To Thyrotropin-releasing Hormone Research Articles

Dynamics of thyroid diseases and thyroid-axis gland masses.

Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid‐stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life‐years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto's thyroiditis and Graves' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.

Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line

Background: Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations. A previous study showed that exposure of human and mouse embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborns but also subsequently reduces thyrotroph sensitivity to TH during adult life. The current investigation set out to determine if this epigenetic effect is transmitted by humans not exposed in utero to high TH levels to their offspring. Methods: The study took advantage of the high frequency of intrauterine exposure to high TH in the Azorean wild-type population born to healthy mothers with high TH levels because of a heterozygous TH receptor beta gene mutation. Wild-type individuals from F2 (second) and F3 (third) generations were studied, whose parents and grandparents, respectively, were not exposed to high maternal TH levels. Twenty-six individuals belonging to 17 nuclear families were tested for their sensitivity to TH using their thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) after administration of liothyronine (LT3). Results: Preservation of reduced sensitivity to TH (RSTH) was found in descendants of males but not of females with likewise RSTH. In F2, offspring of fathers but not of mothers exposed to high TH levels had RSTH (TRH-stimulated TSH of 6.39 ± 0.63 vs 1.58 ± 0.41 mIU/L [p < 0.001], respectively, after treatment with LT3). In F3, whose parents nor themselves were exposed to TH excess during their fetal life, descendants of fathers and not mothers had RSTH (TRH-stimulated TSH of 4.60 ± 0.61 vs 1.37 ± 0.23 mIU/L [p < 0.01], respectively, after pretreatment with LT3). Conclusions: Since intrauterine total body and gonadal exposure to elevated TH can potentially affect only the F1 and F2, respectively, the results obtained from F3 confirm a true inheritance of an epigenetic effect, scarcely observed in humans. While the exact mechanism underlying the inheritance of this epigenetic effect remains unknown, it correlates with type 3 deiodinase overexpression demonstrated in pituitary glands of mice born to dams with high TH. This enzyme inactivates TH, and is encoded by an imprinted gene with specific parent of origin expression.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Serum Thyroid Hormone and Thyrotropin Concentrations in Adult Horses as They Age

With more horses remaining active longer in life, it is important to characterize changes that occur normally with aging, so that these can be differentiated from development of disease. The objective of the study was to test the hypotheses that geriatric horses have lower circulating concentrations of thyroid hormones and/or higher serum thyrotropin (TSH) concentrations compared to younger horses. Serum thyroid hormone and TSH concentrations from 71 normal, healthy horses that had participated in prior research projects were analyzed for effects of age, sex, and season when samples were obtained. All samples had been assayed in the same previously validated radioimmunoassays. There were no differences in serum concentrations of thyroid hormones or TSH by sex or season. Serum total thyroxine (T4) was greater in 3- to 6-year-old horses compared to all other age groups and was negatively correlated with age. There were no differences among age groups for free T4 and total and free tri-iodothyronine (T3). Serum TSH concentration was significantly greater in old horses (≥15 or ≥20 years) compared to young (3–10 years) and intermediate (11–14 years) age groups. Serum TSH was positively correlated with age. There were no significant differences in thyroid hormone responses to thyrotropin releasing hormone (TRH) among young, intermediate, or old horses. However, the TSH response to TRH was significantly different in both groups of older horses compared to intermediate and young horses. Serum total thyroxine concentrations decrease and serum TSH concentrations increase in horses as they age, with no changes in free T4 or T3.

Incipient iron deficiency in primary hypothyroidism

Background: Hypothyroidism affects around 1% of general population. Anemia in association with hypothyroidism has been studied since 1881. Iron deficiency has multiple adverse affects on thyroid metabolism. It decreases circulating thyroid hormone concentration, blunts thyrotropic response to thyrotropin-releasing hormone (TRH) and decreases serum triiodothyronine (T3). Objectives: To find the prevalence of iron deficiency in primary hypothyroids. Material and Methods: In our study, 70 patients were selected, out of which 50 were females and 20 were males, who were suffering from hypothyroidism. Iron deficiency in the study group was confirmed at baseline using multiple iron status indicators (serum ferritin, serum iron, total iron-binding capacity and percentage saturation). These patients were between age group 18–65 years. Results: In our study, only 14 patients (20%) manifested with anemia (which was defined as HB < 12 gm/dl), whereas the prevalence of iron deficiency (with or without anemia) was 34.2%), in which 28.5% were females and 5.70% were males, thus showing that prevalence of iron deficiency (with or without anemia) can be higher than iron deficiency anemia itself, which is supported by literature. Conclusion: Iron deficiency was present in a significant portion of patients with primary hypothyroidism. It also concluded that frequency of iron deficiency (with or without anemia) was higher than iron-deficiency anemia.

Association of TSH With Cardiovascular Disease Risk in Overweight and Obese Children During Lifestyle Intervention.

Overweight and obese children have an increased risk to develop cardiovascular diseases (CVDs) in which thyroid-stimulating hormone (TSH) has been suggested as an intermediary factor. However, results of cross-sectional studies are inconclusive, and intervention studies investigating changes in TSH concentrations in association with changes in cardiovascular risk parameters in overweight and obese children are scarce. To gain insight in associations of circulating TSH concentrations and cardiovascular risk parameters in overweight and obese children. Nonrandomized lifestyle intervention. Centre for Overweight Adolescent and Children's Healthcare. Three hundred thirty euthyroid overweight and obese children. Long-term lifestyle intervention. TSH concentrations, pituitary TSH release in response to thyrotropin-releasing hormone (TRH), and cardiovascular risk parameters. At baseline, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triacylglycerol (TAG), and monocyte chemotactic protein 1 concentrations were significantly associated with serum TSH concentrations. TSH release by the pituitary in response to exogenous TRH was not associated with cardiovascular risk parameters. During lifestyle intervention, several cardiovascular risk parameters significantly improved. In children whose body mass index z score improved, changes in TSH concentrations were significantly associated with changes in TC, LDL-C, and TAG concentrations. In euthyroid overweight and obese children, circulating TSH concentrations are positively associated with markers representing increased CVD risk. Changes in TSH concentrations are also associated with changes in lipid concentrations in children with successful weight loss, which is consistent with TSH being an intermediary factor in modulating lipid and lipoprotein metabolism.

Thyroid Hormone and Thyrotropin Concentrations and Responses to Thyrotropin Releasing Hormone in Ageing Horses

Reasons for performing studyThyroid hormones (THs) decrease with age in healthy dogs and cats, although they tend to remain within established reference ranges. Thyrotropin (TSH) is increased in elderly people, with or without mild alterations in THs.ObjectivesTo test the hypothesis that geriatric horses will have lower THs and/or higher TSH compared with younger horses.Study designCross‐sectional study.MethodsResting THs and TSH, and responses to thyrotropin releasing hormone (TRH) were compared between young and old horses. Data from 71 normal, healthy horses that had participated in prior research projects were examined, and found to contain 42 horses 3–10 years of age, 16 horses &gt;15 years and 10 horses &gt;20 years. All samples had been assayed in the same previously validated radioimmunoassays. Statistical analysis was performed with commercial software.ResultsAlthough lower, THs were not significantly different between young and old horses when compared with the Mann–Whitney rank sum test. However, TSH concentration was significantly higher in horses aged &gt;20 (median 0.52 ng/ml) or &gt;15 years (0.44 ng/ml) compared to younger horses (0.33 ng/ml). TRH stimulation tests were performed in 19 of the younger horses, 7 of the horses &gt;20, and 11 of the horses &gt;15. Two‐way repeated measures ANOVA on ranks revealed no significant differences in TH responses to TRH. The TSH response to TRH appeared to be slightly greater in the older horses, but did not quite reach significance (P = 0.06).ConclusionSimilar to reports in elderly humans, aged horses have higher serum TSH concentrations than younger horses.Ethical animal research: All horses in this study were part of a NCSU IACUC approved study. Owners gave informed consent for their horses' inclusion in the study. Sources of funding: College of Veterinary Medicine North Carolina State University, USA Equestrian. Competing interests: None declared.

Relationship between the thyroid axis and alcohol craving.

A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients. Forty-two treatment-seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]. At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029). If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking.

Thyroid function and dysfunction in term and premature equine neonates.

BackgroundThis study was performed to compare thyroid function of premature foals to term foals.HypothesisPremature foals are more markedly hypothyroxinemic than expected for their severity of illness alone.AnimalsTwenty clinically normal term foals; 28 sick, hospitalized term foals; 24 sick, hospitalized premature foals.MethodsThyroid hormones (TH) and thyrotropin (TSH) were measured, both at rest and in response to thyrotropin‐releasing hormone (TRH), in the 3 groups of foals. Clinical and clinicopathologic data were recorded.ResultsNormal foals had high TH at birth, which decreased over the first month into the normal reference range for adult horses. TSH was within the normal adult reference range soon after birth, and did not change over time. At 24–36 hours of age, triiodothyronine (T3) was significantly lower in both premature and term hospitalized foals compared to normal foals; premature foals were not different from term hospitalized foals. Thyroxine (T4) was not different between normal and term hospitalized foals, but was significantly lower than in premature foals of both of these groups. TSH was not different among the 3 groups. TRH stimulation tests identified significant differences in T4 among all 3 groups of foals, whereas T3 was similar in premature and term hospitalized foals and different from normal foals. TSH response to TRH was significantly higher in premature foals compared to normal foals.Conclusions and Clinical ImportanceThe hypothalamic‐pituitary‐thyroid axis is different in foals compared to adult horses. Sick foals exhibit nonthyroidal illness syndrome. Premature foals are more markedly hypothyroxinemic than can be accounted for by their severity of illness alone.

Hypothalamic Hypopituitarism Caused by Pituitary Stalk Dysgenesis

본 증례는 9세경 ì €ì‹ ìž¥ìœ¼ë¡œ 성장호르몬 및 ê°‘ìƒì„ í˜¸ë¥´ëª¬ 이상을 ì§„ë‹¨ë°›ê³ ë¶ˆê·œì¹™í•˜ê²Œ 치료받았던 ê³¼ê±°ë ¥ì´ 있는 28세 남자 환자가 성기능 ìž¥ì• ì— 대한 불안으로 내원하여 뇌하수체 줄기 ë‹¨ì ˆì— 의한 시상하부성 뇌하수체 호르몬 이상을 ì§„ë‹¨ë°›ê³ ì‚¬ì¶˜ê¸° 발현과 생식기능의 ìœ ì§€ë¥¼ 위한 치료를 시행하게 된 1예를 경험하였기에 ë¬¸í—Œê³ ì°°ê³¼ 함께 ë³´ê³ í•˜ëŠ” 바이다. 중심 단어: 시상하부성 뇌하수체 ê¸°ëŠ¥ì €í•˜ì¦; 뇌하수체줄기 í˜•ì„±ë¶€ì „; 사춘기 지연

Perivagal capsaicin alters the response of vagal motoneurons to Thyrotropin Releasing Hormone (TRH)

A supposedly selective degeneration of vagal afferent C‐fibers by perivagal capsaicin (CAP) has often been used to identify the mechanism of action of GI‐ peptides. The actions of many of these peptides have been attributed to activation of vagal afferent fibers based on the dramatic reduction of their effects following perivagal CAP pretreatment. We have reported recently that, similar to surgical vagotomy, perivagal CAP induces dendritic degeneration, reduction of ChAT‐immunoreactivity and, possibly, death of a subpopulation of vagal preganglionic (DMV) neurons.We tested the hypothesis that perivagal CAP treatment induces functional impairment of rat DMV neurons.Monolateral perivagal CAP treatment (0.1 and 1%) was performed 7–10 days prior to monitoring gastric motility response induced by DMV microinjection of TRH (100pmoles), which increases motility via actions exclusively at DMV.Microinjection of TRH in DMV reduced gastric motility by 42±16 and 76±5% in rats pretreated with 0.1 or 1% CAP vs control (N=5 for all). Conversely, gastric motility in response to microinjection of TRH in the contralateral DMV was not altered (N=3–4).Our data show that perivagal CAP treatment induces functional impairment of DMV neurons and indicates that perivagal CAP treatment should not be used as an exclusive means to investigate the site of action of gastrointestinal peptides.Funds: NIDDK 55530

Hypoglycemic effects of Cyclo (His-Pro) in streptozotocin-induced diabetic rats

The effects of Cyclo (His-Pro) (CHP), a cyclic dipeptide structurally related to thyrotropin-releasing hormone (TRH), on glucose metabolism, blood insulin level, lipid profile, and the viability of pancreatic cells were investigated in streptozotocin (STZ)-induced diabetic rats. The rats (Sprague-Dawley) with a blood glucose level above 300 mg/dL after induction with STZ (50 mg/kg of body weight) were considered to be diabetic and used for the treatment with CHP (4 mg/day/kg of body weight). The blood glucose level in the CHP-fed rats was reduced remarkably by approximately 56% as compared to the untreated diabetic group at 21 days of feeding. In an oral glucose tolerance test, blood glucose levels were restored to baseline at 120 min after CHP treatment, although the levels increased significantly after 30 min. Plasma insulin levels in the CHP-treated group were also enhanced by 2-fold compared to the untreated group. Triglyceride and total cholesterol levels in CHP-treated rats almost returned to normal levels. Moreover, histological examination showed that CHP treatment restored impaired β-cells in the pancreas up to two-thirds of the normal level. The transcriptional level of C-reactive protein (CRP), used mainly as a marker of inflammation, was also restored mimicking normal level in the CHP-treated-group, suggesting that the β-cells destroyed by STZ were, at least in part, recovered. Accordingly, CHP was concluded to have an excellent hypoglycemic effect by lowering average plasma glucose levels, increasing insulin secretion, and restoring the viability of pancreatic β-cells in diabetic rats. We suggest that CHP might be a potential candidate to control Type I diabetes mellitus.

Comparison of Cortisol andACTHResponses after Administration of Thyrotropin Releasing Hormone in Normal Horses and Those with Pituitary Pars Intermedia Dysfunction

Changes in both adrenocorticotropin (ACTH) and cortisol concentration in response to thyrotropin releasing hormone (TRH) administration have been used to diagnose equine pituitary pars intermedia dysfunction (PPID), but the use of the 2 hormones has not been compared. Measuring ACTH concentration is superior to measuring cortisol concentration after TRH administration in differentiating between normal horses and those with PPID, and the 2 hormone concentrations are disassociated in PPID horses. Eleven horses and 2 ponies with PPID and 19 normal horses. A study evaluating cortisol and ACTH concentrations before and at 14, 30, and 60 minutes after TRH administration. At 14 and 30 minutes after TRH administration, cortisol concentration increased in PPID horses, and ACTH increased in all groups; ACTH, but not cortisol concentration, was significantly higher in PPID horses compared with normal horses. A relationship between cortisol concentration and ACTH concentration was seen in normal horses, but not in horses with PPID. Compared with normal castrated males, normal female horses had a greater change in cortisol concentration per unit change of ACTH concentration. ACTH and cortisol concentrations are disassociated in horses with PPID. Measuring ACTH concentration after TRH administration appears superior to measuring cortisol concentration as a diagnostic test for PPID.

Isotretinoin Associated Reversible Hypothyroidism

Isotretinoin (13-cis retinoic acid) has been regarded as an effective drug for the treatment of acne. Its wide range of adverse effects limits its use, however (1). Isotretinoin has been reported to disturb thyroid function, causing both reversible hypoand hyperthyroidism (1–3), but this impression is not conclusive. The patient presented here supports an association between use of oral 13-cis retinoic acids and reversible hypothyroidism. A 25-year-old woman presented to the Endocrinology Clinic of Aga Khan University Hospital in February 2010 with complains of a weight gain of 3 kg, along with dull mood and mennorrhagia for the previous 3–4 months. There was no history of cold intolerance, constipation, excessive sleep, lethargy, or hair loss. There was no family history of hypothyroidism. Drug history revealed that for 6 months she had taken isotretinoin, 20 mg once daily, for the treatment of acne. This had been stopped about 6 weeks before her presentation. There was no history of alcohol consumption or any other drug intake during this period. On examination, her pulse was 86 beats per minute, blood pressure was 130/80 mm Hg, and weight was 50.5 kg. A small diffuse goiter was noted; the remainder of her physical examination was unremarkable. Thyroid function tests done 1 month before visit, approximately 2 weeks after stopping the isotretinoin, showed a serum thyroid-stimulating hormone (TSH) of 78.97 mIU/mL (normal range 0.4–4.2), triiodothyronine of 1.51 nM (normal range 1.3–3.1), and thyroxine of 4.42 mg/dL (normal range 5.0–12.0). As she reported progressive improvement in her symptoms over the previous month, thyroid hormone replacement therapy was not instituted and she was asked to repeat her serum TSH. Her TSH done on the day of visit, that is, 6 weeks after stopping isotretinoin, was 15.03 mIU/mL. There was no history of thyrotoxic phase during the preceding several months that could have suggested the hypothyroid phase of thyroiditis. She was advised to follow-up in 6 weeks. When she presented again in March for another visit, she was symptom free. Her lab work-up on that day, 12 weeks after stopping isotretinoin, showed a serum TSH of 3.33 mIU/mL and antithyroid peroxidase enzyme levels of 3.30 IU/mL (<12 IU/mL). She was advised to follow-up in case of recurrence of symptoms and have her serum TSH repeated after 6 months. The effects of vitamin A derivatives on thyroid function have been a topic of interest for a number of years. Bexarotene, a compound closely related to isotretinoin, causes hypothyroidism both by central mechanism and by increasing the peripheral degradation of thyroid hormones by a nondeiodinase mediated pathway (4). In the study conducted by Marsden et al. (2), seven patients with severe rosacea were treated with 1 mg/kg per day isotretinoin for 12 weeks. Their levels of serum triiodothyronine and thyroxine were significantly lower after treatment, but the response to thyrotropin releasing hormone (TRH) stimulation was retained. These findings were partially attributed to induction of hepatic microsomal enzymes by isotretinoin. Another study conducted by Lyons et al. (1) showed mild decrease in the indices of thyroid function after treatment with 0.8 mg/kg 13-cis retinoic acid for 3 months. It was noticed that these changes reverted to normal 1 month after discontinuation of therapy. Oral isotretinoin therapy is increasingly used as an effective antiacne medication. It needs to be kept in mind that this drug could have antithyroid effects in susceptible patients. Therefore, there should be a low threshold for checking thyroid function tests in patients taking isotretinoin even if they have subtle signs or symptoms of thyroid dysfunction.

Protective Effect of Cyclo(His-Pro) on Streptozotocin-Induced Cytotoxicity and Apoptosis In Vitro

Cyclo(His-Pro) (CHP) is a naturally occurring, cyclic dipeptide structurally related to thyrotropin-releasing hormone (TRH). CHP was efficiently obtained from soybean meal by hydrolysis with flavourzyme and alcalase. In this study, the effects of CHP on streptozotocin (STZ)-induced beta-cell dysfunction and apoptosis were investigated in rat insulinoma cells (RINm5F) secreting insulin. When the RINm5F cells were treated with 2mM STZ, insulin secretion decreased to approximately 54% that of control cells. However, CHP treatment restored the insulin-secreting activity of RINm5F cells to approximately 71% that of the untreated control cells. Moreover, CHP significantly protected the cells from STZ-mediated cytotoxicity via reduction of nitric oxide (NO) production (2.3-fold) and lipid peroxidation (1.9-fold), which were induced by STZ. Moreover, CHP treatment also attenuated STZ-induced apoptotic events, such as activation of caspase-3, poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation in RINm5F cells, indicating that CHP could protect the cells from apoptotic cell death induced by oxidative stress of STZ by increasing the expression of an anti-apoptotic protein, Bcl-2. These results suggest that CHP could be a candidate material for a protective and therapeutic agent against STZ-mediated cytotoxicity and apoptosis.

Hypothalamus–pituitary–thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system

Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus-pituitary-thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.

Allan–Herndon–Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH

Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan–Herndon–Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343–1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.

Testicular function and prolactin responsiveness to TRH and cimetidine after renal transplantation.

The hypothalamic-pituitary-testicular axis and the regulation of prolactin secretion were investigated in eleven male renal transplant recipients. Mean serum levels of testosterone and estrone were normal, whereas those of androstenedione and estradiol were low. Mean basal luteinizing hormone (LH) levels were slightly elevated, but the peak responses to 50 micrograms i.v. gonadotropin-releasing hormone (GnRH) were not dissimilar from controls. Both basal and GnRH-stimulated follicle-stimulating hormone (FSH) levels were elevated (p less than 0.02-0.05) and also positively correlated with the time spent on hemodialysis (p less than 0.005-0.002). Basal prolactin (PRL) levels were normal, in all subjects. Nine out of 11 patients had a normal PRL response to Thyrotropin-releasing Hormone (TRH). However only six out of 11 had a normal response to 200 mg i.v. Cimetidine (Cim). Three subjects normally responding to TRH failed to respond to Cim. Uremic primary hypogonadism is not fully reversed by renal transplantation: a slight defect in the pituitary LH release may persist and the impairment of the tubular testicular function is left unchanged. While uremic hyperprolactinemia is corrected, the responsiveness to PRL-stimulating agents, particularly Cim, is not restored to normal, reflecting a derangement at the pituitary as well as the hypothalamic level.

Functional central hypothyroidism in the elderly

Previous studies have shown that blood concentrations of free thyroxin and basal thyroid-stimulating hormone (TSH) decrease during adult life. Suggested mechanisms include reduced thyroid activity resulting from decreased serum TSH concentrations, impairment of peripheral 5'-deiodinase, and an increase in reverse 3,5,3'-triiodothyronine due to non-thyroidal illness. However, testing of pituitary reserves leads to contradictory results and has infrequently been evaluated in studies. We investigated whether the response of TSH to thyrotropin-releasing hormone (TRH) is preserved during aging. This was tested in a cohort of 387 subjects aged 13 to 100 years in whom thyroid disease was excluded by normal thyroid ultrasound, normal values for free thyroxin, free triiodothyronin, TSH, and negative thyroid peroxidase antibodies. Serum concentrations of free thyroxin remained almost unchanged, whereas free triiodothyronin and TSH levels were lower in older subjects. In addition, the TSH response to TRH was blunted in older subjects, especially in male individuals. There is evidence that the decreased thyroid hormone levels observed in aging are due to lower TSH concentrations, and that lower TSH concentrations may be linked to an impaired pituitary activity.

HPT axis, CSF monoamine metabolites, suicide intent and depression severity in male suicide attempters

A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters.