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Clinical Studies |
Department of Molecular and Clinical Endocrinology and Oncology (A.C., D.F., P.M., A.D.S., G.C., F.S., B.M., G.L.) and Department of Radiology (S.C.), University Federico II, Naples, 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, via S. Pansini 5, 80131 Naples, Italy.
| Abstract |
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2 = 7.985, P < 0.005).
Three patients had significant adenoma shrinkage. Slight nausea and
hypotension, which spontaneously disappeared within therapy
progression, were referred by 5/16 patients during CV 205502 and 2/7
during BRC-LAR. The results of this study indicate that CAB and BRC-LAR cannot be considered as useful medical approaches for acromegalics, whereas CV 205502 normalized circulating GH and IGF-I levels in 47.8% of patients.
| Introduction |
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It has been reported recently that quinagolide (CV 205502) causes a suppression of GH levels more prolonged than BRC (7) and that it is effective either alone or combined with octreotide in a few acromegalics (8). In contrast, little experience has been accumulated so far with cabergoline (CAB) and long-acting depot preparation of BRC (BRC-LAR) in acromegaly (9, 10, 11, 12).
In this study, we report on the chronic treatment with CV 205502, CAB, and BRC-LAR in acromegaly. Because silent GH, PRL-mixed adenomas might affect the results of chronic administration of dopaminergic agents, GH suppression during therapy was correlated to serum PRL inhibition, assessed both in baseline conditions and after TRH stimulation. In addition, the results of immunohistochemical staining carried out a posteriori were correlated with the response to chronic treatments.
| Subjects and Methods |
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Thirty-four patients with active acromegaly (12 males and 22 females, aged 2564 yr) entered this study after their written consent had been obtained. Twenty-five were untreated and 9, previously subjected to unsuccessful surgery, had a detectable residual mass and/or high circulating GH and IGF-I levels. Sixteen patients had been treated previously with oral BRC at the daily dose of 7.520 mg before starting CV 205502, CAB, or BRC-LAR without normalizing GH/IGF-I levels. Moreover, 9 of 16 were given octreotide (300450 µg/day, sc) but withdrew the treatment because of the appearance of side effects. Active acromegaly was diagnosed in accordance with high serum GH levels being not suppressible below 2 µg/L after glucose administration (oGTT) and high plasma IGF-I levels. Computed tomography (CT) and/or magnetic resonance imaging (MRI) showed macroadenoma in 20 patients, microadenoma in 4, remnant tumor in 9, and empty sella in 1. Four patients showed temporal quadranopia. The 34 patients were divided into three groups in line with treatment schedule.
Group 1
Sixteen patients were treated with CV 205502 at the dose of 0.30.6 mg/day for 6 months. The drug was given once daily at 1900 h (after dinner) (0.3 mg) or twice daily at 1300 h and 1900 h. (after lunch and dinner) (0.6 mg). Baseline serum GH levels were 30.1 ± 6.1 µg/L (mean ± SEM); plasma IGF-I levels were 315.6 ± 20 µg/L.
Group 2
Eleven patients were treated with CAB at the dose of 1.02.0 mg weekly for 6 months. The starting dose was 0.5 mg twice/week, increased to 1.0 mg twice/week after the first month of treatment. Baseline serum GH levels were 20.4 ± 3.1 µg/L; plasma IGF-I levels were 336.4 ± 13.9 µg/L.
Group 3
Seven patients were treated with BRC-LAR at the dose of 100 mg/month for 612 months. The drug was administered during hospitalization at 0800 h, after breakfast. Baseline serum GH levels were 72.7 ± 11 µg/L; plasma IGF-I levels were 460 ± 50.4 µg/L.
Screening and follow-up
Routine clinical and endocrinological evaluations did not show any evidence of thyroid or adrenal abnormalities. Five males referred decrease of libido and/or potency, whereas 10 females had oligoamenorrhea. Serum GH and PRL levels in multiple samplings at hourly intervals during 6 h (08001400 h) and plasma IGF-I levels were assessed in baseline and at 0800 h after 15 days, and 1, 2, 3, 6 and 12 months of treatment. Serum GH levels during oGTT and GH and PRL levels during TRH test were assayed before and after 3, 6, and 12 months of treatment. A general clinical examination was performed every month. The study protocol of BRC-LAR therapy already has been reported in detail (13).
Radiological imaging
A CT scan was carried out with a CGR 10,000 apparatus (General Electric, Milwaukee, WI) in axial and coronal projections with injection of contrast medium. MRI was carried out using a super conductive magnetic resonance (0.51.0 Tesla, Siemen, Germany) and superficial coil in axial, coronal and sagittal sections. The acquisitions were spin echo with 1000-ms repetition time and 40120-ms echo time 21 ms. CT or MRI was performed before and after 3, 6, and 12 months of drug administration. A reduction more than 30% of tumor volume was considered significant shrinkage.
Visual field
Visual field examination was performed with the Goldmann-Friedmann perimetry (Maag-Streit, Bern, Switzerland), and it was carried out in all the patients in baseline, then quarterly during the follow-up in patients with visual field defects.
Assay
Serum GH and PRL levels were assessed by RIA using commercial kits. The normal ranges were below 5 µg/L and 520 µg/L, respectively. Plasma IGF-I levels were assessed by immunoradiometric assay using commercial kits. The normal range was 90210 µg/L.
Statistical analysis
Data are expressed as mean ± SEM. The
statistical analysis was performed using ANOVA followed by the Neumann
and Keuls test, when appropriate. Serum PRL response to TRH was
evaluated as area under the curve calculated by the trapezoid
integration method. Serum GH levels during oGTT was evaluated as nadir
value. Linear correlation analysis was used to correlate the
suppression of GH values to both PRL suppression and PRL response to
TRH. The
2 test was used to calculate the association
between GH and PRL staining and serum GH normalization.
| Results |
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The chronic administration of CV 205502, CAB, and BRC-LAR
caused a significant decrease of circulating GH, IGF-I, and PRL levels
(P < 0.005; Tables 1
, 2
, and 3
and Figs. 1
, 2
, and 3
). After 3 months of CV 205502 therapy, GH and IGF-I
levels normalized in 7 (43.8%) patients, but (31.3%) they remained
normalized after 6 months of therapy only in 5. Conversely, no patient
normalized GH and IGF-I levels during CAB and BRC-LAR therapy. The
percent GH suppression during chronic CV 205502 and BRC-LAR therapy
was significantly greater than that obtained during chronic CAB
treatment (71.4 ± 5.3% and 72.4 ± 3.3% vs.
48.5 ± 4.0%; P < 0.05).
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Serum PRL levels and PRL and GH response to TRH test
Basal serum PRL levels were in the normal range in all the
patients except in 7 with mild hyperprolactinemia (21.531 µg/L).
TRH administration caused a significant increase of serum PRL (from 60
to 250% of baseline) in all 34 patients and a paradoxical GH increase
in 15 of them. During treatments, serum PRL levels were suppressed in
all the patients, whereas the paradoxical GH response disappeared in 5
patients responsive to CV 205502 (nos. 2, 3, 4, 11, and 14; Table 1
).
No difference in pretreatment PRL levels was found between patients
with and without GH/IGF-I normalization during different treatments
(14.9 ± 1.5 vs. 17.1 ± 1.1 µg/L). Moreover, no
correlation was found either between the percent of PRL suppression or
PRL area under the curve after TRH and the GH suppression during
treatments (Table 4
).
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2 = 7.985,
P < 0.005). Effects on tumor mass and visual perimetry
Two patients treated with CV 205502 (nos. 9, 12; Table 1
) and 1
with BRC-LAR (no. 5; Table 3
) had a significant adenoma shrinkage.
Visual field and acuity improved in all the four patients suffering
visual abnormalities.
Tolerability
Four of the 16 patients had nausea and 1 had postural hypotension during chronic CV 205502 treatment. No patient had notable side effects during CAB therapy, whereas 2 patients treated with BRC-LAR experienced nausea, postural hypotension, and headache after the first injection. Side effects spontaneously disappeared without any specific cure.
| Discussion |
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In conclusion, CAB and BRC-LAR do not seem to play a main role in the pharmacotherapy of acromegalics, whereas CV 205502 stably normalized GH and IGF-I levels in 37.5% of our patients, and it caused a significant adenoma shrinkage in 2 of 11 patients not previously treated by surgery. However, taking into account that a combined treatment with dopaminergic agents and octreotide has been reported to be useful in selected acromegalic patients (8, 17, 18), this therapeutic strategy using CV 205502, CAB, and BRC-LAR combined with octreotide could be advisable.
| Acknowledgments |
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Received April 5, 1996.
Revised July 17, 1996.
Accepted August 21, 1996.
| References |
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