Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

24.Thyrotropin-Induced Thyrotoxicosis

Paolo Beck-Peccoz

Luca Persani

Thyrotoxicosis results much more frequently from autoantibody stimulation or primary disorders of the thyroid than from excessive secretion of thyrotropin (TSH). However, with the advent of ultrasensitive immunometric TSH assays, an increased number of patients with normal or high levels of TSH in the presence of high thyroid hormone concentrations have been recognized. In this situation, the negative feedback mechanism is clearly disrupted and TSH itself is responsible for the hyperstimulation of the thyroid gland and the consequent thyrotoxicosis. Therefore, it has been proposed this entity be termed central hyperthyroidism. Indeed, the old term, inappropriate secretion of TSH, which refers to the fact that TSH is not suppressed as expected, owing to the high thyroid hormone concentrations, appears inadequate, as it does not reflect the pathophysiological events underlying this unusual disorder.

Central hyperthyroidism is mainly due to an autonomous TSH hypersecretion from a TSH-secreting pituitary adenoma. However, signs and symptoms of thyrotoxicosis along with biochemical findings similar to those found in TSH-secreting tumors may be recorded in a minority of patients affected with resistance to thyroid hormones (RTH). This form of RTH is called pituitary RTH (PRTH), as the RTH action appears more severe at the pituitary than at the peripheral tissue level (see Chapter 81). The clinical importance of these rare entities is based on the diagnostic and therapeutical challenges they present. Failure to recognize these different disorders may result in dramatic consequences, such as improper thyroid ablation in patients with a TSH-secreting tumor or unnecessary pituitary surgery in patients with RTH. Conversely, early diagnosis and correct treatment of TSH-secreting tumor may prevent the occurrence of complications (visual defects by compression of the optic chiasm, hypopituitarism, etc.) and should improve the rate of cure. In this chapter, the salient clinical features of patients with a TSH-secreting tumor, as well as the diagnostic and therapeutic approaches and the prognostic criteria, will be discussed.

EPIDEMIOLOGY

TSH-secreting tumors are rare (1,2). The first patient was documented in 1960 by measuring serum TSH with a bioassay (3). These tumors account for about 0.5% to 1% of all pituitary adenomas, whose prevalence in the general population is about 0.02%. Thus, the prevalence of TSH-secreting tumors is about one case per million. However, this figure is probably underestimated, as the number of reported cases has tripled in the last decade. This trend is comparable to that observed in a large surgical series of pituitary tumors where an increased occurrence of TSH-secreting tumors (from < 1% to 2.8% in the period 1989 to 1991) was documented (4). The increased number of reported cases principally results from the introduction of ultrasensitive immunometric assays for TSH as the first-line test for the evaluation of thyroid function. Based on the finding of measurable serum TSH levels in the presence of thyrotoxicosis, many patients previously thought to have Graves' disease can be correctly diagnosed as patients with TSH-secreting tumor or, alternatively, RTH (2,5,6).

The presence of a TSH-secreting tumor has been observed in patients of any age, from 8 to 84 years. However, most patients are diagnosed between the third and the sixth decade of life. Unlike the female predominance seen in the other common thyroid disorders, these tumors occur with equal frequency in men and women. Familial presentation has been reported only as part of the multiple endocrine neoplasia type 1 syndrome (MEN-1).

PATHOLOGICAL AND PATHOGENETIC ASPECTS

Almost all TSH-secreting tumors originate from pituitary thyrotrophs. Indeed, only two cases of ectopic nasopharynx adenoma overproducing TSH and causing thyrotoxicosis have been reported (7,8). These tumors are nearly always benign, and transformation into a TSH-secreting carcinoma with metastases has been reported in only one patient (9).

The great majority of TSH-secreting tumors are macroadenomas having a diameter of more than 10 mm at the time of diagnosis, while fewer than 15% are microadenomas. Extrasellar extension is present in more than two thirds of cases. Most of the tumors show localized or diffuse invasiveness into the surrounding structures, especially into the dura and bone. The occurrence of invasive macroadenomas is particularly frequent in patients with previous thyroid ablation by surgery or radioiodine, underlying the deleterious effects of incorrect diagnosis and treatment (Fig. 24.1). Such an aggressive transformation of the tumor resembles that occurring in Nelson's syndrome after adrenalectomy for Cushing's disease. By light microscopy, adenoma cells are often arranged in cords, usually with chromophobic appearance, though they occasionally stain with either basic or acid dyes. They appear large and polymorphous, with frequent nuclear atypia and mitoses, thus being often mistakenly recognized as a pituitary malignancy or metastasis from distant carcinomas (10). Electron microscopy demonstrates mostly monomorphous tumors, characterized by the presence of fusiform cells with long cytoplasmic processes, scanty rough endoplasmic reticulum, poorly developed Golgi apparatus, and a low number of small secretory granules (80–200 nm) mainly aligned under the plasma membrane (10,11).

FIGURE 24.1. Effects of previous thyroid ablation on the size of TSH-producing adenomas. “Intrasellar” refers to both microadenomas and intrasellar macroadenomas, “extrasellar” to macroadenomas with suprasellar extension, and “invasive” to invasive macroadenomas. Data have been calculated from 264 reported patients (169 with an intact thyroid and 95 with thyroid ablation). Note the significant increase of invasive tumors in patients with thyroid ablation. Statistical analysis between the two groups was carried out by Fisher's exact test.

About 75% of these tumors secrete TSH alone, which is often accompanied by an unbalanced hypersecretion of the α-subunit of glycoprotein hormones. Thus, cosecretion of other anterior pituitary hormones occurs in about 25% of patients. Hypersecretion of growth hormone (GH) and/or prolactin (PRL), resulting in acromegaly and/or amenorrhea/galactorrhea, are the most frequent associations. This may be due to the fact that GH and PRL share with TSH the common transcription factor Pit-1. The occurrence of a mixed adrenocorticotropic hormone (TSH)/gonadotropin adenoma is rare, while no association with ACTH hypersecretion has been documented to date.

Immunostaining studies show the presence of TSH/β-subunit and/or α-subunit in the great majority of cases. By double immunostaining, the existence of mixed TSH/ β-subunit adenomas composed of one cell type secreting α-subunit alone and another cosecreting α-subunit and TSH has been documented (11). In addition to α-subunit, TSH frequently colocalizes with other pituitary hormones in the same tumor cell. Nonetheless, immunopositivity for one or more pituitary hormones does not necessarily result in in vivo hypersecretion. Indeed, positive immunostaining for ACTH and gonadotropins generally occurs without evidence of hypersecretion of the corresponding hormone.

Due to the rarity of TSH-secreting tumors, in vitro hormone secretion from cultured tumors and its regulation by different agents have been investigated only rarely. Although some responses would be predicted from in vivo data, in vitro studies suggest that the majority of tumors express receptors for thyrotropin-releasing hormone (TRH) and somatostatin, while dopamine receptors seem to be variably present (12,13).

As for most pituitary tumors the pathogenesis of TSH-secreting tumors is largely unknown. Screening studies for genetic abnormalities resulting in transcriptional activation have yielded negative results (14). In particular, no activating mutations of putative protooncogenes, such as ras, G-protein, TRH, and Pit-1, or loss of genes with tumor suppressor activity, such as p53 and menin gene, have been reported (14,15). Evidence for local overproduction of growth factors was provided in some tumors, in agreement with the constant presence of these substances in almost all pituitary adenomas. Recently, somatic mutations (16) and aberrant alternative splicing (17) of thyroid hormone receptor β have been reported, along with dysregulation of deiodinase expression and function (18,19). These findings may at least in part explain the defects in negative regulation of TSH by thyroid hormones in some tumors. Collectively, available data on a small number of tumors are too preliminary to draw definite conclusions on transcriptional and/or expression abnormalities in the tumors.

SIGNS AND SYMPTOMS

Patients with TSH-secreting tumor present with signs and symptoms of thyrotoxicosis that are frequently associated with those related to the pressure effects of the pituitary adenomas, causing loss of vision, visual field defects, and/or loss of other anterior pituitary functions (Table 24.1). Most patients have a long history of thyroid dysfunction, often misdiagnosed as Graves' disease, and about one third had an inappropriate thyroidectomy or radioiodine ablation (1,2,20,21). Clinical features of thyrotoxicosis are sometimes milder than expected on the basis of circulating thyroid hormone levels. In some acromegalic patients, signs and symptoms of thyrotoxicosis may be missed, as they are overshadowed by those of acromegaly. Contrary to what is observed in patients with primary thyroid disorders, atrial fibrillation and/or cardiac failure are rare events.

TABLE 24.1. CLINICAL CHARACTERISTICS OF PATIENTS WITH TSH-SECRETING TUMORa


 

Patients with a tumor n/total (%)b


Age range (years)

8–84

Female/male ratio

1.3

Previous thyroidectomy

95/301 (31.6)

Severe thyrotoxicosis

48/190 (25.2)

Goiter

177/194 (91.2)

Thyroid nodule (s)

47/65 (72.3)

Macroadenomas

229/264 (86.7)

Visual field defect

60/148 (40.5)

Headache

23/114 (20.2)

Menstrual disordersc

26/80 (32.5)

Galactorrheac

11/36 (30.5)

Acromegaly

48/306 (15.7)


aData from reports published through December 2003 and personal unpublished observations.

bn/total refers to the number of patients for whom the information was available.

cData include women with or without associated prolactin hypersecretion.

The presence of a goiter is the rule, even in patients with a previous thyroidectomy, since the remaining thyroid may regrow as a consequence of TSH hyperstimulation. Occurrence of uni- or multinodular goiter is frequent (about 72% of reported cases), whereas differentiated thyroid carcinoma was documented in a few cases (22,23). Progression toward functional autonomy seems to be infrequent (24). In contrast with Graves' disease, the occurrence of antithyroid autoantibodies is similar to that found in the general population, being about 8%. Bilateral exophthalmos occurred in a few patients who subsequently developed autoimmune thyroiditis, while unilateral exophthalmos due to orbital invasion by a pituitary tumor was reported in three patients (2).

Most patients with a TSH-secreting macroadenoma seek medical attention because of 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. Visual field defects are present in about 40% and headache in 20% of patients (Table 24.1). Partial or total hypopituitarism occurs in about 25% of cases.

LABORATORY AND BIOCHEMICAL FEATURES

Serum Thyroid Hormone and Thyrotropin Levels

Serum TSH levels in untreated patients with TSH-secreting tumors may be high or in the normal range, whereas total and free thyroxine (T4) and triiodothyronine (T3) levels are definitely high (Table 24.2). 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 free T4 and free T3, and goiter as well. Recent studies indicate that TSH molecules secreted by pituitary tumors may have normal, reduced, or increased biological activity relative to immunological activity, probably due to modification of glycosylation processes secondary to alterations of the posttranslational processing of the hormone within tumor cells (25,26).

TABLE 24.2. BIOCHEMICAL DATA OF PATIENTS WITH TSH-SECRETING TUMORSa


Serum parameter

Patients with intact thyroid

Patients with previous thyroidectomy

p


TSH (mU/L)b

9.3 ± 1.0 (125)

55.8 ± 10.2 (81)

< 0.01

Normal TSH levelsc

35.3% (60/170)

11.4% (9/79)

< 0.01

α-subunit (mg/L)b

17.8 ± 5.4 (74)

14.5 ± 2.7 (46)

NS

α-subunit/TSH (m.r.)b,d

43.3 ± 15.5 (73)

3.7 ± 0.7 (46)

< 0.03

High α-subunit levelsc

66.6% (68/102)

72.9% (35/48)

NS

High α-subunit/TSH (m.r.)c

86.9% (86/99)

77.1% (37/48)

NS

TT4(nmol/L)b

239.8 ± 18.7 (33)

177.1 ± 9.8 (45)

< 0.01

FT4(pmol/L)b

41.7 ± 2.3 (70)

28.7 ± 2.5 (30)

< 0.01

TT3(nmol/L)b

4.9 ± 0.6 (33)

4.1 ± 0.3 (42)

NS

FT3(pmol/L)b

16.2 ± 0.8 (54)

10.5 ± 0.9 (20)

< 0.01

High SHBG levelsc

92.0% (23/25)

66.6% (6/9)

NS

Blunted TSH response to TRH testc

82.8% (116/140)

83.0% (58/70)

NS

Abnormal TSH response to T3 suppression testc, e

100% (51/51)

100% (33/33)

NS


aData from reports published through December 2003 and personal unpublished observations.

bMean ± SE (n).

c% (n/total).

dTo calculate α-subunit/TSH molar ratio divide α-subunit (mUg/liter) by TSH (mU/liter) and multiply by 10.

eLack of complete TSH inhibition after 8–10 days of T3 administration (80–100 mg/day).

In patients previously treated with thyroid ablation who still present with thyrotoxicosis serum, TSH levels are higher than in untreated patients, suggesting that tumoral thyrotroph cells may increase their TSH secretion in response to an even small reduction in thyroid hrmone levels (2,21). Therefore, while tumoral thyrotrophs are totally or partially resistant to the inhibitory action of high thyroid hormone levels, they have a preserved or even increased sensitivity to low serum thyroid hormone levels.

Particular clinical situations and possible laboratory artifacts may cause a biochemical profile similar to that characteristic of central thyrotoxicosis (2,5,6). Since these conditions are more common than are TSH-secreting tumors and RTH, they should be excluded before performing an extensive evaluation of the hypothalamic-pituitary-thyroid axis. Most of the other conditions may be recognized by measuring free, instead of total, thyroid hormones (27). It is most important to measure serum free T4 and T3 by direct methods, not only to prevent possible misinterpretation due to variations in transport proteins, but also to assess true thyroid hormone production. Indeed, normal levels of total T4 were reported in several patients, and only measurement free T4 of led to the correct diagnosis (2,28).

Genetic alterations or treatment with certain drugs may cause quantitative/qualitative alterations of thyroxine-binding globulin, albumin, or transthyretin leading to increases in serum T4 (see Chapter 6). Hyperthyroxinemia associated with measurable TSH may also be found in patients treated with the iodine-containing drug, amiodarone. In clinically ambiguous situations, the differential diagnosis rests on the recognition of the underlying disorder, as well as documenting normalization of thyroid function tests after drug withdrawal. Indeed, if patients with one of the above conditions were truly thyrotoxic, serum TSH levels should be undetectable.

Laboratory artifacts may cause falsely high levels of either thyroid hormones or TSH. Circulating anti-T4 and/or anti-T3 autoantibodies can interfere in the immunometric assay, leading to an overestimation of both total and free thyroid hormone levels (see Chapter 13). As far as the free T4 and T3 measurements are concerned, such overestimation is frequently observed when “one-step” analog methods are employed (29). The interference of the above autoantibodies may be counteracted by measuring free T4 and free T3 concentrations by equilibrium dialysis or by direct “two-step” methods, that is, methods able to avoid contact between serum proteins and tracer at the time of the assay. The more common factors interfering in TSH measurement are heterophilic antibodies directed against or cross-reacting with mouse IgG (30), and anti-TSH antibodies in patients previously treated with contaminated pituitary extracts. However, prevention of the formation of the “sandwich” anti-TSH antibodies usually leads to an underestimation of the actual levels of TSH and rarely to an overestimation.

Pituitary Glycoprotein Hormone α-Subunit

A helpful diagnostic tool for the diagnosis of a TSH-secreting tumor is the determination of the concentrations of the α-subunit common to each of the glycoprotein hormones, which are elevated in the majority of patients (Table 24.2) (1,2). Indeed, hypersecretion of the α-subunit is not unique to TSH-secreting tumors, being present in the majority of gonadotropinomas, in a subset of nonfunctioning pituitary adenomas, and in a low percentage of GH- or PRL-secreting tumors. TSH-secreting tumors commonly secrete excessive quantities of the free α-subunit, probably due to altered hormone synthesis within the tumoral cells. Secretion of the α-subunit by these tumors is in excess not only of the TSH β- subunit but also of the intact TSH molecule. This results in an α-subunit/TSH molar ratio, which usually is higher than 1.

Although previous studies have suggested that a ratio above 1 is indicative of the presence of a TSH-secreting tumor, similar values may be recorded in normal subjects, particularly postmenopausal women, indicating the need for appropriate control groups matched for TSH and gonadotropin levels (31).

Parameters of Peripheral Thyroid Hormone Action

Patients with central thyrotoxicosis may present with mild signs and symptoms of thyroid hormone overproduction. Therefore, the measurements of several parameters of peripheral thyroid hormone action both in vivo (basal metabolic rate, cardiac systolic time intervals, Achilles' reflex time) and in vitro (sex hormone–binding globulin: (SHBG), cholesterol, angiotensin–converting enzyme, osteocalcin, red–blood–cell sodium content, carboxyterminal cross-linked telopeptide of type I collagen, have been proposed to quantify the degree of thyrotoxicosis (2,5,6,7,21). Some of these parameters, and in particular SHBG, have been used to differentiate patients with TSH-secreting tumors from those with PRTH (Table 24.2). As occurs in the common forms of thyrotoxicosis, patients with TSH-secreting tumors have high SHBG levels, while they are in the normal range in patients with PRTH (32,33).

DIAGNOSTIC TESTING

In the past, several stimulatory and inhibitory tests have been proposed for the diagnosis of TSH-secreting tumors. None of these tests is of clear-cut diagnostic value, but the combination may increase their specificity and sensitivity. Classically, the T3 suppression test has been used to assess the presence of a TSH-secreting tumor. From the analysis of different cases, complete inhibition of TSH secretion after T3 administration (80 to 100 µg/day for 8 to 10 days) has never been recorded in patients with a TSH-secreting tumor (Table 24.2). In patients with previous thyroid ablation, T3 suppression seems to be the most sensitive and specific test in assessing the presence of a TSH-secreting tumor (20,21). This test is contraindicated in elderly patients or those with coronary heart disease. The TRH test is another test that has been used to investigate the presence of a TSH-secreting tumor. In 83% of patients, TSH and α-subunit levels did not increase after TRH injection (34).

The majority of patients with a TSH-secreting tumor are sensitive to somatostatin or its analogs. Indeed, administration of native somatostatin or its analogs (octreotide and lanreotide) induces a reduction of TSH levels in the majority of cases, and these tests may be predictive of the efficacy of long-term treatment (35).

IMAGING STUDIES AND LOCALIZATION

When considering the diagnosis of a TSH-oma, full imaging studies, particularly magnetic resonance imaging (MRI) or high-resolution computed tomography (CT), are mandatory. Nevertheless, since most TSH-omas are macroadenomas, in the majority of cases plain radiograms may reveal abnormalities of the sella turcica. Various degrees of suprasellar extension or sphenoidal sinus invasion are present in two thirds of cases.

Microadenomas are now reported with increasing frequency, accounting for about 15% of all recorded cases in both clinical and surgical series. Recently, pituitary scintigraphy with radiolabeled octreotide has been shown to successfully image TSH-omas (8,13,20,35). However, the specificity of these nuclear scans is very low, since pituitary tumors of different types, either secreting or nonsecreting, and even nonspecific pituitary lesions may have positive scans due to the presence of somatostatin receptors.

DIFFERENTIAL DIAGNOSIS

In a patient with signs and symptoms of hyperthyroidism, the presence of elevated TH and detectable TSH levels rules out primary hyperthyroidism. In patients receiving T4 replacement therapy, the finding of measurable TSH in the presence of high TH levels may be due to poor compliance or to an incorrect high T4 dose of T4 ingested before blood sampling. In the case of euthyroid hyperthyroxinemia, it is mandatory to measure the concentrations of free, rather than total, thyroid hormones. If FT4 and FT3 concentrations are elevated in the presence of measurable TSH levels, it is important to exclude methodological interference due to the presence of circulating autoantibodies or heterophilic antibodies.

When the existence of central hyperthyroidism is confirmed, several diagnostic steps should be carried out to differentiate a TSH-oma from PRTH (2,5,6,7). Indeed, the possible presence of neurological signs and symptoms (visual defects, headache) 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 on MRI or CT scan strongly supports the diagnosis of TSH-oma. Nevertheless, the differential diagnosis may be difficult when the pituitary adenoma is undetectable by CT scan or MRI, or in the case of confusing lesions, such as empty sella or pituitary incidentalomas.

No significant differences in age, sex, previous thyroid ablation, TSH levels, or free thyroid hormone concentrations occur between patients with TSH-oma and those with RTH (Table 24.3). However, in contrast with RTH patients, familial cases of TSH-secreting tumors have never been documented. Serum TSH levels within the normal range are more frequently found in RTH, while high α-subunit concentrations and/or high α-subunit/TSH molar ratio are typically present in patients with TSH-secreting tumors. Moreover, TSH unresponsiveness to TRH stimulation and/or to T3 suppression favors the presence of a TSH-secreting tumor. Circulating SHBG levels are in the thyrotoxic range in patients with TSH-secreting tumors, while they are normal/low in RTH. Exceptions are the findings of normal SHBG levels in patients with mixed GH/TSH adenomas, due to the inhibitory action of GH on SHBG secretion, and of high SHBG in RTH patients treated with estrogen who have profound hypogonadism.

TABLE 24.3. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-SECRETING TUMORS AND RESISTANCE TO THYROID HORMONES (RTH)a


Parameter

TSH-omas

RTH

P


Female/male ratio

1.4

1.3

NS

Familial cases

0/18 (0%)

58/68 (85%)

< 0.01

TSH (mU/L)

2.8 ± 0.6

2.0 ± 0.3

NS

FT4(pmol/L)

42.0 ± 4.5

28.5 ± 2.7

NS

FT3(pmol/L)

14.2 ± 1.5

11.9 ± 1.0

NS

SHBG (nmol/L)

117.0 ± 17.6

60.0 ± 4.1

< 0.01

Lesions at CT or MRI

17/18 (95%)

1/54 (1.9%)

< 0.01

High α-subunit levels

12/18 (66.7%)

1/60 (1.7%)

< 0.01

High α-subunit/TSH m.r.

15/18 (83.3%)

1/60 (1.7%)

< 0.01

Blunted TSH response to TRH

15/18 (83.3%)

3/68 (4.4%)

< 0.01

Abnormal TSH response to T3 suppression testb

17/17 (100)

40/40 (100%)c

NS


aOnly patients with intact thyroid are included. Data are obtained from patients followed at our Institute (18 TSH tumors and 68 RTH cases) and are expressed as mean ± SE.

bWerner's test (80–100 µg T3 for 8–10 days). Quantitatively normal responses to T3, i.e. complete inhibition of both basal and TRH-stimulated TSH levels, have never been recorded in either group of patients.

cAlthough abnormal in quantitative terms, TSH response to T3 suppression test was qualitatively normal in all RTH patients.

Finally, an apparent association between TSH-secreting tumor and RTH has been recently reported in a few patients (36,37), though genetic studies of possible mutations in the T3-receptor β1 were not carried out in the Japanese case. Nonetheless, the occurrence of tumors in RTH patients is theoretically possible (37).

TREATMENT AND OUTCOME

Surgical resection is the recommended therapy for TSH-secreting pituitary tumors, with the aim of restoring normal pituitary/thyroid function. However, radical removal of large tumors, that still represent the majority of these tumors, is particularly difficult because of the marked fibrosis and the local invasion involving the cavernous sinus, internal carotid artery, or optic chiasm. Considering this high invasiveness, surgical removal or debulking of the tumor by transsphenoidal or subfrontal surgery, depending on the tumor volume and its suprasellar extension, should be undertaken as soon as possible. Particular attention should be paid to presurgical preparation of the patient: antithyroid drugs or octreotide along with propranolol should be given to restore the patient to euthyroidism. After surgery, partial or complete hypopituitarism may result. Evaluation of pituitary function, particularly ACTH secretion, should be 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 is mandatory. The recommended dose is no less than 45 Gy fractionated at 2 Gy/day or 10 to 25 Gy in a single dose if a stereotactic gamma unit is available. Experience with proton-beam and heavy particle radiotherapy in TSH-secreting tumors is lacking, though they have been successfully used in other pituitary tumors. Indeed, the radiosensitivity of these tumors has not been clearly evaluated.

Although earlier diagnosis has improved the surgical cure rate, some patients require medical therapy in order to control their thyrotoxicosis. Dopamine agonists, and particularly bromocriptine, have been given to some patients, with variable results, positive effects being mainly observed in some patients with a mixed PRL/TSH adenoma. Medical treatment depends upon long-acting somatostatin analogs, such as octreotide or lanreotide (35,38,39,40,41,42). Treatment with these analogs leads to a reduction in TSH and α-subunit secretion in almost all cases, with restoration of the euthyroid state in the majority of them. In patients with a GH/TSH-producing adenoma such treatment not only restores euthyroidism, but also resolves acromegaly (Fig. 24.2). During octreotide therapy tumor shrinkage occurs in about a half of the patients and vision improvement in 75% (38). Resistance to octreotide treatment has been documented in only 4% of cases. Patients treated with somatostatin analogs should 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 and tolerance (including gastrointestinal side effects). Whether somatostatin analog treatment may be an alternative to surgery and irradiation in patients with TSH-secreting tumor remains to be established.

FIGURE 24.2. Treatment with long-acting somatostatin analogs (octreotide LAR, 20 mg every 28 days) of one acromegalic and thyrotoxic patient with a GH-/TSH-producing adenoma. α-GSU indicates the alpha subunit of pituitary glycoprotein hormones, whereas nv (normal values) indicates the upper limit of normal ranges for the various hormones. Note the normalization of GH, α-GSU, FT3 and FT4 levels along with the small decrement of TSH concentrations. Changes in the biological activity of secreted TSH may explain such a finding.

CRITERIA OF CURE AND FOLLOW-UP

The criteria of cure and follow-up of patients operated and/or irradiated for TSH-secreting tumors have not been clearly established, due to the rarity of the disease and the heterogeneity of parameters used. In particular, clinical remission of thyrotoxicosis, disappearance of neurological symptoms, resolution of neuroradiological alterations, and normalization of thyroid hormones, TSH, α-subunit, or the α-subunit/TSH molar ratio have been considered for evaluation of the efficacy of surgery or radiotherapy. It is obvious that previous thyroid ablation makes some of these criteria not applicable. In untreated patients, it is reasonable to assume that cure will result in clinical and biochemical reversal of thyroid hyperfunction. However, the finding of normalization of serum free T4and free T3 concentrations or indices of peripheral thyroid hormone action (SHBG, etc.) is not synonymous with complete removal or destruction of tumoral cells, since transient clinical remission accompanied by normalization of thyroid function tests has been observed (21). Disappearance of neurological signs and symptoms is a good prognostic event, but it may occur even after an incomplete debulking of the tumor. In our experience, undetectable TSH levels one week after surgery are likely to indicate complete adenomectomy, provided that presurgical treatments were stopped at least 10 days before surgery (21). The most sensitive and specific test to document the complete removal of the adenoma remains the T3 suppression test. In fact, only patients in whom T3administration completely inhibits basal and TRH-stimulated TSH secretion, appear to be truly cured (21).

No data on recurrence rates of TSH-secreting tumors in patients judged cured after surgery or radiotherapy have been reported. However, recurrence of the adenoma does not appear to be frequent, at least in the first years after successful surgery (20,21). 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 2 or 3 years, but should be done promptly whenever an increase in serum TSH and thyroid hormone levels or clinical symptoms occur. In the case of a persistent macroadenoma, close follow-up of visual fields is required, as visual function is threatened.

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