LT4 Supplementation Research Articles

One sip of water with LT-4 supplementation—a key to euthyroidism in Hashimoto’s thyroiditis

PurposeRecommended pharmacotherapy for hypothyroidism in Hashimoto’s thyroiditis (HT) is oral supplementation with levothyroxine (LT-4). However, serum thyrotropin (TSH) levels within normal range are not consistently achieved with LT-4 medication.Patients and methodsWe report on 35 HT patients with LT-4 therapy in this retrospective evaluation. In general, we recommend that a maximum of two sips of water, which would then amount to < 50 mL, be ingested at the same time as LT-4. We report on follow up examinations measuring TSH and antibodies against thyroid peroxidase (TPOAb) after 6 months to five years.ResultsAfter median time of 643 days (range 98-1825) we found in 35 HT patients a statistical significant reduction of serum TSH (p < 0.001) and TPOAb (p = 0.006). The patients median body weight was 71 kg (range 48–98) and a daily LT-4 dosage was used with median 69.1 µg (range 25–150). This results in a daily LT-4 dose of median 1.01 µg/kg bodyweight (range 0.3–2.3).ConclusionsThe reduction of water ingestion to a maximum of two sips, which is <50 mL, combined with LT-4 supplementation helps to achieve euthyroidism in HT. In addition, it reduces the L-T4 medication dosage needed to lower TSH serum levels and decreases TPO antibodies in HT.

Body composition changes in patients with differentiated thyroid cancer after iodine-131 treatment and short-term levothyroxine replacement and suppression therapy.

The purposes of this study were to assess the changes in body composition in patients who underwent thyroidectomy due to differentiated thyroid cancer (DTC) after radioactive iodine therapy (RAI) and short-term levothyroxine (LT4) supplementation and to explore the correlations between body composition distribution and corresponding blood indices. Fifty-seven thyroidectomized DTC patients were included. Serum was tested for several biochemical indices of thyroid function, lipids, and bone metabolism, and body composition parameters were measured via dual-energy X-ray absorptiometry before and 4-6 weeks after RAI and LT4 supplementation. The body composition of DTC patients changed after RAI. Fat mass in all parts of the body decreased (range of relative change (RRC) -12.97--2.80%). Bone mineral content (BMC) increased throughout the body (relative change (RC) 12.12%), head (RC 36.23%), pelvis (RC 9.00%), and legs (RC 3.15%). Similarly, bone mineral density (BMD) increased in different regions (RRC 3.60-26.43%), except for the arms. Notably, lean mass in the arms (RC 4.30%) and legs (RC 3.67%) increased, while that in the head decreased (RC -2.75%), while total lean mass did not change at 4-6 weeks after LT4 supplementation. Furthermore, changes in fat distribution in the android region were related to the changes in total cholesterol (r = -0.390) and low-density lipoprotein cholesterol (r = -0.354), and changes in the BMC and BMD of the lumbar spine were positively associated with the changes in calcitonin (r = 0.302 and 0.325, respectively). After RAI and short-term LT4 supplementation in DTC patients, body composition rapidly and positively changed and was characterized by decreased fat mass and increased BMC and BMD.

Effect of Levothyroxine Supplementation on the Cardiac Morphology and Function in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.

The impact of abnormal thyroid hormone levels on the cardiovascular system has been explored for decades. Recent emerging evidence suggests that subclinical thyroid dysfunction, especially subclinical hypothyroidism (SCH), significantly affects cardiac indices. We aimed to determine whether levothyroxine (LT4), commonly used to treat hypothyroidism, affects cardiovascular indices in SCH patients. This is a systematic review and meta-analysis. We searched online databases for studies analyzing cardiac morphology and functional changes in SCH patients before and after LT4 supplementation. A total of 294 SCH patients participated and finished the follow-up. The standard mean difference and 95% CI were calculated in fixed or random-effects models. The clinical outcomes analyzed in this study included 18 indicators, mainly covering cardiac morphology, myocardial performance (including various indicators of systolic and diastolic function), mitral wave flow, and systemic vascular resistance. A total of 11 studies met our search criteria. All studies explicitly mentioned that serum thyrotropin levels decreased to normal at follow-up. Our results suggest that the cardiac output (CO), left ventricular ejection fraction (LVEF), and the ratio of peak E velocity/peak A velocity were all significantly increased after LT4 supplementation compared with the baseline level. However, we found no clear evidence of significant morphological changes in the heart. Judging from the obvious changes in the CO, LVEF, and E/A ratio, LT4 supplementation can effectively improve the cardiac systolic and diastolic dysfunction prevalent in SCH patients. This study provides evidence of the recommendation for LT4 supplementation in adult SCH patients.

Pregnancy outcomes and newborn characteristics in women with follicular fluid thyroid autoantibodies undergoing assisted reproduction.

Higher levels of thyroid autoantibodies in follicular fluid (FF) of thyroid autoimmunity (TAI) positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development. Literature highlights that levothyroxine (LT4) treatment may attenuate the risk of adverse pregnancy outcomes. The aim of the study was to estimate the pregnancy and newborn outcomes in women with FF thyroid autoantibodies undergoing assisted reproductive technology (ART). The study population included 24 women with confirmed clinical pregnancy, 8 TAI positive and 16 TAI negative women. LT4 supplementation was applied in 20.8% patients, TAI positive. Pregnancy outcomes were: twin pregnancy rate 41.7%, early miscarriage rate 8.3%, late miscarriage rate 4.2%, preterm birth rate 16.7%, term birth rate 70.8%, live birth rate 96.0%. There was significant difference in serum and in FF TgAbs (p< 0.001)between the groups according to TAI, while serum fT3 was lower in the group with TAI (p = 0.047). Serum P4 was higher in LT4 treated group (p = 0.005), with TAI, and newborns in this group had higher birth weight (p = 0.001) and height (p = 0.008). Maternal complications occurred in 23.8% of patients. No congenital malformations in newborns were noted. Thyroid autoantibodies present in FF may have an effect on the post-implantation embryo development, but have no effect on further course of pregnancy. The special benefit of LT4 treatment for successful ART outcome was demonstrated for newborn anthropometric parameters.

Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of Hungarian physicians

Hypothyroidism has a high prevalence in the adult population. Levothyroxine (LT4) supplementation is considered to be the gold-standard treatment method. In Hungary, LT4 tablets and soft gel capsules are the available formulations. Similarly to the international trends, hypothyroidism is earlier recognised, leading to early LT4 supplementation. Up till now, there has been no survey on the treatment of hypothyroidism among Hungarian endocrinologists. THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) had been conducted to assess treatment preferences among European endocrinologists. Here we report the results on the use of thyroid hormones in hypothyroid patients and euthyroid individuals in Hungary. An e-mail invitation to participate, containing the link to the online survey was sent to members of the Hungarian Society for Endocrinology and Metabolism. There were 165 responses with full demographics which were included in the analysis. By the majority (99.4%) of them, LT4 was the first treatment of choice. LT4 + LT3 combination was considered an option in patients with persistent symptoms despite biochemical euthyroidism while on LT4 (36,1%). In euthyroid individuals, 60.3% of the respondents would consider starting LT4 in euthyroid infertile women with high antibody levels, which is hardly supported by evidence. In the presence of comorbidities and interfering medications which may hinder LT4 absorption, 66.4% of Hungarian endocrinologist anticipate significant improvement after switching from tablets to soft gel capsules. The treatment of choice for hypothyroidism is LT4 in Hungary. Combination therapy with LT4 + LT3 was considered for patients with persistent symptoms. In the presence of diseases and interfering medications affecting bioavailability, a high number of Hungarian endocrinologists prefer the new LT4 formulation. The administration of LT4 in euthyroid conditions awaits explanation and calls for intensive discussions at local conferences and courses. Orv Hetil. 2022; 163(12): 463-472.

Levothyroxine Supplementation in Euthyroid Pregnant Women With Positive Autoantibodies: A Systematic Review and Meta-Analysis.

ObjectivesTo explore the role of levothyroxine (LT4) supplementation in affecting the outcome of pregnant euthyroid women with thyroperoxidase (TPO) antibodies.MethodsMEDLINE, EMBASE, Google Scholar, and the Web of Science databases were searched. The primary outcome was pre-term birth (PTB), defined as live birth before 37 weeks of gestation; secondary outcomes were gestational hypertension, pre-eclampsia (PE), placental abruption, miscarriage, intra-uterine death (IUD), and admission to neonatal intensive care unit (NICU). All these outcomes were explored in euthyroid women with TPO antibodies receiving compared to those not receiving LT4 supplementation in pregnancy. Random-effect meta-analyses were used to analyze the data and results reported as pooled odds ratios (OR) with their 95% confidence intervals (CI).ResultsThe risk of PTB was lower in women with TPO antibodies receiving compared to those not receiving LT4 supplementation (OR of 0.60 (95% CI 0.4-0.9). However, this association came mainly from observational studies (OR: 0.29, 95% CI 0.1-0), while RCTs did not show any beneficial effect of LT4 supplementation in affecting such outcomes. Conversely, there was no difference in the risk of gestational hypertension, preeclampsia, placental abruption, miscarriage, and admission to NICU between the two groups.ConclusionsLT4 supplementation in TPO euthyroid women is not associated with a reduced risk of PTB in TPO-positive women with normal thyroid function.

Treatment of Isolated Idiopathic Growth Hormone Deficiency in Children and Thyroid Function: Is the Need for LT4 Supplementation a Concern in Long-Term Therapy?

IntroductionRecombinant human growth hormone (rhGH) replacement therapy might be able to induce hypothyroidism, but this is a controversial issue. Previous studies evaluated the effects of rhGH replacement therapy on thyroid function, but little information is available in the subset of children with isolated idiopathic growth hormone deficiency (GHD). Our aim was to assess the effects of rhGH replacement therapy on thyroid function in children with isolated idiopathic GHD.MethodsRetrospective analysis of the medical files of 64 children with confirmed GHD treated with rhGH. After review, 56 children with isolated idiopathic GHD and treated with rhGH for at least one year were included. Auxological (weight standard deviation score [SDS], height SDS, growth velocity [GV] SDS) and biochemical (free thyroxine [FT4], thyroid-stimulating hormone [TSH], and insulin-like growth factor 1 [IGF-1]) parameters were recorded before, during, and after treatment with rhGH.ResultsFT4 and TSH levels decreased significantly during rhGH therapy in children with isolated idiopathic GHD. Twenty-one percent (n=12) of the children developed hypothyroidism, on average 47 months after initiation of rhGH. Higher baseline FT4 levels were protective against the need for levothyroxine (LT4) (OR=0.8, CI 0.592-0.983; p=0.036). Hypothyroidism was reversed after interruption of rhGH, except in one patient; FT4 levels returned to baseline in the first year after completing the treatment. Final height SDS of the children who developed hypothyroidism was not different from their counterparts without hypothyroidism (-1.24 [-1.52 to -1.10] vs -1.13 [-1.78 to -0.74], p=1.000). Predicted adult height (PAH) SDS in patients who completed rhGH treatment was similar in both LT4 supplemented (n=7; final Ht SDS -1.16 [-1.31 to -1.10] vs PAH -1.00 [-1.42 to -0.48]; p=0.398) and not supplemented patients (n=25; final Ht SDS -1.46 [-1.83 to -0.78] vs PAH SDS -0.88 [-1.35 to -0.56]; p=0.074).ConclusionsOur results show that patients with isolated idiopathic GHD may transiently need LT4 during GH treatment. Properly supplemented patients achieved PAH.

Levothyroxine Cessation After Thyroid Lobectomy for Papillary Thyroid Cancer Can Be Achieved at the Same Rate as that for Benign Tumors Regardless of the Duration of Thyroid-stimulating Hormone Suppression.

Thyroid lobectomy may cause post-lobectomy hypothyroidism. We investigated the difference in levothyroxine (LT4) supplementation and cessation between patients with benign disease and those with papillary thyroid carcinoma (PTC) and found that the rate of LT4 cessation could be decreased after thyroid-stimulating hormone (TSH) suppression in PTC. We retrospectively reviewed 88 patients with benign tumor and 463 patients with PTC and investigated the risk factors for LT4 supplementation after thyroid lobectomy. During the median follow-up of 73.0 months, 207 (37.6%) patients maintained the euthyroid state, while 344 (62.4%) patients continued LT4 supplementation for LT4 replacement or TSH suppression. In patients with benign tumors, only high pre-TSH level (>1.98 mIU/l) was a significant risk factor (odds ratio [OR]=10.09). However, in patients with PTC, pre-TSH level ≥1.98 mIU/l (OR=3.28), pregnancy planning (OR=2.97), and age ≥42.5 years (OR=1.94) were significant risk factors. Moreover, the most potent risk factor was tumor aggressiveness (OR=4.00), which was found to be more significant than high pre-TSH. The overall rate of LT4 cessation in all patients was 37.6%; however, in the 303 patients who underwent the LT4-Off trial, there was no difference in the rate in the benign tumor, low-risk PTC, and intermediate-risk PTC groups (66.2%, 68.8%, and 70.8%, respectively; p=0.886). When post-lobectomy TSH levels were adequate and the risk of recurrence was reduced, LT4 cessation in PTC could be achieved at the same rate as that in benign tumors, regardless of the duration of TSH suppression.

SUN-007 Elevated Levothyroxine Requirements Post-Partum as Initial Presentation of Placenta Accreta

Introduction: It is well known that estrogen plays an important role in thyroid regulation. We report an unusual case of post-partum placenta accreta causing pathologic estrogen secretion leading to increased levothyroxine (LT4) requirements and inability to lactate. Case: A 36-year-old woman with history of Hashimoto’s hypothyroidism presented post-partum day 11 after a normal vaginal delivery with inability to produce breast milk and mildly elevated TSH levels. Prior to her pregnancy, she required an equivalent dose of 142 mcg of LT4 supplementation daily, which increased appropriately to 171 mcg during pregnancy. After delivery, LT4 was decreased to 150mcg in anticipation of normalization of levothyroxine requirements to pre-pregnancy level. However, she had difficulty lactating and was found to have elevated prolactin, estradiol, and TSH levels. The following day, she presented to her obstetrician for persistent vaginal bleeding and was found to have placenta accreta requiring dilation and curettage (D&C). Her LT4 requirements eventually dropped to 125 mcg with decreasing beta-HCG and estrogen levels after successful D&C treatment. She was also then able to produce sufficient breast milk for lactation. Discussion: This case highlights the effect of estrogen on LT4 requirements during physiologic pregnancy and postpartum with placenta accreta. It is expected that hypothyroid patients have approximately 25-50% increased thyroid replacement requirements during pregnancy, which normalizes soon after delivery.1 Estrogen increases thyroxine-binding globulin and lowers circulating free thyroxine2,, which causes higher thyroid replacement requirements. Estrogen is also known to inhibit lactation. Our patient demonstrates that this holds true even in a pathologically high estrogen state from placenta accreta. Our case uniquely demonstrates a temporal association between estrogen levels and LT4 requirements in the post-partum hypothyroid patient. Patients with inappropriately high TSH levels after delivery should prompt investigation into pathologic causes of elevated estrogen-states, as levothyroxine requirements are expected to normalize immediately post-partum.

Effect of antithyroid antibodies on women with recurrent miscarriage: A meta-analysis.

ProblemThe effect of thyroid autoimmunity (TAI) on the prevalence of recurrent miscarriage (RM) is highly debatable. No meta‐analysis has been published in the past decade to investigate the impact of TAI on women with RM.Method of StudySystemic literature search was conducted on PubMed, Embase, Cochrane, and Web of Science databases. English language literatures published between 1993 and 2019 were selected. We assessed the relationship between the prevalence of RM and thyroid peroxidase antibodies (TPO‐Ab) or antithyroid antibodies (ATA) and evaluated the thyroid‐stimulating hormone (TSH) level in TPO‐Ab‐positive women with RM. We also observed the treatment effect with levothyroxine (LT4) for RM. Review Manager 5.3 software was used to obtain the pooled odds ratios (OR).ResultsAnalysis of 22 eligible studies revealed significant association between TPO‐Ab and the prevalence of RM (OR = 1.85; 95% CI, 1.38 to 2.49; P < .001)(n ≥ 3), (OR = 1.82; 95% CI, 1.13 to 2.92; P = .01) (n ≥ 3). Women with ATA + had higher risk of RM (OR = 2.36; 95% CI, 1.71 to 3.25; P < .00001)(n ≥ 3), (OR = 2.34; 95% CI, 1.70 to 3.22; P < .00001)(n ≥ 2). RM women with TPO‐Ab had higher TSH level when compared with those negative for TPO‐Ab (random‐effect SMD = 0.60; 95% CI, 0.31 to 0.90; P < .0001). We also found beneficial effects of LT4 supplementation on the outcome of live birth rate (LBR) among pregnant women with TPO‐Ab (OR = 3.04; 95% CI, 0.69 to 13.36; P = .14).ConclusionThe presence of serum antithyroid antibodies does harms to women and can even lead to recurrent miscarriage; LT4 treatment may have beneficial to RM women.

A Meta-Analysis of Pregnancy Outcomes With Levothyroxine Treatment in Euthyroid Women With Thyroid Autoimmunity.

Thyroid autoimmunity (TAI), the most common cause of (sub)clinical hypothyroidism, is associated with adverse pregnancy outcomes. The benefits of levothyroxine (LT4) intervention in women with TAI remain controversial. The purpose of this analysis is to determine the effect of LT4 on pregnancy outcomes in euthyroid women with TAI. Databases were searched up to May 2019. Randomized controlled trails (RCTs) and retrospective studies that reported effects of LT4 administration on pregnancy outcomes in euthyroid women with TAI were screened. Quality assessment and data extraction were conducted independently by 2 researchers. Conflicts were settled by a third researcher. Six trials comprising 2249 women were included. Overall, no beneficial effect on pregnancy outcomes was observed with LT4 supplementation. For women with individualized initial LT4 dosages, the risk of miscarriage decreased (relative risk [RR] 0.62, 95% CI: 0.41-0.93, I2 = 28%); there was no difference among women with fixed LT4 dosages (RR 0.96, 95% CI: 0.74-1.24, I2 = 0%). Women who initiated LT4 treatment in early pregnancy had a significantly lower preterm birth rate (RR 0.54, 95% CI: 0.31-0.92, I2 = 0%) than those who received no treatment or placebo. No improvement was observed among women who initiated treatment before conception (RR 1.14, 95% CI: 0.71-1.84, I2 = 0%). No definitive evidence showed improvement of pregnancy outcomes with LT4 supplementation in euthyroid women with TAI. However, therapeutic strategies, especially dosages and initial times of intervention, may be of great importance. Additional large RCTs are needed in the future.

Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis.

Subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes such as pregnancy loss and preterm birth. However, the ability of levothyroxine (LT4) supplementation to attenuate the risks of these outcomes remains controversial. This systematic review and meta-analysis was conducted to determine the effect of LT4 supplementation on pregnancy loss rate (PLR) and preterm birth rate (PBR) among pregnant women with SCH and TAI. A systematic literature search of the PubMed, EMBASE, Web of Science and Cochrane Controlled Trials Register databases and Clinicaltrials.gov was performed to identify all relevant English studies published up to April 2018. The following terms were used for the search: [subclinical hypothyroidism OR thyroid autoimmunity OR thyroperoxidase antibody (TPO-Ab) OR thyroglobulin antibodies (Tg-Ab)] AND (levothyroxine OR euthyrox) AND [pregnancy outcome OR miscarriage OR abortion OR pregnancy loss OR preterm birth OR premature delivery OR early labo(u)r]. The reference lists of the relevant publications were also manually searched for related studies. Published manuscripts were included if they reported data on pregnancy loss, preterm birth or both. We separately analysed the pooled effects of LT4 supplementation on PLR and PBR in women with SCH and TAI. Overall, 13 eligible studies including 7970 women were included in the meta-analysis. Eight and five of these studies were randomized controlled trials (RCTs) and retrospective studies, respectively. The pooled results indicated that LT4 supplementation significantly decreased the PLR [relative risk (RR) = 0.56, 95% confidence interval (CI): 0.42-0.75, I2 = 1%, 12 studies] and PBR (RR = 0.68, 95% CI: 0.51-0.91, I2 = 21%, eight studies) in women with SCH and/or TAI. We further found that LT4 supplementation significantly decreased the risk of pregnancy loss (RR = 0.43, 95% CI: 0.26-0.72, P = 0.001, I2 = 0%) but not of preterm birth (RR = 0.67, 95% CI: 0.41-1.12, P = 0.13, I2 = 0%) in women with SCH. Furthermore, LT4 supplementation significantly decreased the risks of both pregnancy loss (RR = 0.63, 95% CI: 0.45-0.89, P = 0.009, I2 = 0%) and preterm birth (RR = 0.68 95% CI: 0.48-0.98, P = 0.04, I2 = 46%) in women with TAI. These results were consistent when only RCTs were included in the analysis. Further, in women with SCH, LT4 supplementation reduced the risk of pregnancy loss in pregnancies achieved by assisted reproduction (RR = 0.27, 95% CI: 0.14-0.52, P < 0.001, I2 = 14%) but not in naturally conceived pregnancies (RR = 0.60, 95% CI: 0.28-1.30, P = 0.13, I2 = 0%). By contrast, in women with TAI, LT4 supplementation reduced the risks of both pregnancy loss (RR = 0.61, 95% CI: 0.39-0.96, P = 0.03, I2 = 0%) and preterm birth (RR = 0.49, 95% CI: 0.30-0.79, P = 0.003, I2 = 0%) in naturally conceived pregnancies but not in pregnancies achieved by assisted reproduction (RR = 0.68, 95% CI: 0.40-1.15, P = 0.15, I2 = 0% for pregnancy loss and RR = 1.20, 95% CI: 0.68-2.13, P = 0.53, I2 not applicable for preterm birth). This meta-analysis confirmed the beneficial effects of LT4 supplementation, namely the reduced risks of pregnancy loss and preterm birth, among pregnant women with SCH and/or TAI. The different effects of LT4 supplementation on naturally conceived pregnancies and pregnancies achieved by assisted reproduction in women with SCH and/or TAI suggest that these women should be managed separately. Due to the limited number of studies included in this meta-analysis, especially in the subgroup analysis, further large RCTs and fundamental studies are warranted to confirm the conclusions and better clarify the molecular mechanism underlying these associations.

Levothyroxine Sodium Administration and Late Circulatory Collapse in Premature Infants with Thyroid Dysfunction

Objective: Levothyroxine sodium (LT4) is considered safe, and widely administered to premature infants with thyroid dysfunction. Late circulatory collapse (LCC) has not been defined clearly, but it has been characterized as refractory hypotension in premature infants. Recently, LCC after LT4 administration was reported in Japan. However, there is controversy on the aspect of LT4 as a risk factor of LCC. The purpose of this study was to investigate relations between LT4 administration and LCC in premature infants. Methods: We retrospectively reviewed medical records of premature infants (≤32 weeks gestation) admitted in Gyeongsang National University Hospital between 2011 and 2018. To investigate the relation between LT4 supplementation and LCC, clinical and laboratory findings were reviewed and compared between premature infants with and without LCC. Results: Among 347 premature infants, LCC occurred in 21 (6.1%) on median 19.0th day. Sixteen (76.2%) of 21 infants with LCC were receiving LT4 and LCC was developed on median 3.0 days after LT4 initiation. Gestational age ≤28 weeks, birth weight <1.5 kg, hemodynamically significant patent ductus arteriosus, culture proven sepsis, necrotizing enterocolitis, congenital hypothyroidism, use of LT4 and diuretics, values of serum thyroid stimulating hormone, free thyroxine and sodium were significantly statistically different between LCC and no LCC group. Prematurity ≤28 weeks of gestation and LT4 replacement were risk factors of LCC on multivariate logistic regression analysis. Conclusion: Supplementation of LT4 should be carefully considered in premature infants with thyroid dysfunction and serial monitoring of blood pressure should be warranted if LT4 was administered.

Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials

BackgroundEvidence suggests that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes. This systematic review and meta-analysis was conducted to determine whether levothyroxine (LT4) supplementation would improve pregnancy outcomes among infertile women with SCH and/or TAI who underwent in vitro fertilization (IVF) or intracytoplastic sperm injection (ICSI).MethodsWe searched databases of PubMed, EMBASE, Web of Science, Cochrane Controlled Trials Register databases, and Clinicaltrials.gov up to April 2018 to identify eligible studies. Studies that focused on the treatment effect of LT4 on pregnancy outcomes of women with SCH and/or TAI who underwent IVF/ICSI were included in the data synthesis. We only included randomized controlled trials (RCTs). Relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effects model to assess the results of pregnancy outcomes, including clinical pregnancy rate, miscarriage rate, live birth rate and preterm birth rate.ResultsFour published RCTs including 787 infertile couples undergoing IVF/ICSI were included in this meta-analysis. Notably, the study observed no significant associations of LT4 treatment with the clinical pregnancy rate (RR = 1.46, 95% CI: 0.86–2.48), live birth rate (RR = 2.05, 95% CI: 0.96–4.36), or preterm birth rate (RR = 1.13, 95% CI: 0.65–1.96). However, patients receiving LT4 supplementation had a significantly decreased miscarriage rate relative to those receiving a placebo or no treatment (RR = 0.51, 95% CI: 0.32–0.82). A further sub-group analysis showed that LT4 supplementation did not improve the miscarriage rates among patients with SCH (RR = 0.67, 95% CI: 0.39–1.15) or TAI (RR = 0.28, 95% CI: 0.07–1.06).ConclusionsGiven its potential to reduce the miscarriage rate, LT4 supplementation is recommended for infertile women with SCH and/or TAI who are undergoing IVF/ICSI. However, additional population-based RCTs are needed to confirm this recommendation.

Levothyroxine supplementation improves serum anti-Müllerian hormone levels in infertile patients with Hashimoto's thyroiditis.

Thyroid dysfunction and autoimmunity are associated with an adverse effect on fertility. An aberrant high thyroid stimulating hormone level is associated with diminished ovarian reserve in women of reproductive age; however, the utility of levothyroxine (LT4) replacement for infertile patients with subclinical hypothyroidism is still under discussion. The aim of this study was to investigate whether LT4 supplementation for infertile patients with subclinical hypothyroidism improves impaired ovarian function. We measured levels of serum thyroid-related hormones and a biomarker of ovarian function, anti-Müllerian hormone (AMH) in infertile women from 2014 to 2015. Out of a consecutive 1431 infertile patients, 311 patients with an elevated thyroid stimulating hormone level (≥ 2.5 μIU/mL) underwent detailed thyroid examinations, including blood tests of thyroid antibodies. We recruited 174 infertile patients, excluding patients with factors impacting ovarian and thyroid function. We evaluated alterations in AMH and thyroid related hormone levels during LT4 supplementation and infertility treatment with assisted reproductive technology. After LT4 supplementation, no significant change in the average AMH level was detected overall. However, the AMH level in 35 patients with Hashimoto's disease increased significantly after treatment (1 month 1.3 ± 0.5 fold, P = 0.007; 3 months 1.3 ± 0.4 fold, P = 0.040). The AMH level in patients with thyroglobulin antibody-positive and thyroid peroxidase antibody-negative also significantly increased after LT4 treatment (1 and 3 months 1.5 fold; P = 0.023). In the patients with Hashimoto's disease, preconception LT4 treatment may relieve adverse effects, including autoimmune antibodies, and support follicular development.

Association between the clinical classification of hypothyroidism and reduced TSH in LT4 supplemental replacement treatment for pregnancy in China

The study was aimed to evaluate the effects of levothyroxine (LT4) supplemental replacement treatment for pregnancy and analyze the associations between the clinical classification of hypothyroidism and reduced thyroid-stimulating hormone (TSH) in LT4 therapy. Totally, 195 pregnant women with hypothyroidism receiving routine prenatal care were enrolled. They were categorized into three groups: overt hypothyroidism (OH), subclinical hypothyroidism (SCH) with negative thyroperoxidase antibody (TPOAb), and SCH with positive TPOAb. The association between the clinical classification and reduced TSH in LT4 supplemental replacement treatment was assessed. The results indicated that reduced TSH was significantly different among the groups according to the clinical classifications (p = 0.043). The result was also significantly different between patients with OH and patients with SCH and negative TPOAb (p = 0.036). Similar result was reported for the comparison between patients with OH and patients with SCH and positive TPOAb (p = 0.016). Multiple variable analyses showed that LT4 supplementation, gestational age and the variable of clinical classifications were associated with reduced TSH independently. Our data suggested that the therapeutic effect of substitutive treatment with LT4 was significantly associated with different clinical classifications of hypothyroidism in pregnancy and the treatment should begin as soon as possible after diagnosis.

Effect of thyroxine on brain microstructure in extremely premature babies: magnetic resonance imaging findings in the TIPIT study

In order to assess relationships between thyroid hormone status and findings on brain MRI, a subset of babies was recruited to a multi-centre randomised, placebo-controlled trial of levothyroxine (LT4) supplementation for babies born before 28 weeks' gestation (known as the TIPIT study, for Thyroxine supplementation In Preterm InfanTs). These infants were imaged at term-equivalence. Forty-five TIPIT participants had brain MRI using diffusion tensor imaging (DTI) to estimate white matter development by apparent diffusion coefficient (ADC), fractional anisotropy (FA) and tractography metrics of number and length of streamlines. We made comparisons between babies with the lowest and highest plasma FT4 concentrations during the initial 4 weeks after birth. There were no differences in DTI metrics between babies who had received LT4 supplementation and those who had received a placebo. Among recipients of a placebo, babies in the lowest quartile of plasma-free thyroxine (FT4) concentrations had significantly higher apparent diffusion coefficient measurements in the posterior corpus callosum and streamlines that were shorter and less numerous in the right internal capsule. Among LT4-supplemented babies, those who had plasma FT4 concentrations in the highest quartile had significantly lower apparent diffusion coefficient values in the left occipital lobe, higher fractional anisotropy in the anterior corpus callosum and longer and more numerous streamlines in the anterior corpus callosum. DTI variables were not associated with allocation of placebo or thyroid supplementation. Markers of poorly organised brain microstructure were associated with low plasma FT4 concentrations after birth. The findings suggest that plasma FT4 concentrations affect brain development in very immature infants and that the effect of LT4 supplementation for immature babies with low FT4 plasma concentrations warrants further study.

Levothyroxine and lung cancer in females: the importance of oxidative stress

BackgroundLevothyroxine (LT4) treatment can lead to iatrogenic hyperthyroidism and oxidative stress that can cause patient discomfort. Oxidative stress is also recognized as one of the causes of chronic diseases and cancer.MethodsThe prevalence of breast, colorectal, gastric and lung cancer in 18 Italian Regions during 2010 was correlated with the sales of LT4 in 2009. The cancer prevalence was analyzed in women aged 30–84. This age range corresponds to more than 80% of the consumers of the drug and to about 99% of all malignant cancers. The correlation between sales of LT4 and cancers was determined with the technique of Density Ellipses. The age and smoking contribution for lung cancer was determined with the Sequential test.ResultsNo significant correlation was seen between LT4 sales and breast, colorectal and gastric cancers. A significant correlation was instead found for lung cancer (p < 0.05) corrected for smoking and age.ConclusionsLT4 consumption in Italy is about 0.7 boxes/women/year. There is a correlation between lung cancer and LT4 treatment and oxidative stress caused by LT4 supplementation can be one of the causes. Although we cannot exclude that dysthyroidism needing LT4 supplementation might be the ground for lung cancer itself and measuring oxidative stress could be helpful in avoiding excessive use of the drug.

Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs

BACKGROUND Previous meta-analyses of observational data indicate that pregnant women with subclinical hypothyroidism have an increased risk of adverse pregnancy outcome. Potential benefits of levothyroxine (LT4) supplementation remain unclear, and no systematic review or meta-analysis of trial findings is available in a setting of assisted reproduction technologies (ART). METHODS Relevant trials published until August 2012 were identified by searching MEDLINE, EMBASE, Web of Knowledge, the Cochrane Controlled Trials Register databases and bibliographies of retrieved publications without language restrictions. RESULTS From 630 articles retrieved, we included three trials with data on 220 patients. One of these three trials stated 'live delivery' as outcome. LT4 treatment resulted in a significantly higher delivery rate, with a pooled relative risk (RR) of 2.76 (95% confidence limits 1.20-6.44; P = 0.018; I(2) = 70%), a pooled absolute risk difference (ARD) of 36.3% (3.5-69.0%: P = 0.030) and a summary number needed to treat (NNT) of 3 (1-28) in favour of LT4 supplementation. LT4 treatment significantly lowered miscarriage rate with a pooled RR of 0.45 (0.24-0.82; P = 0.010; I(2) = 26%), a pooled ARD of -31.3% (-48.2 to -14.5%: P < 0.001) and a summary NNT of 3 (2-7) in favour of LT4 supplementation. LT4 treatment had no effect on clinical pregnancy (RR 1.75; 0.90-3.38; P = 0.098; I(2) = 82%). In an ART setting, no data are available on the effects of LT4 supplementation on premature delivery, arterial hypertension, placental abruption or pre-eclampsia. CONCLUSIONS Our meta-analyses provide evidence that LT4 supplementation should be recommended to improve clinical pregnancy outcome in women with subclinical hypothyroidism and/or thyroid autoimmunity undergoing ART. Further research is needed to determine pregnancy outcome after close monitoring of thyroid function to maintain thyroid-stimulating hormone and free T4 levels within the trimester-specific reference ranges for pregnancy.

Management of Thyroid Peroxidase Antibody Euthyroid Women in Pregnancy: Comparison of the American Thyroid Association and the Endocrine Society Guidelines

The presence of thyroid autoantibodies is relatively high in women of childbearing age. There is evidence that positive thyroperoxidase antibody even in euthyroid women may increase the risk of spontaneous and recurrent pregnancy loss and preterm delivery. However, the evidence is not enough to justify recommendation on the screening of pregnant women for thyroid autoantibodies or LT4 supplementation for reducing maternal or fetal complications. In this paper we reviewed the related evidence and compared the new guidelines of the American Thyroid Association and Endocrine Society with respect to the screening and management of positive thyroperoxidase antibody in euthyroid pregnant women. As there was no major contradiction or disagreement between the two guidelines, either one of two guidelines may be used by clinicians for the appropriate management of thyroid autoimmunity during pregnancy.