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Background To determine the incidence, etiology, and outcomes of thyroid-stimulating hormone (TSH) elevation in extremely low-birth-weight infants (ELBWIs). Methods Newborn thyroid screening data of 584 ELBWIs (birth weight, < 1000 g; gestational age, ≥ 23 weeks) were retrospectively analyzed to identify initial (≤ 2 postnatal weeks) and delayed (> 2 weeks) TSH elevations. Growth and neurodevelopmental outcomes at 2 years’ corrected age (CA) were assessed according to levothyroxine replacement. Results Initial and delayed TSH elevations were detected at CAs of 27 and 30 weeks, respectively, with incidence rates of 0.9 and 7.2%, respectively. All infants with initial TSH elevations had perinatal asphyxia, and 95% of those with delayed TSH elevation were exposed to various stressors, including respiratory support, drugs, and surgery within 2 weeks before diagnosis of TSH elevation. Free thyroxine (T4) levels were simultaneously reduced in 80 and 57% of infants with initial and delayed TSH elevations, respectively. Both initial and delayed TSH elevations were transient, regardless of levothyroxine replacement. Infants receiving levothyroxine replacement therapy had significantly higher TSH elevations, significantly lower free T4 levels, and significantly reduced mortality, compared to untreated infants. However, levothyroxine replacement had no significant effect on long-term growth and neurodevelopmental outcomes. Conclusions The timing of insult superimposition on hypothalamic–pituitary–thyroid axis maturation is a major determinant of initial or delayed TSH elevation in ELBWIs. Levothyroxine replacement did not affect growth or neurodevelopmental outcomes in this population.

Abstract Background Thyroid dysfunction is associated with the use of tyrosine kinase inhibitors (TKI) in people. Hypothesis/Objectives To determine whether dysfunction in the hypothalamic-pituitary-thyroid axis occurs in dogs receiving the TKI, toceranib phosphate. Animals Forty-three client-owned dogs with cancer. Methods Prospective, observational study. Concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) were evaluated on day 0, 30, and 90. Dogs also were evaluated for the presence of thyroglobulin autoantibodies. Results The proportion of dogs with low TT4, low FT4, low TT3, high TSH, or primary hypothyroidism (increased TSH and decreased TT4, FT4 or both) did not change over 90 days. Hormone concentrations remained within laboratory reference intervals, but FT4 (P = 0.0032) and TSH (P < 0.0001) changed over time. Mean FT4 was 1.22 ng/dL (95% confidence interval [CI], 1.10–1.34) on day 0 and 1.00 ng/dL (95% CI, 0.86–1.16) on day 90. Mean TSH was 0.17 ng/mL (95% CI, 0.13–0.23) on day 0 and 0.34 ng/mL (95% CI, 0.24–0.48) on day 90. Furthermore, TT4/TT3 ratio also changed over time (P = 0.0086). Mean TT4/TT3 ratio was 2.57 (95% CI, 2.26–2.88) on day 0 and 2.02 on day 90 (95% CI, 1.61–2.44). Thyroglobulin autoantibodies were not detected in any dog. Conclusions and Clinical Importance Toceranib phosphate can disrupt the hypothalamic-pituitary-thyroid axis in dogs. Periodic evaluation of TT4, FT4, TT3, and TSH should be carried out in dogs receiving long-term treatment with this medication.

Neuropeptides have been known for over 50 years as chemical signals in the brain. However, it is now well established that the synthesis of this class of peptides is not restricted to neurons. For example, human skin not only expresses several functional receptors for neuropeptides but, also, can serve as a local source of neuroactive molecules such as corticotropin-releasing hormone, melanocortins, and β-endorphin. In contrast, an equivalent of the hypothalamic-pituitary axis in the oral mucosa has not been well characterized to date. In view of the differences in the morphology and function of oral mucosal and skin cells, in this review I surveyed the existing evidence for a local synthesis of hypothalamic-pituitary, opiate, neurohypophyseal, and neuroendocrine neuropeptides in both epidermal and oral keratinocytes.

Thyroid cancer usually begins with thyroid dysfunction and nodules and has become the most common cancer globally, especially in women. Although the causes of thyroid dysfunction are complex, the presence of environmental pollutants, especially certain pesticides as established mutagens, has been widely accepted. Zebrafish (Danio rerio) have similar toxic reactions and signal transduction pathways to humans and are very similar to humans in physiology, development, and metabolic function. Here, the direct toxicity effects and mechanisms of different insecticides and herbicides on zebrafish thyroid functions and indirect toxicity effects originating from thyroid dysfunction were summarized and compared. The overall toxicity of insecticides on the zebrafish thyroid was greater than that of herbicides based on effective concentrations. Penpropathrin and atrazine were more typical thyroid disruptors than other pesticides. Meanwhile, chiral pesticides showed more sophisticated single/combined toxicity effects on both parental and offspring zebrafish. Besides thyroid hormone levels and HPT axis-related gene expression alteration, developmental toxicity, immunotoxicity, and oxidative damage effects were all observed. These data are necessary for understanding the thyroid interference effect of pesticides on humans and for screening for thyroid disruptors in surface water with zebrafish models for the pre-assessment of human health risks and ecological risk control in the future.

The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.

Hormones regulate development, as well as many vital processes in the daily life of an animal. Many of these hormones are peptides that act at a higher hierarchical level in the animal with roles as organizers that globally orchestrate metabolism, physiology and behavior. Peptide hormones can act on multiple peripheral targets and simultaneously convey basal states, such as metabolic status and sleep-awake or arousal across many central neuronal circuits. Thereby, they coordinate responses to changing internal and external environments. The activity of neurosecretory cells is controlled either by (1) cell autonomous sensors, or (2) by other neurons that relay signals from sensors in peripheral tissues and (3) by feedback from target cells. Thus, a hormonal signaling axis commonly comprises several components. In mammals and other vertebrates, several hormonal axes are known, such as the hypothalamic-pituitary-gonad axis or the hypothalamic-pituitary-thyroid axis that regulate reproduction and metabolism, respectively. It has been proposed that the basic organization of such hormonal axes is evolutionarily old and that cellular homologs of the hypothalamic-pituitary system can be found for instance in insects. To obtain an appreciation of the similarities between insect and vertebrate neurosecretory axes, we review the organization of neurosecretory cell systems in Drosophila . Our review outlines the major peptidergic hormonal pathways known in Drosophila and presents a set of schemes of hormonal axes and orchestrating peptidergic systems. The detailed organization of the larval and adult Drosophila neurosecretory systems displays only very basic similarities to those in other arthropods and vertebrates.

Skin is the largest organ of the human body and undergoes both intrinsic (chronological) and extrinsic aging. While intrinsic skin aging is driven by genetic and epigenetic factors, extrinsic aging is mediated by external threats such as UV irradiation or fine particular matters, the sum of which is referred to as exposome. The clinical manifestations and biochemical changes are different between intrinsic and extrinsic skin aging, albeit overlapping features exist, eg, increased generation of reactive oxygen species, extracellular matrix degradation, telomere shortening, increased lipid peroxidation, or DNA damage. As skin is a prominent target for many hormones, the molecular and biochemical processes underlying intrinsic and extrinsic skin aging are under tight control of classical neuroendocrine axes. However, skin is also an endocrine organ itself, including the hair follicle, a fully functional neuroendocrine “miniorgan.” Here we review pivotal hormones controlling human skin aging focusing on IGF-1, a key fibroblast-derived orchestrator of skin aging, of GH, estrogens, retinoids, and melatonin. The emerging roles of additional endocrine players, ie, α-melanocyte-stimulating hormone, a central player of the hypothalamic-pituitary-adrenal axis; members of the hypothalamic-pituitary-thyroid axis; oxytocin, endocannabinoids, and peroxisome proliferator-activated receptor modulators, are also reviewed. Until now, only a limited number of these hormones, mainly topical retinoids and estrogens, have found their way into clinical practice as anti-skin aging compounds. Further research into the biological properties of endocrine players or its derivatives may offer the development of novel senotherapeutics for the treatment and prevention of skin aging.

The Yi-nao-jie-yu decoction (YNJYD) is a herbal preparation widely used in the clinics of traditional Chinese medicine and has been recently used as an important new therapeutic agent in poststroke anxiety (PSA). The neuroendocrine-immune system plays an important role in PSA mechanisms, although the modulating effects of YNJYD remain unknown. This study investigated the potential effects of YNJYD on the neuroendocrine-immune system in a rat model of PSA. The PSA model was induced by injecting collagenase (type VII) into the right globus pallidus, accompanied by empty water bottle stimulation for 2 weeks. The sham group and the PSA model group were gavaged with saline, while the treatment groups received buspirone (BuSpar) or YNJYD. Behavior was evaluated with the open field test and elevated plus maze once a week. Pathological changes were observed by hematoxylin and eosin staining. Serum levels of tumor necrosis factor, interleukin (IL)-6, adrenocorticotropic hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, IL-1α, and cortisol were detected by radioimmunoassay. Expression of the γ-aminobutyric acid type A receptor (GABA R) α subunit was examined by Western blot and real-time polymerase chain reaction. YNJYD-treated rats exhibited significantly better recovery than BuSpar-treated rats at 21 days and 28 days in the open field test and elevated plus maze. Hematoxylin and eosin staining revealed neural repair in the hippocampus in the treatment groups. Serum levels of IL-1α in the YNJYD group were significantly less than those in the model group and the BuSpar group. GABA R protein and mRNA expressions were higher in the PSA model group than in the sham group, and YNJYD reversed these effects. YNJYD alleviated the symptoms of PSA mainly by decreasing IL-1α levels and downregulating GABA R expression in the hippocampus to maintain a neuroendocrine-mmune system balance.

The hypothalamic–pituitary–thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin-releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic. Here, we demonstrate that stimulation of the TRH receptor 1 increases intracellular calcium in tanycytes of the median eminence via Gα q/11 proteins. Activation of Gα q/11 pathways increases the size of tanycyte endfeet that shield pituitary vessels and induces the activity of the TRH-degrading ectoenzyme. Both mechanisms may limit the TRH release to the pituitary. Indeed, blocking TRH signaling in tanycytes by deleting Gα q/11 proteins in vivo enhances the response of the HPT axis to the chemogenetic activation of TRH neurons. In conclusion, we identify new TRH- and Gα q/11 -dependent mechanisms in the median eminence by which tanycytes control the activity of the HPT axis. The hypothalamic-pituitary-thyroid (HPT) axis regulates a wide range of physiological processes. Here the authors show that hypothalamic tanycytes play a role in the homeostatic regulation of the HPT axis; activation of TRH signaling in tanycytes elevates their intracellular Ca 2+ via Gα q/11 pathway, ultimately resulting in reduced TRH release into the pituitary vessels.

Fasting induces profound changes in the hypothalamic–pituitary–thyroid (HPT) axis. After binding thyroid hormone (TH), the TH receptor beta 2 isoform (THRB2) represses Trh and Tsh subunit genes and is the principle negative regulator of the HPT axis. Using mass spectrometry, we identified a major phosphorylation site in the AF-1 domain of THRB2 (serine 101, S101), which is conserved among many members of the nuclear hormone receptor superfamily. More than 50% of THRB2 is phosphorylated at S101 in cultured thyrotrophs (TαT1.1) and in the mouse pituitary. All other THR isoforms lack this site and exhibit limited overall levels of phosphorylation. To determine the importance of THRB2 S101 phosphorylation, we used the TαT1.1 cell line and S101A mutant knock-in mice (Thrb2S101A ). We found that TH promoted S101 THRB2 phosphorylation and was essential for repression of the axis at physiologic TH concentrations. In mice, THRB2 phosphorylation was also increased by fasting and mimicked Trh and Tshb repression by TH. In vitro studies demonstrated that a master metabolic sensor, AMP-activated kinase (AMPK) induced phosphorylation at the same site and caused Tshb repression independent of TH. Furthermore, we identified cyclin-dependent kinase 2 (CDK2) as a direct kinase phosphorylating THRB2 S101 and propose that AMPK or TH increase S101 phosphorylation through the activity of CDK2. This study provides a physiologically relevant function for THR phosphorylation, which permits nutritional deprivation and TH to use a common mechanism for acute suppression of the HPT axis.