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Thyroxine and treatment of hypothyroidism: seven decades of experience.

ABSTRACT: Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations.

SUBMITTER: Mateo RCI

PROVIDER: S-EPMC6794242 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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Thyroxine and treatment of hypothyroidism: seven decades of experience.

Mateo Roselyn Cristelle I RCI Hennessey James V JV

Endocrine 20190718 1

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh ...[more]

PMID: 31321670

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Project description:Thyroxine metabolism is an important topic of pathogenesis research and treatment schedule of subclinical hypothyroidism (SCH). L-Thyroxine replacement therapy (LRT) is usually recommended for severe SCH patients only. Our previous studies reported that disordered serum lipid of mild SCH people could also benefit from LRT. However, the benefits were different among individuals, as shown by the variations in drug dosage that required to maintain thyroid-stimulating hormone (TSH) stability. Alternative pathways, such as sulfation and glucuronidation of iodothyronine, may play a role in thyroid hormones metabolism in peripheral tissues aside from thyroid. Conjugated thyroxine can be hydrolyzed and reused in tissues including gastrointestinal tract, in which gut microbiota are one of the most attractive physiological components. On this site, the roles of gut microbiota in thyroidal metabolism should be valued. In this study, a cross-sectional study was performed by analyzing 16S rDNA of gut microbiota in mild SCH patients treated with L-thyroxine or not. Subjects were divided by serum lipid level, L-thyroxine treatment, or L-thyroxine dosage, respectively. Relationship between gut microbiome and serum profile, L-thyroxine treatment, and dose were discussed. Other metabolic disorders such as type 2 diabetes and hypertension were also taken into consideration. It turned out that microbiome varied among individuals divided by dose and the increment of L-thyroxine but not by serum lipid profile. Relative abundance of certain species that were associated with thyroxine metabolism were found varied among different L-thyroxine doses although in relatively low abundance. Moreover, serum cholesterol may perform relevance effects with L-thyroxine in shaping microbiome. Our findings suggested that the differences in L-thyroxine dosage required to maintain TSH level stability, as well as the SCH development, which was displayed by the increased L-thyroxine doses in subsequent follow-up, had relationship with gut microbial composition. The reason may due to the differences in thyroxine metabolic capacity in gut. In addition, the metabolic similarity of iodothyronines and bile acid in gut also provides possibilities for the correlation between host's thyroxine and cholesterol levels. This study was registered with ClinicalTrials.gov as number NCT01848171.

Project description:ObjectiveTo estimate the effect of antenatal treatment of subclinical hypothyroidism on maternal depressive symptoms.MethodsWe conducted an ancillary study to a multicenter trial in women with singleton pregnancies diagnosed with subclinical hypothyroidism randomized to antenatal thyroxine therapy or placebo. Treatment was discontinued at the end of pregnancy. Women with overt thyroid disease, diabetes, autoimmune disease, and those diagnosed with depression were excluded. Participants were assessed for depressive symptoms using the Center for Epidemiological Studies-Depression scale (CES-D) before starting the study drug (between 11 and 20 weeks of gestation), between 32 and 38 weeks of gestation, and at 1 year postpartum. The primary outcome was maternal depressive symptoms score as assessed using the CES-D. Secondary outcome was the percentage of women who scored 16 or higher on the CES-D, as such a score is considered screen-positive for depression.ResultsTwo hundred forty-five (36.2% of parent trial) women with subclinical hypothyroidism were allocated to thyroxine (n=124) or placebo (n=121). Median CES-D scores and the proportion of participants with positive scores were similar at baseline between the two groups. Treatment with thyroxine was not associated with differences in CES-D scores (10 [5-15] vs 10 [5-17]; P=.46) or in odds of screening positive in the third trimester compared with placebo, even after adjusting for baseline scores (24.3% vs 30.1%, adjusted odds ratio 0.63, 95% CI 0.31-1.28, P=.20). At 1 year postpartum, CES-D scores were not different (6 [3-11] vs 6 [3-12]; P=.79), nor was the frequency of screen-positive CES-D scores in the treated compared with the placebo group (9.7% vs 15.8%; P=.19). Treatment with thyroxine during pregnancy was also not associated with differences in odds of screening positive at the postpartum visit compared with placebo even after adjusting for baseline scores. Sensitivity analysis including women who were diagnosed with depression by the postpartum visit did not change the results.ConclusionsThis study did not achieve its planned sample size, thus our conclusions may be limited, but in this cohort of pregnant women with subclinical hypothyroidism, antenatal thyroxine replacement did not improve maternal depressive symptoms.

Project description:BackgroundYunnan Province was considered the most difficult place in China for malaria elimination because of its complex malaria epidemiology, heterogeneous ecological features, relatively modest economic development, and long, porous border with three malaria endemic countries: Lao People's Democratic Republic, Myanmar, and Viet Nam.MethodsAcademic publications and grey literature relevant to malaria elimination in Yunnan covering the period from 1950 until 2020 inclusive were considered. The following academic indexes were searched: China Science Periodical Database, China National Knowledge Infrastructure Database, and MEDLINE. Grey literature sources were mainly available from the National Institute of Parasitic Diseases (NIPD), the Chinese Center for Diseases Control and Prevention, and the Yunnan Institute of Parasitic Diseases (YIPD).ResultsA malaria elimination campaign in the 1950-1960s, based mainly on mass administration of antimalarial drugs and large-scale vector control, reduced morbidity and mortality from malaria and interrupted transmission in some areas, although elimination was not achieved. Similar strategies were used to contain outbreaks and a resurgence of disease during the 1970s, when malaria services were discontinued. From the 1980s, malaria incidence declined, despite the challenges of large numbers of mobile and migrant populations and an unstable primary health care system in rural areas following economic transformation. Launch of the national malaria elimination programme in 2010 led to adoption of the '1-3-7' surveillance and response strategy specifying timely detection of and response for every case, supported by the establishment of a real-time web-based disease surveillance system and a new primary health care system in rural areas. Border malaria was addressed in Yunnan by strengthening the surveillance system down to the lowest level, cross-border collaboration with neighbouring countries and non-governmental organizations, and the involvement of other sectors.ConclusionsSeven decades of work to eliminate malaria in Yunnan have shown the importance of political commitment, technically sound strategies with high quality implementation, a robust surveillance and response system at all levels, community participation and effective management of border malaria. The experiences and lessons learned from elimination remain important for prevention re-establishment of malaria transmission in the Province.

Project description:OBJECTIVES:To determine whether thyroxine treatment is effective in patients with symptoms of hypothyroidism but with thyroid function tests within the reference range, and to investigate the effect of thyroxine treatment on psychological and physical wellbeing in healthy participants. DESIGN:Randomised double blind placebo controlled crossover trial. SETTING:Outpatient clinic in a general hospital. PARTICIPANTS:25 patients with symptoms of hypothyroidism who had thyroid function tests within the reference range, and 19 controls. METHODS:PARTICIPANTS were given thyroxine 100 microgram or placebo to take once a day for 12 weeks. Washout period was six weeks. They were then given the other to take once a day for 12 weeks. All participants were assessed physiologically and psychologically at baseline and on completion of each phase. MAIN OUTCOME MEASURES:Thyroid function tests, measures of cognitive function and of psychological and physical wellbeing. RESULTS:22 patients and 19 healthy controls completed the study. At baseline, patients' scores on 9 out of 15 psychological measures were impaired when compared with controls. Patients showed a significantly greater response to placebo than controls in 3 out of 15 psychological measures. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo (mean (SD) 60 (17) v 73 (16), P<0.01). However, patients' scores from psychological tests when taking thyroxine were no different from those when taking placebo except for a poorer performance on one visual reproduction test when taking thyroxine. Serum concentrations of free thyroxine increased and those of thyroid stimulating hormone decreased in patients and controls while they were taking thyroxine, confirming compliance with treatment. Although serum concentrations of free triiodothyronine increased in patients and controls taking thyroxine, the difference between the response to placebo and to thyroxine was significant only in the controls. CONCLUSIONS:Thyroxine was no more effective than placebo in improving cognitive function and psychological wellbeing in patients with symptoms of hypothyroidism but thyroid function tests within the reference range. Thyroxine did not improve cognitive function and psychological wellbeing in healthy participants.

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Thyroxine and treatment of hypothyroidism: seven decades of experience.

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Thyroxine and treatment of hypothyroidism: seven decades of experience.

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