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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 708-711
Copyright © 2004 by The Endocrine Society

Treatment of Hyperthyroidism Associated with Thyrotropin-Secreting Pituitary Adenomas with Iopanoic Acid

Kimvir S. Dhillon, Pejman Cohan, Daniel F. Kelly, Christine H. Darwin, Kris V. Iyer and Inder J. Chopra

Department of Medicine, Division of Endocrinology, and Gonda Diabetes Center (K.S.D., P.C., C.H.D., I.J.C.), and Department of Surgery (D.F.K.), Division of Neurosurgery, University of California, Los Angeles School of Medicine; University of California, Los Angeles Pituitary Tumor and Neuroendocrine Program (K.S.D., P.C., D.F.K., C.H.D., I.J.C.), Los Angeles, California 90024; and Hoag Memorial Hospital (K.V.I.), Newport Beach, California 92658

Address all correspondence and requests for reprints to: Pejman Cohan, M.D., 200 UCLA Medical Plaza, Suite 530, Los Angeles, California 90095-7065. E-mail: pcohan{at}mednet.ucla.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results and Discussion
 References
 
TSH-secreting tumors comprise less than 2% of all pituitary adenomas. All patients present with hyperthyroidism with a detectable TSH level, and a majority have macroadenomas. Oral cholecystographic agents (e.g. iopanoic acid) potently inhibit the activation of T4 to the more potent T3. They have been used successfully to treat primary thyroidal hyperthyroidism and thyroxine overdose. However, they have not been employed in the treatment of central hyperthyroidism. We report, herein, the first two patients with thyrotropinomas, in whom iopanoic acid (Telepaque) has been used perioperatively to safely and rapidly achieve euthyroidism. In case 1, free T3 index improved from a value of 634 to 175 (normal range 78–162) after 3 d of therapy with iopanoic acid. In case 2, free T3 by dialysis improved from 697 pg/dl (10.7 pmol/liter) to 195 pg/dl (3.0 pmol/liter) (normal range 210–440 pg/dl; 3.2–6.7 pmol/liter) after 7 d of therapy with iopanoic acid.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results and Discussion
 References
 
TSH-SECRETING PITUITARY tumors are rare, comprising less than 2% of all pituitary tumors (1). Clinically, these patients present with hyperthyroidism with elevated serum-free T4 and free T3 levels, with inappropriately normal or elevated serum TSH. The majority of patients present with macroadenomas, possibly due to a delay in diagnosis. Definitive treatment of patients with a thyrotropinoma is transsphenoidal removal of the tumor (1, 2, 3). Preoperative management of these patients mandates restoring euthyroidism to minimize the risk of intraoperative and postoperative complications. Classically, somatostatin analogs, antithyroid medications, or a combination of these drugs are used preoperatively to normalize serum T4 and T3 levels. However, both of these drugs require several weeks of treatment before euthyroidism can be achieved, and in some patients they are associated with significant adverse reactions and treatment failures.

Oral cholecystographic agents (OCAs) have been used successfully to rapidly restore euthyroidism in patients with common forms of hyperthyroidism such as Graves’ disease, thyroiditis, or thyrotoxicosis factitia due to levothyroxine overdose. OCAs potently inhibit the conversion of T4 to the more biologically active T3, and the iodine liberated from the metabolism of OCAs helps to significantly decrease release of these hormones from the thyroid gland through the Wolf-Chaikoff effect. To our knowledge, there is no previous report of using OCAs to treat central (pituitary) hyperthyroidism. We report herein the first two patients with thyrotropinomas, in whom iopanoic acid (Telepaque) has been used successfully perioperatively to rapidly achieve euthyroidism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results and Discussion
 References
 
Case 1

A 38-yr-old male was evaluated at University of California, Los Angeles Medical Center in September 2002 for thyrotoxicosis. Six weeks before presentation, he had presented to an outside emergency department with palpitations and was found to be tachycardic and hypertensive. Thyroid function testing at that time revealed a TSH of 5.74 mIU/liter (normal range 0.46–4.68), Free T4 elevated at 4.43 ng/dl (57 pmol/liter) [normal range 0.7–2.2 ng/dl; 9.0–28 pmol/liter], and free T3 elevated at 1030 pg/dl (15.8 pmol/liter) [normal range 210–440 pg/dl; 3.2–6.7 pmol/liter]. Thyroid ultrasonography revealed bilateral thyromegaly with multiple small nodules. I-123 thyroid uptake scan revealed elevated homogeneous radioiodine uptake of 41% at 7 h, and 51% at 24 h (normal range 6–30%). Magnetic resonance imaging (MRI) of the pituitary demonstrated a 7 x 6 x 5-mm area of decreased enhancement within the sella turcica, consistent with a pituitary tumor. There was no evidence of cavernous sinus invasion, optic chiasmal compression, or stalk deviation (Fig. 1Go). The patient had been treated with methimazole at doses up to 45 mg daily for the previous 6 wk. However, he remained thyrotoxic and was noted to have a generalized pruritic maculopapular skin rash. Serum TSH was 5.4 mIU/liter (normal range, 0.3–4.7), free T4 (FT4) index 39.8 (normal range, 4.5–10.5), FT4 by dialysis 8.0 ng/dl (103 pmol/liter), free T3 (FT3) by dialysis 1100 pg/dl (16.8 pmol/liter) and FT3 index 634 (normal range, 78–162), undetectable thyroid antibodies, {alpha}-subunit 0.5 ng/ml (34.5 pmol/liter) [normal <1.0 ng/ml; < 69 pmol/liter], and {alpha}-subunit/TSH molar ratio of 9.2 (normal, <5.7). Euthyroidism was achieved soon after starting iopanoic acid 500 mg bid (twice daily) and substituting propylthiouracil (450 mg/d) for methimazole due to the skin rash. After five doses of iopanoic acid, the FT3 index dropped from 634 to 175.



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  		FIG. 1. Preoperative gadolinium-enhanced sagittal and coronal MRIs in case 1. Microadenoma seen in left anterior aspect of sella (arrows).

 
The patient subsequently underwent uncomplicated endonasal transsphenoidal resection of the pituitary adenoma. Histopathological analysis and immunostaining indicated a pituitary adenoma with strong immunoreactivity only for TSH. On postoperative d 1, TSH dropped to 0.65 mIU/liter with FT3 index 136 (normal range, 78–162) and FT4 index 36.2 (normal range, 4.5–10.5). On postoperative d 4, iopanoic acid was discontinued after near normalization of T4 and T3 with TSH 0.13 mIU/liter (normal range, 0.46–4.68), FT4 by dialysis 3.70 ng/dl (47.6 pmol/liter), and FT3 by dialysis 200 pg/dl (3.06 pmol/liter). Close monitoring of thyroid function tests over the ensuing 2 months revealed a persistently suppressed serum TSH level, with normal FT4 concentration (Fig. 2Go). On post postop d 7, {alpha}-subunit/TSH molar ratio had decreased markedly to 2.9 (normal, <5.7). Three-month postoperative MRI showed no evidence of residual tumor.



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  		FIG. 2. Serum FT3, FT4, and TSH in case 1 before and after pituitary surgery. The arrows indicate the administration of specific agents. The shaded area indicates the normal range for FT3, FT4, and TSH, respectively.

 
Case 2

A 32-yr-old female was evaluated at UCLA Medical Center in September 2002 for thyrotoxicosis. One year earlier in August 2001, she reported symptoms of fatigue, tremor, anxiety, heat intolerance, and insomnia with thyroid function testing revealing an elevated FT4 of 2.79 ng/dl (35.9 pmol/liter), normal TSH of 1.86 mIU/ml (normal range, 0.47–6.20), and negative thyroid antibodies. In December 2001, I-123 thyroid uptake scan showed homogeneously elevated uptake of 23.4% at 5 h (normal 5–15%) and high normal uptake of 36% at 24 h (normal 16–36%) without evidence of nodules or masses. The patient had been misdiagnosed with Graves’ disease and treated with methimazole (10 mg/d) and atenolol for 6 months before transferring her care to UCLA in September 2002. On presentation at UCLA, the patient remained thyrotoxic with an elevated FT3 by dialysis of 697 pg/dl (10.7 pmol/liter), FT4 by dialysis of 4.4 ng/dl (56.6 pmol/liter), with a normal TSH of 2.4 mIU/liter (0.3–4.7), {alpha}-subunit of 1.0 ng/ml (69 pmol/liter), and {alpha}-subunit/TSH molar ratio of 41.6 (normal, <5.7). Pituitary MRI disclosed a 13 x 12 x 10-mm sellar mass (Fig. 3Go). Treatment with iopanoic acid 500 mg bid and propylthiouracil 150 mg three times a day was started 11 d before pituitary resection. After 7 d on iopanoic acid and propylthiouracil, FT3 by dialysis decreased to 195 pg/dl (3.0 pmol/liter) and FT4 by dialysis to 3.5 ng/dl (45.0 pmol/liter) with a serum TSH of 3.8 mIU/liter.



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  		FIG. 3. Preoperative gadolinium-enhanced sagittal and coronal MRIs in case 2. Macroadenoma seen in right and central aspect of sella (arrows).

 
The patient underwent uncomplicated endonasal transsphenoidal resection of the pituitary tumor in October 2002. Histopathological analysis and immunostaining indicated a pituitary adenoma with strong immunoreactivity only for TSH. Postoperatively, propylthiouracil was discontinued, but iopanoic acid was continued at a dose of 500 mg bid. On postop d 1, TSH dropped to 0.08 mIU/liter (normal range, 0.3–4.7), FT3 index to 66 (normal range, 78–162), and FT4 index to 13.3 (normal range, 4.5–10.5). On postoperative d 17, TSH normalized to 1.58 mIU/liter (normal range, 0.3–4.7), FT4 by dialysis to 0.93 ng/dl (12.0 pmol/liter), and {alpha}-subunit/TSH molar ratio to 0.7 (normal <5.7). On postop d 24, TSH remained normal at 1.45 mIU/liter and FT4 by dialysis at 0.95 ng/dl (12.2 pmol/liter). Two months after surgery, serum total T3 dropped to 68 ng/dl (1.05 nmol/liter) (normal range 70–180 ng/dl; 1.08–2.77 nmol/liter), with a TSH of 1.2 mIU/liter and {alpha}-subunit/TSH molar ratio of 0.9 at which time iopanoic acid was discontinued. After 3 months, the patient remained euthyroid with a normal TSH of 1.01 mIU/liter, FT3 by dialysis of 301 pg/dl (4.60 pmol/liter), FT4 by dialysis of 2.0 ng/dl (25.7 pmol/liter), {alpha}-subunit/TSH molar ratio of 0.7 (Fig. 4Go). Three-month postoperative MRI shows no evidence of residual tumor.



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  		FIG. 4. Serum FT3, FT4, and TSH in case 2 before and after pituitary surgery. The arrows indicate the administration of specific agents. The shaded area indicates the normal range for FT3, FT4, and TSH, respectively.

 

   Results and Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results and Discussion
References
 
Iopanoic acid (Telepaque) is an OCA with high iodine content of 67% by weight (4). It potently and reversibly inhibits type I 5'-deiodinase activity, thereby reducing peripheral T3 production. Hepatic metabolism of iopanoic acid releases large amounts of inorganic iodine into the circulation, resulting in the suppressive effects of iodine on thyroid hormone release and synthesis, later by the involvement of the Wolff-Chaikoff effect (5, 6). Treatment of hyperthyroid patients with iopanoic acid rapidly reduces serum T3 concentration to near normal levels within 24–36 h and generally normalizes it within 2–5 d after initiation of treatment. Interestingly, most studies have demonstrated little or no adverse effects with short or long-term treatment with OCAs. These properties of OCAs have made them a useful adjunct in the treatment of patients with primary (thyroidal) hyperthyroidism, including Graves’ disease, amiodarone-induced thyroiditis, subacute thyroiditis, and thyrotoxicosis factitia (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).

Conventional treatment of primary hyperthyroidism with antithyroid drugs generally takes 4–6 wk to restore euthyroidism. The ability of OCAs to rapidly reduce peripheral T3 formation and inhibit synthesis and release of thyroid hormones by the thyroid gland has made them highly effective drugs in the preoperative management of patients with primary hyperthyroidism. Thus, Baeza et al. described the use of iopanoic acid in conjunction with propanolol and betamethasone to normalize serum-free T4 and T3 within 5 d in patients with severe hyperthyroidism (21). Similarly, we and others have used the OCA sodium ipodate (Oragrafin) alone or in combination with propylthiouracil and propanolol to restore euthyroidism within 3–4 d in patients with Graves’ disease before thyroidectomy (7). However, to date, there have been no reports on the use of OCAs to treat secondary (pituitary-mediated) hyperthyroidism.

Thyrotropinomas are a rare cause of central hyperthyroidism. Definitive treatment of these tumors involves surgical resection. Conventionally, preoperative management of these tumors involves restoring euthyroidism either from suppression of TSH with somatostatin analogs or through inhibition of thyroid hormone synthesis by antithyroid drugs. However, somatostatin analogs fail to restore euthyroidism in up to 25% of patients, and their use can be limited due to their side effect profile (22, 23, 24). As exemplified by the two cases presented herein, antithyroid medications have also been associated with treatment failures, either from their inability to restore euthyroidism, possibly related to persistent unregulated TSH secretion by the pituitary tumor, or due to the development of adverse reactions (25, 26, 27). Additionally, their use is complicated by the need for prolonged treatment (frequently 4–6 wk) with these drugs to restore euthyroidism.

The two cases presented herein demonstrate the first reported use of OCAs in the treatment of hyperthyroidism associated with thyrotropinomas. The use of iopanoic acid allowed for safe and rapid normalization of serum-free T4 and T3 levels in these two patients in whom antithyroid drugs had failed to restore euthyroidism for prolonged periods. Treatment with OCAs allowed our patients to undergo prompt and safe transsphenoidal resection of the pituitary tumor with subsequent remission of hyperthyroidism and hopefully a long-term cure of their disease.

The safety and efficacy profile of OCAs makes them highly effective drugs in the preoperative management of thyrotropinomas, particularly in those patients who require early surgery and those who have failed to achieve euthyroidism with conventional drugs including thionamides and somatostatin analogs or when these drugs are contraindicated. We find that the short-term use of OCAs offer an effective alternative for treating the hyperthyroidism associated with TSH-secreting pituitary adenomas, in preparation for pituitary surgery. Further studies with OCAs will be helpful in establishing their relative efficacy in controlling hyperthyroidism associated with thyrotropinomas, compared with antithyroid drugs and somatostatin analogs.


   Footnotes
 
Abbreviations: FT3, Free T3; FT4, free T4; MRI, magnetic resonance imaging; OCA, oral cholecystographic agent.

Received September 22, 2003.

Accepted October 31, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results and Discussion
 References
 

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