Thyrotropin-releasing Hormone Research Articles

7170 Plasticity of the Hypothalamic Tuberoinfundibular Dopaminergic Neuronal Network in Lactating Rats

Abstract Disclosure: P. Papaioannou: None. T. Georgescu: None. D.R. Grattan: None. S. Bunn: None. S. Yip: None. The tuberoinfundibular dopaminergic (TIDA) neurons play a crucial role in regulating prolactin secretion. Their synchronized network activity with slow but highly rhythmic firing pattern is important for dopamine release in rats[1]. While this unique TIDA network activity is vital for prolactin negative feedback in non-lactating conditions, its behaviour during lactation, when prolactin demand is high, remains unknown. Our hypothesis posited that the TIDA neuronal network in lactating rats becomes desynchronized, disrupting the negative feedback loop. To test this, we utilized ex-vivo Ca2+ imaging to simultaneously monitor population-wide TIDA neuron activity in non-lactating (NL; n=13) and lactating (L; n=10) rats injected with a cre-inducible adeno-associated virus (AAV) containing the Ca2+ indicator, GCaMP6s, into their arcuate nucleus. Analysis of neuronal network synchronicity revealed significant desynchronization in the TIDA network during lactation, as indicated by a markedly lower mean correlation coefficient matrix (CM) compared to non-lactating conditions (NL: 0.87±0.02, n= 26 sections vs L: 0.22±0.03, n=29 sections; p<0.001, Student’s t-test). Furthermore, the oscillatory activity patterns of these desynchronized TIDA neurons displayed a significantly lower cell rhythmicity index (RI) in lactating animals compared to non-lactating ones (NL: 0.17±0.01, n=186 cells vs L: 0.70±0.02, n=77 cells; p<0.001, Student’s t-test). Interestingly, within these low rhythmic neurons, some exhibited higher while others showed lower firing frequencies compared to non-lactating TIDA neurons. After 7 days post-weaning (n=4 animals), the TIDA network activity returned to non-lactating behaviour (CM = 0.85 ± 0.04, n=6 sections and RI = 0.17±0.01; n=47 cells). In summary, our findings demonstrate a reversible reconfiguration of the TIDA neuronal networks during lactation, characterized by low rhythmic oscillations and individual unique firing patterns, leading to diminished intercellular synchrony that may impede dopamine release, ultimately facilitating prolactin release to support lactation. Once weaned, the TIDA neuronal network reset to NL state to allow a new reproductive cycle. [1] Lyons, D. J., Horjales-Araujo, E. & Broberger, C. Synchronized network oscillations in rat tuberoinfundibular dopamine neurons: switch to tonic discharge by thyrotropin-releasing hormone. Neuron 65, 217-229, doi:10.1016/j.neuron.2009.12.024 (2010). Presentation: 6/2/2024

Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3

Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1+/Onecut1/2+ proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropin-releasing hormone (TRH)+ glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1+ progenitors in the hypothalamus.

8759 Mild Iodine Deficiency During Pregnancy Impairs Hypothalamus-Pituitary-Thyroid Function Programing of the Adult Male Offspring

Abstract Disclosure: M. Oliveira: None. E. Tavares: None. G. Henrique: None. J. Pinto: None. C. Serrano-Nascimento: None. Introduction: Iodine plays a crucial role in the biosynthesis of thyroid hormones and is essential for proper thyroid embryonic development. While severe iodine deficiency during pregnancy and lactation has well-documented deleterious effects, the consequences of mild iodine deficiency (MID) remain not fully understood. MID during pregnancy is a reality in numerous countries, even in regions with seemingly adequate iodine supply in the diet. Previous studies have highlighted the adverse impact of MID on neurological development in offspring, but comprehensive data on thyroid function, particularly in progeny at different developmental stages, are lacking. This study aimed to investigate the repercussions of MID during pregnancy on the programming of thyroid dysfunctions during adulthood. Methods: Female CD1 mice were subjected to iodine-deficient animal chow and iodine-supplemented water, either at normal (NI; 0.2 mg/L) or mild iodine deficiency (MID; 0.8 mg/L) levels during pregnancy. Gene and protein expression in the hypothalamus, pituitary, and thyroid of adult male offspring animals (PND90) were evaluated using qPCR and Western blotting. Additionally, this study explored MID-induced programming of offspring thyroid gene expression through epigenetic mechanisms. Results: Maternal MID exposure led to increased gene and protein expression of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) in the hypothalamus and pituitary of the offspring animals. Thyroid protein and gene expression of sodium iodide symporter (NIS), TSH receptor (TSHR), thyroid peroxidase (TPO), thyroglobulin (TG), paired box 8 (PAX8), NK2 homeobox 1 (NKX2.1), and monocarboxylate transporter 8 (MCT8) were elevated in the offspring of MID-exposed animals. Epigenetic mechanisms appeared to contribute to the augmented thyroid gene expression in MID-exposed animals, with decreased DNA methyltransferase expression and reduced thyroid DNA global methylation. Additionally, histone 3 hypomethylation and increased acetylation of histones 3 and 4 were observed. Conclusion: The study suggests that MID exposure during pregnancy can be as harmful as severe iodine deficiency in programming the hypothalamus-pituitary-thyroid (HPT) axis, leading to HPT dysfunction during adult life. Consequently, our data suggest that monitoring iodine intake throughout pregnancy is crucial to prevent the occurrence of thyroid disorders in offspring during adulthood. Presentation: 6/1/2024

Thyroid Endocrine Disruption and Mechanism of the Marine Antifouling Pollutant 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one.

The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) is an emerging pollutant in the marine environment, which may disrupt the thyroid endocrine system. However, DCOIT toxicity in relation to thyroid endocrine disruption and the underlying mechanisms remains largely unclear. In this study, in vivo, in silico, in vitro, and ex vivo assays were performed to clarify DCOIT's thyroid toxicity. First, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT for an entire life cycle. The results demonstrated that DCOIT exposure potently stimulated the hypothalamic-pituitary-thyroid axis, characterized by hyperthyroidism symptom induction and prevalent key gene and protein upregulation in the brain. Moreover, the in silico and in vitro results evidenced that DCOIT could bind to thyroid hormone receptor β (TRβ) and interact synergistically with triiodothyronine, thus promoting GH3 cell proliferation. The CUT&Tag experiment found that DCOIT interfered with the affinity fingerprint of TRβ to target genes implicated in thyroid hormone signaling cascade regulation. Furthermore, ex vivo, Chem-seq revealed that DCOIT directly bound to the genomic sequences of thyrotropin-releasing hormone receptor b and thyroid-stimulating hormone receptor in marine medaka brain tissues. In conclusion, the current multifaceted evidence confirmed that DCOIT has a strong potency for thyroid endocrine system disruption and provided comprehensive insights into its toxicity mechanisms.

Age-Related Features of the Function of the Hypothalamic-Pituitary-Thyroid (HPT) Axis in Nonhuman Primates under Constant Lighting.

We studied the features of the functioning of the hypothalamic-pituitary-thyroid (HPT) axis under conditions of constant (4 weeks) lighting (LED lamps intended for office and residential premise) on a translational model of young adult and old female rhesus monkeys, in particular taking into account their behavior. Constant lightning had no significant effect on the levels of thyroid-stimulating hormone, thyroxine, and triiodothyronine under basal conditions in all animals, regardless of age and behavioral characteristics, but induced a decrease in thyroid function under conditions of its activation with thyrotropin-releasing hormone, mainly in old animals.

Roger Guillemin: A Century of Life, A Legacy of Endocrine Discoveries.

Dr. Roger Guillemin was a French physiologist who won the Nobel Prize in 1977. His pioneering research and fierce competition led to the isolation and identification of hypothalamic hormones, including thyrotropin-releasing factor (TRF), luteinizing hormone-releasing factor (LRF), and somatostatin. These discoveries transformed the knowledge of the role of the hypothalamus in endocrine control. His work not only helped in the advancement of scientific understanding but also directed the field for decades. His research continues to resonate today, shaping modern endocrinology and impacting the global treatment of endocrine disorders.

Eje hipotálamo-hipofisario. Regulación neurohormonal, implicaciones patológicas, pruebas funcionales hipofisarias, indicaciones e interpretación

The hypothalamic-pituitary axis is a crucial system for maintaining homeostasis by integrating hormonal and neuronal inputs and outputs. Almost all bodily functions are regulated directly or indirectly by this axis. The hypothalamus, a small but vital brain region, monitors various inputs and maintains physiological set points through hormonal secretion, coordinating with the pituitary gland. This regulation involves multiple feedback mechanisms and interactions with other brain areas.The hypothalamus is anatomically divided into several regions and nuclei, each with specific functions. It produces a variety of hormones, including growth hormone-releasing hormone, corticotropin-releasing hormone, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. These hormones regulate the secretion of corresponding hormones from the anterior pituitary gland, which control several physiological processes, including growth, metabolism, reproduction, and stress response.Pathological implications of hypothalamic-pituitary axis dysfunctions include endocrine disorders such as hyperprolactinemia, growth hormone deficiency, and hypogonadism. In addition, hypothalamic damage can lead to neurological and behavioral problems such as sleep disturbances and thermoregulation.

Gene expression in the hypothalamic-pituitary-thyroid axis in Seriola rivoliana early larvae development at different temperatures

We analyzed the expression of genes involved in the hypothalamic-pituitary-thyroid axis (HPT-axis) in the longfin yellowtail Seriola rivoliana early larva, including temperature effects (22, 26 and 28 °C) and days of development (day one, day two, and day six after hatching). We aimed to determine if egg and larval incubation at different temperatures could disrupt this critical endocrine axis, which, in an aquaculture context, it could provoke mortality during early metamorphosis. There was a significant interaction between temperature and developmental timing on the relative expression of thyrotropin releasing hormone (trh). Larvae at 22 °C was the longest and increased more trh expression than larvae at higher temperatures. Interestingly, thyrotropin stimulating hormone (tsh) was highly expressed after hatching. Subsequently, it was downregulated at any temperature at least until day four, suggesting a temporal inhibition of the HPT axis. Therefore, we suggest that tsh-binding (tshr) to follicles should have occurred from hatching, creating a further “cascade effect” of upregulation of larval thyroglobulin (tg) from day two in a temperature-dependent manner. Consequently, new thyroid hormones should have been produced after yolk sac absorption. The above may indicate a narrow window of larval survival, where the larval transition from endogenous to exogenous feeding would depend on the correct timing to synthesize tg. Temperature significantly affected the expressions of deiodinase 1 (dio1-downregulated) and deiodinase 2 (dio2-upregulated) after hatching. The expressions of thyroid receptors alpha (trα) and beta (trβ) remained constant after hatching without significant effects of temperature and days of development. Then, the differential expression on day six showed that all HPT-axis transcripts increased their expressions as larvae developed, which suggested a functional HPT. Finally, there was no evidence that any temperature would disrupt the endocrine’s larval axis, which indicated that the longfin yellowtail has a wide temperature adaption. Nevertheless, based on tg upregulation, we suggest that larvae should be maintained around 25–26 °C after hatching for a better chance of survival and development.

Perinatal exposure to Aroclor 1254 disrupts thyrotropin-releasing hormone mRNA expression in the paraventricular nucleus of male and female rats

Polychlorinated biphenyls (PCBs) are industrial pollutants that act as endocrine disruptors and alter thyroid function. However, it is still unclear whether PCBs can affect hypothalamic thyrotropin releasing hormone (Trh) mRNA expression through TH signaling disruption. As salt-loading dehydration induces tertiary hypothyroidism in the hypothalamic parvocellular paraventricular nuclei (paPVN), and perinatal exposure to Aroclor 1254 (A1254) disrupts the hydric balance in rats, we hypothesized that TRH synthesis could be altered during dehydration in TRH neurons that control the hypothalamic–pituitary–thyroid (HPT) axis activity in rats perinatally exposed to A1254. We examined Trh mRNA expression in the paPVN and the response to salt-loading dehydration (hyperosmotic (hyper) stress) in the progeny of Wistar pregnant rats receiving 0 mg/kg BW (control) or 30 mg/kg BW A1254 daily from gestational days 10–19. Three-month-old offspring were subjected to normosmotic or hyper conditions and Trh mRNA, glucocorticoid receptor (GR) mRNA expression were measured in the PVN by RT-PCR. TRH mRNA and TRH+ neurons were measured in the paPVN by fluorescent in situ hybridization (FISH). As expected, Trh mRNA levels were decreased in the paPVN of male and female rats in the hyper group. Basal Trh mRNA expression and serum TSH were decreased in male rats in the A1254 group. Notably, Trh mRNA levels were further decreased in the paPVN of male and female A1254 + hyper rats, in which the GR mRNA expression was significantly decreased. These results support the hypothesis that perinatal exposure to A1254 results in inadequate adaptive response of the HPT axis in adulthood and contributes to dysregulation of the HPT axis response to salt-loading dehydration.

The influence of extended fasting on thyroid hormone: local and differentiated regulatory mechanisms.

The hypometabolism induced by fasting has great potential in maintaining health and improving survival in extreme environments, among which thyroid hormone (TH) plays an important role in the adaptation and the formation of new energy metabolism homeostasis during long-term fasting. In the present review, we emphasize the potential of long-term fasting to improve physical health and emergency rescue in extreme environments, introduce the concept and pattern of fasting and its impact on the body's energy metabolism consumption. Prolonged fasting has more application potential in emergency rescue in special environments. The changes of THs caused by fasting, including serum biochemical characteristics, responsiveness of the peripheral and central hypothalamus-pituitary-thyroid (HPT) axis, and differential changes of TH metabolism, are emphasized in particular. It was proposed that the variability between brain and liver tissues in THs uptake, deiodination activation and inactivation is the key regulatory mechanism for the cause of peripheral THs decline and central homeostasis. While hypothalamic tanycytes play a pivotal role in the fine regulation of the HPT negative feedback regulation during long-term fasting. The study progress of tanycytes on thyrotropin-releasing hormone (TRH) release and deiodination is described in detail. In conclusion, the combination of the decrease of TH metabolism in peripheral tissues and stability in the central HPT axis maintains the basal physiological requirement and new energy metabolism homeostasis to adapt to long-term food scarcity. The molecular mechanisms of this localized and differential regulation will be a key research direction for developing measures for hypometabolic applications in extreme environment.

Medium-Chain Chlorinated Paraffins Trigger Thyroid Hormone Synthesis and Interfere with Mitochondrial Function in the Thyroid Gland.

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb's cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

Features of the functioning of the hypothalamic-pituitary-thyroid axis in mice with Lewis carcinoma on the background of induced hyperthyroidism

Thyroid hormones (TH) influence the processes of cell proliferation and differentiation, but their role in the processes of carcinogenesis is contradictory. The purpose of the study. To study the effect of induced hyperthyroidism in mice of both sexes with intertwined Lewis carcinoma (LLC) on the activity of the hypothalamic-pituitary-thyroid axis (GGT). Materials and methods. The experimental model was mixed-sex mice of the C57BL/6 line with subcutaneously transplanted LLC on the background of induced hyperthyroidism (main group). Two control groups were used: control group I – mice with sodium liothyronine- induced hyperthyroidism and control group II – mice with subcutaneously transplanted LLC. On the 25th day after tumor transplantation, the level of thyrotropin- releasing hormone (TRH), thyroid- stimulating hormone (TSH), triiodothyronine (T3), total and free thyroxine (T4, FT4) was determined in the homogenates of GGT organs and in blood serum. Results. In female mice, hyperthyroidism caused an increase in the level of TRH in the hypothalamus and a decrease in TSH in the pituitary gland; in males, a decrease in TRH only in the hypothalamus. In control group II, euthyroid disorder syndrome developed: In mice of both sexes, serum levels of T4 and FT4 were found to decrease against the background of unchanged T3 levels and an increase in TSH content only in females. In the females of the main group, an increase in the level of TSH in the thyroid gland caused a decrease in T3 content in 73 % of animals against the background of normal T4 and elevated FT4 levels, in 27 % of females the T3 level increased. In males, in 73 % of the observations, the T3 level was increased against the background of high T4 and FT4 values and unchanged TSH levels. In the skin and LLC samples of the mice of the main group, an increase in T3 levels was noted. Conclusion. The growth of LLC against the background of hyperthyroidism is a process with multifactorial effects. High levels of T3 in blood serum and skin stimulated the proliferation of tumor cells, which led to the formation of subcutaneous tumors of a larger volume in the mice of the main group. Sex differences in the GGT response indicate different mechanisms that implement pathological processes.

The genetic link between thyroid dysfunction and alopecia areata: a bidirectional two-sample Mendelian randomization study.

Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this studyis to investigate the causal relationship between the two and the specific directions. We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves' disease (GD), Hashimoto's thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results. Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P=0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P=0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (β=-0.029, 95%CI=-0.051 to -0.007, P=0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P>0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P>0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results. This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients.

The Effects of Intra-Articular Triamcinolone and Autologous Protein Solution on Metabolic Parameters in Horses.

Intra-articular corticosteroids are a popular treatment choice for joint-associated pain and inflammation in horses despite recent work on the metabolic effects of these drugs. The goal of this project was to compare metabolic effects between intra-articular (IA) triamcinolone acetonide (TA) and an autologous protein solution (APS). Five mixed-breed geldings (4-9 years) were utilized for this project. Three identical and consecutive 28-day treatment blocks were used, with metacarpophalangeal IA treatments consisting of equal volumes of saline, a commercially available APS, or 9 mg of TA. Regular plasma and serum samples were collected for ACTH, cortisol, glucose, insulin, and thyroid hormone analysis, in addition to thyrotropin-releasing hormone (TRH) and oral sugar tests (OSTs). Significant treatment effects of IA TA were present at 48 h post-injection in both the TRH and the OST. There was also significant suppression by IA TA of baseline ACTH and cortisol between 2 h and 96 h post-treatment, hyperglycemia between 12 h and 48 h, and hyperinsulinemia at 32 h post-treatment. There were no treatment effects with respect to any measured thyroid hormones, nor were there any significant treatment effects of APS noted. Results suggest at least 2 days and up to 7 days should elapse between a single 9 mg IA TA treatment and OST and/or TRH testing. This study found that TA exhibits significant effects on ACTH, cortisol, glucose, and insulin, while the APS does not.

Contribution of chemical permeation enhancers to the process of transdermal drug delivery: Adsorption, microscopic interactions, and mechanism

Transdermal drug delivery (TDD) has attracted widespread attention because of the advantage of its non-invasive nature, easy self-administration, and low side effects. The key to this pathway of drug delivery is how to overcome the barrier of the lipid matrix in the stratum corneum (SC). In this work, molecular dynamics (MD) were employed to investigate the adsorption of thyrotropin-releasing hormone (TRH) on the SC, and the effects of three different chemical permeation enhancers (ethanol (ETOH), carveol (CAV), and borneol (BOR)) on the SC were analyzed. The results showed that ETOH hardly altered the order of lipids in the SC, while CAV and BOR disrupted the morphology of the SC. The primary target of CAV was the CHOL in SC, which not only disrupted the ordered arrangement of CHOL, but also “extracted” CHOL from SC. The thickness distribution of SC became more inhomogeneous in the presence of CAV and BOR, which facilitated the penetration of drug molecules. Compared to no chemical permeation enhancers, the free energy of permeation in the presence of chemical permeation enhancers was less than 4–10 kcal mol−1, which suggested that chemical permeation enhancers were more favorable for the permeation of drugs from viewpoints of thermodynamics. All the results provided theoretical insights into the effect of chemical permeation enhancers on the transdermal permeation of drugs.

Association between thyroid hormone resistance and obesity: a cross-sectional study and mouse stimulation test.

Thyroid hormone influences key metabolic pathways, and reduced sensitivity to thyroid hormone is considered a new risk factor for adverse metabolic outcomes. However, the association between thyroid hormone resistance and obesity in euthyroid individuals is still unknown. We enrolled 8021 euthyroid individuals, calculated thyroid hormone resistance indices, and analyzed the association between thyroid hormone resistance and obesity by regression analysis. Furthermore, we conducted the thyrotropin-releasing hormone stimulation test in both control and obese mice (n = 5) to demonstrate the association. The euthyroid adults with overweight and obesity had increased thyroid hormone resistance indices (all p < 0.05). BMI and prevalence of overweight and obesity increased (odds ratio of thyroid feedback quantile-based index [ORTFQI] = 1.164, p = 0.036; OR of free triiodothyronine/free thyroxine [ORFT3/FT4] = 1.508, p < 0.001) following the elevation of thyroid hormone resistance indices. Mediation analysis indicated a complete mediation effect (beta coefficient of indirect effect [βInd]= 6.838, p < 0.001) of metabolic disorders in the relationship. Furthermore, in the mice with obesity, the thyrotropin response to thyrotropin-releasing hormone stimulation (68.33-90.89 pg/mL) was comparatively blunted (p = 0.029). Euthyroid individuals with obesity exhibit both central and peripheral thyroid hormone resistance, a phenomenon that is more pronounced in individuals with metabolic abnormalities. Thyroid hormone resistance is associated with an increased prevalence of overweight and obesity mediated by metabolic disorders.

Diagnosis of hypoprolactinemia.

Prolactin is a polypeptide hormone composed of 199 amino acids, synthesized by lactotroph cells. Its primary effects are on the mammary gland and gonadal axes, but it also influences different organs and systems, particularly metabolic functions. Current literature has mainly focused on the diagnosis, monitoring, and treatment of hyperprolactinemia. Due to the lack of a well-established effective treatment for hypoprolactinemia, it is not clinically emphasized. Therefore, data on its diagnosis is limited. Hypoprolactinemia has been associated with metabolic dysfunctions such as type 2 diabetes mellitus, fatty liver, dyslipidemia, fertility problems, sexual dysfunction, and increased cardiovascular disease. While often seen as a part of combined hormone deficiencies due to pituitary damage, isolated prolactin deficiency is rare. Hypoprolactinemia can serve as a marker for extensive pituitary gland damage and dysfunction.Low or undetectable serum prolactin levels and the absence of a sufficient prolactin peak in the thyrotropin-releasing hormone (TRH) stimulation test are considered diagnostic for hypoprolactinemia. Gender appears to influence both basal prolactin levels and TRH stimulation test responses. Basal prolactin levels of, at least, 5 ng/mL for males and 7 ng/mL for females can be used as cut-off levels for normal prolactin reserve. Minimum peak prolactin responses of 18 ng/mL for males and 41 ng/mL for females to TRH stimulation can exclude hypoprolactinemia. However, larger population studies across different age groups and sexes are needed to better define normal basal prolactin levels and prolactin responses to the TRH stimulation test.

Evidence for thyroid hormone regulation of amygdala-dependent fear-relevant memory and plasticity.

The amygdala is an established site for fear memory formation, and clinical studies suggest involvement of hormone signaling cascades in development of trauma-related disorders. While an association of thyroid hormone (TH) status and mood disorders is established, the related brain-based mechanisms and the role of TH in anxiety disorders are unknown. Here we examine the role that TH receptor (TR, a nuclear transcriptional repressor when unbound and a transcriptional activator when bound to TH) may have in mediating the initial formation of fear memories in the amygdala. We identified mRNA levels of TR and other TH pathway regulatory genes, including thyrotropin-releasing hormone (Trh), transthyretin (Ttr), thyrotropin-releasing hormone receptor (Trhr), type 2 iodothyronine deiodinase (Dio2), mediator complex subunit 12 (Med12/Trap230) and retinoid X receptor gamma (Rxrg) to be altered in the amygdala following Pavlovian fear conditioning. Using TH agonist and antagonist infusion into the amygdala, we demonstrated that this pathway is both necessary and sufficient for fear memory consolidation. Inhibition of TH signaling with the TR antagonist 1-850 decreased fear memory consolidation; while activation of TR with T3 (triiodothyronine) resulted in increased memory formation. Using a systemic hypothyroid mouse model, we found that intra-amygdala infusions of T3 were sufficient to rescue deficits in fear memory. Finally, we demonstrated that T3 was sufficient to activate TR-specific gene pathways in the amygdala. These findings on the role of activity-dependent TR modulation support a model in which local TH is a critical regulator of fear memory-related plasticity in the amygdala.

Low molecular inverse agonist of the thyrotropin receptor is active both intraperitoneal and oral administration

Autoimmune hyperthyroidism (Graves’ disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone (TSH) receptor, and thyroid gland (TG) tumors, caused by constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are not very effective and have many side effects. One of the approaches for the treatment of these thyroid diseases may be the use of allosteric regulators of the TSH receptor with the activity of inverse agonists. The purpose of the work was to study the effects of our previously developed compound TP48 and the new compound TPY5, belonging to the class of thieno[2,3-d]-pyrimidines, on the basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the blood of rats and on the expression of genes responsible for the synthesis of THs in the TG. The effectiveness of TP48 and TPY5 was studied both with intraperitoneal (i.p., 20 mg/kg) and oral (40 mg/kg) administration. Using ELISA, the levels of free (fT4) and total (tT4) thyroxine and free (fT3) and total (tT3) triiodothyronine in the blood were assessed, including during TRH stimulation (intranasally, 300 μg/kg). The gene expression for thyroid peroxidase (Tpo), thyroglobulin (Tg), Na+/I–-symporter (Nis), type 2 deiodinase (Dio2) and TSH receptor (Tshr) in the TG was assessed using PCR. TPY5, with both routes of administration, reduced both basal and TRH-stimulated TH levels, while TP48 suppressed TH production only with i.p. administration. Orally administered TPY5 significantly reduced basal Tpo gene expression and TRH-stimulated Tg and Dio2 gene expression. I.p. administered TP48 reduced only TRH-stimulated expression of the Tg and Dio2 genes. Quite surprisingly, TPY5 (oral) and TP48 (i.p.) reduced basal Tshr gene expression and did not prevent its inhibition by TRH. Thus, the TPY5 compound we developed has the activity of an inverse agonist of the TSH receptor, is effective when administered orally, which is more in demand in medicine, and can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors.

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly.

We previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly. The clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared. No differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression. The increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.