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Thyroid peroxidase antibodies may increase the risk of miscarriage and preterm birth. In this controlled trial, the use of levothyroxine before conception and through birth did not improve live-birth rates among euthyroid women with such antibodies and a history of miscarriage or infertility.

A double-blind, randomized, placebo-controlled, parallel-group trial aimed to determine whether levothyroxine provided clinical benefits in older persons with subclinical hypothyroidism. No apparent benefits were observed. Subclinical hypothyroidism is defined as an elevated serum thyrotropin level and a serum free thyroxine level within the reference range. 1 Between 8% and 18% of adults 65 years of age or older have these biochemical features, and the prevalence is higher among women than among men. 2 Subclinical hypothyroidism is a possible contributor to many problems in older persons. Thyroid hormones have multiple effects, since they act as an essential regulatory factor in numerous physiological systems, including the vascular tree and the heart, 3 the brain (including cognition), 4 skeletal muscle, and bone. 5 Tiredness is the most important symptom of overt hypothyroidism, 6 but . . .

Two placebo-controlled trials involving pregnant women with subclinical hypothyroidism or hypothyroxinemia showed that levothyroxine beginning between 8 and 20 weeks of gestation did not significantly improve cognitive outcomes in children through 5 years of age. Observational studies spanning almost three decades suggest that subclinical thyroid disease during pregnancy is associated with adverse outcomes. 1 – 5 In 1999, interest in undiagnosed maternal thyroid dysfunction was heightened by studies suggesting an association between subclinical thyroid hypofunction and impaired fetal neuropsychological development. 6 , 7 In one report, children of women whose serum thyrotropin levels during pregnancy were greater than the 98th percentile had a lower IQ than children of matched controls who had a normal thyrotropin level. 6 In another study, children whose mothers had a serum free thyroxine (T 4 ) level of less than the 10th percentile in early . . .

Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.

In this randomized trial, antenatal screening (at a median gestational age of 12 weeks 3 days) and treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. Active secretion of thyroid hormone in the fetus does not start until about 18 to 20 weeks' gestation. 1 Studies in animals suggest that until fetal hormone secretion begins, the fetus is dependent on circulating free thyroxine (T 4 ) in the mother for growth and development, including central nervous system maturation. 1 Iodine is essential for free T 4 synthesis, and in iodine-deficient populations, an increase in cognitive performance has been observed after iodine supplementation before pregnancy. 2 – 4 High levels of thyrotropin in women during pregnancy have been associated with impaired cognitive development in their offspring. This finding suggests that antenatal . . .

Objective This multicenter, open-label, randomized controlled trial (RCT) aims to assess the efficacy and safety of levothyroxine monotherapy in lowering the risk of cardiovascular disease (CVD) in untreated older adults with subclinical hypothyroidism (SCH) who are diagnosed according to population-specific TSH reference values. Methods A total of 254 patients with SCH who meet the diagnostic criteria will be recruited, and the baseline clinical data of the patients will be collected. Then, a total of 127 patients will be randomly divided into each of the treatment and control groups, and the treatment group will receive daily levothyroxine doses (Merck Euthyrox® levothyroxine 50 mcg tablet). Specifically, 50 µg of levothyroxine per day will be administered to patients in the treatment group (or 25 µg to patients with a body weight < 50 kg) for at least 48 weeks to maintain thyroid-stimulating hormone (TSH) levels within the normal range. The participants in the control group will be subjected only to thyroid status evaluation, and the results will be recorded. The participants will complete five visits before and after the start of the trial, and differences in the change in carotid intima–media thickness (CIMT), maximum mean change in plaque burden, and changes in lipid profiles, bone mineral densities, and incidences of fatal and nonfatal cardiovascular events between the initial visit and the last follow-up visit will be evaluated via vascular ultrasound. Discussion We will explicitly address whether levothyroxine replacement therapy provides cardiovascular benefits for older adults with subclinical hypothyroidism. Clinical trial registration ClinicalTrials.gov, No. ChiCTR2400092634. Registered on 30 November 2024. Recruitment for this study began on December 1, 2024, and continues until at least until November 30, 2025.

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI:-0.717,-1.946; p = 2 × 10⁻⁵) SHBG and a 0.103 nmol/l lower (-0.051, V0.154; p = 9 × 10⁻⁵) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.

Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food/drug interactions, and patient adherence. XP‐8121 (levothyroxine for subcutaneous administration) is a ready‐to‐use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single‐center, 2‐part study aimed to characterize the PK and dose proportionality of XP‐8121 SC compared to 600 μg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP‐8121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open‐label, crossover, fixed‐sequence study (n = 30). Dose linearity was evaluated by escalating XP‐8121 SC doses up to 1200 μg. Part 2 was an open‐label, single‐period study (n = 30) evaluating PK characteristics of a single dose of XP‐8121 SC (1500 μg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline‐adjusted levothyroxine concentration increased rapidly in plasma (Tmax median: 3.1 h); absorption for all XP‐8121 SC doses was slower compared to 600 μg oral levothyroxine, and levels remained elevated for 4–5 days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP‐8121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUCss). Overall, these data for XP‐8121 provide adequate predictive performance to inform future phase 2 studies.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings. (1) Contrary to postulations that TTR and/or ALB are the major local T4 contributors, the three THBPs may unload comparable amounts of T4 in Liver , a rapidly perfused organ; however, their contributions in slowly perfused tissues follow the order of abundances of T4TBG, T4TTR, and T4ALB. The T3 amounts unloaded from or loaded onto THBPs in a tissue acting as a T3 sink or source respectively follow the order of abundance of T3TBG, T3ALB, and T3TTR regardless of perfusion rate. (2) Any THBP alone is sufficient to maintain spatially uniform TH tissue distributions. (3) The TH amounts unloaded by each THBP species are spatially dependent and nonlinear in a tissue, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end. (4) Spatial gradients of TH transporters and metabolic enzymes may modulate these contributions, producing spatially invariant or heterogeneous TH tissue concentrations depending on whether the blood-tissue TH exchange operates in near-equilibrium mode. In summary, our modeling provides novel insights into the differential roles of THBPs in local TH tissue distribution.

Background There are emerging controversies regarding the priority of T4 + T3 combination therapy over standard care with levothyroxine (LT4) monotherapy in the management of hypothyroid subjects. Combination therapy with a slow-release form of liothyronine (SRT3) and levothyroxine may restore T3 concentrations and provide better outcomes, especially in individuals with persistent complaints despite having normal serum TSH levels. Methods One hundred patients aged ≥ 20 years with hypothyroidism who have achieved and maintained euthyroidism under LT4 monotherapy for at least 3 months will be randomized into two groups of LT4 + SRT3 combined therapy (75 µg LT4 + 25 µg SRT3) and LT4 monotherapy for 48 weeks. Participants will be evaluated at baseline and three subsequent follow-ups, 12, 24, and 48 weeks after treatment allocation. Before and after the intervention, body weight, heart rate, blood pressure, ECG, quality of life (by ThyPRO-39 and SF-12), resting energy expenditure, and body composition will be evaluated. Also, serum TSH, total T3, total T4, free T4, free T3, total cholesterol, LDL, HDL, triglycerides, fasting blood sugar (FBS), insulin, HbA1C, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), sex hormone-binding globulin (SHBG), enolase, lactate dehydrogenase (LDH), creatin kinase (CK), ferritin, and metabolomics will be assessed at baseline and compared with their corresponding values at 24 and 48 weeks. Epigenetic-related markers will be measured and compared between the responders and non-responders. Conclusion It is expected that LT4 + SRT3 combined therapy more closely mimics the serum levels of T3, T4, and the T3/T4 ratio of euthyroid subjects than LT4 monotherapy, and improves health outcomes and quality of life, especially in hypothyroid patients with persistent symptoms under LT4 monotherapy. Genetic polymorphism sequencing may identify hypothyroid patients who are not responding well to levothyroxine alone. Trial registration  Trial ID: 44220 ID: IRCT20100922004794N12 IRCT ID: IRCT20100922004794N12 Registration date: 2020-02-27 Expected recruitment start date: 2024-10-06 Expected recruitment end date: 2025-10-23