Thyrotropin-releasing Hormone Levels Research Articles

Modelling the Effect of the Exposure to Perfluorooctanoate (PFOA) and Perfluorooctane Sulfonate (PFOS) on Thyroid Homeostasis

Thyroid homeostasis is crucial for the human body. The imbalance of thyroid homeostasis might cause diseases such as hypothyroidism. Humans are exposed to PFOS/PFOA frequently since they have been used in various industrial products. As reported that PFOS/PFOA increase the metabolic clearance rate of thyroid hormones, we then develop a mathematical model in terms of a system of differential equations to investigate thyroid homeostasis based on the changes in the levels of thyrotropin-releasing hormone, thyroid-stimulating hormone and thyroid hormones when the effect of the exposure to PFOS and PFOA is also incorporated as well. The geometric singular perturbation technique is then employed to identify the possible dynamic behaviours obtained from the model. Numerical investigations are also presented to illustrate the results from theoretical analysis. Both theoretical and numerical results imply that a periodic behaviour that has been observed clinically in the pulsatile secretions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone could be obtained from our model. In addition, the numerical experiment also shows that the levels of thyroid hormones and thyroid-stimulating hormone for the case when there is the effect of exposure to PFOS and PROA are lower than those of the case when there is no effect of the exposure to PFOS and PFOA which might lead to the imbalance of thyroid homeostasis.

Tris(2-chloroethyl) Phosphate Exerts Hepatotoxic Impacts on Zebrafish by Disrupting Hypothalamic-Pituitary-Thyroid and Gut-Liver Axes.

The ubiquitous environmental presence of tris(2-chloroethyl) phosphate (TCEP) poses a potential threat to animals; however, little is known about its hepatotoxicity. In this study, the effects of TCEP exposure (0.5 and 5.0 μg/L for 28 days) on liver health and the potential underlying toxification mechanisms were investigated in zebrafish. Our results demonstrated that TCEP exposure led to hepatic tissue lesions and resulted in significant alterations in liver-injury-specific markers. Moreover, TCEP-exposed fish had significantly lower levels of thyrotropin-releasing hormone and thyroid-stimulating hormone in the brain, evidently less triiodothyronine whereas more thyroxine in plasma, and markedly altered expressions of genes from the hypothalamic-pituitary-thyroid (HPT) axis in the brain or liver. In addition, a significantly higher proportion of Bacteroidetes in the gut microbiota, an elevated bacterial source endotoxin lipopolysaccharide (LPS) in the plasma, upregulated expression of LPS-binding protein and Toll-like receptor 4 in the liver, and higher levels of proinflammatory cytokines in the liver were detected in TCEP-exposed zebrafish. Furthermore, TCEP-exposed fish also suffered severe oxidative damage, possibly due to disruption of the antioxidant system. These findings suggest that TCEP may exert hepatotoxic effects on zebrafish by disrupting the HPT and gut-liver axes and thereafter inducing hepatic inflammation and oxidative stress.

Effects of intracerebroventricular MOTS-c infusion on thyroid hormones and uncoupling proteins.

This study was conducted to determine the possible effects of intracerebroventricular MOTS-c infusion on thyroid hormones and uncoupling proteins (UCPs) in rats. Forty male Wistar Albino rats were divided into 4 groups with 10 animals in each group: control, sham, 10 and 100µM MOTS-c. Hypothalamus, blood, muscle, adipose tissues samples were collected for thyrotropin-releasing hormone (TRH), UCP1 and UCP3 levels were determined by the RT-PCR and western blot analysis. Serum thyroid hormone levels were determined by the ELISA assays. MOTS-c infusion was found to increase food consumption but it did not cause any changes in the body weight. MOTS-c decreased serum TSH, T3, and T4 hormone levels. On the other hand, it was also found that MOTS-c administration increased UCP1 and UCP3 levels in peripheral tissues. The findings obtained in the study show that central MOTS-c infusion is a directly effective agent in energy metabolism.

PSAT328 Primary Hypothyroidism Presenting with Galactorrhea and Pituitary Hyperplasia

Abstract Introduction Pituitary Hyperplasia (PH) refers to diffuse enlargement of pituitary gland and is most commonly physiological as in pregnancy and lactation. PH can also be associated with end organ hormone deficiencies like primary hypothyroidism, Addison's disease and some neuroendocrine tumors. Primary hypothyroidism is a known cause of prolactin elevation however hyperprolactinemia in the presence of pituitary enlargement can often be mistaken for pituitary adenoma. We report a case of PH caused by primary hypothyroidism presenting with galactorrhea and hyperprolactinemia and successfully treated with thyroid hormone replacement. Case presentation 21-year-old female presented to the Primary Care Provider's office with galactorrhea from bilateral breasts for 2 months. Pregnancy was ruled out and prolactin levels were checked and noted to be elevated at 51.3 ng/mL. Subsequently MRI of Pituitary was done which showed diffusely enlarged, homogenously enhancing anterior pituitary gland with convex superior margin, measuring 12 mm in superior to inferior dimension, contacting and slightly elevating optic chiasm. Further testing showed TSH >100µIU/mL, and undetectable Free T4. She was started on Levothyroxine and then referred to Endocrinology for evaluation of Pituitary mass. Upon further questioning she reported headaches for few weeks associated with intermittent dizziness, fatigue, weight gain of 30-40 pounds, irregular menstrual periods, cold intolerance, and low libido for several months. Physical exam was remarkable for bradycardia, dry skin. Thyroid was normal on exam. Pituitary hyperplasia was thought to be secondary to primary hypothyroidism and patient was continued on Levothyroxine. At 3 month follow up visit, patient reported improvement in her symptoms of fatigue, menstrual periods and lost few pounds of weight. Her galactorrhea resolved completely. Repeat labs showed normal prolactin levels and her thyroid levels normalized after few dose adjustments. Follow up MRI done 1 year from initial presentation showed decrease in the anterior pituitary enlargement, now measuring 8 mm, and the superior margin was no longer contacting the optic chiasm. Conclusion Primary hypothyroidism is common, but often under recognized cause of Pituitary hyperplasia. The underlying pathophysiology is lack of negative feedback of Thyroid hormones on Hypothalamus resulting in elevated levels of Thyrotropin releasing hormone (TRH). Excess TRH leads to thyrotroph cell hyperplasia in anterior pituitary and elevated TSH levels, TRH also leads to lactotroph hyperplasia and can result in hyperprolactinemia. Neurological symptoms related to PH and symptoms related to hyperprolactinemia, can sometimes be the initial presenting symptoms of primary hypothyroidism. It is important to recognize primary hypothyroidism as the cause for pituitary hyperplasia and hyperprolactinemia (especially those with TSH > 50-100 microIU/mL) as the primary treatment is thyroid hormone replacement and not surgery. These patients should be followed closely with repeat MRI to document the resolution of pituitary hyperplasia. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Role of N-methyl-d-aspartate receptors in anxiety disorder with thyroid lesions

ObjectivePatients with anxiety disorder (AD) often have structural and functional abnormalities of the thyroid gland, but their specific causes remain unclear. N-methyl- d-aspartate receptors (NMDARs) play an important role in many psychosomatic diseases and tumorigenesis, but there are few reports on the role of NMDARs in AD with thyroid lesions, especially thyroid nodules (TNs). MethodsA cross-sectional study was conducted on patients admitted to the hospital with AD (n = 71) as the main diagnosis from April to October 2021. Meanwhile, patients with TNs with no AD (NAD-TN group, n = 20) and healthy subjects (HS group, n = 37) with matched age, sex, and education were randomly collected as controls. Patients with AD were sub-grouped into the AD with TNs (AD-TN group, n = 41) and the AD with no TNs (AD-NTN group, n = 30). The thyroid ultrasound reports, Hamilton Anxiety Scale (HAMA) scores, and the expression of NMDARs and their subunits (NR1, NR2A, and NR2B) and hypothalamic-pituitary-thyroid (HPT) axis-related hormones were analyzed in all subjects. Some patients with TNs underwent surgery and postoperative pathological examination. ResultsPatients with AD showed a lower level of free triiodothyronine (FT3) and higher levels of thyrotropin-releasing hormone (TRH) and NMDARs and their subunits compared to the healthy controls. The expression of the NR2A subunit was higher in the AD-TN group than that in other three groups (AD-NTN, NAD-TN, and HS groups, F = 13.650, p < 0.001). Regression analysis showed that the level of NMDARs was positively correlated with the HAMA scores (B = 1.622, p = 0.029) and the maximum diameter of TNs (B = 3.836, p = 0.005). Immunohistochemical results showed that the NR2A subunit was widely expressed in multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) tissues, while the expression of the NR2B subunit was lower in PTC adjacent and MNG tissues and almost absent in PTC tissues. ConclusionIn a sample of mostly women hospitalized with generalized anxiety disorder (GAD) or panic disorder, abnormal expression of NMDARs is closely related to AD with thyroid lesions, NMDAR subunits may have various activities and exert diverse effects in TNs, and the NR2A subunit may be an important regulator in AD with TNs.

Filtered air intervention modulates hypothalamic-pituitary-thyroid/gonadal axes by attenuating inflammatory responses in adult rats after fine particulate matter (PM2.5) exposure.

We have previously reported that filtered air (FA) intervention reduces inflammation and hypothalamus-pituitary-adrenal axis activation after fine particulate matter (PM2.5 exposure). Whether FA also modulates the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes in rats after PM2.5 exposure is still unknown. Adult Sprague-Dawley rats were exposed to PM2.5 by using a "real-world" PM2.5 exposure system, and the FA intervention was conducted by renewing for 15 days. PM2.5 inhalation decreased thyrotropin-releasing hormone (TRH) and thyroxine (T4) levels in both male and female rats, and thyroid-stimulating hormone (TSH) level in male rats. FA intervention attenuated the reduction in TRH and TSH levels in male rats and reduction in T4 level in female rats. PM2.5 inhalation also reduced testosterone (T) level in male rats, and estradiol (E2) and progesterone (PROG) levels in female rats, and these changes were attenuated after FA intervention. The FA intervention attenuated the decreases in CD8 T cells and T cells induced by PM2.5 inhalation in female rats only by flow cytometry analysis. In blood, FA interventions ameliorated IL-6 and IL-1β mRNA levels in both male and female rats after PM2.5 exposure. FA intervention restored the IL-4 and IL-10 levels in female rats after PM2.5 exposure. Moreover, FA intervention ameliorated the inflammatory responses induced by PM2.5 inhalation in the thyroid and gonads in both male and female rats. These data indicate that FA intervention exerted an effect on modulating the hormonal balance of the HPT and HPG axes, and this may be related to a reduction in the inflammatory responses in the thyroid and gonads of PM2.5-treated rats, respectively.

Effects of meteorin-like hormone on endocrine function of hypothalamo-hypophysial system and peripheral uncoupling proteins in rats.

Meteorin-like hormone (Metrnl) is a peptide secreted from the adipose tissue and modulates the whole-body energy metabolism. Metrnl release into the circulation is influenced by obesity, cold exposure, and exercise. Thyroid hormones also exert many of their effects on metabolism through uncoupling proteins (UCPs). This study aimed to determine effect of Metrnl on hypothalamo-hypophysier-thyroid axis and energy metabolism and reveal the possible involvement of UCPs in this process. Fourty male Sprague-Dawley rats were divided into 4 groups with 10 animals in each group: control, sham, 10 and 100nM Metrnl. Hypothalamus, muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) samples were collected to detect thyrotropin-releasing hormone (TRH), and UCP1 and UCP3 protein levels by western blot analysis. Serum thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) hormone levels were determined by enzyme-linked immunosorbent assay. Central infusion of Metrnl caused significant increase in serum TSH, T3 and T4 levels compared to control (p < 0.05). After Metrnl treatment, there were significant increases in TRH in hypothalamus tissue, UCP1 in WAT and BAT; and UCP3 protein in the muscle tissue (p < 0.05). The findings that Metrnl induced increases in the peripheral UCPs and hypothalamus-pituitary-thyroid axis hormones implicate a role for this hormone in body energy homeostasis through UCP-mediated mechanisms.

Role of the thyrotropin-releasing hormone of the limbic system in mood and eating regulation.

Thyrotropin-releasing hormone (TRH) and its receptors are expressed in the hypothalamus and limbic regions. Brain thyrotropin-releasing hormone actions are exerted directly through its receptors and indirectly by modulating the effects of neurotransmitters such as glutamate, gamma-aminobutyric acid, acetylcholine, and dopamine. The thyrotropin-releasing hormone has been implicated in eating and mood regulation. We integrate studies that analyze the role of limbic thyrotropin-releasing hormone on displaying depressive- and anxiety-like behaviors and anorexia or hyperphagia. Since the decade of 1970s, different efforts have been made to identify some of the thyrotropin-releasing hormone effects and its analogs in feeding regulation or to ameliorate symptoms in patients diagnosed with mood disorders, and to correlate anxious or depressive parameters with thyrotropin-releasing hormone levels in the cerebrospinal fluid or its expression in postmortem brain areas of affected patients. Pharmacological studies where the thyrotropin-releasing hormone is administered to animals by different routes and to distinct brain areas have elucidated its actions in behavioral changes of mood and feeding parameters. In addition, a variety of animal models of depression, anxiety, or anorexia and hyperphagia has suggested the association between the hypothalamic and limbic TRHergic system and the regulation of mood and feeding alterations. Different approaches employ the administration of anti-depressant, anxiolytic or anorectic agents to animals and describe changes in thyrotropin-releasing hormone content or expression in hypothalamic or limbic regions. The different effects on mood that result from modulating thyrotropin-releasing hormone expression may be beneficial to treat patients diagnosed with eating disorders.

Effects of iodine excess on serum thyrotropin-releasing hormone levels and type 2 deiodinase in the hypothalamus of Wistar rats.

Iodine is an important element in thyroid hormone biosynthesis. Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis. Excessive iodine leads to elevated thyroid-stimulating hormone (TSH) levels, but the mechanism is not yet clear. Type 2 deiodinase (Dio2) is a Se-containing protease that plays a vital role in thyroid function. The purpose of this study was to explore the role of hypothalamus Dio2 in regulating TSH increase caused by excessive iodine and to determine the effects of iodine excess on thyrotropin-releasing hormone (TRH) levels. Male Wistar rats were randomised into five groups and administered different iodine dosages (folds of physiological dose): normal iodine, 3-fold iodine, 6-fold iodine, 10-fold iodine and 50-fold iodine. Rats were euthanised at 4, 8, 12 or 24 weeks after iodine administration. Serum TRH, TSH, total thyroxine (TT4) and total triiodothyronine (TT3) were determined. Hypothalamus tissues were frozen and sectioned to evaluate the expression of Dio2, Dio2 activity and monocarboxylate transporter 8 (MCT8). Prolonged high iodine intake significantly increased TSH expression (P < 0·05) but did not affect TT3 and TT4 levels. Prolonged high iodine intake decreased serum TRH levels in the hypothalamus (P < 0·05). Dio2 expression and activity in the hypothalamus exhibited an increasing trend compared at each time point with increasing iodine intake (P < 0·05). Hypothalamic MCT8 expression was increased in rats with prolonged high iodine intake (P < 0·05). These results indicate that iodine excess affects the levels of Dio2, TRH and MCT8 in the hypothalamus.

Av-UCP single nucleotide polymorphism affects heat production during cold exposure in chicks.

Uncoupling protein one (UCP1) is involved in thermogenesis, especially in non-shivering heat production. In chickens, a single nucleotide polymorphism (SNP) of the av-UCP (avian UCP) gene has been reported to be associated with body weight gain and increased abdominal fat. The purpose of this study was to examine the relationship between the av-UCP gene SNP and heat production in chicks. C/C and T/T male chicks (Rhode Island Red) of av-UCP gene SNP (g. 1270, C>T) were exposed to a low temperature environment (16°C for 15min) and their physiological responses were compared. After cold exposure, mean rectal temperatures of C/C chicks were higher than those of T/T chicks. In pectoral muscle, genes expression of av-UCP and carnitine palmitoyltransferase-1 were higher in C/C chicks than T/T chicks. Hypothalamic expression levels of thyrotropin-releasing hormone and proopiomelanocortin genes were higher in C/C chicks than T/T chicks. Expression of hypothalamic corticotropin-releasing hormone, arginine vasotocin, brain-derived neurotrophic factor and neuropeptide Y genes did not differ between C/C and T/T chicks. In addition, plasma free fatty acid levels in C/C chicks were lower than those of T/T chicks. These results suggest that the av-UCP gene SNP affects non-shivering heat production via the hypothalamo-pituitary-thyroid axis and fatty acid metabolism in the chicken.

Reproductive injury in male BALB/c mice infected with Neospora caninum

BackgroundNeospora caninum is one of the main causes of abortion in pregnant animals. However, N. caninum-induced reproductive injury in male mice is still unclear.MethodsMale BALB/c mice were infected with a bovine isolate of N. caninum, and the organ coefficients of the testis and epididymis were measured. Lesions in the testis and epididymis were observed by light microscopy and transmission electron microscopy. Expression of the spermatogenic cell apoptosis-related proteins p53 and caspase-3 was detected by western blot. The expression of spermatogenesis-related genes in the testis was detected by reverse transcription-PCR. Sperm morphology and motility were observed. The levels of nitric oxide (NO) and antisperm antibody (AsAb) in the testicular homogenates and hormones in the serum were detected by enzyme-linked immunosorbent assay. The reproductive capacity of the male mice was detected using a reproduction test.ResultsThe organ coefficients of the testis and epididymis of the experimental group were significantly downregulated. Light microscopy examination revealed that the spermatogenic cells of the testis were arranged in a disordered manner, and the number was reduced. The number of sperm in the epididymal lumen was significantly reduced, and the cytoplasm exhibited vacuolation and degeneration. Ultrastructural studies revealed that the cells of the testis and epididymis tissues showed varying degrees of disease. The level of p53 and caspase-3 expression in the testis was significantly upregulated. The expression of the testicular spermatogenesis-related genes Herc4, Ipo11 and Mrto4 were strongly downregulated. Observation of sperm by microscopic examination revealed significantly reduced sperm density and sperm motility, and the number of sperm deformities was significantly increased. The level of NO and AsAb was significantly increased. The levels of luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone were significantly upregulated, whereas the levels of testosterone, thyrotropin-releasing hormone, thyroxine and thyroid-stimulating hormone were significantly downregulated. After challenge, the infected male mice and healthy female mice were caged together: the subsequent fetal death rate was increased, and the conception rate, litter size, number of live births and the birth weight were significantly reduced.ConclusionsInfection of male BALB/c mice with the bovine isolate of N. caninum induced varying degrees of injury to the testis, epididymis and sperm of the mice, destroyed spermatogenesis and affected the reproductive capacity.Graphical

Chapter 7 - The supraoptic and paraventricular nuclei in healthy aging and neurodegeneration

The supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus undergo structural and functional changes over the course of healthy aging. These nuclei and their connections are also heterogeneously affected by several different neurodegenerative diseases. This chapter reviews the involvement of the SON and PVN, the hypothalamic-pituitary axes, and the peptide hormones produced in both nuclei in healthy aging and in neurodegeneration, with a focus on Alzheimer's disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis, progressive supranuclear palsy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy, and Huntington's disease. Although age-related changes occur in several regions of the hypothalamus, the SON and PVN are relatively preserved during aging and in many neurodegenerative disorders. With aging, these nuclei do undergo some sexually dimorphic changes including changes in size and levels of vasopressin and corticotropin-releasing hormone, likely due to age-related changes in sex hormones. In contrast, oxytocinergic cells and circulating levels of thyrotropin-releasing hormone remain stable. A relative resistance to many forms of neurodegenerative pathology is also observed, in comparison to other hypothalamic and brain regions. Mirroring the pattern observed in aging, pathologic hallmarks of AD, and some subtypes of FTD are observed in the PVN, though to a milder degree than are observed in other brain regions, while the SON is relatively spared. In contrast, the SON appears more vulnerable to alpha-synuclein pathology of DLB and PD. The consequences of these alterations may help to inform several of the physiologic changes observed in aging and neurodegenerative disease.

Effects of simulated 5 500 m hypobaric and hypoxia on HPT axis and intestinal flora in rats

Objective: To investigate the effects of simulated hypoxia environment at an altitude of 5 500 meters on hypothalamic-pituitary-thyroid (HPT) axis and intestinal flora of rats and the correlation between them. Methods: The hypoxia model of adult male SD rats was established by hypobaric chamber with simulated altitude of 5 500 m. The hypoxia groups were set for 1, 3, 7, 14, 21 and 28 days, and the normoxic recovery group were set for 1 and 3 days after hypoxia (8 rats per group, hypoxia time 24h per day). Daily body weight and food intake of rats were recorded. The serum levels of HPT axis hormones were detected by enzyme-linked immunosorbent assay (ELISA). Intestinal flora was analyzed by 16s rDNA sequencing. The correlation between intestinal flora and serum HPT axis hormone was analyzed by Spearman correlation analysis. Results: Compared with the normoxic group, the body weight and food intake were significantly reduced (P＜0.01). In the 1-day and 3-day groups, the levels of thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) were decreased significantly (P＜0.05), the levels of total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4) and free triiodothyronine (FT3) were increased significantly (P＜0.05), and the abundance of Prevotella was decreased significantly (P＜0.05), while those of Parabacteroides, Lactobacillus, Butyricimonas, Bacteroides, Odoribacter and RC4-4 were increased significantly (P＜0.05). In the 14-day, 21-day and 28-day hypoxia groups, the levels of TRH and TSH were decreased significantly (P＜0.05), and the levels of TT4 and TT3 were increased significantly (P＜0.05), and there was no significant difference in other indexes, the abundance of Parabacteroides, Sphaerochaeta, Akkermansia, Elusimicrobium was increased significantly, but that of Lactobacillus and Sutterella was decreased significantly (P＜0.05). Correlation analysis of intestinal flora and HPT axis hormones showed that Butyricimonas, Elusimicrobium and Sutterella were significantly negatively correlated with TRH and TSH (P＜ 0.05), Prevotella, Bacteroides, Odoribacter and Parabacteroides were significantly correlated with TSH, TT4, TT3 and FT4 (P＜ 0.05), respectively. Lactobacillus was significantly correlated with TRH, TSH and FT4 (P＜0.05). Akkermansia was significantly correlated with TRH and FT4 (P＜0.05). RC4-4 was significantly associated with TSH and TT3 (P＜0.05). Conclusion: Hypoxia stress at an altitude simulating 5500 meters significantly changed the composition of the intestinal flora of SD rats. This may be a change in thyroid function adapted to the hypoxia environment, and the degree of change is related to the time of hypoxia stress. The change of intestinal microflora is significantly correlated with the hormone level of HPT axis.

THE PROFILE OF THYROTROPIN-RELEASING HORMONE, T-REGULATOR, AND INTERLEUKIN-4 OF UNTREATED GRAVES’ DISEASE IN INDONESIA

Objective: This study was conducted to the profile of hormonal and immunological aspects, which is thyrotropin-releasing hormone (TRH), T-regulator (T-reg) Forkhead box P3 (FOXP3) gene polymorphism, and interleukin-4 (IL-4) of untreated Graves’ disease with hyperthyroid in M Djamil General Hospital Padang, Indonesia.&#x0D; Methods: A cross-sectional study was conducted to observe Graves’ disease with hyperthyroid in the Internal Medicine Department in Dr. M. Djamil Hospital, Padang, West Sumatera, Indonesia. Graves’ disease was confirmed by measuring free thyroxine (FT4), thyroid-stimulating hormone (TSH), and antithyroid peroxidase (anti-TPO). TRH, T-reg FOXP3 gene polymorphism, and IL-4 were examined with an enzyme-linked immunosorbent assay method.&#x0D; Results: Twenty-five subjects with Graves’ disease included in this study with an average of age is 27.48 (5.6) years. Mean Wayne index is 23.44 (1.4), mean serum FT4 level is 55.55 (17.98) pmol/l, median serum TSH level is 0.041 (0.004–0.053) mU/l, and mean anti-TPO level is 2697.539 (479.72) pg/ml. Median serum TRH level is 92.589 (24.843–253.186) pg/ml, mean T-reg FOXP3 gene polymorphism is 0.621 (0.23) ng/ml, and mean serum IL-4 level is 19.759 (7.03) pg/ml).&#x0D; Conclusion: Graves’ disease with hyperthyroid has median serum TRH level 92.589 (24.843-253.186) pg/ml and high levels of T-reg FOXP3 gene polymorphism and IL-4.

Abstract P5-05-15: Pregnancy inhibits mammary carcinogenesis by persistently altering the hypothalamic-pituitary axis

Abstract Pregnancy, carried to term at an early age, is probably the best natural protection against breast cancer development. The relative life-long breast cancer risk for women that give birth to their first child before the age of 20 years is approximately half that of nulliparous women. In contrast, if a woman undergoes her first full-term pregnancy after the age of 35, her risk for breast cancer is increased even more than nulliparous women. In the current generation many women are career oriented and have children later in life. Universally the average age at first birth is on the rise. It is critical to understand the underlying mechanism of this protective effect of pregnancy against breast cancer to develop novel prevention strategies to reduce the risk of breast cancer without women having to undergo pregnancy early in life. Earlier, we and others have demonstrated that post-pregnancy there were persistent changes in circulating levels of hormones. In order to understand the significance of these systemic changes we determined alterations in the hypothalamic-pituitary axis in parous rats. In particular, we examined the static and dynamic alterations in the hypothalamic-pituitary axis in response to pregnancy. Seven weeks old female Lewis rats were injected with the chemical carcinogen N-methyl-N-nitrosourea (MNU) at a dose of 50mg/kg body weight intraperitoneally. Two weeks post-carcinogen treatment these rats were housed with a male rat. On the observation of the vaginal plug the male was removed from the cage. Once the rats gave birth they nursed the pups for three weeks and were weaned after that period. Mammary tumorigenesis was monitored through weekly palpation for a period of nine months. A subset of rats at 6, 12 and 24 weeks post-weaning were used to study static and dynamic changes in the level of hormones. We investigated the static alterations in the hypothalamic-pituitary axis in response to pregnancy by measuring the levels of thyrotropin releasing hormone (TRH), growth hormone releasing hormone (GHRH), somatostatin (SS), dopamine (DA), growth hormone (GH) and prolactin (PRL). Next we investigated if the dynamic alterations in the hypothalamic-pituitary axis in response to pregnancy. Control and parous animals were subjected to secretogogue treatments (Growth Hormone Related Peptide 6 for GH and Perphenazine for PRL) and the levels of GH and PRL were measured. We also isolated the pituitary and treated them with the secretogogues and measured the levels of GH and PRL. Our data demonstrated that pregnancy resulted in persistent static and dynamic alterations in circulating levels of hormones. Parous rats response to the secretogogues was severely blunted compared to the control nulliparous rats. The levels of TRH, GHRH, GH and PRL were significantly lowered in parous rats while DA and SS levels were higher in nulliparous rats. As expected mammary carcinogenesis was significantly inhibited in parous rats. Overall, these preliminary results suggest that pregnancy induces persistent changes in hypothalamic-pituitary axis, which results in a lowered hormonal promotion environment resulting in inhibition of mammary carcinogenesis. Citation Format: Subramani R, Galvez A, Pedroza D, Lakshmanaswamy R. Pregnancy inhibits mammary carcinogenesis by persistently altering the hypothalamic-pituitary axis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-15.

A study on thyroid profile and prolactin level in hypothyroid females of a rural population of a developing country

Background: In patients with primary hypothyroidism, there are increased levels of thyrotropin-releasing hormone (TRH) which can cause rise of prolactin (PRL) levels and these patients may have galactorrhea. Aims: Considering the clinical importance of hyperprolactinemia in ovulation disorders, sterility, and menstruation disorders, the present study was conducted to observe the prevalence of hyperprolactinemia and related galactorrhea in newly diagnosed hypothyroid females and correlate serum PRL level with thyroid-stimulating hormone (TSH) in hypothyroid females in a rural population of East India. Materials and Methods: This pilot study was conducted in Burdwan Medical College on 200 newly diagnosed female hypothyroid participants after taking institutional ethical clearance and informed consent of the participants. Age and gender-matched 100 controls were taken. Serum TSH, serum free thyroxine (fT4), and serum PRL levels were assessed. A questionnaire was designed for the evaluation of hypothyroidism symptoms for all the participants. These symptoms were galactorrhea, dryness of skin, feeling cold, hair loss, weakness, weight gain, constipation, loss of libido, and menstrual abnormalities. A total number of hyperprolactinemic patients were 42; out of them, 30 females were clinical and 12 were subclinical hypothyroid patients. One hundred and fifty-eight patients had normal PRL level. Results: Significant difference was found between clinical and subclinical hypothyroid females for body mass index (BMI) (P = 0.002), TSH (P

Angiotensin II requires an intact cardiac thyrotropin-releasing hormone (TRH) system to induce cardiac hypertrophy in mouse

Cardiac tyhrotropin-releasing hormone (TRH) is overexpressed in the hypertrophied left ventricle (LV) of spontaneously hypertensive rats (SHR) and its inhibition prevents both hypertrophy and fibrosis. In a normal heart, the TRH increase induces fibrosis and hypertrophy opening the question of whether TRH could be a common mediator of left ventricular hypertrophy (LVH). We used angiotensin II (AngII) as an inductor of LVH to evaluate if the blockade of LV-TRH prevents hypertrophy and fibrosis in mice. We challenged C57BL/6 adult male mice with an infusion of AngII (osmotic pumps; 2 mg/kg.day) to induce LVH. Groups of mice were injected with an intracardiac siRNA-TRH or scrambled siRNA (siRNA-Con). Body weight, water intake and systolic arterial blood pressure (SABP) were measured daily. AngII significantly increased water intake and SABP (p < .05). Cardiac hypertrophy (heart weight/body weight) was evident in the group with the normal cardiac TRH system. In fact, it was found an AngII-induced increase of TRH precursor mRNA (p < .05) in conjunction with elevated TRH levels measured by immunohistochemistry and western blot. These changes were not observed in the AngII + siRNA-TRH group. Furthermore, AngII increased significantly (p < .05) BNP (hypertrophic marker), collagens I and III and TGF-β (fibrosis markers) expression in the group with the native cardiac TRH system. These increases were attenuated in the groups with the TRH system blocked despite the high blood pressure. Similar and stronger results were observed “in vitro” with NIH3T3 and H9C2 cell culture models, where, when the TRH system is blocked, AngII stimulus was not able to induce the markers of its fibrotic and hypertrophic effects, so we believe that these effects are independent of any other physiological modifications.Our results point out that cardiac TRH is required for AngII-induced hypertrophic and fibrotic effects.

Iodoacetic Acid Disrupting the Thyroid Endocrine System in Vitro and in Vivo.

Exposure to drinking water disinfection byproducts (DBPs) is potentially associated with adverse developmental effects. Iodoacetic acid (IAA), an unregulated DBP, has been shown to be cytotoxic, mutagenic, genotoxic, and tumorigenic. However, its endocrine-disrupting effects remain unknown. This study evaluated the IAA-induced disruption of the thyroid endocrine system using in vitro and in vivo assays. Rat pituitary tumor GH3 cells were treated with IAA in the presence and absence of triiodothyronine (T3). IAA exposure significantly reduced T3-activated GH3 cell proliferation, indicating the antagonistic activity of IAA in vitro. Sprague-Dawley rats were also subjected to IAA treatment through oral gavage for 28 consecutive days. IAA exposure significantly down-regulated the mRNA expression levels of the thyrotropin receptor (TSHR), the sodium/iodide symporter (NIS), and type I deiodinase and simultaneously reduced the protein expression levels of TSHR and NIS. IAA exposure decreased T3 levels but increased the weights of hypothalamus and the levels of thyrotropin releasing hormone and thyrotropin. In addition, IAA induced the formation of smaller and more depleted follicles or even vacuolization in the thyroid. These results suggested that IAA potentially disrupts the thyroid endocrine system both in vitro and in vivo.

Exposure to PFDoA causes disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae.

Perfluorododecanoic acid (PFDoA), a kind of perfluorinated carboxylic acid (PFCA) with 12 carbon atoms, has an extensive industrial utilization and is widespread in both wildlife and the water environment, and was reported to have the potential to cause a disruption in the thyroid hormone system homeostasis. In this study, zebrafish embryos/larvae were exposed to different concentrations of PFDoA (0, 0.24, 1.2, 6 mg/L) for 96 h post-fertilization (hpf). PFDoA exposure caused obvious growth restriction connected with the reduced thyroid hormones (THs) contents in zebrafish larvae, strengthening the interference effect on the growth of fish larvae. The transcriptional level of genes within the hypothalamic-pituitary-thyroid (HPT) axis was analyzed. The gene expression levels of thyrotropin-releasing hormone (trh) and corticotrophin-releasing hormone (crh) were upregulated upon exposure to 6 mg/L of PFDoA, and iodothyronine deiodinases (dio2) was upregulated in the 1.2 mg/L PFDoA group. The transcription of thyroglobulin (tg) and thyroid receptor (trβ) were significantly downregulated upon exposure to 1.2 mg/L and 6 mg/L of PFDoA. PFDoA could also decrease the levels of sodium/iodide symporter (nis) and transthyretin (ttr) gene expression in a concentration-dependent manner after exposure. A significant decrease in thyroid-stimulating hormoneβ (tshβ), uridinediphosphate-glucuronosyltransferase (ugt1ab) and thyroid receptor (trα) gene expression were observed at 6 mg/L PFDoA exposure. Upregulation and downregulation of iodothyronine deiodinases (dio1) gene expression were observed upon the treatment of 1.2 mg/L and 6 mg/L PFDoA, respectively. All the data demonstrated that gene expression in the HPT axis altered after different PFDoA treatment and the potential mechanisms of the disruption of thyroid status could occur at several steps in the process of synthesis, regulation, and action of thyroid hormones.

Lentivirus-mediated microRNA-124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of spinal cord injury in rats

Our study aims to explore the effects of lentivirus-mediated microRNA-124 (miR-124) gene-modified bone marrow mesenchymal stem cell (BMSC) transplantation on the repair of spinal cord injury (SCI) in rats. BMSCs were isolated from the bone marrow of rats. The target gene miR-124 was identified using a luciferase-reporter gene assay. Seventy-two rats were selected for construction of the SCI model, and the rats were randomly divided into the blank group, sham group, SCI group, negative control (NC) group, overexpressed miR-124 group and si-PDXK group. The mRNA expression of miR-124 and the mRNA and protein expression of pyridoxal kinase (PDXK) were detected by quantitative real-time polymerase chain reaction and western blotting. The locomotor capacity of the rats was evaluated using the Basso, Beattie and Bresnahan (BBB) scale. Brdu, neuron-specific enolase (NSE), neurofilament (NF) and microtubule-associated protein 2 (MAP2) were detected using immunohistochemistry. The expression levels of thyrotropin-releasing hormone (TRH), prostacyclin (PGI2) and gangliosides (GM) were measured using an enzyme-linked immunosorbent assay. PDXK was identified as the target gene of miR-124. The overexpressed miR-124 group exhibited higher miR-124 expression than the SCI, NC and si-PDXK groups. Compared with the SCI and NC groups, the PDXK expression was downregulated in the overexpressed miR-124 and si-PDXK groups, and the BBB scores were significantly increased 7, 21 and 35 days after transplantation. The double-labeled positive cell densities (Brdu+NSE/NF/MAP2) and the expression levels of TRH, PGI2 and GM in the overexpressed miR-124 group were significantly higher than those in the NC and SCI groups. These results indicated that miR-124 targeted PDXK to accelerate the differentiation of BMSCs into neurocytes and promote SCI repair.