Keywords

Introduction

Central hyperthyroidism (i.e., elevated serum circulating free thyroid hormone levels in the presence of measurable serum TSH concentrations) is a rare condition related to the presence of two different clinical entities: TSH-secreting pituitary adenomas (TSHomas) and resistance to thyroid hormone action (Refetoff Syndrome , RTH) [1, 2]. While patients with TSHoma develop signs and symptoms of hyperthyroidism, subjects with RTH are in general clinically euthyroid (generalized RTH, GRTH), except for those with the so-called pituitary RTH who may present features related to the involvement of some organs such as the heart (tachycardia) and brain (attention deficit, nervousness, insomnia) [2].

Negative feedback mechanism is affected in both RTH and TSHomas. While in THSomas TSH is secreted autonomously, T3 receptor mutations reduce thyrotropes sensitivity to T3 in RTH [1, 2]. Moreover, in TSHomas TSH circadian rhythm is disrupted, and its secretion is characterized by increased pulse frequency and basal secretion [3].

The introduction of both ultrasensitive TSH immunometric assays and circulating free thyroid hormones direct immunoassays greatly improved the recognition of patients with central hyperthyroidism previously misdiagnosed as having a Graves’ disease [1, 2].

Once central hyperthyroidism has been diagnosed, it is mandatory to correctly differentiate TSHoma and RTH to avoid improper thyroid ablation or pituitary surgery in patients with RTH. It is worth noting that early diagnosis and correct treatment of pituitary tumors prevent the occurrence of neurological complications (i.e., visual defects, headache, hypopituitarism) and should improve cure rate.

Epidemiology

In 1970, the first case of TSHoma was documented. Since then, about 500 patients have been reported. TSHoma is a rare condition accounting for 0.5 to 2% of all pituitary adenomas [2], the prevalence being 1–2 cases per million. Interestingly, the number of reported cases of TSHomas has significantly increased in the last 25 years. This increase in TSHoma diagnosis was related to the introduction of ultrasensitive immunometric assays for TSH as a first-line test for the evaluation of thyroid function that allowed to correctly identify the presence of central hyperthyroidism in patients previously thought to have Graves’ disease [2]. The increase in TSHomas incidence has been confirmed by Swedish Pituitary Registry [5]. In fact, an increased incidence of TSHomas overtime was observed (from 0.05 per 1 million per year in 1990–1994 to 0.26 per 1 million per year in 2005–2009), the Swedish prevalence in 2010 being 2.8 per 1 million inhabitants [4].

Although most patients are diagnosed in the third to sixth decade of life, TSHomas may occur at any age (11 to 84 years) with equal frequency in males and females [2].

Macroadenomas (diameter > 1 cm) were recorded in more than 85% of the cases before 1996 [2, 5,6,7,8]. Interestingly, the prevalence of microadenomas is progressively increasing as confirmed by data collected by Malchiodi et al. showing that the percentage of microadenomas ranges between 30 and 35% of all TSHomas [9]. However, most TSHomas are diagnosed at the stage of invasive macroadenomas [2, 5,6,7,8,9], extra- and parasellar extension being present in most of cases.

Pathology and Etiopathogenesis

TSHomas are benign tumors that arise from adenomatous transformation of thyrotropes. Up to now TSH-secreting carcinomas with multiple metastases have been described in three patients [10,11,12], loss of pituitary glycoprotein hormone alpha-subunit (α-GSU) secretion being considered as a marker of malignant transformation [10]. Though the majority of TSHomas secretes TSH alone, about one fourth of them are mixed adenomas that cosecrete TSH and other anterior pituitary hormones. Hypersecretion of TSH and GH is the most frequent association (15–20%), followed by cosecretion of TSH and PRL (8–10%), while no TSHomas cosecreting ACTH have been so far identified. Occasionally pituitary adenomas cosecreting TSH and gonadotropins have been described [2, 13, 14] leading to precocious puberty during childhood or to ovarian hyperstimulation in adult female. The notion that GH and PRL share with TSH common transcription factors (e.g., PROP-1, Pit-1, and HESX-1) justifies why GH and PRL are frequently cosecreted in TSHomas [15]. However, it is important to remember that a positive immunohistochemistry for pituitary hormones other than TSH does not necessarily correlate with their hypersecretion in vivo [16, 17].

As mentioned before, most TSHomas are macroadenomas that are characterized by high local invasiveness at morphologic and histopathologic analysis. Interestingly, previous thyroid ablation negatively affects clinical behavior. In fact, invasive macroadenomas are found in 49% of patients who had undergone thyroid ablation (i.e., radioiodine or thyroidectomy) versus 27% in those who were untreated thus suggesting that a reduction in T3 and T4 circulating levels might stimulate neoplastic thyrotrope cells growth through an altered feedback mechanism, a situation like that observed in some patients after bilateral adrenalectomy for Cushing’s disease (Nelson’s syndrome ) [2]. TSHomas are frequently very fibrous and sometimes are so hard that they are defined “pituitary stones ” [18]. It this respect, overexpression of basic fibroblast growth factor by some TSHomas suggests that it may play a role in the development of fibrosis of this pituitary neoplasm [19].

In patients with confirmed biochemical findings of TSHoma and neuroradiological imaging negative for the presence of a pituitary adenoma , an ectopic TSH secretion should be taken into consideration [20]. TSHoma ectopically occurring in the nasopharyngeal pituitary residue has been reported [21,22,23].

The molecular pathogenetic mechanisms leading to TSHomas formation are presently unknown. As demonstrated in other secreting and nonsecreting pituitary adenomas, TSHomas originate from the clonal expansion of a single transformed cell [24]. Therefore, a transforming event leading to an increased cell proliferation and secondary mutations or alterations favoring tumor progression is needed to induce TSHoma formation. However, no mutations in oncogenes commonly activated in human neoplasia have been so far reported in TSHomas. Moreover, none of the screened TSHomas has been shown to express activating mutations of genes encoding for stimulatory or inhibitory G protein subunits (i.e., αs, αq, α11, or αi2) or TRH receptor [25]. Since Pit-1 is a transcription factor involved in TSH gene expression, it has been studied and shown to be overexpressed but not mutated in a series of TSHomas [26]. As for oncogenes, no mutations affecting common antioncogenes (i.e., p53, Rb, Menin) have been so far identified. Though the presence of a TSHoma has been reported in five cases within a familial setting of MEN1, a screening study carried out on sporadic TSHomas found LOH on 11q13, where menin is located, but none of these tumors had a menin mutation [27]. Finally, a mutation of aryl hydrocarbon receptor-interacting protein (AIP) was found in a single patient with TSHoma [28]. A recently published whole-exome sequencing study of 12 TSHomas identified several candidate somatic mutations (e.g., SMOX and SYTL3) and changes in copy numbers [29]. However, the low number of mutations, as well as the absence of recurrence of mutations in the tumors studied, seems to further confirm the benign nature of these tumors.

TSHomas are characterized by an extreme refractoriness to the negative feedback mechanism exerted by thyroid hormones, this observation leading to search for alterations in thyroid hormone receptor (TR) expression and function [30, 31]. While the absence of TRα1, TRα2, and TRβ1 expression was reported in one TSHoma, aberrant alternative splicing of TRβ2 mRNA encoding TRβ variant lacking T3-binding activity was recently shown as a mechanism responsible for impaired T3-dependent negative regulation of both TSHβ and α-GSU in tumoral tissue [32]. Recently it has been suggested that somatic mutations of TRβ may be responsible for the defective negative feedback mechanism at least in some TSHomas [33]. Finally, knock-in mutant mice harboring a mutation in the TRβ gene spontaneously develop TSHomas via phosphatidylinositol 3-kinase signaling activation [34].

Tumorous thyrotropes express somatostatin receptor type 2 and 5 (SST2 and SST5), this expression explaining the antisecretory and antiproliferative effects exerted by somatostatin analogs in patients with TSHoma [35]. Though no mutations affecting somatostatin receptor genes have been identified, LOH and polymorphisms at the somatostatin receptor type 5 gene locus seem to be associated with an aggressive phenotype and resistance to medical treatment [36].

Clinical Features

Patients with TSHomas present signs and symptoms of hyperthyroidism frequently associated with the consequences of tumor compression on the surrounding anatomical structures (i.e., visual field defects, loss of vision, headache, and partial or complete hypopituitarism) (Table 8.1). In this respect, while the occurrence of bilateral exophthalmos may be the consequence of a coexistent autoimmune thyroiditis, unilateral exophthalmos may represent the consequence of orbital invasion by pituitary tumor [2, 37, 38]. In many cases, patients are diagnosed after a long history of thyroid dysfunction (diagnosed as Graves’ disease or toxic multinodular goiter), and about 30% of them underwent inappropriate surgical or radiometabolic thyroid ablation [2, 39, 40] that may negatively affect tumor behavior, invasive macroadenomas being found in half of patients who had undergone thyroid ablation [2]. Interestingly, Macchia et al. observed a mean estimated latency of 39 months between first symptom appearance and diagnosis of TSHoma, this latency being significantly shorter in the case of macroadenomas (mean, 24 vs 50 months) [41].

Table 8.1 Clinical features in patients with TSHoma
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In general, clinical features of hyperthyroidism are milder than expected on the basis of circulating thyroid hormone levels [42, 43]. Though severe thyrotoxic features (e.g., atrial fibrillation, cardiac failure) are observed in 25% of cases, some patients with untreated TSHoma may be clinically asymptomatic, thus suggesting that tumorous thyrotropes may secrete TSH molecules with a reduced biological activity [44]. The presence of these clinically “silent” TSHomas makes mandatory the systematic measurement of both TSH and FT4 in all patients with pituitary tumor, this approach being useful also to rule out the presence of a central hypothyroidism in non-TSH-secreting pituitary tumors.

It is worth noting that in patients bearing pituitary tumors cosecreting TSH and other pituitary hormones, hyperthyroidism may be missed. This is the case of GH cosecretion that leads to the appearance of acromegaly symptoms that overshadow those related to TSH hypersecretion [2, 40]. Disorders of the gonadal axis are frequently seen not only in patients with mixed TSH/PRL or mixed TSH/FSH adenomas but also in 30% of patients with pure TSHoma [2].

Goiter is observed in more than 90% of patients, and the presence of multinodular goiter has been reported in several patients. Progression toward functional autonomy seems to be infrequent [45], and circulating antithyroid autoantibodies are found in 8% of patients, this figure being similar to that found in the general population. However, Graves’ hyperthyroidism may coexist with TSHoma in some patients [46].

The presence of differentiated thyroid carcinoma (DTC) has been reported [2, 47, 48]. In a recently published series of 62 TSHomas, DTC incidence of 4.8% has been reported as possibly related to the chronic TSH hypersecretion [48]. However, it has been demonstrated that the outcome of patients with the coexistence of TSHoma and DTC is in general favorable despite the presence of non-suppressible TSH [47]. Finally , though all these data suggest the opportunity to perform a high-resolution ultrasound of the thyroid in all patients with TSHoma [48], no consensus regarding the management of patients with DTC and TSHoma has been so far agreed. It remains to be demonstrated that an aggressive management of these patients might result in a more favorable outcome (i.e., the complete removal of the tumor followed by radioablation and attempts to reduce serum TSH to the lowest tolerable level).

The diagnosis of TSHoma may be delayed in patients in whom hypothyroidism is coexistent with the pituitary tumor [2, 48,49,50]. In these patients, an autonomous TSH hypersecretion should be suspected when TSH does not adequately normalize/suppress during LT4 replacement therapy.

Diagnostic Work-Up

Elevated levels of circulating thyroid hormones in the presence of detectable TSH concentrations are the biochemical characteristics of central hyperthyroidism. Diagnosis of central hyperthyroidism should be suspected in patients who have undergone thyroid ablation in whom high/normal TSH levels are found in the presence of high FT4 and FT3 levels during L-T4 treatment [2].

It is necessary to exclude all those factors (i.e., abnormalities in the pituitary-thyroid axis, laboratory artifacts, or drugs) that may lead to wrongly diagnose a condition of central hyperthyroidism . In this respect, inhibition of T4 to T3 conversion induced by iodine-containing drugs (e.g., povidone, amiodarone, iodinated contrast media) or nonthyroidal illness may induce the presence of high FT4 levels with detectable TSH that are, however, associated with normal or low-normal T3. Some laboratory artifacts can give spuriously high hormone levels and possibly simulate the biochemical characteristics of central hyperthyroidism. This is the case of heterophilic antibodies directed against mouse gamma globulins or anti-TSH antibodies. The presence of anti-T4 or anti-T3 autoantibodies or both as well as the familial dysalbuminemic hyperthyroxinemia (a condition characterized by abnormal circulating albumin with increased T4 affinity) may cause FT4 and/or FT3 overestimation, particularly when “one-step” analog methods are used [2, 51].

In TSHomas, extremely variable levels of serum TSH and thyroid hormones have been reported, and no difference in basal values of TSH and free thyroid hormone levels was seen between patients with TSHoma and those with RTH [1, 2]. Interestingly, any significant correlation between immunoreactive TSH and free thyroid hormone levels has been observed in patients with TSHoma, as demonstrated by the observation that in 30% of them, high levels of free thyroid hormones are associated with immunoreactive TSH levels within the normal range. In this respect, it has hypothesized that adenomatous thyrotropes secrete TSH molecules with peculiar glycosylation and biologic properties [44, 52, 53].

An unbalanced excess of circulating free α-GSU levels and elevated α-GSU/TSH molar ratio are detected in patients with TSHoma [2, 54], a ratio greater than 1.0 being possibly indicative of the presence of TSHoma provided that appropriate control groups matched for TSH and gonadotropin levels are considered. Interestingly, normal α-GSU levels and α-GSU/TSH molar ratio are observed in the majority of microadenomas [6], this finding demonstrating a possible relationship between the size of the tumor and its secretory activity. Furthermore, it has been suggested that a spontaneous and marked decrease in both TSH and α subunit might indicate that the tumor is becoming less differentiated and might correlate with invasive and metastatic behavior [10].

The degree of tissue hyperthyroidism may be evaluated by measuring several parameters of peripheral thyroid hormone action [2]. Sex hormone-binding globulin (SHBG) , cholesterol, angiotensin-converting enzyme, osteocalcin, red blood cell sodium content, and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) have been proposed, SHBG and ICTP being those more frequently used in differentiating patients with TSHoma from those with RTH [55, 56]. In fact, as it occurs in all forms of hyperthyroidism, patients with TSHoma have high ICTP and SHBG levels, while they are into the normal range in patients with central hyperthyroidism due to RTH [1, 2].

Though several stimulatory and inhibitory tests have been proposed to confirm the diagnosis of TSHoma, none of them has a clear-cut diagnostic value. Recently, the guideline for the diagnosis of TSHoma endorsed by the European Thyroid Association suggests that both stimulatory and inhibitory tests (i.e., TSH stimulation test and T3 suppression test) should be used in the differential diagnosis of central hyperthyroidism [54]. Patients with TSHoma are characterized by a blunted/absent TSH increase after TRH stimulation test (200 μg bolus intravenously, sampling at 0, 20, 60, 90, and 120 min) and fail to completely suppress TSH following T3 suppression test (80–100 μg/day divided in three administrations for 10 days, sampling at 0, 5 and, 10 days). T3 suppression is considered as the most specific and sensitive test to be used when a TSHoma is suspected in previously thyroidectomized patients [2, 6].

High-resolution computed tomography (CT) and nuclear magnetic resonance imaging (MRI) are used to visualize a TSHoma. Though microadenomas are now reported with increasing frequency (up to 30%), 70% of TSHomas are diagnosed with frequent suprasellar extension or sphenoidal sinus invasion [2]. However, ectopic tumors in the pharyngeal region have been reported [21, 23]. In these cases, pituitary scintigraphy with radiolabeled octreotide (octreoscan) has been shown to successfully localize TSHomas [2, 58].

The coexistence of high thyroid hormones levels and measurable circulating TSH is sufficient to rule out the diagnosis of Graves’ disease , uni- or multinodular toxic goiter or activating mutations of TSH receptor. Once the presence of methodological interferences is excluded [2, 51, 57], it is mandatory to exclude a possible RTH (Table 8.2). The presence of neurological signs and symptoms (e.g., visual defects and headache) or clinical features of concomitant hyper- or hyposecretion of other pituitary hormones are characteristically seen in patients with TSHoma. Furthermore, an alteration of the pituitary gland at MRI or CT scan strongly supports the diagnosis of TSHoma. In this respect , it is worth noting that a nonfunctioning pituitary incidentaloma may be found in a patient with RTH, thus suggesting that pituitary imaging should be performed only when all clinical and biochemical finding point to the presence of TSHomas [57]. Elevated α-GSU concentrations or high α-GSU/TSH molar ratio, high circulating levels of parameters of peripheral thyroid hormone action (SHBG, ICTP), and TSH unresponsiveness to TRH stimulation or to T3 suppression tests are characteristically associated with the presence of a TSHoma [1, 2, 57]. Since familial cases of TSHomas have not been documented, the finding of a similar biochemical profile in relatives points to the presence of RTH. Finally, an apparent association between TSHoma and RTH has been recently reported, and somatic mutations in the thyroid hormone receptor have been found in some tumors [32, 33], thus the occurrence of TSHoma in patients with RTH should be carefully considered [59,60,61].

Table 8.2 Parameters useful in differentiating patients with TSH-secreting pituitary adenomas (TSHomas) from those with resistance to thyroid hormones (RTH) [3]
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Treatment and Follow-Up

As recently stated by the European Thyroid Association guideline for the diagnosis and treatment of TSHomas, surgical removal of the adenoma remains the first-line therapy [57]. Though methimazole (or propylthiouracil) or somatostatin analogs (i.e., octreotide and lanreotide ) along with propranolol could be administered to restore euthyroidism before surgery, it has been demonstrated that presurgical medical treatment seems not to significantly improve surgical outcome (63% vs 57%) [9]. Complete removal of the tumor is achieved in up to 80% of patients with microadenoma , whereas no more than 50–60% of patients with macroadenoma may be considered as cured after the surgical procedure [9, 40]. The reasons of surgical failure are the marked fibrosis frequently seen in TSHomas and the frequent extra- and parasellar extension of the tumor [5,6,7,8,9, 40, 62]. If surgery is contraindicated or declined, pituitary fractionated stereotaxic radiotherapy or radiosurgery might be considered. The therapeutic dose is suggested to be between 45 and 55 Gy administered by conventional fractionated radiotherapy or 10–25 Gy if radiosurgery is used. Available studies do not show any significant difference between conventional fractionated radiotherapy and radiosurgery [9]. Recently, Malchiodi et al. demonstrated that radiotherapy was effective in controlling hormone hypersecretion in 37% of patients within 2 years, 32% of patients developing new pituitary deficiencies from 18 to 96 months from treatment [9]. In summary, while thyroid hormone level normalization and apparent complete removal of tumor mass are achieved by surgery alone or combined with radiotherapy in one third of patients, thyroid hormone normalization without complete removal of the adenoma is demonstrated in a third of patients, thus indicating that about 60–70% of TSHomas are controlled with surgery, irradiation, or both.

Tumorous thyrotropes express somatostatin receptor subtypes 1, 2A, 3, and 5, and it has been demonstrated that long-acting somatostatin analogs (i.e., octreotide LAR® or lanreotide SR® or lanreotide Autogel®) are highly effective in reducing TSH secretion in patients with TSHomas [57]. Interestingly, FT4 and FT3 circulating level normalization is observed in up to 90% of cases, goiter size being significantly reduced in 30% of them [5,6,7,8,9, 54]. As demonstrated in patients with acromegaly, somatostatin analog treatment induces a significant tumor mass shrinkage in about 40% of patients [57]. Resistance to somatostatin analog treatment, tachyphylaxis (i.e., escape of TSH secretion from the inhibitory effects of the drug), or discontinuation of treatment due to side effects (e.g., nausea, abdominal discomfort, bloating, diarrhea, glucose intolerance, and cholelithiasis) was documented in a minority of cases. If somatostatin analogs are not tolerated, dopamine agonists (bromocriptine, cabergoline) can be used even though only partial TSH suppression is seen in most of cases [57].

Thyroidectomy is reserved to patients with goiter in whom pharmacotherapy or surgery of the pituitary lesion has failed; in these patients thyroid hormone replacement should be initiated at a dose which maintains the serum-free T4 concentration in the upper 50 percent of the normal range; in fact serum TSH cannot be used to monitor therapy, since it is not suppressible [57].

There are no well-established criteria to define as cured a TSHoma after transsphenoidal surgery [57]. However, some parameters can help to assess the efficacy of the treatment. Clinical remission of hyperthyroidism, disappearance of neurological symptoms, resolution of neuroradiological alterations, and normalization of thyroid hormones, TSH, or α-GSU/TSH molar ratio may reflect the cure of a TSHoma [57]. Interestingly, the presence of undetectable TSH levels 1 week after surgery seems to be a sign of a complete adenomectomy, provided that presurgical treatment with antithyroid drugs or daily somatostatin analog injections were stopped at least 10 days before surgery [63]. Since only patients in whom T3 administration completely inhibits basal and TRH-stimulated TSH secretion may be considered as cured, T3 suppression test remains the most sensitive and specific test to document the complete removal of the adenoma [57, 63].

The recurrence of the TSHomas does not appear to be a frequent event, at least in the first years after successful surgery [2, 9]. In general, the evaluation of the patient should include the measurement of TSH and circulating free thyroid hormones two or three times the first year and then every year. Pituitary imaging should be performed 4 months postoperatively and then every 2 or 3 years. In patients with persistent macroadenoma, a close follow-up of visual fields is required.

TSHoma patients should be evaluated clinically and biochemically two or three times the first year postoperatively and then every year. TSH and circulating free thyroid hormones should be measured. Pituitary imaging (MRI) should be performed 3–4 months after surgery, and then every 2 or 3 years, but should be promptly done in the presence of a sudden rise in THS and FT4/FT3 levels. In the case of persistent macroadenoma , a close follow-up of visual fields is required to ensure that visual function is not threatened [57].

Data on the recurrence rate of TSHoma in patients who are judged to be cured after surgery or radiotherapy are area scarce. In this respect, Malchiodi et al. recently observed a tumor or hormonal recurrence within the first 2 years after surgery [9].

TSHomas in Children and Adolescents

Only eight cases (four boys and four girls) of TSHomas in patients aged 15 and under (range 8–15 years) have been so far reported [61, 64,65,66,67,68,69,70]; presenting symptoms were mainly related to T4 and T3 excess (Table 8.3). Tumors were reported to be microadenomas in two cases and macroadenomas in five cases. All patients underwent surgical treatment and in one case patient was pre-treated with octreotide without any significant effect on TSH secretion. Interestingly, in one of these cases, the coexistence of TSHoma and RTH was demonstrated [61]. Finally, TSHoma was considered as cured in three patients only.

Table 8.3 Clinical presentation and outcome of pediatric patients with TSHoma
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Summary

Patients with TSHoma present with high levels of circulating free thyroid hormones in the presence of normal/high concentrations of TSH. It is mandatory to check the results using different methods of measurement and to establish a close collaboration with the Institution laboratory to exclude any methodological interference in the measurement technique of both TSH and free thyroid hormones that may mimic the biochemical picture of TSHomas.

The clinical appearance of hyperthyroidism may be mild, sometimes overshadowed by signs and symptoms of concomitant acromegaly or by neurological symptoms (headache, visual field defect). It is mandatory to differentiate between a TSHoma and syndromes of thyroid hormone resistance by performing both TRH stimulation test and T3 suppression test to avoid unnecessary treatments.

Since the restoration of euthyroidism and the prevention of neurological symptoms due to the mass effect exerted by the tumor on surrounding structures are the main objective of the treatment, the first-line approach to TSHomas remains the surgical removal of the adenoma. If surgery is contraindicated or declined, as well as in the case of surgical failure, long-acting somatostatin analog administration is indicated, octreotide or lanreotide being successful in most patients with TSHoma.