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Department of Endocrinology, University Hospital (P.Ca.), 31403 Toulouse; Department of Endocrinology, University Hospital (S.A.), 80054 Amiens; Department of Endocrinology, University Hospital (C.B.), 59037 Lille; Department of Endocrinology, University Hospital (P.Ch.), 94276 Paris; Department of Endocrinology, University Hospital (J.M.K.), 76233 Rouen; Department of Endocrinology, University Hospital (M.P.), 69321 Lyon; Department of Endocrinology, University Hospital (R.M.)., 86021 Poitiers; Department of Endocrinology, University Hospital (C.T.), 63003 Clermont-Ferrand; Department of Endocrinology, University Hospital (E.V.), 87042 Limoges; and Novartis Pharma SA (P.S.), 92506 Rueil Malmaison, France
Address all correspondence and requests for reprints to: Philippe Caron, M.D., Service d’Endocrinologie et Maladies Métaboliques, University Hospital Rangueil, 1 avenue J. Poulhés, 31403 Toulouse Cedex, France. E-mail: caron.p{at}chu-toulouse.fr
Abstract
The presence of somatostatin receptors on TSH-secreting pituitary
adenomas allows treatment of central hyperthyroidism with somatostatin
analogs. Six women and 5 men (mean ± SEM age, 43
± 3 yr) presented TSH-secreting pituitary adenomas (micro, n = 2;
macro, n = 9). Seven patients had previously been treated with
partial surgical removal (n = 6) and/or external radiation (n
= 4) of their adenoma at least 1 yr before the study, whereas 4
patients had not been treated before somatostatin analog therapy. TSH,
free T4, and free T3 levels were in the normal
range during treatment with sc injections (n = 9) or continuous
infusion (n = 2) of octreotide (280 ± 25 µg/day). Mean
thyroid hormone levels increased (P < 0.01) after
the washout period (34 ± 6 days). The patients received monthly
im injections of 20 mg Octreotide-LAR. In patients with an elevated
free T4 level after 3 months (n = 1) the
Octreotide-LAR dose was increased to 30 mg. After 3 months of
Octreotide-LAR treatment, TSH, free T4/T3, and
-subunit levels decreased, and 10 patients were euthyroid with
normal free T4 levels. These results remained at the same
level over the next 3 months. There were no statistically significant
differences in the TSH and free T4 responses to sc
octreotide or im Octreotide-LAR between previously untreated patients
and patients who had undergone surgical resection and/or pituitary
radiation before somatostatin analog treatment. During Octreotide-LAR
treatment, minor digestive problems or moderate discomfort at the
injection site, lasting less than 48 h, were reported in 6 and 5
patients, respectively. Gallbladder echographies did not reveal new
gallstones during Octreotide-LAR treatment. In conclusion, this study
shows that monthly im Octreotide-LAR is as effective as daily sc
octreotide in controlling hyperthyroidism in patients with
TSH-secreting pituitary adenomas, in both previously untreated patients
and patients treated with surgery and/or pituitary radiotherapy.
Octreotide-LAR is well tolerated, except for minor digestive problems
or mild pain at the injection site. Therefore, Octreotide-LAR appears
to be a useful therapeutic tool to facilitate medical treatment of
TSH-secreting pituitary adenomas in patients who need long-term
somatostatin analog therapy.
THE PRESENCE OF somatostatin receptors on TSH- secreting pituitary adenomas (1, 2, 3, 4, 5) has allowed consideration of treatment with somatostatin in patients with TSH-dependent hyperthyroidism related to TSH-secreting pituitary tumors. Somatostastin is an endogenous hypothalamic peptide with a short half-life that inhibits TSH secretion either in physiological conditions (6, 7) or in patients with TSH-secreting pituitary adenomas (8). Octreotide, a synthetic somatostatin analog with a half-life of between 80–110 min, is administered sc two or three times daily or continuously using portable pumps. Octreotide treatment suppresses TSH secretion in more than 90% of TSH-secreting pituitary adenomas, normalizes thyroid hormone concentrations in about 70% of the patients, and decreases adenoma size in about 50% of all cases (9, 10, 11, 12). To avoid drawbacks such as multiple daily injections or the use of portable pumps, a long-acting release form of the somatostatin analog octreotide has been produced. It consists of octreotide acetate encapsulated with a biodegradable polymer (Octreotide-LAR), and this depot formulation is injected im every 4 weeks.
The aim of this open multicenter study was to evaluate the efficacy of the depot formulation of somatostatin analog octreotide (Octreotide-LAR) in a cohort of patients with active TSH-secreting pituitary adenomas previously responsive to sc injections or continuous infusion of octreotide. The data indicate that Octreotide-LAR retains effectiveness in decreasing TSH and thyroid hormone concentrations in patients with TSH-secreting pituitary adenomas, either previously untreated or treated with surgery and/or pituitary radiotherapy. Thus, the study shows that monthly im Octreotide-LAR is as effective as daily sc octreotide in the control of hyperthyroidism in patients with TSH-secreting pituitary adenomas.
Experimental Subjects
Patients
Eleven patients were included in this open multicenter study
(six women and five men; mean ± SEM age, 43 ± 3
yr). These patients presented pure TSH-secreting tumors (n = 10),
and one had a mixed TSH-PRL-secreting adenoma. On a computed tomography
scan or nuclear magnetic resonance imaging, nine of these patients had
macroadenomas with suprasellar extensions, and two had intrasellar
microadenoma or postoperative intrasellar tumor residue. Seven patients
had previously been treated with transsphenoidal incomplete surgical
resection (n = 6) and/or radiotherapy (conventional, n = 3;
-knife, n = 1), carried out at least 1 yr before this study
(group 1), whereas four patients had not been treated previously with
somatostatin analogs (group 2). The individual characteristics of each
patient are summarized in Table 1
.
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The present study was approved by the institutional ethics committee of the University of Toulouse (Toulouse, France), and each patient gave written informed consent. The diagnosis of TSH-dependent hyperthyroidism related to TSH-secreting pituitary adenomas was based on physical examination, elevated free thyroid hormone concentrations in the presence of normal or elevated TSH levels, and pituitary adenoma. In all patients, TSH, free T4, and T3 levels were in the normal range during treatment with sc injections (n = 9) or continuous infusion (n = 2) of octreotide (mean dose, 280 ± 25 µg/day) for at least 4 weeks. Subcutaneous octreotide treatment was withdrawn until hyperthyroid symptoms reappeared (34 ± 6 days), to include patients with active TSH-secreting pituitary tumors. Then the patients received one monthly im injection of 20 mg Octreotide-LAR for a period of 6 months. In patients who had an elevated free T4 level after 3 months, the Octreotide-LAR dose was increased to 30 mg (n = 1) for the next 3 months.
Materials and Methods
The clinical evaluation of the patients (i.e. weight
loss, heart rate, tachycardia, nervousness, tremors, and sudation) and
side-effects (abdominal pains, diarrhea, softened stools, and pain or
induration at the injection site) were assessed during the washout
period and after 3 and 6 months of Octreotide-LAR treatment. Blood for
the measurements of TSH, -subunit, and free thyroid hormone
(T4 and T3) concentrations
was withdrawn during the octreotide treatment, when hyperthyroid
symptoms reappeared after the octreotide withdrawal, 3 and 6 months
during the Octreotide-LAR treatment (just before the next im
injection). All plasma hormone levels were measured in a single
laboratory using the following techniques: TSH, Microparticule Enzyme
Immunoassay (Abbott Laboratories, Chicago, IL); free
T4, Microparticule Enzyme Immunoassay
(Abbott Laboratories); free T3, RIA
(Diagnostic Products, Los Angeles, CA); and free
-subunit, immunoradiometric assay (Biocode SA, Liege, Belgium). A
gallbladder echography was performed before enrollment in this study
and again after 6 months of treatment with Octreotide-LAR.
Data analysis
The results, presented as the mean ± SEM, were compared during octreotide withdrawal, octreotide, or Octreotide-LAR treatments and between groups of patients either previously untreated or treated by surgery and/or pituitary radiotherapy. The main efficacy parameter was defined as free T4 level, and the main comparison of interest was that of 6 months vs. end of washout. This was carried out by means of paired t test. Other comparisons (other time points, other parameters) were carried out in the same way. P < 0.05 was considered significant in all tests.
Results
Clinical evaluation
All patients were euthyroid during the sc octreotide treatment.
During octreotide withdrawal (34 ± 6 days), significant symptoms
of hyperthyroidism recurred for most patients. During Octreotide-LAR
administration, clinical signs improved again (Table 2), and all patients continued monthly im
injections of Octreotide-LAR after the end of the study.
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In this cohort of 11 patients with TSH-secreting pituitary
adenomas, the mean basal plasma free T4 and
T3 levels were 33.5 ± 3.5 and 9.85 ±
0.66 pmol/L, respectively, before any treatment was started. Free
T4 and T3 decreased to
15.8 ± 1.3 and 3.91 ± 0.45 pmol/L, respectively (Table 2
),
and all patients were considered to be euthyroid (normal free
T4 and T3 concentrations)
during the octreotide treatment. Mean serum free
T4 (29.1 ± 3.5 pmol/L; P <
0.01) and T3 (7.40 ± 0.93 pmol/L;
P < 0.01) levels increased after octreotide
withdrawal. Serum free T4 and
T3 levels decreased again during Octreotide-LAR
administration, and 10 patients were euthyroid during the 6-month
treatment with Octreotide-LAR. In 1 patient free
T4 and T3 levels remained
abnormal at the 6 month evaluation despite the increase in
Octreotide-LAR dose to 30 mg (Fig. 1).
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). After the withdrawal of octreotide, plasma TSH levels were
2.81 ± 0.40 mU/L (P < 0.01). After a 3-month
period of monthly im injections of Octreotide-LAR, the mean TSH value
recorded on day 28 after the last injection was 1.63 ± 0.34 mU/L
(P < 0.01). Mean TSH levels stayed in the normal range
and were significantly lower than the pretreatment value. In these
patients with TSH-secreting pituitary adenomas there was no evidence of
tachyphylaxis. In previously treated patients (group 1) the mean TSH level fell from 3.90 ± 0.70 to 1.25 ± 0.28 mU/L (P < 0.01) during octreotide and from 2.42 ± 0.47 mU/L after the cessation of octreotide to 0.99 ± 0.19 mU/L (P < 0.01) at the end of the study. In previously untreated patients (group 2), mean TSH fell from 3.95 ± 1.12 mU/L at diagnosis to 1.27 ± 0.33 mU/L (P < 0.01) during sc octreotide treatment and from 3.50 ± 0.88 mU/L at the end of the washout period to 1.12 ± 0.42 mU/L after 6 months of Octreotide-LAR therapy. Mean TSH levels during treatment with octreotide and Octreotide-LAR were not different between the two groups.
Free T4 concentrations fell from 35.9 ± 5.2
to 15.5 ± 2.0 pmol/L, and from 29.4 ± 2.6 to 16.5 ±
1.7 pmol/L during octreotide treatment in both patients previously
treated (group 1) and untreated subjects (group 2). Free
T4 values also fell from 30.0 ± 5.1 and
27.9 ± 6.6 pmol/L at the end of the washout period to 16.8
± 2.3 and 14.7 ± 2.0 pmol/L after 3 months of Octreotide-LAR
treatment in the secondary (group 1) or in the primary (group 2)
treatment group, respectively, and remained in the normal range for the
rest of the study (Fig. 2). Free
T4 values before and during somatostatin analog
treatments were not statistically different between the two groups.
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-subunit value was 0.62 ± 0.24 IU/L during
octreotide treatment. After octreotide withdrawal, the mean serum free
-subunit value was 1.41 ± 0.58 IU/L. After 3 months of
treatment with Octreotide-LAR, the mean free -subunit levels
significantly decreased to 0.67 ± 0.25 (P <
0.05) compared with the pretreatment value (Table 2). During
Octreotide-LAR treatment, the mean free - subunit level remained
suppressed throughout the follow-up period. Tolerance
Minor digestive problems (nausea, mild abdominal pain, and softened stools) were reported by six patients for less than 48 h after im injections. Moderate discomfort at the injection site, lasting less than 24 h, was reported in five patients. These side-effects did not lead to the interruption of treatment in any patient. Two patients presented abnormal gallbladder echographies during sc octreotide (gallstones and sludge). After the completion of the study, the gallstones were not modified in one patient, and the remaining patients had normal gallbladder echography.
Discussion
Pituitary surgery is considered the first therapeutic approach in patients with TSH-secreting pituitary adenomas (13) to restore euthyroidism in hyperthyroid patients with TSH-secreting adenomas and to eliminate the symptoms of mass effect in patients with macroadenomas. Pituitary surgery led to normalization of thyroid hormone levels and the disappearance of pituitary tumors in 44% of the patients, produced normalization of thyroid hormone secretion despite incomplete tumor removals in 25% of the patients, and was unsuccessful in 29% (9). Therefore, in patients with TSH-secreting pituitary adenomas, the results of surgery alone are rather disappointing, and radiation therapy has been considered the most appropriate adjuvant therapy for patients not in remission after surgery. However, the percent remission of hyperthyroidism is low after radiotherapy or stereotactic radiosurgery (9, 10, 13, 14). On the other hand, the presence of somatostatin receptor subtypes detected by both in vitro and in vivo techniques on TSH-secreting pituitary adenomas (1, 2, 3, 4, 5) has allowed treating patients with TSH-dependent hyperthyroidism with somatostatin analogs. Subcutaneous octreotide treatment suppressed TSH secretion in more than 90% of cases, with normalization of thyroid hormone levels in 75% of them (10, 11, 12, 15, 16). Thus, in patients with TSH-secreting pituitary adenomas, surgical removal of the tumor is the first line treatment in patients with microadenomas, whereas medical treatment with somatostatin analogs is usually indicated for patients with persistent TSH-dependent hyperthyroidism or incomplete tumor removal of macroadenomas.
The effectiveness of somatostatin analogs in patients with TSH-secreting pituitary adenomas has been correlated with the presence of somatostatin receptors on adenoma cells (4, 5) as well as the mode of therapy and the plasma concentration of the somatostatin analogs (17, 18). In our population of patients with TSH-secreting pituitary adenomas, multiple daily injections (n = 9) or continuous infusion (n = 2) of sc octreotide decreased mean TSH, free T4, and T3 levels in the normal range, and long-term treatment with somatostatin analog (37 ± 8 months) maintained euthyroidism in all patients. As observed in patients with GH-secreting pituitary adenomas (19, 20), TSH and thyroid hormone suppression by long-term octreotide treatment did not persist after drug withdrawal, and no rebound of TSH hypersecretion was observed after stopping octreotide treatment. Therefore, the effects of somatostatin analogs are reversible, and the need for long-term administration is indicated in patients with TSH-secreting pituitary adenomas. Long-acting release forms of somatostatin analogs might avoid the drawbacks of repeated daily sc injections or continuous infusion using a pump. Long-acting octreotide formulation has been produced by incorporation of the drug in microspheres of biodegradable polymer (Octreotide-LAR), and this depot formulation is injected im every 4 weeks. In our patients with TSH-secreting pituitary adenomas, monthly im injections of Octreotide-LAR also decreased TSH and free T4 levels, and 10 patients were euthyroid after 3 months of long-acting octreotide treatment. These results remained unchanged, and no escape from the Octreotide-LAR treatment occurred over the next 3 months. A similar control of TSH-dependent hyperthyroidism in patients with TSH-secreting pituitary adenomas has been reported with a slow release formulation of the somatostatin analog lanreotide (17, 18). A reduction in tumor size has been reported in approximately half of the patients with TSH-secreting pituitary adenomas treated with octreotide (9, 10, 21). Such an effect usually occurred within 3 months in patients treated with this somatostatin analog (22). In this study 7 patients had previously been operated on and/or treated with external radiation, and all were treated with somatostatin analog for a long period (37 ± 8 months). Therefore, the effect of Octreotide-LAR on pituitary tumor size was not evaluated in this group of patients previously treated by somatostatin analog. Thus, this clinical study shows that in patients with TSH-secreting pituitary adenomas, monthly im injections of Octreotide-LAR are as efficacious as daily sc administrations of octreotide in controlling TSH-dependent hyperthyroidism.
Long-term medical therapy with somatostatin analogs is indicated adjunctively in patients with TSH-secreting pituitary adenomas who failed to be cured after surgery or who were awaiting the effects of radiation. The use of somatostatin analogs as primary therapy was generally reserved to patients who refused surgery or who were poor surgical candidates. In our series of patients with TSH-secreting pituitary adenomas, the effects of somatostatin analogs as primary therapy in four patients were compared with the effects in seven patients previously treated with surgery, radiotherapy, or both. There was no statistically significant difference in the TSH and free T4 responses to sc octreotide and im Octreotide-LAR in the two groups of patients. Although the patients were not randomized to primary treatment with either surgery and/or radiotherapy or somatostatin analogs, and the study was performed with a small number of patients (due to a low incidence of the disease), the results suggest that primary treatment with somatostatin analogs may be as beneficial as the combination of surgery or radiation plus octreotide. Therefore, primary treatment with somatostatin analogs may be a reasonable option in patients with TSH-secreting pituitary microadenomas to preoperatively control TSH-dependent hyperthyroidism (23) and with TSH-secreting macroadenomas or invasive tumors that are at high risk of not being cured by surgery. However, a definitive conclusion requires a randomized study in which more patients with TSH-secreting pituitary tumors are treated with long-acting release somatostatin analogs vs. surgery and/or radiotherapy.
Octreotide-LAR was well tolerated throughout the study. Minor digestive problems (nausea, mild abdominal pain, and softened stools) or moderate discomfort at the injection site, lasting less than 48 h, were reported by six and five patients, respectively, and did not require interruption of the treatment. The most potentially important side-effect of long-term administration of somatostatin analogs is an increased tendency of gallstones formation. In our patients, gallbladder echographies did not reveal the occurrence of gallstones in any patient during Octreotide-LAR treatment as also reported during slow release lanreotide therapy (18). The results observed in these studies may be the consequence of their relatively short duration and/or related to the small number of patients treated with long-acting release forms of somatostatin analogs. On the other hand, after long-term treatment with multiple daily injections or continuous infusion of sc octreotide, the patients noted the convenience of monthly injections and continued im Octreotide-LAR after the end of the study.
In conclusion, this study shows the efficacy and safety of Octreotide-LAR in patients with TSH-secreting pituitary adenomas that were responsive to the somatostatin analog octreotide, who were either previously untreated or treated with surgery and/or pituitary radiotherapy. Therefore, Octreotide-LAR appears to be a useful therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary tumors in patients who need long-term somatostatin analog therapy.
Received October 4, 2000.
Revised January 10, 2001.
Revised February 23, 2001.
Accepted March 2, 2001.
References
ckinger U, Liehr RM, Quabbe HJ. 1993 Octreotide long term treatment of acromegaly: effect of drug withdrawal
on serum growth hormone/insulin like growth factor-I concentrations and
on serum gartrine/24-hour intragastric pH values. J Clin
Endocrinol Metab. 77:157–162.[Abstract]
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) with TSH-secreting pituitary adenoma.
The shaded area indicates the normal range of TSH and
free T4 concentrations.