GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression.

Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.

Random Forest for Predicting Treatment Response to Radioiodine and Thyrotropin Suppression Therapy in Patients With Differentiated Thyroid Cancer But Without Structural Disease.

BACKGROUND: We aimed to develop a machine-learning model for predicting treatment response to radioiodine (131I) therapy and thyrotropin (TSH) suppression therapy in patients with differentiated thyroid cancer (DTC) but without structural disease, based on pre-treatment information. PATIENTS AND METHODS: Overall, 597 and 326 patients with DTC but without structural disease were randomly assigned to "training" cohorts for predicting treatment response to 131I therapy and TSH suppression therapy, respectively. Six supervised algorithms, including Logistic Regression, Support Vector Machine, Random Forest (RF), Neural Networks, Adaptive Boosting, and Gradient Boost, were used to predict effective response (ER) to 131I therapy and biochemical remission (BR) to TSH suppression therapy. RESULTS: Stimulated and suppressed thyroglobulin (Tg) and radioiodine uptake before the current course of 131I therapy were mostly attributed to ER to 131I therapy, while thyroid remnant available on the post-therapeutic whole-body scan at the last course of 131I therapy and TSH were greatly contributed to Tg decline under TSH suppression therapy. RF showed the best performance among all models. The accuracy and area under the receiver operating characteristic curve (AUC) for segregating ER from non-ER during 131I therapy with RF were 81.3% and 0.896, respectively. The accuracy and AUC for predicting BR to TSH suppression therapy with RF were 78.7% and 0.857, respectively. CONCLUSION: This study demonstrates that machine learning models, especially the RF algorithm are useful tools that may predict treatment response to 131I therapy and TSH suppression therapy in DTC patients without structural disease based on pre-treatment routine clinical variables and biochemical markers.

The saccus vasculosus of the neotropical cichlid fish Cichlasoma dimerus: characterization, developmental studies and its response to photoperiod.

The saccus vasculosus is an organ present in gnathostome fishes, located ventral to the hypothalamus and posterior to the pituitary gland, whose structure is highly variable among species. In some fishes, this organ is well-developed; however, its physiological function is still under debate. Recently, it has been proposed that this organ is a seasonal regulator of reproduction. In the present work, we examined the histology, ultrastructure, and development of the saccus vasculosus in Cichlasoma dimerus. In addition, immunohistochemical studies of proteins related to reproductive function were performed. Finally, the potential response of this organ to different photoperiods was explored. C. dimerus presented a well-developed saccus vasculosus consisting of a highly folded epithelium, composed of coronet and supporting cells, closely associated with blood vessels, and a highly branched lumen connected to the third ventricle. Coronet cells showed all the major characteristics described in other fish species. In addition, some of the vesicles of the globules were positive for thyrotropin beta subunit, while luteinizing hormone beta subunit immunostaining was observed at the edge of the apical processes of some coronet cells. Furthermore, neuropeptide Y and gonadotropin inhibitory hormone innervation in the saccus vasculosus of C. dimerus were shown. Finally, animals exposed to the long photoperiod showed lower levels of thyrotropin beta and common alpha subunits expression in the saccus compared to those of animals exposed to short photoperiod. All these results support the hypothesis that the saccus vasculosus is involved in the regulation of reproductive function in fish.

Screening for Delayed Thyroid Stimulation Hormone Rise and Atypical Congenital Hypothyroidism in Infants Born Very Preterm and Infants with Very Low Birth Weight.

OBJECTIVE: To determine among infants born very preterm (VPT) or with very low birth weight (VLBW) the incidence of alterations in thyroid function and associated comorbidities; the incidence of atypical congenital hypothyroidism (CH) requiring thyroxine therapy; and reference ranges for rescreening at 1 month of age. STUDY DESIGN: A retrospective review of infants born VPT or with VLBW and admitted to UC Irvine Medical Center between January 1, 2012, and December 31, 2020. Repeat thyroid screening was obtained at 1 month of life (+10 days). Infants with thyroid-stimulating hormone (TSH) >5 µIU/mL or free thyroxine <0.8 ng/dL underwent follow-up testing and endocrinology consultation. Initial newborn screening (NBS) and repeat thyroid screening data were collected via chart review. Demographic data and short-term outcomes were abstracted from the California Perinatal Quality Care Collaborative database. RESULTS: In total, 430 patients were included; 64 of 429 patients (14.9%) had TSH >5 µIU/mL and 20 of 421 patients (4.8%) had free thyroxine <0.8 ng/dL. Logistic regression analysis identified small for gestational age (P = .044), patent ductus arteriosus (P = .013), and late-onset sepsis (P = .026) as risk factors associated with delayed TSH rise. Atypical CH requiring treatment through neonatal intensive care unit discharge was diagnosed in 6 patients (incidence of 1.4%); none were identified by NBS. The 90th percentile TSH for infants with extremely low birth weight (<1000 g) was 7.2 µIU/mL, and the 95th percentile for those with birth weight of 1000-1500 g was 6.1 µIU/mL; using these cutoff values identified all infants diagnosed with atypical CH with 100% sensitivity and 90%-95% specificity. CONCLUSIONS: Abnormal thyroid function is common in infants born preterm. Those infants, including some with atypical CH, are missed by NBS. We recommend repeat thyroid screening with TSH at 1 month of age in infants born VPT or infants with VLBW to identify CH that may require therapy.

ZmELF3.1 integrates the RA2-TSH4 module to repress maize tassel branching.

Tassel branch number (TBN) is a key agronomic trait for adapting to high-density planting and grain yield in maize. However, the molecular regulatory mechanisms underlying tassel branching are still largely unknown. Here, we used molecular and genetic studies together to show that ZmELF3.1 plays a critical role in regulating TBN in maize. Previous studies showed that ZmELF3.1 forms the evening complex through interacting with ZmELF4 and ZmLUX to regulate flowering in maize and that RA2 and TSH4 (ZmSBP2) suppresses and promotes TBN in maize, respectively. In this study, we show that loss-of-function mutants of ZmELF3.1 exhibit a significant increase of TBN. We also show that RA2 directly binds to the promoter of TSH4 and represses its expression, thus leading to reduced TBN. We further demonstrate that ZmELF3.1 directly interacts with both RA2 and ZmELF4.2 to form tri-protein complexes that further enhance the binding of RA2 to the promoter of TSH4, leading to suppressed TSH4 expression and consequently decreased TBN. Our combined results establish a novel functional link between the ELF3-ELF4-RA2 complex and miR156-SPL regulatory module in regulating tassel branching and provide a valuable target for genetic improvement of tassel branching in maize.

Current utility of first-line FT4 and TSH in screening for central hypothyroidism.

BACKGROUND: Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking. OBJECTIVES: We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice. DESIGN, PATIENTS, AND MEASUREMENTS: The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism. RESULTS: The incidence of low-FT4 varied according to FT4 assay method (range: 98-301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%-4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates. CONCLUSIONS: Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities.

Agreement between routinely used immunoassays for thyroid function testing in non-pregnant and pregnant adults.

OBJECTIVE: Thyroid function tests are common biochemical analyses, and agreement between the routinely used immunoassays is important for diagnosis and monitoring of thyroid disease. Efforts are continuously made to align the biochemical assays, and we aimed to evaluate the agreement between immunoassays used in a clinical laboratory setting among non-pregnant and pregnant adults. DESIGN: Cross-sectional study. PARTICIPANTS: Serum samples were obtained from 192 blood donors (non-pregnant adults) and from 86 pregnant women in the North Denmark Region with no known thyroid disease. MEASUREMENTS: Each sample was used for measurement of thyroid-stimulating hormone (TSH) with the routinely used automatic immunoassays in the regional Departments of Clinical Biochemistry (Alinity, Abbott Laboratories, Cobas, Roche Diagnostics, and Atellica, Siemens Healthineers) and reported as the median with 95% confidence interval (95% CI). RESULTS: In nonpregnant adults, the level of TSH was higher with Cobas and Atellica than with Alinity as reflected by median (Alinity: 1.39 mIU/L (95% CI: 1.30-1.51 mIU/L); Cobas: 1.57 mIU/L (95% CI: 1.48-1.75 mIU/L); Atellica: 1.74 mIU/L (95% CI: 1.61-1.83 mIU/L)). Similarly, a trend was seen towards higher median TSH with Cobas than with Alinity among pregnant women (Alinity: 1.90 mIU/L (95% CI: 1.37-2.82 mIU/L); Cobas: 2.33 mIU/L (95% CI: 1.69-3.62 mIU/L)). CONCLUSION: Results of thyroid function tests obtained with different immunoassays were not interchangeable when evaluated among pregnant and non-pregnant adults. The distinct differences are relevant for clinical decision making and emphasize the necessity of clinical laboratory information when different assays are used for diagnosis and monitoring of patients with thyroid disease.

Subclinical central hypothyroidism in patients with hypothalamic-pituitary disease: does it exist?

Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.

Neural thyroid hormone metabolism integrates seasonal changes in environmental temperature with the neuroendocrine reproductive axis.

We asked if environmental temperature alters thyroid hormone metabolism within the hypothalamus, thereby providing a neuroendocrine mechanism by which temperature could be integrated with photoperiod to regulate seasonal rhythms. We used immunohistochemistry to assess the effects of low-temperature winter dormancy at 4 °C or 12 °C on thyroid-stimulating hormone (TSH) within the infundibulum of the pituitary as well as deiodinase 2 (Dio2) and 3 (Dio3) within the hypothalamus of red-sided garter snakes (Thamnophis sirtalis). Both the duration and, in males, magnitude of low-temperature dormancy altered deiodinase immunoreactivity within the hypothalamus, increasing the area of Dio2-immunoreactivity in males and females and decreasing the number of Dio3-immunoreactive cells in males after 8-16 weeks. Reciprocal changes in Dio2/3 favor the accumulation of triiodothyronine within the hypothalamus. Whether TSH mediates these effects requires further study, as significant changes in TSH-immunoreactive cell number were not observed. Temporal changes in deiodinase immunoreactivity coincided with an increase in the proportion of males exhibiting courtship behavior as well as changes in the temporal pattern of courtship behavior after emergence. Our findings mirror those of previous studies, in which males require low-temperature exposure for at least 8 weeks before significant changes in gonadotropin-releasing hormone immunoreactivity and sex steroid hormones are observed. Collectively, these data provide evidence that the neuroendocrine pathway regulating the reproductive axis via thyroid hormone metabolism is capable of transducing temperature information. Because all vertebrates can potentially use temperature as a supplementary cue, these results are broadly applicable to understanding how environment-organism interactions mediate seasonally adaptive responses.

Serum levels of glucose, thyroid stimulating hormone, and free thyroxine in boys diagnosed with attention deficit hyperactivity disorder: a cross-sectional pilot study.

BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, its aetiology remains unclear. We aimed to establish a relationship between ADHD diagnosis and serum levels of glucose, free thyroxine (FT4), and thyroid stimulating hormone (TSH) in primary school aged boys. METHODS: In a cross-sectional study, we enrolled 133 participants aged 6.5-12.5 years, 67 of whom met DSM-5 criteria for ADHD and 66 healthy age-matched boys. The ADHDT test (ADHDT) was used to assess ADHD symptoms and the Wechsler Intelligence Scale for Children - Revised was used to exclude participants with cognitive deficits. The ADHD participants were tested using the Iowa Conners' Teacher Rating Scale. RESULTS: The ADHD participants had lower glucose levels, higher TSH values, and significantly lower FT4 values than the control group. The multiple logistic regression analysis showed that TSH is a parameter that is 2.7% more likely to occur in the ADHD group. We found a significant correlation between the TSH level and the symptoms of hyperactivity (r = 0.318, p = 0.009) and impulsivity (r = 0.275, p = 0.024) as well as between the glucose level and the symptoms of hyperactivity (r = 0.312, p = 0.010). CONCLUSIONS: Certain ADHD symptoms may correlate with certain hormonal patterns. Our results suggest that the likelihood of suffering from ADHD was lower when FT4 levels were elevated. One biochemical parameter that was significantly and independently associated with the diagnosis of ADHD was the serum TSH level. TRIAL REGISTRATION: On June 26, 2018, at its VI session in 2018, the Ethics Committee of the Institute for Mental Health in Belgrade, Serbia, has considered and unanimously approved the conduct of the research, under the number 1704/1.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Effects of laparoscopic sleeve gastrectomy on thyroid hormones and relationship between metabolic parameters and long-term total weight loss.

BACKGROUND: Bariatric surgery has significant effects on metabolic parameters and hormone levels. However, the specific impact of laparoscopic sleeve gastrectomy (LSG) on thyroid hormones and other metabolic parameters remains unclear. This study aimed to investigate the short and long-term effects of LSG on thyroid hormone levels, HbA1c, and other metabolic parameters. METHODS: A total of 619 euthyroid patients without a history of thyroid disease or thyroid hormone replacement therapy were included in the study. Patients with diabetes were excluded from the study. Preoperative, 1-year postoperative, and 5-year postoperative levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), HbA1c, and other metabolic parameters were recorded and analyzed. RESULTS: LSG resulted in significant weight loss and improvements in metabolic parameters. At 1 year postoperatively, there were significant reductions in BMI, HbA1c, TSH, fT3, and triglyceride levels, while fT4 levels increased. A statistically significant negative correlation was found between preoperative HbA1c level and percentage of total weight loss (%TWL) value at the fifth postoperative year. Additionally, a statistically significant negative correlation was found between the 5-year change in TSH and %TWL. CONCLUSION: Being the first study to predict long-term total weight loss based on preoperative HbA1c, it is significant. This finding has important implications for personalized patient management and could aid clinicians in identifying individuals who may benefit most from sleeve gastrectomy as a treatment modality. This is valuable in that it emphasizes multidisciplinary work, including the endocrinologist and dietician.

Elevated thyroid stimulating hormone and metabolic syndrome risk in patients with first-episode and drug-naïve major depressive disorder: a large-scale cross-sectional study.

BACKGROUND: Metabolic syndrome (MetS) is common in major depressive disorder (MDD), but its relationship with thyroid hormones remains unclear. We aimed to examine the association of thyroid hormones and MetS in first-episode drug-naïve (FEDN) MDD patients. METHODS: We recruited 1718 unmedicated MDD patients in this cross-sectional study. MetS was defined based on the 2004 Chinese Diabetes Society Criteria. Serum thyroid hormones including free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies (TPOAb), and anti-thyroglobulin (TGAb) were examined. We used the logistic regression model to determine risk factors for MetS and examined the performance of the regression model by using the Area Under the Curve (AUC). In addition, we performed the trend test to test whether the results were robust. RESULTS: The prevalence of MetS in unmedicated MDD patients was 34.4%. MDD patients with MetS had higher levels of serum TSH, TGAb, and TPOAb (all P < 0.001). Concurrently, serum TSH levels were independent risk factors for MetS in MDD patients (OR:1.49, 95%CI: 1.40-1.58), which could also distinguish MDD patients with and without MetS (AUC was 0.77). Additionally, in the trend test, the results also indicated a similar trend when TSH was used as a categorical variable (P for trend < 0.001). CONCLUSIONS: This study suggests that TSH levels were independent risk factors for MetS in FEDN MDD patients (OR:1.49). The examination of thyroid function may contribute to the early detection of MetS.

Non-linear relationship between TSH and psychotic symptoms on first episode and drug naïve major depressive disorder patients: a large sample sized cross-sectional study in China.

INTRODUCTION: Psychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical outcomes. TSH may involve in the development of PD. This study aims to explore relationship between TSH and PD. METHODS: A total of 1718 outpatients diagnosed as FEDN MDD were recruited in this study. The relationship between PD and TSH was evaluated using multivariable binary logistic regression analysis. To assess the presence of non-linear associations, a two-piecewise linear regression model was employed. Furthermore, interaction and stratified analyses were conducted with respect to sex, education, marital status, comorbid anxiety, and suicide attempt. RESULTS: Multivariable logistic regression analysis revealed that TSH was positively associated with the risk of PD after adjusting for confounders (OR = 1.26, 95% CI: 1.11 to 1.43; p < 0.05). Smoothing plots showed a nonlinear relationship between TSH and PD, with the inflection point of TSH being 4.94 mIU/L. On the right of the inflection point, for each unit increase in serum TSH level on the right side of the inflection point, the probability of PD increased substantially by 47% (OR = 1.47, 95% CI: 1.25 to 1.73, p < 0.001), while no significant association was observed on the left side of the inflection point (OR = 0.87, 95% CI: 0.67 to 1.14, p = 0.32). CONCLUSION: Our investigation showed a nonlinear TSH-PD relationship in FEDN MDD patients, thus contributing to effective intervention strategies for psychotic symptoms in depression patients.

Elevated TSH Levels: A Database Study of General Practitioners' Course of Action.

OBJECTIVE: To investigate general practitioners' course of action after detection of elevated thyroid stimulating hormone (TSH) levels regarding repeat testing, direct levothyroxine replacement, or neither. METHODS: We conducted a retrospective study of adults without prior evidence of thyroid disease and with a first detection of elevated TSH levels from January 1, 2015, to December 31, 2020, using data from electronic medical records of a Swiss primary care database. We determined the occurrence of either repeat TSH testing or direct levothyroxine initiation in primary care during 12-month follow-up and determined associations with demographic and clinical factors. RESULTS: Of the 1 591 patients included (median age 65 years, 64.4% female, median TSH 5.7 mIU/L), 34.3% received repeat TSH testing and 12.4% received direct levothyroxine replacement in primary care during follow-up. Repeat TSH testing showed the strongest association with overt hypothyroidism and was more common among patients with high primary care utilization and among patients aged 40-64 years compared to patients aged <40 years. Direct levothyroxine initiation was more likely for TSH levels >7 mIU/L, overt hypothyroidism, female patients, and nonurban practices. CONCLUSIONS: While the degree of thyroid dysfunction was the main driver of follow-up, we identified important gaps in the primary care-based monitoring of elevated TSH levels in young patients and in patients with infrequent consultations. We also observed potential overtreatment of women and patients in nonurban areas. Our findings highlight the need for standardization and dissemination of guidelines for the management of elevated TSH levels among general practitioners.

Effect of Thyroid-Stimulating Hormone Suppression Therapy on Cardiac Structure and Function in Patients With Differentiated Thyroid Cancer After Thyroidectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppression therapy on cardiac structure and function in patients with differentiated thyroid cancer (DTC) following thyroidectomy. METHODS: Two investigators independently searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published from inception to January 6, 2023, without any restrictions on language. Standard mean differences and 95% confidence intervals were calculated using fixed or random effects models. Thirteen clinical outcomes were analyzed, mainly evaluating cardiac morphology, systolic function, and diastolic function. RESULTS: Thirteen studies were included in the quantitative analysis. Compared to healthy controls, left ventricular mass index, left ventricular posterior wall thickness, interventricular septal thickness, and isovolumic relaxation time values increased; the ratio of E-wave velocity to A-wave velocity and E-wave velocity values decreased. The left ventricular ejection fraction and cardiac output did not change in patients with DTC who underwent long-term TSH suppression therapy. Interventricular septal thickness values were significantly correlated with the duration of TSH suppression therapy. CONCLUSION: Long-term TSH suppression therapy leads to cardiac hypertrophy and impaired cardiac diastolic function in patients with DTC. These changes may be related to the duration of TSH suppression therapy. Large prospective studies with long follow-up periods are needed to validate these findings.

Clinical Characteristics and Management of Cosecreting Thyroid Stimulating Hormone or Prolactin Pituitary Growth Hormone Adenomas: A Case-Control Study.

OBJECTIVE: Cosecreting thyroid stimulating hormone (TSH) or prolactin (PRL) in patients with pituitary growth hormone (GH) adenomas has been rarely reported. Our study aimed to elucidate their clinical characteristics. METHODS: We retrospectively collected data of 22 cases of cosecreting GH and TSH pituitary adenomas [(GH+TSH)oma] and 10 cases of cosecreting GH and PRL pituitary adenomas [(GH+PRL)oma] from Beijing Tiantan Hospital, Capital Medical University between January 2009 and January 2023. The clinical manifestation, preoperative hormone levels, imaging features, pathologic characteristics, and biochemical remission rates were compared among 335 patients with solo-secreting GH adenomas (GHoma) and 49 patients with solo-secreting TSH adenoma (TSHoma). Patients with (GH+TSH)oma and (GH+PRL)oma were grouped according to biochemical remission to explore the risk factors leading to biochemical nonremission. RESULTS: Cosecreting pituitary GH adenomas had various clinical manifestations and a larger tumor volume and were more likely to invade the cavernous sinus bilaterally and compress the optic chiasm. GH and TSH levels were lower in (GH+TSH)oma than in GHoma or TSHoma. Solo part remission was observed both in (GH+TSH)oma and (GH+PRL)oma. Cavernous sinus invasion was an independent risk factor for biochemical nonremission in patients with (GH+TSH)oma and (GH+PRL)oma. CONCLUSIONS: The clinical manifestation of (GH+TSH)oma and (GH+PRL)oma may be atypical. When screening for pituitary adenomas, a comprehensive evaluation of all pituitary target gland hormones is needed. Cosecreting pituitary GH adenomas are more aggressive and surgery is often unable to completely remove the tumor, requiring pharmacologic or radiological treatment if necessary. Clinicians should give high priority to biochemical remission, although solo part remission may occur.

Role of thyroid stimulating hormone in the maintenance and functioning of the human corpus luteum.

PURPOSE: To evaluate the impact of high thyroid stimulating hormone (TSH) levels on human granulosa-luteal (hGL) cells. METHODS: hGL cells were isolated from follicular aspirates derived from patients undergoing IVF treatment without any thyroid disorder (serum TSH 0.5-2 mU/L). Cells were cultured at 37 °C in DMEM, supplemented with 5% FBS. The cells were treated with 1 nM LH and increasing concentrations of TSH. At the end of culture, conditioned medium and cells were collected to analyze progesterone production, cell viability, and mRNA levels of genes involved in the steroidogenesis process. Human ovarian tissues were analyzed for TSH receptor (TSHR) expression by IHC. RESULTS: The expression of TSHR was detected in human corpus luteum by IHC and in hGL by RT-PCR. In hGL cells, TSH treatment did not modulate progesterone production nor the expression of steroidogenic genes, such as p450scc and HSD3b 1/2. However, TSH induced a dose-dependent increase in cell death. Finally, TSH did not affect LH-induced p450scc and HSD3b1/2 expression while LH partially reverted TSH negative effect on cell death in hGL. CONCLUSIONS: Elevated TSH levels in hypothyroid women may be associated with impaired CL functioning and maintenance. These findings open a new line of research for the importance of the treatment of women with thyroid dysfunction that could contribute to the onset of infertility.

Prognostic implications of thyroid disease in patients with atrial fibrillation.

Atrial fibrillation (AF) is often accompanied by thyroid disease (THD). This study aimed to explore the relationship between THD and the occurrence of significant clinical outcomes in patients with AF. This post hoc analysis utilized data from the MISOAC-AF trial (NCT02941978), which enrolled hospitalized patients with AF. Patients were categorized based on their THD history into hyperthyroidism, hypothyroidism, or euthyroidism. Cox regression models were employed to calculate unadjusted and adjusted hazard ratios (aHRs). The primary outcomes of interest included all-cause mortality, cardiovascular death, and hospitalizations during the follow-up period. The study included 496 AF patients (mean age 73.09 ± 11.10 years) with available THD data, who were followed-up for a median duration of 31 months. Among them, 16 patients (3.2%) had hyperthyroidism, 141 (28.4%) had hypothyroidism, and 339 (68.4%) had no thyroid disease. Patients with hypothyroidism exhibited higher rates of hospitalization during follow-up (aHR: 1.57, 95% CI 1.12 to 2.20, p = 0.025) compared to the euthyroid group. Elevated levels of thyroid-stimulating hormone (TSH) were correlated with an increased risk of cardiovascular mortality (aHR: 1.03, 95% CI 1.01 to 1.05, p = 0.007) and hospitalizations (aHR: 1.06, 95% CI 1.01 to 1.12, p = 0.03). Conversely, lower levels of triiodothyronine (T3) were associated with higher risks of all-cause mortality (aHR: 0.51, 95% CI 0.31 to 0.82, p = 0.006) and cardiovascular mortality (aHR: 0.42, 95% CI 0.23 to 0.77, p = 0.005). Among patients with AF, hypothyroidism was associated with increased hospitalizations. Furthermore, elevated TSH levels and decreased T3 levels were linked to higher cardiovascular and all-cause mortality risks, respectively.

Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.