TSH adenoma and syndrome of resistance to thyroid hormones—Two cases report of syndrome of inappropriate secretion of thyrotropin

Abstract SITSH (syndrome of inappropriate secretion of thyrotropin) is a rare clinical state defined as uninhibited serum thyroid stimulating hormone in the presence of elevated thyroid hormone. This state is complicated and mainly caused by the abnormal feedback of hypothalamus–pituitary thyroid axis. The TSH adenoma (TSH‐oma) and resistance to thyroid hormones (RTH) are the main etiologies of SITSH. As is well known that the treatment strategies of RTH and TSH‐oma are apparently different, thus identifying the difference between RTH and TSH‐oma is of great significance for the diagnosis and treatment of SITSH. Case description A 62‐year‐old man with a state of elevated thyroid hormones and inappropriate elevated serum TSH level was hospitalized in 2016. Results of the pituitary enhanced magnetic resonance imaging and the somatostatin test respectively demonstrated a space‐occupying lesion of pituitary and an elevated serum sex hormone binding globulin (SHBG) and inhibited TSH secretion, which indicated the occurrence of TSH‐oma. In 2019, a 23‐year‐old girl with a state of elevated thyroid hormones and inappropriate normal serum TSH was hospitalized. Interestingly, whole exome sequencing detection suggested a pathogenic mutation in thyroid hormone receptor β (THRB) gene, which has been shown to be associated with RTH. Conclusions The difference between TSH‐oma and RTH ought to be clarified for their accurate diagnose and treatment. The clinical experiences of the two cases reported here suggest that more detail information such as family medical history, serum SHBG level, and THRB gene test is helpful for the diagnose and treatment of TSH‐oma and RTH. Additionally, we also summarized the identification points, diagnosis process, and treatment strategies for these two rare diseases.


| INTRODUC TI ON
SITSH is a clinical state defined as inappropriately uninhibited serum thyrotropin (TSH) in the presence of elevated thyroid hormones . TSH adenoma (TSH-oma) and resistance to thyroid hormones (RTH) are the two main etiologies of SITSH. The mobility of TSH-oma is around 1 case per million, which accounts for 0.5% to 3% of all pituitary tumors (Amlashi & Tritos, 2016;Beck-Peccoz et al., 2000). TSH-oma is the main cause of central thyroid dysfunction, which could interpret the corresponding changes of pituitary mass and thyrotoxicosis (Amlashi & Tritos, 2016;Beck-Peccoz et al., 2000). Due to the complicated manifestation and limited clinicians' understanding, the diagnosis and treatment of TSH-oma are often delayed (Cossu et al., 2019;Fujio & Yoshimoto, 2018).
RTH is characterized by hyposensitivity to thyroid hormone of corresponding targeting tissues. Almost 85% patients with RTH have the mutation of thyroid hormone receptor α (THRB) gene (Cossu et al., 2019). The mutation of thyroid hormone receptors (THR) decreases their affinity for thyroid hormone and may result in an inhibitory effect on normal thyroid hormone receptor. According to the resistance degree of different tissues to thyroid hormone, RTH could be divided into 3 types: generalized resistance, selective pituitary resistance, and selective peripheral resistance. Most patients with generalized resistance to thyroid hormone have few manifestations, and some of them may have hypothyroidism. Selective pituitary resistance usually occurs in adults with the main clinical feature of thyrotoxicosis. Selective peripheral resistance is extremely rare. The clinical features are characterized by enlarged goiter, elevated serum TH level, and hypothyroidism (Kassak et al., 2017;Murata, 2012).

| Case one
A 62-year-old man was referred to our hospital due to thyrotoxicosis.
At first sight, he complained of changes in stool traits for 11 months and his hands shook and palpitation for more than 2 months in January 2016. His past history and family history were unremarkable. He was 173 cm tall, weighed 63 Kg, and the BMI (body mass index) was 21.5 kg/m 2 . The pulse rate was 72 beats/min, blood pressure was 120/82 mmHg, and body temperature was 36.5 ℃. Routine blood tests, including complete blood cell count, electrolyte, and renal and liver function were all within normal limits. Thyroid function test was performed and revealed a state of elevated thyroid hormones with an inappropriate increasing of serum TSH level (Table 1). No obvious abnormality in the cortisol axis and gonad axis was found. Additionally, an elevated serum sex hormone binding globulin (SHBG) (84.9 nmol/L; normal range: 13-71 nmol/L) was revealed through serum hormone test. Results of the somatostatin suppression test  demonstrated a significant serum TSH inhibition (Figure 1). Cardiac ultrasound revealed a mild regurgitation of the mitral, tricuspid, aortic, and pulmonary valves, along with a decreased early diastolic function of the left ventricle (Left ventricular ejection fraction, EF = 59%; fractional shortening, FS = 32%). Thyroid radionuclide imaging and iodine uptake rate examination showed no remarkable changes in thyroids.  Abbreviations: ACTH, adrenocorticotropic hormone; E2, Estradiol; FSH, follicle stimulating-hormone; FT3, free triiodothyronine; FT4, free thyroxine; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; P, progesterone; PRL, prolactin; T, testosterone; TSH, thyrotropin.

| D ISCUSS I ON
The basic feature of SITSH is that serum thyroid hormones increase with the TSH level inappropriately elevated or remaining normal (Murata, 2012). It is currently believed that SITSH is mainly caused by RTH or TSH-oma. Failure to accurately diagnose may result in inappropriate treatment. In order to better understand RTH and TSH-oma, we summarized the predominant features of these two cases as shown in Table 2 and carried out several diagnosis and treat-

ment procedures according to 2013 European Thyroid Association
Guidelines for diagnosis and treatment of TSH-oma ( Figure 5).
The TSH adenoma is the most rare form of functional pituitary adenoma (Tjornstrand & Nystrom, 2017 Elsarrag et al., 2020). In this case, we found and the serum TSH decreased by more than 84% in the somatostatin suppression test (Figure 1a), which is consistent with the features of TSH-oma. After the diagnosis of TSH-oma, surgery is the prioritized treatment strategy.
At present, the pathogenesis of RTH is not fully understood, THβ1, THβ2, and THβ3 (Cheng, 2000;Rurale et al., 2019). These four different subtypes distribute in different tissues. THRα1 is mainly expressed in the gastrointestinal tract, heart, skeleton, muscle, and central nervous system, and lowly expressed in kidney, skeletal muscle, lung, heart, and liver. THRβ1 is mainly distributed in brain, liver, kidney, heart, and thyroid. THRβ2 is mainly distributed in hypothalamus, pituitary, cochlea, and retina. THRβ3 is mainly distributed in kidney, liver, and lung (Cheng, 2000;Kohrle, 2018;Samarut & Plate roti, 2018). RTH patients could show normal, or insensitive to thyroxine of the whole body or some specific tissues, or organs (Smallridge et al., 1989). The significant difference in clinical symp- Similarly, the mutation of THRB in liver cells could reduce the sensitivity of liver tissue to thyroid hormones, and this may be the reason why SHBG did not increase as the thyroid hormone raised (Mok et al., 2013;Murata, 2012). Moreover, the increased heart rate of this patient could be induced by THRα1 expression in myocardial cells (Mok et al., 2013;Murata, 2012). It is common for the reported cases of RTH without obvious clinical manifestations like this patient y (Murata, 2012). In fact, the diagnoses for these patients remain complicated, and more critically, the confirmed diagnosis mainly depends on the gene sequencing testing. So, we need to strengthen our understanding of this disease for better diagnosis and treatment.
In addition to the diagnosis of RTH, this patient also has hypotha-

| CON CLUS ION
The cases reported here presented our experience in the diagnosis and management of RTH and TSH-oma. The clinical experiences of the two cases reported here suggest that more detail information such as family medical history, serum SHBG level, and THRB gene test is helpful for the diagnose and treatment of TSH-oma and RTH.
In addition, we summarized the identification points, diagnosis process, and treatment strategies of these two rare diseases.

ACK N OWLED G M ENTS
Special thanks to Medical-Eng-School for the guidance in the writing of the manuscript.

CO N FLI C T S O F I NTE R E S T
The authors declare that there is no conflict of interest of this paper.

AUTH O R CO NTR I B UTI O N
Fan Zhang and Jiong-yu Hu contributed to the conception and manuscript revision of the study; Fang Deng performed the data collection; Fang Deng and Zeyu Yang contributed significantly to analysis and manuscript preparation; Zeyu Yang performed the data analyses and wrote the manuscript; Yu-ping Zhang, Yu-lin Wang helped perform the analysis with constructive discussions.

E TH I C A L A PPROVA L
According to the institution guideline, case report does not require ethical approval.

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.2081.
[Correction added on March 20, 2021, after first online publication: Peer review history statement has been added.]

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.