Correlation between maternal thyroid stimulating hormone and birth weight of neonate

Background: The aim of this study is to determine the pregnancy outcomes in women with thyroid disorders.Methods: This is a retrospective observational study conducted in the department of obstetrics and gynaecology of AJ institute of medical sciences and research centre from the month of March to September 2021. The first trimester thyroid stimulating hormone (TSH) level and birth weight of new born is collected from hospital records, study participants included all the pregnant mothers who were admitted and delivered in the labour ward of AJ institute of medical sciencesResults: According to our study low birth weight in neonates in euthyroid, hypothyroid, hyperthyroid participants were 21.4%, 61.5%, and 100% respectively.Conclusions: This study indicates that there is an association between maternal thyroid levels and neonatal birth weight. A higher TSH concentration during first trimester of pregnancy is associated with low birth weight. Based on these findings, it is recommended that maternal thyroid levels be monitored closely in the first trimester and initiate timely treatment in case of altered thyroid levels during pregnancy in order to have a healthy pregnancy and healthy baby with no compromise in the fetal weight.

Urinary Phthalate Metabolites in Pregnant Women: Occurrences, Predictors, and Association with Maternal Hormones

Phthalate have been detected in human urine and may cause endocrine disruption. However, research on the prediction of exposure and the association with thyroid hormones during gestation is limited. We recruited 463 pregnant women and collected urine and blood samples, and questionnaire data at initial maternity examination. We analyzed ten phthalate metabolites: mono-isobutyl phthalate (MiBP), mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-n-octyl phthalate (MOP), mono-benzyl phthalate (MBzP), as well as metabolite of di-2-ethylhexyl phthalate (DEHP): mono (2-ethylhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-carboxypentyl) phthalate. Multivariable generalized estimating equation models and liner mixed models were used to predict urinary biomarker concentrations and assessed associations between phthalate exposure and thyroid hormones. We observed negative associations between phthalate metabolites and old age (MMP, MnBP), and physical activity (MiBP, MOP). Positive associations with lower education (MEP, MOP), living near the road (MEP, MnBP, ∑DEHP), living space (MiBP, MnBP, ∑DEHP), consuming more puffed food (MEP, MBzP), and take-out food (MEP, MnBP,∑DEHP). MnBP (percent change [%△] = 4.25; 95% CI = 0.32, 8.18) and ∑DEHP (%△=5.12; 95% CI = 1.25, 8.99) were positively associated with thyroid stimulating hormone, and this suggested MEP and MnBP were inversely associated with free thyroxine (%△=-1.26; 95% CI=-2.34, -0.18) and total triiodothyronin (%△=-2.62; 95% CI=-3.17, -2.07). Our findings suggest that lower consumption of puffed food, cosmetics use and moderate physical activity were predictive of lower phthalate biomarker concentration. Certain phthalate esters are associated with altered thyroid hormone levels.

Thyroid Hormones—An Underestimated Player in Dilated Cardiomyopathy?

Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy, typified by left ventricular dilation and systolic dysfunction. Many patients with DCM have altered thyroid status, especially lower levels of free triiodothyronine (T3) and elevated levels of thyroid-stimulating hormone. Moreover, growing evidence indicates that even subtle changes in thyroid status (especially low T3) are linked with a worse long-term prognosis and a higher risk of mortality. Notably, recent discoveries have shown that not only local myocardial thyroid hormones (THs) bioavailability could be diminished due to impaired expression of the activating deiodinase, but virtually all genes involved in TH biosynthesis are also expressed in the myocardium of DCM patients. Importantly, some studies have suggested beneficial effects of TH therapy in patients suffering from DCM. Our aim was to discuss new insights into the association between TH status and prognosis in DCM, abnormal expression of genes involved in the myocardial synthesis of TH in DCM, and the potential for TH use in the future treatment of DCM.

Alteration of Thyroid Hormone among Patients with Ischemic Stroke visiting a Tertiary Care Hospital: A Descriptive Cross-sectional Study

Introduction: Stroke is broadly classified as cerebral infarction, intracerebral hemorrhage and subarachnoid hemorrhage. Neuroendocrine profile is altered in acute ischemic stroke and there is a link between hypothyroidism and atherosclerosis which in turn may lead to stroke. The objective of this study was to find out the prevalence of alteration of thyroid hormones in patients with ischemic stroke in a tertiary care center. Methods: This descriptive cross-sectional study was conducted from June to December 2019 in a tertiary care center. Ethical approval was taken from Institutional review board of National Academy of Medical Sciences (reference number: IM 175). Patients with a diagnosis of stroke, without evidence of cardioembolic source, history of liver disease, renal failure and thyroid disease and who do not use thyroidal supplementation within 180 days prior the event were included. Convenience sampling was done. Data was entered in Microsoft Excel and analyzed using Statistical Package for the Social Sciences version 22. Point estimate at 90% Confidence Interval was calculated along with frequency and percentage for binary data. Results: The prevalence of altered thyroid levels among 73 patients was 13 (17.8%) (90% Confidence Interval= 10.44-25.16). Among them 11 (15.1%) were hypothyroid and 2 (2.7%) were hyperthyroid. Among severity of hypothyroid cases, subclinical hypothyroidism grade IA was seen in 51 (70%), subclinical hypothyroidism grade IB was seen in 22 (30%), Conclusions: The prevalence of altered thyroid levels among patients undergoing ischemic stroke was similar to the findings of other international studies.

Altered Thyroid Function amongst the Infertile Insulin Resistant Women with Polycystic Ovarian Syndrome

Background: Polycystic ovarian syndrome (PCOS) is a hormonal disorder common among women of the child-bearing age. Likewise, women with PCOS are more likely to be obese or overweight, which may be due to their higher Insulin resistance and TSH levels. Aim: The study's objectives were to assess the prevalence of subclinical hypothyroidism in infertile PCOS, distribution of insulin resistant in PCOS women with subclinical hypothyroidism, and the efficacy of Metformin treatment in these women. Methods: It was a single-center study which included all infertile patients who visited the Department of Obstetrics and Gynecology at a Karachi hospital between January 2019 and September 2019. The infertile PCOS patients were then divided into two groups: Group A (Insulin Resistant with Subclinical Hypothyroidism) and Group B. (Non-Insulin Resistant with Subclinical Hypothyroidism). Following the written consent, both the treatment groups received Metformin 500mg T.D. for three months. Results: The infertile PCOS patients showed a higher prevalence of subclinical hypothyroidism. Insulin resistance was found to be 63.3% among subclinical hypothyroid PCOS women. Finally, three months of Metformin treatment resulted in a significant reduction in TSH levels in Insulin resistant PCOS women. Conclusion: We identified a positive link between TSH levels and insulin resistance in PCOS women, both in terms of incidence and treatment.

The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice

Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.

Selpercatinib efficacy and safety in patients with RET-altered thyroid cancer: A clinical trial update.

6073 Background: Selpercatinib, is a first-in-class, highly selective, CNS active and potent RET inhibitor approved in multiple countries for treatment of RET-fusion positive lung or thyroid cancers. Reported is an update of efficacy and safety results in RET-altered thyroid cancer, with a longer follow up (30 Mar 2020 data cutoff vs 16 Dec 2019) and additional enrolment. Methods: Patients (pts) with RET-mutant medullary thyroid cancer (MTC) and RET-fusion positive thyroid cancer (TC) were enrolled in the global (16 countries, 89 sites) Phase 1/2 LIBRETTO-001 trial (NCT03157128). The primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. The integrated analysis set (IAS, n = 143) includes efficacy evaluable MTC pts previously treated with cabozantinib and/or vandetanib (cabo/vande). The primary analysis set (PAS), a subset of IAS, is the first 55 enrolled pts. Cabo/vande naïve MTC pts (N = 112) and TC pts with prior systemic treatment (N = 22) were also analyzed. Safety population includes all pts who received ≥1 dose of selpercatinib (MTC N = 315; TC N = 42) by data cutoff. Results: For MTC patients, the ORR for IAS was 69.2%, in the PAS it was 69.1%, and 71.4% for cabo/vande naïve MTC pts. The ORR for TC pts (n = 22) was 77.3% (see table). Most treatment-emergent adverse events (TEAEs) were low grade; the most common (≥25% of MTC and/or TC pts treated with selpercatinib) were dry mouth, diarrhea, hypertension, fatigue and constipation for both MTC and TC pts, increased ALT/AST, peripheral edema and headache in MTC pts and nausea in TC pts. 4.8% of MTC and TC pts discontinued selpercatinib due to TEAEs but only 1.9% with MTC and none with TC discontinued due to treatment-related adverse events. Conclusions: In this updated analysis, selpercatinib continued to show marked and durable antitumor activity in pts with RET-altered thyroid cancers. Selpercatinib was well tolerated and no new safety concerns were identified. A global, randomized, phase 3 trial (LIBRETTO-531) evaluating selpercatinib compared to cabo/vande in kinase inhibitor naïve MTC pts is ongoing. Clinical trial information: NCT03157128. [Table: see text]

Efficacy of selpercatinib after prior systemic therapy in patients with RET mutant medullary thyroid cancer.

6074 Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.