An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone.

Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hyperthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Similarly, the term syndrome of IST (SITSH) is widely used in Japan to refer to a closely related condition; however, unlike that for IST, an elevated serum free triiodothyronine concentration is not a requisite criterion for SITSH diagnosis. IST or SITSH is an important indicator of resistance to thyroid hormone ß (RTHß) caused by germline mutations in genes encoding thyroid hormone receptor ß (TRß) and TSH-secreting pituitary adenoma. Recent evidence has accumulated for several conditions associated with IST, including RTH without mutations in the TRß gene (non-TR-RTH), the phenomenon of hysteresis involving the hypothalamus-pituitary-thyroid axis (HPT-axis), methodological interference, and Cushing's syndrome after surgical resection. However, little information is available on the systematic pathophysiological aspects of IST in previous review articles. This report presents an overview of the recent advances in our understanding of the etiological aspects of IST that are relevant for diagnosis and treatment. Moreover, the report focuses on the potential mechanism of IST caused by hysteresis in the HPT-axis (lagging TSH recovery) in terms of epigenetic regulation.

An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.

Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of ß type of resistance to thyroid hormone (RTHß). The differential diagnoses of RTHß include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHß, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHß and TSHoma. The FT3/FT4 values in RTHß were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.

A remarkable case of thyrotoxicosis initially caused by graves' disease followed by a probable TSHoma - a case report.

BACKGROUND: Graves' disease is the commonest cause of thyrotoxicosis whilst thyrotropin (TSH)-producing pituitary adenomas (thyrotropinomas, TSHomas) are very rare and account for just 1-2% of all pituitary adenomas. Coexistence of a TSHoma and Graves' disease has been very rarely reported. Here, we report a case of a patient whose initial presentation with primary thyrotoxicosis due to Graves' disease, was subsequently followed by a relapse of thyrotoxicosis due to a probable TSHoma. CASE: A sixty-eight year old woman was referred to our department with classical features of thyrotoxicosis. Initial biochemistry confirmed hyperthyroxinaemia [free thyroxine (fT4) 20.4 pmol/L (reference range 7.0-16.0)] and a suppressed TSH [< 0.02mIU/L (0.50-4.20)]. A technetium pertechnetate uptake scan was consistent with Graves' Disease. She was treated with carbimazole for 18 months and remained clinically and biochemically euthyroid. After stopping carbimazole her fT4 started to rise but TSH remained normal. Laboratory assay interference was excluded. A TRH stimulation test demonstrated a flat TSH response and pituitary MRI revealed a microadenoma. Remaining pituitary hormones were in the normal range other than a slightly raised IGF-1. An 11C-methionine PET/CT scan coregistered with volumetric MRI (Met-PET-MRICR) demonstrated high tracer uptake in the left lateral sella region suggestive of a functioning adenoma. The patient declined surgery and was unable to tolerate cabergoline or octreotide. Thereafter, she has elected to pursue a conservative approach with periodic surveillance. CONCLUSION: This is a very unusual case of thyrotoxicosis caused by two different processes occurring in the same patient. It highlights the importance of considering dual pathology when previously concordant thyroid function tests become discordant. It also highlights a potential role of Met-PET-MRICR in the localisation of functioning pituitary tumours.

A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH).

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT4), moderately elevated free triiodothyronine (FT3), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT3, FT4, and TSH were similar when measured by three different laboratory kits, and FT4 was still high when measured by equilibrium dialysis. By affinity chromatography, FT4, TT4, and albumin were extracted to the same fraction, and the levels of FT4 and TT4 were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT4 and moderately high serum FT3 levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

[Endocrine abnormalities in a patient with borderline personality disorder--case 8/2014]. / Endokrinopathie bei einer Patientin mit Persönlichkeitsstörung vom Borderline-Typ--Fall 8/2014.

HISTORY AND ADMISSION FINDINGS: We report on a 44-year-old woman who was treated for borderline personality disorder in the Department of Psychiatry. In addition, symptoms of hyperthyroidism (anxiety, weight loss, hyperdefecation) were noticeable. Thyroid stimulating hormone (TSH) was marginally elevated, free triiodothyronine (T3) and free thyroxine (T4) were clearly elevated. Hence, the patient was transferred to the Department of Endocrinology. INVESTIGATIONS: Thyroid ultrasound revealed a diffuse goiter with a total volume of 24,8 ml. Antibody screening did not show elevated titers. The thyrotropin releasing hormone (TRH) test depicted a blunted TSH response. Serum levels of free glycoprotein hormone alpha-subunit, prolactin and insulin-like growth factor 1 were increased. DIAGNOSIS, TREATMENT AND COURSE: In cranial magnetic resonance imaging (MRI), a hypointense lesion on the left side of the anterior pituitary gland was detected indicating a thyrotropin-secreting microadenoma with concomitant secretion of prolactin and possible secretion of human growth hormone (HGH). A thyreostatic therapy was initiated aiming at euthyreosis. For symptom control, betablockers were administered. Subsequently, the patient underwent an uncomplicated transsphenoidal resection. Histological examination confirmed the diagnosis of a pituitary adenoma with expression of TSH, prolactin and HGH. As expected, thyroid hormones declined afterwards. CONCLUSIONS: TSHoma is rare. Diagnosis is confirmed by endocrinological testing and cranial imaging. Therapeutic options comprise transsphenoidal adenomectomy, drug therapy (somatostatin analogues, dopaminergic agonists) and irradiation. Resistance to thyroid hormones should be included in the differential diagnosis.

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 ß.

OBJECTIVE: The syndrome of resistance to thyroid hormone (RTH) is caused by a mutation of TH receptor ß (TRß) in 80% of cases. Patients without mutation (non-TR-RTH) may have a biochemical pattern that is difficult to differentiate from that of pituitary TSH-secreting adenoma (TSHoma). Herein, we report a large monocentric series of RTH focusing on patients with non-TR-RTH, to evaluate possible clinical or biochemical parameters able to distinguish them from TSHoma. DESIGN AND PATIENTS: We retrospectively reviewed the data of 99 consecutive patients with inappropriate TSH secretion (IST) syndrome referred to our Department between 1983 and 2011, identifying 68 patients with RTH and 31 patients with TSHomas. MEASUREMENTS: Patient records were reviewed for the main clinical, biochemical and imaging characteristics. RESULTS: Of our 68 patients with RTH, 16 (23·5%) did not show a TRß mutation and did not have affected family members. Of these 16 patients, three developed a TSHoma, during follow-up. To distinguish non-TR-RTH from TSHoma, we identified appropriate cut-off values for the main biochemical parameters that demonstrated the greatest sensitivity and specificity (T3 suppression test, α-subunit/TSH molar ratio, α-subunit assay and TRH test) and we calculated the probability for each patient to develop a TSHoma. CONCLUSIONS: The application of the identified cut-offs could become a very useful tool in the challenging differential diagnosis between sporadic non-TR-RTH and TSHoma. It would then be possible to select the patients at higher risk of developing a TSHoma and therefore needing a closer follow-up.

[Thyroid disease caused by receptor abnormality].

Hormone receptor abnormality is a syndrome of an abnormal mechanism caused by defective receptor function in hormone action. Resistance to thyroid hormone is a syndrome in which the responsiveness of the target organ to thyroid hormone is reduced. Resistance to thyroid hormone exhibits unsuppressed thyrotropin(TSH) despite elevated free thyroxin (FT4) and free 3,5,3'-triiodothyronine (FT3), termed the syndrome of the inappropriate secretion of TSH (SITSH). Resistance to thyroid hormone is mainly caused by a mutation in the thyroid hormone receptor beta (TRbeta) gene. Genetic analysis of the TRbeta gene is important to diagnose resistance to thyroid hormone. TSH receptor (TSHR) abnormality is classified as a gain-of-function mutation and loss-of-function mutation. Loss-of-function mutations in the TSHR gene occur as TSH resistance, which is found to have euthyroid hyperthyrotropinemia or hypothyroidism because of the reduced responsiveness of the receptor to TSH. R450H mutation in the TSHR gene is occasionally observed in Japanese patients with TSH resistance. In Japan, it is suggested that analysis of the R450H mutation in the TSHR gene is useful to determine the cause of hyperthyrotropinemia or hypothyroidism.

Sixteen years post radiotherapy of nasopharyngeal carcinoma elicited multi-dysfunction along PTX and chronic kidney disease with microcytic anemia.

BACKGROUND: The hypothalamic-pituitary (h-p) unit is a particularly radiosensitive region in the central nervous system. As a consequence, radiation-induced irreversible, progressively chronic onset hypopituitarism (RIH) commonly develops after radiation treatments and can result in variably impaired pituitary function, which is frequently associated with increased morbidity and mortality. CASE PRESENTATION: A 38-year-old male subject, previously having received radiotherapy for treatment of nasopharygeal carcinoma (NPCA) 16 years ago, appeared at OPD complaining about his failure in penile erection, loss of pubic hair, atrophy of external genitalia: testicles reduced to 2×1.5 cm; penile size shrunk to only 4 cm long. Characteristically, he showed extremely lowered human growth hormone, (HGH, 0.115 ng/mL), testosterone (<0.1 ng/mL), total thyroxine (tT4: 4.740 g/mL), free T4 (fT4, 0.410 ng/mL), cortisol (2.34 g/dL); lowered LH (1.37 mIU/mL) and estradiol (22 pg/mL); highly elevated TSH (7.12 IU/mL). As contrast, he had low end normal ACTH, FSH, total T3, free T3, and estriol; high end normal prolactin (11.71 ng/mL), distinctly implicating hypopituitarism-induced hypothyroidism and hypogonadism. serologically, he showed severely lowered Hb (10.6 g/dL), HCT (32.7%), MCV (77.6 fL), MCH (25.3 pg), MCHC (32.6 g/dL), and platelet count (139×103/L) with extraordinarily elevated RDW (18.2%), together with severely lowered ferritin (23.6 ng/mL) and serum iron levels; highly elevated total iron binding capacity (TIBC, 509 g/dL) and transferrin (363.4 mg/dL), suggesting microcytic anemia. Severely reduced estimated glomerular filtration rate (e-GFR) (89 mL/mim/1.73 m2) pointed to CKD2. Hypocortisolemia with hyponatremia indicated secondary adrenal insufficiency. Replacement therapy using androgen, cortisol, and Ringer's solution has shown beneficial in improving life quality. CONCLUSIONS: To our believe, we are the first group who report such complicate PTX dysfunction with adrenal cortisol insufficiency concomitantly occurring in a single patient.

[TSH secreting adenoma of pituitary gland (TSHom) - rare cause of hyperthyroidism in pregnancy]. / TSH-sezernierendes Hypophysenadenom (TSHom) - seltene Ursache einer Hyperthyreose in der Schwangerschaft.

HISTORY AND ADMISSION FINDINGS: A 28 year-old woman in her first pregnancy was referred to the department of obstetrics and gynecology at 24 weeks of gestation because of pregnancy-induced hypertension. INVESTIGATIONS: Thyroid stimulating hormone (TSH), free T3 and free T4 were elevated. Antibody screening did not show antithyroid peroxidase (anti-TPO) antibodies and TSH receptor antibodies. Clinical findings were suspicious of TSH secreting pituitary tumour (TSH-om) or thyroid hormone resistance (RTH). In absence of clinical sings of elevated intracranial pressure magnetic resonance imaging (MR) was discussed but not carried out and planned after delivery. A visual-field defect was ruled out by orbital field evaluation. TREATMENT AND COURSE: Treatment with 3 × 50 mg propylthiouracil daily was initiated. However, normal fT3/fT4 titers could not be achieved. Serum levels were in the high normal ranges and TSH remained increased. The clinical situation of the patient improved resulting in a normal delivery at term. The healthy newborn was breast feed and MR imaging of the mother revealed a 5×8 mm tumor of the pituitary gland. CONCLUSION: In pregnant women with pregnancy-induced hypertension thyroid diseases have to be ruled out. Rare causes of hyperthyreoidism are TSH secreting pituitary tumors or thyroid hormone resistance (RTH). Treatment of choice for hyperthyreoidism in pregnancy is propylthiouracil. Normal vaginal delivery and breast feeding are possible. Following delivery it is mandatory to determine an individual treatment strategy.

[Syndromes of resistance to thyroid hormone and inappropriate secretion of TSH (SITSH)].

Resistance to thyroid hormone (RTH) is a syndrome in which the responsiveness of end organs to thyroid hormone (TH) is reduced. Given that the TH-responsive end-organs include pituitary thyrotrophs, almost all patients with RTH manifest unsuppressed thyrotropin (TSH) despite elevated free-T4 and free-T3 levels. This abnormal finding in the thyroid function test is termed "syndrome of inappropriate secretion of TSH" (SITSH) or "central hyperthyroidism". Patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSHoma is sometimes difficult and challenging. In this review article, the etiology of RTH and diagnostic approach for SITSH are explained and an algorithm for differential diagnosis of RTH vs. TSHoma is proposed.

Falso incremento de la hormona estimulante del tiroides asociado a la presencia de macro-TSH / Falsely elevated levels of thyrotropin caused by macro-TSH

Mujer que presentó un importante incremento de la hormona estimulante del tiroides (TSH) (62,2 mU/L) con hormonas tiroideas dentro de los intervalos de referencia. La paciente se encontraba eutiroidea y no presentaba bocio. Se realizó un estudio inicial para determinar la posible causa del incremento en la concentración de TSH. La recuperación de TSH tras precipitación con polietilenglicol fue del 1%, sugiriendo la presencia de alguna molécula de elevado peso molecular que podría interferir en la determinación. Mediante cromatografía de exclusión, se confirmó la presencia de macro-TSH, un complejo autoinmune formado por TSH unido a una Inmunoglobulina G que es inmunorreactivo pero biológicamente inactivo, por lo que, si no se detecta, induce a una interpretación errónea de la concentración de TSH (AU)

Woman showing an important increase of serum TSH (62.2 mU/L) with thyroid hormones within the reference interval. The patient was clinically euthyroid and without goitre. Investigations were carried out to determine the origin of the unexpected high TSH. Polyethylene glycol precipitation test showed low TSH recovery (1%), indicating the presence of large molecules that could interfere with the measurement. The serum sample was fractionated by gel filtration chromatography and the presence of a macro-TSH form was confirmed, an immunoreactive but biologically inactive TSH-Immunoglobulin G autoantibody complex. Its detection is important to avoid a misleading interpretation of the TSH concentration (AU)

Pituitary tumours: TSH-secreting adenomas.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of all pituitary adenomas. In the last years, the diagnosis has been facilitated by the routine use of ultra-sensitive TSH immunometric assays. Failure to recognise the presence of a TSHoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumour volume to further expand. The diagnosis mainly rests on dynamic testing, such as T3 suppression tests and TRH, which are useful in differentiating TSHomas from the syndromes of thyroid hormone resistance. The first therapeutical approach to TSHomas is the pituitary neurosurgery. The medical treatment of TSHomas mainly rests on the administration of somatostatin analogues, such as octreotide and lanreotide, which are effective in reducing TSH secretion in more than 90% of patients with consequent normalisation of FT4 and FT3 levels and restoration of the euthyroid state.

[Imaging of pituitary adenomas]. / Imagerie des adénomes hypophysaires.

In cases of pituitary hormone hypersecretion, magnetic resonance imaging (MRI) can demonstrate the causal lesion, which is often small (microadenoma). In pituitary adenomas with suprasellar extension, MRI shows the tumor's relation to the surrounding structures: the optic chiasm, the internal carotid artery, the sphenoidal sinus, etc. MRI usually makes it possible confirm or rule out any cavernous sinus invasion by the pituitary adenoma, a determination essential for planning treatment. After pituitary surgery, MR imaging is again essential for visualizing any residual tumor tissue and - if the MRI is carefully performed to be reproducible - for assessing its development over time.

Thyroid hormone resistance and pituitary enlargement after thyroid ablation in a woman on levothyroxine treatment.

We report a patient with inappropriate secretion of thyrotropin (TSH) and a pituitary mass. Although she had been treated for biochemical hyperthyroidism with thyroid surgery and radioiodine ablation, she had never complained of specific symptoms or demonstrated signs of overt thyroid dysfunction. On evaluation, she had increased free thyroxine and TSH levels, normal serum glycoprotein alpha-subunit levels, and a significant TSH over-response to exogenous thyrotropin-releasing hormone stimulation. Magnetic resonance imaging with gadolinium enhancement showed a pituitary enlargement with suprasellar extension. An indium In 111 pentetreotide scan showed an abnormal focus of radionuclide accumulation in the pituitary area. Sequencing of the TRbeta gene showed that the patient was heterozygous for a new single nucleotide substitution resulting in the replacement of the normal arginine with a serine at amino acid 320 (R320S). We review the difficulties encountered in establishing a correct diagnosis in patients with inappropriate secretion of TSH in combination with pituitary enlargement. Due to its possible false-negative results, we do not recommend the use of indium In 111 pentetreotide as a tool in the differential diagnosis of inappropriate secretion of TSH.

Pituitary testing: a reappraisal.

Due to the pulsatile pituitary hormone secretion, their involvement in the acute stress response and feed-back with peripheral hormones, baseline pituitary hormone levels may overlap among normal and pathological subjects. Therefore, dynamic testing has been widely used for the diagnosis and follow-up of pituitary diseases. An ideal test should be sensitive, specific, well tolerated, easy to be standardized and performed and cost-effective. Emerging issues are cost and widespread availability of ultrasensitive hormone assays, increased knowledge of the pathophysiological and pharmacological mechanisms regulating pituitary function and need for better discrimination between clinically useful tests and research tools. In this special issue experts from US and Europe practically approached testing in specific pituitary diseases in the context of current guidelines. Drug effects on different axes are discussed since pharmacologic treatments may influence testing outcome.

[Treatment of pituitary gland hyperfunction: from acromegaly to prolactinoma]. / Therapie der Hypophysenüberfunktion: Von der Akromegalie zum Prolaktinom.

Evidence based drug therapy is currently available for the treatment of prolactinomas and growth hormone secreting adenomas (acromegaly). Dopamine agonists such as bromocriptine, quinagolide or cabergoline represent the standard therapy for the treatment of micro- and macro-prolaktinomas. In pregnancy, more differentiated, individual and patient-adapted therapeutic procedures have to be considered. Transsphenoidal adenomectomy is the treatment of choice for patients suffering from acromegaly. If biochemical cure (defined by normalized IGF-1 serum levels or by a GH nadir <1 microg/l during a 3-h oral glucose tolerance test) cannot be achieved, somatostatin analogues such as octreotide and lanreotide are effective. In some cases, dopamine agonists can be added. In therapy-resistant cases, growth hormone receptor antagonists can be used.

Common disorders of the pituitary gland: hyposecretion versus hypersecretion.

An understanding of pituitary disorders requires much more than a knowledge of the definitions associated with them. To grasp fully their complexity, one must recognize not only the powerful role the pituitary gland plays in the endocrine system, but also its effects on homeostasis throughout the entire human body, its association with the hypothalamus, and ultimately its associated end organs. Because of the many hormones stored or produced by the pituitary, associated disorders often are confusing and challenging. However, by simplifying the classification of these disorders into the categories of hyposecretion and hypersecretion, the understanding of pituitary disorders is made simple, and the associated interventions become apparent.

[Cycle disorders, polydipsia, decline of vision. Is it the fault of the hypophysis?]. / Zyklusstörungen, Polydipsie, Visusminderung. Ist die Hypophyse schuld?

Apart from partial or complete insufficiency, further diseases of the pituitary with clinical impact are those associated with hormone overproduction such as acromegaly, Cushing's disease and prolactinoma. The cardinal symptom of pituitary insufficiency or disruption of the female cycle, loss of libido or sexual potency reflecting a lesion of the gonadotrophic axis. Hyperprolactinemia also results in a loss of gonadotrophic function. Macroadenomas of the pituitary gland often give rise to visual field defects, so that an ophthalmological work-up is a must. With the exception of hyperprolactinemia, measurement of basic hormone levels is not always sufficient to detect pituitary diseases. For the establishment of hormone deficiency, therefore, stimulation tests, and for detection of hypersecretion suppression tests, are carried out. Owing to the increasing utilization of cranial MRI, incidental detection of intrasellar tumors, the so-called incidentalomas, is becoming ever more common, and these lesions require at least an endocrinological investigation.