TRH Stimulation Research Articles

The diagnosis and prevalence of hypoprolactinemia in patients with panhypopituitarism and the effects on depression and sexual functions

PurposeWe aimed to investigate the prevalence and the diagnostic criteria of hypoprolactinemia in patients with panhypopituitarism and the effects of hypoprolactinemia on depression and sexual functions.Materials and methodsForty-eight patients with panhypopituitarism and 20 healthy volunteers were included. Basal hormone levels were measured and a TRH stimulation test was performed. For the evaluation of sexual functions, questionnaries of Female Sexual Functional Index (FSFI) for females and International Erectile Functional Index for males were performed to the subjects. Depressive symptoms were evaluated by Beck Depression Envontory score (BDI-II).ResultsThe peak PRL response to TRH stimulation test at 5th percentile in the control group was 18.6 ng/ml in males and 41.6 ng/ml in females and accepted as the cut-offs for sufficient response of PRL. Prolactin was insufficient in 42(87.5%) patients. A basal PRL level of ≤ 5.7 ng/ml in males and 7.11 ng/ml in females was 100% specific in predicting an inadequate response to TRH stimulation test with 80% and 70% sensitivity respectively. A basal PRL level of ≥ 8.5 ng/dl in males was 100% specific and 76% sensitive, and in females a level of ≥ 15.2 ng/dl was 96% specific and 66% sensitive in predicting an adequate response to TRH. PRL deficient patients with panhypopituitarism had higher depression scores compared to the controls, lower sexual function scores in males.ConclusionPRL deficiency is prevalent among individuals with panhypopituitarism, with the potential to result in elevated depression scores in both sexes and impaired sexual functions in males. A basal PRL level seems to be sufficient for the diagnosis of hypoprolactinemia in routine clinical practice.

Resistance to thyroid hormone and nonfunctioning pituitary microadenoma in a 13-year-old boy with THRB mutation.

Resistance to thyroid hormone (RTH) is a rare syndrome characterized by elevated serum free iodothyronines levels and non-suppressed thyroid stimulating hormones (TSH). The most common cause of RTH is heterozygous pathogenic mutations in thyroid hormone receptor β gene (THRB). Because of the similarities in biochemical profiles, differential diagnosis between RTHβ and TSH-secreting pituitary adenoma (TSHoma) is important, and accurate RTHβ diagnosis is essential to prevent inappropriate treatment. A 13-year-old boy was referred to our hospital for a microadenoma and uncontrolled hyperthyroidism despite use of methimazole for more than one year. He suffered from thyrotoxic clinical features and elevated serum T3 and fT4, and normal ranges for TSH and other pituitary hormones were noted. TSH receptor antibody was undetectable, and pituitary MRI revealed a 3mm-sized microadenoma. A TRH stimulation test showed normal TSH response, and the TSH-α-subunit level was not elevated, which is consistent with RTH. The patient was diagnosed with RTHβ and coexistent non-functioning pituitary microadenoma based on identification of a heterozygous mutation, c.1021C>G (p.Leu341Val), in THRB. Methimazole treatment was stopped, and a β-adrenergic blocking agent was started, subsequently thyrotoxic symptoms were relieved. Currently, only one pediatric case diagnosed with RTH and TSHoma has been reported so far, and this case is the first to report a pediatric case of coexistence of RTH and non-functioning pituitary microadenoma. Also, this case shows that inappropriate secretion of thyroid hormones requires careful clinical diagnosis to avoid unnecessary and potentially harmful management.

A reference center study in thyrotropin-secreting pituitary adenomas: clinicopathological, therapeutic and long-term follow-up outcomes.

This study aims to analyze the clinicopathological features, diagnostic steps, and therapeutic results of TSHomas and to reveal the effective factors on remission. The clinical, radiological, and pathological features and surgical and endocrinological results of 41 TSHoma cases followed between 2005 and 2022 were retrospectively analyzed. The factors affecting the surgical cure were investigated by comparing the groups with and without remission. A total of 41 patients (23 male,18 female) were included in the study and the mean age was 42 (31.5-49). Palpitation and headache were the most common complaints. The time from the onset of symptoms to diagnosis was 8 (3-20) months. There were 8 patients with a preoperative clinical and biochemical diagnosis of TSH + GH co-secretion. In the TRH stimulation test, a blunted TSH response was obtained in 18 patients (90.0%). Complete suppression could not be obtained in any of the patients who underwent the T3 suppression test. The median maximum tumor diameter was 19.0 mm (6.8-41). There was microadenoma in 4 (9.8%) patients and macroadenoma in 37 patients (92.8%). Remission was achieved in 31 (75.6%) of 40 patients who underwent endoscopic transsphenoidal surgery (eTSS). The Ki-67 labeling index was 2% (1.00-4.00) in the entire patient group. Preoperative use of antithyroid drugs appears to be significantly associated with surgical cure. Diagnosis of TSHoma is still full of challenges and dynamic tests remain important. Recognition and good management of inappropriate TSH secretion states affect subsequent surgical outcomes.

Thyrotropin Secreting Pituitary Adenoma: A Clinical Case of Postoperative Re-Onset Thyrotoxicosis with Adenoma Recurrence.

Thyrotropin-secreting pituitary adenomas are rare benign tumours. Proper diagnosis can be challenging, requiring TSH autonomous production and differentiation from resistance to thyroid hormone action (RTH).Undetectable TSH levels one week after surgery and/or positive T3 suppression test or no response to TRH stimulation test seem to be the criteria with the best prognostic value post-treatment.Close clinical, biochemical and imaging follow-up is crucial to detect TSHoma recurrence.

Abstract #1411806: A Case of Thyrotropin Secreting Adenoma and Review of Literature

Elevations of TSH, FT4, and FT3 are a feature of secondary hyperthyroidism which could occur in the setting of resistance of thyroid hormone at the pituitary gland, alteration of certain deiodinase enzymes causing lower T3 at the pituitary or a TSH secreting tumor in the pituitary. Other conditions include pregnancy and the use of drugs (amiodarone, heparin). We present a case of secondary hyperthyroidism that was diagnosed with a TSH-secreting adenoma (TSHoma). A 72-year-old male presented with complaints of chest pain. He had a past medical history of primary hyperaldosteronism, occipital lobe ischemic infarct, osteoporosis with low-intensity rib, wrist, and vertebral fractures, coronary artery disease, and had undergone CABG. He was diagnosed with paroxysmal atrial fibrillation and had thyroid function testing which showed a TSH of 7.72μIU/mL (0.42-4.50), FT3 6.2pg/mL (2.0-4.4) and FT4 1.74ng/dL (0.70-1.48). A subsequent CT Head revealed a sellar mass measuring 1.4 cm craniocaudally with abutment of the optic chiasm. Repeat thyroid testing continued to show an elevated TSH, FT3, and FT4. αsubunit glycoprotein was 4.1ng/mL (< 0.5), IGF-1 by LC/MS was 31ng/mL (32-200), prolactin was 46.5ng/mL (4.0-15.2) and SHBG 131.6nmol/L (13.3-89.5). He was managed with methimazole and underwent trans-sphenoidal resection of the tumor. Pathology showed a 3.5 x 1.8 x 0.3 cm mass that on immunoperoxidase stains demonstrated expression of synaptophysin by many of the neoplastic cells. Some expressed GH, few expressed prolactin while rare neoplastic cells expressed TSH. TSHomas are rare pituitary adenomas with a prevalence of 1-2 cases/million. Up to 30% can be associated with hypersecretion of GH, prolactin, LH and FSH. The cells express TRH, somatostatin, and dopamine receptors. Clinical features include headaches, visual field defects, goiter, signs/symptoms of hyperthyroidism, pressure effects of the adenoma, cardiac manifestations (atrial fibrillation, heart failure, pericardial effusion) and vertebral fractures. αsubunit glycoprotein is elevated and an αsubunit to TSH molar ratio >1 can be used with 90% sensitivity to differentiate it from other causes of elevated TSH, FT3 and FT4. Elevations in SHBG are also found in patients. Resistance to the thyroid hormone at the pituitary level can give rise to a similar presentation. Elevated levels of SHBG and αsubunit glycoprotein seen in TSHoma can aid in differentiation. Dynamic testing such as a T3 suppression test with LT3 fails to suppress TSH production in cases of TSHoma. In addition, a TRH stimulation test fails to increase levels of TSH or αsubunit in TSHomas. Due to the presence of somatostatin receptors, TSH reduction starts to occur within hours after the use of somatostatin analogs. Surgical removal is the cornerstone of management and helps achieve normal TSH levels in more than 75% of patients. Pre-operative treatment with octreotide is shown to reduce TSH levels by up to 50% and cause a reduction in size by 20-50%. Undetectable TSH 1-week post-op has good prognostic value and a reduction in TSH on a T3 suppression test has optimal sensitivity and specificity to demonstrate cure.

Utility of basal and peak TSH values in TRH stimulation testing for predicting the long-term therapeutic prognosis of primary congenital hypothyroidism.

In Japan, most neonates undergo screening for congenital hypothyroidism (CH). A TRH stimulation test (TRH-T) may be performed after initial treatment as a useful method for reevaluating the patient's thyroid status. However, no studies have compared basal and peak TSH values in TRH-T in patients with long-term follow-up. This was a retrospective and observational study. The inclusion criteria were as follows: (1) CH diagnosis based on positive newborn screening, (2) follow-up > 15 yr, and (3) TRH-T after LT4 discontinuation. The participants were divided into a no-treatment group (No-T group) and a treatment group (T group). The No-T and T groups included 14 and nine patients, respectively. The age at TRH-T was 5.38 yr for the No-T group and 4.25 yr for the T group, with no significant difference. The basal and peak TSH levels were significantly lower in the No-T group. The areas under the Receiver operating characteristic curve for basal and peak TSH values were 0.984 and 0.905, respectively. When the basal TSH level was under 4.594 IU/mL, the No-T group had a sensitivity of 1.00 and a specificity of 0.93. Basal TSH levels alone may be sufficient for predicting the long-term therapeutic prognosis of patients with CH.

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients.

Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 μIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75-150) μg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = -0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

A remarkable case of thyrotoxicosis initially caused by graves\u2019 disease followed by a probable TSHoma \u2013 a case report

BackgroundGraves’ 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.CaseA 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.ConclusionThis 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.

SAT-244 Inflammatory Rathke Cleft Cyst Caused Hypothalamic Panhypopituitarism

Background: Hypothalamic panhypopituitarism was a rare disease which was caused by brain tumors such as Rathke cyst, germinoma, malignant lymphoma and craniopharyngioma, and vascular accidents such as thrombosis and hemorrhage. We have found a rare case of hypothalamic panhypopituitarism occurred by the inflammation of Rathke cyst. Case presentation: A 77-year-old woman was admitted to our hospital because of severe headache, nausea, vomiting and fever. Hyponatremia (Na 131 meq/L) and increased CRP level (0.20 mg/dl) and no finding of gastroenterological examination and abdominal CT scanning were observed. Endocrinological examination revealed low levels of anterior pituitary hormones such as GH, LH, FSH and ACTH and increased PRL levels and low level of serum cortisol. Simultaneous CRH, TRH and LH-RH stimulations tests indicated low responses of TSH, LH, FSH and PRL and hyperesponse of ACTH (from 2.4 to 251 pg/ml). Radiological examination by enhanced MRI revealed high intensity of T2-weighted images and low and partial high intensities of T1-weighted images in swelling of pituitary gland and vanishment of high intensity of posterior lobe in T2-weighted images suggesting that the inflammatory wall of Rathke cyst. We searched previous data of ACTH and cortisol levels which showed normal level of ACTH (55.2 pg/ml) and cortisol 18.8 μ;g/dl) when headache and nausea arouse on 50 days before. Based on above results patient was diagnosed as hypothalamic hypopituitarism due to inflammatory Rathke cyst. Therefore, patient was treated with hormone replacement therapy by 20 mg of hydrocortisone. After these treatment, polyuria, urinary low osmotic pressure and hypernatremia appeared due to partial diabetes insipidus caused by the impairment of posterior lobe in pituitary gland, and diagnosed by the examination of vasopressin test. This patient was also treated by the oral desmopressin acetate hydrate (60 μ;g/day), and has been well-tolerated in the outpatient clinic. Conclusion: These results suggested that inflammatory Rathke cyst with inflammatory changes in hypothlamo-pituitary system raised a rare case of hypothalamic panhypopituitarism.Reference: Nishioka H. et al.: Clin Endocrinology (Oxf) 2006:64:184–188

MON-478 Impaired Sensitivity to Thyroid Hormone - A Diagnostic and Therapeutic Challenge

Background: Impaired sensitivity to thyroid hormone refers to any process that negatively affects its action, including defects in its transport, metabolism and action on the receptor. Resistance to thyroid hormone due to beta-receptor mutations (RTH-beta) is the most common form of this entity and is characterized by reduced response of peripheral tissues to the action of thyroid hormone. The genetic variability of cofactors involved in the action of thyroid hormone explains the heterogeneity of resistance among affected individuals. Generally, patients with this disorder, have increased levels of free T4 and free T3 in association with normal or high TSH. Clinical case: 11-year-old boy, with personal history of Attention-deficit/hyperactivity disorder (ADHD). A pediatric endocrinology consultation was requested to evaluate abnormalities in his thyroid function tests. A few months earlier, his father was referred to endocrinology consultation because of thyroid function tests abnormalities: TSH - 3.01 μIU / mL (N: 0.35 - 4.94); Free T4 1.7 ng / dL (N: 0.7-1.48); Free T3 4.77 pg / mL (N: 1.71-3.71). Initially, two diagnostic hypotheses were considered: central hyperthyroidism or impaired sensitivity to thyroid hormone. The adult underwent pituitary magnetic resonance, which raised the hypothesis of a pituitary microadenoma, and TRH stimulation test, whose result was strongly suggestive of the second diagnostic possibility. A genetic study was requested and the presence of the c700 G> A variant (p. Ala 324 trh) in the THRB gene was identified, which confirmed the most likely hypothesis. At the time of the pediatric endocrinology consultation, the 11-year-old boy had the results of his lab tests: TSH - 6.67 μIU / mL (N: 0.35 - 5); T4L 2.27 ng / dL (N: 0.88-1.58); T3L 7.79 pg / mL (N: 2-4.20). Given his perfect height and weight evolution and the absence of symptoms suggestive of hypo or hyperthyroidism, it was decided not to start any medication, keeping only periodic surveillance. Conclusion: This case exemplifies unusual thyroid function tests. This discordance between serum thyroid hormone and TSH concentrations should raise the possibility of impaired sensitivity to thyroid hormone. In this condition, patients may present with symptoms of hypo or hyperthyroidism and the etiology of thyroid function tests abnormalities are not easily recognized. This can lead to misdiagnosis and consequently unnecessary treatment.

SAT-268 Thyrotropin Secreting Pituitary Adenoma Initially Misdiagnosed as Primary Hyperthyroidism in a Taiwanese Man

Background:TSH (Thyrotropin) secreting pituitary adenoma (TSHoma) account for less than 1% of all causes of hyperthyroidism and 1% of all functioning pituitary tumors. Definite diagnosis and treatment of TSHoma are clinical challenges in practice. Here we report laboratory data, imaging findings, endocrine dynamic test, and treatment outcomes in a 50-year-old Taiwanese man with pituitary plurihormonal adenoma secreting TSH and LH.Clinical case:The patient was initially diagnosed as goiter with primary hyperthyroidism and DM while medical check-up by primary care physician in 2014. He had no significant hyperthyroidism symptoms and signs except goiter and mild palpitation. He received propylthiouracil and Metformin. Two years later, he visited to Endocrinologist’s clinic for poor glycemic control. Central hyperthyroidism was diagnosed due to measurable TSH level in the presence of increased serum thyroid hormone level. Moreover sella MRI revealed left sided pituitary lesion. He was referred to Taipei Veteran General Hospital for further management. There was no family history of thyroid disease. Physical examination was not remarkable except diffuse grade 3 goiter and tachycardia (HR 100~115 bpm). Follow up laboratory data showed TSH 4.89; range 0.4~4.0 uIU/ml, free T4: 3.05; range 0.9~1.8 ng/dl, T4: 16.02; range 4.50~12.50 μg/dl, T3: 249; range 58~159 ng/dl, free T3: 8.0; range 2.3~4.3 pg/ml. Two times of TRH stimulation test showed blunted TSH response. Normal limit of thyroid autoantibodies level were found. Thyroid sonography revealed heterogenous echogenicity with increased size and vascularity of both lobes. I-131 uptake was homogenous uptake (94%). Other pituitary hormones level were within normal limit except mild elevation of testosterone 12.69 ng/ml. Sella MRI with contrast showed macroadenoma (size 10x10x7.6 mm) at left pituitary gland. Taken together, he was diagnosed as central hyperthyroidism related to left sided pituitary macroadenoma. Surgery was performed after one year of definite diagnosis due to personal reason. TSH level returned to normal ranges (0.799 uIU/ml) in 1st post operative day. Histologically, the pituitary mass was compatible with plurihormonal adenoma and immunohistochemistry showed positivity for TSH (4+) and LH (3+). Post operative condition was well. Antithyroid agent was discontinued after operation. His blood glucose became well controlled after operation.Clinical lessons:A biochemical hallmark of TSHoma is an escape of TSH from the feedback loop that is detectable TSH levels in the presence of increased serum thyroid hormone level. Diagnosis of TSHoma was frequently unrecognized and thus much delayed despite its relatively straightforward. Physician should keep in mind that the importance interpretation of simple laboratory tests to avoid delay diagnosis and unnecessary treatments.

MON-465 Novel Thyroid Hormone β Mutation L266s Causes Atrial Fibrillation &amp; Cerebral Infarction

Background: Resistance against thyroid hormone β (RTHβ) is characterized by reduced tissue sensitivity to thyroid hormone. Patients with RTHβ resistance typically demonstrate increases in FT3 and FT4 accompanied by inappropriately elevated TSH. Mutations in the TRβ gene are the most common genetic disorder in thyroid hormone resistance and result in impaired thyroid receptor functions due to a dominant negative effect. Here, we describe a case with a novel TRβ mutation, presenting atrial fibrillation and cerebral infarction.Clinical case: A 55-year-old man presented chronic atrial fibrillation and tachycardia as the onset of cerebral infarction. Because blood tests revealed 5.6 pg/ml FT3 (reference range: 2.36–4.06), 3.39 ng/ml FT4 (0.71–1.5), 0.98 TSH μIU/ml (0.541–4.261), and negative TRAb, suggesting inappropriate secretion of TSH (SITSH). He was referred to our department for further investigation. All three test kits, including LUMIPULSE, ECLusys, and TOSOH, showed an unsuppressed TSH value despite hyperthyroxinemia, demonstrating genuine SITSH. His family history was unclear, but his father had died of heart disease. A pituitary MRI suggested microadenoma, but TSH-secreting pituitary adenoma was excluded because of a negative α subunit and responsiveness to a TRH stimulation test. The TRβ gene was analyzed with informed consent from the patient, and a novel mutation replacing the 266th amino acid serine (TCG) with leucine (TTG) in the 8th exon was found, confirming the diagnosis of RTHβ. Tachycardia and atrial fibrillation were considered to be caused by thyrotoxicosis in heart, which dominantly expresses TRα rather than TRβ. Therefore, β-blockers and anticoagulants, were continued.Conclusion: This is the first report of a case of RTHβ with the TRβ L266S mutation. This novel mutation is located in the thyroid hormone-binding area of the TRβ gene, suggesting that reduced hormone binding may cause thyroid hormone resistance.

The effect of freeze-thaw cycles on determination of immunoreactive plasma adrenocorticotrophic hormone concentrations in horses.

BackgroundDetermination of plasma adrenocotrophic hormone (ACTH) concentration (endogenous or thyrotropin‐releasing hormone [TRH] stimulation test) is the most commonly used diagnostic test for pituitary pars intermedia dysfunction (PPID) in horses. Because ACTH is unstable, samples often are frozen to be shipped to laboratories or to allow for batch analysis of research samples. However, the effect of multiple freeze‐thaw cycles on equine ACTH is unknown.ObjectiveTo determine the effects of multiple freeze‐thaw cycles on immunoreactive ACTH concentration.AnimalsTwenty‐eight horses ranging from 10 to 27 years of age were used.MethodsProspective study. Horses were divided into 4 groups: group 1, PPID‐negative, without TRH stimulation; group 2, PPID‐negative, with TRH stimulation; group 3, PPID‐positive, without TRH stimulation; and group 4, PPID‐positive, with TRH stimulation. Whole blood was collected from each horse at baseline or 30 minutes after TRH stimulation. Immunoreactive plasma ACTH concentration was determined using a chemiluminescence assay. Plasma samples then were frozen at −80°C >24 hours, thawed at 4°C and reanalyzed for 5 freeze‐thaw cycles. Changes in plasma ACTH concentration were analyzed using a linear mixed‐effect model.ResultsSignificant effects of freeze‐thaw cycles (P = .001) and PPID status (P = .04) on plasma ACTH concentration were observed, but no significant effect of TRH stimulation was identified.Conclusions and Clinical ImportanceThe plasma ACTH concentration is altered by freeze‐thaw cycles, and the effect is observed sooner in horses with PPID. To diagnose PPID, multiple freeze‐thaw cycles should be avoided when measuring plasma ACTH concentration.

Evidence of Pituitary Hypoplasia Associated with Partial Central Diabetes Insipidus in a Young Persian Cat

Background: Congenital anomalies are an uncommon pituitary hypofunction cause associated to multiple hormone deficiencies. Congenital hyposomatotropism is often related to an inherited anomaly, characterized mainly by delayed growth. It is not uncommon to find associated thyroid-stimulating hormone and gonadotropin deficiencies. Pituitary malformation may be associated to progressive cystic lesion expansion. Central diabetes insipidus (CDI) is another rare disease associated to polyuria (PU) and polydipsia (PD) secondary to antidiuretic hormone (ADH) deficient secretion. The aim of this report is to describe a likely case of pituitary hypoplasia, associated with partial CDI in a cat.Case: A 9-month-old unneutered male Persian cat weighing 2 kg was presented due to severe polyuria and polydipsia associated with growth deficit when compared with its sibling. After clinical and laboratory evaluations during the months in which the patient was monitored, a reduced serum concentration of insulin-like growth factor-1 (IGF-1), thyroid-stimulating hormone (TSH), thyroid hormones, and testosterone was documented, confirming the diagnosis of hyposomatotropism, hypogonadism, and secondary hypothyroidism. Furthermore, therapeutic diagnosis with desmopressin revealed partial central diabetes insipidus (CDI). As the sibling showed normal development aging 13-months, a radiographic examination of the forelimb (carpus) was performed on both cats. There was lack of growth plate fusion in the patient, without any other evidence of dysgenesis, whereas complete epiphyseal closure was observed in the sibling. Despite desmopressin and levothyroxine therapeutic prescription the owners refuse further follow-up to the case.Discussion: Notwhistanding neuroimaging was not available for investigation of pituitary aspect in this particular case, the clinical symptoms added to the results of the complementary tests were consistent with pituitary hypoplasia, associated with hyposomatotropism, secondary hypothyroidism, hypogonadism, and partial CDI. Hyposomatotropism was presumably diagnosed based on the patient’s clinical characteristics, which included proportional growth delay, delayed tooth eruption, delayed growth plate fusion, associated with serum reduced IGF-1 results in comparison with its sibling. The report of low free T4 by equilibrium dialysis and of low total T4 levels, associated with low TSH levels, was considered compatible with secondary hypothyroidism. TRH stimulation test is considered the gold standard for secondary hypothyroidism diagnosis since low TSH could be secondary to assay´s low sensibility. However, normal TSH and thyroid hormone results in the sibling results ruled out this possible dismissed diagnose. The patient’s lack of sexual interest, associated with hypotestosteronemia and underdeveloped genitals (absence of penile spines and testicular hypoplasia), indicates hypogonadism. Finally, partial CDI diagnosis was demonstrated by cat´s partial ability to increase urinary specific gravity under water deprivation often made by the owners, as well as the response pattern to desmopressin therapy. Owing the lack of neurological signs expected to be associated with neoplastic or traumatic hypopituitarism etiology, hypoplasia hypothesis was raised. Quite often, patients with pituitary hypoplasia develop Rathke cleft cysts that might expand over time. In the present case, partial CDI is likely to be caused by the compression of the neurohypophysis by cyst formation secondary to adenohypophyseal hypoplasia since this kind of pituitary congenital anomaly does not justify per se neurohypophysis implications.

Is there merit in utilising the TRH stimulation test in horses with an equivocal ACTH concentration?

Is there merit in utilising the TRH stimulation test in horses with an equivocal ACTH concentration?

SAT-480 Clinical Cases TSH Secreting Adenomas

Introduction:TSH-secreting pituitary tumors represent about 2% of all pituitary adenomas and cause central hyperthyroidism. These tumors are characterized by high levels of free thyroid hormones in the presence of nonsuppressed serum TSH concentrations.Clinical cases: 1:A 52-year womanwith menstrual irregularity and hyperprolactinemia (127ng/mL). The pituitary´s MR showed a lesion (2.0 x1.8 x1.8cm). The diagnosis of TSHoma was made later when TSH achieved 4,78µU/mL (0.27-4.2), FT4 1.9ng/dL(0.93-1.7) and TRH stimulation test compatible. Treated with Ocreotide LAR (OCT LAR) and cabergoline, but the tumor became invasive. The surgery was indicated but the patient refused. 2:A 56-year womanwith weight loss, insomnia and hair loss. TSH 5.66µU/mL(0.5-5.3), FT4 2.4ng/mL(0.7-1.6), SHBG elevated, negativeantibodies andα-GSU in the normal range. The TRH stimulation test was compatible with TSHoma. The MR presented a tumor with 0.9x0.8x0.7cm. Treated with OCT LAR: good control of hyperthyroidism symptoms. 3: A 55-year man with headachesand visual field loss. TSH 2.47µU/mL(0.5-5.3), FT4 2.3ng/mL(0.7-1.6) and negative antibodies. The pituitary MR presented a tumor with 1.1x1.0x1.0cm and compression of the optic chiasm. The diagnosis was confirmed with the TRH stimulation and high level of α-GSU. The patient had an arrhythmia and the surgery was cancelled. He has been treated successfully with OCT LAR. 4: A 45-year-old asymptomatic woman with routine tests: TSH 5.11 μUI/mL(0.27-5.0), FT4 1.97ng/dL(0.75-1.10) and negative antibodies. The diagnosis was confirmed by α-GSU, TRH stimulation andpituitary lesion with 2.1x1.9x1.8cm. She has been treated with OCTand presented normalization of hormones, α-GSU and tumorreduction. 5:A 62-year-old woman with tremors, TSH 13.9 µUI/mL (0.45-4,5), FT4 2.2 ng/mL (0.6-1.3) and positive anti-TPO. The α-GSU was normal for postmenopausal woman, but had a high α-GSU/TSH molar ratio. The pituitary´s MR showed a lesion with 5 mm. The treatment with OCT LAR was indicated. 6:A 59-year-old woman withhyperthyroidism clinic and liver cirrhosis. TSH 6.29µUI/L (0.27-4.2), FT4 3.2ng/dL(0.93-1.7),α-GSU 2251ng/L (340-4000) and a 0.9 cm pituitary lesion. There was no tumor control with OCT LAR. Transesphenoidal surgery couldn'tbe considered because of coagulation disorders. Antithyroid drugs was contraindicated due to its hepatotoxicity. Then weperformed a radiosurgery but the patient lead to death after intestinalhemorrhage. 7:A 51-year-old man complaining of palpitations, irritability and tiredness. Laboratory tests showed an increase in FT4L: 2.3ng/dL (0.9-1.7) with inappropriately normal TSH: 1.77 μUI/L (0.27-4.2) and presence of pituitary microadenoma.Conclusion: In the presence of inappropriate normal or increased TSH levels and high FT4 levels the TSH- secreting pituitary adenoma should be considered even though is a rare disease.

OR10-3 Contributions of the Hypothalamus and Pituitary in Expressing the Thyroid Phenotype of SBP2 Deficiency: Other Regulatory Tiers in Addition to the Thyroid Gland

Background: Selenocysteine insertion sequence binding protein 2 (SBP2) is essential for selenoprotein synthesis, including the selenoenzymes deiodinases. Selenoprotein deficiency in individuals with SBP2 deficiency results in a multi-organ syndrome with characteristic thyroid function tests (TFTs) abnormalities of high serum T4, rT3, TSH and low T3. Sbp2 deficient mice (Sbp2 iCKO) replicate most of the TFTs except for normal T3. Previously, we reported the thyroid gland contribution in expressing the thyroid phenotype in Sbp2 iCKO mice with increased thyroid hormone (TH) content and increased synthesis capacity. The decreased expression and activity of selenoenzyme glutathione peroxidase and accumulation of hydrogen peroxide was implicated to promote iodine organification and TH synthesis. Methods: In this study, we evaluated the role of hypothalamus and pituitary in expressing the thyroid phenotype. TH content and gene expression were measured in cerebrum. mRNA expression, TSH content and TRH stimulation test were assessed in pituitary. Results: In the brain, Sbp2 iCKO mice had similar T4 levels compared to WT mice, 9.9 vs 8.4 pg/mg prot, while T3 content was decreased, 12 vs 17 pg/mg prot, discrepant to the respective serum levels. An indicator of local TH status, the expression of TH responsive gene Hr was decreased, 66% of that in WT mice, also indicative of local hypothyroidism. In addition, the expression of TH transporters Mct8 and Oatp1c1 was decreased in cerebrum, 78% and 71% vs WT mice, respectively. While the direct mechanisms for this finding remain elusive, this together with the low deiodinase 2 activity, likely contribute to the low cerebral T3 level. In contrast, at the level of pituitary, which is outside the blood brain barrier, Sbp2 iCKO mice had normal expression of Hr and Tshb gene, indicating adequate local T3. However, pituitary Trhr1 gene expression was increased in Sbp2 iCKO mice, 139% of that in WT, indicative of hypothyroidism at the level of hypothalamus, in line with the aforementioned findings in cerebrum. Although Sbp2 iCKO mice had higher baseline serum TSH, the peak TSH 15 minutes after TRH stimulation was significantly lower, 70% of that in WT mice. This is in part due to the decreased baseline pituitary TSH content by RIA, 71 vs 147 mU/mg prot in Sbp2 iCKO vs WT mice, indicating lower availability of preformed TSH in the pituitary gland. Thus, the observed different T3 availability between brain/hypothalamus and pituitary in Sbp2 deficiency contribute to the characteristic thyroid phenotype through complex regulation of thyrotroph function, dependent on both local and hypothalamic TH status and signaling. Conclusions: In the expression of thyroid phenotype of Sbp2 deficiency, there are contributions not only from the impaired TH metabolism due to deficiency of the deiodinases, but also from each level of the hypothalamic-pituitary-thyroid axis.

SUN-577 A Remarkable Case of Thyrotoxicosis Initially Caused by Graves' Disease Followed by a TSHoma

Background: Graves’ disease is the commonest cause of thyrotoxicosis while thyrotropin producing pituitary adenomas (TSHoma) are very rare and represent 2-3.5% of all pituitary adenomas. Coexistence of a TSHoma and Graves’ disease has been very rarely reported. We present a case of a lady with a TSHoma initially presenting with primary thyrotoxicosis, likely Graves’ Disease. Case: A sixty-eight year old lady was referred to our department with thyrotoxicosis, a fT4 of 20.4pmol/L (7.0-16.0) and a TSH of <0.02mIUL (0.50-4.20). A technetium pertechnetate 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 with normal TSH. This was confirmed on multiple platforms. A TRH stimulation test demonstrated a flat TSH response and a pituitary MRI showed pituitary microadenoma. Prolactin, IGF-1 and other pituitary profile were normal. She had a 11C-Metionine PET/CT and SPGR MRI scan which demonstrated high activity on the left lateral side of the pituitary fossa consistent with a functioning adenoma. She was treated with cabergoline and octreotide but failed to tolerate either. For now the patient has decided to manage this lesion conservatively. Conclusion: This is a very unusual case of thyrotoxicosis caused by two different processes in the same patient. This case highlights the need to reconsider the diagnosis of a TSHoma when faced with discordant thyroid function tests. It also highlights the utility of 11C-Methionine PET/CT scans in the diagnosis of functional endocrine tumours.

MON-433 The Spectrum Of Growth Hormone Excess In Carney Complex: Characterizing A Common Finding In A Rare Syndrome

Objective: Carney complex (CNC) is a familial lentiginosis and multiple endocrine neoplasia syndrome, caused by PRKAR1A gene mutations in 70% of patients. Involvement of the pituitary somatotrophs may lead to growth hormone (GH) excess; however, little is published about the progress and management of these patients. Objective: To describe the relative frequency of GH excess in a large cohort of patients with CNC, and to identify the characteristics and the natural history of the disorder. Methods: Via retrospective chart review, we identified 135 patients who have been diagnosed with CNC and had at least one clinical and biochemical evaluation of GH secretion at the Clinical Center, NIH, from 1995-2018. GH secretion was considered abnormal if any of the following criteria occurred: elevated IGF1 (according to sex and age- or Tanner-stage reference range), lack of suppression to Oral Glucose Tolerance Test (GH >2ng/mL for samples collected before 1/1/1999, or GH >1ng/mL for samples collected afterwards), increase of GH by > 50% after TRH stimulation test, and mean GH level > 4.5 ng/mL during serial GH sampling. Results: Fifty-five subjects (40.7%) had at least one abnormal result in the diagnostic tests for GH secretion. Twenty-eight subjects (20.7%) had at least 2 abnormal diagnostic tests, and fit the diagnosis of GH excess. The mean age at diagnosis was 26.7 yo (range:5.8-61.2), which was similar with the age at the latest follow up of the remaining patients (p=NS). The presence of PRKAR1A gene mutation was not associated with the presence of GH dysregulation (p= 0.63). Of the patients with dysregulation of GH secretion, 75% had abnormal pituitary MRI at any time of their evaluation: 23.5% before biochemical diagnosis, 41% at the time of the first biochemical finding and 9.8% after biochemical diagnosis. Of the patients with normal GH results, 45% had abnormal findings in the pituitary MRI, including enlargement of the gland or pituitary lesions, which was lower than the GH excess cohort (p=0.001) however clinically significant. Management of the patients differed according to their biochemical findings and clinical symptoms. Of the patients with GH excess and available follow up, 15 patients (55.5%) required more definite treatment: 7/15 were treated with somatostatin analogues and 8/15 underwent transsphenoidal resection of a pituitary adenoma, while the remaining retained mild GH excess despite no intervention. Conclusion: Dysregulation of GH secretion is a common finding in CNC. The spectrum of the disorder ranges from isolated structural abnormalities identified at imaging studies, mild dysregulation of growth hormone secretion, and clinically significant GH excess. The diagnosis of growth hormone excess and the selection of patients requiring any intervention is of outmost importance given the potential implication of GH excess in tumor progression and subsequent comorbidities.

Evaluation of dynamic testing for pituitary pars intermedia dysfunction diagnosis in donkeys.

Endocrine disorders are common in donkeys. Pituitary pars intermedia dysfunction (PPID) is thought to be a frequent disturbance in donkeys due to their longevity. However, information on PPID dynamic testing in donkeys is lacking. The objective of this study was to evaluate the previously described guidelines for PPID diagnosis in horses in donkeys with suspicion of PPID. Prospective experimental study. Eighty donkeys were evaluated for PPID suspicion based on clinical signs and baseline adrenocorticotropic hormone (ACTH) concentrations. Six mix-breed donkeys (one jack and five non-pregnant jennies) fulfilling inclusion criteria were subjected to dexamethasone suppression test (DST), thyrotropin-releasing hormone stimulation test (TRH) and combined DST-TRH challenge. Tests were interpreted according to guidelines for PPID diagnosis in horses. Donkeys fulfilling inclusion criteria were diagnosed with PPID by TRH stimulation test (six of six). Both DST (three of six) and DST-TRH (4/6) challenges failed to detect those animals and showed conflicting results. Similarly, cortisol basal concentrations were not consistent with PPID suspicion. Characterisation of seasonal and geographical location effect on baseline ACTH concentrations and response to TRH is compelling in this species. Further studies with a larger number of donkeys are needed. This is the first study in donkeys to evaluate common dynamic tests used for PPID diagnosis in horses. Preliminary results agree with the guidelines for PPID diagnosis in horses and baseline ACTH measurement followed by TRH challenge are recommended tests for diagnosis of PPID in donkeys.