DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma

in European Journal of Endocrinology
View More View Less
  • 1 Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 2 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 3 Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden

Correspondence should be addressed to A Tjörnstrand; Email: axel.tjornstrand@vgregion.se

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.

Abstract

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.

Invited Author’s profile

Helena Filipsson Nyström is a senior consultant within thyroidology at Sahlgrenska University Hospital in Göteborg, Sweden, and the leader of the largest thyroid unit in the country. Her research currently focuses on mental consequences in two groups of patients: women with Graves’ disease and children whose mothers have had mild iodine deficiency during pregnancy. She is the national representative for the Iodine Global Network and is part of the EUthyroid collaboration.

Introduction

In 1960, Jailer and Holub proposed that the pituitary could be responsible for excessive production of thyrotropin (TSH) and secondary hyperthyroidism (1). It was later confirmed (2) that the underlying cause was a TSH-secreting pituitary adenoma (TSHoma). After that, TSHoma reports were scarce in the literature. It was not until the 1980s that a few limited reports on the diagnosis of TSHomas were published (3, 4, 5, 6, 7, 8). Subsequently, the diagnostic and therapeutic management of these rare pituitary adenomas has evolved substantially. This is due to the following reasons: use of ultrasensitive TSH methods since the late 1980s (9, 10); the introduction of the concept ‘syndrome of inappropriate TSH secretion’ (11); advances in imaging procedures, moving from computed tomography (CT) to magnetic resonance imaging (MRI) with superior visualization of the pituitary area (12); and the use of somatostatin analogs in the therapeutic management of these patients (13, 14).

Although a rare disease, noteworthy cohorts have been published. The six largest patient cohorts reported are from Japan (N = 90) (15), Italy (N = 70) (16), Belgium and France (N = 43) (17), England (N = 32) (18), Sweden (N = 28) (19) and the United States (N = 25) (20) (Table 1). These series and other reports have contributed to the collation of substantial knowledge on TSHomas over 50 years.

Table 1

Case series with >5 TSHoma cases is presented with demographic and radiologic data including the plurihormonal activity from biochemical and immunohistochemical evaluation.

Study (reference no)Study periodCases (n)Men, n (%)Macroadenoma (≥10 mm), n (%)Invasiveb (%)Mean age, years (range)CohortPlurihormonal (%)
Wynne et al. (4)1970–199064 (67)5 (83)8345 (25–72)Neurosurgery50d
Bertholon-Gregoire et al. (6)1971–1996124 (33)11 (92)5838 (20–62)Endocrine42d
Beckers et al. (5)1976–198973 (43)6 (86)N/A50 (18–84)Endocrine60c
Socin et al. (17)1976–20014323 (53)34 (83)7244 (N/A)Endocrine40c
Mindermann et al. (8)1978–1991197 (37)19 (100)6335 (N/A)Neurosurgery50d
Gesundheit et al. (7)1982–198692 (22)7 (78)6737 (24–51)Neurosurgery100c
Brucker-Davis et al. (20)1982–1996258 (32)25 (92)8044 (15–80)Neurosurgery20c
Losa et al.a (123)1982–19961710 (59)14 (82)N/A42 (22–63)Endocrine29c
Malchiodi et al.a (16)1982–20127034 (49)49 (70)5444 (N/A)Endocrine/neurosurgery24c
Sanno et al. (124)1983–1999164 (25)14 (88)3841 (23–60)Neurosurgery38c
Elton-Conaglen (125)1983–200363 (50)5 (83)5043 (20–58)Endocrine50c
Clarke et al. (126)1987–20032115 (71)16 (89)2846 (26–73)Neurosurgery5c
Ness-Abramof et al. (127)1989–2007116 (55)10 (91)9145 (18–80)Endocrine36c
Varsseveld et al. (128)1989–20111812 (67)13 (72)7248 (N/A)Endocrine17c
Onnestam et al. (19)1990–20102811 (39)16 (59)2856 (16–81)Endocrine46c
Perticone et al.a (98)1990–20136230 (48)45 (73)2943 (14–76)NeurosurgeryN/A
Yamada et al. (15)1991–20139043 (48)74 (82)2342 (11–74)Neurosurgery28c
Marucci et al. (119)1992–2006105 (50)10 (100)6047 (19–71)Neurosurgery/pathology20d
Gatto et al. (129)1993–2011139 (69)10 (77)3842 (27–61)Endocrine0c
Azzalin et al. (silent) (130)1993–2013147 (50)14 (100)N/A47 (28–75)Neurosurgery33c
Azzalin et al. (overt) (130)1993–201365 (83)5 (83)N/A41 (24–57)Neurosurgery79c
Kirkman et al. (18)2002–20123216 (50)28 (87)5653 (20–75)Neurosurgery84d
Total1970–2013535261 (49)435 (81)5844 (11–84)50 (mean)

Cases have to some extent been previously reported; binvasive includes extrasellar extension and/or invasion to the cavernous sinus; cplurihormonal activity is reported from clinical manifestation and biochemistry; dplurihormonal activity is reported from immunohistochemic analysis.

N/A, not available.

In 2013, a comprehensive guideline from the European Thyroid Association (ETA) on diagnosis and treatment of TSHomas was published (21). The aims of this review are to put TSHoma diagnosing into a practical perspective and present up-to-date information on the differential diagnoses, concurrent diseases, and highlight on recent advances and indicate future areas of research in the imaging area. In this review, the reader will approach the diagnosis step by step. In the majority of cases, TSHomas are located in the pituitary, but a few cases of ectopic TSH production have been described with suprasellar localization (22) or in the nasopharynx (23, 24, 25, 26, 27). This review will also cover the possibility of these rare cases.

Epidemiology

Pituitary adenomas are the most common type of abnormal cell growth in the pituitary (28) with a high prevalence in the normal population. In a meta-analysis from 2004, the authors found an overall prevalence of 16.7% (29) (14.4% in autopsy studies and 22.5% in radiologic studies). Clinical manifestations of pituitary adenomas imply a much lower prevalence. A series of studies on well-defined populations report a prevalence of 75.7–94/100 000 inhabitants of clinically overt cases (30, 31, 32), and the reported incidence is 3.9–4.1 cases/100 000 inhabitants per year (31, 33, 34). Pituitary adenomas are one of the most frequently occurring intracranial tumors, and the occurrence of pituitary adenomas seems to be similar despite geographic or ethnic differences (29, 35, 36).

TSHomas are the rarest among the pituitary adenomas, only representing 0.7–0.94% of all pituitary adenomas (31, 33, 34). A comprehensive study of the Swedish national Pituitary Registry found a national prevalence of 2.8 clinically overt cases per million inhabitants and an incidence rate of 0.15 cases per million inhabitants per year (19). Moreover, during the study period 1991–2011, the detection rate increased fivefold (Fig. 1). This follows a general trend of higher detection rate for all pituitary adenomas, which may be attributed to more sensitive diagnostic methods and the more widespread use of MRI scanners.

Figure 1
Figure 1

Time trend in national incidence of TSH-secreting pituitary adenoma (TSHoma) in Sweden 1990–2009, and number of TSHoma micro- and macroadenomas (<1 cm/≥1 cm) 1990–1994, 1995–1999, 2000–2004 and 2005–2010 (17). Republished with the permission from Journal of Clinical Endocrinology and Metabolism.

Citation: European Journal of Endocrinology 177, 4; 10.1530/EJE-16-1029

Before the 1990s, when the diagnosis of secondary hyperthyroidism was facilitated by modern ultrasensitive TSH methods (9, 10, 37), tumor size was often large at time of diagnosis (17, 20). Since the introduction of the ultrasensitive TSH methods, TSH-producing adenomas are more frequently found at the stage of microadenomas (17, 19, 38, 39, 40). However, macroadenomas (>10 mm in any dimension) still represent approximately 80–85% of all newly discovered TSHomas (Table 1). An inappropriate thyroid ablation seems also to promote the development of macroadenomas (17), suggesting a similar mechanism to the Nelson syndrome in ACTH-producing tumors when cortisol (or T4/T3) feedback is removed. Therefore, a prompt and proper diagnosis is highly warranted.

TSHomas are predominantly diagnosed in middle age, but there are cases reported in the range of 11–84 years of age (Table 1).

Histopathology of TSHomas

TSH-secreting pituitary tumors are presumed to represent a clonal expansion of abnormal cells. The TSH-producing cells represent <5% of all pituitary cells (41). This may explain why TSHomas are so rare (19, 33, 34). Chromophobic polygonal or short-spindled tumor cells are often seen in a diffuse pattern. Also globoid or whorl-like appearance with intertwined cytoplasmic processes, stromal fibrosis, and calcification are often noted (42). This has been attributed to an expression of the basic fibroblast growth factor (bFGF) (43) and corresponds well with clinical findings of fibrotic characteristics (41), seen in approximately 40% of TSHomas (17).

In TSHomas, co-secretion of PIT-1 factor-dependent hormones (growth hormone (GH) and prolactin (PRL)) is common (Table 1). The frequency seems to vary considerably depending on clinical or histopathological classification. In the largest case series of TSHoma patients (15), clinical manifestations of acromegaly and hyperprolactinemia were observed in 14 (16%) and 11 cases (12%), respectively. Microscopically, however, positive immunostaining for GH was found in 36%, GH and PRL in 27% and PRL in 10% of cases (15). In this study, KI-67 was low; in only two patients, KI-67 was >3%.

Pituitary cells express several regulatory receptors. Somatostatin analogs (SSA) have inhibitory effect on the hormone production in TSH-, ACTH- and GH-secreting pituitary tumors (44), which is mediated by somatostatin receptors (SSTR), of which six subtypes have been characterized. TSHomas express SSTR 1, 2, 3, and 5, where SSTR 2 (with subtype 2A and 2B) is most frequent (45). Endogenous somatostatin binds with high affinity to all its receptors, SSTR 1–5, and the activation of SSTR 1, 2, 4 and 5 appears to induce cell-cycle arrest (44, 46).

First-generation SSAs, such as octreotide and lanreotide, show preferential affinity for SSTR2 and moderate affinity for SSTR5. The newly available SSA, pasireotide, shows a preferential binding affinity for SSTR5 > SSTR2 > SSTR1 > SSTR3. Recent clinical studies have shown the efficacy of pasireotide in acromegaly and Cushing’s disease, respectively (47, 48).

Clinical presentation

Although TSHomas are rare, they are an important entity with a spectrum of clinical manifestations. Pituitary adenomas can be discovered accidentally in the workup with CT/MRI that is done for other reasons, such as in the diagnostic procedure for a headache, through symptoms connected to hormonal hyperproduction, or on suspicion of visual symptoms. Clinically silent TSHomas or TSHomas that present with active hormone production have similar prognosis and outcome (18). Only a quarter of surgically treated patients with a positive histopathological TSH-immunostaining present clinically (18). In clinically active TSHomas, often mild-to-moderate classic hyperthyreotic symptoms are common (17, 19, 20), although the time to diagnosis may be long (17, 19, 20). As symptoms may be discrete and the diagnostic procedures are complicated, a referral to tertiary referral centers is often needed.

Also, patients may present by symptoms from local compression, which is the reason for detection in 29–38% of cases (19, 20). The clinical presentation of a TSHoma can also be blurred by the co-production of other hormones from the tumor, predominantly PRL and/or GH (6, 17, 19, 20, 38) (Table 1). Clinically detectable co-production of any of these PIT-1 factor-dependent hormones increases with tumor size, even if many tumors histopathologically express all three hormones regardless of size (17, 49).

In TSHomas, TSH is characteristically unsuppressed, and thyroid hormones are elevated above the upper reference (19). A subgroup represents cases where an initial diagnosis has been missed and the patients have been improperly treated with thyroidectomy or radioactive iodine (RAI). In these cases, TSH increases to supranormal levels when l-thyroxin is administered (19, 20, 27) (Fig. 2A and B). The patient may be referred due to an inability to normalize TSH with increasing l-thyroxin doses without causing supranormal FT4 levels. In these cases, an undiagnosed TSHoma must be considered.

Figure 2
Figure 2

TSH (A) and FT4 (B) at diagnosis of 28 TSH-secreting pituitary adenoma (TSHoma) patients with intact or treated thyroid gland. Hormone levels are related to upper limit of normal (dotted line) (17). Republished with the permission from Journal of Clinical Endocrinology and Metabolism.

Citation: European Journal of Endocrinology 177, 4; 10.1530/EJE-16-1029

Diagnostic approach

TSH secretion in the pituitary is regulated by thyrotropin-releasing hormone (TRH), somatostatin, dopamine and thyroid hormones and is characterized by a diurnal pattern with small bursts (50). In the abnormal cells in a TSHoma, TSH secretion is disorganized, which may be explained by altered functional properties within the tumor. An increased pulse frequency is seen with enhanced non-pulsatile release (51). In TSHomas, the TSH level varies from normal to elevated that can be explained by a change in glycosylation of TSH molecules with higher bioactivity (52): TSHomas also secrete a mixture of isoforms, where the alpha subunit of the glycoprotein is the major component (53).

As mentioned earlier, guidelines for the diagnosis of TSHoma were published in 2013 by the ETA (21). Clinicians are used to work in an evidence-based manner. However, predictive values are not available for different diagnostic tests as TSHomas are rare and there is a lack of power. The frequency of abnormal tests in TSHoma patients is described below.

Laboratory assessment

First step

Before conducting further investigations for central hyperthyroidism in the presentation as syndrome of inappropriate TSH secretion (SITSH) with unsuppressed TSH and elevated thyroid hormone levels, interference from medications, like estrogens, pregnancy state, non-thyroidal illness and subacute/silent autoimmune thyroiditis, need to be excluded (54). The timing of the sampling should not be underestimated, and repeated sampling at months’ interval is needed to exclude transitory changes. To exclude thyroid disease, thyroid autoantibodies (thyreoperoxidase (TPO) and TSH receptor-antibodies) are of value. Also, the euthyroid, hypothyroid and hyperthyroid states of the patient need to be assessed. Laboratory interference and genetic causes are more common than TSHomas (see differential diagnoses below). Therefore, when a patient is referred with SITSH, the first diagnostic procedures include a blood test to evaluate pituitary function, thyroid hormone evaluation through testing with several laboratory methods and to take thyroid hormone function tests in first-degree relatives (Fig. 3). Although patients with TSHomas and resistance to thyroid hormones (RTH) have increased production of thyroid hormones in common, the peripheral response differs because of the insensitive TRβ in RTH. To distinguish hyperthyroidism from RTH, carboxy-terminal cross-linked telopeptide of type-I collagen (ITCP) may be used (55). Patients with hyperthyroidism have significantly higher ITCP levels than RTH patients, illustrating the hypermetabolic state in the bone in hyperthyroidism, whereas in RTH, the resistance in the TRβ influences bone resorption markers (56). Furthermore, sex hormone-binding globulin (SHBG) is usually elevated in thyrotoxicosis and is reported to be normal in RTH (57, 58). Therefore, SHBG and ITCP may be used in the first diagnostic workup.

Figure 3
Figure 3

Flowchart on the diagnosis of thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) when it is presented as the syndrome of inappropriate TSH secretion.

Citation: European Journal of Endocrinology 177, 4; 10.1530/EJE-16-1029

Second step

If there are no indications of laboratory error and if first-degree relatives do not demonstrate a similar laboratory picture, then a TRH test is done regardless if pituitary function tests do indicate a pituitary origin or not. This may also be the step of choice for heredity indications in parallel with mutation tests for RTH and/or familial dysalbuminemic hyperthyroxinemia. The normal response in TSH from TRH stimulation is defined as an increase of >50% and/or an increase of >4 IU/L (17). According to this definition of a normal response, 81% of TSHomas have an abnormal response to the TRH test (17), whereas in the ETA guidelines Beck-Peccoz et al. reported 90% with an abnormal TRH test (21, 59).

Third step

Alpha subunit (αSU) may also be used as a diagnostic tool and is elevated in 30% of cases with a TSHoma (17). Stimulated αSU, defined as a 100% increase after TRH administration, is positive in 44% of cases (17). The molar ratio between αSU and TSH is no longer recommended (21) (Table 2). To possibly confirm or discard the hypothesis of TSHoma requires a thorough detective work.

Table 2

Comparison of the clinical presentation and laboratory findings in TSH-secreting adenomas (TSHomas) and resistance to thyroid hormones (RTH).

TSHomaRTH
Goiter (%)9480
Pituitary over/under production of other hormones+
Increased α subunit+
Increase in TSH after a TRH testNegativePositive
Increase in α subunit after TRH testPositiveNegative
MRI pituitary+
Visual field disturbancesMaybe +
T3 suppression testNo TSH suppressionSuppression of TSH
DNA mutation analysis+
Somatostatin testFT4 ↓ >30%FT4 is not affected
Sinus petrosus catheterization+

MR, magnetic resonance imaging; RTH, resistance to thyroid hormone; TRH, thyrotropin releasing hormone; TSH, thyroid-stimulating hormone.

A somatostatin test may also be used in order to distinguish between a TSHoma and RTH. The patient is given somatostatin subcutaneously and thyroid hormones are checked after 6 h. If this is well tolerated, 20 mg of the somatostatin analog octreotide long-acting release (LAR) may be given intramuscularly every fourth week. After 8 weeks, thyroid hormones are measured. In RTH, there is no reduction in thyroid hormones, whereas in 6 out of 8 cases, TSHomas normalize thyroid hormone levels despite minor changes in immunoreactive TSH levels (13). The thyreotropic cells and TRH-producing hypothalamic cells are regulated through the negative feedback mechanism from the thyroid hormones and react on small changes. The thyroid hormone regulatory feedback mechanism is superior to that of somatostatin regulation. In TSHomas, the TSH production is autonomous, and the negative feedback is redundant. Hence, in most cases of TSHomas, thyroid hormone levels will be lower.

Fourth step

A difficulty in the diagnosis of TSHomas is that incidentalomas (non-functioning pituitary adenomas (NFPA)) are more common and occur in 10–20% of the normal population (29). There is also a special diagnostic dilemma in differentiating a TSHoma from RTH in combination with a pituitary incidentaloma (60). If the suspicion of a TSHoma arises from a pituitary tumor during MRI and the classical laboratory test results are in accordance with SITSH, the occurrences of a NFPA are more frequent than a TSHoma and autonomous TSH production needs to be established (38).

The T3 suppression test, the liothyronine test, is only used if doubts are raised during diagnosis or a NFPA needs to be excluded. When a MRI scan is performed due to symptoms of an expansive process in the pituitary gland and an adenoma is found in combination with high FT4 and normal TSH and the TRH test is abnormal, the patient could be referred directly for surgery without a T3 suppression test. However, there are situations when results are contradictory, such as in cases of an abnormal TRH test when the MRI does not reveal a pituitary adenoma, or if there is a normal response to TRH in the presence of a pituitary adenoma, or if the patient is thyroidectomized. Also, it has been reported that the frequency of hyperplasia/adenomas in the pituitary from RTH is approximately 20% (61). In cases with long-term primary hypothyreosis, there is hyperplasia of the pituitary (62, 63), and sporadic reports on TSHomas in RTH (64, 65, 66).

The T3 suppression test should not be done in cases of severe pulmonary or cardiovascular disease or any disease that may decompensate from a short period of hyperthyroidism, such as heart disease or psychiatric disease. An example of the T3 test used at our institution, at Sahlgrenska University Hospital Gothenburg, is presented in Fig. 4; this version is modified from Dare et al. (67) and from personal communication with the last author of that publication. The autonomous TSH production is proven by an inability of T3 to suppress TSH. This test is abnormal in 100% of TSHomas (21, 59).

Figure 4
Figure 4

T3 test used at our institution, this version is modified from Dare et al. (99) and from personal communication with the last author of that publication. The autonomous TSH production is proven by an inability of T3 to suppress TSH.

Citation: European Journal of Endocrinology 177, 4; 10.1530/EJE-16-1029

If MRI does not reveal an adenoma despite laboratory findings indicative of a TSHoma, there are some reports on sinus petrosus catheterization with TRH stimulation used in order to evaluate the presence of a TSHoma (17, 68), but its performance and validity are not described. Perhaps functional imaging may play a future role in these cases. Although less common, an ectopic TSHoma may also be considered (17).

Imaging assessment

Imaging of the pituitary has developed rapidly. Earlier, evaluation with plain skull radiographs was the modality of choice; however, this technique was poor in delineating the soft tissue. The technique focused mainly on secondary findings of pathology in the sella, i.e. calcifications and enlargement. These findings are not considered sensitive indicators of pituitary gland abnormalities. Thus, plain radiographs were replaced by cross-sectional imaging techniques such as the CT scan and MRI.

Structural imaging

MRI

MRI techniques for diagnosing pituitary lesions have witnessed a rapid evolution since it first came to use in the early 1980s. The resolution and sensitivity of these techniques were until the early 1990s comparable to those of CT-scans, but presented a superior soft-tissue resolution and a greater delineation to adjacent structures. With the introduction of dynamic contrast-enhanced MRI in the early 1990s (69), the sensitivity for diagnosing pituitary microadenomas increased vastly (70).

MRI is usually the only method needed for the morphological investigation of endocrine active pituitary adenomas. Radiologic evaluations differ in regard to the size of the lesion, i.e. macroadenomas (>10 mm) and microadenomas (<10 mm). Pituitary macroadenomas are usually located in the center of the sella turcica with extra sellar extension, growing upward toward the third ventricle and sometimes the foramen of Monro (71, 72).

Studies on TSH-producing adenomas using MRI, describe macroadenomas in the majority of cases and usually hypoechoic appearance in respect to normal pituitary tissue after gadolinium administration (73). In comparison to other similar, and more common, pituitary adenomas (such as GH- and PRL-producing adenomas), TSH-producing adenomas tend to have a higher degree of microscopic invasion and intra- and peritumoral fibrosis, which correlate with the findings in surgical material (15). In this regard, a protocol with several sequences (such as dynamic, contrast enhanced, spin echo T1 and T2) is preferable to not just detect elusive lesions but also to delineate tumor tissue to adjacent structures and normal pituitary tissue. Such signs of microscopic invasion can contribute with important prognostic information before surgical treatment (73).

Microadenomas are more difficult to detect, but have often a hypoechoic signal on contrast-enhanced T1 sequences. Microadenomas are now reported with an increased frequency in TSHomas, accounting for about 20% of all recorded cases (Table 1). Smaller lesions require more complex methods and high-field scanners. Different methods and approaches have been assessed in regard to optimize the detection rate of microadenomas. Pinker et al. demonstrated that the use of high-field MRI scanners, i.e. 3.0 T, was superior to low-field scanners of 1.0 T or 1.5 T in predicting local invasion of adjacent structures. They also showed that the use of a 3.0 T scanner improved surgical planning of sellar lesions (74). Lee et al. evaluated the technique of simultaneous acquisition of contrast-enhanced coronal and sagittal images on a 3.0 T MRI and found a detection rate of more than 92% for microadenomas in the pituitary region (75). In comparison, the detection rate was only 82% for uniplanar coronal and 75% for uniplanar sagittal projections (75). The multiplanar combination of sagittal and coronal projections in gadolinium-enhanced MRI are now the preferred tools for visualization and is considered the modality of choice for pituitary imaging (71, 72). There are however some disadvantages that comes with the use of MRI at 3.0 T. Prolonged T1 relaxation time, radiofrequency magnetic field inhomogeneity and increased susceptibility artifacts have been proposed (76). The spoiled gradient recalled acquisition in the steady-state (SPGR) sequence and fast SPGR (fSPGR) are relatively new sequencing techniques that challenge these disadvantages. Kakite et al. demonstrated that vascular pulsation artifacts and partial volume effect were significantly reduced on the SPGR sequence (77). SPGR and fSPGR also demonstrate superior soft-tissue contrast compared with the spin echo technique and can be performed in notably thin-slice sections (78). As SPGR can be performed in sections of 1 mm, the risk of missing small lesions in the pituitary is far less. SPGR has primarily been used in the evaluation of suspected adenomas in Cushing’s disease, since they often manifest as microadenomas (usually <2 mm) and are notoriously difficult to detect with the standard T1 spin echo MRI sequence. Currently, modern pituitary MRI sequences fail to detect approximately 40% of Cushing’s disease cases (79). In these patients, SPGR has increased the detection rate by 10–15%. Masopust et al. achieved a remarkable sensitivity of 100% in 41 Cushing’s disease patients by combining three MR sequences: spin echo, SPGR and fSPGR (80).

To our knowledge, SPGR sequences have not been studied on TSH-producing adenomas. SPGR seems to provide higher sensitivity in the MRI evaluations in ACTH-producing adenomas, but these results cannot be generalized to TSHomas. TSHomas usually manifest as macroadenomas and with a fibrous consistency, and thus the sensitivity of the spin echo sequence is, in most cases, sufficient. A diagnostic imaging with higher specificity would be a better contribution in the current diagnostic workup. In this regard, functional imaging seems to have the potential to provide a better detection rate with higher specificity in pituitary adenomas in general and in TSHomas in particular.

Functional imaging

Scintigraphy

As pituitary gland and pituitary adenomas express somatostatin receptors, SSTR, as oppose to adjacent structures and brain tissue, these receptors provide excellent conditions for functional imaging. TSHomas have a high expression density of somatostatin receptors compared to normal pituitary tissue, in particular SSTR 2 and 5, which makes it a good candidate for scintigrahpic evaluation. Scintigraphy with radio-labeled octreotide can successfully localize most hormone-producing adenomas due to high expression rate of somatostatin receptors (81). TSHomas are detectable with this technique (82); however, the specificity of this technique is low, as positive scans can occur in the case of a pituitary mass of different types, either secreting or non-secreting, and even in normal pituitary tissue.

Position emission tomography (PET)

PET/CT has superior resolution and imaging quality over scintigraphy, and there have been promising results in identifying pituitary adenomas. In a case series with seven TSHoma patients examined with 111In-pentreotide-SPECT (single-photon emission CT) and two patients with 11C-l-methionine PET/CT, both SPECT and PET/CT imaging revealed positive uptake in patients with microadenomas that was not detected by MRI (17). The PET/CT evaluation even detected 2 microadenomas in cases where the 111In-pentreotide scan did not detect any pathology (17). However, the study was unable to predict the response to somatostatin analog treatment.

PET/CT technique has the advantages of better resolution and the ability to quantify, compared to SPECT. The use of somatostatin receptor PET/CT for the detection of TSHomas has not yet been widely evaluated. A new line of gallium-labeled somatostatin receptor analogs (68Ga-DOTANOC, DOTATATE, DOTATOC) has been increasingly used in the evaluation of neuroendocrine tumors, NETs. This technique has only been evaluated in a small number of case series with successful results in diagnosing an ectopic TSH-producing adenoma (83) and pituitary carcinoma (84), thus implying a promising prospect for better functional imaging in future diagnostic workup of TSHomas. A study evaluating the uptake of 68Ga-DOTATOC in pituitary adenomas is ongoing and will hopefully bring more clarity to the matter (clinicaltrials.gov identifier: Nbib2419664).

Differential diagnoses

In the workup of a patient’s syndrome of inappropriate TSH secretion, diagnoses other than TSHomas must first be considered, given the low incidence of TSHomas (19). The most important differential diagnoses are laboratory interference and mutations resulting in a changed affinity for the thyroid hormone receptor or to carrier molecules. Also, rarely, thyroxin binding globulin (TBG) deficiency can result in decreased levels of total thyroid hormone and thereby increased free T4 (85), from lower binding capacity, even if TBG deficiency is most commonly presented as central hypothyroidism. Another rare cause of SITSH is inadequate hydrocortisone replacement after surgery in Cushing’s syndrome (86).

Laboratory interference is not a true increase in thyroid hormone production, but results from interfering substances in the laboratory method used, such as thyroid hormone antibodies (87), heterophilic antibodies (88) or other method specific interferences (89, 90), result in falsely increased thyroid hormone levels (54). In clinical practice, different forms of laboratory interference are rarely diagnosed, as the important issue is to find a TSHoma. Laboratory interference can be suspected when thyroid hormone levels vary among different laboratory methods: this can be detected through comparing the results from one sample with several analytical platforms. The TRH- and α-subunit-tests are normal in laboratory interference.

When disturbances due to the laboratory method are excluded, the main differential diagnosis to TSHomas is mutation in the thyroid hormone receptor with the syndrome of RTH (91) (Table 2) or mutations in thyroid hormone transport proteins, familiar FDH (92). These conditions have a variety of mutations. In RTH, both TRH in the hypothalamus and TSH from the anterior pituitary is inappropriately increased in relation to thyroid hormone levels. In RTH, both T4 and T3 are elevated, whereas in the typical scenario, in FDH, only T4 levels are disturbed. However, practically, not only total T4 but also total T3 or free T3 and free T4 are disturbed (elevated) in many patients with FDH. Individuals with genetic variations in thyroid hormone transport proteins are clinically euthyroid, but present with altered thyroid function tests, and do not require treatment. In FDH, laboratory interference may occur as the change of binding affinity to prealbumin interacts differently in different methods.

Unlike in TSHomas, in RTH and FDH, familial cases are common. RTH is an autosomal dominant inherited mutation in the β-isoform of the T3 receptor (93), and FDH is a familiar autosomal dominant disease caused by a mutation in the albumin gene that results in a 10-fold higher affinity of T4 in homozygotic cases; in heterozygote people T4 affinity is doubled (94). FDH is the most common inherited cause of increased T4 (94). In cases of SITSH where the TRH- and α-subunit-tests are normal, FDH may be suspected, especially if the results vary depending on the methods used.

Mutation analyses are costly compared to FT4 and TSH blood samples, thus, a first step may be to analyze thyroid hormones in first-degree relatives, in order to strengthen the suspicion of a heredity cause for the syndrome of inappropriate TSH secretion.

As many patients approach health care with a laboratory constellation of unsuppressed TSH and increased thyroid hormone levels, all differential diagnoses need to be considered in parallel for an effective clinical workup.

In Italy, 99 patients were referred for SITSH, of these, 68 were determined as RTH and 31 as TSHomas (95). In 24% of the RTH cases, no mutation was found, and there were no familial cases; eventually three TSHomas were detected, illustrating the difficulties of distinguishing between the etiologies. To support the investigation, clinical presentation can be useful (Table 2). Goiter is common in patients with TSHomas and RTH, but the response to stimulatory tests differs due to the pituitary involvement (Table 2). Diagnosing a patient with a syndrome of inappropriate TSH secretion is complicated and requires special competences, especially in situations where patients have received treatment for an assumed primary hyperthyroidism (17, 19, 27) or in the rare cases where RTH is coexisting with a TSHoma (64). RTH is considered to predispose to both pituitary hyperplasia and to the development of adenomas and, even in some rare cases, ectopic TSHomas (22, 23, 24, 25, 26, 27), making regular monitoring of these patients a necessity.

Concomitant diseases in association with TSHomas

In 1994, a case with autonomous functioning thyroid nodules preceded by a TSHoma was first reported (96). Thus, a plausible relationship between TSH stimulation from the pituitary on the thyroid gland was established. A trophic hormone may cause autonomous secretion in the thyroid gland, which resembles what happens in other target glands. Patients exposed to unregulated and inappropriate TSH levels may have an increased risk for well-differentiated thyroid cancer (97). In 62 patients with TSHomas, three cases with this thyroid cancer were found (97), and it is also reported in other case reports (98, 99, 100, 101). A common disease can inevitably co-exist with a more rare disorder without any causal relationship, but there may be a rationale for excluding neoplastic lesions in the thyroid gland, e.g. with an ultrasound.

There may also be an etiologic link between Graves’ disease and TSHomas. Autoimmunity may be induced when TSH levels rapidly decrease after surgical and/or SSA treatment (102). Graves’ disease may also be triggered through affected intrathyroidal lymphocytes harboring the same SSTR 2A as the TSHoma cells. The development of Graves’ disease after treatment for a TSHoma is reported (103, 104, 105), as is Graves’ disease before the detection of a TSHoma (106, 107, 108, 109, 110). The combination of TSHoma and Graves’ disease may be further complicated by the coexistence of exophthalmia. Exophthalmos is reported in TSHoma because of tumor invasion in the orbit (111).

Autoimmune hypothyroidism may co-exist with TSHoma, but any causality is yet unclear (112, 113, 114). Pituitary hyperplasia from increased TSH production in hypothyroidism may in some rare cases mimic a macroadenoma (115). In the same way as TSHoma is reported, in RTH, where longstanding stimulation may promote tertiary tumor evolvement (66, 116), a secondary hyperplasia may mimic a pituitary tumor (117). However, primary hypothyroidism in parallel may complicate the diagnosis of TSHoma and cause delay (118).

Even if most TSHomas are sporadic, there are reports that TSHomas may be the pituitary component in multiple endocrine neoplasia type 1 (MEN-1). In a report from six Belgian and French centers where 43 patients with TSHoma were described, 2 patients were diagnosed with clinical MEN-1, but no MEN-1 mutation was found (17). In another cohort of 166 patients with pituitary tumors, including one TSHoma (119), patients with hyperparathyroidism (n = 8, 4.8%) were selected and screened for other manifestations of MEN-1: the TSHoma case was not found among the group of eight pituitary adenomas selected, and prolactinomas appeared dominate in MEN-1. However, TSHoma cases are described in MEN-1 (120).

Pituitary adenomas rarely turn into pituitary carcinomas. The majority of pituitary carcinomas secrete ACTH or prolactin and only two known cases of TSH-producing carcinomas are described in the literature (121, 122). One of these was a NFPA that transformed into a PRL- and TSH-secreting carcinoma (121). A transforming adenoma should be evaluated for the risk of developing into a carcinoma.

Conclusion

TSHomas are rare tumors that in most cases demand special competence and involve a complicated routine of investigations. There has been much progress in the ability to separate TSHoma from differential diagnoses with a proper laboratory procedure. As TSHomas are rare and incidentalomas in the pituitary gland are common, an autonomous TSH production needs to be established. The ideal diagnostic approach would be to simultaneously receive both hormonal and morphologic information, as with functional imaging. Major advances in the imaging area in recent years contribute to the conviction that next important steps in the TSHomas’ diagnostic approach will be within the imaging field.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Jailer JW & Holub DA. Remission of Graves’ disease following radiotherapy of a pituitary neoplasm. American Journal of Medicine 1960 28 497500. (doi:10.1016/0002-9343(60)90181-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Hamilton CR Jr, Adams LC & Maloof F. Hyperthyroidism due to thyrotropin-producing pituitary chromophobe adenoma. New England Journal of Medicine 1970 283 10771080. (doi:10.1056/NEJM197011122832003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Grisoli F, Leclercq T, Winteler JP, Jaquet P, Guibout M, Diaz-Vasquez P, Hassoun J & Nayak R. Thyroid-stimulating hormone pituitary adenomas and hyperthyroidism. Surgical Neurology 1986 25 361368. (doi:10.1016/0090-3019(86)90211-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Wynne AG, Gharib H, Scheithauer BW, Davis DH, Freeman SL & Horvath E. Hyperthyroidism due to inappropriate secretion of thyrotropin in 10 patients. American Journal of Medicine 1992 92 1524. (doi:10.1016/0002-9343(92)90009-Z)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Beckers A, Abs R, Mahler C, Vandalem JL, Pirens G, Hennen G & Stevenaert A. Thyrotropin-secreting pituitary adenomas: report of seven cases. Journal of Clinical Endocrinology and Metabolism 1991 72 477483. (doi:10.1210/jcem-72-2-477)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Bertholon-Gregoire M, Trouillas J, Guigard MP, Loras B & Tourniaire J. Mono- and plurihormonal thyrotropic pituitary adenomas: pathological, hormonal and clinical studies in 12 patients. European Journal of Endocrinology 1999 140 519527. (doi:10.1530/eje.0.1400519)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Gesundheit N, Petrick PA, Nissim M, Dahlberg PA, Doppman JL, Emerson CH, Braverman LE, Oldfield EH & Weintraub BD. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Case reports and follow-up of nine patients. Annals of Internal Medicine 1989 111 827835. (doi:10.7326/0003-4819-111-10-827)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mindermann T & Wilson CB. Thyrotropin-producing pituitary adenomas. Journal of Neurosurgery 1993 79 521527. (doi:10.3171/jns.1993.79.4.0521)

  • 9

    Caldwell G, Kellett HA, Gow SM, Beckett GJ, Sweeting VM, Seth J & Toft AD. A new strategy for thyroid function testing. Lancet 1985 1 11171119. (doi:10.1016/S0140-6736(85)92429-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ross DS, Ardisson LJ & Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. Journal of Clinical Endocrinology and Metabolism 1989 69 684688. (doi:10.1210/jcem-69-3-684)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Gershengorn MC & Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of ‘inappropriate secretion of TSH’. Journal of Clinical Investigation 1975 56 633642. (doi:10.1172/JCI108133)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Kucharczyk W, Davis DO, Kelly WM, Sze G, Norman D & Newton TH. Pituitary adenomas: high-resolution MR imaging at 1.5 T. Radiology 1986 161 761765. (doi:10.1148/radiology.161.3.3786729)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Mannavola D, Persani L, Vannucchi G, Zanardelli M, Fugazzola L, Verga U, Facchetti M & Beck-Peccoz P. Different responses to chronic somatostatin analogues in patients with central hyperthyroidism. Clinical Endocrinology 2005 62 176181. (doi:10.1111/j.1365-2265.2004.02192.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Webster J, Peters JR, John R, Smith J, Chan V, Hall R & Scanlon MF. Pituitary stone: two cases of densely calcified thyrotrophin-secreting pituitary adenomas. Clinical Endocrinology 1994 40 137143. (doi:10.1111/j.1365-2265.1994.tb02456.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Yamada S, Fukuhara N, Horiguchi K, Yamaguchi-Okada M, Nishioka H, Takeshita A, Takeuchi Y, Ito J & Inoshita N. Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: a single-center study of 90 cases. Journal of Neurosurgery 2014 121 14621473. (doi:10.3171/2014.7.JNS1471)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Malchiodi E, Profka E, Ferrante E, Sala E, Verrua E, Campi I, Lania AG, Arosio M, Locatelli M & Mortini P et al. Thyrotropin-secreting pituitary adenomas: outcome of pituitary surgery and irradiation. Journal of Clinical Endocrinology and Metabolism 2014 99 20692076. (doi:10.1210/jc.2013-4376)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    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. European Journal of Endocrinology 2003 148 433442. (doi:10.1530/eje.0.1480433)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kirkman MA, Jaunmuktane Z, Brandner S, Khan AA, Powell M & Baldeweg SE. Active and silent thyroid-stimulating hormone-expressing pituitary adenomas: presenting symptoms, treatment, outcomes, and recurrence. World Neurosurgery 2014 82 12241231. (doi:10.1016/j.wneu.2014.03.031)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Onnestam L, Berinder K, Burman P, Dahlqvist P, Engstrom BE, Wahlberg J & Nystrom HF. National incidence and prevalence of TSH-secreting pituitary adenomas in Sweden. Journal of Clinical Endocrinology and Metabolism 2013 98 626635. (doi:10.1210/jc.2012-3362)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL & Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. Journal of Clinical Endocrinology and Metabolism 1999 84 476486. (doi:10.1210/jcem.84.2.5505)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Beck-Peccoz P, Lania A, Beckers A, Chatterjee K & Wemeau JL. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. European Thyroid Journal 2013 2 7682. (doi:10.1159/000351007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wang Q, Lu XJ, Sun J, Wang J, Huang CY & Wu ZF. Ectopic suprasellar thyrotropin-secreting pituitary adenoma: case report and literature review. World Neurosurgery 2016 95 617.e13– 617.e18. (doi:10.1016/j.wneu.2016.08.062)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Song M, Wang H, Song L, Tian H, Ge Q, Li J, Zhu Y, Li J, Zhao R & Ji HL. Ectopic TSH-secreting pituitary tumor: a case report and review of prior cases. BMC Cancer 2014 14 544.

  • 24

    Nishiike S, Tatsumi KI, Shikina T, Masumura C & Inohara H. Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx. Auris Nasus Larynx 2014 41 586588. (doi:10.1016/j.anl.2014.07.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Tong A, Xia W, Qi F, Jin Z, Yang D, Zhang Z, Li F, Xing X & Lian X. Hyperthyroidism caused by an ectopic thyrotropin-secreting tumor of the nasopharynx: a case report and review of the literature. Thyroid 2013 23 11721177. (doi:10.1089/thy.2012.0574)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Pasquini E, Faustini-Fustini M, Sciarretta V, Saggese D, Roncaroli F, Serra D & Frank G. Ectopic TSH-secreting pituitary adenoma of the vomerosphenoidal junction. European Journal of Endocrinology 2003 148 253257. (doi:10.1530/eje.0.1480253)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Cooper DS & Wenig BM. Hyperthyroidism caused by an ectopic TSH-secreting pituitary tumor. Thyroid 1996 6 337343. (doi:10.1089/thy.1996.6.337)

  • 28

    Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 2007 156 203216. (doi:10.1530/eje.1.02326)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML & McCutcheon IE. The prevalence of pituitary adenomas: a systematic review. Cancer 2004 101 613619. (doi:10.1002/cncr.20412)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA & Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. Journal of Clinical Endocrinology and Metabolism 2006 91 47694775. (doi:10.1210/jc.2006-1668)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Gruppetta M, Mercieca C & Vassallo J. Prevalence and incidence of pituitary adenomas: a population based study in Malta. Pituitary 2013 16 545553. (doi:10.1007/s11102-012-0454-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Fernandez A, Karavitaki N & Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clinical Endocrinology 2010 72 377382. (doi:10.1111/j.1365-2265.2009.03667.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Tjornstrand A, Gunnarsson K, Evert M, Holmberg E, Ragnarsson O, Rosen T & Filipsson Nystrom H. The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011. European Journal of Endocrinology 2014 171 519526. (doi:10.1530/EJE-14-0144)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Raappana A, Koivukangas J, Ebeling T & Pirila T. Incidence of pituitary adenomas in Northern Finland in 1992–2007. Journal of Clinical Endocrinology and Metabolism 2010 95 42684275. (doi:10.1210/jc.2010-0537)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Melmed S. Pathogenesis of pituitary tumors. Nature Reviews Endocrinology 2011 7 257266. (doi:10.1038/nrendo.2011.40)

  • 36

    Gold EB. Epidemiology of pituitary adenomas. Epidemiologic reviews 1981 3 163183.

  • 37

    Hay ID & Klee GG. Linking medical needs and performance goals: clinical and laboratory perspectives on thyroid disease. Clinical Chemistry 1993 39 15191524.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC & Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocrine Reviews 1996 17 610638. (doi:10.1210/er.17.6.610)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Beck-Peccoz P, Persani L, Mannavola D & Campi I. Pituitary tumours: TSH-secreting adenomas. Best Practice and Research: Clinical Endocrinology and Metabolism 2009 23 597606. (doi:10.1016/j.beem.2009.05.006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Macchia E, Gasperi M, Lombardi M, Morselli L, Pinchera A, Acerbi G, Rossi G & Martino E. Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience. Journal of Endocrinological Investigation 2009 32 773779. (doi:10.1007/BF03346535)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Kovacs KHE. Tumours of the pituitary gland. In Atlas of Tumour Pathology, Fascicle 21, Series 2. Washington, D.C.: Armed Forces Institute of Pathology, 1986.

    • Search Google Scholar
    • Export Citation
  • 42

    Wang EL, Qian ZR, Yamada S, Rahman MM, Inosita N, Kageji T, Endo H, Kudo E & Sano T. Clinicopathological characterization of TSH-producing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas. Endocrine Pathology 2009 20 209220. (doi:10.1007/s12022-009-9094-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Ezzat S, Horvath E, Kovacs K, Smyth HS, Singer W & Asa SL. Basic fibroblast growth factor expression by two prolactin and thyrotropin-producing pituitary adenomas. Endocrine Pathology 1995 6 125134. (doi:10.1007/BF02739875)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Colao A, Pivonello R, Di Somma C, Savastano S, Grasso LF & Lombardi G. Medical therapy of pituitary adenomas: effects on tumor shrinkage. Reviews in Endocrine and Metabolic Disorders 2009 10 111123. (doi:10.1007/s11154-008-9107-z)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Horiguchi K, Yamada M, Umezawa R, Satoh T, Hashimoto K, Tosaka M, Yamada S & Mori M. Somatostatin receptor subtypes mRNA in TSH-secreting pituitary adenomas: a case showing a dramatic reduction in tumor size during short octreotide treatment. Endocrine Journal 2007 54 371378. (doi:10.1507/endocrj.K06-177)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Cuevas-Ramos D & Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. Journal of Molecular Endocrinology 2014 52 R223R240. (doi:10.1530/JME-14-0011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47

    Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, Fleseriu M, van der Lely AJ, Farrall AJ & Hermosillo Resendiz K et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. Journal of Clinical Endocrinology and Metabolism 2014 99 791799. (doi:10.1210/jc.2013-2480)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48

    Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR & Biller BM. A 12-month phase 3 study of pasireotide in Cushing’s disease. New England Journal of Medicine 2012 366 914924. (doi:10.1056/NEJMoa1105743)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Asa SL, Puy LA, Lew AM, Sundmark VC & Elsholtz HP. Cell type-specific expression of the pituitary transcription activator pit-1 in the human pituitary and pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 1993 77 12751280. (doi:10.1210/jcem.77.5.8077321)

    • Search Google Scholar
    • Export Citation
  • 50

    Morley JE. Neuroendocrine control of thyrotropin secretion. Endocrine Reviews 1981 2 396436. (doi:10.1210/edrv-2-4-396)

  • 51

    Roelfsema F, Pereira AM, Keenan DM, Veldhuis JD & Romijn JA. Thyrotropin secretion by thyrotropinomas is characterized by increased pulse frequency, delayed diurnal rhythm, enhanced basal secretion, spikiness, and disorderliness. Journal of Clinical Endocrinology and Metabolism 2008 93 40524057. (doi:10.1210/jc.2008-1145)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    Beck-Peccoz P & Persani L. Variable biological activity of thyroid-stimulating hormone. European Journal of Endocrinology 1994 131 331340. (doi:10.1530/eje.0.1310331)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Mason M, Zarate A, Miranda R, Fonseca E & Mendoza C. Patients with TSH-secreting pituitary tumor possess different TSH molecular isoforms. Archives of Medical Research 1995 26 239243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Koulouri O, Moran C, Halsall D, Chatterjee K & Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Practice and Research: Clinical Endocrinology and Metabolism 2013 27 745762. (doi:10.1016/j.beem.2013.10.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55

    Persani L, Preziati D, Matthews CH, Sartorio A, Chatterjee VK & Beck-Peccoz P. Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndromes of inappropriate secretion of TSH. Clinical Endocrinology 1997 47 207214. (doi:10.1046/j.1365-2265.1997.2351057.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Monfoulet LE, Rabier B, Dacquin R, Anginot A, Photsavang J, Jurdic P, Vico L, Malaval L & Chassande O. Thyroid hormone receptor beta mediates thyroid hormone effects on bone remodeling and bone mass. Journal of Bone and Mineral Research 2011 26 20362044. (doi:10.1002/jbmr.432)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Sarne DH, Refetoff S, Rosenfield RL & Farriaux JP. Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. Journal of Clinical Endocrinology and Metabolism 1988 66 740746. (doi:10.1210/jcem-66-4-740)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    Beck-Peccoz P, Roncoroni R, Mariotti S, Medri G, Marcocci C, Brabant G, Forloni F, Pinchera A & Faglia G. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. Journal of Clinical Endocrinology and Metabolism 1990 71 1925. (doi:10.1210/jcem-71-1-19)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 59

    Beck-Peccoz P & Persani L. TSH-Producing Adenomas. Philadelphia: Saunders, 2010.

  • 60

    Akiyoshi F, Okamura K, Fujikawa M, Sato K, Yoshinari M, Mizokami T, Hattori K, Kuwayama A, Takahashi Y & Fujishima M. Difficulty in differentiating thyrotropin secreting pituitary microadenoma from pituitary-selective thyroid hormone resistance accompanied by pituitary incidentaloma. Thyroid 1996 6 619625. (doi:10.1089/thy.1996.6.619)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Beck-Peccoz P, Persani L, Lania A. Thyrotropin-Secreting Pituitary Adenomas. [Updated 2015 May 1]. In: De Groot LJ, Chrousos G, Dungan K et al. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

    • Search Google Scholar
    • Export Citation
  • 62

    Passeri E, Tufano A, Locatelli M, Lania AG, Ambrosi B & Corbetta S. Large pituitary hyperplasia in severe primary hypothyroidism. Journal of Clinical Endocrinology and Metabolism 2011 96 2223. (doi:10.1210/jc.2010-2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 63

    Beck-Peccoz P, Persani L, Asteria C, Cortelazzi D, Borgato S, Mannavola D & Romoli R. Thyrotropin-secreting pituitary tumors in hyper- and hypothyroidism. Acta Medica Austriaca 1996 23 4146.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Safer JD, Colan SD, Fraser LM & Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid 2001 11 281291. (doi:10.1089/105072501750159750)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 65

    Sriphrapradang C, Srichomkwun P, Refetoff S & Mamanasiri S. A novel thyroid hormone receptor beta gene mutation (G251V) in a thai patient with resistance to thyroid hormone coexisting with pituitary incidentaloma. Thyroid 2016. Epub

    • Search Google Scholar
    • Export Citation
  • 66

    Teng X, Jin T, Brent GA, Wu A, Teng W & Shan Z. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). Journal of Clinical Endocrinology and Metabolism 2015 100 25112514. (doi:10.1210/jc.2014-3994)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67

    Dare GL, de Castro M & Maciel LM. Hypothalamic-pituitary axis and peripheral tissue responses to TRH stimulation and liothyronine suppression tests in normal subjects evaluated by current methods. Thyroid 2008 18 401409. (doi:10.1089/thy.2007.0237)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Stadnik T, Stevenaert A, Beckers A, Luypaert R & Osteaux M. Diagnosis of primary thyrotrophin-secreting microadenoma by 1.5 T MR. European Journal of Radiology 1992 14 1821. (doi:10.1016/0720-048X(92)90055-E)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 69

    Miki Y, Matsuo M, Nishizawa S, Kuroda Y, Keyaki A, Makita Y & Kawamura J. Pituitary adenomas and normal pituitary tissue: enhancement patterns on gadopentetate-enhanced MR imaging. Radiology 1990 177 3538. (doi:10.1148/radiology.177.1.2399335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Sumida M, Uozumi T, Mukada K, Arita K, Kurisu K, Yano T, Onda J, Satoh H & Ikawa F. MRI of pituitary adenomas: the position of the normal pituitary gland. Neuroradiology 1994 36 295297. (doi:10.1007/BF00593264)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Rennert J & Doerfler A. Imaging of sellar and parasellar lesions. Clinical Neurology and Neurosurgery 2007 109 111124. (doi:10.1016/j.clineuro.2006.11.001)

  • 72

    Bonneville JF, Bonneville F & Cattin F. Magnetic resonance imaging of pituitary adenomas. European Radiology 2005 15 543548. (doi:10.1007/s00330-004-2531-x)

  • 73

    Sarlis NJ, Gourgiotis L, Koch CA, Skarulis MC, Brucker-Davis F, Doppman JL, Oldfield EH & Patronas NJ. MR imaging features of thyrotropin-secreting pituitary adenomas at initial presentation. American Journal of Roentgenology 2003 181 577582. (doi:10.2214/ajr.181.2.1810577)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 74

    Pinker K, Ba-Ssalamah A, Wolfsberger S, Mlynarik V, Knosp E & Trattnig S. The value of high-field MRI (3T) in the assessment of sellar lesions. European Journal of Radiology 2005 54 327334. (doi:10.1016/j.ejrad.2004.08.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    Lee HB, Kim ST, Kim HJ, Kim KH, Jeon P, Byun HS & Choi JW. Usefulness of the dynamic gadolinium-enhanced magnetic resonance imaging with simultaneous acquisition of coronal and sagittal planes for detection of pituitary microadenomas. European Radiology 2012 22 514518. (doi:10.1007/s00330-011-2291-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    Sasaki M, Inoue T, Tohyama K, Oikawa H, Ehara S & Ogawa A. High-field MRI of the central nervous system: current approaches to clinical and microscopic imaging. Magnetic Resonance in Medical Sciences 2003 2 133139. (doi:10.2463/mrms.2.133)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 77

    Kakite S, Fujii S, Kurosaki M, Kanasaki Y, Matsusue E, Kaminou T & Ogawa T. Three-dimensional gradient echo versus spin echo sequence in contrast-enhanced imaging of the pituitary gland at 3T. European Journal of Radiology 2011 79 108112. (doi:10.1016/j.ejrad.2009.12.036)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78

    Patronas N, Bulakbasi N, Stratakis CA, Lafferty A, Oldfield EH, Doppman J & Nieman LK. Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors. Journal of Clinical Endocrinology and Metabolism 2003 88 15651569. (doi:10.1210/jc.2002-021438)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 79

    Chittiboina P, Montgomery BK, Millo C, Herscovitch P & Lonser RR. High-resolution(18)F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging for pituitary adenoma detection in Cushing disease. Journal of Neurosurgery 2015 122 791797. (doi:10.3171/2014.10.JNS14911)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    Masopust V, Netuka D, Benes V, Majovsky M, Belsan T, Bradac O, Horinek D, Kosak M, Hana V & Krsek M. Magnetic resonance imaging and histology correlation in Cushing’s disease. Neurologia i Neurochirurgia Polska 2017 51 4552. (doi:10.1016/j.pjnns.2016.10.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81

    Lamberts SW, Hofland LJ, de Herder WW, Kwekkeboom DJ, Reubi JC & Krenning EP. Octreotide and related somatostatin analogs in the diagnosis and treatment of pituitary disease and somatostatin receptor scintigraphy. Frontiers in Neuroendocrinology 1993 14 2755. (doi:10.1006/frne.1993.1002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82

    Losa M, Magnani P, Mortini P, Persani L, Acerno S, Giugni E, Songini C, Fazio F, Beck-Peccoz P & Giovanelli M. Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels. European Journal of Nuclear Medicine 1997 24 728731. (doi:10.1007/bf00879659)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83

    Naswa N, Das CJ, Sharma P, Karunanithi S, Bal C & Kumar R. Ectopic pituitary adenoma with empty sella in the setting of MEN-1 syndrome: detection with 68Ga-DOTANOC PET/CT. Japanese Journal of Radiology 2012 30 783786. (doi:10.1007/s11604-012-0117-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84

    Novruzov F, Aliyev JA, Jaunmuktane Z, Bomanji JB & Kayani I. The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma. Clinical Nuclear Medicine 2015 40 4749. (doi:10.1097/RLU.0000000000000589)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85

    Premachandra BN, Gossain VV & Perlstein IB. Increased free thyroxine in a euthyroid patient with thyroxine-binding globulin deficiency. Journal of Clinical Endocrinology and Metabolism 1976 42 309318. (doi:10.1210/jcem-42-2-309)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86

    Tamada D, Onodera T, Kitamura T, Yamamoto Y, Hayashi Y, Murata Y, Otsuki M & Shimomura I. Hyperthyroidism due to thyroid-stimulating hormone secretion after surgery for Cushing’s syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid-stimulating hormone. Journal of Clinical Endocrinology and Metabolism 2013 98 26562662. (doi:10.1210/jc.2013-2135)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 87

    Pietras SM & Safer JD. Diagnostic confusion attributable to spurious elevation of both total thyroid hormone and thyroid hormone uptake measurements in the setting of autoantibodies: case report and review of related literature. Endocrine Practices 2008 14 738742. (doi:10.4158/EP.14.6.738)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 88

    Fiad TM, Duffy J & McKenna TJ. Multiple spuriously abnormal thyroid function indices due to heterophilic antibodies. Clinical Endocrinology 1994 41 391395. (doi:10.1111/j.1365-2265.1994.tb02563.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 89

    Ohba K, Noh JY, Unno T, Satoh T, Iwahara K, Matsushita A, Sasaki S, Oki Y & Nakamura H. Falsely elevated thyroid hormone levels caused by anti-ruthenium interference in the Elecsys assay resembling the syndrome of inappropriate secretion of thyrotropin. Endocrine Journal 2012 59 663667. (doi:10.1507/endocrj.EJ12-0089)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 90

    Rulander NJ, Cardamone D, Senior M, Snyder PJ & Master SR. Interference from anti-streptavidin antibody. Archives of Pathology and Laboratory Medicine 2013 137 11411146. (doi:10.5858/arpa.2012-0270-CR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 91

    Weiss RE & Refetoff S. Resistance to thyroid hormone. Reviews in Endocrine and Metabolic Disorders 2000 1 97108. (doi:10.1023/A:1010072605757)

  • 92

    Pappa T, Ferrara AM & Refetoff S. Inherited defects of thyroxine-binding proteins. Best Practice and Research: Clinical Endocrinology and Metabolism 2015 29 735747. (doi:10.1016/j.beem.2015.09.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 93

    Weiss RE & Refetoff S. Treatment of resistance to thyroid hormone – primum non nocere. Journal of Clinical Endocrinology and Metabolism 1999 84 401404. (doi:10.1210/jcem.84.2.5534)

    • Search Google Scholar
    • Export Citation
  • 94

    Pannain S, Feldman M, Eiholzer U, Weiss RE, Scherberg NH & Refetoff S. Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine. Journal of Clinical Endocrinology and Metabolism 2000 85 27862792. (doi:10.1210/jc.85.8.2786)

    • Search Google Scholar
    • Export Citation
  • 95

    Macchia E, Lombardi M, Raffaelli V, Piaggi P, Macchia L, Scattina I & Martino E. Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor beta. Clinical Endocrinology 2014 81 921928. (doi:10.1111/cen.12556)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 96

    Abs R, Stevenaert A & Beckers A. Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause – effect relationship. European Journal of Endocrinology 1994 131 355358. (doi:10.1530/eje.0.1310355)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 97

    Perticone F, Pigliaru F, Mariotti S, Deiana L, Furlani L, Mortini P & Losa M. Is the incidence of differentiated thyroid cancer increased in patients with thyrotropin-secreting adenomas? Report of three cases from a large consecutive series. Thyroid 2015 25 417424. (doi:10.1089/thy.2014.0222)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98

    Gasparoni P, Rubello D, Persani L & Beck-Peccoz P. Unusual association between a thyrotropin-secreting pituitary adenoma and a papillary thyroid carcinoma. Thyroid 1998 8 181183. (doi:10.1089/thy.1998.8.181)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 99

    Poggi M, Monti S, Pascucci C & Toscano V. A rare case of follicular thyroid carcinoma in a patient with thyrotropin-secreting pituitary adenoma. American Journal of the Medical Sciences 2009 337 462465. (doi:10.1097/MAJ.0b013e3181949948)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 100

    Ohta S, Nishizawa S, Oki Y & Namba H. Coexistence of thyrotropin-producing pituitary adenoma with papillary adenocarcinoma of the thyroid – a case report and surgical strategy. Pituitary 2001 4 271274.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 101

    Nguyen HD, Galitz MS, Mai VQ, Clyde PW, Glister BC & Shakir MK. Management of coexisting thyrotropin/growth-hormone-secreting pituitary adenoma and papillary thyroid carcinoma: a therapeutic challenge. Thyroid 2010 20 99103. (doi:10.1089/thy.2009.0160)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102

    Koriyama N, Nakazaki M, Hashiguchi H, Aso K, Ikeda Y, Kimura T, Eto H, Hirano H, Nakano S & Tei C. Thyrotropin-producing pituitary adenoma associated with Graves’ disease. European Journal of Endocrinology 2004 151 587594. (doi:10.1530/eje.0.1510587)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 103

    Kamoi K, Mitsuma T, Sato H, Yokoyama M, Washiyama K, Tanaka R, Arai O, Takasu N & Yamada T. Hyperthyroidism caused by a pituitary thyrotrophin-secreting tumour with excessive secretion of thyrotrophin-releasing hormone and subsequently followed by Graves’ disease in a middle-aged woman. Acta Endocrinologica 1985 110 373382. (doi:10.1530/acta.0.1100373)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 104

    Kageyama K, Ikeda H, Sakihara S, Nigawara T, Terui K, Tsutaya S, Matsuda E, Shoji M, Yasujima M & Suda T. A case of thyrotropin-producing pituitary adenoma, accompanied by an increase in anti-thyrotropin receptor antibody after tumor resection. Journal of Endocrinological Investigation 2007 30 957961. (doi:10.1007/BF03349244)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105

    O’Donnell J, Hadden DR, Weaver JA & Montgomery DA. Thyrotoxicosis recurring after surgical removal of a thyrotrophin-secreting pituitary tumour. Proceedings of the Royal Society of Medicine 1973 66 441442.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 106

    Frandsen NJ & Transbol I. Basedow’s disease and thyroid stimulating hormone producing pituitary adenoma in a patient. Ugeskrift for Laeger 1991 153 854855.

    • Search Google Scholar
    • Export Citation
  • 107

    Lee MT & Wang CY. Concomitant Graves hyperthyroidism with thyrotrophin-secreting pituitary adenoma. Southern Medical Journal 2010 103 347349. (doi:10.1097/SMJ.0b013e3181d3ce93)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 108

    Okuyucu K, Alagoz E, Arslan N, Taslipinar A, Deveci MS & Bolu E. Thyrotropinoma with Graves’ disease detected by the fusion of indium-111 octreotide scintigraphy and pituitary magnetic resonance imaging. Indian Journal of Nuclear Medicine 2016 31 141143. (doi:10.4103/0972-3919.178322)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 109

    Kamoun M, d’Herbomez M, Lemaire C, Fayard A, Desailloud R, Huglo D & Wemeau JL. Coexistence of thyroid-stimulating hormone-secreting pituitary adenoma and graves’ hyperthyroidism. European Thyroid Journal 2014 3 6064. (doi:10.1159/000355386)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 110

    Ogawa Y & Tominaga T. Thyroid-stimulating hormone-secreting pituitary adenoma presenting with recurrent hyperthyroidism in post-treated Graves’ disease: a case report. Journal of Medical Case Reports 2013 7 27. (doi:10.1186/1752-1947-7-27)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111

    Yovos JG, Falko JM, O’Dorisio TM, Malarkey WB, Cataland S & Capen CC. Thyrotoxicosis and a thyrotropin-secreting pituitary tumor causing unilateral exophthalmos. Journal of Clinical Endocrinology and Metabolism 1981 53 338343. (doi:10.1210/jcem-53-2-338)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 112

    Losa M, Mortini P, Minelli R & Giovanelli M. Coexistence of TSH-secreting pituitary adenoma and autoimmune hypothyroidism. Journal of Endocrinological Investigation 2006 29 555559. (doi:10.1007/BF03344147)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 113

    Iskandar SB, Supit E, Jordan RM & Peiris AN. Thyrotropin-secreting pituitary tumor and Hashimoto’s disease: a novel association. Southern Medical Journal 2003 96 933936. (doi:10.1097/01.SMJ.0000054784.64420.8B)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114

    Ma W, Ikeda H, Watabe N, Kanno M & Yoshimoto T. A plurihormonal TSH-producing pituitary tumor of monoclonal origin in a patient with hypothyroidism. Hormone Research 2003 59 257261. (doi:10.1159/000070227)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115

    Young M, Kattner K & Gupta K. Pituitary hyperplasia resulting from primary hypothyroidism mimicking macroadenomas. British Journal of Neurosurgery 1999 13 138142. (doi:10.1080/02688699943880)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116

    Watanabe K, Kameya T, Yamauchi A, Yamamoto N, Kuwayama A, Takei I, Maruyama H & Saruta T. Thyrotropin-producing microadenoma associated with pituitary resistance to thyroid hormone. Journal of Clinical Endocrinology and Metabolism 1993 76 10251030. (doi:10.1210/jcem.76.4.8473377)

    • Search Google Scholar
    • Export Citation
  • 117

    Gurnell M, Rajanayagam O, Barbar I, Jones MK & Chatterjee VK. Reversible pituitary enlargement in the syndrome of resistance to thyroid hormone. Thyroid 1998 8 679682. (doi:10.1089/thy.1998.8.679)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 118

    Marucci G, Faustini-Fustini M, Righi A, Pasquini E, Frank G, Agati R & Foschini MP. Thyrotropin-secreting pituitary tumours: significance of ‘atypical adenomas’ in a series of 10 patients and association with Hashimoto thyroiditis as a cause of delay in diagnosis. Journal of Clinical Pathology 2009 62 455459. (doi:10.1136/jcp.2008.061523)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 119

    Corbetta S, Pizzocaro A, Peracchi M, Beck-Peccoz P, Faglia G & Spada A. Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types. Clinical Endocrinology 1997 47 507512. (doi:10.1046/j.1365-2265.1997.3311122.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 120

    Taylor TJ, Donlon SS, Bale AE, Smallridge RC, Francis TB, Christensen RS & Burma KD. Treatment of a thyrotropinoma with octreotide-LAR in a patient with multiple endocrine neoplasia-1. Thyroid 2000 10 10011007. (doi:10.1089/thy.2000.10.1001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 121

    Brown RL, Muzzafar T, Wollman R & Weiss RE. A pituitary carcinoma secreting TSH and prolactin: a non-secreting adenoma gone awry. European Journal of Endocrinology 2006 154 639643. (doi:10.1530/eje.1.02141)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122

    Mixson AJ, Friedman TC, Katz DA, Feuerstein IM, Taubenberger JK, Colandrea JM, Doppman JL, Oldfield EH & Weintraub BD. Thyrotropin-secreting pituitary carcinoma. Journal of Clinical Endocrinology and Metabolism 1993 76 529533. (doi:10.1210/jc.76.2.529)

    • Search Google Scholar
    • Export Citation
  • 123

    Losa M, Giovanelli M, Persani L, Mortini P, Faglia G & Beck-Peccoz P. Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 1996 81 30843090. (doi:10.1210/jc.81.8.3084)

    • Search Google Scholar
    • Export Citation
  • 124

    Sanno N, Teramoto A & Osamura RY. Long-term surgical outcome in 16 patients with thyrotropin pituitary adenoma. Journal of Neurosurgery 2000 93 194200. (doi:10.3171/jns.2000.93.2.0194)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 125

    Elston MS & Conaglen JV. Clinical and biochemical characteristics of patients with thyroid-stimulating hormone-secreting pituitary adenomas from one New Zealand centre. International Medical Journal 2010 40 214219. (doi:10.1111/j.1445-5994.2009.02107.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 126

    Clarke MJ, Erickson D, Castro MR & Atkinson JL. Thyroid-stimulating hormone pituitary adenomas. Journal of Neurosurgery 2008 109 1722. (doi:10.3171/jns/2008/109/7/0017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 127

    Ness-Abramof R, Ishay A, Harel G, Sylvetzky N, Baron , Greenman & Shimon I. TSH-secreting pituitary adenomas: follow-up of 11 cases and review of the literature. Pituitary 2007 10 307310. (doi:10.1530/eje.1.02141)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 128

    van Varsseveld NC, Bisschop PH, Biermasz NR, Pereira AM, Fliers E & Drent ML. A long-term follow-up study of eighteen patients with thyrotrophin-secreting pituitary adenomas. Clinical Endocrinology 2014 80 395402. (doi:10.1111/cen.12290)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 129

    Gatto F, Grasso LF, Nazzari E, Cuny T, Anania P, Di Somma C, Colao A, Zona G, Weryha G, Pivonello R & Ferone D. Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: Might somatostatin analogs have a role as first-line therapy? Pituitary 2015 18 583591. (doi:10.1007/s11102-014-0611-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 130

    Azzalin A, Appin CL, Schniederjan MJ, Constantin T, Ritchie JC, Veledar E, Oyesiku NM & Ioachimescu AG. Comprehensive evaluation of thyrotropinomas: single-center 20-year experience. Pituitary 2016 19 183193. (doi:10.1007/s11102-015-0697-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 6348 2431 159
PDF Downloads 3102 1506 206
  • View in gallery

    Time trend in national incidence of TSH-secreting pituitary adenoma (TSHoma) in Sweden 1990–2009, and number of TSHoma micro- and macroadenomas (<1 cm/≥1 cm) 1990–1994, 1995–1999, 2000–2004 and 2005–2010 (17). Republished with the permission from Journal of Clinical Endocrinology and Metabolism.

  • View in gallery

    TSH (A) and FT4 (B) at diagnosis of 28 TSH-secreting pituitary adenoma (TSHoma) patients with intact or treated thyroid gland. Hormone levels are related to upper limit of normal (dotted line) (17). Republished with the permission from Journal of Clinical Endocrinology and Metabolism.

  • View in gallery

    Flowchart on the diagnosis of thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) when it is presented as the syndrome of inappropriate TSH secretion.

  • View in gallery

    T3 test used at our institution, this version is modified from Dare et al. (99) and from personal communication with the last author of that publication. The autonomous TSH production is proven by an inability of T3 to suppress TSH.

  • 1

    Jailer JW & Holub DA. Remission of Graves’ disease following radiotherapy of a pituitary neoplasm. American Journal of Medicine 1960 28 497500. (doi:10.1016/0002-9343(60)90181-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Hamilton CR Jr, Adams LC & Maloof F. Hyperthyroidism due to thyrotropin-producing pituitary chromophobe adenoma. New England Journal of Medicine 1970 283 10771080. (doi:10.1056/NEJM197011122832003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Grisoli F, Leclercq T, Winteler JP, Jaquet P, Guibout M, Diaz-Vasquez P, Hassoun J & Nayak R. Thyroid-stimulating hormone pituitary adenomas and hyperthyroidism. Surgical Neurology 1986 25 361368. (doi:10.1016/0090-3019(86)90211-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Wynne AG, Gharib H, Scheithauer BW, Davis DH, Freeman SL & Horvath E. Hyperthyroidism due to inappropriate secretion of thyrotropin in 10 patients. American Journal of Medicine 1992 92 1524. (doi:10.1016/0002-9343(92)90009-Z)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Beckers A, Abs R, Mahler C, Vandalem JL, Pirens G, Hennen G & Stevenaert A. Thyrotropin-secreting pituitary adenomas: report of seven cases. Journal of Clinical Endocrinology and Metabolism 1991 72 477483. (doi:10.1210/jcem-72-2-477)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Bertholon-Gregoire M, Trouillas J, Guigard MP, Loras B & Tourniaire J. Mono- and plurihormonal thyrotropic pituitary adenomas: pathological, hormonal and clinical studies in 12 patients. European Journal of Endocrinology 1999 140 519527. (doi:10.1530/eje.0.1400519)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Gesundheit N, Petrick PA, Nissim M, Dahlberg PA, Doppman JL, Emerson CH, Braverman LE, Oldfield EH & Weintraub BD. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Case reports and follow-up of nine patients. Annals of Internal Medicine 1989 111 827835. (doi:10.7326/0003-4819-111-10-827)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mindermann T & Wilson CB. Thyrotropin-producing pituitary adenomas. Journal of Neurosurgery 1993 79 521527. (doi:10.3171/jns.1993.79.4.0521)

  • 9

    Caldwell G, Kellett HA, Gow SM, Beckett GJ, Sweeting VM, Seth J & Toft AD. A new strategy for thyroid function testing. Lancet 1985 1 11171119. (doi:10.1016/S0140-6736(85)92429-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ross DS, Ardisson LJ & Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. Journal of Clinical Endocrinology and Metabolism 1989 69 684688. (doi:10.1210/jcem-69-3-684)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Gershengorn MC & Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of ‘inappropriate secretion of TSH’. Journal of Clinical Investigation 1975 56 633642. (doi:10.1172/JCI108133)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Kucharczyk W, Davis DO, Kelly WM, Sze G, Norman D & Newton TH. Pituitary adenomas: high-resolution MR imaging at 1.5 T. Radiology 1986 161 761765. (doi:10.1148/radiology.161.3.3786729)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Mannavola D, Persani L, Vannucchi G, Zanardelli M, Fugazzola L, Verga U, Facchetti M & Beck-Peccoz P. Different responses to chronic somatostatin analogues in patients with central hyperthyroidism. Clinical Endocrinology 2005 62 176181. (doi:10.1111/j.1365-2265.2004.02192.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Webster J, Peters JR, John R, Smith J, Chan V, Hall R & Scanlon MF. Pituitary stone: two cases of densely calcified thyrotrophin-secreting pituitary adenomas. Clinical Endocrinology 1994 40 137143. (doi:10.1111/j.1365-2265.1994.tb02456.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Yamada S, Fukuhara N, Horiguchi K, Yamaguchi-Okada M, Nishioka H, Takeshita A, Takeuchi Y, Ito J & Inoshita N. Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: a single-center study of 90 cases. Journal of Neurosurgery 2014 121 14621473. (doi:10.3171/2014.7.JNS1471)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Malchiodi E, Profka E, Ferrante E, Sala E, Verrua E, Campi I, Lania AG, Arosio M, Locatelli M & Mortini P et al. Thyrotropin-secreting pituitary adenomas: outcome of pituitary surgery and irradiation. Journal of Clinical Endocrinology and Metabolism 2014 99 20692076. (doi:10.1210/jc.2013-4376)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    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. European Journal of Endocrinology 2003 148 433442. (doi:10.1530/eje.0.1480433)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kirkman MA, Jaunmuktane Z, Brandner S, Khan AA, Powell M & Baldeweg SE. Active and silent thyroid-stimulating hormone-expressing pituitary adenomas: presenting symptoms, treatment, outcomes, and recurrence. World Neurosurgery 2014 82 12241231. (doi:10.1016/j.wneu.2014.03.031)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Onnestam L, Berinder K, Burman P, Dahlqvist P, Engstrom BE, Wahlberg J & Nystrom HF. National incidence and prevalence of TSH-secreting pituitary adenomas in Sweden. Journal of Clinical Endocrinology and Metabolism 2013 98 626635. (doi:10.1210/jc.2012-3362)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL & Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. Journal of Clinical Endocrinology and Metabolism 1999 84 476486. (doi:10.1210/jcem.84.2.5505)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Beck-Peccoz P, Lania A, Beckers A, Chatterjee K & Wemeau JL. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. European Thyroid Journal 2013 2 7682. (doi:10.1159/000351007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wang Q, Lu XJ, Sun J, Wang J, Huang CY & Wu ZF. Ectopic suprasellar thyrotropin-secreting pituitary adenoma: case report and literature review. World Neurosurgery 2016 95 617.e13– 617.e18. (doi:10.1016/j.wneu.2016.08.062)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Song M, Wang H, Song L, Tian H, Ge Q, Li J, Zhu Y, Li J, Zhao R & Ji HL. Ectopic TSH-secreting pituitary tumor: a case report and review of prior cases. BMC Cancer 2014 14 544.

  • 24

    Nishiike S, Tatsumi KI, Shikina T, Masumura C & Inohara H. Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx. Auris Nasus Larynx 2014 41 586588. (doi:10.1016/j.anl.2014.07.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Tong A, Xia W, Qi F, Jin Z, Yang D, Zhang Z, Li F, Xing X & Lian X. Hyperthyroidism caused by an ectopic thyrotropin-secreting tumor of the nasopharynx: a case report and review of the literature. Thyroid 2013 23 11721177. (doi:10.1089/thy.2012.0574)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Pasquini E, Faustini-Fustini M, Sciarretta V, Saggese D, Roncaroli F, Serra D & Frank G. Ectopic TSH-secreting pituitary adenoma of the vomerosphenoidal junction. European Journal of Endocrinology 2003 148 253257. (doi:10.1530/eje.0.1480253)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Cooper DS & Wenig BM. Hyperthyroidism caused by an ectopic TSH-secreting pituitary tumor. Thyroid 1996 6 337343. (doi:10.1089/thy.1996.6.337)

  • 28

    Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 2007 156 203216. (doi:10.1530/eje.1.02326)