A 2019 update on TSH-secreting pituitary adenomas
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Thyrotropin-secreting pituitary adenomas (TSH-omas) present with signs and symptoms of hyperthyroidism and they are characterized by elevated serum levels of free thyroid hormones with measurable TSH levels. TSH-omas are very infrequent, accounting for less than 1% of all pituitary adenomas, thus representing a very rare cause of hyperthyroidism. For this reason, data collected on these rare disorders are relatively few, but some new researches shed new light on the etiopathogenesis, the diagnosis and the treatment of such a remarkable disease. Since the same biochemical picture is present in the syndromes of thyroid hormone resistance (RTH), in particular in the form of pituitary RTH, failure in distinguishing these clinical entities may lead to improper patient management. Conversely, early diagnosis and correct treatment of TSH-omas may prevent the occurrence of neurological and endocrinological complications, thus leading to a better rate of cure. In the present short review article, the most relevant recent advances in the pathophysiology of TSH-omas are described.
KeywordsThyrotropin-secreting pituitary adenoma TSH-oma Central hyperthyroidism Thyrotropin Free T4 Free T3 Resistance to thyroid hormones Transsphenoidal surgery Somatostatin analogs
TSH-omas are characterized by an autonomous TSH secretion that is unresponsive to the negative feedback exerted by thyroid hormones. The continuous TSH overstimulation leads to T4 and T3 hypersecretion, this condition being classified as “central hyperthyroidism” [1, 2].
TSH-omas account for 0.5–2% of all pituitary adenomas , and the prevalence in the general population is estimated to be 1–2 cases per million. However, recent data obtained from the Swedish Pituitary Registry  demonstrated an increase in TSH-omas incidence from 1990 to 2009, the national prevalence in 2010 being 2.8 per 1 million inhabitants. TSH-omas have been documented both as part of multiple endocrine neoplasia type 1 syndrome (MEN 1)  and in a single patient with familial isolated pituitary adenoma (FIPA) with AIP mutation .
In the past, TSH-omas were diagnosed at the stage of invasive macroadenomas. Nowadays, hyperthyroid patients with unsuppressed TSH are more readily detected, thanks to the ultrasensitive immunometric assays for TSH and the measurement of circulating free thyroid hormones (FT4 and FT3), which are now routinely used. The recent introduction of the so called TSH with Reflex Free T4 strategy (i.e., FT4 measurement only in the presence of abnormal TSH) fails to recognize both central hypo and hyperthyroidism, thus leading to TSH-omas misdiagnosis.
In patients with resistance to thyroid hormones (RTH), thyroid function tests are indistinguishable from those found in TSH-oma patients  and signs and symptoms of hyperthyroidism are frequently found in the so called pituitary RTH (PRTH), a condition that is characterized by a more pronounced resistance to TH at the pituitary level.
These rare entities represent a diagnostic and therapeutic challenge, because failure in distinguishing between the two disorders may result in improper treatment, while the correct identification of a TSH-oma may prevent both neurological and endocrinological complications, thus leading to a better cure rate [4, 5, 6, 7, 8, 9, 10, 11, 12].
In this update we will give some new insights in the diagnosis and treatment of this unusual disorder. A number of reviews dealing with the management of TSH-omas have been published in the last few years by many groups [4, 5, 6, 7, 8, 9, 10, 11, 12] and they may help the readers of this update in the clinical assessment of such an unusual disorder.
Different types of TSH-secreting pituitary adenomas (updated end of November 2018)
% of total
Total TSH-secreting adenomas (TSH-omas)
It is worth noting that a positive immunohistochemistry for one or more pituitary hormones does not necessarily correlate with its or their in vivo hypersecretion, thus leading to silent TSH-omas . Moreover, the coexistence of Hashimoto’s thyroiditis and hypothyroidism with TSH-secreting tumors has been described [2, 17].
Most TSH-omas are macroadenomas invading the surrounding structures (i.e., the dura mater and bone) at the time of diagnosis . Interestingly, patients who underwent previous thyroid ablation by surgery or radioiodine present a significantly higher occurrence of invasive macroadenomas as compared with those with an intact thyroid [1, 2]. To explain this observation, it is conceivable that the reduction of circulating TH levels caused by thyroid ablation alters feedback mechanisms, thus augmenting tumor ability to grow. In the last decade, microadenomas (diameter \(\le\) 1 cm) have been increasingly recorded (up to 30–35%) due to more sensitive an specific assays used to evaluate thyroid function and greater awareness among endocrinologists and general practitioners [6, 18].
The molecular mechanisms leading to the formation of TSH-omas still need to be thoroughly elucidated. According to X-chromosomal inactivation analysis, a number of TSH-omas are monoclonal in origin and molecular analysis failed to identify any mutations affecting either oncogenes (Ras, protein kinase C, G-protein subunits, TRH receptor) or proto oncogenes (Rb, MEN1) . Recently, several candidate somatic mutations and change in copy numbers in 12 sporadic TSH-omas have been identified by whole-exome sequencing . Moreover, somatic mutations of thyroid hormone receptor beta have been reported to be responsible for the defect in negative regulation of TSH secretion in some TSH-omas . Finally, TSH-omas express a variable number of somatostatin receptors, the highest densities being found in mixed GH/TSH adenomas , thus explaining the extraordinary efficacy of somatostatin analogs in controlling TSH secretion by neoplastic thyrotropes.
TSH-omas are usually benign, and only few cases of TSH-secreting pituitary carcinomas have been described [2, 22]. TSH-omas can be diagnosed at any age and there is no major incidence in females as in common thyroid disease. TSH-oma patients generally show signs and symptoms of hyperthyroidism, frequently combined with symptoms of optic chiasm compression (visual field defects or loss of vision) and/or compression of normal pituitary cells (anterior pituitary function deficits). Nonetheless, several untreated patients with TSH-omas are completely asymptomatic.
About one-third of patients with TSH-oma underwent inappropriate thyroidectomy and/or radioiodine treatment as a consequence of an incorrect diagnosis of primary hyperthyroidism (i.e., Graves’ disease or toxic multinodular goiter). Interestingly, atrial fibrillation and/or cardiac failure has been described in sporadic cases and episodes of periodic paralysis have been reported in few patients [2, 23]. Finally, the coexistence of Graves’ disease and TSH-oma has been reported in few cases .
In about 65% of cases an enlargement of the thyroid gland is reported and the occurrence of uni- or multinodular goiter is frequently seen in patients with TSH-omas, progression towards functional autonomy having seldom been documented . The coexistence of differentiated thyroid carcinomas was reported in several patients [2, 26]. As a result, Though the prevalence of circulating antithyroid autoantibodies is similar to that found in the general population, some patients develop Graves’ disease after pituitary surgery and others present bilateral exophthalmos due the coexistence of an autoimmune thyroiditis. Finally, it should be taken into account the possibility that a unilateral exophthalmos might be due to orbital invasion by the pituitary tumor .
In 30% of female patients, menstrual disorders are reported, mainly in mixed TSH/PRL adenomas. The presence of TSH-omas and/or mixed TSH/FSH adenomas may induce central hypogonadism and decreased libido in a number of males [1, 17].
The biochemical hallmarks of hyperthyroidism secondary to TSH-omas are high serum free T3 and T4 concentrations in the presence of inappropriately normal or high serum TSH concentrations. The first step in the differential diagnosis is exclusion of methodological interference in the measurement of either thyroid hormones or TSH. FT4 and/or FT3 overestimation may be related to the presence of anti-T4 and/or anti-T3 antibodies or abnormal albumin/transthyretin forms (e.g., familial dysalbuminemic hyperthyroxinemia [27, 28, 29]. The direct “two-step” method for FT4 and FT3 concentration measurement is now considered the best, since it is able to prevent any interference due to the contact between serum factors and tracers at the time of the assay (e.g., equilibrium dialysis + RIA, adsorption chromatography + RIA, and back-titration) . Considering TSH immunometric assays, the most common factors causing spurious TSH overestimation are circulating heterophilic antibodies, i.e., antibodies directed against mouse gamma-globulins .
About 30% of TSH-oma patients with an intact thyroid present normal TSH levels together with high levels of FT4 and FT3 , this finding being likely due to an increased biological activity of secreted TSH molecules. A case of TSH-oma with cyclic fluctuations in serum TSH levels has been recently reported . Several patients with macroadenoma are biochemically characterized by elevated circulating free α-GSU levels and α-GSU/TSH molar ratio, these data being in the normal range in the presence of a microadenoma [1, 6, 31]. It has been suggested that the measurements of parameters of peripheral thyroid hormone action in vivo (basal metabolic rate, cardiac systolic time intervals, “Achilles” reflex time) and in vitro (SHBG, cholesterol, angiotensin converting enzyme, soluble interleukin-2 receptor, osteocalcin, carboxyterminal cross-linked telopeptide of type I collagen (ICTP), etc.) could be useful to evaluate the presence of tissue hyperthyroidism [2, 3, 4, 5]. In particular, liver (SHBG) and bone parameters (ICTP) are higher in patients with TSH-oma in comparison to patients with PRTH [1, 2, 3].
Dynamic tests have been recommended for the diagnosis of TSH-oma. The T3 suppression test (80–100 μg/day for 8–10 days) is generally used to diagnose patients with TSH-oma whose TSH does not suppress in response to T3 administration. Thus, T3 suppression test is actually considered the most sensitive and specific test, particularly in patients with previous thyroid ablation [2, 10]. However, this test is contraindicated in elderly patients or in those with coronary heart disease. As far as stimulatory tests are considered, TRH administration (200 μg i.v.) does not increase either TSH or α-GSU in up to 85% of TSH-oma patients . Interestingly, TSH is significantly reduced by native somatostatin and somatostatin analogs (i.e., octreotide or lanreotide) in the majority of TSH-omas and this response may predict the efficacy of long-term treatment with SSAs .
Imaging studies and localization of the tumor
TSH-omas localization relies on nuclear magnetic resonance imaging (MRI) and high-resolution computed tomography (CT). As previously described, the majority of TSH-omas are macroadenomas and in 60% of cases they present with various degrees of suprasellar extension or sphenoidal sinus invasion. Interestingly, few ectopic localizations of TSH-oma have been reported in both the nasopharyngeal and the suprasellar regions [33, 34]: these tumors have been histologically and immunohistochemically proven to be unequivocally TSH-secreting adenomas and the mass resection has been effective in normalizing TSH levels.
The coexistence of elevated serum FT4/FT3 and measurable TSH levels in a patient with signs and symptoms of hyperthyroidism is sufficient to exclude Graves’ disease or other causes of primary hyperthyroidism. It is worth noting that a measurable TSH associated with high FT4/FT3 levels during a substitutive therapy with LT4 is generally due to poor compliance or to the administration of LT4 before blood sampling.
Once the diagnosis of central hyperthyroidism is confirmed, it is mandatory to differentiate a TSH-oma from RTH [1, 2, 3, 4, 5, 32, 35]. In particular, we should suspect a TSH-oma in the presence of visual defects and/or headache (possible expression of a macroadenoma), and when the synchronous hypersecretion of other pituitary hormones leads to the manifestation of clinical features (i.e., acromegaly, galactorrhea/amenorrhea). Although the presence of a pituitary lesion at neuroradiological imaging strongly favors the diagnosis of TSH-oma, it has been demonstrated that a pituitary lesion is likely to be identified at MRI in about 20% of RTH, thus suggesting the possible coexistence of pituitary incidentaloma and RTH .
Though serum TSH levels within the normal range are more frequently found in RTH and elevated α-GSU concentrations and/or high α-GSU/TSH molar ratio are typical of TSH-omas, no differences in terms of age, sex, TSH levels or free thyroid hormone concentrations have been described as significant between patients with TSH-oma and those with RTH . As far as dynamic tests are concerned, typically TSH-omas do not respond to TRH stimulation and/or to T3 suppression tests. Chronic therapy with long-acting somatostatin analogs in patients with central hyperthyroidism is effective in reducing FT3 and FT4 levels in patients with TSH-oma, but not in those with PRTH . Thus, in selected cases, it s possible to administer long-acting somatostatin analogs for at least 2–3 months to make the differential diagnosis. Finally, TRβ gene analysis may be useful in the differential diagnosis, as genomic TRβ mutations have been detected in patients with RTH only .
Treatment and outcomes
The European Thyroid Association guidelines  recommend surgical resection as first-line therapy for TSH-secreting pituitary tumors, aimed at removing tumor mass and normalizing thyroid function. However, the presence of invasive macroadenomas or the marked fibrosis that characterizes a number of these tumors may affect the radicality of the surgery. According to the largest published series, surgery can effectively restore euthyroidism in up to 80% of patients with TSH-omas [5, 6, 7, 8, 9, 10, 11, 18].
Antithyroid drugs along with propranolol could be administered to restore normal thyroid function before surgery . In this respect, pre-surgical treatment with somatostatin analogs (i.e., Octreotide LAR and Lanreotide autogel) might be effective in reducing TSH-oma size and normalizing circulating thyroid hormones levels in patients with severe hyperthyroidism .
A possible consequence of neurosurgical intervention is partial or complete hypopituitarism, thus suggesting the need for a complete anterior pituitary function evaluation to start a replacement therapy if needed. Interestingly, a single case of thyroid storm after pituitary surgery was recently reported . Total thyroidectomy or thyroid ablation with radioiodine are indicated only when pituitary surgery is not curative and the patient suffers from life-threatening hyperthyroidism .
Alternative treatments are pituitary radiotherapy and/or medical treatment with somatostatin analogs, they should be considered when the patient is not amenable to surgery or he declines it, and in case of failure [35, 42]. According to published series, somatostatin analogs are effective in restoring normal thyroid function in about 95% and in causing a significant tumor shrinkage in up to 50% of patients [2, 18]. Somatostatin analogs are safe even though untoward side effects, such as cholelithiasis and carbohydrate intolerance, may appear. Interestingly, somatostatin analogs treatment may be safely continued even during pregnancy . If radiotherapy is prescribed, 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 and this procedure succeeds in normalizing thyroid function in 37% of patients within 2–4 years .
Criteria evaluating the results of neurosurgical treatment of a TSH-oma
Normalization of circulating TSH levels
Not applicable to patients with normal TSH
Normalization of free thyroid hormone levels
Biochemical remission may be transient
Disappearance of neurological manifestations (adenoma imaging, visual field defects, headache)
May be transient
Remission from hyperthyroid manifestations (clinical and biochemical)
Clinical improvement may be transient
Undetectable TSH 1 week after neurosurgery
Applicable to hyperthyroid patients that stopped treatments at least 10 days before surgery
Normalization of α-GSU levels and α-GSU/TSH m.r.
Not applicable to patients with normal values before neurosurgery
Positive T3-suppression test, i.e., undetectable TSH and no response to TRH (or central hypothyroidism)
Optimal sensitivity, specificity and predictive value. However, the test is contraindicated in elderly patients or in those with cardiac diseases
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The article does not contain any studies with human participants or animals performed by any of the authors.
There is no identifying patient information present in this manuscript; therefore, informed consent is unnecessary.
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