TRH Test Research Articles

Factors associated with survival, laminitis and insulin dysregulation in horses diagnosed with equine pituitary pars intermedia dysfunction.

Pituitary pars intermedia dysfunction (PPID) is a commonly described endocrine disorder in higher latitudes of the Northern hemisphere but the description of the disease at lower latitudes and in the Southern hemisphere is limited. Document the clinical features of PPID at different Australian latitudes and climates, and investigate factors associated with survival, laminitis and insulin dysregulation (ID). Retrospective study of 274 equids from eight institutions across Australia. A diagnosis of PPID was based on endogenous ACTH, overnight dexamethasone suppression test, thyrotropin-releasing hormone stimulation test or necropsy. Clinical and clinicopathologic characteristics of PPID and therapeutic responses were investigated. Laminitis was diagnosed by radiographic or histologic changes and ID was diagnosed based on endogenous insulin, an oral glucose test or a 2-step insulin-response test. Being a pony, having a higher body condition score and pergolide administration were associated with survival. The clinical presentation of PPID changed with latitude and climate, with anhidrosis and polyuria/polydipsia more commonly recognised at lower latitudes. Laminitis was diagnosed in 89.9% of cases and ID was present in 76.5% of cases in which they were investigated. Despite the sample size, the lack of uniform testing at all locations (primary or referral cases) and the incompleteness of data sets limited the power of the statistical analyses. PPID can present with variable signs at different latitudes and climates, and ID should be investigated in equids diagnosed with PPID. Adequate body condition and administration of pergolide are fundamental in PPID management.

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.

Two cases of traumatic isolated ACTH deficiency

Case 1: A 65- year-old man was accidentally injured by wooden hammer on his top of head on 34 years before. He was suffered from vomiting, diarrhea and hypotension, and the laboratory examination revealed increased CRP level, hyponatremia and decreased plasma cortisol and ACTH levels, suggesting isolated ACTH deficiency and Crohn disease diagnosed by colonoscopic biopsy, and finally transferred to University Hospital. LH-RH, TRH, CRH and GHRP stimulation tests showed normal response of plasma pituitary hormones except for no response of plasma ACTH and cortisol levels by CRH stimulation. ACTH stimulation test showed no response of plasma cortisol levels although hydrocotisone replacement therapy had already been started. MRI imaging showed bottom of anterior lobe was crushed and pituitary gland was atrophied, which suggested brain might be injured by any strong trauma.

Thyroid Hormone Treatment of Mood Disorders

Both excess and insufficient thyroid hormones can lead to depression that is generally reversible with adequate thyroid treatment. On the other hand, major depression is associated with subtle chronobiological hypothalamic-pituitary-thyroid (HPT) axis dysregulation and thyroid hormones can be an effective adjunct to antidepressant treatment. However, the links between HPT axis status and efficacy of thyroid hormone supplementation in depression remain to be further clarified. While generally, depressed patients are chemically euthyroid, most exhibit a chronobiological HPT axis dysregulation (i.e., loss of the nocturnal thyrotropin [TSH] rise, blunted evening TSH response to protirelin [TRH], reduced difference in TSH response between 11 PM and 8 AM TRH tests [ΔΔTSH]), possibly associated with blunted 8 AM-TSH response to TRH and/or altered levels of circulating thyroxine (FT4) and triiodothyronine (T3). Usually, chronobiological HPT axis abnormalities are unrelated to increased cortisol levels. Normalization of thyroid function tests by antidepressants, especially the ΔΔTSH test, may occur before the clinical response. In patients who are resistant to antidepressants, there is good evidence for adjuvant therapy with thyroid hormones. While there is a limited evidence base to guide long-term adjunctive use, thyroid hormone augmentation can be a safe and effective alternative treatment for euthyroid-depressed patients who receive appropriate baseline and follow-up safety monitoring. However, it remains to be established which bio-clinical subtypes of depression respond preferentially to thyroid hormone supplementation. In the next future, metabolically stable TRH analogs could be used in order to maintain or restore homeostasis, which is frequently disrupted in depressive states.

Circannual variability in adrenocorticotropic hormone responses to administration of thyrotropin-releasing hormone in clinically normal horses in Australia

Thyrotropin releasing hormone (TRH)-stimulation testing for pituitary pars intermedia dysfunction (PPID) in horses is only recommended at certain times of the year. Current diagnostic cut-off values reflect testing in the northern hemisphere during this time. The aims of this study were to evaluate TRH stimulation testing during two different phases of the circannual pituitary cycle and to determine whether diagnostic cut-off values developed in the northern hemisphere are appropriate in Australia. Thirteen clinically normal horses at Perth, Western Australia, and 23 horses at Townsville, Queensland, Australia, had TRH stimulation tests performed at two different time points during the circannual pituitary cycle. At both locations, post-TRH adrenocorticotropic hormone (ACTH) concentrations were significantly different between testing time points (Perth: P=0.001; Townsville: P<0.0001). In Perth, the mean ACTH concentrations 10min post-TRH in September and March were 51.4pg/mL (95% confidence interval, CI, 46.4–56.4pg/mL) and 248.5pg/mL (95% CI 170.2–326.9pg/mL), respectively. The median percentage change in ACTH concentrations in March was 361.9%. In Townsville, the mean ACTH concentrations 30min post-TRH in September and April were 35.3pg/mL (95% CI 29.6–40.9pg/mL) and 112.3pg/mL (95% CI 93.4–131.2pg/mL), respectively. The median percentage change in ACTH concentrations in April was 144.7%. The ACTH cut-off value after TRH stimulation in normal horses in September in Perth and Townsville was similar to the values established in the northern hemisphere. However, TRH stimulation testing in March/April was highly variable at both locations.

The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications

Thyrotropin-releasing hormone (TRH) causes a variety of thyroidal and non-thyroidal effects, the best known being the feedback regulation of thyroid hormone levels. This was employed in the TRH stimulation test, which is currently little used. The role of TRH as a cancer biomarker is minor, but exaggerated responses to TSH and prolactin levels in breast cancer led to the hypothesis of a potential role for TRH in the pathogenesis of this disease. TRH is a rapidly degraded peptide with multiple targets, limiting its suitability as a biomarker and drug candidate. Although some studies reported efficacy in neural diseases (depression, spinal cord injury, amyotrophic lateral sclerosis, etc.), therapeutic use of TRH is presently restricted to spinocerebellar degenerative disease. Regulation of TRH production in the hypothalamus, patterns of expression of TRH and its receptor in the body, its role in energy metabolism and in prolactin secretion are addressed in this review.

TRH-induced secretion of adrenocorticotropin and cortisol in dogs with pituitary-dependent hypercortisolism

Background: In dogs, spontaneous Cushing’s syndrome is most often pituitary-dependent and caused by hypersecretion of adrenocorticotropic hormone (ACTH), resulting in increased adrenocortical glucocorticoid secretion similar to horses. In horses with Cushing’s syndrome (or pituitary pars intermedia dysfunction [PPID]) a thyrotropin-releasing hormone (TRH) stimulation test can be used for diagnosis, as TRH administration results in increased circulating ACTH and cortisol concentrations in affected horses.Objective: The aim of this study was to investigate the effect of TRH administration on the circulating ACTH and cortisol concentrations in dogs with pituitary-dependent hypercortisolism (PDH).Methods: Ten clinically normal control dogs and 10 dogs with PDH, all client owned, underwent a TRH stimulation test with measurement of plasma concentrations of ACTH and cortisol, before and after intravenous administration of 10 μg TRH/kg bodyweight.Results: Plasma ACTH concentration did not rise significantly after TRH stimulation, neither in PDH dogs nor in clinically normal dogs. In contrast, the plasma cortisol concentration did increase significantly after TRH stimulation in both groups (p = .003 in PDH and p < .001 in control). Immunohistochemistry of normal adrenal glands demonstrated the presence of TRH receptors in the whole adrenal cortex.Conclusions: The results of this study demonstrate that the TRH stimulation test should be rejected as a tool to diagnose PDH in dogs. The observed TRH-induced increase in plasma cortisol concentration without a significant rise in plasma ACTH concentration may be explained by a direct effect of TRH on adrenocortical cells mediated by adrenocortical TRH receptors.

A Patient With Dual Ectopic Thyroid Starting Thyroid Hormone Replacement Therapy at Age 25 Years

In pediatric patients, ectopic thyroid, a form of congenital hypothyroidism, is commonly detected during neonatal mass screening. A variety of clinical manifestations of ectopic thyroid have been reported. We present herein a patient with dual ectopic thyroid showing an atypical clinical course, who was observed over a long-term follow-up period. The patient, an 8-year-old female, received the diagnosis of ectopic thyroid after a mass in her anterior neck was analyzed. Initially, her thyroid function was normal. Imaging data revealed an ectopic thyroid at the lingual root and on the thyroid cartilage. The patient showed late-onset hypothyroidism. The mass gradually enlarged (to 3 cm in length and 4 cm in width) until age 25 year when the patient’s TSH level increased. The peak TSH level at the TRH test was 40.1 μU/ml. Thyroid hormone replacement therapy was started. Ectopic thyroid should be carefully followed-up even when asymptomatic because the clinical course may be late-onset, especially in patients with dual ectopic thyroid.

Effect of dietary carbohydrates and time of year on ACTH and cortisol concentrations in adult and aged horses

Diagnosis of equine pituitary pars intermedia dysfunction (PPID) remains a challenge as multiple factors (stress, exercise, and time of year) influence ACTH and cortisol concentrations. To assess endocrine status in a study designed to evaluate the effects of age and diet on glucose and insulin dynamics, we performed thyrotropin-releasing hormone (TRH) stimulation tests and overnight dexamethasone suppression tests in March, May, August, and October on 16 healthy Thoroughbred and Standardbred mares and geldings. Horses were grouped by age: adult (mean ± SD; 8.8 ± 2.9 yr; n = 8) and aged (20.6 ± 2.1 yr; n = 8). None of the horses showed clinical signs (hypertrichosis, regional adiposity, skeletal muscle atrophy, lethargy) of pituitary pars intermedia dysfunction. Horses were randomly assigned to groups of 4, blocked for age, and fed grass hay plus 4 isocaloric concentrate diets (control, starch-rich, fiber-rich, and sugar-rich) using a balanced Latin square design. Data were analyzed using a multivariable linear mixed regression model. Baseline ACTH was significantly higher in aged horses (mean ± standard error of the mean; 60.0 ± 10.7 pg/mL) adapted to the starch-rich diet compared to adult horses (15.7 ± 12.0 pg/mL) on the same diet (P = 0.017). After controlling for age and diet, baseline ACTH concentrations were significantly increased in October (57.7 ± 7.1 pg/mL) compared to March (13.2 ± 7.1 pg/mL; P < 0.001), May (12.4 ± 7.1 pg/mL; P < 0.001), and August (24.2 ± 7.1 pg/mL; P < 0.001), whereas post-TRH ACTH was higher in August (376.6 ± 57.6 pg/mL) and October (370.9 ± 57.5 pg/mL) compared to March (101.9 ± 57.3 pg/mL; P < 0.001) and May (74.5 ± 57.1 pg/mL; P < 0.001). Aged horses had significantly higher post-dexamethasone cortisol on the starch-rich diet (0.6 ± 0.1 μg/dL) compared to the sugar-rich diet (0.2 ± 0.1 μg/dL; P = 0.021). Post-dexamethasone cortisol was significantly higher in October (0.6 ± 0.1 μg/dL) compared to March (0.3 ± 0.1 μg/dL; P = 0.005), May (0.2 ± 0.1 μg/dL; P < 0.001), and August (0.3 ± 0.1 μg/dL; P = 0.004). Breed did not influence ACTH or cortisol measurements. In conclusion, in addition to age and time of year, diet is a potential confounder as animals on a starch-rich diet may be incorrectly diagnosed with pituitary pars intermedia dysfunction.

Effects of dietary selenium and moisture on the physical activity and thyroid axis of cats.

Consumption of canned cat food is considered a risk factor for the development of feline hyperthyroidism. Because selenium and water are substantially higher in canned diets compared to dry diets, objectives of this study were to determine whether increased dietary selenium or water alters the function of the hypothalamic-pituitary-thyroid axis and leads to an increase in activity level. Employing a 28-day latin square design with a 14-day washout, six lean, neutered male domestic shorthair cats were fed (i) commercially available adult dry feline diet containing 0.8ppm selenium (control), (ii) control diet with added sodium selenite to achieve a dietary selenium concentration of 1.125ppm (selenium treatment) and (iii) the control diet with additional water to achieve a moisture content of 75% wt/wt (water treatment). Water consumption was determined using deuterium oxide washout. Actical activity monitors were placed on each cat's collar to allow quantification of the activity of each cat. Circulating serum T3 and T4 was measured on days 0, 14, and 28. On day 28, a thyrotropin-releasing hormone (TRH) stimulation test was conducted to determine treatment effects on serum concentrations of thyroid hormones. There was a significant increase in daily water consumption with dietary water treatment (192ml±7.85 SEM) compared to the control (120ml±20.4) and selenium (116ml±14.6) treatments. Both water and selenium treatments were associated with greater (p<.05) activity over that of the control treatment by 20.5% and 11% respectively. Serum TT3 AUC concentrations (0-4hr) of TRH stimulation tests were greater (p<.05) by 16% with water compared to control treatments. The results of this study indicate that dietary water content may alter the function of the thyroid axis and that this effect is associated with an increase in physical activity.

Relationship between chronobiological thyrotropin and prolactin responses to protirelin (TRH) and suicidal behavior in depressed patients

BackgroundSo far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results. MethodsWe studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800h and 2300h protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n=71], or in early remission [n=51]); and 50 healthy hospitalized controls. ResultsBaseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Δ]) were indistinguishable from controls. Current SBDs showed (1) lower 2300h-ΔTSH and lower ΔΔTSH values (differences between 2300h-ΔTSH and 0800h-ΔTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT4B) levels than controls. In the current SBD group, ΔΔPRL values (differences between 2300h-ΔPRL and 0800h-ΔPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n=15) showed lower FT4B levels, lower TSH-TRH responses (both at 0800h and 2300h), and lower ΔΔTSH and ΔΔPRL values than controls, while (2) non-violent suicide attempters (n=56) showed lower ΔΔTSH values than controls and higher TSH-TRH responses (both at 0800h and 2300h) than violent suicide attempters. ConclusionsOur results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT4B levels and decreased evening TSH responses (and consequently, decreased ΔΔTSH values) support the hypothesis that hypothalamic TRH drive is reduced—leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior.

Review of European Thyroid Association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumours

Тиреотоксикоз в большинстве случаев обусловлен аутоиммунными заболеваниями щитовидной железы или многоузловым токсическим зобом; крайне редко его причиной являются ТТГ-секретирующие аденомы гипофиза (ТТГ-омы). Эти опухоли характеризуются высоким уровнем циркулирующих тиреоидных гормонов в сочетании с отсутствием подавления или повышенным уровнем ТТГ. Неправильная диагностика ТТГ-ом зачастую является причиной неоправданных тиреоидэктомий или проведения терапии радиоактивным йодом, что в свою очередь сопровождается существенным увеличением размера опухоли гипофиза. Диагноз может быть подтвержден при помощи определения уровня ТТГ на фоне супрессивной терапии L-Т3 или в тесте с тиреолиберином. Эти тесты в комбинации с МРТ гипофиза и генетическим исследованием лежат в основе дифференциальной диагностики ТТГ-ом и синдромов резистентности к тиреоидным гормонам. Методом выбора в лечении ТТГ-ом является хирургическая транссфеноидальная аденомэктомия. При невозможности проведения или неэффективности оперативного лечения эффективным методом нормализации продукции ТТГ в 90% случаев является назначение аналогов соматостатина.

A Japanese Family with Central Hypothyroidism Caused by a NovelIGSF1Mutation

Hemizygous mutations in the immunoglobulin superfamily member 1 (IGSF1) gene have been demonstrated to cause congenital central hypothyroidism in males. This study reports a family with a novel mutation in the IGSF1 gene located on the long arm of the X chromosome.A two-month-old boy was diagnosed with central hypothyroidism because of prolonged jaundice. A thyrotropin-releasing hormone (TRH) stimulation test indicated dysfunction in both the hypothalamus and the pituitary gland, and prompted the IGSF1 gene to be analyzed. The patient had a novel nonsense variant, c.2713C>T (p.Q905X), in exon 14 of the IGSF1 gene. Studies of the family revealed that the patient's sister and mother were heterozygous carriers of the IGSF1 mutation. The patient's maternal uncle carried the same mutation as the proband but had no overt symptoms. The mother and uncle started levothyroxine supplementation because of subclinical hypothyroidism.A novel mutation (c.2713C>T, p.Q905X) of the IGSF1 gene was identified that causes congenital central hypothyroidism in a Japanese family. The findings further expand the clinical heterogeneity of this entity.

Innapropriate TSH secretion: the challenging diagnosis

Background. The elevation of thyroid hormone with a normal or elevated TSH occurs uncommonly. This has different causes and pose a diagnosis challenge namely between TSH-secreting pituitary adenoma (TSHoma) and resistance to thyroid hormone. The accurate diagnosis is essential, because delayed diagnosis of TSHoma can lead to tumour growth and poor surgical cure rates, whereas medical, surgical or radioablative treatments in patients with resistance to thyroid hormone are usually unnecessary and potentially harmful.Case Report. A 23-years-old women with palpitations, fatigue, insomnia and exophthalmia with elevated serum free T4 and TSH, medicated with methimazole 5mg 3id was sent to evaluation in endocrinology department. She did not report headaches or visual problems. Patient’s laboratory tests at admission: TSH 9,6 µUI/mL (0,4–4,0 µUI/mL), Free T4 2,1 pg/dL (0,8–1,9 pg/dL). After stopping anti-thyroid drug presented TSH 2,9 µUI/mL (0,4-4,0 µUI/mL), Free T4 3,7 pg/dL (0,8–1,9 pg/dL), Free T3 11 pg/mL (1,8–4,2 pg/mL); antithyroid peroxidase and antithyroglobulin antibodies and thyroid stimulating immunoglobulin were undetectable; thyroid ultrasound revealed small heterogeneous goiter; thyroid technetium scintigraphy showed diffuse glandular hyperfunctioning; Magnetic resonance imaging revealed a microadenoma with 7,5mm in the left side of pituitary. Remaining anterior pituitary hormones were within normal ranges. The thyrotropin-releasing hormone stimulation test was performed and revealed TSH at 0’ 1,7 µUI/mL, 20’ 14 µUI/mL and 60’ 11 µUI/mL, with free T4 2,3 pg/dL and free T3 5,9 pg/mL, which was consistent with thyroid hormone resistance syndrome. In this clinical setting genetic test was performed and revealed mutation in heterozygosity in THRβ gene: c.1030G&gt;A, p.Gly344Arg. Patient’s mother was also tested and no mutation was found. Her father was not available to do the genetic test. No pituitary surgery or thyroidectomy was performed, nor were prescribed any anti-thyroid drugs.Conclusions. In this case, an innapropriate TSH secretion was identified and the clinical, biochemical and genetic investigations were consistent with resistance to thyroid hormone. Known that as many as 15% non-ill people may have a small, nonfunctioning pituitary adenoma, patients with thyroid hormone resistance may have incidentally abnormal imaging findings. The high level of clinical suspicion and the proper laboratory, genetic and radiological studies, conduct to a correct diagnosis and prevent unnecessary and potential harmful therapies.

A new mutation in thyroid hormone resistance

Introduction. Thyroid Hormone Resistance (THR) is a rare syndrome with a variable and fluctuating clinical course depending on complex genetic and molecular defects.Case report. SCPR, a caucasian female patient aged 23, was referred to outpatient endocrine department because of increased T4 levels. There was no evidence of thyroid dysfunction or goiter. Past medical history was negative with normal growth and neurophysiological development and regular menstrual cycles. There was no family history of thyroid disease. Analytical evaluation revealed T4 – 17.9 µg/dL [Reference Value (RV): 4.5-12.5], T3 – 247 ng/mL (RV: 72-170), TSH – 4.9 µU/mL (RV: 0.4-4.0), FT3 – 7.8 pg/mL (RV: 1.8-4.2), FT4 – 2.6 ng/dL (RV: 0.8-1.9), TPOAb 11 U/mL (RV: &lt;35), TgAb &lt; 20 U/mL (RV: &lt;40), TRAb &lt; 1 (RV: &lt;2). The TRH test (200 µg, ev) revealed a normal but high TSH response up to 23 µU/mL (5-25) and a sellar NMR scan showed no abnormalities. No medical treatment was prescribed. Over the follow up period of 10 years thyroid function fluctuated with borderline high FT4 and TSH. Clinical course was marked by the development of obesity, depressive syndrome and the diagnosis of chronic fatigue syndrome with two uneventful pregnancies. Over that period, either Hyperthyroidism or Hypothyroidism were diagnosed and treated at other institutions. Recently genetic testing revealed a new mutation on exon 10 of the β thyroid hormone receptor form c790G&gt;T (p.Val264Phe) with unknown significance.Discussion. Several important points are illustrated by this case. 1) thyroid function tests may fluctuate over time, only sometimes with clear evidence of THR. 2) clinical manifestations of the syndrome are multiform and the relation to thyroid hormone levels is far from clear with abnormalities of growth and neurophysiological development, infertility, obesity, psychiatric disorders or subtle symptoms suggesting thyroid dysfunction variably reported; 3) interpretation of analytical abnormalities may be difficult with thyroid dysfunction commonly misdiagnosed; 4) medical treatment is controversial; 5) More than 100 mutations have been reported and the particular complexity of thyroid hormone effects – several isoforms of the receptor, homo- or heterodimerization of the receptor with the retinoid X receptor and dominant negative effects making the interpretation of the functional significance of new mutations difficult.

An atypical presentation of Graves’ disease

Observation A 25-year-old man was hospitalized for weight loss, abdominal pain and palpitations. Diagnosis of hyperthyroidism caused by Graves’ disease was made and methimazol was started. During biological monitoring, despite decreasing methimazol dosage and the addition of L-thyroxine, the patient kept an atypical hormonal profile with very low T4, and normal or slightly elevated T3 and TSH [T4 0.19 ng/dL (N: 0.8–1.7) T3 3.8 pg/mL (1.8–4.6), TSH 9.5 mIU/L (N: 0.4–4)]. Given this profile, persistent fatigue and abdominal pain, pituitary failure was suspected but a basal morning cortisol of 260 ng/mL and a normal TRH stimulation test excluded pituitary insufficiency. Finally, we kept the diagnosis of T3-predominant Graves’ disease. Since thyroid function was difficult to normalize, our patient underwent total thyroidectomy 9 months after the diagnosis. Discussion T3-predominant Graves’ diseases are characterized by the rising of T3/T4 ratio emerging only after the onset of antithyroid drugs and are associated with particularly elevated TSI levels. High T3/T4 ratio seems to be linked to an increase in the activity and/or the expression of type 1 and type 2 iodothyronine deiodinases. Usual T3/T4 ratios (pg/mL/ng/dL) described in the literature in T3-predominant Graves’ diseases fluctuate between 4 and 10 (N: 1.8–3.3). Here, we observed much higher T3/T4 ratios (up to 20) associated with particularly low T4 levels. Rising of the T3/T4 ratio at the beginning of antithyroid drugs and normalization after thyroidectomy on L-Thyroxine therapy suggests a role of antithyroid drugs in the activation of iodothyronine deiodinases.

Relationship of each anterior pituitary hormone deficiency to the size of non-functioning pituitary adenoma in the hospitalized patients.

Non-functioning pituitary adenoma (NFPA) is often associated with hypopituitarism. Diagnosis of hypopituitarism is important because of its poor prognosis and low quality of life. Among hypopituitarism, it is difficult to diagnose secondary adrenocortical insufficiency and GH deficiency without hormone stimulation test. Therefore, the aim of our study was to identify patients with NFPA who require more careful endocrinological examination. We examined the relationship between NFPA size and the prevalence of each hypopituitarism or the response of each anterior pituitary hormone by insulin tolerance test, LHRH test and TRH test. We studied 63 patients with NFPA admitted for evaluation of pituitary function and surgical indication. They were classified three groups by tumor diameter. The prevalence of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were higher in the group of larger tumor diameter (p<0.0001, p<0.05, p<0.05 and p<0.05, respectively). However, that of secondary adrenocortical insufficiency only tended to be higher (p=0.07). In the group with small NFPA (less than 20 mm), the prevalence of secondary adrenocortical insufficiency was 38% although those of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were 0%, 0% and 8% and 9%, respectively. Anterior pituitary hormone responses except TSH had significantly negative correlation with tumor diameter (ACTH: r=-0.40, GH: r=-0.57, LH: r=-0.69, FSH: r=-0.46, PRL: r=-0.36). The results suggested physicians should proactively suspect GH deficiency, male secondary hypogonadism and secondary hypothyroidism in patients with larger NFPA. On the other hand, adrenocortical function should be examined even in patients with small NFPA.

Three novel mutations of the MCT8 (SLC16A2) gene: individual and temporal variations of endocrinological and radiological features.

.We performed genetic analysis and clinical investigations for three patients with suspected monocarboxylate transporter 8 (MCT8) deficiency. On genetic analysis of the MCT8(SLC16A2) gene, novel mutations (c.1333C>A; p.R445S, c.587G>A; p.G196E and c.1063_1064insCTACC; p.R355PfsX64) were identified in each of three patients. Although thyroid function tests (TFTs) showed the typical pattern of MCT8 deficiency at the time of genetic diagnosis in all patients, two patients occasionally were euthyroid. A TRH test revealed low response, exaggerated response and normal response of TSH, respectively. Endocrinological studies showed gonadotropin (Gn) deficiency in two adult patients. On ultrasonography, goiter was detected in one patient. Interestingly, pituitary magnetic resonance imaging (MRI) demonstrated atrophy and thinness of the pituitary gland in two patients. Our findings suggest that thyroid status in patients with MCT8 deficiency varies with time of examination, and repeated TFTs are necessary for patients suspected of MCT8 deficiency before genetic analysis. In addition, it is noteworthy that some variations were observed on the TRH test and ultrasonography of the thyroid gland in the present study. Morphological abnormality of the pituitary gland may be found in some patients, while Gn deficiency should be considered as one of the complications.

The Role of Thyrotropin-Releasing Hormone Stimulation Test in Management of Hyperthyrotropinemia in Infants.

Objective:Hyperthyrotropinemia, which can be either a permanent or a transient state, is an asymptomatic condition and there is a controversy in management and long-term consequences. The aim of this study was to evaluate the results of thyrotropin-releasing hormone (TRH) test in infants with hyperthyrotropinemia.Methods:Data of the patients who underwent a TRH test for mildly elevated thyroid-stimulating hormone (TSH) levels between 2004 and 2011 in a single academic pediatric endocrinology unit were retrospectively reviewed from the case files.Results:Twenty infants (13 female, 7 male) with the median (range) age of 33 days (25-50) were enrolled into the study. The median basal TSH was 7.0 mIU/L (4.9-8.9) and free thyroxine level was 1.4 ng/mL (1.2-1.6) at the time of the TRH test. Thyroid ultrasonography was performed to 10 of the cases, and one of them had thyroid hypoplasia. TRH test revealed normal results in four infants, while sixteen infants had exaggerated response suggestive of primary hypothyroidism. The median follow-up period was 3.5 years (2.3-3.7). Therapy was discontinued in seven cases (2 had normal TRH response, 5 had exaggerated response) with the median age of 3.2 years (2.5-4). Of these seven infants, three had an elevated TSH on follow-up and L-thyroxine was restarted. All of the infants, in whom therapy was restarted, had exaggerated response to TRH.Conclusion:TRH test response could be a useful diagnostic test to evaluate the persistence of the disease during the infantile age period.

Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism.

Mitotane, a steroidogenesis inhibitor with adrenolytic properties used to treat adrenocortical cancer (ACC), can affect thyroid function. A reduction of FT4 levels with normal FT3 and TSH has been described in these patients. Using an in vitro murine model, the secretory capacity of thyrotrophic cells has been shown to be inhibited by mitotane. To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC. In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 μg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10). Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal. Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes observed in hypothyroid conditions. This finding thus confirms in vitro studies and may have a therapeutic implication for treatment with thyroid hormones, as suggested by current guidelines for this specific condition.