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Abstract Introduction Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. Methodology Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. Results Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). Conclusions As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.

Background Preeclampsia is a leading cause of maternal mortality and morbidity in South Africa. Iodine deficiency in pregnancy, which is amenable to correction through iodine supplementation, has been reported to increase the risk of preeclampsia. However, the association of iodine nutrition status with preeclampsia in South Africa has not been studied. Methods We enrolled 51 randomly selected normotensive pregnant controls at term together with 51 consecutively selected cases of preeclampsia and 51 cases of severe preeclampsia/eclampsia, all in the third trimester, from Mthatha Regional and Nelson Mandela Academic Hospital in the Eastern Cape Province. Urinary iodine concentration (UIC), serum thyroid-stimulating hormone (TSH), triiodothyronine (FT3), thyroxine (FT4) and thyroglobulin (Tg) levels were compared between cases and controls. Results The respective chronological and gestational ages at enrolment for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were: age 23, 24 and 19 years ( p  = 0.001), and gestational age 38, 34, and 35 weeks ( p  < 0.001). The median gravidity was 1 for all three groups. The median UIC, FT4, FT3 revealed a decreasing and Tg a rising trend with the severity of preeclampsia ( p  < 0.05). TSH had a non-significant rising trend ( p  > 0.05). The respective median values for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were UIC 217.1, 127.7, and 98.8 μg/L; FT4 14.2, 13.7, and 12. pmol/L; FT3 4.8, 4.4, and 4.0 pmol//L; Tg 19.4, 21.4, and 32. Nine microgram per liter; TSH 2.3, 2.3, and 2.5 mIU/L. UIC < 100 μg/L, Tg > 16 μg/L and FT4 < 11.3 pmol/L were independent predictors of preeclampsia/eclampsia syndrome. Conclusion Women with severe preeclampsia/eclampsia had significantly low UIC and high Tg, suggesting protracted inadequate iodine intake. Inadequate iodine intake during pregnancy severe enough to cause elevated Tg and FT4 deficiency was associated with an increased risk of severe preeclampsia/eclampsia.

This study assessed the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of patients with chronic primary insomnia. Hundred and twenty patients with chronic primary insomnia were randomly assigned to three study groups ( n  = 40 per group): rTMS, medication, or psychotherapy treatment (both latter as controls). The treatments proceeded for 2 weeks, after which treatment efficacies were assessed in each study group based on changes in polysomnography parameters, Pittsburgh sleep quality index, and indices of HPA and HPT axes (serum cortisol, adrenocorticotropic hormone, highly sensitive thyrotropin, free T3, and free T4). Further, the relapse and recurrence rates within 3 months after respective treatments were also measured. rTMS treatment significantly better ( p  < 0.05) improved stage III sleep and REM sleep cycle compared with both control groups. Further, rTMS treatment group was more advantageous in improving the indices of HPA and HPT axes ( p  < 0.05 vs. both control groups). In addition, the relapse and recurrence rates were also the lowest in rTMS treatment group. In conclusion, rTMS treatment is more advantageous than both medication and psychotherapy treatments in improving the sleep architecture. Further, rTMS significantly decreases the body awakening level and provides a better long-term treatment effect.

Reverse T3 (rT3) is a biologically inactive form of T3 (triiodothyronine), a thyroid hormone, that is created by peripheral 5 deiodination of T4 (thyroxine) by type 1 and type 3 deiodinase enzymes (D1 and D3 respectively) and may block T3 binding to the thyroid hormone receptor. Approximately 15% of patients on L-T4 replacement therapy with a normalized thyroid-stimulating hormone (TSH) report experience continued fatigue and other hypothyroid symptoms; therefore, efforts are needed to understand why this occurs and how it can be corrected. Decades ago, endocrinologists realized that in patients with severe illnesses, rT3 is typically high and T3 is typically low; this was termed \"euthyroid sick syndrome\". More recently, functional medicine and other doctors, have argued that high rT3 is detrimental and can block T3 from binding to the thyroid hormone receptor. Due to the lack of peer-reviewed publications on this topic, functional medicine doctors continue to rely heavily on rT3 levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe L-T3-only preparations to patients in an effort to lower rT3. The initial rT3 measurements done by liquid chromatography/tandem mass spectrometry (LC/MS-MS) were retrospectively analyzed from the initial blood tests in 976 consecutive patients, with symptoms of fatigue and treated for hypothyroidism, in a private Endocrinology practice. TSH, free T3 and free T4 were measured by electrochemiluminescence immunoassay (ECLIA). The upper limit of normal rT3 (24.1 ng/dL) was used as a cut-off for results above the normal range. The number of patients with rT3 levels above normal range varied significantly with the type of thyroid hormone replacement prescribed. The highest rate of an elevated rT3 was 20.9% (29/139) in patients taking T4 alone. Nine% (31/345) of patients not taking thyroid hormone replacement had elevated rT3. Patients on all types of L-T4 treatment had higher rT3 levels than those not on L-T4 treatment (p < 0.00001) and they also had a higher percentage of rT3 levels above the cutoff of 24.1 ng/dL (p < 0.00001). Linear regression analysis showed rT3 levels correlated with free T4 and free T3 levels and inversely with log TSH levels. This study found elevated rT3 levels in patients with symptoms of fatigue on various thyroid hormone replacements with the highest levels of rT3 in those taking L-T4 replacement alone and the lowest levels of rT3 in those on preparations that contained L-T3 alone.

Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results. To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland. Randomized, double-blind, crossover trial. Academic research hospital. 28 women with overt primary hypothyroidism. Crossover trial comparing treatment with l-thyroxine, 100 microg/d (standard treatment), versus treatment with L-thyroxine, 75 microg/d, plus liothyronine, 5 microg/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d (add-on combination treatment), for a final 8-week add-on period. Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes. Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015). Treatment with L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d, was an add-on regimen and was not randomized. Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (−0.2 ± 0.19 nmol/L, p = 0.0327; respectively −0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.

Abstract Introduction The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients. Objective To explore the impact of calorie exposure on NTIS over time in critically ill patients. Methods Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio. Results Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1. Conclusions Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.

Besides its typical role as an amino acid in protein synthesis, methionine is an important intermediate in methylation reactions. In addition, it can also be converted to cysteine and hence plays a role in the defence against oxidative stress. The present study was conducted to investigate further the role of dl-methionine (DLM) and its hydroxy analogue, dl-2-hydroxy-4-methylthiobutanoic acid (DL-HMTBA), on zootechnical performance and oxidative status of broiler chickens. Male broiler chickens were reared on two diets differing in crude protein (CP) content (low-protein, 18·3 % v. high-protein, 23·2 % CP) and were supplemented either with 0·25 % DLM or 0·25 % DL-HMTBA. Reducing the dietary protein content resulted in an impaired body weight gain (P < 0·0001). However, supplementation of DL-HMTBA to the low-protein diet partially alleviated these negative effects (P = 0·0003). This latter phenomenon could be explained by the fact that chickens fed DL-HMTBA-supplemented diets displayed a better antioxidant status as reflected in lower lipid peroxidation probably as a consequence of their higher hepatic concentrations of total and reduced glutathione compared with their DLM counterparts. On the other hand, within the high protein levels, uric acid might be an important antioxidant to explain the lower lipid peroxidation of high-protein DL-HMTBA-supplemented chickens. Hepatic methionine sulfoxide reductase-A gene expression was not significantly affected by the dietary treatments. In conclusion, the present study indicates that there are interactions between dietary protein content and supplementation of methionine analogues with respect to broiler performance and antioxidant status, also suggesting a causal link between these traits.

Eprotirome, a liver specific thyroid hormone agonist, was shown to induce significant increases in markers of liver injury along with a modest decrease in atherogenic lipids and lipoproteins. To get more insight into whether these effects on liver parameters were compound specific or the effect of mimicking thyrotoxicosis, we studied the effects of supra-physiological levothyroxine dosages on liver parameters, lipids and lipoproteins. We used data of a single-blinded, randomized controlled crossover trial. Herein, healthy volunteers received levothyroxine or no medication for 14 days. Thyroid hormone excess did not induce clinically relevant changes in liver parameters, while significant reductions in total cholesterol, low-density lipoprotein-cholesterol as well as apolipoprotein-B levels were observed in the intervention periods compared with the control periods. Supra-physiological thyroid hormone levels did not induce clinically relevant increases in markers of liver injury after 2 weeks of exposure, while it reduced total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B levels. This suggests that the effects of eprotirome on liver parameters in previous studies were either off-target and compound specific or due to drug-drug interaction at the level of the liver. The results of our study are relevant for the development of novel thyroid hormone agonists to reduce atherogenic lipoproteins.

There are two thyroid hormones, thyroxine and triiodothyronine. The daily production of thyroxine is about 100 μg, all produced by the thyroid gland. The daily production of triiodothyronine is about 30 μg, of which about 20 percent is produced by the thyroid gland and 80 percent by deiodination of thyroxine in extrathyroidal tissues. 1 Not all tissues that need thyroid hormone are equally able to convert thyroxine to triiodothyronine, the active form of the hormone. 2 Nevertheless, most patients with hypothyroidism are treated only with thyroxine (levothyroxine). Although this treatment is effective, some patients with hypothyroidism treated with thyroxine are not entirely . . .