0021-972X/99/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 9
Printed in U.S.A.
Hormonal and Volumetric Long Term Control of a
Growth Hormone-Releasing Hormone-Producing
Carcinoid Tumor
A. VAN
DEN
BRUEL, J. FEVERY, J. VAN DORPE, L. HOFLAND,
AND
R. BOUILLON
Laboratory and Clinic of Experimental Medicine and Endocrinology (A.V.d.B., R.B.), the Department
of Internal Medicine, Hepatology (J.F.), and the Department of Pathology (J.V.D.), Universitaire
Ziekenhuizen, Gasthuisberg, B-3000 Leuven, Belgium; and the Department of Internal Medicine III,
Erasmus University (L.H.), Rotterdam, The Netherlands
A 25-yr-old female was referred for symptoms of acromegaly. Two months before admission she mentioned profuse sweating and complained of severe headache. Seven
years earlier a large neuroendocrine tumor in the liver was
detected. At that time she presented with secondary amenorrhea of 2-yr duration accompanied by fatigue, perspiration, diarrhea, weight loss, and disturbed liver tests (Table 1)
and a large tumor in the right liver lobe palpable 10 cm below
the right lower costal margin [23 3 18 3 25 cm by magnetic
resonance imaging (MRI); Fig. 1A]. During laparatomy a
highly vascular tumor was found invading the left liver lobe.
Abdominal exploration did not reveal other tumor foci. The
tumor biopsy showed characteristics of a neuroendocrine
tumor (Fig. 2A) with positive chromogranin and neuronspecific enolase staining. Serum pancreatic polypeptide (PP),
chromogranin, serotonin, and urinary 5-hydroxyindole acetic acid (5-HIAA) were markedly elevated. Urinary catecholamines (dopamine and norepinephrine) as well as its
degradation products (homovanillic acid and vanillylmandelic acid) were elevated as well (Table 2). Somatostatin
receptor scintigraphy with [111In-DTPAo]octreotide showed
major, but heterogeneous, uptake by the hepatic tumor without evidence of other tumor sites (Fig. 3). The search for a
primary tumor site, especially in the pancreas, was negative
after investigation by computed tomography scan, MRI, endoultrasonography, and somatostatin receptor scintigraphy.
The hepatic tumor was considered unresectable by its size
and site; chemoembolization (with cisplatinum/lipiodol)
was performed in 1992 and 1994 for relief of mass symptoms.
Tumor volume was considered unchanged in July 1996.
At the time of referral in 1996, soft tissue enlargement, an
enlarged tongue, and prominence of the jaw pointed to the
diagnosis of acromegaly, confirmed by the markedly elevated GH and insulin-like growth factor I (IGF-I) levels.
Retrospective determination of the GH and IGF-I in samples
collected at the time of the initial diagnosis showed comparable high values (Table 2). The patients’ visual fields were
Received January 14, 1999. Revision received June 4, 1999. Accepted
June 17, 1999.
Address all correspondence and requests for reprints to: Dr. R. Bouillon, Laboratory for Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Email: [email protected].
normal, but pituitary enlargement with chiasmatic compression was present on MRI of the sella (Fig. 4A).
Differential diagnosis
The differential diagnosis at this time (1996) included conditions that would cause a combination of a carcinoid tumor
along with symptoms of GH excess. Acromegaly is usually
caused by a pituitary GH-secreting adenoma and can be
associated with a carcinoid tumor in the case of multiple
endocrine neoplasia type 1 (MEN 1). Serum calcium and PRL
levels were normal in the patient. Her family history was also
negative for endocrine neoplasia. DNA analysis showed no
mutations in the coding region of the MEN 1 gene. The
suspicion of MEN type 1 could therefore not be confirmed.
GHRH-producing tumors may rarely induce excess GH secretion and thus cause the ectopic acromegaly syndrome.
Tumors causing this syndrome include carcinoids localized
in the lung or gastrointestinal tract and islet cell tumors.
The clinical course of our patient at the presentation in
1996 was compatible with a hepatic carcinoid secreting
GHRH and ectopic acromegaly. This syndrome was reviewed in 1992 by Faglia, who reported 39 cases fulfilling this
definition (1). In the meantime 12 additional cases have been
reported (2–7), making a total of 51 cases. The majority of
such patients have symptoms related to the ectopic tumor
mass and its production of other peptides at the time they
present with symptoms related to excess GH secretion.
Follow-up course
Serum samples were sent for determination of GHRH
levels, which were elevated at 101 and 212 pg/mL (,50
pg/mL; RIA, Nichols Institute Diagnostics, Quest Diagnostics, Inc., San Juan Capistrano, CA). These values should be
interpreted with caution, as the samples exceeded stability
upon arrival at the laboratory. A third sample drawn in May
1998 (after a temporary 2-week withdrawal of therapy)
showed a GHRH level of 1045 pg/mL. GHRH levels in
ectopic acromegaly are above 1 ng/mL in the majority of
cases. Paraffin sections of the tumor tissue obtained in 1992
were stained for GHRH and GH. GHRH immunostaining
was positive in 15% of the tumor cells; staining for GH was
negative. The diagnosis of a GHRH-secreting carcinoid tumor causing ectopic acromegaly was thus confirmed.
3162
CLINICAL CASE SEMINAR
3163
TABLE 1. Biochemistry at diagnosis and during follow-up
1992
Calcium (mg/dL)
GOT (U/L)
GPT (U/L)
LDH (U/L)
g-GT (U/L)
ALP (U/L)
9.4
113
80
1196
135
540
Sept 1996
Dec 1996
Oct 1997
Feb 1998
May 1998
Normal values
10.1
46
35
241
152
264
9.5
18
17
198
36
161
8.8
9
5
216
25
239
9.6
23
16
240
25
183
9.7
19
13
238
26
192
8.9–10.5
5–37
5– 40
240– 480
7–23
90–260
FIG. 1. The hepatic tumor before (A) and after 15 months (B) of
treatment with somatostatin (SS) analogs. A marked volume reduction (by 70%) was observed.
Treatment with somatostatin analogs was initiated because of the positive in vivo [111In-DTPAo]octreotide scan
showing marked uptake at the hepatic tumor site (Fig. 3). The
presence of somatostatin receptors in the tumor was confirmed by the somatostatin receptor autoradiography technique, using [125I-Tyr3]octreotide (8). A very high density of
somatostatin receptors could be demonstrated (Fig. 5).
Excessive sweating and headache promptly disappeared
after institution of therapy with octreotide. Serum GH concentrations were acutely lowered by octreotide (100 mg, sc),
but IGF-I levels were not normalized after 3 months of therapy with octreotide (100 mg, three times daily), probably due
to a rebound rise of GH 6 –7 h after the injection, reflected by
the wide variation of GH levels obtained during a 24-h profile (Table 3). Therefore, therapy with long acting lanreotide
FIG. 2. The neuroendocrine tumor consists of anastomosing nests
and cords supported by a fibrovascular stroma. Tumor cells have a
moderate amount of lightly eosinophilic granular cytoplasma. There
is only minimal nuclear atypia. Hematoxylin and eosin staining; original magnification, 3110 (A). The lesion shows focal positivity for
GHRH. Immunoperoxidase; original magnification, 3125 (B).
(30 mg, once every 10 days) was instituted. As GH, IGF-I,
chromogranin, and serum PP decreased substantially but
were not normalized after 9 months of treatment, the therapy
was switched from lanreotide to octreotide (500 mg daily) by
continuous sc infusion (CSI). After 9 months of this therapeutic regimen we interrupted the treatment for 2 weeks and
evaluated a dose-response curve to determine whether a
higher dose of octreotide could further ameliorate the GH
excess. Indeed, octreotide lowered GH, IGF-I, and GHRH
levels in a dose-dependent way (Fig. 6). Finally, normal or
near-normal GH, IGF-I, chromogranin, and PP levels were
3164
VAN DEN BRUEL ET AL.
JCE & M • 1999
Vol 84 • No 9
TABLE 2. Hormonal characteristics at baseline (at diagnosis of
the neuroendocrine tumor in 1992, at diagnosis of acromegaly in
1996)
Mean GH (mg/L),
range in daily profile
IGF-I (ng/mL)
GHRH (pg/mL)
Chromogranin (ng/mL)
Serotonin (mmol/L)
PP (pg/mL)
Somatostatin (pg/mL)
Gastrin (pg/mL)
Motilin (pg/mL)
VIP (pg/mL)
Glucagon (pg/mL)
PRL (ng/mL)
U-5-HIAA (mg/24 h)
U-VMA (mg/24 h)
U-HVA (mg/24 h)
U-DOPA (mg/24 h)
U-NE (mg/24 h)
U-E (mg/24 h)
1992
1996
107a
54, 13– 61
0–5
515
101b
5,277
3,949
54,124
7.9
96
903
147
325
ND
105
ND
ND
ND
ND
ND
100–300
,50
40–150
280–1400
0–500
0–110
0–100
0– 400
0–250
0–250
0–20
2– 8
1–10
1–10
90–500
10–100
0–20
723a
ND
6,642
3,504
41,276
,3.1
92
250
246
,19
,0.2
132
25
1,178
20,528
1,213
,1.2
Normal values
ND, Not determined.
Measured in stored samples.
b
Value to be interpreted with caution; sample exceeded stability.
a
reached with octreotide (1000 mg daily) by CSI, whereas
GHRH remained elevated. Serotonin and urinary 5-HIAA
normalized during treatment. Urinary norepinephrine and
vanillylmandelic acid normalized, whereas urinary DOPA
and homovanillic acid remained elevated (Table 3).
This biochemical control was accompanied by stable or
even decreased clinical signs of acromegaly and a reduction
of the pituitary mass, as pituitary height decreased by 58%
(Table 4 and Fig. 4, A and B). Moreover, liver tests normalized, and the hepatic tumor volume decreased markedly. The
liver became palpable only 2–3 cm below the right costal
margin, and the volume measured by MRI was reduced by
70% (Table 4 and Fig. 1, A and B).
Discussion
Twenty-five years ago the first case of a bronchial carcinoid tumor suspected to secrete a substance with GHRH
activity and causing acromegaly was described. The patient
was cured by resection of the carcinoid tumor. Since then, the
syndrome of ectopic GHRH-induced acromegaly remains a
rare disorder, as only 51 cases have been reported to date
(1–7). The most frequent tumors causing this syndrome are
carcinoids (66%), usually localized in the lung (79%) or gastrointestinal tract (8%); in 28% of the cases islet cell tumors
are responsible. The present case represents the third patient
with a carcinoid tumor of unknown primary site causing
GHRH-induced acromegaly. Carcinoids as well as islet cell
tumors express a broad variety of hormones. In 7 of 14
pancreatic GHRH tumors the secretion of other hormones
was documented: insulin (4 patients), gastrin (3 patients),
somatostatin (2 patients), glucagon (1 patient), and PP (1
patient). Elevated urinary 5-HIAA and/or circulating serotonin were observed in 7 of 34 carcinoid tumors, increased
ACTH production in 3 patients, and elevated urinary dopamine levels in one case. Serum chromogranin (measured
infrequently) was increased in 1 case. In our patient we
FIG. 3. In vivo [111In-DTPAo]octreotide scan showing major uptake at
the hepatic tumor site.
describe elevated chromogranin, PP, serotonin, urinary
5-HIAA, urinary dopamine, and norepinephrine. Evidence
of hyperparathyroidism or familial disease suggestive of
MEN 1 syndrome was reported in 9 cases, but in our patient
there was no evidence of MEN 1.
Most tumors causing GHRH-induced acromegaly are
large, as in our patient. Pituitaries from patients with GHRHinduced acromegaly show a morphological continuum from
typical hyperplasia to adenomas; in our patient MRI suggests
pituitary hyperplasia, although there is no histological proof.
The clinical features of ectopic acromegaly are those of
patients with classical acromegaly in addition to the manifestations attributable to the primary tumor. The latter include mass symptoms for large tumors, as in our case. Symptoms due to other cosecreted hormones or to the associated
hyperparathyroidism in MEN 1 have been reported in other
cases.
The strong suspicion of the carcinoid tumor causing ectopic GHRH-induced acromegaly was confirmed in our case
by the following. 1) An elevated GHRH level of 1045 pg/mL
was found (normal, ,50 pg/mL, compared to levels of 300 –
145,000 pg/mL in other cases of GHRH-induced acromegaly). The slightly elevated values for GHRH in 1996 and 1997
have to be interpreted with caution, as these samples exceeded stability upon arrival at Quest Nichols. 2) There was
positive immunohistochemical detection of GHRH in the
biopsy of the hepatic tumor. The strongest proof would consist of cure of acromegaly by resection of the carcinoid, but
this could not be obtained because the hepatic localization is
presumably a metastatic site and was by its size unresectable.
Visualization with in vivo octreotide scintigraphy indicated substantial concentrations of somatostatin receptors in
the hepatic tumor as previously reported in the culprit tumors of four patients with GHRH-induced acromegaly (5–7,
CLINICAL CASE SEMINAR
3165
FIG. 4. Pituitary before (A) and after 15 months (B) of treatment with somatostatin analogs. A significant reduction of pituitary height was
observed.
9). The absence of positive uptake in the pituitary could be
a problem of sensitivity of the scanning, the high tumor
burden, and uptake at the hepatic tumor site.
A very high density of somatostatin receptors in the liver
tumor could be confirmed by somatostatin receptor autoradiography. This case therefore adds to the two cases reported
by Bertherat, who documented the presence of somatostatin
receptors negatively coupled to adenylate cyclase in ectopic
GHRH-secreting tumors from acromegalic patients responsive to octreotide (3).
Twenty years after the first description of a therapeutic
trial with somatostatin in two patients with a carcinoid tumor
and acromegaly (10), we can now evaluate the long term (22
months) use of somatostatin analogs in our patient compared
to its use (3 months to 3 yr) in 14 patients with GHRHinduced acromegaly in the literature (Table 5). As one third
of the patients with GHRH-induced acromegaly presented
with widespread or metastatic disease, surgical cure of the
culprit tumor is not possible, and octreotide treatment is the
current treatment option.
An excellent biochemical response, with GH levels becoming normal or near normal and IGF in the normal range,
was documented in 5 of 14 patients. GHRH in these patients
decreased by 64% (11–14, 18). An intermediate response,
with clinical improvement of acromegalic features and a
major reduction in GH and IGF-I levels, has been described
in 7 patients. GH decreased by 40 –90%, and IGF-I decreased
by 47–75%, accompanied by GHRH reductions of 54 –70%
FIG. 5. Photomicrograph of the results of somatostatin receptor
autoradiography of the GHRH producing tumor using [125ITyr3]octreotide. A, Hematoxylin-eosin-stained section; B, autoradiogram showing total binding of [125I-Tyr3]octreotide; C, autoradiogram
showing displacement of [125I-Tyr3]octreotide binding by excess (1
mmol/L) unlabeled octreotide. Bar, 1 mm.
from baseline (4, 6, 7, 15–17). Treatment failure was described
in 2 of 14 patients (2, 3). Our patient showed an intermediate
biochemical response during treatment with lanreotide and
octreotide (500 mg daily) by CSI. An excellent response, however, during treatment with octreotide (1000 mg daily) by CSI
was observed. We thus confirmed a dose-response effect
with regard to octreotide (12–14) and superiority of a continuous infusion therapy compared to intermittent sc injec870
ND
2,271
ND
7,620
9
9
233
.1,000
68
3
Octreotide, 100 mg,
TID, sc
3 months
780
ND
4,040
3,275
34,286
26.5
ND
ND
ND
ND
ND
Chemo-embolization
Dec 1996
44, 4.8 –152
Sept 1996
33, 28 –38
Oct 1997
431
212a
453
1,070
6,123
4.8
ND
ND
ND
ND
ND
Lanreotide, 30 mg,
once every 10 days
9 months
14, 4.3–18
Feb 1998
321
ND
475
1,294
1,245
3
6.1
32
22,304
76
6
Octreotide, 500 mg,
daily, CSI
3 months
2.7, ,0.5– 6.9
May 1998
364
1,045
564
1,335
4,655
ND
ND
ND
ND
ND
ND
Octreotide, 500 mg,
daily, CSI
6 months
11.7, 3.2–16
July 1998
214
790
150
1,271
585
5
7
10
2,090
98
10
Octreotide, 1000 mg,
daily, CSI
6 weeks
5, 2.9 –7.8
100–300
,50
40–150
280–1,400
0–500
2– 8
1–10
1–10
90–500
10–100
0–20
0–5
Normal values
VAN DEN BRUEL ET AL.
ND, Not determined.
a
Value to be interpreted with caution: sample exceeded stability.
During preceeding
Mean GH (mg/L),
range in daily profile
IGF-I (ng/mL)
GHRH (pg/mL)
Chromogranin (ng/mL)
Serotonin (mmol/mL)
PP (pg/mL)
U-5-HIAA (mg/24 h)
U-VMA (mg/24 h)
U-HVA (mg/24 h)
U-DOPA (mg/24 h)
U-NE (mg/24 h)
U-E (mg/24 h)
Treatment regimen
TABLE 3. Hormonal characteristics during follow-up and treatment with somatostatin analogs
3166
JCE & M • 1999
Vol 84 • No 9
18a
Octreotide, 500 mg
daily, CSI
6 months
1348
18
Octreotide, 500 mg,
daily, CSI
3 months
17a
Lanreotide, 30 mg
once every 10 days
9 months
During preceeding
ND, Not determined.
a
By ultrasound; only maximal diameter was evaluated.
21a
Octreotide, 100 mg,
TID, sc
3 months
4576
23
Chemo-embolization
(3/92; 11/94)
5419
25
Feb 1998
5
8
Oct 1997
Dec 1996
ND
12
Sept 1996
1992
ND
Pituitary ht (mm), by
MRI
Hepatic tumor vol (cm3)
Maximal diameter (cm)
Treatment regimen
tion, as had been observed by Wilson (13) and Lefebvre (4).
The lack of a parallel decline in GH and GHRH levels after
treatment with somatostatin analogs could be explained as a
consequence of the action of the somatostatin analog not only
at the hepatic tumor site, but also at the pituitary level.
The evolution of the pituitary volume was evaluated in
five patients in the literature. It decreased in three patients
with a biochemical response to octreotide treatment (4, 12,
13) and remained unchanged in two patients, of whom one
responded (7) and the other failed to respond biochemically
(2) to treatment with octreotide. We observed a clear decrease
in pituitary size (pituitary height decreased by 58%).
The volume of the primary tumor was unchanged in patients with treatment failures and in the majority of patients
with intermediate or even excellent biochemical responses.
In two patients with an intermediate biochemical response
there was even progression of tumor volume, with evidence
of new metastases during treatment (4, 15). In one patient
with excellent biochemical response von Werder described
some evidence of tumor shrinkage of a hepatic metastasis
(18), although clear evidence of tumor shrinkage was demonstrated in only one patient in the literature (12). In our
TABLE 4. Tumor features at diagnosis and during follow-up and treatment with somatostatin analogs
FIG. 6. Dose-response effect of octreotide; GHRH, GH, and IGF-I at
baseline and after 500 and 1000 mg octreotide by CSI for the preceding
14 days. The dashed line represents the upper limit of normal values.
ND
3167
May 1998
CLINICAL CASE SEMINAR
Bronchial carcinoid
Lung carcinoid
Pancreatic islet cell tumor
(GHRH- & gastrin-secreting)
Jejunum carcinoid
Breast carcinoid
Pancreatic islet cell tumor
(GHRH- & insulin-secreting)
Bronchial carcinoid
Metastatic carcinoid
Bronchial carcinoid
Bronchial carcinoid
Thymic carcinoid (GHRH- &
ACTH-secreting)
Bronchial carcinoid
11
12
13
18
14
3
16
2
4
6
7
100 sc
300
200 sc
100 sc
400 sc
2000 sc
1500 CSI
300 sc
LAN, Weekly, 30 mg sc
OCT,
OCT,
OCT,
OCT,
OCT,
OCT,
OCT,
OCT,
OCT, 100 sc
OCT, 1500 CSI
OCT, 100 sc
SS, 500 iv/60 min
SS, 500 iv/75 min
OCT, 100 sc
OCT, 150 – 800 sc
OCT, 60 –720 CSI
OCT, 400 –1500 sc
OCT, 600 –1000 CSI
OCT, 50 –500 sc
OCT, 750 sc
OCT, 150 sc
OCT, 400 –1000 sc
OCT, 150 sc
Treatment with somatostatin
or analog
(daily dosage, mg)
SS, Somatostatin; OCT, octreotide; LAN, lanreotide.
a
NR, Normal range; —, No data.
Lung carcinoid
17
3
Hepatic metastasis
Bronchial carcinoid
Pancreatic apudoma
Lung carcinoid
Type of tumor
10
10
15
17
Ref.
no.
6.9
0.6–1.5
6.5
5.1–39.5
26.1
145
15
5.9
500
5.5
3.3
8.5
4.4
—
—
15
33.1
GHRH
(mg/L)a
17
7.3
187
31.4
88
16.4
—
8 –55
191
38
9
31.5
13
222
13
53.1
GH
(mg/L)a
Baseline
675
748
1005
—
730
767
—
1038
431
383
750
885
—
—
—
—
IGF-I
(mg/L)a
TABLE 5. GHRH-producing tumors treated by somatostatin analogs: review of the literature
3
75
132
,7.6
—
—
3
3
—
1.14
2–7
5
3
—
10.66
—
.1.5
1– 4
2
3.3
1–1.3
2.7
6
—
—
GHRHa
Near normal
2
9.6
18
2.7
—
2– 40
2–18
4.37
19
NR
NR
,1
2
89
4
6.15
15.4
10–20
,10
4–15
2–10
NR
NR
292
GHa
During therapy
450
—
682
—
—
765
900
450
386
241
NR
—
—
—
—
—
—
—
300 – 450
2.5
NR
125
NR
NR
398
IGF-Ia
—
—
—
—
Pituitary
vola
—
—
Improvement No change
Improvement Decrease
—
—
Improvement No change
—
—
Improvement Decrease
Improvement
—
Improvement Decrease
Improvement
Improvement
Improvement
Improvement
Symptomsa
—
Progress
—
No change
No change
—
No change
Shrinkage
Decrease
No change
No change
No change
Progression
Tumor vola
3168
VAN DEN BRUEL ET AL.
JCE & M • 1999
Vol 84 • No 9
CLINICAL CASE SEMINAR
patient, the hepatic tumor, considered to be a huge metastasis, showed a clear decrease (70%) in size as measured by
MRI. Along with the volumetric decrease we demonstrated
a clear decrease in chromogranin, serotonin, urinary
5-HIAA, and PP.
In conclusion, a new case of acromegaly due to a GHRHsecreting neuroendocrine liver tumor is described, and the
results of treatment with somatostatin analogs are compared
with those from previously reported cases. Distinctive from
previous reports, an excellent control of GH excess was accompanied by a significant reduction of the tumor volume.
The clear tumor shrinkage during treatment might be due to
the high density of somatostatin receptors, as revealed by in
vitro and in vivo studies, and/or by the continuous infusion
therapy.
5.
6.
7.
8.
9.
10.
Acknowledgments
We thank W. Heyns, T. Peeters, J. Billen, and K. Desmet for the
hormonal assays; Pharmacia & Upjohn, Inc. for the GHRH antibodies,
Ipsen for the compassionate use of Lanreotide, and Novartis for the
compassionate use of high doses of Sandostatine. We thank Mrs. L.
Janssens and C. Lauwers for excellent secretarial assistance and nursing
assistance, respectively.
Note Added in Proof
During the preceding 12 months, treatment with octreotide has been
continued. Hormonal and volumetric control is now obtained for a
long-term period of 34 months, one of the longest treatment terms
reported in cases of GHRH-secreting tumors (July 1999).
11.
12.
13.
14.
15.
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