The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 634-636
Copyright © 2000 by The Endocrine Society
Growth Hormone Replacement Therapy Is Not Associated with Retinal Changes
Doris Blank,
Michaela Riedl,
Andreas Reitner,
Christoph Schnack,
Guntram Schernthaner,
Martin Clodi,
Herwig Frisch and
Anton Luger
Department of Medicine III, Division of Endocrinology and
Metabolism (D.B., M.R., M.C., A.L.), and Departments of Ophthalmology
(A.R.) and Pediatrics (H.F.), University of Vienna; and Department of
Medicine 1, Hospital Rudolfstiftung (C.S., G.S.), 1090 and 1030
Vienna, Austria
Address correspondence and requests for reprints to: Anton Luger, M.D., Department of Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail: anton.luger{at}akh-wien.ac.at
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Abstract
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GH and/or growth factors are thought to play a role in the pathogenesis
of diabetic retinopathy. In addition, the occurence of retinal changes
mimicking diabetic retinopathy in two GH-deficient (GHD) patients
receiving GH replacement therapy (GHRT) has recently been reported. The
present study was performed to evaluate whether this was a coincidence
or whether GHRT might regularly induce retinal changes. Sixty-one GHD
patients on GHRT with a mean age of 42.5 ± 17.3 yr were examined
by one ophthalmologist (AR). The mean duration of GHRT was 8.4 ±
3.7 yr in childhood onset and 3.5 ± 2.1yr in adult onset
patients. Plasma insulin-like growth factor I concentrations were
76.4 ± 49.6 ng/mL before GHRT and 244.3 ± 119.2 ng/mL while
receiving GHRT with a dose of 1.7 ± 0.7 IU/day. After pupil
dilatation with tropicamide, fundus examinations of both eyes were
performed using a Volk 90 diopter fundus lens with a slit lamp (Haag
Streit, Bern, Switzerland). In none of the patients were
vascular or retinal changes like macular edema, microaneurysms,
hemorrhages, hard exsudates, cotton wool spots, preproliferative signs,
or proliferations found. The optic discs were also normal in all
patients. We conclude, therefore, that long-term GHRT can be
administered safely in GHD patients without an increased risk of
retinal changes.
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Introduction
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RETINAL neovascularisation is the major
cause of untreatable blindness. Numerous clinical reports have
postulated a causative role for GH in the pathogenesis of proliferative
diabetic retinopathy (1, 2, 3, 4, 5). In addition, increased serum and vitreous
insulin-like growth factor I (IGF-I) concentrations have been reported
to be associated with proliferative retinopathy (6, 7). Furthermore,
IGF-I has been shown to induce angiogenesis in vivo in
rabbit cornea and retina models (8). Ischemia-associated retinal
neovascularisation was also inhibited in transgenic mice expressing a
GH antagonist gene and in normal mice given an inhibitor of GH
secretion (MK678) (9). Whereas this inhibition could be reversed
with exogenous IGF-I administration, transgenic mice expressing the GH
agonist E117L had no increase in retinal neovascularisation (9). A
decreased prevalence of diabetic retinopathy has also been described in
GH-deficient (GHD) diabetics (4, 5), and pituitary ablation has been
reported to stop deterioration of visual acuity in patients with
diabetic retinopathy (3). Furthermore, continuous infusion of
somatostatin has been shown to inhibit development and progression of
proliferative retinopathy (10).
Recently, retinal changes have been reported in two nondiabetic GHD
subjects receiving GH replacement therapy (GHRT) over a period of 14
and 22 months, respectively (11). Because symptoms improved or
disappeared after cessation of GHRT, a possible causative role for GH
has been suggested. To further analyze a possible relation between GHRT
and retinopathy, we have performed fundus examinations in 61 GHD
patients receiving long-term GHRT.
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Patients and Methods
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Sixty-one adult patients with GH deficiency (36 males, 25
females) receiving long-term GHRT were investigated. Characteristics of
the patients are given in Table 1
.
Forty-three percent of the patients had nonfunctioning pituitary
adenomas, 16% had a prolactinoma, 8% had a craniopharyngioma, and
33% had idiopathic GH deficiency. GH deficiency was documented by a GH
response of 3 ng/mL or less to either of the following stimulation
tests: arginine, insulin-induced hypoglycemia, or GH-releasing hormone.
GH was given as a single daily sc injection in the evening. Usually the
dose was adjusted to achieve IGF-I serum concentrations within 2
SD of an age-adjusted control population. In some cases, a
fixed dose without adjustment was used. The GH preparations used were
Genotropin ( Pharnmacia and Upjohn, Stockholm, Sweden),
Humatrope (Lilly Co, Indianapolis, IN), and
Nordi-tropin (Novo Nordisk, Copenhagen, Denmark). IGF-I serum
concentrations were measured by a RIA after treatment of serum samples
with acid ethanol to precipitate and neutralize IGF-I binding proteins
according to the method of Blum et al. (12). The minimum
detectable IGF-I concentration was 20 ng/mL; intra- and interassay
coefficients of variation were 3.1% and 10%, respectively.
All patients were examined by one ophthalmologist (AR). After pupil
dilatation with tropicamide fundus, examinations of both eyes were
performed with a slit lamp (Haag Streit, Bern, Switzerland)
using a Volk 90 diopter fundus lens (Mentor, OH). After
inspection of the posterior pole in primary position, patients had to
look in all directions for careful midperiphery and periphery
examination. Fundus photographs for additional documentation were taken
using a Canon CF-60UV (40 degrees; Tokyo, Japan).
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Results
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Twenty-five percent of the 61 patients studied had hypertension,
and 64% had hyperlipidemia. The age of the patients at the time of
examination was 42.5 ± 17.3 yr (mean ± SD).
Plasma IGF-I concentrations were 76.4 ± 49.6 ng/mL before GHRT
and 244.3 ± 119.2 ng/mL while receiving GHRT with a dose of
1.7 ± 0.7 U/day (mean ± SD). The average
duration of GH therapy for childhood onset GHD patients was 8.4 ±
3.7 yr. Patients with adult onset GHD (adenoma, craniopharyngioma, or
prolactinoma) were treated for 3.5 ± 2.1 yr with GH. When
childhood onset and adult onset GHD patients were taken together an
observation period of 337 patient years was achieved. None of the
patients had a history of retinal disorders.
Ophthalmologic examination
In none of the patients could retinal changes like macular edema,
microaneurysms, hemorrhages, hard exsudates, cotton wool spots,
preproliferative signs, or proliferations be detected in any eye. There
was no swelling of the optic disc or vascular abnormality of the optic
disc vessels.
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Discussion
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In the present study, no retinal changes could be observed in 61
nondiabetic patients with GH deficiency receiving GHRT for a total
period of 337 patient years. This seems to be of interest for the
growing number of adult GHD patients who receive GHRT because of the
well documented beneficial effects on cardiovascular risk factors, body
composition, quality of life, and bone mineral density (13, 14, 15).
Whereas the possibility that mild transient retinal changes in earlier
phases of GHRT might have been missed cannot totally be excluded due to
the cross-sectional design of the study, this seems unlikely because
none of the patients reported visual disturbances or ophthalmologic
treatment during GHRT. The pathogenesis of the retinal changes
mimicking diabetic retinopathy in the two patients receiving GHRT
reported earlier (11) might be multifactorial or independent of GH
therapy. In one case, the episode of pericarditis and intermittent
hypertension with documented blood pressure values of up to 170 over
99, as well as concomittant therapy for obesity (phentermine,
fenfluramine, pemoline), could have influenced the history of blurred
vision; in the other case, the unilateral abnormality might have
represented acceleration of unrecognized preexisting retinopathy.
Our data represent results of a cross-sectional study. With respect to
the alarming above mentioned Food and Drug Administration report (11) a
prospective, randomized, controlled trial seemed unjustified due to the
risk for the GHD patients and the delay until the results of such a
study would have been available. Nevertheless, after this report, we
plan to follow up on our patients and repeat the ophthalmologic
evaluation at yearly intervals. However, because we have found no
retinal changes in 61 patients treated for 337 patient years, we feel
reassured that GHRT can be regarded as a safe treatment if the
contraindications are carefully watched for. In this respect, it is of
interest that long-term GHRT does not seem to increase other risk
factors for retinal changes. In contrast, long-term GHRT has been shown
to be associated with a decrease rather than an increase in blood
pressure (16). Whereas a decrease of insulin sensitivity has been shown
in short-term studies and studies using pharmacological GH doses (17, 18) long-term studies using physiological GH doses document either an
increase or no further decline in insulin sensitivity (19), with no
increased rate of development of diabetes.
From this first systematic investigation of 61 patients treated for 337
patient years it might be concluded that long-term GH substitution in
GHD subjects does not induce retinal changes. However, it cannot be
excluded that mild affections might have been missed by chance due to
their transient nature or very low frequency. We recommend, therefore,
that ophthalmologic evaluations should be performed in all GHD patients
before institution of GHRT and repeated every year until our report
will be confirmed by other larger studies over an even more prolonged
period of time.
Received September 1, 1999.
Revised November 2, 1999.
Accepted November 9, 1999.
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Abstract
Introduction
