0021-972x/92/7403-os90$03.00/0 Journal of Clinical Endocrinology Copyright 0 1992 by The Endocrine
and
Vol. 74, No. 3
Metabolism Society
Printed
in U.S.A.
Reduction in Size of a Thyrotropinand GonadotropinSecreting Pituitary Adenoma Treated with Octreotide Acetate (Somatostatin Analog) ROSA ALLYN G. SY, ROBERT IONE A. KOURIDES
BERNSTEIN,
KU0
YORK
CHYNN,
AND
The Divisions of Endocrinology, Metabolism and Nutrition (R.A.G.S., R.B.), and of Neuroradiology (K. Y.C.), St. Luke$/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons and the Division of Endocrinology, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College (I.A.K.), New York, New York
ABSTRACT. TSH as well as a-subunit, secretion has been shown to decrease after the administration of the somatostatin analog octreotide acetate (SMS 201-995). We have studied a 59yr-old, male patient with a TSH- and gonadotropin-secreting tumor who, because of severe cardiomyopathy, was treated with long-term somatostatin analog rather than surgical resection of the pituitary tumor. Thirteen weeks of treatment with thrice daily SC injection of 100 pg octreotide acetate resulted in decreased TSH and a-subunit secretion, normal serum thyroid hormone levels, reduction in LH and testosterone level, and
T
SH-secreting pituitary adenomas were first described in 1970 (1). Despite widespread use of TSH assays since then, these are still uncommon tumors with only 85 cases reported in the medical literature (2-6). Patients with TSH-producing pituitary adenomas are often misdiagnosed initially, resulting in inappropriate therapy. Hence, these tumors usually become large and are invasive before proper treatment is administered (4, 7). Consequently, surgical resection, radiation therapy or combined modalities are often unsatisfactory (8,9). Various pharmacological agents have been evaluated for control of the neoplastic inappropriate secretion of TSH. Among these agents, octreotide acetate, the long-acting analog of somatostatin (SMS 201-995), has proven to be promising in controlling basal and stimulated thyrotropin secretion from normal and tumorous thyrotropes (7, 10-13). It has been reported to improve visual field abnormalities in one patient (14) suggesting a possible effect on tumor growth. However, of the 17 NIST cases previously reported who were treated with octreotide acetate, only three patients demonstrated clear-cut tuReceived April 9, 1991. Address requests for reprints to: Ione A. Kourides, Pfizer Pharmaceuticals, CSA 219-4, 235 East 42nd Street, New York, New York 10017.
significant tumor size reduction. Long-term treatment for 51 weeks has not been associated with any significant side effects. We have shown that octreotide acetate may be a therapeutically valuable modality for certain patients with neoplastic inappropriate secretion of TSH (NIST). A probable effect of octreotide acetate on neoplastic gonadotropes, as evidenced by the reduction of the LH level with a concomitant decrease in testosterone level, is, likewise, suggested. (J Clin Endocrirwl Metab 74: 690694,1992)
mor shrinkage with the use of this agent (5, 6). Furthermore, although rare, TSH-producing pituitary adenomas may be associated with LH and FSH hypersecretion (2). We now report a patient with a TSH-producing pituitary macroadenoma with FSH/LH excess who showed remarkable adenoma size reduction with concomitant normalization of his LH level with octreotide acetate therapy. Subject
and Methods
Case E.O., a 59-yr-old man with a history of asthma and chronic alcohol abuse,wasfirst admitted to St. Luke’s/Roosevelt Hospital Center in July of 1989for evaluation and managementof right-sided heart failure. He had symptomsof mild hyperthyroidism (palpitation, heat intolerance, nervousness, tachycardia, and tremor) with a decreasein libido of 1% months duration. Jugular veins were distended; no grossvisual field impairment, and no eye signswere noted; the thyroid gland was not enlarged;the liver edgewas palpable, and both lower extremities had peripheral edema. The electrocardiogram showedleft anterior hemiblock with anteroseptal myocardial infarction of indeterminate age.Echocardiogramand first pass radionuclide studies showed four-chamber dilated cardiomyopathy with severeglobal dysfunction and an ejection fraction 690
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 05:24 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS of 20%. Routine thyroid function tests on admission revealed: Ts resin uptake, 0.34 (0.25-0.36); TdRIA, 257 nmol/L (57.9160.8 nmol/L); T3RIA, 4.65 nmol/L (1.32-2.87 nmol/L); TSH, 19 mU/L (0.3-5.0 mu/L). Four hour and 24-h radioactive iodine uptake were 36% and 61%, respectively, whereas the thyroid scan showed homogeneous uptake throughout the gland. Other endocrinological studies revealed: GH, 1.0 pg/L (less than 5 rg/L); PRL, 6 pg/L (O-15 pg/L); FSH, 35 IU/L (O-20 IU/L); LH, 47 IU/L (O-20 IU/L); testosterone, 25 nmol/ L (12.48-34.32 nmol/L). Radiological studies, which included a thin section contrast CAT scan and a high resolution MRI of the sella turcica and hypothalamus, revealed a pituitary macroadenoma measuring approximately 1.9 cm in height with suprasellar extension (Fig. 1, A and B).
691
An initial visual field perimetry showedbitemporal visual field defects. Methods
All RIAs were performedusing a double antibody technique. PlasmaTSH levels wereassayedusingthe immunoradiometric assaytechnique, whereasthe immunoassayfor a-subunit was performed by previously published methodsof Kourides et al. (15-17).
Results Before the initiation of therapy, a TRH stimulation test was done which revealed a blunted TSH response. Basal and stimulated a-subunit levels were elevated, but the incremental increase after TRH was minimal (Fig. 2). The a-subunit to TSH molar ratio was greater than 1.0, both before and after the TRH stimulation test. The patient was placed on propylthiouracil (PTU) 200 mg orally three times a day (TID) which controlled his hypermetabolic state. However, repeat thyroid function tests after 11/2 months of PTU therapy showed a significant increase in the TSH level from 19 mU/L to 38 mU/ L. Because of his cardiomyopathy, it was decided to treat him pharmacologically rather than surgically. Octreotide acetate therapy 50 pg SC twice a day (BID) was commenced in January 1990, and PTU was discontinued. The dose of octreotide acetate was increased to 100 pg SC TID a week later. An initial posttherapy TSH level taken 3 weeks after commencement of therapy showed a significant decrease in TSH (Fig. 2). Repeat magnetic resonance imaging of the sella and the hypothalamus 13 weeks after beginning therapy with octreotide acetate showed a marked reduction in the size of the pituitary adenoma with only a mild upward bulging of the pituitary gland on the left side (Fig. 3, A and B). A repeat visual field perimetry study remained unchanged. Repeat TRH stimulation test at that time showed minimal increase in TSH response. a-Subunit levels during therapy were likewise significantly reduced to normal levels (Fig. 2). During the 9th week of therapy, the dose was tapered
1 FIG. 1. Pituitary adenoma before octreotide acetate therapy. A, PreGadolinium Tl-weighted spin-echo MR image (arrows) which compresses and displaces the optic chiasm upwards (curued arrows). B, Post-Gadolinium MR image shows marked enhancement of the suprasellar tumor (arrows). The pituitary stalk and the suprasellar cistern are completely obliterated by the tumor.
to 100 pg BID. Ten weeks later, it was further decreased to 50’ pg BID. Thyroid hormones remained within the euthyroid range (Fig. 4). The patient gained 10 kg over a period of 40 weeks of therapy, possibly due to remission of his hyperthyroidism. Abdominal ultrasonography was negative for cholelithiasis. Repeat visual field study at the 40th week of therapy still showed a bitemporal field defect. Follow-up hormonal studies were unchanged except for the reduction of LH from 47 IU/L to 25 IU/L (O-20 IU/L) and testosterone from 25 nmol/L to 4.5 nmol/L (12.5-34.3 nmol/L). Repeat LH and testosterone levels done 2 weeks later remained low at 21 IU/L and
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692
COMMENTS
JCE8zM.1992 Vo174.No3 2. ,Alpba-subunit
FIG. 2. A, TSH response; B, a-subunit response to TRH stimulation test before and during octreotide acetate therapy.
04
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FIG. 3. Marked reduction of the pituitary adenoma size after octreotide acetate therapy. A, Pre-Gadolinium Tl-weighted MR image shows enhanced pituitary gland on the left side (black arrow). The pituitary stalk can now be visualized and is tilted towards the left (white arrow). B, Post-Gadolinium Tl-weighted MR image shows enhanced pituitary gland (arrows). Note the appearance and position of the optic chiasm is normal now (curved arrow) as compared with that on Fig. 1.
9.7 nmol/L, respectively. FSH level remained unchanged at 35 IU/L (O-20 IU/L). While on the lowest dose (50 pg SC BID), he started to complain of severe headache relieved by analgesics. For this reason, the dose of oc-
1 I------04 ~~~~~~~~~~~~ 1,. 1, a , ‘ , I2 I5 L, *, 7.4 51 5a 55 5‘ 5, 45 45 40 51 We&
FIG.
4. Effect of octreotide acetate on TSH, T4RIA, and T8RIA.
treotide acetate was increased to 100 pg BID, completely relieved the symptom.
which
Discussion Dopamine and somatostatin are known inhibitors of TSH secretion. A number of studies have described the
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COMMENTS
inhibitory effect of somatostatin on TSH hypersecretion in patients with neoplastic inappropriate secretion of TSH, but the duration of action of the somatostatin was too short to demonstrate real utility (18-21). Octreotide acetate, a long-acting somatostatin analog, has been shown in recent studies not only to reduce TSH secretion in patients with pituitary adenomas but also to restore clinical and biochemical euthyroidism (11-14, 22, 23). The response of our patient to octreotide acetate confirmed its effectiveness (7, 11, 23). Moreover, its administration reduced not only TSH secretion but also (Ysubunit hypersecretion, which is the tumor marker of both gonadotropin and thyrotropin-producing pituitary adenomas. The initial TRH stimulation test on our patient demonstrated an elevated basal TSH with no increase in TSH secretion after TRH, as commonly seen in such patients. This could be due to autonomous neoplastic production of TSH, unresponsiveness to exogenous TRH and thyroid hormone unresponsiveness, as described by Kourides et al. (24) and Weintraub et al. (25), lack of TRH receptors or altered thyroid hormone receptors on the tumor cells, as suggested by Smallridge and Smith (26), or hyperthyroidism itself. A repeat TRH stimulation test during therapy resulted in a minimal increase in TSH level but not to optimal levels, suggesting an inhibitory effect of octreotide acetate on the normal thyrotrope. As the TSH was reduced to a euthyroid level, a-subunit levels also came down to normal. Aside from the significant biochemical improvement of our patient while on the medication, there was also a dramatic shrinkage of tumor size after only 13 weeks of therapy. Recent articles have demonstrated a similar result (5, 6) though not shown by previous studies (4, 7, 22, 23). Approximately 33% of TSH-producing pituitary adenomas may have concomitant hypersecretion of other anterior pituitary hormones (3,27) particularly PRL and GH. Of the 85 reported patients with TSH-secreting pituitary tumors, only two of these patients had elevated gonadotropin (2). Our patient appears to be the third patient with LH and FSH hypersecretion. Repeat gonadotropin levels obtained at the 40th week of therapy showed unchanged FSH but reduced LH levels with a subnormal testosterone level. These results suggest that the patient had a pituitary tumor also secreting LH and possibly FSH. The relatively low testosterone level with slightly elevated LH level in the absence of primary hypogonadism as seen in our patient has been demonstrated in men with gonadotropin-secreting tumors (2830). This could be due to the secretion of a mixture of biologically active and inactive LH by the tumor. The decrease in LH secretion during therapy with somatostatin supports the finding of Vos et al. (31) and suggests the presence of somatostatin receptors in this pituitary
693
tumor (32, 33). Because our patient was treated medically, cell culture or immunocytochemistry analysis is not available for diagnostic confirmation. However, the persistent decrease of testosterone when LH was decreased during octreotide acetate treatment suggested the tumoral origin of the gonadotropin hypersecretion. Although more cases will need to be treated with octreotide acetate to determine how efficacious it is in TSH- and gonadotropin-secreting tumors, the excellent clinical and radiological response of our patient to octreotide acetate provides support for the use of this treatment modality. Acknowledgments
The authors wish to thank F. Xavier Pi-Sunyer, M.D. and Sami Hashim, M.D. for their critical review of the manuscript. We are also grateful to Steven Lichtman M.Ed. for his invaluable help in preparing the figures, to John Lee for performing the a-subunit assay, to Yim Dam, Georgette Cole, and especially to Victor Mascitelli, M.D. and Jeanine Albu, M.D. for their technical assistance. References 1. Hamilton Jr CR, Adams LC, Maloof F. Hyperthyroidism due to thyrotropin producing pituitary adenoma. N Engl J Med. 1970;283:1077-80. 2. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrino1 Metab Clin North Am. 1987;16:765-92. 3. Faglia G, Beck-Peccoz P, Piscitelli G, Medri G. Inappropriate secretion of thyrotropin by the pituitary. Horm Res. 198726: 79-99. 4. Gesundheit N, Petrick PA, Nissim M, et al. Thyrotropin-secreting pituitary adenoma clinical and biochemical heterogeneity, case reports and follow up of nine patients. Ann Intern Med. 1989;111:827-35. 5. Houdent Ch, Armangau MF, Kuhn JM, et al. Adenome thyreotrope traite par un analogue de la somatostatine. Ann Endocrinol (Paris). 1989;50:227-31. 6. Beckers A, Abs R, Mahler C, et al. Thyrotropin-secreting pituitary adenomas: report of seven cases. J Clin Endocrinol Metab. 1991;72:477-83. 7. Comi RJ, Gesundheit N, Murray L, Gorden P, Weintraub BD. Response of thyrotropin secreting pituitary adenomas to a long acting somatostatin analog. N Engl J Med. 1987;317:12-7. 8. Hill SA, Falks JM, Wilson CB, Hunt WE. Thyrotropin producing pituitary adenomas. J Neurosurg. 1982;57:51519. - 9. Weintraub BD. Petrick PA. Gesundheit N. Oldfield EH. TSHsecreting pituitary tumors. In: Medeiros-Neto GA, Gaitan E, eds. Frontiers in thyroidology, New York: Plenum 198671-7. 10. Takamatsu J, Mozai T, Kuma K. Bromocriptine therapy for hyuerthvroidism due to increased thvrotronin secretion. J Clin Endocrinol Metab. 1984;58:934-6. 11. Beck-Peccoz P, Mariotti S, Guillausseau PJ, et al. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with somatostatin analog SMS 201-995. J Clin Endocrinol Metab. 1989;68:208-14. 12. Siler TM, Yen SSC, Vale W, Guillemin R. Inhibition by somatostatin on the release of TSH induced in man by thyrotropin releasing factor. J Clin Endocrinol Metab. 1974;38:742-5. 13. Arimura A, Schally AV. Increase in basal and thyrotropin releasing hormone (TRH) stimulated secretion of thyrotropin (TSH) by passive immunization with antiserum to somatostatin in rats. Endocrinology. 1976;98:1069-72.
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694
COMMENTS
14. Guillausseau PJ, Chanson PH, Timsit J, et al. Visual improvement with SMS 201-995 in a patient with thyrotropin secreting pituitary adenoma, (Letter). N Engl J Med. 1987;317:53-4. 15. Kourides IA. Weintraub BD. Levko A. Maloof F. Alnha and beta subunits of human thyrotropin: purification and development of specific radioimmunoassays. Endocrinology. 1974;94:1411-21. 16. Kourides IA, Weintraub BD, Ridgway EC, Maloof F. Pituitary secretion of free alpha and beta subunit of human thyrotropin in patients with thyroid disorders. J Clin Endocrinol Metab. 1975;40:872-85. 17. Kourides IA, Weintraub BD, Rosen SW, Ridgway EC, Kliman B, Maloof F. Secretion of alpha subunit of glycoprotein hormones by pituitary adenomas. J Clin Endocrinol Metab. 1976;43:97-106. 18. Spada A, Bassetti M, Martin0 E, et al. In vitro studies on TSH secretion and adenylate cyclase activity in a human TSH secreting pituitary adenoma: effects of somatostatin and dopamine. J Endocrinol Invest. 1985;8:193-8. 19. Waldhausl W, Bratusch-Marrain P, Nowotny P, et al. Secondary hyperthyroidism due to thyrotropin hypersecretion: study of pituitary tumor morphology and thyrotropin chemistry and release. J Clin Endocrinol Metab. 1979;49:879-87. 20. Lamberg BA, Pelkonen R, Gordin A, et al. Hyperthyroidism and acromegaly caused by a pituitary TSH and GH secreting tumor. Acta Endocrinol (Copenh). 1983; 103: 7-14. 21. Reschini E, Guistina G, Cantalamessa L, Peracchi M. Hyperthyroidism with elevated plasma TSH levels and pituitary tumor study with somatostatin. J Clin Endocrinol Metab. 1976; 43: 924-7. 22. Malarkey WB, Kovacs K, O’Dorisio TM. Response of a GH and TSH secreting pituitary adenoma to a somatostatin analog (SMS 201-995): evidence that GH and TSH co-exist in the same cell and secretory granules. Neuroendocrinology. 1989;49:267-74. 23. Wemeau JL, Dewailly D, Leroy R, et al. Long term treatment with
24.
25. 26. 27. 28. 29. 30. 31.
32.
33.
JCE&M.1992 Vol74.No3
somatostatin analog SMS 201-995 in a patient with a thyrotropin and GH secreting pituitary adenoma. J Clin Endocrinol Metab. 1988,66:636-g. Kourides IA, Ridgway EC, Weintraub BD, Bigos ST, Gershengorn MC, Maloof F. Thyrotropin induced hyperthyroidism: use of alpha and beta subunit levels to identify patients with pituitary tumors. J Clin Endocrinol Metab. 1977;45:534-43. Weintraub BD, Gershengorn M, Kourides IA, Fein H. Inappropriate secretion of TSH. Ann Intern Med. 1986;95:339-51. Smallridge R, Smith C. Hyperthyroidism due to thyrotropin secreting pituitary tumors. Ann Intern Med. 1983;143:503-7. Clore JN, Sharpe AR, Singh Sahni K, Kalman K, Blackard WG. Thyrotropin induced hyperthyroid&m: evidence for a common progenitor stem cell. Am J Med Sci. 1988;295:3-5. Jameson JL, Klibanski A, Black PMcL, et al. Glycoprotein hormone genes are expressed in clinically non-functioning adenomas. J Clin Invest. 1987;80:1472-78. Snyder PJ. GonadotroDe adenomas of the nituitarv. Endocr Rev. 1985;6:552-63. Snyder PJ, Bigdeli J, Gardner DF, et al. Gonadal function in fifty men with untreated pituitary adenomas. J Clin Endocrinol Metab. 1979;48:309-14. Vos P, Croughs RJM, Thijssen JHH, van’t Verlaat JW, van Ginkel LA. Response of luteinizing hormone secreting pituitary adenoma to a long-acting somatostatin analogue. Acta Endocrinol (Copenh). 1988;118:587-90. Reubi JC, Heitz PU, Landolt AM. Visualization of somatostatin receptors and correlation with immunoreactive growth hormone and prolactin in human pituitary adenoma: evidence for different tumor subclasses. J Clin Endocrinol Metab. 1987;65:65-73. Ikuyama S, Nawata H, Kato K, Karashima T, Ibayashi H, Nakagaki H. Specific somatostatin receptors on human pituitary adenoma cell membranes. J Clin Endocrinol Metab. 1985;61:666-71.
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and
Vol. 74, No. 3
Metabolism Society
Printed
in U.S.A.
Reduction in Size of a Thyrotropinand GonadotropinSecreting Pituitary Adenoma Treated with Octreotide Acetate (Somatostatin Analog) ROSA ALLYN G. SY, ROBERT IONE A. KOURIDES
BERNSTEIN,
KU0
YORK
CHYNN,
AND
The Divisions of Endocrinology, Metabolism and Nutrition (R.A.G.S., R.B.), and of Neuroradiology (K. Y.C.), St. Luke$/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons and the Division of Endocrinology, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College (I.A.K.), New York, New York
ABSTRACT. TSH as well as a-subunit, secretion has been shown to decrease after the administration of the somatostatin analog octreotide acetate (SMS 201-995). We have studied a 59yr-old, male patient with a TSH- and gonadotropin-secreting tumor who, because of severe cardiomyopathy, was treated with long-term somatostatin analog rather than surgical resection of the pituitary tumor. Thirteen weeks of treatment with thrice daily SC injection of 100 pg octreotide acetate resulted in decreased TSH and a-subunit secretion, normal serum thyroid hormone levels, reduction in LH and testosterone level, and
T
SH-secreting pituitary adenomas were first described in 1970 (1). Despite widespread use of TSH assays since then, these are still uncommon tumors with only 85 cases reported in the medical literature (2-6). Patients with TSH-producing pituitary adenomas are often misdiagnosed initially, resulting in inappropriate therapy. Hence, these tumors usually become large and are invasive before proper treatment is administered (4, 7). Consequently, surgical resection, radiation therapy or combined modalities are often unsatisfactory (8,9). Various pharmacological agents have been evaluated for control of the neoplastic inappropriate secretion of TSH. Among these agents, octreotide acetate, the long-acting analog of somatostatin (SMS 201-995), has proven to be promising in controlling basal and stimulated thyrotropin secretion from normal and tumorous thyrotropes (7, 10-13). It has been reported to improve visual field abnormalities in one patient (14) suggesting a possible effect on tumor growth. However, of the 17 NIST cases previously reported who were treated with octreotide acetate, only three patients demonstrated clear-cut tuReceived April 9, 1991. Address requests for reprints to: Ione A. Kourides, Pfizer Pharmaceuticals, CSA 219-4, 235 East 42nd Street, New York, New York 10017.
significant tumor size reduction. Long-term treatment for 51 weeks has not been associated with any significant side effects. We have shown that octreotide acetate may be a therapeutically valuable modality for certain patients with neoplastic inappropriate secretion of TSH (NIST). A probable effect of octreotide acetate on neoplastic gonadotropes, as evidenced by the reduction of the LH level with a concomitant decrease in testosterone level, is, likewise, suggested. (J Clin Endocrirwl Metab 74: 690694,1992)
mor shrinkage with the use of this agent (5, 6). Furthermore, although rare, TSH-producing pituitary adenomas may be associated with LH and FSH hypersecretion (2). We now report a patient with a TSH-producing pituitary macroadenoma with FSH/LH excess who showed remarkable adenoma size reduction with concomitant normalization of his LH level with octreotide acetate therapy. Subject
and Methods
Case E.O., a 59-yr-old man with a history of asthma and chronic alcohol abuse,wasfirst admitted to St. Luke’s/Roosevelt Hospital Center in July of 1989for evaluation and managementof right-sided heart failure. He had symptomsof mild hyperthyroidism (palpitation, heat intolerance, nervousness, tachycardia, and tremor) with a decreasein libido of 1% months duration. Jugular veins were distended; no grossvisual field impairment, and no eye signswere noted; the thyroid gland was not enlarged;the liver edgewas palpable, and both lower extremities had peripheral edema. The electrocardiogram showedleft anterior hemiblock with anteroseptal myocardial infarction of indeterminate age.Echocardiogramand first pass radionuclide studies showed four-chamber dilated cardiomyopathy with severeglobal dysfunction and an ejection fraction 690
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 05:24 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS of 20%. Routine thyroid function tests on admission revealed: Ts resin uptake, 0.34 (0.25-0.36); TdRIA, 257 nmol/L (57.9160.8 nmol/L); T3RIA, 4.65 nmol/L (1.32-2.87 nmol/L); TSH, 19 mU/L (0.3-5.0 mu/L). Four hour and 24-h radioactive iodine uptake were 36% and 61%, respectively, whereas the thyroid scan showed homogeneous uptake throughout the gland. Other endocrinological studies revealed: GH, 1.0 pg/L (less than 5 rg/L); PRL, 6 pg/L (O-15 pg/L); FSH, 35 IU/L (O-20 IU/L); LH, 47 IU/L (O-20 IU/L); testosterone, 25 nmol/ L (12.48-34.32 nmol/L). Radiological studies, which included a thin section contrast CAT scan and a high resolution MRI of the sella turcica and hypothalamus, revealed a pituitary macroadenoma measuring approximately 1.9 cm in height with suprasellar extension (Fig. 1, A and B).
691
An initial visual field perimetry showedbitemporal visual field defects. Methods
All RIAs were performedusing a double antibody technique. PlasmaTSH levels wereassayedusingthe immunoradiometric assaytechnique, whereasthe immunoassayfor a-subunit was performed by previously published methodsof Kourides et al. (15-17).
Results Before the initiation of therapy, a TRH stimulation test was done which revealed a blunted TSH response. Basal and stimulated a-subunit levels were elevated, but the incremental increase after TRH was minimal (Fig. 2). The a-subunit to TSH molar ratio was greater than 1.0, both before and after the TRH stimulation test. The patient was placed on propylthiouracil (PTU) 200 mg orally three times a day (TID) which controlled his hypermetabolic state. However, repeat thyroid function tests after 11/2 months of PTU therapy showed a significant increase in the TSH level from 19 mU/L to 38 mU/ L. Because of his cardiomyopathy, it was decided to treat him pharmacologically rather than surgically. Octreotide acetate therapy 50 pg SC twice a day (BID) was commenced in January 1990, and PTU was discontinued. The dose of octreotide acetate was increased to 100 pg SC TID a week later. An initial posttherapy TSH level taken 3 weeks after commencement of therapy showed a significant decrease in TSH (Fig. 2). Repeat magnetic resonance imaging of the sella and the hypothalamus 13 weeks after beginning therapy with octreotide acetate showed a marked reduction in the size of the pituitary adenoma with only a mild upward bulging of the pituitary gland on the left side (Fig. 3, A and B). A repeat visual field perimetry study remained unchanged. Repeat TRH stimulation test at that time showed minimal increase in TSH response. a-Subunit levels during therapy were likewise significantly reduced to normal levels (Fig. 2). During the 9th week of therapy, the dose was tapered
1 FIG. 1. Pituitary adenoma before octreotide acetate therapy. A, PreGadolinium Tl-weighted spin-echo MR image (arrows) which compresses and displaces the optic chiasm upwards (curued arrows). B, Post-Gadolinium MR image shows marked enhancement of the suprasellar tumor (arrows). The pituitary stalk and the suprasellar cistern are completely obliterated by the tumor.
to 100 pg BID. Ten weeks later, it was further decreased to 50’ pg BID. Thyroid hormones remained within the euthyroid range (Fig. 4). The patient gained 10 kg over a period of 40 weeks of therapy, possibly due to remission of his hyperthyroidism. Abdominal ultrasonography was negative for cholelithiasis. Repeat visual field study at the 40th week of therapy still showed a bitemporal field defect. Follow-up hormonal studies were unchanged except for the reduction of LH from 47 IU/L to 25 IU/L (O-20 IU/L) and testosterone from 25 nmol/L to 4.5 nmol/L (12.5-34.3 nmol/L). Repeat LH and testosterone levels done 2 weeks later remained low at 21 IU/L and
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 05:24 For personal use only. No other uses without permission. . All rights reserved.
692
COMMENTS
JCE8zM.1992 Vo174.No3 2. ,Alpba-subunit
FIG. 2. A, TSH response; B, a-subunit response to TRH stimulation test before and during octreotide acetate therapy.
04
:1 0
IS
30
45
(UCW
60
0
15
Time (mIo)
A
-
befont
-
The
B
durIn6
3so Octrcotide
Acetate
-
b&m
30 (mln) -
45
60
durln6
(uglday)
300 250 200 150 100
50 0
0 5 ‘
2. TSH 1
9 11I5181154115055YJe4~45415t We&S
(mu/L)
- 0 5 6 , 1, I5 I* 7.1 54 7.7 30 15 56 ,e 45 45 45 5,
WC&S 3oo T4RIA
(nmol/L)
1 200 150
100
\
L
SO 250 0 i ---7 0 , ‘ 9 15 I5 $8 II 54 57 50 11 56 59 42 45 45 5, Wdt.9
T3RIA
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51 4 3
h
2
FIG. 3. Marked reduction of the pituitary adenoma size after octreotide acetate therapy. A, Pre-Gadolinium Tl-weighted MR image shows enhanced pituitary gland on the left side (black arrow). The pituitary stalk can now be visualized and is tilted towards the left (white arrow). B, Post-Gadolinium Tl-weighted MR image shows enhanced pituitary gland (arrows). Note the appearance and position of the optic chiasm is normal now (curved arrow) as compared with that on Fig. 1.
9.7 nmol/L, respectively. FSH level remained unchanged at 35 IU/L (O-20 IU/L). While on the lowest dose (50 pg SC BID), he started to complain of severe headache relieved by analgesics. For this reason, the dose of oc-
1 I------04 ~~~~~~~~~~~~ 1,. 1, a , ‘ , I2 I5 L, *, 7.4 51 5a 55 5‘ 5, 45 45 40 51 We&
FIG.
4. Effect of octreotide acetate on TSH, T4RIA, and T8RIA.
treotide acetate was increased to 100 pg BID, completely relieved the symptom.
which
Discussion Dopamine and somatostatin are known inhibitors of TSH secretion. A number of studies have described the
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inhibitory effect of somatostatin on TSH hypersecretion in patients with neoplastic inappropriate secretion of TSH, but the duration of action of the somatostatin was too short to demonstrate real utility (18-21). Octreotide acetate, a long-acting somatostatin analog, has been shown in recent studies not only to reduce TSH secretion in patients with pituitary adenomas but also to restore clinical and biochemical euthyroidism (11-14, 22, 23). The response of our patient to octreotide acetate confirmed its effectiveness (7, 11, 23). Moreover, its administration reduced not only TSH secretion but also (Ysubunit hypersecretion, which is the tumor marker of both gonadotropin and thyrotropin-producing pituitary adenomas. The initial TRH stimulation test on our patient demonstrated an elevated basal TSH with no increase in TSH secretion after TRH, as commonly seen in such patients. This could be due to autonomous neoplastic production of TSH, unresponsiveness to exogenous TRH and thyroid hormone unresponsiveness, as described by Kourides et al. (24) and Weintraub et al. (25), lack of TRH receptors or altered thyroid hormone receptors on the tumor cells, as suggested by Smallridge and Smith (26), or hyperthyroidism itself. A repeat TRH stimulation test during therapy resulted in a minimal increase in TSH level but not to optimal levels, suggesting an inhibitory effect of octreotide acetate on the normal thyrotrope. As the TSH was reduced to a euthyroid level, a-subunit levels also came down to normal. Aside from the significant biochemical improvement of our patient while on the medication, there was also a dramatic shrinkage of tumor size after only 13 weeks of therapy. Recent articles have demonstrated a similar result (5, 6) though not shown by previous studies (4, 7, 22, 23). Approximately 33% of TSH-producing pituitary adenomas may have concomitant hypersecretion of other anterior pituitary hormones (3,27) particularly PRL and GH. Of the 85 reported patients with TSH-secreting pituitary tumors, only two of these patients had elevated gonadotropin (2). Our patient appears to be the third patient with LH and FSH hypersecretion. Repeat gonadotropin levels obtained at the 40th week of therapy showed unchanged FSH but reduced LH levels with a subnormal testosterone level. These results suggest that the patient had a pituitary tumor also secreting LH and possibly FSH. The relatively low testosterone level with slightly elevated LH level in the absence of primary hypogonadism as seen in our patient has been demonstrated in men with gonadotropin-secreting tumors (2830). This could be due to the secretion of a mixture of biologically active and inactive LH by the tumor. The decrease in LH secretion during therapy with somatostatin supports the finding of Vos et al. (31) and suggests the presence of somatostatin receptors in this pituitary
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tumor (32, 33). Because our patient was treated medically, cell culture or immunocytochemistry analysis is not available for diagnostic confirmation. However, the persistent decrease of testosterone when LH was decreased during octreotide acetate treatment suggested the tumoral origin of the gonadotropin hypersecretion. Although more cases will need to be treated with octreotide acetate to determine how efficacious it is in TSH- and gonadotropin-secreting tumors, the excellent clinical and radiological response of our patient to octreotide acetate provides support for the use of this treatment modality. Acknowledgments
The authors wish to thank F. Xavier Pi-Sunyer, M.D. and Sami Hashim, M.D. for their critical review of the manuscript. We are also grateful to Steven Lichtman M.Ed. for his invaluable help in preparing the figures, to John Lee for performing the a-subunit assay, to Yim Dam, Georgette Cole, and especially to Victor Mascitelli, M.D. and Jeanine Albu, M.D. for their technical assistance. References 1. Hamilton Jr CR, Adams LC, Maloof F. Hyperthyroidism due to thyrotropin producing pituitary adenoma. N Engl J Med. 1970;283:1077-80. 2. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrino1 Metab Clin North Am. 1987;16:765-92. 3. Faglia G, Beck-Peccoz P, Piscitelli G, Medri G. Inappropriate secretion of thyrotropin by the pituitary. Horm Res. 198726: 79-99. 4. Gesundheit N, Petrick PA, Nissim M, et al. Thyrotropin-secreting pituitary adenoma clinical and biochemical heterogeneity, case reports and follow up of nine patients. Ann Intern Med. 1989;111:827-35. 5. Houdent Ch, Armangau MF, Kuhn JM, et al. Adenome thyreotrope traite par un analogue de la somatostatine. Ann Endocrinol (Paris). 1989;50:227-31. 6. Beckers A, Abs R, Mahler C, et al. Thyrotropin-secreting pituitary adenomas: report of seven cases. J Clin Endocrinol Metab. 1991;72:477-83. 7. Comi RJ, Gesundheit N, Murray L, Gorden P, Weintraub BD. Response of thyrotropin secreting pituitary adenomas to a long acting somatostatin analog. N Engl J Med. 1987;317:12-7. 8. Hill SA, Falks JM, Wilson CB, Hunt WE. Thyrotropin producing pituitary adenomas. J Neurosurg. 1982;57:51519. - 9. Weintraub BD. Petrick PA. Gesundheit N. Oldfield EH. TSHsecreting pituitary tumors. In: Medeiros-Neto GA, Gaitan E, eds. Frontiers in thyroidology, New York: Plenum 198671-7. 10. Takamatsu J, Mozai T, Kuma K. Bromocriptine therapy for hyuerthvroidism due to increased thvrotronin secretion. J Clin Endocrinol Metab. 1984;58:934-6. 11. Beck-Peccoz P, Mariotti S, Guillausseau PJ, et al. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with somatostatin analog SMS 201-995. J Clin Endocrinol Metab. 1989;68:208-14. 12. Siler TM, Yen SSC, Vale W, Guillemin R. Inhibition by somatostatin on the release of TSH induced in man by thyrotropin releasing factor. J Clin Endocrinol Metab. 1974;38:742-5. 13. Arimura A, Schally AV. Increase in basal and thyrotropin releasing hormone (TRH) stimulated secretion of thyrotropin (TSH) by passive immunization with antiserum to somatostatin in rats. Endocrinology. 1976;98:1069-72.
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14. Guillausseau PJ, Chanson PH, Timsit J, et al. Visual improvement with SMS 201-995 in a patient with thyrotropin secreting pituitary adenoma, (Letter). N Engl J Med. 1987;317:53-4. 15. Kourides IA. Weintraub BD. Levko A. Maloof F. Alnha and beta subunits of human thyrotropin: purification and development of specific radioimmunoassays. Endocrinology. 1974;94:1411-21. 16. Kourides IA, Weintraub BD, Ridgway EC, Maloof F. Pituitary secretion of free alpha and beta subunit of human thyrotropin in patients with thyroid disorders. J Clin Endocrinol Metab. 1975;40:872-85. 17. Kourides IA, Weintraub BD, Rosen SW, Ridgway EC, Kliman B, Maloof F. Secretion of alpha subunit of glycoprotein hormones by pituitary adenomas. J Clin Endocrinol Metab. 1976;43:97-106. 18. Spada A, Bassetti M, Martin0 E, et al. In vitro studies on TSH secretion and adenylate cyclase activity in a human TSH secreting pituitary adenoma: effects of somatostatin and dopamine. J Endocrinol Invest. 1985;8:193-8. 19. Waldhausl W, Bratusch-Marrain P, Nowotny P, et al. Secondary hyperthyroidism due to thyrotropin hypersecretion: study of pituitary tumor morphology and thyrotropin chemistry and release. J Clin Endocrinol Metab. 1979;49:879-87. 20. Lamberg BA, Pelkonen R, Gordin A, et al. Hyperthyroidism and acromegaly caused by a pituitary TSH and GH secreting tumor. Acta Endocrinol (Copenh). 1983; 103: 7-14. 21. Reschini E, Guistina G, Cantalamessa L, Peracchi M. Hyperthyroidism with elevated plasma TSH levels and pituitary tumor study with somatostatin. J Clin Endocrinol Metab. 1976; 43: 924-7. 22. Malarkey WB, Kovacs K, O’Dorisio TM. Response of a GH and TSH secreting pituitary adenoma to a somatostatin analog (SMS 201-995): evidence that GH and TSH co-exist in the same cell and secretory granules. Neuroendocrinology. 1989;49:267-74. 23. Wemeau JL, Dewailly D, Leroy R, et al. Long term treatment with
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