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PURPOSE: Palbociclib has become the standard of care for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer, but real-world evidence in older women remains scarce. Therefore, we investigated tolerability of palbociclib in older women with metastatic breast cancer. METHODS: Consecutive women aged ≥ 70 with ER+/HER2- metastatic breast cancer, treated with palbociclib in any treatment line in six hospitals, were included. Primary endpoint was grade ≥ 3 palbociclib-related toxicity. Predictors of toxicity were identified using logistic regression models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier. RESULTS: We included 144 women with a median age of 74 years. Grade 3-4 toxicity occurred in 54% of patients, of which neutropenia (37%) was most common. No neutropenic fever or grade 5 toxicity occurred. Dose reduction during treatment occurred in 50% of patients, 8% discontinued treatment due to toxicity and 3% were hospitalized due to toxicity. Polypharmacy (odds ratio (OR) 2.50; 95% confidence interval (CI) 1.12-5.58) and pretreatment low leukocytes (OR 4.81; 95% CI 1.27-18.21) were associated with grade 3-4 toxicity, while comorbidities were not. In first-line systemic therapy, median PFS was 12 months and median OS 32 months. In second-line, median PFS was 12 months and median OS 31 months. CONCLUSION: Although grade 3-4 toxicity and dose reductions occurred frequently, most were expected and managed by dose reductions, showing that palbociclib is generally well tolerated and thus represents a valuable treatment option in the older population.
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Neoplasias de la Mama , Piperazinas , Piridinas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/administración & dosificación , Anciano , Anciano de 80 o más Años , Metástasis de la Neoplasia , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Estimación de Kaplan-MeierRESUMEN
Paclitaxel is a commonly used chemotherapeutic agent. To minimize the risk of hypersensitivity reactions (HSRs), which occur in approximately 16-42% of patients, premedication with dexamethasone, clemastine, and ranitidine was standard of care. As of October 2019, ranitidine is no longer available. We compared the risk of HSRs to paclitaxel with and without premedication with ranitidine, hypothesizing that the incidence of HSRs to paclitaxel will be similar. In this retrospective cohort study, all first-time paclitaxel users in the Groene Hart Hospital were included from January 2019 to August 2020. The primary outcome was the incidence of HSRs, using a Student's t-test. One-hundred and eight patients who were first-time users of paclitaxel in the Groene Hart Hospital met the inclusion criteria. Most patients were treated for breast or ovarian cancer, followed by lung cancer. Analysis of all 836 paclitaxel administrations was performed. Following 349 administrations with ranitidine as premedication, eight HSRs occurred (2.3%), while following 487 administrations without ranitidine, 12 HSRs occurred (2.5%), p-value of 0.87. An additional analysis on the occurrence of HSRs per patient was performed: 45 patients received premedication in the form of ranitidine, of which eight patients (17.8%) had a HSR. Sixty-three patients did not receive premedication in the form of ranitidine, of whom 10 (15.8%) had a HSR, p-value of .80. In conclusion, we found no difference in the incidence of HSRs during paclitaxel infusions between patients who received ranitidine as premedication versus those who did not.
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Antineoplásicos Fitogénicos , Hipersensibilidad a las Drogas , Antineoplásicos Fitogénicos/efectos adversos , Dexametasona/uso terapéutico , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/etiología , Humanos , Incidencia , Paclitaxel/efectos adversos , Ranitidina/efectos adversos , Estudios RetrospectivosRESUMEN
Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80-100 mg/m2) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance-expressed as relative difference in geometric means-was 6.8% (90% CI: -16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.
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Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. ©2017 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Taxoides/farmacocinética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Terapia Combinada , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Ensayos Clínicos Controlados Aleatorios como Asunto , Taxoides/administración & dosificación , Resultado del TratamientoAsunto(s)
Carcinoma Hepatocelular/diagnóstico , Cirrosis Hepática Biliar/complicaciones , Neoplasias Hepáticas/diagnóstico , Linfoma no Hodgkin/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Anciano , Antineoplásicos/uso terapéutico , Biopsia , Diagnóstico Diferencial , Imagen de Difusión por Resonancia Magnética , Resultado Fatal , Femenino , Humanos , Cirrosis Hepática Biliar/diagnóstico , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Primarias Múltiples/tratamiento farmacológico , Valor Predictivo de las Pruebas , Factores de Tiempo , Insuficiencia del TratamientoAsunto(s)
Densidad Ósea/genética , Huesos/metabolismo , Sitios Genéticos , Variación Genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Receptores alfa de Hormona Tiroidea/genética , Huesos/diagnóstico por imagen , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/genética , Humanos , Osteoporosis/diagnóstico por imagen , Osteoporosis/genética , Radiografía , Tirotropina/sangre , Tiroxina/sangreRESUMEN
OBJECTIVE: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels. DESIGN AND METHODS: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. RESULTS: For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively). CONCLUSIONS: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.
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Factores de Transcripción Forkhead/genética , Estudios de Asociación Genética/métodos , Transducción de Señal/fisiología , Tiroxina/sangre , Tiroxina/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Factores de Transcripción Forkhead/sangre , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Estudios Prospectivos , Hormonas Tiroideas/sangre , Hormonas Tiroideas/genéticaRESUMEN
The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T(3)) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked N-telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T(4)) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone.
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Sustitución de Aminoácidos/genética , Densidad Ósea/genética , Remodelación Ósea/genética , Cuello Femoral/enzimología , Yoduro Peroxidasa/genética , Polimorfismo de Nucleótido Simple/genética , Alanina/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Treonina/genéticaRESUMEN
Thyroid hormone is a pleiotropic hormone with widespread biological actions. For instance, adequate levels of thyroid hormone are critical for the development of different tissues such as the central nervous system, but are also essential for the regulation of metabolic processes throughout life. The biological activity of thyroid hormone depends not only on serum thyroid hormone levels, but is also regulated at the tissue level by the expression and activity of deiodinases, which activate thyroid hormone or mediate its degradation. In addition, thyroid hormone transporters are necessary for the uptake of thyroid hormone into target tissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a specific thyroid hormone transporter and the finding that mutations in this transporter lead to a syndrome of severe psychomotor retardation and elevated serum 3,3',5-tri-iodothyronine levels known as the Allan-Herndon-Dudley syndrome, the interest in this area of research has greatly increased. In this review, we will focus on the molecular aspects of thyroid hormone transporters, including MCT8, MCT10, organic anion transporting polypeptides, and the effects of genetic variation in these transporters.
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Sistemas de Transporte de Aminoácidos Neutros , Transportadores de Ácidos Monocarboxílicos , Transportadores de Anión Orgánico , Polimorfismo Genético , Hormonas Tiroideas/metabolismo , Secuencia de Aminoácidos , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animales , Genotipo , Humanos , Datos de Secuencia Molecular , Transportadores de Ácidos Monocarboxílicos/química , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Anión Orgánico/química , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Conformación Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Simportadores , Distribución TisularRESUMEN
INTRODUCTION: Thyroid function and genetic variation in the hypothalamus-pituitary-thyroid axis have been implicated in blood pressure regulation and susceptibility to hypertension. However studies conducted thus far were small with controversial results. OBJECTIVE: To examine whether serum thyroid parameters and polymorphisms in the type 2 deiodinase and the TSH receptor are associated with blood pressure and the presence of hypertension in two large cohorts of elderly subjects. DESIGN AND PARTICIPANTS: We studied a random sample of 1444 subjects of the Rotterdam study, and 997 subjects of the Rotterdam Scan study, two population-based cohort studies among elderly individuals aged 55-90 years. Outcome measurements Data on blood pressure and hypertension were obtained, and serum thyroid parameters, D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were determined. RESULTS: In contrast to previous findings, no consistent and/or significant associations were found between serum TSH and FT4 and blood pressure in both cohorts. In addition, the D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were not associated with blood pressure or the risk of hypertension. CONCLUSIONS: In two large populations of elderly subjects, neither serum thyroid parameters nor polymorphisms in the type 2 deiodinase and the TSH receptor, were associated with blood pressure or the presence of hypertension. Our data suggest that thyroid function is not an important determinant of hypertension in elderly Dutch subjects.
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Presión Sanguínea , Hipertensión/genética , Yoduro Peroxidasa/genética , Polimorfismo Genético , Receptores de Tirotropina/genética , Glándula Tiroides/fisiología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Países Bajos , Factores de Riesgo , Pruebas de Función de la Tiroides , Hormonas Tiroideas/sangre , Yodotironina Deyodinasa Tipo IIRESUMEN
INTRODUCTION: Genetic factors have a considerable influence on serum thyroid hormone levels. The C785T and A1814G polymorphisms, located in the 3' untranslated region of the type 1 deiodinase (D1) gene have been associated with serum FT4 and rT3 levels. OBJECTIVE: In healthy Danish twins, we examined the association of these polymorphisms with serum thyroid hormone levels and determined the proportion of genetic influence explained by these variants. We analysed the underlying functional mechanism by performing mRNA stability measurements and analysed the effect of these variants on D1 activity. METHODS: Serum thyroid measurements and genotypes of the D1-C785T and D1-A1814G polymorphisms were determined in 1192 twins. Structural equation modelling was used to determine heritability estimates. Functional analyses were carried out in D1-transfected JEG3 cells. RESULTS: Carriers of the D1-785T allele had 3.8% higher FT4 and 14.3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio. This polymorphism explained 0.87% and 1.79%, respectively, of the variation in serum FT4 and rT3. The D1-A1814G polymorphism was not associated with serum thyroid hormone levels. No differences in D1 mRNA decay rate or D1 activity were observed between wild-type D1 and the two variants. CONCLUSION: The D1-C785T polymorphism is consistently and significantly associated with serum thyroid hormone levels. However, the proportion of genetic influence explained by this particular polymorphism is small. No effect of the polymorphism on D1 mRNA decay rate or D1 activity was observed. The underlying functional mechanism needs to be elucidated.
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Variación Genética , Yoduro Peroxidasa/genética , Hormonas Tiroideas/sangre , Gemelos/genética , Adulto , Línea Celular , Dinamarca , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Gemelos/sangreRESUMEN
BACKGROUND: Triiodothyronine (T3) is used to potentiate the clinical effect of antidepressant drugs. Inter-individual differences in efficacy may be related to genetically-based variability in thyroid function. METHODS: DNA was obtained from 64 patients treated with sertraline plus T3 (SERT-T3, N=35) or plus placebo (SERT-PLB, N=29), for 8 weeks. Antidepressant efficacy was rated with the 21 item Hamilton Rating Scale for Depression (HRSD-21). Functional polymorphisms in type 1 (DIO1-C785T, DIO1-A1814G) and type 2 deiodinase (DIO2-Thr92Ala and DIO2-ORFa-Gly3Asp) were genotyped. RESULTS: DIO1-C785T was associated with efficacy of T3 but not placebo supplementation, as indicated by the interaction of treatment, DIO1-C758T genotype and time (p=0.04) and a stronger effect of SERT-T3 among DIO1-758T allele carriers (p=0.01). HRSD-21 scores of DIO1-758T allele carriers declined by 68.7+26.6% (mean+SD) over 8 weeks compared to 42.9+37.8% among non-carriers (p=0.02). DISCUSSION: DIO1 plays a key-role in T4 to T3 conversion and in clearance of the inactive metabolite, rT3. Previous data associate the DIO1-785T allele with lower DIO1 activity. This is consistent with our observation that responders to T3 supplementation had lower baseline serum T3 levels than non-responders. Depressed patients, who have a genetically determined lower T4 to T3 conversion, may be more likely to benefit from T3 supplementation.
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Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/genética , Yoduro Peroxidasa/genética , Sertralina/uso terapéutico , Triyodotironina/uso terapéutico , ADN , Trastorno Depresivo/enzimología , Quimioterapia Combinada , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Pruebas de Función de la Tiroides , Tirotropina/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
OBJECTIVE: Genetic factors exert considerable influence on thyroid function variables. Single nucleotide polymorphisms (SNPs) in thyroid hormone pathway genes have been associated with serum thyroid parameters implying small alterations in the hypothalamus-pituitary-thyroid axis. However, little is known about SNPs in the THRA (17q11.2) and THRB (3p24.2) genes. The aim of this study was to map THRA and THRB for the occurrence and frequencies of SNPs and relate these to thyroid parameters. DESIGN AND METHODS: SNPs were identified by sequencing all THRA and THRB exons and flanking regions in 52 randomly selected subjects. SNPs were genotyped in 1116 healthy Danish twins by TaqMan assays and related to thyroid parameters. One SNP in THRB was additionally genotyped in the elderly population of the Rotterdam Scan Study (n = 940). MAIN OUTCOME: 15 SNPs (7 novel) in THRA and THRB were identified. Two SNPs in the 3' untranslated region of THRA were genotyped: a novel SNP (2390A/G) and 1895C/A (rs12939700). In THRB, a synonymous (735C/T; rs3752874) and an intronic SNP (in9-G/A; rs13063628) were genotyped. No associations between SNPs and thyroid hormone levels (total and free 3,3',5-triiodo-L-thyronine [T3] and thyroxine, reverse T3) were found. THRB-in9-G/A was significantly associated with higher serum thyroid stimulating hormone (TSH) (p(lnTSH) = 0.01) in the Danish twins, but not in subjects of the Rotterdam Scan Study, although it showed a similar trend. CONCLUSIONS: Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins.
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Polimorfismo de Nucleótido Simple , Receptores alfa de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/genética , Adulto , Anciano , Dinamarca , Femenino , Humanos , Masculino , Países Bajos , Hormonas Tiroideas/sangre , Tirotropina/sangreRESUMEN
Organic anion transporting polypeptide (OATP) 1C1 has been characterized as a specific thyroid hormone transporter. Based on its expression in capillaries in different brain regions, OATP1C1 is thought to play a key role in transporting thyroid hormone across the blood-brain barrier. For this reason, we studied the specificity of iodothyronine transport by OATP1C1 in detail by analysis of thyroid hormone uptake in OATP1C1-transfected COS1 cells. Furthermore, we examined whether OATP1C1 is rate limiting in subsequent thyroid hormone metabolism in cells cotransfected with deiodinases. We also studied the effect of genetic variation in the OATP1C1 gene: polymorphisms were determined in 155 blood donors and 1192 Danish twins and related to serum thyroid hormone levels. In vitro effects of the polymorphisms were analyzed in cells transfected with the variants. Cells transfected with OATP1C1 showed increased transport of T4 and T4 sulfate (T4S), little transport of rT3, and no transport of T3 or T3 sulphate, compared with mock transfected cells. Metabolism of T4, T4S, and rT3 by cotransfected deiodinases was greatly augmented in the presence of OATP1C1. The OATP1C1-intron3C>T, Pro143Thr, and C3035T polymorphisms were not consistently associated with thyroid hormone levels, nor did they affect transport function in vitro. In conclusion, OATP1C1 mediates transport of T4, T4S, and rT3 and increases the access of these substrates to the intracellular active sites of the deiodinases. No effect of genetic variation on the function of OATP1C1 was observed.
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Variación Genética , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo , Animales , Células COS , Chlorocebus aethiops , Estudios de Cohortes , Dinamarca , Haplotipos , Humanos , Radioisótopos de Yodo , Polimorfismo Genético , Sulfatos , Tiroxina/sangre , Transfección , Triyodotironina/sangre , GemelosRESUMEN
Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mock-transfected cells. Metabolism of iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174. Carriers of the OATP1B1-Ala174 allele had higher serum bilirubin, E1S, and T4S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism.
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Estrógenos/metabolismo , Hígado/metabolismo , Transportadores de Anión Orgánico/fisiología , Hormonas Tiroideas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Bilirrubina/metabolismo , Transporte Biológico/genética , Células COS , Chlorocebus aethiops , Estrona/análogos & derivados , Estrona/metabolismo , Femenino , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Modelos Biológicos , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple/fisiología , Sulfatos/metabolismo , Sulfobromoftaleína/farmacocinética , Tiroxina/análogos & derivados , Tiroxina/metabolismoRESUMEN
The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T(4)) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T(4)/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (CI) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T(4) did not have an increased QTc interval (3.2 ms (95% CI -1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% CI 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% CI -4.2, 6.3) in the fifth quintile of free T(4) in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T(4) had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% CI 1.20, 4.80)). High levels of free T(4) are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T(4) is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.
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Electrocardiografía , Tiroxina/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Tirotropina/fisiología , Tiroxina/sangreRESUMEN
INTRODUCTION: Some hypothyroid patients continue to have significant impairments in psychological well-being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood-brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, is considered to play a key role in delivering serum T4 to the brain. OBJECTIVE: To examine whether polymorphisms in OATP1C1 are determinants of well-being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3). DESIGN AND PARTICIPANTS: We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4-LT3 combination therapy. OUTCOME MEASUREMENTS: Different questionnaires on well-being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1-intron3C > T, OATP1C1-Pro143Thr and OATP1C1-C3035T polymorphisms were determined. RESULTS: Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1-intron3C > T and the OATP1C1-C3035T polymorphism, but not the OATP1C1-Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4-LT3 therapy. CONCLUSIONS: OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4-LT3 combination therapy. Future studies are needed to confirm these findings.
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Encéfalo/metabolismo , Depresión/genética , Fatiga/genética , Hipotiroidismo/genética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Cognición/fisiología , Depresión/complicaciones , Depresión/metabolismo , Fatiga/complicaciones , Fatiga/metabolismo , Ligamiento Genético , Terapia de Reemplazo de Hormonas , Humanos , Hipotiroidismo/complicaciones , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Persona de Mediana Edad , Especificidad de Órganos/genética , Transportadores de Anión Orgánico/metabolismo , Polimorfismo de Nucleótido Simple/fisiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Hormonas Tiroideas/administración & dosificación , Hormonas Tiroideas/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T(3)), free thyroxine (FT(4)), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships. DESIGN: We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma. METHODS: We measured BMD of the femoral neck and lumbar spine. FT(4), T(3), TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay. RESULTS: We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT(4) and T(3) levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index. CONCLUSION: We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.
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Densidad Ósea , Hormonas Tiroideas/sangre , Neoplasias de la Tiroides/sangre , Tirotropina/sangre , Absorciometría de Fotón , Adulto , Animales , Huesos , Estudios Transversales , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Tirotropina/genética , Receptores de Tirotropina/fisiología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9 x 10(-4)). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 x 10(-5) in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3',5,5'-tetraiodothyronine (T4) into the active thyroid hormone 3,3',5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.
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Predisposición Genética a la Enfermedad , Yoduro Peroxidasa/genética , Osteoartritis/genética , Femenino , Genoma Humano , Humanos , Yoduro Peroxidasa/metabolismo , Japón , Masculino , Persona de Mediana Edad , Países Bajos , Polimorfismo de Nucleótido Simple , Triyodotironina/metabolismo , Reino Unido , Yodotironina Deyodinasa Tipo IIRESUMEN
BACKGROUND: TSH and thyroid hormone may have independent effects on bone. In this study we investigated the association of TSH and free T4 (FT4) with different bone parameters in human subjects. TSH and FT4 are known to be associated with body mass index (BMI) and a higher BMI gives a higher bone mineral density (BMD). Thus, we aimed to determine whether the effects of TSH and FT4 on bone are mediated by BMI. As TSH exerts its biological effect through the TSH receptor (TSHR), the TSHR gene might be a candidate gene affecting bone mass. The TSHR-Asp727Glu polymorphism is associated with lower TSH levels. We therefore examined the association of this polymorphism with bone parameters. METHOD: Genotypes were determined by Taqman assay in 4934 elderly Caucasian men and women of the Rotterdam Study, of whom BMD and bone geometry data were available. Serum thyroid parameters were available in a random set of 1327 subjects. RESULTS: Femoral neck BMD as well as narrow neck BMD and cortical thickness increased with serum TSH. However, FT4 was more strongly and negatively associated with bone parameters. Regression models showed BMI-dependent and -independent effects of both TSH and FT4 on bone. Carriers of the TSHR-Glu(727) allele had a 2.3% higher femoral neck BMD. CONCLUSION: In line with the effect of TSH on bone in mice, serum TSH shows a positive trend with BMD in human subjects, a finding that is strengthened by the association between the TSHR-Asp727Glu polymorphism and femoral neck BMD. However, serum FT4 has a much greater influence on bone than TSH.