Doses Of L-thyroxine Research Articles

Glucose tolerance and lipid profile in longterm exogenous subclinical hyperthyroidism and the effects of restoration of euthyroidism, a randomised controlled trial

The impact of prolonged subclinical hyperthyroidism on glucose and lipid metabolism is unclear. Therefore, we evaluated glucose and lipid metabolism in patients with differentiated thyroid carcinoma (DTC) on TSH suppressive thyroxine therapy as a model for subclinical hyperthyroidism and investigated whether restoration to euthyroidism affects metabolism. We performed a prospective, single-blinded, placebo-controlled, randomised trial of 6 months duration with 2 parallel groups. Twenty-five subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with l-thyroxine completed the study. l-thyroxine dose was replaced by study medication containing l-thyroxine or l-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group, 13 patients) and euthyroidism (euthyroidism group, 12 patients). We evaluated glucose metabolism by glucose tolerance test and HOMA (IR) and lipid metabolism by lipid profile. In addition, we measured plasma concentrations of glucoregulatory hormones. At baseline, glucose tolerance, HOMA (IR), lipid profile and plasma concentrations of glucoregulatory hormones were within the normal range. No significant differences between the low TSH and euthyroidism group were observed. After 6 months, neither glucose nor lipid metabolism in the low TSH group were different from baseline values. In summary, glucose and lipid metabolism in patients with DTC and long-term subclinical hyperthyroidism in general are not affected. Restoration of euthyroidism in general does not affect glucose and lipid metabolism.

Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients

Standard drug information resources recommend that l-thyroxine be taken half an hour before breakfast on an empty stomach, to prevent interference of its intestinal uptake by food or medication. We observed cases in which TSH levels improved markedly after changing the administration time of l-thyroxine to the late evening. We therefore conducted a pilot-study to investigate whether l-thyroxine administration at bedtime improves TSH and thyroid hormones, and whether the circadian rhythm of TSH remains intact. DESIGN Patients were studied on two occasions: on a stable regimen of morning thyroxine administration and two months after switching to night-time thyroxine using the same dose. On each occasion patients were admitted for 24 h and serial blood samples were obtained. We investigated 12 women treated with l-thyroxine because of primary hypothyroidism, who used no medication known to interfere with l-thyroxine uptake. Patients were admitted to hospital and blood samples were obtained at hourly intervals for 24 h via an indwelling catheter. Following this first hospital admission, all women were asked to switch the administration time from morning to bedtime or vice versa. After 2 months they were readmitted for a 24-h period of hourly blood sampling. Blood samples were analysed for serum TSH (immunometric assay), FT4 and T3 (competitive immunoassay), T4 and rT3 (radioimmunoassay), serum TBG (immunometric assay) and total protein and albumin (colourimetric methods). A significant difference in TSH and thyroid hormones was found after switching to bedtime administration of l-thyroxine. Twenty-four-hour average serum values amounted to (mean +/- SD, morning vs bedtime ingestion): TSH, 5.1 +/- 0.9 vs 1.2 +/- 0.3 mU/l (P < 0.01); FT4, 16.7 +/- 1.0 vs 19.3 +/- 0.7 pmol/l (P < 0.01); T3, 1.5 +/- 0.05 vs 1.6 +/- 0.1 nmol/l (P < 0.01). There was no significant change in T4, rT3, albumin and TBG serum levels, nor in the T3/rT3 ratio. The relative amplitude and time of the nocturnal TSH surge remained intact. l-thyroxine taken at bedtime by patients with primary hypothyroidism is associated with higher thyroid hormone concentrations and lower TSH concentrations compared to the same l-thyroxine dose taken in the morning. At the same time, the circadian TSH rhythm stays intact. Our findings are best explained by a better gastrointestinal uptake of l-thyroxine during the night.

Thyroid hormone in hypopituitarism, Graves’ disease, congenital hypothyroidism, and maternal thyroid disease during pregnancy

Although measurement of serum thyroid-stimulating hormone (TSH) is the single best test to diagnose thyroid disorders and monitor treatment, there are certain situations in which the TSH level cannot be used as a guideline. In the diagnosis of children with hypopituitary hypothyroidism, TSH is often “inappropriately” normal. Treatment is aimed at adjusting the l-thyroxine dose to maintain the serum free thyroxine (T4) in the upper half of the normal range for age. In children with Graves’ disease, serum TSH can be suppressed for several months after a euthyroid state is restored, so the clinician must rely on serum free T4 and triiodothyronine (T3) levels. Up to 30% of infants and 10% of children with congenital hypothyroidism have a mildly elevated TSH level despite other indications that the thyroid hormone dosage is correct. Such resistance to thyroid hormone at the pituitary gland diminishes with age. Pregnancy is another condition in which serum TSH levels are altered (slightly lower); in this situation, it is the result of elevated human chorionic gonadotropin levels that cross-react with the TSH receptor. This alteration must be taken into account when diagnosing or treating maternal thyroid disorders during pregnancy.

Quality of life in longterm exogenous subclinical hyperthyroidism and the effects of restoration of euthyroidism, a randomized controlled trial

The impact of prolonged subclinical hyperthyroidism on quality of life is unclear. Therefore, we evaluated quality of life in patients with differentiated thyroid carcinoma (DTC) on TSH-suppressive thyroxine therapy as a model for subclinical hyperthyroidism and we investigated whether restoration to euthyroidism affects quality of life. We performed a prospective, single-blinded, placebo-controlled, randomized trial of 6 months' duration with two parallel groups. Twenty-four subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with L-thyroxine completed the study. L-thyroxine dose was replaced by study medication containing L-thyroxine or L-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group) and euthyroidism (euthyroid group). Both groups consisted of 12 patients. We evaluated quality of life using five validated questionnaires. At baseline, the somatic disorder questionnaire (SDQ) indicated more somatic dysfunction in patients as compared with reference values, whereas the depression score (HADS) revealed a better score than the reference group. All other quality of life parameters were normal. At baseline, no significant differences between the low-TSH and the euthyroidism groups were observed. After 6 months, none of the quality of life parameters in the low-TSH group was different from baseline values. In the euthyroid group, motivation was significantly improved (Multidimensional Fatigue Index-20, P = 0.003), although this parameter did not differ from the reference group at baseline. A probable worsening in role limitations as a result of physical problems (Short Form-36; P = 0.050) was observed. No improvement in the SDQ score was observed. In summary, quality of life in patients with DTC and long-term subclinical hyperthyroidism in general is preserved. Restoration of euthyroidism in general does not affect quality of life.

Effects on Bone Mineral Density by Treatment of Benign Nodular Goiter with Mildly Suppressive Doses of L-Thyroxine in a Cohort Women Study

Objectives: Thyroid diseases and their treatment may influence the osseous system. The influence that prolonged suppressive L-thyroxine (LT4) therapy may have on inducing subclinical hyperthyroidism on bone metabolism is still a matter of debate. The aim of the present study was to assess the effects of chronic LT4 treatment at mildly inhibiting serum thyroid-stimulating hormone (TSH) doses on bone mineral density (BMD) and biochemical bone remodeling markers in a cohort of women with benign nodular goiter, and to verify the efficacy of the treatment on nodule size. Subjects and Study Design: A total of 200 euthyroid Caucasian women with nodular goiter (age 52.1 ± 9; 80 pre- and 120 postmenopausal) were enrolled: 96 had been treated with LT4 for at least 3 years and a matched group of 104 had untreated goiter. LT4 therapy was given at a dose sufficient to reduce TSH under the lower limit of the normal range (0.27–4.20 µIU/ml) without suppressing it below the limit of assay sensitivity (0.005 µIU/ml) and maintaining normal serum values of free triiodothyronine (FT3) and free thyroxine (FT4). The adequacy of the dose was evaluated on the basis of serum TSH levels. The osteopenic effect of LT4 treatment was evaluated directly by total body and lumbar spine dual-energy X-ray absorptiometry (DEXA) and indirectly by biochemical parameters (alkaline phosphatase, osteocalcin, calcium, parathyroid hormone) at the baseline and throughout the follow-up. The efficacy of LT4 schedule on thyroid nodule size was assessed on the basis of the ultrasonographic evaluation. Results: Mineralometric data showed no significant difference between BMD values for treated and untreated patients in both pre- and postmenopausal status. In all patients, serum markers of bone turnover were in the normal range, with no differences in the treated and control groups. The TSH concentrations were significantly lower in treated than in untreated patients (p < 0.0001); FT3 and FT4 were in the normal range for all patients. Evaluation of nodule size during follow-up showed a reduction of ≧30% in 32 of 96 treated patients (33.3%) versus none in those untreated, whilst nodule size remained unmodified in 60 treated patients (62.5%) versus 35 (33.6%) in those untreated, and an increase in nodule size and/or development of new nodules was found in 4 treated patients (4.2%) versus 69 of the 104 untreated patients (66.3%). Conclusions: This study suggests that at slightly suppressing TSH doses, LT4 therapy has no adverse effects on BMD in both pre- and postmenopausal women, while having an efficacy on nodule size comparable with that reported using an LT4 schedule able to maintain TSH near or below the assay sensitivity limit.

Neurodevelopmental Outcomes in Congenital Hypothyroidism: Comparison of Initial T 4 Dose and Time to Reach Target T 4 and TSH

To compare neurodevelopmental outcomes in severe and moderate congenital hypothyroidism (CH) among 3 different initial L-thyroxine doses and to examine the effect of the time to thyroid function normalization on neurodevelopmental outcomes. Neurodevelopmental assessments of 31 subjects included the Mullen Scales of Early Learning, Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, and Child Behavioral Checklist. Subjects started on higher initial L-thyroxine doses (50 mug) had full-scale IQ scores 11 points higher than those started on lower (37.5 mug) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ among the 3 treatment cohorts. Subjects with moderate CH had higher full-scale IQ scores than subjects with severe CH, regardless of the initial treatment dose. Subjects who took longer than 2 weeks to normalize thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function at 1 or 2 weeks of therapy. Initial L-thyroxine dose and faster time to normalization of thyroid function are important to optimal neurodevelopmental outcome. In severe CH, it is important to choose an initial dose at the higher end of the recommended range to achieve these goals.

Hipotiroidismo autoimune refratário a altas doses de levotiroxina e hipocalcemia grave

The factors that make difficult the normalization of TSH in hypothyroidism need special attention because some patients on thyroxine replacement do not maintain a normal TSH. We report a 50 year-old woman with autoimmune hypothyroidism of difficult compensation, associated with anemia, hypocalcemia with a previous episode of tetany, hypomagnesemia, psychologic alterations and important weight loss. After compensation of the hypothyroidism with doses of L-thyroxine as high as 325 microg/day, the hypothesis of a malabsorptive syndrome was raised. Celiac disease was confirmed by elevated serum antigliadin antibody. A gluten-free diet was instituted which improved the symptoms associated with malabsorption and reduced the L-thyroxine requirement to 125 microg/day. Because several studies have shown an association of both diseases, a routine screening for celiac disease has been widely proposed in patients with autoimmune thyroid disease.

Hip bone mineral density, bone turnover and risk of fracture in patients on long-term suppressive L-thyroxine therapy for differentiated thyroid carcinoma

Untreated hyperthyroidism and treatment with high doses of thyroid hormone are associated with osteoporosis. However, their effect on bone turnover, their contribution to bone mineral density (BMD) in the context of other clinical risk factors for osteoporosis and the prevalence of vertebral fractures is not well documented. Cross-sectional study. We studied 59 patients receiving L-thyroxine suppressive therapy for differentiated thyroid carcinoma (DTC). BMD of the hip was measured by dual X-ray absorptiometry (DXA) and lateral DXA pictures of the lumbar and thoracic vertebrae were performed. Bone resorption was measured by C-telopeptides of type I collagen (ICTP) and bone formation by procollagen type I N-propeptide (PINP). Clinical risk factors for osteoporosis were evaluated using a questionnaire. Z-scores of BMD were similar as the NHANES (National Health and Nutrition Examination Survey) III reference group in women and men, also after long-term (> 10 years) suppression therapy. Patients in the lowest and highest quartile of BMD showed significant differences in the presence of clinical risk factors. ICTP levels were significantly higher than in age-matched controls, PINP levels were not different. We found four patients with a prevalent vertebral fracture. We conclude that patients with well-differentiated thyroid carcinoma are not at increased risk of developing low bone mass nor have a higher prevalence of vertebral fracture at least when treated with relatively low doses of L-thyroxine.

Sympatho-vagal control of heart rate variability in patients treated with suppressive doses of L-thyroxine for thyroid cancer

This study aimed to analyze the autonomic control of heart rate variability (HRV) in subjects receiving chronic l-thyroxine (l-T4) treatment after total thyroidectomy and (131)I therapy for differentiated thyroid carcinoma. Blood pressure (BP) and sympatho-vagal activity (evaluated by power spectral analysis (PSA) of time-domain parameters of HRV) were studied in clinostatism and after orthostatism in 24 healthy controls, and in 12 patients taking l-T4 (125-200 mug/day) to maintain serum TSH levels at <0.01 muIU/ml. The study of HRV by PSA is a non-invasive method of analyzing sympatho-vagal control of HRV by quantifying high-frequency (HF) (0.15-0.4 Hz) and low-frequency (LF) (0.04-0.15 Hz) powers. Patients on L-T4 treatment had undetectable TSH levels, serum free T4 (fT4) above the normal range or at the upper limit in one case, and normal free tri-iodothyronine (fT3) levels. Heart rate and R-R intervals were not different in the two groups, both in clinostatism and in ortostatism. Systolic and mean BP were higher in patients than in controls and were inversely correlated with actual serum fT4 levels. During clinostatism, thyroid patients showed significantly lower LF power (P = 0.035), LF/(LF + HF) (P = 0.008) and LF/HF (P = 0.01) than controls. When patients moved from lying to standing, there was a significantly different decrease in orthostatic LF power (P = 0.001), LF/(LF + HF) (P = 0.044) and LF/HF (P = 0.047) versus controls. Changes in autonomic control of HRV, characterized by decreased sympathetic activity and impaired sympatho-vagal balance with preserved vagal tone, are detectable in patients with hyperthyroxinemia due to suppressive l-T4 therapy and increased systolic and mean, but not diastolic, BP.

Pituitary Hyperplasia Secondary to Primary Hypothyroidism: A Case Report and Review of the Literature

Pituitary hyperplasia secondary to primary hypothyroidism has been reported in the literature in both adults and children. We report a case of a young woman who was diagnosed with hypothyroidism in her teenage years. Despite frequent follow-up, her TSH levels remained greater than 100 mIU/ml. A few years later, pituitary enlargement was found on an MRI at a time when her TSH was 177 mIU/ml and her free T4 was 0.2 ng/dl. Observed administration of 600 mcg of L-thyroxine was performed to determine the effectiveness of hormone absorption. Total T4 levels of 0.2 rose to 7.1 mcg/dl at two hours with a decrease in her TSH levels from 88.6 to 66.8 mIU/ml at 24 hours. With the exception of one short period, her TSH levels have remained elevated over eight years of observation without change in the size of the pituitary mass. In our review of the literature, primary uncontrolled hypothyroidism has been described as a precursor to pituitary hyperplasia. In these patients, TSH-secreting adenomas were distinguished from pituitary hyperplasia by a blunted TRH stimulation test, elevated alpha subunit concentration values, and elevated alpha subunit concentration/TSH ratios. TSH levels ranged from 98 to 732 mIU/ml in adults, and even higher values in children. Following adequate hormone replacement with L-thyroxine doses of 25 to 300 mcg/day, both symptoms and pituitary hyperplasia regressed on average within a few months.

Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing l-Thyroxine plus Liothyronine with l-Thyroxine Alone

Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results. To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland. Randomized, double-blind, crossover trial. Academic research hospital. 28 women with overt primary hypothyroidism. Crossover trial comparing treatment with l-thyroxine, 100 microg/d (standard treatment), versus treatment with L-thyroxine, 75 microg/d, plus liothyronine, 5 microg/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d (add-on combination treatment), for a final 8-week add-on period. Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes. Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015). Treatment with L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d, was an add-on regimen and was not randomized. Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

Exogenous Subclinical Hyperthyroidism During Adolescence: Effect on Peak Bone Mass

Chronic subclinical hyperthyroidism induced by suppressive doses of L-thyroxine (L-T4) therapy, so-called exogenous subclinical hyperthyroidism, may cause diminished bone mass in postmenopausal women. The effect of subclinical hyperthyroidism during childhood and adolescence on peak bone mass, however, has not been evaluated. To determine whether exogenous subclinical hyperthyroidism during adolescence, the period of critical bone mass acquisition, would reduce peak bone mass. Eighteen female adolescents and young adults with Hashimoto's thyroiditis and euthyroid goiter (aged 22.4 +/- 4.4 years) who had been treated with suppressive doses of L-T4, 127.5 +/- 23.7 microg/day, during adolescence (age at onset of subclinical hyperthyroidism, 14.2 +/- 1.5 years) for 6.3 +/- 3.4 years were enrolled in the study. Twenty-nine healthy female volunteers matched for age, weight, height and body mass index served as the controls. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. BMD of the lumbar spine, radius, Ward's triangle and total body were comparable in the two groups. In contrast, BMD of the femoral neck, trochanter and shaft of patients was slightly higher than those of controls. There were no correlations between BMD values and clinical parameters. Exogenous subclinical hyperthyroidism during adolescence has no demonstrable detrimental effect on peak bone mass attainment.

High Prevalence of Congenital Hypothyroidism in the Greek Cypriot Population: Results of the Neonatal Screening Program 1990- 2000

To evaluate the results of the screening program for congenital hypothyroidism (CH) in the Greek Cypriot population. During 1990-2000, 109,532 neonates were screened by TSH determination. Permanent CH was proven with biochemical findings after discontinuation of treatment for scintigraphy at the age of 3 years. Permanent CH was diagnosed in 61 infants, incidence 1/1800, with female/male ratio 2.05/1. The most common clinical findings were omphalocele (61%), large anterior fontanelles (49%) and edema of the eyelids (34%). The more delayed the bone maturation, the lower were initial T4 levels (p = 0.005). Bone maturation tended to be more advanced in thyroid hypoplasia and more delayed in thyroid agenesis (p = 0.049). Scintigraphy of the thyroid with TC99 revealed ectopia in 38%, thyroid agenesis in 36%, thyroid hypoplasia in 24% and dyshormonogenesis in 1.7%. Children with transient CH had significantly lower T4 and higher TSH values initially compared to those with permanent CH after birth; initial TSH level, however, failed to predict the nature of CH. Children with transient CH required less thyroxine dosage to maintain normal thyroid hormone levels and they had a normal thyroid gland on scintigraphy. The TSH level was normalized before the age of 2 months with a starting L-thyroxine dose of 10 microg/kg/daily. The incidence of primary CH in Greek Cypriots is 1/1800 live births. The most common etiology is thyroid dysgenesis. Initial T4 levels correlated with the degree of skeletal maturation and the etiology. Initial TSH level, although lower in children with transient CH, could not predict the nature of CH.

Effects of Psychiatric Disorders and Psychotropic Medications on Prolactin and Bone Metabolism

Osteoporosis occurs in common psychiatric conditions and causes significant morbidity. Many neuroleptic medications can cause hyperprolactinemia, which can then potentially be associated with bone loss. Few reviews have thus far addressed this issue. We have consolidated information from studies that examined effects of psychiatric conditions and their treatment on bone metabolism. We searched PubMed for original articles and reviews published between 1976 and 2004 that described changes in bone metabolism in psychiatric disorders and examined prolactin elevations with neuroleptic medications. Keywords used were major depressive disorder, bipolar disorder, schizophrenia, bone density, bone metabolism, hyperprolactinemia, typical antipsychotics, and atypical antipsychotics. 160 articles published in peer-reviewed journals were identified and are summarized, with greater emphasis given to data from larger, controlled studies. Schizophrenia and major mood disorders are often associated with perturbations in bone metabolism related to factors including nutritional alterations, smoking, and hypogonadotropic hypogonadism, with or without medication-induced hyperprolactinemia. Polydipsia can contribute to bone loss in schizophrenia, whereas hypercortisolemia is often associated with low bone density in depression. Lithium in bipolar disorder and thyroid-stimulating hormone-suppressive doses of L-thyroxine have a negative impact on bone health. Mood stabilizers such as carbamazepine and valproate can also affect bone density. Hyperprolactinemia may lead to bone loss only if associated with untreated amenorrhea in women or testosterone deficiency in men. Some atypical neuroleptics, by causing lesser elevations in prolactin, may therefore have a less marked impact on bone than typical neuroleptics. Because significant morbidity is associated with low bone density and many psychiatric conditions may have a negative impact on bone metabolism, bone density evaluation should be considered an integral component of chronic medical care of these disorders, and risk factors should be identified and addressed.

Effect of long-term l-thyroxine treatment on bone mineral density in young adults with congenital hypothyroidism

To evaluate whether long-term L-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or L-thyroxine dosages at the time of the study or during the pubertal period. The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged L-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.

Effects of thyroid hormone on the cardiovascular system.

Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.

Hypothyroidism as a risk factor for cardiovascular disease.

The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The "traditional" risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH >10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of L-thyroxine outweigh the risk.

Transient Congenital Hypothyroidism due to maternal autoimmune thyroid disease

The neonatal screening program for congenital hypothyroidism (CH) in Greece shows an overall incidence of the disease of 1:2321. The cases with permanent CH have an incidence of 1:2542, whereas the transient forms of CH account for 8.7% of all cases diagnosed as CH. Transplacental passage of maternal thyrotropin receptor-blocking antibodies is a rare cause of transient CH. In our program, a retrospective analysis of 508,358 screened newborns revealed 6 infants with transient CH caused by maternal thyroid autoimmunity, representing 2.7% of all cases of CH. All the newborns with transient CH, due to maternal autoimmune thyroid disease, had high serum TSH concentration (ranging from 98 to 689 mU/L), whereas serum thyroxine (T4) values were low normal to normal in 3 of them. Replacement therapy with L-thyroxine was initiated at a mean age of 6.5 days. The newborns with transient CH belonged to 4 families, one of which had 4 and another 2 children with the same pathology. Thyrotropin-receptor antibodies (TSH-R Abs), present at the initial examination in newborns' serum, had disappeared from the infants' circulation by the third month of life. One mother carried the Abs for at least 8 years during which period she delivered four babies. The diagnosis of transient CH should be suspected if the mother has autoimmune thyroid disease, if there are siblings with transient CH or if there is no need for an increase in L-thyroxine dose with advancing age. The diagnosis is very important for genetic counseling, early treatment initiation of subsequent offspring and adequate control of the mother's thyroid function during subsequent pregnancies so that any neurodevelopmental abnormality of the fetus could be avoided.

Initial treatment dose of L-thyroxine in congenital hypothyroidism

Objectives: To determine the optimal initial treatment dose of L-thyroxine in congenital hypothyroidism (CH) by evaluating the time course of rise of thyroxine (T4) and free T4 concentrations into an established “target range” and normalization of thyroid-stimulating hormone (TSH) and to reevaluate the “target range” for T4 and free T4 concentrations during the first 2 weeks of CH treatment. Study design: Infants of birth weight 3 to 4 kg with CH (n = 47) detected by newborn screening were randomly assigned into three L-thyroxine treatment dose arms: 37.5 μg/day (group 1); 62.5 μg/day for 3 days, then 37.5 μg/day (group 2); and 50 μg/day (group 3). Serum T4, free T4, triiodothyronine (T3), free T3, and TSH were measured before treatment and at 3 days and 1, 2, 4, 8, and 12 weeks after treatment. Results: T4 and free T4 concentrations increased into the target range (10 to 16 μg/dL) by 3 days of therapy in infants in groups 2 and 3 and by 1 week in group 1; 50 μg/day (average 14.5 μg/kg/day) provided the most rapid normalization of TSH by 2 weeks. With the use of linear regression analysis of T4 versus TSH or free T4 versus TSH plots, the intercept at the lower range of normal for TSH (1.7 mU/L) showed T4 = 19.5 μg/dL and free T4 = 5.23 ng/dL. Conclusions: Initial dosing of 50 μg/day (12-17 μg/kg per day) raised serum T4 and free T4 concentrations to target range by 3 days and normalized TSH by 2 weeks of therapy. We recommend consideration of a somewhat higher “target range” of 10 to 18 μg/dL for T4 and 2 to 5.0 ng/dL for free T4 during the first 2 weeks of L-thyroxine treatment. After 2 weeks of treatment, the target range drops to 10 to 16 μg/dL for T4 and 1.6 to 2.2 for free T4. (J Pediatr 2002;141:786-92)

Treatment and therapeutic monitoring of canine hypothyroidism.

Thirty-one dogs with spontaneous hypothyroidism were treated with thyroid hormone replacement therapy (THRT) and monitored for approximately three months. Good clinical and laboratory control was ultimately achieved in all cases with a mean L-thyroxine (T4) dose of 0.026 mg/kg administered once daily. There was a significant increase and decrease in circulating total T4 and canine thyroid stimulating hormone (cTSH) concentrations, respectively, after starting THRT. After commencing treatment, 11 cases subsequently required an increase and three cases required a decrease in dose to achieve optimal clinical control. Median (semi interquartile range [SIR]) circulating six-hour post-pill total T4 (53.6 [27.91 nmol/litre) and cTSH (0.03 [0] microg/litre) concentrations were significantly increased and decreased, respectively, in treated dogs that did not require a dose change; corresponding values in treated dogs in which an increase in dose was required were 29.3 (12.7) nmol/litre and 0.15 (0.62) microg/litre, respectively. However, circulating cTSH measurement was of limited value in assessing therapeutic control because, although increased values were associated with inadequate therapy, reference range cTSH values were common in inadequately treated dogs. Lethargy and mental demeanour were typically the first clinical signs to improve, with significant bodyweight reduction occurring within two weeks of commencing THRT. Routine clinicopathological monitoring was of value in confirming a general metabolic response to THRT, but was of limited value in accurately monitoring cases or tailoring therapy in individual cases.