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Evaluation of the Treatment of Thyrotropin-Secreting Pituitary Adenomas with a Slow Release Formulation of the Somatostatin Analog Lanreotide

Departments of Endocrinology, University Hospital, 76031 Rouen (J.M.K., H.L.), 80054 Amiens (S.A.), 31403 Toulouse (P.C.), 59037 Lille (C.C.), 87042 Limoges (F.A.), 94275 Paris (P.C.), and 33604 Bordeaux (A.T.), France; Department of Endocrinology (M.I.G.), University Hospital, 1389 Budapest; Department of Endocrinology (M.G.), University Hospital, Hungary; Department of Endocrinology (P.B.-P.), University Hospital, 20089 Milan, Italy; Ipsen-Biotech Laboratories (J.B., F.C., S.I.), 75016 Paris, France; IFR Peptides (J.M.K., H.L.) and U-413, INSERM (J.M.K., H.L.), University of Rouen, 76130 Rouen, France

Address all correspondence and requests for reprints to: Dr. J. M. Kuhn, Department of Endocrinology, Hopital de Bois-Guillaume, 147 avenue du Maréchal Juin, 76230 Bois-Guillaume, France.

	Abstract

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Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T₃ (fT₃) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free -subunit, fT₄, fT₃, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (±SEM) plasma lanreotide levels reached 1.11 ± 0.43 and 1.69 ± 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 ± 0.32 to 1.89 ± 0.27 mU/L (P < 0.01), with parallel significant changes in free -subunit. During the same period, plasma fT₄ and fT₃ levels decreased from 37.9 ± 2.9 to 19.7 ± 2.3 pmol/L (P < 0.01) and from 14.6 ± 1.1 to 8.3 ± 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.

	Introduction

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COMPLETE removal of the pituitary tumor through transsphenoidal neurosurgery remains the treatment of choice for TSH-secreting adenomas (1, 2, 3). However, large tumors are frequently found, and consequently surgery does not usually lead to cure. Indeed, postoperative plasma thyroid hormone levels were not normalized in many patients (1, 2, 3, 4). Furthermore, an early drop in plasma free -subunit (fAS) and/or TSH levels (either basal or during suppression by T₃), as markers of complete removal of the tumor, is not achieved by this approach (4). Using additional pituitary radiotherapy, recovery is obtained in less than 40% of cases (1, 2, 3, 5). Somatostatin inhibits TSH secretion either in physiological conditions (6, 7) or in TSH-secreting pituitary adenomas (8). Somatostatin analogs have been used to reduce and/or normalize plasma TSH and thyroid hormone levels in patients with TSH-secreting pituitary tumors and then to improve clinical signs. Octreotide (Sandostatin) is able to acutely inhibit TSH secretion and to reduce T₄ deiodination in acromegalic patients (9). This analog has been shown to suppress TSH secretion in more than 90% of thyrotropinomas and to decrease adenoma size in about 50% of cases (3, 5, 10, 11, 12, 13, 14, 15, 16). The plasma half-life of the formulations actually available for the treatment of thyrotropinomas has been limited to few hours. Therefore, effective treatment requires three daily sc injections or continuous infusion using portable pumps, as previously shown in acromegaly (17, 18). The development of long acting formulations of somatostatin analogs (i.e. octreotide and lanreotide) has been performed to avoid such drawbacks. Long acting formulations of lanreotide and octreotide given twice a month (19, 20) and monthly, respectively, have been proved to be effective in the treatment of acromegaly (21, 22, 23). In addition, a single im injection of 30 mg lanreotide was able to normalize, for 10–15 days, plasma TSH and thyroid hormone levels studied in four patients with thyrotropinoma (24). These results suggested that long acting formulations could be regarded as a new treatment of thyrotropinomas, avoiding the drawbacks of the modes of administration of short acting somatostatin analogs. The aim of the present study was to evaluate the tolerance and efficacy of a long acting formulation of lanreotide on clinical signs, size, and secretion of the pituitary tumor in a large series of patients with hyperthyroidism related to a TSH-secreting pituitary adenoma.

	Subjects and Methods

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Products

Lanreotide (D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂) was provided by Ipsen-Biotech (Paris, France). Slow release formulations (SR-L) are composed of microspheres containing 30 mg of the peptide. The somatostatin analog is encapsulated in polyactide-polyglycolide copolymer. Microspheres are suspended in 2 mL suspension medium immediately before im injection.

Patients

Eighteen patients with TSH-secreting adenoma, 9 women and 9 men, aged 22–72 yr, gave informed consent and were included in an open noncomparative multicentric study. The study protocol was approved by the ethical committee of Haute Normandie (Rouen, France). All patients fulfilled the following inclusion criteria: hyperthyroidism related to TSH hypersecretion attested by increased plasma free T₄ (fT₄) and free T₃ (fT₃) with normal or elevated plasma TSH levels, presence of a pituitary adenoma on computed tomography scan and/or magnetic resonance imaging (MRI), and lack of signs of evolutive optic chiasma compression. Three patients did not receive any therapy before the study. Fifteen patients had been previously treated but were not cured despite pituitary surgery (performed in 9, at least 1 month before the beginning of the study), additional radiotherapy (45 Gy, performed in 4, at least 1 yr earlier than the start of the study), or medical therapy (antithyroid drugs in 4, dopaminergic agonists in 2, or somatostatin analogs in 10), which was stopped at least 1 month before starting the study. Premenopausal women without effective contraception were not eligible for the study.

Table 1 summarizes the clinical and main biological features of evaluable patients at entry into the study. Fasting plasma TSH levels were in or close to the normal range (0.2–4.0 mU/L) in all patients (1.1–4.5 mU/L). Plasma fAS (mean ± SEM, 1.58 ± 0.38 U/L) was in the normal range (0–3.5 U/L) in all but one patient. In response to TRH, plasma TSH and fAS levels did not change. Plasma fT₄ (37.9 ± 2.9 pmol/L) and fT₃ (14.6 ± 1.1 pmol/L) levels were above the normal range (7.5–18.8 and 3.2–9.6 pmol/L, respectively). No other pituitary hypersecretory pattern was found. Several patients had partial pituitary deficiencies: hypogonadotropic hypogonadism in 2, corticotroph failure in 3, and somatotroph deficiency in 7. Visual field examination was normal in 14 and showed a nonevolutive abnormality in 2 patients (1 hemianopsy and 1 quadranopsy). Among the 16 pituitary adenomas (mean size, 1.36 ± 0.2 cm) found on pituitary imaging, 5 were microadenomas. Extrasellar tumor extensions were present in 8 macroadenomas. In 7 patients the diagnosis of pituitary thyrotropinoma was histologically confirmed after removal of the tumor. TSH and -subunit immuno-stainings were positive in 5 and 3 cases, respectively.

Six patients were taking ß-blockers for tachycardia, 3 were substituted with hydrocortisone for corticotroph deficiency, and 2 received testosterone substitution for hypogonadism.

Study protocol

At the beginning of the study, a clinical assessment was performed, and blood was drawn for routine laboratory analysis. Pituitary function was evaluated using combined provocative tests (100 µg GnRH, 0.2 µg/kg GHRH, and 250 µg -corticotropin-(1–24), iv). Concomitantly, basal plasma fT₄, fT₃, and fAS and the TRH-induced (250 µg, iv) changes in TSH levels were measured in all patients. Blood samples were drawn before and then 15, 30, and 60 min after pituitary stimulation. On the same day, the following investigations were performed: visual field assessment, pituitary MRI, and thyroid and gallbladder ultrasonographies. Then, 30 mg SR-L were injected im every 14 days for 6 months. If plasma fT₃ levels remained elevated at month 1, the injections were given every 10 days for the following 5 months.

Clinical and biological efficacy (plasma fT₄, fT₃, fAS, and TSH levels) was evaluated in months 1, 3, and 6 of the study. In month 6 of treatment with SR-L, a similar assessment as at the initial evaluation was performed. Plasma lanreotide levels were measured before and then in months 1, 3, and 6 of treatment. Blood samples were centrifuged (4500 x g, 4 C), and plasma aliquots were kept frozen (-80 C) until assays.

Hormone assays

Plasma hormone levels were measured in a single laboratory using the following techniques. fT₄ and fT₃ were measured by a direct two-step method (Lisophase, Bouty, Milan, Italy). Plasma TSH levels were measured by an immunoradiometric assay method using two monoclonal antibodies (DYNOtest TSH, Brahms, Berlin, Germany) with a sensitivity of 0.037 mIU/L and an intraassay coefficient of variation of 7.8%. Plasma fAS and lanreotide levels were measured using RIAs previously described (19, 25). Briefly the antilanreotide RIA used Tris-HCl buffer plus 0.1% Triton X-100. The antilanreotide rabbit antibody KC 20 was used, and ¹²⁵I-radiolabeled lanreotide served as tracer. The separation of bound and free peptides was carried out using a sheep antirabbit antiserum and precipitation with 4% polyethylene glycol. Neither GH nor somatostatin cross-reacts in this RIA. The detection limit was 0.1 ng/mL, and the coefficient of intraassay variation was 7%.

Tolerance

Clinical side-effects were assessed in months 1, 3, and 6, including local tolerance and general symptoms. Routine laboratory analyses (serum electrolytes, renal and liver function, and blood cell count) were evaluated before treatment and then after 1, 3, and 6 months.

Statistical analysis

Clinical symptoms linked to thyrotropinoma (asthenia, cephalalgia, thermophobia, perspiration, and diarrhea) were evaluated as absent (0), mild (1), moderate (2), or severe (3), and a clinical score was calculated as the sum of the intensity of each clinical value. Comparisons between data obtained at the beginning of the study and those from month 6 were performed using paired Wilcoxon test. The patterns observed for at least three points of time were analyzed using the nonparametric test of Friedman. For comparison of plasma hormone values, paired Student’s t test was used.

	Results

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After inclusion, 2 patients were dismissed from the study, 1 at the first month evaluation for vomiting and 1 at month 3 for noncompliance to the protocol. Among the 16 evaluable patients 14 completed the study, and 2 were not completely evaluated in month 6.

All patients received 30 mg SR-L every 2 weeks during the first month of the follow-up. Then, 9 of 16 patients with normalized fT₃ levels received lanreotide every 14 days throughout the study. In contrast, 7 of 16 patients in whom plasma fT₃ remained above the normal range in month 1 were treated with 1 injection every 10 days from months 1–6. Weight did not change throughout the study. Plasma lanreotide levels rose from undetectable to 1.11 ± 0.43 and 1.69 ± 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively. Then, mean plasma lanreotide levels remained stable until the end of the study (Fig. 1). Within 1 month, all subjects showed clinical improvement. The clinical score dropped significantly (P < 0.01) from 4.6 ± 0.9 (basal score) to 2.3 ± 0.5 in month 6. Similarly, cardiac frequency decreased significantly (P = 0.001) from 80 ± 4 to 66 ± 7 beats/min. As illustrated in Fig. 2, plasma TSH and fAS were significantly (P < 0.05) reduced by the treatment at the 1 month evaluation. Thyroid hormone levels were significantly (P < 0.05) and progressively reduced in all cases (Fig. 2), and plasma fT₄ and fT₃ levels were normalized in 13 of 16 patients (Fig. 3). Clinical and biological improvement was maintained throughout the treatment. Visual field evaluation did not show changes in any patient. Pituitary imaging using MRI performed at month 6 did not show any significant decrease in pituitary adenoma size in both patients previously treated and those free of previous treatment with somatostatin analogs.

View larger version (15K): [in this window] [in a new window]   Figure 1. Mean (±SEM) plasma lanreotide levels measured just before the next injection of the analog. B, Basal levels. *, P < 0.05.

View larger version (17K): [in this window] [in a new window]   Figure 2. Mean (±SEM) plasma TSH () and fAS () levels (top) and free T4 () and free T3 () levels (bottom) measured just before the next injection of the somatostatin analog. B, Basal levels. *, P < 0.05; #, P < 0.003; , P < 0.0005.

View larger version (29K): [in this window] [in a new window]   Figure 3. Individual plasma TSH (top) and free T4 (bottom) levels in the patients before (base) and at month 6 of the study (treated). , Mean (±SEM) plasma hormone levels. #, P < 0.003.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Lanreotide is a cyclic octapeptidic analog of somatostatin that has been demonstrated to be able to inhibit several gut and pituitary hormone secretions in healthy individuals (26, 27, 28). Continuous sc infusion of this analog reduces the physiological nocturnal rise in TSH secretion (28). Slow release formulations of lanreotide encapsulated in microspheres injected two or three times a month has proved to be an effective treatment of acromegaly (19, 20, 29, 30). The use of such formulations avoided the drawbacks of previous modes of administration of somatostatin analogs in such cases (19, 21, 22, 23). SR-L suppresses TSH secretion in normal men for several days (31). TSH hypersecretion was blocked from 10–15 days after one injection of SR-L in four patients bearing TSH-secreting pituitary adenomas (24). Although somatostatin analogs appear effective to normalize TSH secretion of thyrotropinomas (3, 32), none of the long acting formulations (i.e. Sandostatin LAR or Somatulin LP) was available for clinical use in TSH-dependent hyperthyroidism. The demonstrated effects of lanreotide, either administered sc or as SR-L, on physiological (31) and in some cases tumoral TSH secretion (24) led us to assess the efficacy and tolerance of the peptide as treatment in a larger series of patients with TSH-secreting adenomas.

Clinical signs of hyperthyroidism were significantly reduced in all patients. Plasma TSH and thyroid hormone levels decreased progressively. Similar patterns were previously observed for plasma GH and insulin-like growth factor I levels in acromegalic patients treated with either octreotide (33) or SR-L (19, 20, 30). Indeed, pharmacokinetic data have shown that steady state of plasma lanreotide level is obtained after three administrations of SR-L (19, 20, 30). Injection of 30 mg SR-L is followed by the same pharmacokinetic pattern of plasma lanreotide level in all men previously treated with this analog (19, 24, 27). Indeed, after a single injection of SR-L, plasma lanreotide levels increased rapidly and remained at 1 ng/mL or more for 2 weeks in healthy volunteers (34) and patients with pituitary tumors (19, 24). Such a pharmacokinetic pattern characterizes slow release formulations using polyactide-polyglycolide microspheres (35, 36). This pattern is the result of an early release of the peptide localized at the surface of the copolymer followed by a prolonged liberation of the analog by enzymatic breakdown of the microspheres. Results obtained in patients with GH- or TSH-secreting pituitary tumors (19, 20, 24, 37) showed that a sustained plasma lanreotide level over 1 ng/mL is needed to obtain clear therapeutic effects. However, the effects of the drug were not similar in all patients. Differences observed in responsiveness of the patients to the analog are less likely to be explained by the plasma lanreotide level reached than by the sensitivity of the tumor cells to the analog. Indeed, sensitivity could differ from one adenoma to another, leading to different responses to treatment. Although to a lesser extent than normal cells, thyrotropinomas expressed some somatostatin receptor subtypes (3). The in vivo and in vitro somatostatin analog-induced inhibition of TSH secretion from thyrotropinomas is correlated to the presence of binding sites for the analog on the tumor cells (16, 38, 39, 40). Thus, the somatostatin receptor status of the tumor may explain the differences in individual responses to the analog. The clinical consequences of these data could be to select a regimen of injection from every 10 to every 14 days as a function of plasma thyroid hormone levels measured 1 month after starting the treatment with one injection of SR-L twice monthly.

An usually mild decrease in adenoma size has been observed in about 50% of patients with thyrotropinomas receiving octreotide (3, 5, 15, 32, 41). In the present study we did not observe a change in pituitary tumor volume in any patient. Similar data have been reported in four thyrotropinomas treated with SR-L for 3–6 months (24). The treatment with SR-L seems to be prolonged enough to elicit an antitumoral effect. Indeed, such an effect usually occurred within 3 months in thyrotropinomas treated with octreotide (32). The dose of lanreotide used could be high enough to normalize plasma hormone levels but not sufficient to inhibit cell proliferation and then to reduce the tumor size as previously observed with octreotide in acromegaly (42). However, most of the patients were treated with a somatostatin analog before inclusion in the study, which may bias evaluation of the antitumoral effect, as previously observed in acromegalic patients (30). Taken as a whole, these results suggest that SR-L, administered at either 60 or 90 mg monthly, could be used to control TSH oversecretion of thyrotropinomas. SR-L could provide a useful tool for the treatment of patients not cured by pituitary radiotherapy and/or surgery, and the drug may be of interest to preoperatively treat hyper- thyroidism.

The main side-effects included abdominal cramps, diarrhea, and pains at the injection site. They were slight and transient and did not require interruption of the treatment. Tolerance improved with continuation of treatment. Similarly good tolerance has previously been observed in some thyrotropinomas treated 6 months (24) and in acromegalic patients treated with SR-L for years (19, 20, 29, 30). New gallstones did not appear during treatment. As prolonged treatment with SR-L is accompanied by the appearance of gallstones in 12% of patients (19, 20, 29, 30), the results obtained in the present study may be the consequence of its relatively short duration and/or the small number of patients.

In conclusion, these results show that injections of 30 mg lanreotide in a slow release formulation appears to be able to decrease TSH oversecretion of TSH-secreting adenomas. Effective treatment requires that the injection be repeated at either 10- or 14-day intervals to control hyperthyroidism. Long term treatment using injections twice or three times monthly appears well tolerated. Finally, the slow release formulation avoids the drawbacks of the multiple daily sc injections of somatostatin analogs previously available as a treatment of TSH-dependent hyperthyroidism.

Received August 11, 1999.

Revised December 29, 1999.

Accepted January 5, 2000.

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