TSH-secreting pituitary tumours

P Beck-Peccoz, MD

Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Milan, Italy

Summer School 11-14 July 2006
The Møller Centre, Storeys Way, Cambridge, UK

Hyperthyroidism resulting from excessive thyroid stimulation by thyrotropin (TSH) is rare. However, since the advent of ultrasensitive TSH immunometric assays as first line test for thyroid function evaluation, an increased number of patients with normal or elevated levels of TSH in the presence of high free thyroid hormone (FT4 and FT3) concentrations have been recognized. In this situation, thyroid hormone negative feedback mechanism is clearly disrupted and TSH itself is responsible for the hyperstimulation of the thyroid gland and the consequent thyroid hormone hypersecretion.

Central hyperthyroidism is mainly due to an autonomous TSH hypersecretion from a TSH-secreting pituitary adenoma (TSH-oma). However, signs and symptoms of hyperthyroidism accompanied by biochemical findings similar to those found in TSH-omas, may be recorded in some patients affected with resistance to thyroid hormones (RTH). This form of RTH is named pituitary RTH (PRTH), as the resistance to thyroid hormone action appears more severe at the pituitary than at the peripheral tissue level. The clinical importance of these rare entities is based on the diagnostic and therapeutical challenges they present. Failure to recognize these different diseases may result in dramatic consequences, such as improper thyroid ablation in patients with central hyperthyroidism or unnecessary pituitary surgery in RTH patients. Conversely, early diagnosis and correct treatment of TSH-omas may prevent the occurrence of neurological complications, such as visual defects by compression of the optic chiasm, or hypopituitarism, and should improve the rate of cure.

TSH-omas are rare tumors and account for about 0.5%-1% of all pituitary adenomas. Since the prevalence in the general population of all pituitary adenomas is estimated 0.02%, the prevalence of TSH-omas is about one case per million. However, this figure is probably underestimated as the number of reported cases of TSH-omas tripled in the last decade, reaching more than 300 cases.

Patients with TSH-oma present with signs and symptoms of hyperthyroidism that are frequently associated with those related to the copressive effects of the tumour. Clinical features of hyperthyroidism are sometimes milder than expected on the basis of circulating FT4/FT3 levels, likely due to the slowly progressive onset of hyperthyroidism. In some acromegalic patients, signs and symptoms of hyperthyroidism may even be clinically missed, as they are overshadowed by those of acromegaly. The presence of a goiter is the rule, even in patients with previous thyroidectomy, since thyroid residue may regrow as a consequence of TSH hyperstimulation. Occurrence of uni- or multinodular goiter is frequent (about 72% of reported cases), whereas differentiated thyroid carcinomas were documented at least in few cases, indicating the need of a careful evaluation and monitoring of thyroid nodules in patients with TSH-omas. Progression towards functional autonomy seems to be infrequent. In contrast with Graves’ disease, the occurrence of circulating antithyroid autoantibodies is similar to that found in the general population.

Most patients bearing a TSH-secreting macroadenoma seek medical attention with signs or symptoms of an expanding intracranial tumor. Indeed, as a consequence of tumor suprasellar extension or invasiveness, signs and symptoms of tumor mass prevail over those of thyroid hyperfunction in many patients. Partial or total hypopituitarism is seen in about 25% of cases.

Serum TSH levels in the patients with TSH-oma and intact thyroid may be elevated or in the normal range, whereas total and free TH levels are definitely high. Variations of the biological activity of secreted TSH molecules most likely account for the findings of normal TSH in the presence of high levels of FT4 and FT3. Recent studies indicate that TSH molecules secreted by pituitary tumors may have either normal, reduced, or increased ratio between their biological and immunological activities, probably due to modification of glycosylation processes secondary to alterations of the post-traslational processing of the hormone within the tumoral cell. Interestingly, TSH levels are dramatically higher in patients previously treated with thyroid ablation despite they still present FT4/FT3 levels into the hyperthyroid range, suggesting that tumoral thyrotroph cells may increase their TSH secretion in response to an even small reduction in TH levels. Therefore, while tumoral thyrotrophs are totally or partially resistant to the inhibitory action of elevated TH levels, they show a preserved or even increased sensitivity to the reduction of circulating TH levels.

A helpful diagnostic tool for the diagnosis of a TSH-oma is the determination of the concentrations of the a-subunit common to each of the glycoprotein hormones, which are elevated in the majority of subjects. Secretion of the a-subunit in these tumors is in excess not only of the TSHb subunit but also of the intact TSH molecule. This results in a a-subunit/TSH molar ratio which is generally higher than 1. Although previous studies have suggested that a ratio above 1 is indicative of the presence of a TSH-oma, similar values may be recorded in normal subjects, particularly in euthyroid postmenopausal women, indicating the need for appropriate control groups matched for TSH and gonadotropin levels. Interestingly, microadenomas that frequently have a-subunit levels within the normal range may show high a-subunit/TSH molar ratio, further strengthening the importance of this index.

The measurements of several parameters of peripheral thyroid hormone action have been proposed to quantify the degree of tissue hyperthyroidism. Some of them are measured in vivo (basal metabolic rate, cardiac systolic time intervals, Achilles” reflex time) and others in vitro (sex hormone-binding globulin: SHBG, cholesterol, angiotensin converting enzyme, osteocalcin, blood red cell sodium content, carboxyterminal cross-linked telopeptide of type I collagen (ICTP), etc.). Liver (such as SHBG) and bone parameters (such as ICTP), in particular, have been successfully used to differentiate hyperthyroid patients with TSH-oma from those with PRTH. In fact, as it occurs in the common forms of hyperthyroidism, patients with TSH-oma have high SHBG and ICTP levels, while they are into the normal range in patients with hyperthyroidism due to PRTH.

Both stimulatory and inhibitory tests had been proposed for the diagnosis of TSH-oma. Classically, T3 suppression test has been used to assess the presence of a TSH-oma. A complete inhibition of TSH secretion after T3 suppression test (80-100 µg/day per 8-10 days) has never been recorded in with TSH-oma. In particular, in the patients with previous thyroid ablation T3 suppression seems to be the most sensitive and specific test in assessing the presence of a TSH-oma. Obviously, this test is strictly contraindicated in elderly patients or those with coronary heart disease. TRH test is another test that has been widely used to investigate the presence of a TSH-oma. In the 83% of patients, TSH levels do not increase after TRH injection. The lack of TSH response to TRH may also be useful in unusual situation where TSH-oma coexists with primary hypothyroidism.

As with other tumors of the region of the sella turcica, nuclear magnetic resonance imaging (MRI) is nowadays the preferable examination for the visualization of a TSH-oma. High-resolution computed tomography (CT) is the alternative investigation in the case of contraindications, such as in patients with pace-maker. Most TSH-omas were diagnosed at the stage of macroadenomas, and various degrees of suprasellar extension or sphenoidal sinus invasion were seen in two thirds of cases. Microadenomas are now reported with increasing frequency, accounting for about 13% of all recorded cases in both clinical and surgical series. Recently, pituitary scintigraphy with radiolabeled octreotide (octreoscan) has been shown to successfully localize TSH-omas expressing somatostatin receptors. However, the specificity of octreoscan is low, since positive scans can be seen in the case of a pituitary mass of different types, either secreting or non-secreting.

When the existence of central hyperthyroidism is confirmed, several diagnostic steps have to be carried out to differentiate a TSH-oma from PRTH. Indeed, the presence of neurological signs and symptoms (visual defects, headache) of an expanding intra-cranial mass or clinical features of concomitant hypersecretion of other pituitary hormones (acromegaly, galactorrhea, amenorrhea) points to the presence of a TSH-oma. The presence of alterations of pituitary content at MRI or CT scan strongly supports the diagnosis of TSH-oma. Nevertheless, the differential diagnosis may be difficult when the pituitary adenoma is very small, or in the case of confusing lesions, such as an empty sella or ectopic tumours. Moreover, the possible presence of pituitary incidentalomas should always be considered, due to their frequent occurrence.

No significant differences in age, sex, previous thyroid ablation, TSH or FT4/FT3 concentrations occur between patients with TSH-oma and those with RTH. However, in contrast with RTH patients, familial cases of TSH-oma have never been documented. Serum TSH levels within the normal range are more frequently found in RTH, while elevated a-subunit concentrations and/or high a-subunit/TSH molar ratio are typically present in patients with TSH-omas. Moreover, TSH unresponsiveness to TRH stimulation and/or to T3 suppression tests favors the presence of a TSH-oma. Indexes of thyroid hormone action at the tissue level (such as SHBG levels) are in the hyperthyroid range in patients with TSH-oma, while they are normal/low in RTH. Surgical resection is the recommended therapy for TSH-secreting pituitary tumors, with the aim of removing neoplastic tissues and restoring normal pituitary/thyroid function. However, a radical removal of large tumors, that still represent the majority of TSH-omas, is particularly difficult because of the marked fibrosis of these tumors and the local invasion involving the cavernous sinus, internal carotid artery or optic chiasm. Considering this high invasiveness, surgical removal or debulk of the tumor by transsphenoidal or subfrontal adenomectomy, depending on the tumor volume and its suprasellar extension, should be undertaken as soon as possible. Particular attention has to be paid to presurgical preparation of the patient: antithyroid drugs or octreotide along with propranolol should be used aiming the restoration of the euthyroidism. After surgery, partial or complete hypopituitarism may result. Evaluation of pituitary functions, particularly ACTH secretion, should be carefully undertaken soon after surgery and hormone replacement therapy initiated if needed.

If surgery is contraindicated or declined, as well as in the case of surgical failure, pituitary radiotherapy and/or medical treatment with somatostatin analogs are two valid alternatives. In the case of radiotherapy, the recommended dose is no less than 45 Gy fractionated at 2 Gy per day or 10-25 Gy in a single dose if a stereotactic Gamma Unit is available.
Several patients require medical therapy in order to control the hyperthyroidism, though earlier diagnosis has improved the surgical cure rate of TSH-omas. Dopamine agonists, and particularly bromocriptine, have been employed in some TSH-omas with variable results, positive effects being mainly observed in some patients with mixed PRL/TSH adenoma. Today, the medical treatment of TSH-omas rests on long-acting somatostatin analogs, such as octreotide or lanreotide. Treatment with these analogs leads to a reduction of TSH and ?-subunit secretion in almost all cases, with restoration of the euthyroid state in the majority of them. During octreotide therapy tumor shrinkage occurs in about a half of patients and vision improvement in 75%. Resistance to octreotide treatment has been documented in only 4% of cases. Patients on somatostatin analogs have to be carefully monitored, as untoward side effects, such as cholelithiasis and carbohydrate intolerance, may become manifest. The dose administered should be tailored for each patient, depending on therapeutic response.

No data on the recurrence rates of TSH-oma in patients judged cured after surgery or radiotherapy have been reported. However, the recurrence of the adenoma does not appear to be frequent, at least in the first years after successful surgery. In general, the patient should be evaluated clinically and biochemically 2 or 3 times the first year postoperatively, and then every year. Pituitary imaging should be performed every two or three years, but should be promptly done whenever an increase in TSH and thyroid hormone levels, or clinical symptoms occur. In the case of persistent macroadenoma, a close visual fields follow-up is required, as the visual function is threatened.

REFERENCES

Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD: Thyrotropin- secreting pituitary tumors. Endocr Rev 1996; 17: 610-638
Mindermann T, Wilson CB: Thyrotropin-producing pituitary adenomas. J Neurosurg 1993; 79: 521-527
Refetoff S, Weiss RE, Usala SJ: The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14: 348-399
Cooper DS, Wenig BM: Hyperthyroidism caused by an ectopic TSH-secreting pituitary tumor. Thyroid 1996; 6: 337-343
Beck-Peccoz P, Persani L: Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994; 131: 331-340
Watanabe K, Kameya T, Yamauchi A, Yamamoto N, Kuwayama A, Takei I, Mauyama H, Saruta T: Thyrotropin-producing adenoma associated with pituitary resistance to thyroid hormone. J Clin Endocrinol Metab 1993; 76: 1025-1030
Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, Stevenaert A, Beckers A. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.Eur J Endocrinol 2003; 148: 433-42

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 23-Aug-2006