Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma

Objective Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. Design Retrospective study. Methods Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. Results Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4–7) and for a median duration of 3 months (2.5–3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. Conclusions SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.

SUN-293 Acute and Long Term Evaluation of Pituitary Functions in Patients with Advanced Heart Block Requiring Pacemaker Implantation: A Pilot Study

Background: Neuronal hypoxia and neuro-inflammation accompanying conditions like traumatic brain injury, stroke, cerebrovascular accidents and sub-arachnoid haemorrhage has been associated with hypopituitarism. Neuronal insults of similar magnitude and hypopituitarism [Growth Hormone (GH), gonadotropin and TSH deficiency in 27.2%, 9.0% and 2.2% patients respectively] has also been noted in a single study till date conducted in patients of ventricular arrhythmias requiring cardio-pulmonary resuscitation1. Patients with heart block, a more frequent form of cardiac arrhythmia usually presents with haemodynamic compromise and may be predisposed for developing either acute or delayed hypopituitarism which has never been studied before. Aims and objective: Our study was aimed at exploring whether pituitary dysfunction occurs in patients presenting with heart block and requiring pacemaker implantation. We analysed anterior pituitary functions in these cohort of patients during acute hospitalization and later during follow. Study design: Cross sectional prospective study Materials and Methods: Fifty-one patients were included in the study (mean age-65.98±10.9years; 34 men & 17 women). Pituitary hormonal profile was done within 48 hours of presentation and after a mean follow up of 12.52 ± 2.2 months. Total T3, total T4, free T4, TSH, FSH, LH, Testosterone (in men), Estradiol (in women), Prolactin, and random Cortisol were measured in all participants at baseline and in follow-up. Fixed dose Glucagon (weight<90kg-1mg; ≥90kg-1.5mg) stimulation test was done in follow-up to assess GH and cortisol axes. Results: Among 30 (out of 50) patients who turned up for follow-up, GH, cortisol and TSH deficiency was noted in 50% (n-15), 13.3% (n-4) and 3.2% (n-1) of subjects, respectively. Pan-hypopituitarism characterised by deficiency of at least two hormonal axes was seen in 16.7% (n-5) patients. Conclusion: Significant delayed hypopituitarism especially GH deficiency was seen among patients of heart block. Implications: This novel finding if reproduced in subsequent studies will result in unearthing of a significant etiology of hypopituitarism which could potentially become the most common cause of acquired adult onset hypopituitarism considering the huge burden of patients with heart block. Heightened cardiovascular risk due to hypopituitarism in these patients may be reversed by active screening and replacement of deficient hormones. References: (1) Simsek, Kaya, Tanriverdi et al. (2014) Evaluation of long-term pituitary functions in patients with severe ventricular arrhythmia: a pilot study. J Endocrinol Invest 37:1057-1064Keywords: Cortisol, GH deficiency, Heart block, Hypopituitarism, Pituitary Disclosure: Authors have nothing to disclose

MON-288 TSH Deficiency in Patients on Somatostatin Analog for TSH-PitNET

Background: Somatostatin analogs (SSA) are efficiently used to control central hyperthyroidism in patients with thyrotropin-secreting pituitary neuroendocrine tumor (TSH-PitNET). The aim of this study was to describe the frequency of thyrotropin (TSH) deficiency under SSA in patients with TSH-PitNET. Methods: We retrospectively recruited patients presenting a central hyperthyroidism due to TSH-PitNET. Inclusion criteria were patients treated in first, second or third line by short or long-acting SSA, with central hyperthyroidism before SSA. Patients treated by radiotherapy or dopamine agonist were excluded. TSH deficiency was defined by either a low FT4 or low FT4 and FT3, associated with non-elevated TSH concentrations during SSA therapy. We analyzed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. Results: 46 patients were included in the study. SSA were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%), after a median time of 4 weeks (4–7) after the starting of SSA, and for a median duration of 3 months (2.5–3). The TSH deficiency occurred after 1 to 3 injections of long-acting SSA. There were no differences in terms of clinical and hormonal features and size of adenomas between patients with or without TSH deficiency. Conclusions: In patients with central hyperthyroidism due to TSH-PitNET, SSA can induce TSH deficiency. Thyrotropic function should be assessed before each injection of SSA in order to adapt the frequency of injection when control of thyrotoxicosis rather than tumor reduction is purpose of the treatment.

A RECURRENT MUTATION IN TSHB GENE UNDERLYING CENTRAL CONGENITAL HYPOTHYROIDISM UNDETECTABLE IN NEONATAL SCREENING

ABSTRACT Objective: To describe the case of a patient with central congenital hypothyroidism (CCH) due to a recurrent mutation in the TSHB gene, as well as to conduct a genetic study of his family. Case description: It is presented a case report of a 5-month-old boy with a delayed diagnosis of isolated CCH in whom the molecular analysis was performed 12 years later and detected a recurrent mutation (c.373delT) in TSHB gene. The parents and sister were carriers of the mutant allele. Comments: The c.373delT mutation has previously been reported in patients from Brazil, Germany, Belgium, United States, Switzerland, Argentina, France, Portugal, United Kingdom and Ireland. In summary, our case and other ones reported in the literature support the theory that this mutation may be a common cause of isolated TSH deficiency. Isolated TSH deficiency is not detected by routine TSH-based neonatal screening, representing a clinical challenge. Therefore, when possible, molecular genetic study is indicated. Identification of affected and carriers allows the diagnosis, treatment and adequate genetic counseling.

Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review

Context Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. Objectives To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. Patients and Methods Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. Results Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. Conclusions The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

Recent advances in central congenital hypothyroidism

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR,IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic–pituitary–thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.