Thyrotropin-secreting pituitary tumor and Hashimoto's Disease: a novel association.

Abstract: A 69-year-old man was referred for elevated thyroid hormone levels. He had no symptoms apart from mild hyperhidrosis and heat intolerance with occasional headaches. Past medical history included a right hemithyroidectomy for a multinodular goiter and Hashimoto's disease. At presentation the patient had a firm, slightly enlarged left thyroid lobe. There were no visual abnormalities, and the rest of the physical findings were unremarkable. Laboratory findings included elevated values of flee [T.sub.4], free [T.sub.3], total [T.sub.3], thyrotropin-secreting hormone (TSH), antithyroglubulin, and antimicrosomal antibodies. Normal values were found for cortisol, prolactin, testosterone, follicle-stimulating hormone, luteinizing hormone, [alpha]-subunit, and thyroid-stimulating immunoglobulin. Thyroid [sup.123]I scan showed an increased 5-hour uptake of 23% and a 24-hour uptake of 53% with a diffuse uniform enlargement of the left side. TSH level did not increase after a thyrotropin-releasing hormone stimulation test. Serum sex hormone binding globulin was elevated. Magnetic resonance imaging of the pituitary revealed a pituitary macroadenoma with suprasellar extension to the optic chiasm. Histologic examination of the adenoma after transsphenoidal hypophysectomy showed cells that stained positive for TSH. TSH-secreting pituitary adenomas account for 1% of functioning pituitary tumors and are an exceedingly rare cause of hyperthyroidism. To our knowledge, this is the first report of pituitary tumor inducing hyperthyroidism in the setting of Hashimoto's disease. There is a possibility that TSH elevation related to Hashimoto's disease might have contributed to the development of a TSH-secreting pituitary adenoma.

Key Words: Hashimoto's disease, hyperthyroidism, pituitary hormonal resistance, thyrotropin-secreting pituitary adenoma

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Hypothalamic thyrotrupin-releasing hormone (TRH) is the main positive regulator of thyrotropin (TSH) secretion. TSH is secreted by the pituitary and stimulates several steps of thyroid hormone production. Direct negative feedback inhibition of thyroid hormones on hypothalamic TRH and pituitary TSH are integrated for better control of thyroid stimulation. Inappropriate secretion of TSH is seen in patients who have elevated TSH levels despite elevated serum thyroid hormones. It usually results from either a TSH-secreting pituitary adenoma or from a nontumorous TSH hypersecretion as a result of thyroid hormone resistance. To differentiate between those two entities a TRH stimulation test is often obtained. It shows significant elevation of TSH in thyroid hormone resistance but blunted response in pituitary tumors. Increased levels of [alpha]-subunit and serum sex hormone binding globulin are also suggestive of pituitary tumor rather than hormonal resistance. TSH-secreting pituitary adenomas account for 1 to 2% of functioning pituitary tumors and are an exceedingly rare cause of hyperthyroidism. These tumors produce excessive TSH with resultant thyrotoxicosis. We report a case of a pituitary tumor inducing hyperthyroidism in the setting of Hashimoto's disease.

Case Report

A 69-year-old man was referred for elevated serum [T.sub.3] and [T.sub.4]. He had been generally asymptomatic except for mild hyperhidrosis, mild heat intolerance, and an occasional headache. Three years ago he was noted to have a multinodular goiter with cold areas on ultrasound scans. Thyroid fine-needle biopsy was reported as follicular neoplasm, and the patient had a right hemithyroidectomy, which revealed a multinodular goiter. Antithyroglobulin, antithyroperoxidase antibodies, and serum TSH levels were elevated, and the patient was diagnosed with Hashimoto's disease and started on thyroid replacement therapy. His medical history included non-insulin-dependent diabetes, resection of prostatic adenocarcinoma, and anemia of chronic disease. His medications were acetaminophen, aspirin, buspirone, fexofenadine, flunisolide, furosemide, glipizide, hydralazine, Synthroid, metformin, morphine, potassium chloride, prazosin, quetiapine, timolol, and venlafaxine. He is a nonsmoker and nonalcoholic, and denies drug abuse. No thyroid disorder was noted in his family. His review of systems was negative for palpitations, nervousness, disturbed bowel function, tremor, and visual abnormality. The patient had a 25-pound weight gain during the previous year and has remained active with housework. On physical examination, he had normal vital signs except for a pulse of 50 beats/min. He had normal visual fields and normal extraocular and palpebral movement. The head examination was unremarkable. His left thyroid lobe was enlarged, firm, and nontender. The chest, heart, lung, and abdominal examinations were unremarkable. The neurologic examination was normal.

After undergoing thyroidectomy, he was placed on thyroid replacement, but his [T.sub.3] and [T.sub.4] levels started to increase with persistent elevation in TSH levels. L-Thyroxine was gradually decreased and then stopped. He was referred to the endocrine clinic for further management. Laboratory findings included elevated values of free [T.sub.4], free [T.sub.3], total [T.sub.3], TSH, antithyroglobulin, and antimicrosomal antibodies. Normal values were found for cortisol, prolactin, testosterone, follicle-stimulating hormone, luteinizing hormone. [alpha]-subunit, and thyroid-stimulating immunoglobulin. Serum sex binding globulin was elevated (Table 1). His hemoglobin was 10.2 g/dl (hematocrit, 31.1%) with a normal white blood cell count. His liver function test and electrolytes were normal. His basal TSH of 7.4 [micro]IU/ml increased to 9.5 [micro]IU/ml after 500 [micro]g of IV TRH. A thyroid [sup.123]1 scan showed an increased 5-hour uptake of 23% and a 24-hour uptake of 53% with a diffuse uniform enlargement of the left side (Table 2 and Fig. 1). A head magnetic resonance imaging (MRI) scan showed pituitary enlargement suggestive of adenoma with suprasellar extension reaching but not compressing the optic chiasm (Fig. 2). The visual field examination via the perimetry was normal. The patient was referred for surgical intervention.

[FIGURE 1 OMITTED]

Discussion

To our knowledge this is the first report of a pituitary tumor inducing thyrotoxicosis in the setting of Hashimoto's disease. TSII-secreting pituitary adenomas are a rare cause of hyperthyroidism. They account for less than 2% of all functioning pituitary tumors. (1) Approximately 25% of pituitary adenomas secrete one or more other pituitary hormones including growth hormone, prolactin, and rarely gonadotropins. (2) The molecular basis of TSH-secreting adenomas is not known, but could be the result of somatic mutations or abnormal oncogene expression. Some studies demonstrate evidence of overexpression of pituitary-specific transcription factor-1. (3,4)

In our patient, inappropriate secretion of TSH was noted in the presence of elevated serum thyroid hormones. A TRH stimulation test was performed to distinguish thyroid hormone resistance and pituitary tumor-mediated hyperthyroidism. (5,6) The limited TSH elevation in response to TRH is consistent with a pituitary tumor. The elevated sex hormone binding globulin indicates normal peripheral action of thyroid hormone and makes thyroid hormone resistance less likely. (7) Serum [alpha]-subunit was not elevated; however, this may occur in 15% of pituitary tumors. (8) An MRI showed a pituitary macroadenoma, and transsphenoidal hypophysectomy was performed. Surgical histopathology showed a pituitary adenoma staining positive for TSH and human growth hormone and negative for adrenocorticotropin, luteinizing hormone, follicle-stimulating hormone, and prolactin. The patient had no clinical evidence of acromegaly. Six weeks postoperatively TSH levels improved to normal (2.6 [micro]IU/ml).

Pituitary pseudotumor (pituitary thyrotroph hyperplasia) caused by unrecognized and untreated hypothyroidism has been described as a rare condition, mostly in adults. (9-11) To our knowledge, this is the first report of a pituitary tumor inducing hyperthyroidism in the setting of Hashimoto's disease. It is interesting to speculate whether chronic TSH elevation may have contributed to the development of a TSH-secreting pituitary adenoma.

Key Points

* Patient with inappropriately elevated thyrotropin (TSH) in the setting of high free [T.sub.4] and [T.sub.3].

* TSH-secreting pituitary adenoma in the setting of Hashimoto's disease.

* Chronic TSH elevation secondary to Hashimoto's disease may have contributed to the development of a TSH-secreting pituitary adenoma.

Table 1. Laboratory data (a)

                                          Patient's          Normal
Laboratory test                            values           reference

Free [T.sub.4] (ng/dl)                     2.5-3.0           0.7-1.8
Free [T.sub.3] (pg/ml)                       8.1             2.3-4.2
Total [T.sub.3] (RIA) (ng/dl)              195-359            60-181
TSH ([micro]IU/ml)                         5.9-9.5          0.38-4.7
FTI (free [T.sub.4] index)                   6.4               2-3.6
Antithyroglobulin
  (IU/ml)                                   2,770            0.5-55
  (ng/ml)                                  11,357              0-60
Thyroid-stimulating immunoglobulin           96                0-130
  (%)
Antithyroperoxidase (IU/ml)                  331               0-34
Sex hormone binding globulin                 127              13-71
  (mnol/L)
RAIU (radioactive [sup.123]I              23 at 5 h       10-30 at 24 h
  uptake) (%)                            53 at 24 h
TSH [alpha]-subunit (mIU/ml)                 0.9             0.0-1.1
Prolactin (ng/ml)                            8.1             2.1-17.7
Testosterone (ng/dl)                         348             241-827
Cortisol ([micro]g/dl)                       6.7             4.5-22.7
ACTH                                         24
FSH (mIU/L)                                  3.0              14-18
LH (mIU/L)                                   64              1.5-93
TSH response (TRH stimulation test)    9.5 (from basal    Elevation 2X
  ([micro]IU/ml)                           of 7.4)          or more

(a) RIA, radioimmunoassay; ACTH, adrenocorticotropic hormone; FSH,
follicle-stimulating hormone; LH, luteinizing hormone.

Table 2. Radiologic studies (a)

Thyroid FNA (fine-needle
  aspiration)                    Follicular neoplasm
Thyroid surgical cytopathology
  (Sept 1999)                    Right thyroid: multinodular goiter
                                   with dominant nodule
Thyroid ultrasound (July 2001)   Absent right lobe (from hemithyroi-
                                   dectomy). Left lobe with compensa-
                                   tory hypeiplasia, diffusely abnormal
                                   heterogeneous echogenic pattern,
                                   with two semicystic lesions scat-
                                   tered in the upper and midsection of
                                   the left lobe and a complex nodule
                                   in the lower pole of unknown nature.
Thyroid scan (RAIU) (Aug 2001)   The left lobe of the thyroid is
                                   enlarged and shows increased radio-
                                   nuclide uptake. No focal area of
                                   nodularity is noted. A diffuse uni-
                                   form enlargement is seen. The 5-h
                                   uptake was increased The 24h uptake
                                   was also increased (53%).
Head MRI (Aug 2001)              Pituitary macroadenoma, 1.8 x 1.8 x
                                   1.5 cm, with suprasellar extension
                                   abutting but not compressing the
                                   optic chiasin.
Pituitary tumor surgical
  histopathology                 Pituitary adenoma: extensive tumor
                                   architecture on reticulin staining.
                                   Staining showed diffuse faint posi-
                                   tivity for TSH, stronger positivity
                                   for human growth hormone; staining
                                   was negative for ACTH, LH, FSH, and
                                   prolactin.

(a) RAUI, radioactive [sup.123]I uptake; ACTH, adenocorticotropin;
LH, luteinizing hormone; FSH, follicle-stimulating hormone.

Acknowledgment

We are indebted to the Mountain Home VAMC Medical Media Department and Doug N. Allen for assistance with the illustrations.

References

(1.) Gesundheit N, Petrick PA, Nissim M, Dahlberg PA, Doppman JL, Emerson CH, et al. Thyrotropin-secreting pituitary adenomas: Clinical and biochemical heterogeneity--Case reports and follow-up of nine patients. Ann Intern Med 1989:111:827-835.

(2.) Beck-Peccoz P. Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996; 17:610-638.

(3.) Pellegrini I, Barlier A. Gunz G, Figarella-Branger D, Enjalbert A, Grisoil F, et al. Pit-1 gene expression in the human pituitary and pituitary adenomas. J Clin Endocrinol Metab 1994;79:189-196.

(4.) Brucket-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999;84:476 486.

(5.) Safer JD, Colan SD, Fraser LM, Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: A diagnostic dilemma. Thyroid 2001;11:281-291.

(6.) Akiyoshi F, Okamura K, Fujikawa M, Sato K, Yoshinari M. Mizokami T, et al. Difficulty in differentiating thyrotropin secreting pituitary microadenoma from pituitary-selective thyroid hormone resistance accompanied by pituitary incidentaloma. Thyroid 1996;6:619 625.

(7.) Beck-Peccoz P, Roncoroni R, Mariotti S, Medri G, Marcocci C, Brabant G, et al. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): Evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab 1990;71:19-25.

(8.) Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14:348-399.

(9.) Kocova M, Netkov S, Sukarova-Angelovska E. Pituitary pseudotomor with unusual presentation reversed shortly aider the introduction of thyroxin replacement therapy. J Pediatr Endocrinol Metab 2001;14:1665-1669.

(10.) Manocha SM, Moulick ND, Shah NS. Primary hypothyroidism presenting as a pituitary gland enlargement with regression following thyroxine therapy. J Assoc Physicians India 2000;48:651.

(11.) Alkhani AM, Cusimano M, Kovacs K, Bilbao JM, Horvath E, Singer W. Cytology of pituitary thyrotroph hyperplasia in protracted primary hypothyroidism. Pituitary 1999;1:291-295.

From the Veterans Affairs Medical Center, Mountain Home, TN, and the Division of Endocrinology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Alan N. Peiris, MD, PhD, Mountain Home VAMC and Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Dogwood Avenue, Box 70622, Johnson City, TN 37604-1709. Email: [e-mail]

Accepted October 14, 2002.

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