RESUMEN
BACKGROUND: Interest in potential adverse outcomes associated with maternal subclinical hypothyroidism (normal free T4, elevated thyroid-stimulating hormone (TSH)) has increased significantly over recent years. In turn, the frequency of maternal thyroid function testing has risen, despite universal thyroid function screening not being recommended, leading to a marked increase in referrals to obstetric endocrinology clinics. In 2017 the American Thyroid Association revised their diagnostic and management guidelines. Although welcome, these new guidelines contain recommendations that may cause confusion in clinical practice. AIM: To ensure uniform practice in the diagnosis and management of subclinical hypothyroidism in pregnancy across all Melbourne public hospitals. METHODS: Endocrinology and obstetric representatives from all Melbourne public hospital networks reviewed the 2017 American Thyroid Association guidelines and other relevant literature to develop a consensus for diagnosing and treating subclinical hypothyroidism during pregnancy in Melbourne. The consensus guidelines were then referred to the Endocrine Society of Australia for comment and endorsement. RESULTS: Consensus was achieved and the guidelines were endorsed by the Council of the Endocrine Society of Australia. Trimester and assay-specific TSH reference intervals derived from healthy local populations should be used, where available. When unavailable, a TSH cut-off of 4 mU/L (replacing the previously recommended 2.5 mU/L) should be used to initiate treatment, irrespective of thyroid auto-antibody status. The recommended starting dose of levothyroxine is 50 µg daily, with a therapeutic TSH target of 0.1-2.5 mU/L. Levothyroxine should generally be ceased after delivery, with some exceptions. Hospitals will ensure smooth transfer of care back to the woman's general practitioner with clear documentation of pregnancy thyroid management and a recommended plan for follow-up. CONCLUSION: Fewer women will be classified as having subclinical hypothyroidism during pregnancy, which is likely to lead to reductions in emotional stress, hospital visits, repeated blood tests and financial costs. Uniform clinical practice will occur across Melbourne.
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Hipotiroidismo/diagnóstico , Hipotiroidismo/tratamiento farmacológico , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/tratamiento farmacológico , Tiroxina/administración & dosificación , Adulto , Australia , Consenso , Femenino , Hospitales Públicos , Humanos , Hipotiroidismo/sangre , Guías de Práctica Clínica como Asunto , Embarazo , Complicaciones del Embarazo/sangre , Valores de Referencia , Pruebas de Función de la TiroidesRESUMEN
OBJECTIVE: To investigate the safety, tolerability and efficacy of combination phentermine and topiramate therapy for maintenance of weight loss. DESIGN, SETTING AND PATIENTS: Retrospective audit of patients attending the Austin Health Weight Control Clinic who were dispensed phentermine-topiramate between 22 January 2010 and 16 July 2012 and after reaching a target weight by following a very low energy diet (VLED). Data collection continued until July 2013. MAIN OUTCOME MEASURES: Number of patients who ceased pharmacotherapy; duration of use of pharmacotherapy; types and numbers of adverse effects; and mean weight and blood pressure measurements at the initial visit, the end of the VLED and the last observation during pharmacotherapy. RESULTS: Data were available for 103 patients who were dispensed phentermine-topiramate; 61 patients ceased combination pharmacotherapy before the end of the data collection period, 41 due to adverse effects (eg, paraesthesia, cognitive changes, dry mouth and depression). The mean duration of use of pharmacotherapy was 10 months. Mean weight decreased by 10% due to the VLED (from 135.5 kg to 122.5 kg) and this loss was maintained. For 30 patients who continued on phentermine-topiramate, the mean duration of pharmacotherapy was 22 months and the mean weight decreased by 6.7 kg between the end of the VLED and the last observation during pharmacotherapy. CONCLUSION: Phentermine-topiramate therapy was not well tolerated; more than half of the patients in our study stopped taking it because of adverse effects, and more than half of the adverse events reported were ascribed to topiramate. However, in those able to continue with pharmacotherapy, the combination was efficacious for both maintenance of weight loss and ongoing weight loss.
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Fármacos Antiobesidad/administración & dosificación , Fructosa/análogos & derivados , Obesidad/tratamiento farmacológico , Fentermina/administración & dosificación , Pérdida de Peso , Fármacos Antiobesidad/efectos adversos , Australia/epidemiología , Índice de Masa Corporal , Quimioterapia Combinada , Estudios de Seguimiento , Fructosa/administración & dosificación , Fructosa/efectos adversos , Humanos , Auditoría Médica , Obesidad/epidemiología , Fentermina/efectos adversos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Topiramato , Insuficiencia del Tratamiento , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
It is unknown if high prolactin levels during pregnancy contribute to the development of gestational diabetes. We hypothesized that higher prolactin levels are associated with reduced glucose tolerance, as determined by higher 2-h glucose level from an oral glucose tolerance test in pregnancy. The 75-g oral glucose tolerance test was carried out at 28 weeks of gestation in 69 participants. A multiple regression analysis was used to determine the relationship between serum prolactin and 2-h glucose levels. Multivariable regression analysis showed an independent and significant relationship between third trimester prolactin and 2-h glucose levels post oral glucose tolerance test. Higher prolactin levels were associated with higher glucose levels independent of age, body mass index, gravidity and parity. Higher prolactin levels associated with reduced glucose tolerance in the third trimester of pregnancy suggests the possible independent role of prolactin in the pathogenesis of gestational diabetes.
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Glucemia/metabolismo , Prolactina/sangre , Adulto , Diabetes Gestacional/sangre , Femenino , Edad Gestacional , Prueba de Tolerancia a la Glucosa , Humanos , Embarazo , Tercer Trimestre del EmbarazoRESUMEN
CONTEXT: Combined pituitary hormone deficiency (CPHD) in humans is caused by mutations of pituitary-specific transcription factors such as Pit-1. Although many patients with CPHD have an autosomal recessive disorder caused by a Pit-1 DNA-binding mutation, there are a number of reports of mutant Pit-1 molecules that either by prediction or through experimentation bind normally to DNA. OBJECTIVE: The objective of this study was to understand the pathophysiological mechanisms of mutant Pit-1 molecules with intact DNA binding. DESIGN: DNA-binding and functional studies were used to assess five Pit-1 mutations: F135C, R143Q, A158P, K216E, and R271W. RESULTS: In gel-shift studies using well-characterized DNA-binding elements from the GH and prolactin genes, the K126E mutant displayed markedly enhanced Pit-1 dimer binding to either element, whereas the R271W mutant bound with high avidity, but only as a monomer. In contrast, the R143Q mutant was unable to bind these elements, and the F135C and A158P mutants displayed near-normal DNA-binding characteristics. We observed that CBP/p300 bound poorly to the A158P and K216E mutant Pit-1 molecules, but bound normally to the F135C, R143Q, and R271W mutants. In functional assays, CBP/p300 cotransfection with mutant Pit-1 expression vectors resulted in less transactivation of either the GH or prolactin reporter genes. CONCLUSIONS: From these studies, we suggest that CBP/p300 recruitment and Pit-1 dimerization are necessary for Pit-1 target gene activation and are important in the pathogenesis of CPHD.
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Hipopituitarismo/genética , Hormonas Hipofisarias/deficiencia , Factor de Transcripción Pit-1/genética , Factores de Transcripción p300-CBP/fisiología , Secuencia de Bases , Células Cultivadas , Ensayo de Cambio de Movilidad Electroforética , Genes Reporteros/genética , Humanos , Luciferasas/genética , Modelos Moleculares , Unión Proteica , Activación Transcripcional/genética , TransfecciónRESUMEN
OBJECTIVE: Transforming growth factor-beta (TGF-beta) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-beta synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-beta in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS: Twenty-one subjects with hypertension and AER between 10 and 200 microg/min were randomized to receive either 50 mg losartan daily (n = 11) or placebo (n = 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular- or low-sodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-beta concentration, TGF-beta urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion. RESULTS: Plasma TGF-beta was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-beta excretion decreased by 23.2% (-39.2 and 13.6) [median (interquartile range)] and 38.5% (-46.8 and -6.1) in the regular- and low-sodium phases, respectively (P < 0.05 for drug effect). In the placebo group, median changes of 0.0% (-12.1 and 44.4) and 0.0% (-29.2 and 110.7) occurred in the regular- and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-beta excretion in either losartan- or placebo-treated patients (P = 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P = 0.29). CONCLUSIONS: In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-beta excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-beta production.
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Albuminuria , Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/orina , Dieta Hiposódica , Hipertensión/orina , Losartán/uso terapéutico , Sodio/orina , Factor de Crecimiento Transformador beta/orina , Análisis de Varianza , Presión Sanguínea , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/orina , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipertensión/sangre , Masculino , Persona de Mediana Edad , Placebos , Análisis de RegresiónRESUMEN
OBJECTIVE: Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10-200 microg/min. RESEARCH DESIGN AND METHODS: In this study, 20 subjects were randomized to losartan 50 mg/day (n = 10) or placebo (n = 10). Drug therapy was given in two 4-week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low- or regular-sodium diets, in random order. In each phase, 24-h ambulatory blood pressure, urinary albumin-to-creatinine ratio (ACR), and renal hemodynamics were measured. RESULTS: Achieved urinary sodium on a low-sodium diet was 85 +/- 14 and 80 +/- 22 mmol/day in the losartan and placebo groups, respectively. In the losartan group, the additional blood pressure-lowering effects of a low-sodium diet compared with a regular-sodium diet for 24-h systolic, diastolic, and mean arterial blood pressures were 9.7 mmHg (95% confidence interval [CI], 2.2-17.2; P = 0.002), 5.5 mmHg (2.6-8.4; P = 0.002), and 7.3 mmHg (3.3- 11.3; P = 0.003), respectively. In the losartan group, the ACR decreased significantly on a low-sodium diet versus on a regular-sodium diet (-29% [CI -50.0 to -8.5%] vs. + 14% [-19.4 to 47.9%], respectively; P = 0.02). There was a strong correlation between fall in blood pressure and percent reduction in the ACR (r = 0.7, P = 0.02). In the placebo group, there were no significant changes in blood pressure or ACR between regular- and low-sodium diets. There were no significant changes in renal hemodynamics in either group. CONCLUSIONS: These data demonstrated that a low-sodium diet potentiates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low-sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent.
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Antihipertensivos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Dieta Hiposódica , Hemodinámica/fisiología , Losartán/uso terapéutico , Albuminuria , Aldosterona/sangre , Angiotensina II/metabolismo , Glucemia/metabolismo , Creatinina/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sinergismo Farmacológico , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Placebos , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Renina/sangre , Sodio/orinaRESUMEN
The aim of this study is to assess the effects of age on (1) the ability of a spot albumin-creatinine ratio (ACR) to accurately predict 24-hour albumin excretion rate (AER), and (2) the performance of spot ACR as a screening test for microalbuminuria. Three hundred fourteen patients with diabetes aged 18 to 84 years attending a tertiary outpatient clinic underwent one 24-hour urine collection and, immediately after completion, provided one fasting spot morning urine sample. Twenty-four-hour AER and spot ACR were determined. Performance of spot ACR was assessed according to age and sex. Fifty-three percent of men and 32% of women had an AER of 20 microg/min or greater. Multiple regression analysis showed age was an independent predictor of spot ACR. For an AER of 20 microg/min for patients in the age range of 40 to 80 years, there was an increase in corresponding values for spot ACR from 18.2 mg/g (95% confidence interval [CI], 15.6 to 21.3) to 32.5 mg/g (95% CI, 27.5 to 38.4) in men and from 22.1 mg/g (95% CI, 18.0 to 27.1) to 56.4 mg/g (95% CI, 47.2 to 67.4) in women. Using ACR cutoff values of 22.1 mg/g or greater and 30.9 mg/g or greater in conventional units (equivalent to > or =2.5 and > or =3.5 mg/mmol in SI units) in men and women, the spot ACR provided high sensitivities (men, 95.7%; women, 93.35%) and had excellent receiver operator characteristic curves, respectively. However, the spot ACR false-positive rate increased with age from 15.9% (age, 40 to 65 years) to 31.8% (>65 years) in men and from 10.5% (age, 45 to 65 years) to 28.3% (>65 years) in women. Spot ACR is a good screening test for microalbuminuria, but a poor predictor of quantitative AER, and should not be used as a diagnostic test. The increase in spot ACR relative to 24-hour AER with age supports the use of sex- and age-adjusted ACR cutoff values.
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Albuminuria/diagnóstico , Albuminuria/orina , Creatinina/orina , Nefropatías Diabéticas/diagnóstico , Tamizaje Masivo/normas , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Nefropatías Diabéticas/orina , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Curva ROC , Análisis de Regresión , Sensibilidad y Especificidad , Factores SexualesRESUMEN
BACKGROUND: Trimester-specific reference intervals (RIs) for thyroid function tests are lacking for Beckman Dxl 800 analysers. We aimed to establish RIs for thyroid stimulating hormone (TSH), free thyroxine (fT4) and to track intraindividual changes in thyroid function throughout pregnancy. METHODS: One hundred and thirty healthy women without antithyroid peroxidase antibodies were followed longitudinally. Thyroid function was determined at trimester-1 (T1): 9-13 weeks; trimester-2 (T2): 22-26 weeks; trimester-3 (T3): 35-39 weeks and postpartum (PP): 8-12 weeks. A subgroup (n = 47) was used to track intraindividual changes using PP as non-pregnant state (baseline). RESULTS: For trimesters 1-3, TSH (median (2.5th, 5th, 95th and 97.5th percentile)) was 0.77 (0.03, 0.05, 2.33, 3.05), 1.17 (0.42, 0.47, 2.71, 3.36) and 1.35 (0.34, 0.42, 2.65, 2.83) mIU/L, respectively. Free T4 (mean (95%CI)) was 10.7 (5.9-15.5), 8.1 (4.9-11.3), 7.8 (4.5-11.0) pmol/L, respectively. In T2 and T3, 36% and 41% of the fT4 values, respectively, fell below the non-pregnancy lower normal limit. In the subgroup assessed for longitudinal changes, of the women with baseline TSH ≤ median, 71-75% remained at or below the corresponding median for trimesters 1-3. Of the women with baseline fT4 ≤ median, 69-81% also remained at or below the corresponding median for trimesters 1-3. High correlation was observed at different trimesters and baseline for TSH (Spearman's r: 0.593-0.846, P < 0.001) and for fT4 (r: 0.480-0.739, P < 0.001). CONCLUSIONS: Use of trimester-specific RIs would prevent misclassification of thyroid function during pregnancy. In the majority of women, TSH and fT4 tracked on the same side of the median distribution, from a non-pregnant baseline, throughout pregnancy.
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Embarazo/fisiología , Pruebas de Función de la Tiroides/normas , Adulto , Femenino , Humanos , Estudios Longitudinales , Embarazo/sangre , Trimestres del Embarazo/sangre , Trimestres del Embarazo/fisiología , Estándares de Referencia , Tirotropina/sangre , Tiroxina/sangreRESUMEN
OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.