The association between TSH and thyroid hormones in the normal or subclinical dysfunction range with left ventricular diastolic dysfunction.

Thyroid hormones modulate the cardiovascular system. However, the effects of subclinical thyroid dysfunction and euthyroidism on cardiac function remain unclear. We investigated the association between left ventricular (LV) diastolic dysfunction and subclinical thyroid dysfunction or thyroid hormones within the reference range. This cross-sectional study included 26,289 participants (22,197 euthyroid, 3,671 with subclinical hypothyroidism, and 421 with subclinical thyrotoxicosis) who underwent regular health check-ups in the Republic of Korea. Individuals with thyroid stimulating hormone (TSH) levels > 4.2 µIU/mL and normal free thyroxine (FT4, 0.78-1.85 ng/dL) and triiodothyronine (T3, 76-190 ng/dL) levels were defined as having subclinical hypothyroidism. Individuals with serum TSH levels < 0.4 µIU/mL and normal FT4 and T3 levels were defined as having subclinical thyrotoxicosis. The cardiac structure and function were evaluated using echocardiography. LV diastolic dysfunction with normal ejection fraction (EF) was defined as follows: EF of > 50% and (a) E/e' ratio > 15, or (b) E/e' ratio of 8-15 and left atrial volume index ≥ 34 mL/m2. Subclinical hypothyroidism was significantly associated with cardiac indices regarding LV diastolic dysfunction. The odds of having LV diastolic dysfunction was also increased in participants with subclinical hypothyroidism (adjusted odds ratio [AOR] 1.36, 95% confidence interval [CI], 1.01-1.89) compared to euthyroid participants. Subclinical thyrotoxicosis was not associated with LV diastolic dysfunction. Among the thyroid hormones, only serum T3 was significantly and inversely associated with LV diastolic dysfunction even within the normal range. Subclinical hypothyroidism was significantly associated with LV diastolic dysfunction, whereas subclinical thyrotoxicosis was not. Serum T3 is a relatively important contributor to LV diastolic dysfunction compared to TSH or FT4.

Impaired autonomic function and somatosensory disturbance in patients with treated autoimmune thyroiditis.

Despite treatment with levothyroxine, hypothyroidism and autoimmune thyroiditis (AIT) may be associated with reduced quality of life (QoL), an enigmatic condition referred to as "syndrome T". Peripheral neuropathy, described in untreated thyroid disease, could be a contributing mechanism. We analysed autonomic and somatosensory function in 29 patients with AIT and treated hypothyroidism and 27 healthy volunteers. They underwent heart rate variability (HRV) analysis and quantitative sensory testing (n = 28), comprising 13 parameters of small and large nerve fibre function and pain thresholds. Autonomic cardiovascular function was assessed in rest, deep respiration and orthostasis. Additionally, biomarkers for autoimmunity and thyroid function were measured. Anxiety, depression and QoL were assessed using validated questionnaires. 36% of the patients showed at least one sign of somatosensory small or large fibre dysfunction. 57% presented with mild hyperalgesia to at least one stimulus. Several markers of autonomic function and some detection thresholds were related to the antibody titres. Anxiety, depression scores and QoL correlated to antibody titres and HRV measures. Autonomic and somatosensory dysfunction indicate that in treated hypothyroidism and AIT a subgroup of patients suffers from neuropathic symptoms leading to impaired QoL. Additionally, mild hyperalgesia as a possible sensitisation phenomenon should be considered a target for symptomatic treatment.

Actualización en el manejo preoperatorio en pacientes con hipotiroidismo / Preoperative management of patients with hypothyroidism: An update

The preoperative management of patients with hypothyroidism has an impact on the clinical outcomes in the postoperative period, however, it has been found that there is a lack of evidence regarding management recommendations in this scenario. Therefore, we conducted a review of the literature for articles in English and Spanish from the years 2000 to 2020 in the databases PubMed, ProQuest, Scopus and Embase, that highlight the physiology, pathophysiology and current recommendations for preoperative management in this patient population. It is of great importance to understand the physiological changes and implications in the anesthetic management of these patients, in order to assure an adequate approach both preoperatively and in possible serious postoperative complications, as well the common perioperative complications, which tend to be cardiovascular, pulmonary and of the upper airway, especially in patients with a higher degree of thyroid dysfunction (moderate, severe). Additionally, based on this non-systematic review of the literature, we propose a management algorithm for this patient population.

El manejo preoperatorio de los pacientes con hipotiroidismo marca la diferencia en los desenlaces clínicos del posoperatorio, sin embargo, se ha encontrado que hay falta de evidencia en cuanto a recomendaciones en el manejo en este escenario, por lo que realizamos una búsqueda de la literatura en inglés y español de los años 2000 al 2020 en las bases de datos PubMed, ProQuest, Scopus y Embase sobre fisiología, fisiopatología y recomendaciones actuales del manejo preoperatorio en estos pacientes. Es de gran importancia conocer los cambios fisiológicos e implicaciones en el manejo anestésico de estos pacientes, para un adecuado abordaje tanto en el preoperatorio como en posibles complicaciones graves en el posoperatorio, así como las complicaciones más frecuentes, los cuales son cardiovasculares, pulmonares y de la vía aérea superior, esto en pacientes con mayor grado de disfunción tiroidea (moderado, severo). Adicionalmente, basado en esta revisión no sistemática de la literatura, proponemos un algoritmo de manejo en esta población de pacientes.

Mecanismos fisiopatológicos del hipotiroidismo en la infertilidad femenina / Physiopathological mechanisms of hypothyroidism on feminine infertility

INTRODUCCIÓN Y OBJETIVO: El hipotiroidismo es una condición frecuente en mujeres en Chile. Existe evidencia contundente de una fuerte asociación entre esta patología e infertilidad femenina. El objetivo de esta revisión es resumir los principales mecanismos fisiopatológicos descritos en la literatura que explicarían la infertilidad femenina en mujeres hipotiroideas. MÉTODOS: Se llevó a cabo una búsqueda bibliográfica por medio PubMed con los términos: hipotiroidismo, infertilidad y fisiopatología. De todos los artículos se seleccionaron únicamente los correspondientes a población femenina. Incluimos tanto hipotiroidismo clínico como subclínico, y mujeres eutiroideas con anti-TPO (+). RESULTADOS: Clasificamos la literatura disponible en tres grupos de mecanismo fisiopatológicos. En primer lugar, la deficiencia de hormonas tiroideas T3 y T4 producirían alteraciones en la foliculogénesis, ovulación, implantación y placentación. En segundo lugar, la hiperprolactinemia secundaria al hipotiroidismo llevaría a un hipogonadismo hipogonadotrópico e insuficiencia en la fase lútea. En tercer lugar, los anticuerpos anti-TPO, independientemente de los niveles de hormonas tiroideas, podrían tener una reacción cruzada con proteínas presentes en el útero, afectando el proceso de implantación. CONCLUSIONES: El hipotiroidismo produce infertilidad femenina por variados mecanismos fisiopatológicos. Dada la variabilidad de estos, existe un mayor espectro de aproximaciones terapéuticas para tratar mujeres hipotiroideas con problemas de fertilidad.

INTRODUCTION AND OBJECTIVE: Hypothyroidism is a frequent condition in Chile in women in Chile. There is strong evidence of an association between this pathology and feminine infertility. The objective of this review is to summarize the main physiopathological mechanisms described in the literature that explain infertility in women with hypothyroidism. METHODS: We performed a bibliographic search on PubMed with the terms: hypothyroidism, infertility, physiopathology. Among all the articles we selected only the ones regarding to feminine population. We included both clinical and subclinical hypothyroidism, and euthyroid women with Anti-TPO (+). RESULTS: We classified the available literature into three groups of physiological mechanisms. In the first place, decreased thyroid hormones T3 and T4 may lead to alterations on folliculogenesis, ovulation, implantation and placentation. Secondly, hyperprolactinemia secondary to hypothyroidism would produce hypogonadotropic hypogonadism and luteal phase insufficiency. Thirdly, anti-TPO antibodies, independently on thyroid hormones levels, may have a cross reactivity towards proteins in the womb, negatively affecting the process of implantation. CONCLUSIONS: Hypothyroidism produces infertility through varied physiopathological mechanisms. Due to their variability, there is a wider scope for therapeutical approaches to treat women with hypothyroidism and fertility problems.

A Prospective Observational Study of 42 Patients with COVID-19 infection and a History of Hepatitis C Virus Infection and Thyroid Disease with Follow-Up Thyroid Function and Autoantibody Testing.

BACKGROUND Thyroiditis is an important extrahepatic association in chronic hepatitis C virus (HCV) infection. There have been reports of an association between SARS-CoV-2 infection and the onset or re-activation of autoimmune hypothyroidism. Therefore, we performed this prospective observational study of 42 patients with COVID-19 infection and a history of hepatitis C virus infection and thyroid disease with follow-up thyroid function and autoantibody testing. MATERIAL AND METHODS From April 2020 to October 2020, we performed a prospective observational study of patients with cured hepatitis C virus (HCV) infection and documented thyroid disease who became infected with SARS-CoV-2 (confirmed by SARS-CoV-2 RNA detection via reverse-transcription polymerase chain reaction [RT-PCT] from the upper respiratory tract, both nasal and pharyngeal swabs). Evaluation at 1 and 3 months after SARS-CoV-2 infection included serum determination of antithyroid antibodies (anti-thyroglobulin [anti-Tg] and antithyroid peroxidase [ATPO]), thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and evaluation of thyroid medication, with dose adjustment if required. RESULTS One-month follow-up showed that both patients with autoimmune thyroiditis as well as patients without antibodies had increased ATPO levels. Also, levels of TSH, fT3, and fT4 were significantly decreased. At 3-month follow-up, levels of ATPO were decreased in all patient groups and the levels of thyroid hormones increased to normal values. CONCLUSIONS This study supports previous reports of an association between SARS-CoV-2 infection and thyroid dysfunction associated with thyroid autoantibodies. Thyroid function tests may be considered as part of the laboratory work-up in patients with COVID-19.

Relación entre hipotiroidismo y síndrome de ovario poliquístico / The relationship between hypothyroidism and polycystic ovary syndrome

INTRODUCCIÓN: Se ha documentado la asociación del síndrome de ovario poliquístico con alteraciones metabólicas y enfermedades cardiovasculares. Su relación con trastornos autoinmunitarios no está claramente establecida, pero se ha encontrado una importante prevalencia de desórdenes tiroideos en pacientes con síndrome de ovario poliquístico. OBJETIVO: Describir las diferentes teorías existentes que puedan explicar la relación entre hipotiroidismo y síndrome de ovario poliquístico, junto con su posible impacto en la morbilidad asociada. Método: Se realizó una búsqueda en PubMed y LILACS con las palabras clave "Polycystic ovary síndrome", "Hypotyroidism", "thyroid disease" y sus respectivos términos en español, durante julio de 2020. Resultados: Se seleccionaron 51 artículos relacionados con el tema, publicados en los últimos 10 años. La fisiopatogenia entre ambos trastornos no está claramente establecida. Se ha encontrado un importante impacto metabólico en este grupo de pacientes y se considera que su riesgo cardiovascular podría estar aumentado. CONCLUSIONES: Al considerarse la prevalencia significativa y las complicaciones que tanto a corto como a largo plazo podrían tener las mujeres con ambas alteraciones, se hace necesario discutir la necesidad de la exclusión del hipotiroidismo de los criterios diagnósticos aplicados para el síndrome, la tamización temprana y el estudio de las implicaciones terapéuticas que trae su abordaje.

INTRODUCTION: The association of polycystic ovary syndrome with other metabolic disorders and cardiovascular diseases has been documented; nevertheless, its relationship with autoimmune disorders is not clearly established, however, an important prevalence of thyroid disorders has been found in this group of patients. OBJECTIVE: To describe the different existing theories that can explain the relationship between hypothyroidism and polycystic ovary syndrome along with its possible impact on associated morbidities. Method: A search was conducted in PubMed and LILACS with the keywords of "Polycystic ovary syndrome", "Hypothyroidism", "Thyroid disease" and with its respective Spanish terms, in July 2020. Results: 51 articles related to the subject were selected, published in the last 10 years. The pathogenesis between both disorders is not clearly established. An important impact has been found at the metabolic level in this group of patients and it is considered that their cardiovascular risk could be increased. CONCLUSIONS: Considering the significant prevalence and complications that both short and long term, women with both alterations could have, it is necessary to discuss the need for the exclusion of hypothyroidism from the diagnostic criteria applied for the syndrome, early screening of the syndrome, and the study of the therapeutic implications that its approach brings.

The Impact of Subclinical Hypothyroidism on Patients with Polycystic Ovary Syndrome: A Meta-Analysis.

The association between subclinical hypothyroidism (SCH) and polycystic ovary syndrome (PCOS) has been shown in many studies. These findings are still controversial, however. It is unclear whether the co-incidence of subclinical hypothyroidism and polycystic ovary syndrome will affect the severity of metabolism. Therefore, we performed this meta-analysis to investigate the association. A comprehensive search strategy was developed to obtain all relevant studies published in PubMed, EMBASE, Cochrane Library, and Chinese Academic Journal Full-text Database (CNKI) up to 31 December 2020. We adopted the standardized mean difference (SMD) with 95% confidence intervals (CI) for evaluation, and sensitivity analysis was performed. Publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger's test. Twenty-seven studies with 4821 participants (1300 PCOS patients with SCH, 3521 PCOS patients without SCH) were included in the present meta-analysis,among which 71.31% chinese patients out of the total. The results showed that PCOS patients with SCH had higher levels of HOMA-IR, TG, TC, LDL, FBG, FCP, PRL and lower levels of HDL, LH and T. It also recognized the limitation of the lack of a consistent definition of hypothyroidism in the 27 studies included. The results of this study indicated that SCH may aggravate lipid and glucose metabolism in patients with PCOS.

Understanding the Pathogenesis of Gestational Hypothyroidism.

Pregnancy is a complex state with many endocrinological challenges to a woman's physiology. Gestational Hypothyroidism (GHT) is an emerging condition where insufficiency of the thyroid gland has developed during pregnancy in a previously euthyroid woman. It is different to overt hypothyroidism, where marked elevation of thyroid-stimulating hormone with corresponding reduction in free thyroxine levels, is well known to cause detrimental effects to both the mother and the baby. During the past couple of decades, it has been shown that GHT is associated with multiple adverse maternal and fetal outcomes such as miscarriage, pre-eclampsia, placental abruption, fetal loss, premature delivery, neurocognitive and neurobehavioral development. However, three randomized controlled trials and a prospective cohort study performed within the last decade, show that there is no neurodevelopmental improvement in the offspring of mothers who received levothyroxine treatment for GHT. Thus, the benefit of initiating treatment for GHT is highly debated within the clinical community as there may also be risks associated with over-treatment. In addition, regulatory mechanisms that could possibly lead to GHT during pregnancy are not well elucidated. This review aims to unravel pregnancy induced physiological challenges that could provide basis for the development of GHT. During pregnancy, there is increased renal clearance of iodine leading to low iodine state. Also, an elevated estrogen level leading to an increase in circulating thyroglobulin level and a decrease in free thyroxine level. Moreover, placenta secretes compounds such as human chorionic gonadotropin (hCG), placental growth factor (PIGF) and soluble FMS-like tyrosine kinase-1 (s-Flt1) that could affect the thyroid function. In turn, the passage of thyroid hormones and iodine to the fetus is highly regulated within the placental barrier. Together, these mechanisms are hypothesized to contribute to the development of intolerance of thyroid function leading to GHT in a vulnerable individual.

Investigation of thermal changes in the thyroid gland region of individuals with hypothyroidism and fibromyalgia by analyzing the temperature of brown adipose tissue.

This exploratory retrospective study aims to investigate the thermal changes in the thyroid gland region of patients with hypothyroidism and fibromyalgia by analyzing the temperature of the brown adipose tissue (BAT). A total of 166 individuals from 1000 thermographic electronic medical records were classified into four groups: Group HP + FM-50 individuals with hypothyroidism and fibromyalgia; Group FM-56 individuals with fibromyalgia only; Group HP-30 individuals with hypothyroidism only, and Group Control-30 healthy individuals. The thermal images from the electronic medical records were acquired by a FLIR T650SC infrared camera (used for thermometry) and the temperature data for each group were statistically analyzed. Group HP + FM showed r = 0, meaning that the average temperatures of the thyroid and BAT are independent of each other. Groups FM, HP and Control showed r = 1, meaning that the average temperatures of the thyroid and BAT were directly related. Our findings showed that the average temperatures of the thyroid and BAT regions are similar. Also, there was no correlation between thyroid gland temperature and the presence of hypothyroidism or fibromyalgia using thermometry.

Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report.

BACKGROUND: Hypothyroidism is diagnosed on the basis of laboratory tests because of the lack of specificity of the typical clinical manifestations. There is conflicting evidence on screening for hypothyroidism. CASE PRESENTATION: We report a case of an apparently healthy 19-year-old Kuwaiti woman referred to our clinic with an incidental finding of extremely high thyroid-stimulating hormone (TSH), tested at the patient's insistence as she had a strong family history of hypothyroidism. Despite no stated complaints, the patient presented typical symptoms and signs of hypothyroidism on evaluation. Thyroid function testing was repeated by using different assays, with similar results; ultrasound imaging of the thyroid showed a typical picture of thyroiditis. Treatment with levothyroxine alleviated symptoms and the patient later became biochemically euthyroid on treatment. CONCLUSION: There is controversy regarding screening asymptomatic individuals for hypothyroidism; therefore, it is important to maintain a high index of suspicion when presented with mild signs and symptoms of hypothyroidism especially with certain ethnic groups, as they may be free of the classical symptoms of disease.

The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions.

The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs. The hypothalamus and the pituitary gland are in close anatomical proximity at the base of the brain and extended through the pituitary stalk to the sella turcica. The pituitary stalk allows passage of stimulatory and inhibitory hormones and other signal molecules. The target organs are placed in the periphery and function through stimulation/inhibition by the circulating pituitary hormones. The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear. The diagnosis of central hypothyroidism is complicated by itself but challenged further by concomitant affection of other hypothalamus-pituitary-hormone axes, the dysfunction of which influences the diagnosis of central hypothyroidism. Treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes also influence the function of the others by complex mechanisms involving both central and peripheral mechanisms. Clinicians managing patients with neuroendocrine disorders should become aware of the strong integrative influence from each hypothalamus-pituitary-hormone axis on the physiology and pathophysiology of central hypothyroidism. As an aid in this direction the present review summarizes and highlights the importance of the hypothalamus-pituitary-thyroid axis, pitfalls in diagnosing central hypothyroidism, diagnosing/testing central hypothyroidism in relation to panhypopituitarism, pointing at interactions of the thyroid function with other pituitary hormones, as well as local hypothalamic neurotransmitters and gut-brain hormones. Furthermore, the treatment effect of each axis on the regulation of the others is described. Finally, these complicating aspects require stringent diagnostic testing, particularly in clinical settings with lower or at least altered à priori likelihood of hypopituitarism than in former obvious clinical patient presentations.

Thyroid complications of SARS and coronavirus disease 2019 (COVID-19).

We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.

MANAGEMENT OF ENDOCRINE DISEASE: Thyroid and female infertility: more questions than answers?!

Severe thyroid dysfunction may lead to menstrual disorders and infertility via direct and indirect interactions with the hypothalamo-pituitary-ovarian axis and the reproductive organs. However, the exact prevalence of infertility in women with thyroid disorders remains unknown. Fertility problems may persist even after restoring normal thyroid function, and then surgery and/or an assisted reproductive technology (ART) may be necessary to obtain a pregnancy. The initial step in an ART treatment is the ovarian stimulation, putting strain on the thyroid gland, potentially leading to (permanent) hypothyroidism in women with thyroid autoimmunity (TAI) or when already treated with thyroid hormones (LT4). Moreover, women with ovarian and unexplained causes of infertility have a higher prevalence of TAI. In women treated with LT4, a serum TSH level <2.5 mIU/L should be targeted before ART. In women with TSH levels >4.0 mIU/L, fertilisation rates, embryo quality and live birth rates may be impaired but also improved with LT4 therapy. In euthyroid women with TAI, LT4 should not be given systematically, but on a case-by-case basis if serum TSH is >2.5 mIU/L. For all of the above reasons, women of infertile couples should be screened routinely for the presence of thyroid disorders. In this review, we will focus on the gaps in the current knowledge, the remaining questions on the associations between thyroid (disorders) and (assisted) reproduction and make proposals for future investigations that may lead to a better understanding and contribute to novel treatment options in the long term.

Brain Gene Expression in Systemic Hypothyroidism and Mouse Models of MCT8 Deficiency: The Mct8-Oatp1c1-Dio2 Triad.

Background: The monocarboxylate transporter 8 (Mct8) protein is a primary thyroxine (T4) and triiodothyronine (T3) (thyroid hormone [TH]) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alter thyroid function and TH metabolism and severely impair neurodevelopment (Allan-Herndon-Dudley syndrome [AHDS]). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is believed that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase, thus preventing brain hypothyroidism. The Slc16a2/Slco1c1 (MO) and Slc16a2/Dio2 (MD) double knockout (KO) mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, respectively, should be appropriate models of AHDS. Our goal was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KO mice. Methods: We performed RNA sequencing by using RNA from the cerebral cortex and striatum of SH mice and the double KO mice on postnatal days 21-23. Real-time polymerase chain reaction was used to confirm RNA-Seq results in replicate biological samples. Cell type involvement was assessed from cell type-enriched genes. Functional genomic differences were analyzed by functional node activity based on a probabilistic graphical model. Results: Each of the three conditions gave a different pattern of gene expression, with partial overlaps. SH gave a wider and highest variation of gene expression than MD or MO. This was partially due to secondary gene responses to hypothyroidism. The set of primary transcriptional T3 targets showed a tighter overlap, but quantitative gene responses indicated that the gene responses in SH were more severe than in MD or MO. Examination of cell type-enriched genes indicated cellular differences between the three conditions. Conclusions: The results indicate that the neurological impairment of AHDS is too severe to be fully explained by TH deprivation only.

BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis.

PURPOSE: BRAFV600E, a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin. METHODS: Immunohistochemical expressions of BRAFV600E, TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983-2004. RESULTS: BRAFV600E was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. BRAFV600E prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAFV600E mutation in classic papillary tumors significantly increased from 56 to 72% over the 21-year period of diagnoses, while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival, but did not remain significant after adjustment for demographic and clinical factors. CONCLUSIONS: Our study provides the first evidence of the potential interaction of BRAFV600E mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of BRAFV600E in thyroid carcinogenesis. BRAFV600E mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy.

Severe metabolic disorders coexisting with Werner syndrome: a case report.

Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.

Proteinuria in Severe Hypothyroidism: A Prospective Study.

CONTEXT: Hypothyroidism is associated with reversible decline in kidney function as measured by estimated glomerular filtration rate (eGFR). eGFR and proteinuria are the most important markers for clinical assessment of kidney function. Though hypothyroidism is associated with proteinuria in cross-sectional data, the impact of treatment on proteinuria is unknown. OBJECTIVE: This study explores the effect of thyroid hormone replacement therapy on eGFR and 24-hour urine protein excretion in patients with severe primary hypothyroidism. DESIGN AND PARTICIPANTS: This study was a prospective, observational cohort study in adults with severe primary hypothyroidism (serum thyrotropin [TSH] > 50 µIU/mL). Individuals with preexisting or past kidney disease, kidney or urinary tract abnormalities, calculi or surgery, diabetes mellitus, or hypertension were excluded. The participants received thyroid hormone replacement therapy. Thyroid functions, eGFR, 24-hour urine protein excretion, and biochemical parameters were measured at baseline and 3 months. SETTING: This study took place at a single center, a tertiary care referral and teaching hospital. RESULTS: Of 44 enrolled participants, 43 completed 3 months of follow-up. At 3 months, serum TSH levels decreased and thyroxine levels increased (P < .001 for both). Significant increases in eGFR (mean difference, 18.25 ± 19.49 mL/min/1.73 m2; 95% CI, 12.25 to 24.25, P < .001) and declines in 24-hour urine protein excretion (mean difference, -68.39 ± 125.89 mg/day; 95% CI, -107.14 to -29.65, P = .001) were observed. Serum cholesterol and low-density lipoprotein levels also significantly decreased (P < .001). CONCLUSIONS: Thyroid hormone replacement therapy in patients with severe primary hypothyroidism improves eGFR and decreases 24-hour urine protein excretion, thereby suggesting reversible alterations.

Fetal Hypothyroidism Impairs Aortic Vasorelaxation Responses in Adulthood: Involvement of Hydrogen Sulfide and Nitric Oxide Cross talk.

ABSTRACT: Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.

Exposure to the Chinese Great Famine in Early Life and Thyroid Function and Disorders in Adulthood: A Cross-Sectional Study.

Background: Malnutrition in early life may permanently change the structure and function of the body, which lead to a number of diseases in adulthood. The effect of famine exposure during the early life on thyroid function and disorders remains unclear. This study investigated the association between exposure to the Great Chinese Famine (1959-1961) in early life and thyroid function and disorders in adulthood. Methods: Nine thousand eight hundred eighty-one subjects with appropriate birth dates derived from the Thyroid disorders, Iodine status, and Diabetes Epidemiological survey were included. Thyroid function and disorders were defined by the test results of blood sample and ultrasonography of all participants. Associations between famine exposure in early life and thyroid function and disorders in adulthood were assessed with binary logistic regression and linear regression. Results: Participants exposed to the Great Chinese Famine during the fetal stage was associated with a higher thyrotropin (TSH) level in adulthood (ß = 0.024; p = 0.038), compared with the nonexposed participants. The association was significant among rural participants (ß = 0.039; p = 0.02) but not in urban participants (ß = 0.005; p = 0.77). Fetal-exposed group did not show a higher risk of thyroid disorders than the age-matched balanced control group, including overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and thyroid nodules (p > 0.05). Conclusions: Famine exposure during the fetal stage was associated with a higher TSH level in adulthood. The fetal stage could be the critical period for programming the pituitary-thyroid axis.

Neuroendocrine Dysfunction in the Acute Setting of Penetrating Brain Injury: A Systematic Review.

BACKGROUND: Data on neuroendocrine dysfunction (NED) in the acute setting of penetrating brain injury (PBI) are scarce, and the clinical approach to diagnosis and treatment remains extrapolated from the literature on blunt head trauma. METHODS: Three databases were searched (PubMed, Scopus, and Cochrane). Risk of bias was computed using the Newcastle-Ottawa Scale, or the methodological quality of case series and case reports, as indicated. This systematic review was registered in PROSPERO (42020172163). RESULTS: Six relevant studies involving 58 patients with PBI were included. Two studies were prospective cohort analyses, whereas 4 were case reports. The onset of NED was acute in all studies, by the first postinjury day. Risk factors for NED included worse injury severity and the presence of cerebral edema on imaging. Dysfunction of the anterior hypophysis involved the hypothalamic-pituitary-thyroid axis, treated with hormonal replacement, and hypocortisolism, treated with hydrocortisone. The prevalence of central diabetes insipidus was up to 41%. Most patients showed persistent NED months after injury. In separate reports, diabetes insipidus and hypocortisolism showed an association with higher mortality. The available literature for this review is poor, and the studies included had overall low quality with high risk of bias. CONCLUSIONS: NED seems to be prevalent in the acute phase of PBI, equally involving both anterior and posterior hypophysis. Despite a potential association between NED and mortality, data on the optimal management of NED are limited. This situation defines the need for prospective studies to better characterize the clinical features and optimal therapeutic interventions for NED in PBI.