Effect of a polyherbal formulation on L-thyroxine induced hyperthyroidism in a rat model: In vitro and in vivo analysis and identification of bioactive phytochemicals.

An excess of thyroid hormones in the blood characterizes hyperthyroidism. Long-term use of prescription medications to treat hyperthyroidism has substantial adverse effects and when discontinued, the symptoms frequently recur. Several plant species have been utilized to cure hyperthyroidism. In the present work, we investigated the impact of polyherbal extract (POH) of four medicinal plants to treat hyperthyroidism. Biochemical analysis revealed the presence of a high concentration of phytochemicals in the POHs. The in vitro antioxidant study revealed their antioxidant and free radical scavenging capacity. The gas chromatography coupled mass spectrometry analysis of the POHs showed the presence of 13 bioactive phytochemical compounds. The effect of various concentrations of POHs on L-thyroxine-induced hyperthyroidism in Wistar albino rats was evaluated for 18 days. The TSH, T3 and T4 levels increased significantly and reduced the increase of liver enzymes caused by hyperthyroidism in POH-treated rats. The data showed that POH therapy could restore thyroid function to normal. The injection of POH increased the size comprising vacuolated cells, columnar follicular cells and highly coloured nuclei with increasing POH content and the number of normal thyroid follicles rose. The findings indicate that polyherbal formulations of these medicinal plants include credible antithyroid compounds that may offer a protective and an effective alternative treatment to synthetic thyroid medications.

Thyroid Antibody Titers and Hypothalamic-Pituitary-Thyroid Axis Activity in Levothyroxine-Treated Women With Autoimmune Subclinical Hypothyroidism Receiving Atorvastatin or Metformin.

Both metformin and statins reduce thyroid antibody titers in individuals with Hashimoto thyroiditis. The present study compared the impact of low-grade systemic inflammation and insulin resistance on levothyroxine action in subjects with this disorder. The study included 3 groups of women with autoimmune subclinical hypothyroidism matched for thyroid antibody titers and hormone levels: patients receiving atorvastatin (group A) or metformin (group B) and statin- and metformin-naïve women (group C). Over the entire study period (6 months), all individuals received levothyroxine. Titers of thyroid antibodies, as well as concentrations of thyrotropin, free thyroid hormones, prolactin, lipids, glucose, insulin, high-sensitivity C-reactive protein (hsCRP), and 25-hydroxyvitamin D were assessed at baseline and 6 months later. At baseline, the study groups differed in plasma lipids, insulin sensitivity, and hsCRP. In all groups of patients, levothyroxine decreased thyroid antibody titers, reduced thyrotropin levels and increased free thyroid hormone levels. Treatment-induced changes in antibody titers and free thyroid hormone levels were strongest in group A, while the changes in thyrotropin were most pronounced in group B. The decrease in antibody titers correlated to a greater degree with hsCRP levels than with insulin sensitivity. The obtained results suggest that low-grade systemic inflammation is a more important factor determining the impact of levothyroxine on thyroid autoimmunity and thyroid hormone levels than insulin resistance.

AMIODARONE AND THYROID DYSFUNCTION.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels. Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups. Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016). Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Ameliorative effect of Aloe gel against L-T4-induced hyperthyroidism via suppression of thyrotropin receptors, inflammation and oxidative stress.

Untreated hyperthyroidism may develop serious complications. This attempt was made to investigate the potential of Aloe vera gel in regulating experimentally induced hyperthyroidism in rats. Female Wistar rats were made hyperthyroid with L-thyroxine (L-T4) at 0.5 mg/kg/day, i.p. for 14 days and the effects of Aloe vera methanolic fraction (AVMF) (50 or 500 mg/kg/day, p.o.,) and a conventional antithyroid drug propylthiouracil (PTU) (10 mg/kg, i.p.) for 30 days were studied in those hyperthyroid rats. At the end, alterations in serum thyroid hormones and thyroid stimulating hormone (TSH); hepatic 5'mono-deiodinase-1(5'D1) activity, oxidative stress markers and antioxidants; serum inflammatory cytokines and the expression of thyrotropin receptor in thyroid gland were evaluated in all experimental animals. Hyperthyroid condition was confirmed by an increase in thyroid hormone levels and hepatic 5'D-1 activity with a decrease in TSH. However, either AVMF or PTU treatment in hyperthyroid rats decreased the levels of thyroid hormones and 5'D1 activity. AVMF administration in T4-induced rats also decreased the oxidative stress markers such as thiobarbituric acid reactive substances and lipid hydroperoxides and increased the antioxidant levels in liver tissues. Levels of liver marker enzymes, cytokines and different lipids were decreased in T4-induced AVMF treated rats. Further, a down regulation in the TSHR expression in thyroid was observed in AVMF or PTU treated groups. All these thyroid inhibiting effects were supported by an improvement in thyroid histology in hyperthyroid rats. It appears, about 15 compounds, as evidenced by LC-MS/MS study, mostly phenolics are involved in this anti-thyroid effects of the test compound.

Identifying Predictors of Prolonged Levothyroxine Dose Adjustment After Thyroidectomy.

BACKGROUND: Levothyroxine (LT4) is one of the most prescribed drugs in the United States; however, many patients started on LT4 after thyroidectomy suffer from symptoms of hyper- or hypo-thyroidism before achieving euthyroidism. This study aims to describe the time required for dose adjustment before achieving euthyroidism and identify predictors of prolonged dose adjustment (PDA+) after thyroidectomy. METHODS: This is a single institution retrospective cohort study of patients who achieved euthyroidism with LT4 therapy between 2008 and 2017 after total or completion thyroidectomy for benign disease. Patients who needed at least three dose adjustments (top quartile) were considered PDA+. Binomial logistic regression was used to identify predictors of PDA+. RESULTS: The 605 patients in this study achieved euthyroidism in a median of 116 d (standard deviation 124.9) and one dose adjustment (standard deviation 1.3). The 508 PDA- patients achieved euthyroidism in a median of 101 d and one dose adjustment. The 97 PDA+ patients achieved euthyroidism in a median of 271 d and three dose adjustments. Iron supplementation (odds ratio = 4.4, 95% confidence interval = 1.4-13.5, P = 0.010) and multivitamin with mineral supplementation (odds ratio = 2.4, 95% confidence interval = 1.3-4.3, P = 0.004) were independently associated with PDA+. Age, gender, preoperative thyroid disease, and comorbidities did not independently predict PDA+. CONCLUSIONS: After thyroidectomy, achieving euthyroidism can take nearly 4 mo. Iron and mineral supplementation are associated with PDA+. This information can inform the preoperative counseling of patients and suggests that this may expedite achieving euthyroidism.

Pycnogenol® prevents oxidative stress and side effects in patients with hypothyroidism during levothyroxine treatment.

BACKGROUND: In this study we aimed to evaluate the efficacy of Pycnogenol® supplementation in controlling oxidative stress levels and in reducing the frequency and severity of side effects of levothyroxine (LT4) treatment in patients who had recently started this therapy. METHODS: The registry included 60 females affected by primary hypothyroidism with multi-nodular goiter. LT4 was administered at the dosage of 100 µg/day.The registry study included only subjects under initial treatment, and followed up for a period of at least 30 days. A group took 150 mg Pycnogenol® daily and another served as control. RESULTS: The global occurrence of symptoms during the 30-day period was significantly lower with the supplement (P<0.05). CONCLUSIONS: Pycnogenol® may represent a useful tool to reduce LT4- related side effects in patients treated with hormone replacement therapy for hypothyroidism.

Is Parenteral Levothyroxine Therapy Safe in Intractable Hypothyroidism?

CASE: A 32-year old woman was admitted to the hospital due to intractable hypothyroidism refractory to high dose of oral l-thyroxine therapy. She underwent total thyroidectomy and radioactive iodine therapy due to papillary thyroid cancer. After excluding poor adherence to therapy and malabsorption, levothyroxine absorption test was performed. No response was detected. Transient neurologic symptoms developed during the test. She developed 3 attacks consisting of neurologic symptoms during high dose administration. The patient was considered a case of isolated l-thyroxine malabsorption. She became euthyroid after intramuscular twice weekly l-thyroxine therapy. DISCUSSION: There are a few case reports regarding isolated l-thyroxine. We report successful long term results of twice weekly administered intramuscular l-thyroxine therapy. We also draw attention to neurologic side effects of high dose l-thyroxine therapy.

High Prevalence of Radiological Vertebral Fractures in Women on Thyroid-Stimulating Hormone-Suppressive Therapy for Thyroid Carcinoma.

Context: Bone loss and nonvertebral fractures have been reported in patients with differentiated thyroid carcinoma (DTC) undergoing thyroid-stimulating hormone (TSH) suppressive therapy. Radiological vertebral fractures (VFs) are an early and clinically crucial marker of bone fragility. Objective and Design: A cross-sectional study to evaluate the prevalence and determinants of radiological VFs in women receiving l-thyroxine (L-T4) therapy for DTC. Patients and Interventions: A total of 179 consecutive women (median age, 59 years; n = 178 postmenopausal) who had undergone thyroidectomy for DTC and were currently receiving L-T4 were evaluated for radiological VFs and bone mineral density (BMD). There were three TSH target levels [<0.5 mU/L, group 1 (n = 83); 0.5 to 1.0 mU/L, group 2 (n = 50); >1.0 mU/L, group 3 (n = 46)]. Results: VFs were found in 51 patients (28.5%), with significantly (P < 0.001) higher prevalence in group 1 (44.6%) as compared with group 2 (24.0%) and group 3 (4.3%). VF prevalence was not significantly different among patients in group 1 with normal BMD, osteopenia, or osteoporosis, whereas in groups 2 and 3, VFs were more frequent in patients with osteoporosis than in those with either osteopenia or normal BMD. In the whole population, VFs were significantly and independently associated with TSH level <1.0 mU/L; densitometric diagnosis of osteoporosis at lumbar spine, femoral neck, or total hip; age of patients; and duration of L-T4 therapy. Conclusion: The prevalence of VFs was high in women with DTC who were undergoing long-term, suppressive L-T4 therapy.

Case report: fast reversal of severe osteoporosis after correction of excessive levothyroxine treatment and long-term follow-up.

This case report describes a 38-year-old woman, who presented with bilateral femoral stress fractures and osteoporosis after years of excessive levothyroxine treatment. Her bone health was restored rapidly and long-lasting with the reduction of levothyroxine dosage. No bone-active treatment was warranted. INTRODUCTION: Hyperthyroidism is a known risk factor for osteoporosis and fractures. Recent studies on patients with serum thyrotropin-suppressive therapy have not, however, indicated adverse effects on bone during long-term follow-up. METHODS: This case report describes long-term follow-up data of a clinically euthyreoid patient, who developed symptomatic osteoporosis due to excessive levothyroxine treatment. RESULTS: After correction of levothyroxine dosage, her bone mineral density (BMD) and previously elevated serum osteocalcin levels normalized rapidly and she remained free from fractures during 23 years of follow-up over menopause. CONCLUSION: Excessive TSH suppression contributed to the secondary osteoporosis in this patient; BMD normalized after dose reduction of levothyroxine and no fractures occurred during 23 years' follow-up. Some patients develop severe osteoporosis if they are over-substituted with levothyroxine, and decent follow-up of patients with levothyroxine supplementation is mandatory.

Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth.

Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.

Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation.

Long-term management of patients with differentiated thyroid cancer (DTC) commonly includes TSH-suppressive therapy with L-T4 and, in case of postsurgical hypoparathyroidism, Calcium-D3 supplementation, both of which may affect skeletal health. Experience with female patients treated for DTC at a young age and who were then receiving long-term therapy with L-T4 and Calcium-D3 medication is very limited to date. This cross-sectional study set out to investigate effects of Calcium-D3 supplementation and TSH-suppressive therapy on bone mineral density (BMD) in 124 young female patients treated for DTC at a mean age of 14 years and followed-up for an average of 10 years. BMD was found to be significantly higher in patients receiving Calcium-D3 medication than in patients not taking supplements. The level of ionized calcium was the strongest factor determining lumbar spine BMD in patients not receiving Calcium-D3 supplementation. Pregnancy ending in childbirth and HDL-cholesterol were associated with a weak adverse effect on spine and femoral BMD. No evidence of adverse effects of L-T4 and of radioiodine therapies on BMD was found. We conclude that Calcium-D3 medication has a beneficial effect on BMD, and that TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up.

Controversies in endocrinology: On the need for universal thyroid screening in pregnant women.

There is a well-known controversy among scientific societies regarding the recommendation to screen for thyroid dysfunction (TD) during pregnancy. Although several studies have shown an association between maternal subclinical hypothyroidism and/or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, there is only limited evidence on the possible positive effects of thyroxine (T4) treatment in such cases. Despite the scarcity of this evidence, there is a widespread agreement among clinicians on the need for treatment of clinical hypothyroidism during pregnancy and the risks that could arise due to therapeutic abstention. As maternal TD is a quite prevalent condition, easily diagnosed and for which an effective and safe treatment is available, some scientific societies have proposed to assess thyroid function during the first trimester of pregnancy and ideally before week 10 of gestational age. Given the physiologic changes of thyroid function during pregnancy, hormone assessment should be performed using trimester-specific reference values ideally based on locally generated data as geographic variations have been detected. Screening of TD should be based on an initial determination of TSH performed early during the first trimester and only if abnormal should it be followed by either a free or total T4 measurement. Furthermore, adequate iodine supplementation during pregnancy is critical and if feasible it should be initiated before the woman attempts to conceive.

Thyroxine and triiodothyronine content in commercially available thyroid health supplements.

BACKGROUND: As defined by the Dietary Supplement Health and Education Act 1997, such substances as herbs and dietary supplements fall under general Food and Drug Administration supervision but have not been closely regulated to date. We examined the thyroid hormone content in readily available dietary health supplements marketed for "thyroid support." METHODS: Ten commercially available thyroid dietary supplements were purchased. Thyroid supplements were dissolved in 10 mL of acetonitrile and water with 0.1% trifloroacetic acid and analyzed using high-performance liquid chromatography for the presence of both thyroxine (T4) and triiodothyronine (T3) using levothyroxine and liothyronine as a positive controls and standards. RESULTS: The amount of T4 and T3 was measured separately for each supplement sample. Nine out of 10 supplements revealed a detectable amount of T3 (1.3-25.4 µg/tablet) and 5 of 10 contained T4 (5.77-22.9 µg/tablet). Taken at the recommended dose, 5 supplements delivered T3 quantities of greater than 10 µg/day, and 4 delivered T4 quantities ranging from 8.57 to 91.6 µg/day. CONCLUSIONS: The majority of dietary thyroid supplements studied contained clinically relevant amounts of T4 and T3, some of which exceeded common treatment doses for hypothyroidism. These amounts of thyroid hormone, found in easily accessible dietary supplements, potentially expose patients to the risk of alterations in thyroid levels even to the point of developing iatrogenic thyrotoxicosis. The current study results emphasize the importance of patient and provider education regarding the use of dietary supplements and highlight the need for greater regulation of these products, which hold potential danger to public health.

Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study.

CONTEXT: Patients previously treated with desiccated thyroid extract (DTE), when being switched to levothyroxine (L-T4), occasionally did not feel as well despite adequate dosing based on serum TSH levels. OBJECTIVE: Our objective was to investigate the effectiveness of DTE compared with L-T4 in hypothyroid patients. DESIGN AND SETTING: We conducted a randomized, double-blind, crossover study at a tertiary care center. PATIENTS: Patients (n = 70, age 18-65 years) diagnosed with primary hypothyroidism on a stable dose of L-T4 for 6 months were included in the study. INTERVENTION: Patients were randomized to either DTE or L-T4 for 16 weeks and then crossed over for the same duration. OUTCOME MEASURES: Biochemical and neurocognitive tests at baseline and at the end of each treatment period were evaluated. RESULTS: There were no differences in symptoms and neurocognitive measurements between the 2 therapies. Patients lost 3 lb on DTE treatment (172.9 ± 36.4 lb vs 175.7 ± 37.7 lb, P < .001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred L-T4, and 23 (32.9%) had no preference. In the subgroup analyses, those patients who preferred DTE lost 4 lb during the DTE treatment, and their subjective symptoms were significantly better while taking DTE as measured by the general health questionnaire-12 and thyroid symptom questionnaire (P < .001 for both). Five variables were predictors of preference for DTE. CONCLUSION: DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTE over L-T4. DTE therapy may be relevant for some hypothyroid patients.

Loss of antinociceptive effectiveness of morphine and oxycodone following titration of levothyroxine: case reports and a brief review of published literature.

Chronic pain management is a complex process involving numerous facets of care. Although pharmacotherapy is a part of the treatment plan for these patients, it often represents the most complex of the modalities to manage. Two chronic pain patients with loss of pain control following dosage increase in levothyroxine supplementation are presented. The authors sought to identify relationships among thyroid status, opioid pharmacokinetics, and nociceptive processing. In conclusion, well-designed human studies using pain models and controlling for thyroid status are warranted to better understand the impact this system has on pain control.

[Nourishing-yin effect and mechanism of different parts of Cornu Elaphuri Davidiani in rats].

OBJECTIVE: To investigate nourishing-yin effect and mechanism of different parts of Cornu Elaphuri Davidiani in rats. METHOD: The model of yin asthenia rats was built by thy roxine. The substance metabolism, pain threshold, hormone levels and biochemical indicators in serum were measured. RESULTS: The ethanol extract of Cornu Elaphuri Davidiani could regulate the substance metabolism and raise the pain threshold in yin asthenia model rats. Furthermore, it could regulate the hormone levels, biochemical indicators in serum and it could improvte the antioxidant ability. CONCLUSION: The ethanol extract of Cornu Elaphuri Davidiani showed significant nourishing-yin effect in rats and the possible mechanism is correlated with regulating the neuroendocrine network.