean myocardial thickness[MMT=(IVS+LVPW)/2] [13].
Statistics
Results are expressed as means k SEM. Treatment
responses were assessed by analysis of co-variance using
baseline data as the co-variate, and where repeat
measures were made a mean of treatment data was used
for comparison. Significance was recognized at the 5%
level. Reported percentage changes in variables are those
in excess of changes in the placebo group. Relationships
between changes in single variables in the two groups
were explored with multiple linear regressions, using
treatment group as a stratifying variable.
RESULTS
Randomization resulted in two evenly matched populations with respect to age, sex, body size and drug history
(see Table 1).Two patients in each group had undergone a
Table 1. Characteristics of the patients studied
Characteristics of the rhGH and placebo groups at the
beginning of the trial. Age, height and weight are shown as
means k SEM. No statistically significant differences were
observed between the two groups.
rhGH
group
(n=12)
Age (years)
39+3
8:4
Sex (M/F)
Height (cm)
170.0 2.7
82.5 3.9
Weight (kg)
Initial diagnosis (no.)
Cushing’s disease
6
Prolactinoma
0
Chromophobe adenorna
3
Craniopharyngiorna
3
Idiopathic
0
Radiotherapy (medulloblastoma)
0
**
Pituitary replacement hormones (no.)
Corticosteroids
Thyroxine
Sex steroids
Desarnino-o-arginine
vasopressin
Fludrocortisone
10
Placebo
group
( n = 12)
38+3
8:4
169.0 3.2
79.3 k 6.8
+
3
2
3
0
3
1
10
3
9
10
8
2
2
2
11
589
Cardiovascular effects of growth hormone
bilateral adrenalectomy as treatment for Cushing’s
disease.
Before treatment, no patient had values of wall thicknesses or chamber dimension outside the adult reference
range for our laboratory. After treatment, no changes
were noted in left ventricular wall thicknesses (Table 2).
LVED increased by 2% in the rhGH group (P=0.039).
Fractional shortening was significantly lower in the rhGH
group at baseline ( P = 0.004), but the increment after
treatment was not different between the two groups (P=
0.77). Stroke volume increased by 6.1% in the rhGH
group ( P =0.001). Left ventricular wall mass increased by
4.8% in the rhGH group (P=O.O45; see Fig. 1).Because
there was no change in body weight after rhGH treatment
[ 13, left ventricular wall mass expressed per body surface
area showed equally significant changes (rhGH, 110 f 10
to 1 2 0 f 10 g/m2; placebo, 100 f 10 to 100 f 10 g/m2;
P = 0.046).
Mean arterial blood pressure increased slightly, but not
significantly, at 1 month and was not different between the
groups (rhGH, 87 f3, 96 f4, 91 f2 and 88 f 3 mmHg;
placebo, 93 f3,95 f4,94 f 5 and 90 k 4 mmHg; see Fig.
2). One patient became hypertensive at 1 month (blood
pressure 141/105 mmHg); subsequent halving of the
rhGH dose resulted in a prompt normalization of blood
pressure for the remainder of the trial. In two other
Table 2. Echocardiographic results
Echocardiographic measurements (means fSEM) in the
rhGH and placebo groups before and after 6 months of
treatment. Statistical significance (analysisof co-variance):
*P<O.O5, **P<O.OOl compared with placebo; tP<O.Ol
compared with placebo group before treatment. Normal
values: LVED, 3.5-5.6 cm; LVES, 2.3-3.7 cm; IVS, < 1.2
cm; LVPW, < 1.1cm.
Before
treatment
After 6 months
of treatment
LVED (cm)
rhGH
Placebo
4.9 k 0.1
4.9 f 0.2
5.1 k0.1*
5.0 k 0.2
LVES (cm)
rhGH
Placebo
3.3 k 0.1
2.9 k 0.1
3.3 k 0.1
3.0 k 0.0
IVS (cm)
rhGH
Placebo
1.1 k O . 1
1.OkO.1
1.1 kO.1
1.0 k 0.1
LVPW (cm)
rhGH
Placebo
0.9 k 0.1
0.9 k 0.1
1.0 kO.1
0.9 k 0.1
Fractional shortening (70)
rhGH
Placebo
34 k 21
40f1
35f2
39fl
Stroke volume (ml)
rhGH
Placebo
71 k 4
79f6
78 k 4**
82f7
210f 10
200 f 20
230 k 20*
210f20
Left ventricular wall mass (gm)
rhGH
Placebo
patients, the rhGH dose was halved due to carpal tunnel
compression symptoms or peripheral oedema. One
patient in the rhGH group withdrew after 3 days treatment due to agitation.
The mean PRA in adults with GH deficiency before
treatment was 2.43 f0.28 (range 1.38-6.1 1) pmol of
angiotensin I (ANG I) h-’ ml-I in patients with intact
zona glomerulosae (95% confidence intervals for normal
samples collected after overnight recumbency, 1.14-2.65
pmol of ANG I h-I ml-I). In the patients with previous
adrenalectomies, PRA was 2.84, 4.12, 5.55 and 17.2
pmol of ANG I h-I ml-*, and plasma aldosterone
concentrations were undetectable. The plasma aldosterone concentration in the patients with intact adrenals
was 199 f28 pmol/l (recumbent reference range,
100-400 pmol/l).
In patients with intact adrenals after treatment, PRA
rose in the rhGH group and remained elevated throughout the trial (rhGH, 2.64f0.32, 3.08f0.42, 3.18k0.42
and 3.02f0.38 pmol of ANG I h-I ml-’at entry, 1, 3
and 6 months, respectively; placebo, 2.22 f0.44,
1.86f0.22, 1.78f0.26 and 2.01f0.27pmolofANGI
h-1 d - 1 . , p = 0.019; see Fig. 2). The plasma aldosterone
concentration did not change appreciably in either group
(rhGH, 185f34,144+24,163+34and 1 5 2 f 3 5 pmol/
1; placebo, 2 1 1 f 4 5 , 2 0 0 f 4 1 , 1 6 8 f 3 2 and 1 9 8 f 2 5
pmol/l). Treatment data were analysed after excluding
patients with prior adrenalectomies, although the conclusions were not altered by their inclusion. As previously
reported [ 11, the plasma potassium concentration fell
marginally after rhGH treatment (rhGH, 3.8 f0.1,
3.6f0.1, 3.7f0.1 and 3.6f0.1 mmol/l; placebo,
3.7k0.1, 3.7f0.1, 3.9f0.1 and 3.8f0.1 mmol/l at
entry, 1, 3 and 6 months, respectively; P=O.O5). The
plasma sodium concentration was normal and was unaffected by treatment with rhGH.
As previously reported [9], vo2,max.
during subjectlimited, maximal cycle ergometry increased in the rhGH
group (rhGH, 1.88 f0.17 to 2.34 f0.20 l/min; placebo,
1.84 f0.17 to 1.98 f0.13 l/min at baseline and 6 months,
respectively; P = 0.016). Increases in left ventricular
350 1
100
:
1
Pre
I
I
Post
Pre
,
i
Post
Fig. 1. Mean (bars) and individual values of left ventricular wall mass in the rhGH (m) and placebo (0)groups
before and after 6 months treatment.
R. C. Cuneo et al.
590
DISCUSSION
0
1
3
6
0
1
3
6
1
lo5
80
'
d i " "3'
6
Time (months)
Fig. 2. Changes in PRA (a),plasma aldosterone concentration ( b ) and mean arterial blood pressure (c) during
treatment with rhGH (m) or placebo ( 0 )for 6 months.
Data are presented as means & SEM. Statistical significance
(analysis of co-variance) between treatment groups: ( a )
P=O.O19, ( b )not significant and (c) not significant. Data
presented for PRA and plasma aldosterone concentration
include only patients with intact adrenal glands.
diastolic volume, but not in stroke volume, were
associated with increases in
( P = 0.03).
Changes in left ventricular wall mass were associated
with changes in stroke volume ( P = 0.01 3), but not with
the changes in lean body mass, thigh muscle mass, plasma
insulin-like growth factor-1 (IGF-1) concentration,
volmax,,
nor with the age or sex of the patients, nor with a
history of cured Cushing's disease. Increases in left
ventricular diastolic volume and wall mass were not
associated with changes in mean arterial blood pressure
from baseline to either 1 or 6 months.
v02,max,
GH treatment in adults with GH deficiency has been
shown to increase and normalize lean body mass [l], to
increase skeletal muscle mass [2, 31, to substantially
reduce fat mass [ l , 21 and to increase maximal [2,9] and
sub-maximal [9] exercise performance.
We have shown an increase in left ventricular myocardial wall mass of approximately 5% after rhGH treatment in adults with GH deficiency, comparable with
increases in thigh muscle (5-8'/0) and lean body (approximately looh)mass in the same patients [l, 31. Atrophy of
visceral organs after hypophysectomy has been shown to
include the heart [ 141. Treatment of hypophysectomized
rats with either human GH or human IGF-1 significantly
increased heart weight, suggesting that this anabolic
action of GH is mediated by IGF-1 [15]. No correlation
between the plasma IGF-1 concentration and the myocardial mass could be shown, due to either insufficient
numbers of patients or to alterations in serum IGF-1binding proteins or in IGF-1 receptor status. While
changes in lean body mass might be expected to be
paralleled by changes in myocardial mass, the absence of
such an association probably reflects the small number of
patients studied.
Cardiomegaly in human acromegaly is usually, but not
always, associated with hypertension [ 16, 171. The cardiomegaly resulting from implantable GH-secreting tumours
appears to be due to both direct cardiac effects
(anabolism) and volume overload [ 181. Since no increase
in training activities was recorded [9] and no statistically
significant effect from changes in systemic arterial blood
pressure were detected, the increase in left ventricular
myocardial wall mass most likely reflected the anabolic
action of rhGH.
We attempted to minimize the variability involved in
the measurement of left ventricular wall mass and
volumes by echocardiography [12, 13, 371 by the use of a
single echocardiographer, blinded as to the treatment
code, and by using well-validated procedures. Due to the
age of the patients and the successful completion of
maximal exercise tests, ventricular asynergy was considered unlikely, allowing the assumptions in the calculations of ventricular volumes [12] and wall mass [13] to be
met. The statistical design, testing for differences in mean
responses between rhGH and placebo groups, accounts
for this variability. The lack of change in myocardial wall
mass in young GH-deficient adults treated with rhGH for
4 months [2] may thus reflect the lower dose and/or the
shorter duration of treatment.
This study demonstrated small increases in resting
LVED. Admittedly, these changes were at the limit of
detectable changes with echocardiography, but they are
consistent with the clinical signs of sodium retention
noted in this trial [l], particularly during the first 3
months. Sodium retention and/or reduced urinary sodium
excretion have been noted after GH treatment in GHdeficient [2, 19, 201 and normal [21] human subjects.
Extracellular fluid volume has been shown to increase with
GH treatment in GH-deficient children [22]. Patients with
Cardiovascular effects of growth hormone
acromegaly have increased plasma and erythrocyte
volumes [23], total body water and total body sodium
contents [24], and extracellular/intracellular water ratio
[25]. Thus the increase in LVED has been interpreted as
an increase in pre-load secondary to increased circulating
blood volume.
That improved maximal exercise performance was
associated with increased resting LVED suggests that the
observed echocardiographic changes were beneficial. The
increases in maximal oxygen pulse [9], an index of
maximal stroke volume, supports the contention that
some of the improvement in exercise performance was
related to increased cardiac output.
GH-induced sodium retention involves the renal
tubules [26], a process stimulated directly by IGF-1 [27,
281. The antinatriuresis can occur independently of the
adrenal glands [26, 291. The increase in PRA demonstrated in this study suggests an additional factor, activation of the renin-aldosterone system, after long-term GH
replacement. The lack of suppression of plasma aldosterone concentrations in the face of an apparent increase
in blood volume supports this contention. Similarly, the
small reduction in plasma potassium concentration in the
rhGH-treated group may have contributed to the reduced
aldosterone response to the PRA stimulus.
An increased plasma aldosterone concentration [21] or
an increased urinary aldosterone excretion [30] in normal
adults or hypopituitary humans, respectively, have been
reported after GH treatment. Others have noted no
change in aldosterone secretion rate after GH treatment
in hypopituitary humans [311.In acromegaly, normal [32],
suppressed [33] or stimulated [34] aldosterone systems,
usually with suppressed PRA, have been reported. The
variety of alterations in the renin-aldosterone system
described in acromegaly may reflect the chronicity of
volume expansion and the dual mechanisms of sodium
retention by GH and IGF-1.
The increase in stroke volume after rhGH treatment
may reflect increased pre-load (the Starling effect) or
possibly enhanced myocardial contractility. In neonatal
rat cardiocytes, increased contractility has been noted
after the addition of IGF-1 at physiological concentrations [35]. Increases in myocardial contractility (measured
as increased fractional shortening) have been reported in
some patients with acromegaly [17, 361, in normal subjects treated with human GH for 2 weeks [37], and in one
patient with GH deficiency and cardiomyopathy [38]. No
such change was noted in the present study. Whether the
reported change in fractional shortening was due to
increased contractility or to reduced after-load is uncertain.
In summary, echocardiographic studies before and 6
months after rhGH treatment (0.07 unit/kg) in adults with
GH deficiency showed an increased left ventricular wall
mass, reflecting the anabolic action of GH. Secondly,
small increases in LVED and stroke volume were noted,
probably due to increased circulating blood volume.
Finally, the antinatriuretic effect of rhGH treatment
involves, in part, stimulation of the renin-aldosterone
system.
591
ACKNOWLEDGMENTS
We sincerely thank Ms Nadia Payne and the late Dr
J. D. H. Slater, The Middlesex Hospital, London, for
assaying PRA and plasma aldosterone concentrations. We
are also grateful to Dr C. Lowy and Professor H. Jacobs
for allowing us to study their patients, and to Ms Sue Chin
and Mr Richard Morris for statistical advice. This study
was supported in part by KabiVitrum, Stockholm,
Sweden, who also provided the rhGH. F.S. was supported
by a grant from the Swiss National Foundation for
Scientific Research.
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