Increase In Free T4 Research Articles

Thyroid Hormone Homeostasis in Levothyroxine-treated Patients: Findings From ELSA-Brasil.

The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. This work aimed to assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. The ELSA-Brasil study follows 15 105 adult Brazilians (aged 35-74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyrotropin (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. Initiation of therapy with LT4 resulted in an 11% to 19% decrease in TSH, an approximately 19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and antidiabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least 1 serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least 1 serum FT3 below the reference range (<0.23 ng/dL). The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.

OR14-06 Serum Thyroid Hormones Increase At The Onset Of Lactation And Promote Metabolic Pathways Required For Human Milk Synthesis

Abstract Disclosure: H. Rostom: None. X. Meng: None. R. Humphrey: None. A. Fry: None. T. Elajnaf: None. F. Hannan: None. An increase in mammary metabolism is critical for initiating lactation during postpartum days 1-4. We utilised clinical and cellular approaches to investigate whether thyroid hormones, which promote lactation in rodents, are involved in initiating human lactation and regulating mammary metabolism. We recruited n=35 healthy pregnant women intending to breastfeed following informed consent and measured serum thyroid hormones (TSH and free T4) at 36 weeks’ gestation and on postpartum days 1-4 (1). Serum TSH significantly increased at post-partum day 1 compared with 36 weeks’ gestation (2.5±0.3 vs. 1.6±0.1 mU/L, p=0.001). This early postpartum rise in TSH was followed by a significant increase in free T4 on post-partum days 3 and 4 (11.7±0.2 vs. 10.5±0.2pmol/L at 36 weeks’ gestation, p&amp;lt;0.01). We hypothesised that thyroid hormones increase mammary metabolism to promote breast milk production. Reverse transcription-quantitative PCR (RT-qPCR) of genes encoding deiodinase enzymes (DIO1-3), which regulate intracellular thyroid hormone activity, was undertaken in lactating human mammary epithelial cells (HMECs) isolated from breast milk. This showed that DIO1, which converts T4 to T3, was expressed in lactating HMECs, whereas DIO2 and DIO3 were not detected. Moreover, RT-qPCR of the thyroid hormone receptor alpha and beta (THRA and THRB) genes in lactating HMECs showed that THRB has ∼4-fold greater expression than THRA (p&amp;lt;0.05, n=4). THRB phosphorylates Akt, which is required for initiating lactation. Consistent with this, cultured HMECs stimulated with 10nM T3, the most potent thyroid hormone, for 15min showed an ∼2-fold increase in Akt phosphorylation (p&amp;lt;0.0001, n=4). Akt regulates oxidative phosphorylation, which we assessed by measuring oxygen consumption rate (OCR) and ATP synthesis. HMECs treated with 10nM T3 for ≤8hrs showed a 2-fold increase in OCR (p&amp;lt;0.05, n=4) without any change in cellular ATP. These findings suggested that T3 uncoupled mitochondrial respiration from ATP synthesis. In support of this, RT-qPCR of cultured HMECs stimulated with 10nM T3 showed increased expression of genes encoding uncoupling proteins 2 and 3 (≥2-fold, p&amp;lt;0.01, n=4), which also function to divert substrates away from mitochondrial catabolism; and &amp;gt;20-fold increased expression of PPARGC1A (p&amp;lt;0.0001, n=4), which promotes mitochondrial biogenesis. In summary, these findings demonstrate that serum TSH and free T4 are increased at the onset of lactation. Moreover, our cellular studies indicate that thyroid hormones promote mammary mitochondrial biogenesis and may divert substrates used for ATP generation towards the synthesis of breast milk. Reference: (1) Rostom, H. et al. Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study. BMJ Open 12, e062478. Presentation: Friday, June 16, 2023

Peculiarities of treatment of patients with comorbid pathology: chronic pancreatitis and hypothyroidism, taking into account SEPP1 gene polymorphism (RS7579)

Optimization of therapeutic regimens during the treatment of the polymorbid course of chronic pancreatitis combined with hypothyroidism is an important task of modern science.&#x0D; Aim: to treat patients with comorbid pathology: chronic pancreatitis and hypothyroidism, taking into account the polymorphism of the SEPP1 gene (RS7579)&#x0D; Materials and methods. During the research, we examined 128 people. Patients were divided into 3 groups. The first group included 48 patients with chronic pancreatitis, the second - 50 patients with chronic pancreatitis in combination with hypothyroidism, and the third - 30 practically healthy people.&#x0D; Results. Symptoms of maldigestion decreased in 72 % of the examined patients. Signs of nutritional deficiency have significantly decreased, and general well-being has improved. Multicomponent therapy also affected mood, sleep, and reduced irritability and symptoms of depression and anxiety disorders. A multisystemic polysyndromic approach to treatment led to improvements in both pancreatic and thyroid function. The effectiveness of the treatment strategy for patients with chronic pancreatitis was dependent on individual characteristics, such as the severity of chronic pancreatitis, the presence of primary hypothyroidism, the degree of selenium deficiency and concomitant symptoms, taking into account polymorphic variants of the SEPP1 (rs7579) gene. Selenoid deficiency decreased, especially in the group with a combination of chronic pancreatitis and hypothyroidism. The improvement in thyroid hormone activity included a 40.46 % decrease in blood TSH and a 2.5-fold increase in free T4.&#x0D; Conclusions. The program of complex therapy led to the normalization of the condition of patients with the G-allele genotype of the SEPP1 gene (rs7579), as evidenced by significant improvements in most of the analyzed indicators. The concentration of fecal elastase 1 and blood selenoprotein P significantly increased, and the level of serum pancreatic α-amylase significantly decreased in carriers of the AA genotype. Under the influence of therapy, there were also changes in the hormonal activity of the thyroid gland, a decrease in the concentration of total metabolites of NO, and an improvement in the health indicators of the cardiovascular system. However, for patients with the AA genotype of the SEPP1 (rs7579) gene, continuation of therapy remains important to achieve an optimal condition, in particular, to manage cholesterol levels and other cardiovascular risk factors

Sex, menopause, and age differences in the associations of persistent organic pollutants with thyroid hormones, thyroxine-binding globulin, and peripheral deiodinase activity: A cross-sectional study of the general Korean adult population

Persistent organic pollutants (POPs) can disrupt the thyroid hormone system in humans. We assessed the associations of several POPs with serum thyroid hormones (T3 and T4) and thyroid-stimulating hormone, and investigated the modulating effects of sex, menopausal status, and age on these associations, in a subgroup of the adult population (n = 1250) from the Korean National Environmental Health Survey. PCB105 and PCB118 were negatively associated with total T4 in premenopausal females and males aged <50, whereas the associations were insignificant in other groups. PCB180, p,p′-DDE, and p,p′-DDT showed positive associations with total T3 in postmenopausal females; however, among males aged ≥50, PCB118, PCB138, and p,p′-DDE showed negative associations with total T3. The effects of exposure to multiple POPs were examined in multi-factor analyses. Factor 2 comprised PCB52, hexachlorobenzene, and BDE-47 was associated with an increase in free T4 in premenopausal females (β = 0.015, p = 0.024), while Factor 1, which contained most POPs, was associated with a change in total T3 in postmenopausal females (β = 0.032, p = 0.040) and males aged ≥50 (β = −0.039, p = 0.023). Changes in total T4 or total T3 could be explained by differences in thyroxine-binding globulin (TBG) and peripheral deiodinase activity (GD). Negative associations of TBG with PCB105 in premenopausal females and PCB153 in males aged <50 may mediate the effect of decreasing total T4. PCB180, p,p′-DDE, p,p′-DDT, and Factor 1 were positively associated with GD, which is consistent with an increased total T3 in postmenopausal females. PCB118 was negatively associated with GD and total T3 in males aged ≥50. BDE-47 and β-hexachlorocyclohexane were associated with thyroid autoantibodies in premenopausal females and males aged <50. Our observations suggest that the thyroid-disrupting effects of POPs may differ by sex, sex hormonal status, and age, and may be mediated by TBG and GD.

Exposure to Multiple Per- and Polyfluoroalkyl Substances In Relation To Thyroid Function Among Adolescents and Young Adults from NHANES 2011-2012

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFASs) are persistent chemicals with a wide range of industrial applications, measured in human serum samples. Experimental studies have identified PFASs as endocrine disrupting chemicals and epidemiological studies suggest that PFASs can affect normal thyroid function in humans. We investigated the association between exposure to mixtures of serum PFASs and changes in serum thyroid hormone levels among 12 to 20 year olds. METHODS: Using data from the NHANES 2011-2012 cycle, we employed principal component analysis (PCA) and identified three factors, describing mixtures of PFASs. Using multivariable linear regression models, we estimated associations between exposure to PFAS mixtures and changes in serum thyroid hormone concentrations. RESULTS:Factor 1 was characterized by carboxylates, comprising of PFUnA, PFDA, and PFNA, Factor 2 was described by sulfonates which included PFHxS, PFOS, PFA, and MeFOSAA and Factor 3 was described PFHpA alone. Greater exposure to Factor 1 PFASs was associated with an overall increase in free T4, TSH, and thyroid peroxidase antibodies levels, without any statistical significance. Exposure to Factor 2 PFASs was associated with an overall decrease in free T3, total T3, free T4, and total T4 levels. Factor 3 resulted in an increase in most of the serum thyroid hormone levels with the exception of thyroglobulin and thyroglobulin antibodies levels. CONCLUSIONS:Our results suggest the importance of modeling the effects of exposure to a mixture of PFASs simultaneously. The findings of this analysis can better inform researchers and policy makes on which PFASs behave analogously or inversely in an effort to better assess the effect PFASs may have on health effects. KEYWORDS: biomarkers, chemical mixtures, endocrine disruptors, polyfluoroalkyl substances, thyroid function

Difficulties in Differential Diagnosis of Thyrotoxicosis: Clinical Case

Introduction: Thyrotoxicosis (T) develops as a result of persistent excess of thyroid hormones (TH). There are two groups of diseases that are fundamentally different in pathogenesis. The first group includes those in which the production of TH increases. Diseases of the second group are accompanied by T caused by destruction of the thyroid gland tissue. Therapeutic approaches for different pathogenetic types of T are different, therefore, a careful differential diagnosis of T is necessary, even if at first glance the diagnosis seems obvious. Clinical Case: A 35-year-old patient consulted a physician complaining of weakness, weight loss by 11 kg in 1.5 months, tremors, palpitations, which first appeared about a month ago. The examination revealed TSH <0.0083 mU/l (0.4-4.0), and an endocrinologist’s consultation was recommended. On examination, the thyroid gland is no larger than the distal phalanx of the subject’s thumb, BMI=24 kg/m2, HR=100 bpm, BP=115/80 mm Hg. Laboratory examination: TSH <0.0083 mU/l, free T4 =28.29 pmol/l (9.0-19.05). Ultrasound of the thyroid gland: signs of diffuse changes in tissue, the total volume=16.8 ml3. For differential diagnosis of T, antibodies to TSH receptors were determined, the titer of which turned out to be slightly increased 1.43 IU / L (<1). A diagnosis of Graves’ disease (GD) was made and treatment was prescribed (Tyrozol 30 mg, Bisoprolol 2.5 mg per day). After 3 weeks, the patient noted an improvement in well-being, but weakness, tremor, an increase in free T4 (23.33 pmol/l) and total T3 (3.26nmol / l at a rate of 0.98-2.33) remained. The lack of achievement of the target values of TH levels was regarded as inadequacy of the received dose of Tyrozol, in connection with which it was decided to increase the dose to 40 mg per day. After 2 weeks, an increase in free T4 (27.26 pmol/L) and total T3 (3.84 nmol/L) remained. The lack of positive dynamics called into question the diagnosis of GD. With a more thorough collection of anamnesis, it was found that 1.5 years ago, the patient took amiodarone for 6 months as prescribed by a cardiologist (he does not remember the dose). In this connection, to establish the cause of T, scintigraphy was performed: revealed a weak accumulation of a radiopharmaceutical with diffuse uneven distribution. Based on the data obtained, amiodarone-induced T type 2 was verified. Treatment was corrected: Tyrosol withdrawal and Prednisolone administration, 40 mg/day with positive dynamics from treatment. Conclusion: Clinical case demonstrates how important it is to carefully collect the patient’s history and follow the algorithms for differential diagnosis. Errors in diagnosis lead to incorrectly prescribed treatment, lengthening the duration of symptoms, which affects not only the patient’s quality of life, but also reduces the level of his trust in medical professionals.

Peripheral T3 signaling is the target of pesticides in zebrafish larvae and adult liver.

The intra-tissue levels of thyroid hormones (THs) regulate organ functions. Environmental factors can impair these levels by damaging the thyroid gland and/or peripheral TH metabolism. We investigated the effects of embryonic and/or long-life exposure to low-dose pesticides, ethylene thiourea (ETU), chlorpyrifos (CPF) and both combined on intra-tissue T4/T3 metabolism/signaling in zebrafish at different life stages. Hypothyroidism was evident in exposed larvae that showed reduced number of follicles and induced tshb mRNAs. Despite that, we found an increase in free T4 (fT4) and free T3 (fT3) levels/signaling that was confirmed by transcriptional regulation of TH metabolic enzymes (deiodinases) and T3-regulated mRNAs (cpt1, igfbp1a). Second-generation larvae showed that thyroid and TH signaling was affected even when not directly exposed, suggesting the role of parental exposure. In adult zebrafish, we found that sex-dependent damage of hepatic T3 level/signaling was associated with liver steatosis, which was more pronounced in females, with sex-dependent alteration of transcripts codifying the key enzymes involved in 'de novo lipogenesis' and β-oxidation. We found impaired activation of liver T3 and PPARα/Foxo3a pathways whose deregulation was already involved in mammalian liver steatosis. The data emphasizes that the intra-tissue imbalance of the T3 level is due to thyroid endocrine disruptors (THDC) and suggests that the effect of a slight modification in T3 signaling might be amplified by its direct regulation or crosstalk with PPARα/Foxo3a pathways. Because T3 levels define the hypothyroid/hyperthyroid status of each organ, our findings might explain the pleiotropic and site-dependent effects of pesticides.

Urinary Isoflavones Levels in Relation to Thyroid Function in Adults from NHANES 2007-2010

Background: Isoflavones are phytoestrogens commonly found in plant-based foods and nutritional supplements. Some studies have reported inverse associations between isoflavone intake and selected health outcomes, including cancer, cardiovascular disease, and osteoporosis. However, there is growing concern that isoflavones may affect thyroid status. Experimental studies have shown a relationship between isoflavones and hypothyroidism, but human studies have reported conflicting results.Method: Using cross-sectional data from the National Health and Nutrition Examination Survey (2007-2010), we examined the association between urinary isoflavone concentrations and serum measures of thyroid function in adults free of thyroid disease. Specifically, we conducted multivariable analyses relating the concentrations of each urinary isoflavone (genistein, daidzein) and their metabolites (equol, O-desmethylangolensin [O-DMA]) to serum concentrations of thyroid stimulating hormone [TSH], free triiodothyronine [T3], total T3, free thyroxine [T4], total T4, thyroperoxidase [TPO] antibodies, adjusting for sociodemographics, creatinine, iodine and thiocyanate.Results: We observed positive associations between daidzein and O-DMA and free T4, and an inverse association between equol and total T4. Daidzein and O-DMA associations were stronger among women: a 10-fold increase in daidzein was related to a 3.2% (95% CI: 1.9%, 4.5%) increase in free T4, and a 10-fold increase in O-DMA was related to a 2.0% (95% CI: 1.1%, 2.9%) increase in free T4. The equol association was stronger among men: a 10-fold increase in equol was related to a 1.8% decrease (95% CI: -3.4%, -0.13%) in total T4.Conclusion: In the present study, isoflavone intake was associated with selected thyroid hormones in a sex-dependent fashion.

Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: A repeated measures study

BackgroundMaternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy. ObjectivesWe aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation. MethodsOur study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility. ResultsIn our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: −14.2, −1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4. ConclusionsOur results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes.

Insulin Plant (Costus pictus) Extract Restores Thyroid Hormone Levels in Experimental Hypothyroidism.

Background:The aim of the present study was to investigate the preventive effect of Costus pictus leaf extract in experimental hypothyroidism.Materials and Methods:Forty male Wistar rats were randomly divided into four groups with ten rats in each group: Control (C), hypothyroid (H), control+extract (C+E), and hypothyroid+extract (H+E). Rats in C group did not receive any intervention throughout the experimental period. The rats in the C+E and H+E groups received pretreatment with C. pictus leaf extract for 4 weeks. Subsequently, for the next 6 weeks, rats in the H group received 0.05% propylthiouracil in drinking water while C+E group received C. pictus leaf extract and H+E group received propyl thiouracil and C. pictus leaf extract.Results:Hypothyroid group rats exhibited dramatic increase in thyroid-stimulating hormone (TSH) levels with concomitant depletion in the levels of thyroid hormones. Treatment with the extract resulted in remarkable improvement in thyroid profile. Extract produced 10.59-fold increase in plasma free T3, 8.65-fold increase in free T4, and 3.59-fold decrease in TSH levels in H+E group in comparison with H group. Treatment with the extract ameliorated hypercholesterolemia, decreased levels of plasma C-reactive protein and tumor necrosis factor alpha, suppressed tissue oxidative stress and prevented hepatic and renal damage caused due to thyroid hormone depletion in the H+E group. Pentacyclic triterpenes alpha and beta amyrins were identified and quantified in the extract.Conclusions:This is the first study to reveal that C. pictus extract has therapeutic potential to restore thyroid hormone levels and prevent the biochemical complications due to thyroid hormone insufficiency in the animal model of experimental hypothyroidism.SUMMARY The preventive effect of Costus pictus leaf extract in experimental hypothyroidism was evaluated in the present study.Hypothyroidism was induced in the experimental animals by giving 0.05% propylthiouracil in drinking water.Hypothyroid rats exhibited dramatic increase in thyroid-stimulating hormone (TSH) levels with concomitant depletion in the levels of thyroid hormones.Treatment with Costus pictus leaf extract in hypothyroid rats significantly improved the thyroid profile. It also ameliorated hypercholesterolemia, decreased the levels of plasma inflammatory markers, suppressed tissue oxidative stress and prevented hepatic and renal damage caused due to thyroid hormone depletion.The possible active principles alpha and beta amyrins were identified and quantified in the extract through LC-MS. Abbreviations Used: APCI: Atmospheric pressure chemical ionization; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; C group: Control group; C+E group: Control+extract group; C. pictus: Costus pictus; CRP: C-reactive protein; DPPH: 2,2-diphenyl-1-picrylhydrazyl; FRAP: Ferric reducing antioxidant power; HDL: High-density lipoprotein; H group: Hypothyroid group; H+E group: Hypothyroid+extract group; LDL: Low-density lipoprotein; LC-MS: Liquid chromatography-mass spectrometry; MDA: Malondialdehyde; PTU: 6-Propyl-2-thiouracil; SRM: Single reaction monitoring; TSH: Thyroid-stimulating hormone; TPTZ: 2,4,6-tri-(2-pyridyl)-5-triazine; TBA: 2-Thiobarbituric acid; TG: Triglyceride; TNFα: Tumor necrosis factor alpha; TAS: Total antioxidant status

Effect of vitamin D3 on thyroid function and de-iodinase 2 expression in diabetic rats

Objective: This study aimed to assess the effect of vitamin D3 administration to diabetic rats on thyroid profile and deiodinase 2 (D2). Methods: Thirty male Wistar rats were included into three groups; control, streptozotocin-induced diabetic and diabetic supplemented with vitamin D3 groups. Ten weeks later, serum levels of free T4, free T3 and TSH were measured. Tissue homogenates from liver, kidney, muscle, femur bone, heart and brain were obtained and assessed for D2 mRNA. Results: Diabetic rats demonstrated significant increase in free T4 and significant decrease in free T3. These changes were ameliorated by vitamin D3 administration. D2 mRNA was significantly reduced in all tissue homogenates obtained from diabetic rats, while vitamin D3 treatment significantly enhanced D2 in liver and brain homogenates. Conclusion: Diabetes mellitus inhibited peripheral conversion of T4 into T3 secondary to reduction in D2 expression. Vitamin D3 greatly corrected the alterations in thyroid profile and D2 expression.

Increased Thyroxin During Therapeutic Hypothermia Predicts Death in Comatose Patients After Cardiac Arrest.

The course and prognostic value of pituitary-thyroid axis hormones is not well studied after cardiac arrest. We aimed to study the prognostic role of the pituitary-thyroid axis response to resuscitation from cardiac arrest before, during and after therapeutic hypothermia. We conducted a retrospective cohort study in consecutive comatose patients after out-of-hospital cardiac arrest who were sampled before, during and up to 48 h after a 24-h period of therapeutic hypothermia in the intensive care unit (ICU). Thyroid-stimulating hormone, total and free thyroxine (T4) and triiodothyronine (T3) were determined and compared between ICU outcome groups. We included twenty-nine patients. TSH levels were comparable in non-survivors (n = 17) and survivors (n = 12). The free T4 levels were higher in non-survivors than in survivors (P = 0.001), whereas the free T3 levels were comparable. All samples' results similarly declined in both outcome groups up to 72 h after start of 24 h hypothermia. ROC curves analyses showed a maximum AUC of 0.83 (P = 0.003) for free T4 at the end of hypothermia with an optimal cut off ≥17.8 pmol/L to obtain 100 % specificity and positive predictive value for non-survival. Non-survival after cardiac arrest, coma, and therapeutic hypothermia following successful resuscitation is associated with a transient increase in free T4, most probably due to inhibition of free T4 to T3 conversion. However, before routine clinical application, external validation of our finding to assess generalizability is warranted.

Research in brief

Research in brief

Reference ranges for TSH and thyroid hormones

Though TSH remains the most commonly used endocrine test in clinical practice, the issue of an appropriate TSH, and to a lesser extent, free T4 and free T3 reference ranges is still under debate. First of all the distribution of TSH reference range is not normal, with median values (also depending on population iodine intake) usually between 1-1.5 mU/L [1-3]. On the other hand, upper TSH reference limit is (assay-dependent) usually around 4.2-4.5 mU/L. There is also an argument that significant number of patients (up to 30%) with TSH above 3.0 mU/L have an occult autoimmune thyroid disease [4]. On the other hand the upper normal TSH reference range in elderly subjects (i.e. 70 plus years) may extend up to around 6.0 mU/L, with relative small changes in free hormones. This phenomenon also applies to elderly patients, where autoimmune thyroid disease had been ruled out [1,2]. Furthermore, there is little evidence of any adverse effects of autoimmune thyroid disease in the elderly in the absence of an overt hypothyroidism. Indeed, Wang et al [5] surprisingly demonstrated decreased frailty in elderly subjects with raised titres of thyroid autoantibodies. It is also well known that in the setting of subclinical hypothyroidism, concentrations of free T4 start to decline below 10 pmol/L only with TSH above 6-7 mU/L in elderly subjects, though a decline in free T4 is more pronounced in the young (particularly in those aged 20-29 years), where free T4 starts to decline for TSH concentrations above 4.5 mU/l [6]. Another issue pertains to the risk of cardiovascular disease in subjects with subclinical hypothyroidism. There are data from post-menopausal women enrolled into the Women Health Initiative study, where an increase in the risk of myocardial infarction was demonstrated only for TSH concentrations above 7.0 mU/L [7]. A separate issue, extensively discussed elsewhere [8], pertains to alterations of TSH and free thyroid hormones during pregnancy. In particular there is decrease in TSH in the first trimester followed by a gradual return to pre-pregnancy values. In contrast, there is an increase in free T4 in the first trimester, while in the third trimester free T4 concentrations are usually at the lower end of the standard (i.e. pre-pregnancy) reference range, or even just below the lower reference limit. Hence, there is an urgent need (postulated in the Endocrine Society Guidelines [8]) to create separate reference ranges for TSH and free thyroid hormones during pregnancy, possible with reference to each trimester. There are also recent data from China [9], where the authors demonstrated that the above-mentioned first trimester-related alterations in TSH and free T4, become only really visible after about 5th-6th week of gestation. The authors of this study suggest that standard reference ranges for TSH and free T4 can be applied up to this point of gestation.

Increases in Thyrotropin Within the Near-Normal Range Are Associated With Increased Triiodothyronine But Not Increased Thyroxine in the Pediatric Age Group

TSH has been shown in vitro to increase conversion of T4 to T3 and to preferentially increase thyroidal T3 secretion. Whether or not these effects are significant in vivo, other than in obesity, is unclear. To test whether the incremental relationships between free T4 (FT4), free T3 (FT3), and TSH are compatible with TSH enhancement of a preferential increase in serum FT3. A large database of pediatric and adolescent thyroid test results drawn in community clinics from children and adolescents without known thyroid disease was analyzed. RESULTS of FT3, FT4, and TSH were studied anonymously. They were crossed with electronic charts to exclude a history of positive thyroid autoantibodies and use of thyroid hormone preparations, antithyroid medication, or drugs known to affect thyroid function. All samples from patients appearing more than once in the database were removed. After exclusions, 3276 samples remained. FT4, FT3, and the FT3/FT4 ratios were correlated with TSH for the entire group, and the same parameters were segregated by TSH quartile. RESULTS were stratified for body mass index and studied separately in a normal-weight subgroup. Stepwise correlations of FT4, FT3, and FT3/FT4 ratios with TSH. There was a significant positive linear correlation of TSH with FT3 and FT3/FT4 ratios (R = 0.12; P < .0001 in both), but not with FT4. Within the near-euthyroid range, increasing TSH levels are associated with increasing FT3 levels, without an increase in FT4. This provides in vivo support for TSH enhancing preferentially T3 production and/or secretion.

Effect of vitamin D3 supplementation on thyroid hormones and deiodinase 2 expression in streptozotocin‐induced diabetic rats (688.9)

Aim: The present study aimed to assess the effect of vitamin D3 administration on deiodinase 2 (D2) mRNA expression in various tissues of diabetic rats.Methods: Thirty male Wistar rats (200‐250 g) were included into; control, diabetic and diabetic supplemented with vitamin D3 groups. Diabetes was induced by single intraperitoneal injection of streptozotocin 45 mg/kg. Vitamin D3 was administered orally in a dose of 500 IU/kg/day in olive oil for 10 weeks. Serum levels of free T4, free T3 and TSH were measured. Tissue homogenates from liver, kidney, muscle, femur bone, heart and brain were obtained and assessed for expression of D2 mRNA.Results: Diabetic rats demonstrated significant increase in free T4 and significant decrease in free T3 with non significant increase in TSH compared to control rats. The changes in thyroid profile were ameliorated by vitamin D3 administration to diabetic rats. D2 mRNA expression was significantly reduced in all tissue homogenates of diabetic rats, however vitamin D3 did enhance D2 mRNA expression especially in liver and brain of diabetic rats.Conclusion: Diabetes mellitus inhibited peripheral conversion of T4 into T3 secondary to reduction in the expression of D2 in almost all body tissues. Vitamin D3 greatly corrected the alterations in thyroid profile and D2 expression in diabetic rats and protected against the subclinical hypothyroid state that could associate diabetes mellitus.Grant Funding Source: No

Progesterone therapy increases free thyroxine levels—data from a randomized placebo‐controlled 12‐week hot flush trial

Thyroid hormones and progesterone both influence core temperature, metabolism and are crucial during pregnancy. Our objective was to discover whether progesterone therapy caused changes in thyroid physiology compared with placebo. Post hoc analysis from a randomized (1:1) placebo-controlled 12-week trial of oral micronized progesterone (Progesterone, 300 mg/d at bedtime) for hot flushes (vasomotor symptoms, VMS) conducted in an academic medical centre. Postmenopausal euthyroid, healthy (without cardiovascular diseases or risks) women, 1-11 years since last flow on no thyroid or ovarian hormone therapy with VMS participated. Primary outcomes were final and 12-week changes in TSH, FreeT3 and FreeT4 on progesterone vs placebo. Women with thyroid data (69 of 133 in original trial) were randomized to progesterone (n = 39) or placebo (n = 30)-baseline thyroid values were normal. There were no VMS-thyroid interactions-VMS Score (number × intensity) did not correlate with TSH, FreeT3 or FreeT4 (Spearman's rank correlations: -0.03 to -0.19, respectively; all P > 0.15). At 12 weeks on progesterone, TSH levels tended to be lower (1.7 mU) than on placebo (2.2), P = 0.06; FreeT4 levels were higher (16.4 pmol/l) than on placebo (15.3), P = 0.02. FreeT3 was unchanged throughout. Analysis of covariance showed a significant increase in FreeT4 on progesterone (+2.5 pmol/l; 1.9-3.0) vs on placebo (+1.7; 1.1-2.4) with 95% CI of difference = 0.8 pmol/l [0.0, 1.6], P = 0.04. Progesterone caused a significant FreeT4 increase that was discovered during this randomized controlled VMS trial. The clinical importance of this increased FreeT4 level remains to be documented. Registered at ClinialTrials.gov#NCT00152438.

Prevalence of thyroid dysfunction and effect of contrast medium on thyroid metabolism in cardiac patients undergoing coronary angiography

Iodinated contrast media (CM) may influence thyroid function. Precautions are generally taken in patients with hyperthyroidism, even if subclinical, whereas the risks in patients with hypothyroidism or low triiodothyronine (T3) syndrome are not considered as appreciable. To assess the presence and type of thyroid dysfunction in patients admitted for coronary angiography (CA), to assess the concentration of free-iodide in five non-ionic CM, and to evaluate changes in thyroid function after CA in patients with low T3 syndrome. We measured free T3, free thyroxine (T4), and thyroid-stimulating hormone (TSH) in 1752 consecutive patients prior to CA and free-iodide in five non-ionic CM. Urinary free-iodide before and 24 h after CA, and thyroid hormone profile 48 h after CA were also made in 17 patients with low T3 syndrome. Patients were followed up for an average duration of 63.5 months. The patients were divided into four groups: euthyroidism (60%), low T3 syndrome (28%), hypothyroidism (10%), and hyperthyroidism (2%). The free-iodide resulted far below the recommended limit of 50 µg/mL in all tested CM. In low T3 syndrome, 24-h free-iodide increased after CA from 99.9 ± 63 ug to 12276 ± 9285 ug (P < 0.0001). A reduction in TSH (4.97 ± 1.1 vs. 4.17 ± 1.1 mUI/mL, P < 0.01) and free T3 (1.44 ± 0.2 vs. 1.25 ± 0.3 pg/mL, P < 0.01), with an increase in free T4 (11.3 ± 2.9 vs. 12.5 ± 3.4 pg/dL, P < 0.001), was found. Patients with functional thyroid disease in the follow-up had a significant lower rate survival compared to euthyroid patients (90.7 vs. 82.2%, P < 0.00001). Thyroid dysfunction is frequent in patients who perform a CA, and low T3 syndrome is the predominant feature. The administration of contrast medium may further compromise the thyroid function.

Significant association between thyroid hormones and erythrocyte indices in euthyroid subjects

Hypothyroidism and hyperthyroidism are each associated with anaemia, but relationships between thyroid function and erythrocyte indices in euthyroid subjects have not been examined. The aim of this study was to examine these relationships in a community-based cohort. Linear regression models with free T4, free T3 and TSH as predictors of erythrocyte indices and serum iron parameters were fitted to data from a cohort of 1179 participants in the 1994 Busselton health study and a subset of 1011 euthyroid participants. All models were adjusted for age, age(2), sex and an age-sex interaction. In the full cohort and euthyroid subset, there were significant, positive linear relationships between free T4 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·01 for each), such that in euthyroid participants, each 1·0 pM increase in free T4 was associated with an increase in haemoglobin of 0·39 g/l. There were significant relationships between free T3 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·001 for each), with the best model fits obtained using free T3(2), indicating curved relationships. TSH had a significant (P < 0·05) inverse relationship with serum iron and transferrin saturation in the full cohort and the euthyroid subset. Serum iron concentrations were lower in participants with subclinical hypothyroidism (n = 87) than euthyroid subjects [mean (SD) 15·9 (4·7) vs 18·4 (6·0) μM, P = 0·001]. In euthyroid subjects, small differences in thyroid function are associated with significant differences in erythrocyte indices.

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers

There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects. Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross-sectional, community-based sample of 1853 euthyroid subjects in Busselton, Western Australia. There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0.12 kg/m(2) (95% CI 0.06, 0.18; P < 0.001). The mean BMI +/- SD of subjects in the highest quintile of free T4 concentration was 24.4 +/- 3.5 kg/m(2), compared with 26.1 +/- 3.8 kg/m(2) for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0.001) and former smokers (P = 0.011), but not in current smokers (P = 0.77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0.08 kg/m(2) (95% CI -0.16, 0.32; P = 0.53). In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.