Normal TSH Values Research Articles

TGB Deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature

Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects lead to a complete (TBG-CD) or a partial (TBG-PD) deficiency and have a diagenic transmission, being clinically fully expressed only in hemizygous males and in homozygous females. In the present study, seven patients from two unrelated families with TBG-CD were studied and two novel TBG mutations were documented. In particular, a T insertion at the 5' donor splice site of exon 0, between nucleotides 2 and 3 at the beginning of intron 1 (g.IVS1+2_3insT) was found in one family and was named TBG-Milano. The other novel mutation is a T deletion at nucleotide 214 of exon 1, which leads to a frameshift at codon 50 with a premature stop codon at position 51 (c.214delT, P50fsX51) and was named TBG-Nikita. According to the X-linked transmission of the defect, females harboring the mutation showed a reduction in TBG levels with normal TSH and total thyroid hormone values at the lower limit of normal. Males harboring either TBG-Milano or TBG-Nikita, showed normal TSH values and low levels of total thyroid hormones and lacked TBG. In conclusion, we report two novel mutations of the TBG gene associated with a complete TBG defect. The first mutation lies at the 5' donor splice site of exon 0 and probably alters the start of translation, while the second is a single nucleotide deletion and leads to a premature stop codon.

Thyroid Function Is Intrinsically Linked to Insulin Sensitivity and Endothelium-Dependent Vasodilation in Healthy Euthyroid Subjects

Levels of TSH respond to fluctuations in serum free T(4) (fT(4)) but remain in a very narrow individual range. There exists current controversy regarding the upper limit of normal serum TSH values above which treatment should be indicated. We aimed to study whether the individually determined fT(4)-TSH relationship was associated with plasma lipids, insulin sensitivity, and endothelial dysfunction in healthy subjects with strictly normal thyroid function according to recent recommendations (0.3-3.0 mU/liter). This was a cross-sectional study. The study consisted of a cohort of healthy men from the general population (n = 221). Oral glucose tolerance, insulin sensitivity (S(I), minimal model), endothelium-dependent vasodilation (high-resolution ultrasound), and plasma lipids were measured in relation to thyroid function tests. Both serum TSH and fT(4).TSH product were positively associated with fasting and postload insulin concentration and negatively with S(I). After body mass index stratification, these associations were especially significant among lean subjects. Serum TSH and fT(4).TSH product also correlated positively with fasting triglycerides and negatively with high-density lipoprotein cholesterol. In a multiple linear regression analysis, age (P = 0.007) and S(I) (P = 0.02) but not body mass index, fasting triglycerides, or serum high-density lipoprotein concentration contributed independently to 3.7 and 3.3%, respectively, of the variance in fT(4).TSH. Those subjects over the median of fT(4).TSH showed reduced endothelium-dependent vasodilation. Thyroid function tests are intrinsically linked to variables of insulin resistance and endothelial function. It is possible that underlying factors lead simultaneously to increased serum TSH, insulin resistance, ensuing dyslipidemia, and altered endothelial function even within current normal TSH levels.

Abnormal endothelial function in female patients with hypothyroidism and borderline thyroid function

Background It has been suggested that hypothyroidism is associated with an increased risk for cardiovascular disease. The aim of this study was to assess non-invasively NO-dependent endothelial function of resistance arteries in subjects with hypothyroidism of varying severity. Methods Ninety-six female subjects (aged: 42 ± 13 years) comprised the study population. Subjects were divided into five groups based on TSH levels at presentation: Group 0 ( n = 23) with TSH: 0.3–2.0 μU/ml, Group 1 ( n = 22) with TSH: 2.1–4.0 μU/ml (upper normal), Group 2 ( n = 18) with TSH: 4.1–10 μU/ml (subclinical hypothyroidism), Group 3 ( n = 22) with TSH > 10 μU/ml (overt hypothyroidism). One additional group with well-controlled hypothyroidism on l-thyroxine therapy (Group 4, n = 11, TSH: 0.3–2.0 μU/ml) was also studied. Endothelial function of resistance arteries was assessed by measuring forearm blood flow response during reactive hyperemia utilizing venous occlusion strain-gauge plethysmography. Results Duration of reactive hyperemia was significantly different among groups of subjects with varying hypothyroidism (83.7 ± 58.3 s, 53.2 ± 35.7 s, 52.8 ± 47.5 s, 12.9 ± 13.3 s and 69.5 ± 26.2 s in Groups 0, 1, 2, 3 and 4, respectively, p < 0.001, ANOVA). Duration of reactive hyperemia was significantly shorter in subjects with upper normal TSH values (Group 1) compared to controls (53.2 ± 35.7 s vs. 83.7 ± 58.3 s, p = 0.013), while it was comparable to that of subjects with subclinical hypothyroidism (Group 2) (52.8 ± 47.5 s). However, duration of reactive hyperemia in Group 1 was significantly longer compared to Group 3 (overt hypothyroidism) (53.2 ± 35.7 s vs. 12.9 ± 13.3 s, p = 0.002). Similarly, duration of reactive hyperemia in subjects with subclinical hypothyroidism was significantly longer compared to subjects with overt hypothyroidism (52.8 ± 47.5 s vs. 12.9 ± 13.3 s, p = 0.003). Duration of reactive hyperemia in Group 4 (well-controlled hypothyroidism on l-thyroxine therapy) did not differ significantly compared to controls. There was a highly significant linear correlation between duration of reactive hyperemia and TSH ( r = − 0.383, p < 0.001). Conclusion Endothelial dysfunction was detected in the microvasculature of patients with hypothyroidism. Duration of reactive hyperemia decreased with increasing TSH levels. Since endothelial dysfunction is a factor leading to atherosclerosis, this abnormality may partly explain predisposition of patients with thyroid failure to cardiovascular disease.

Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium

This study aimed to evaluate the effects of radioiodine ((131)I), alone or in combination with lithium, on thyroid volume and the prevention of radioiodine-induced thyrotoxicosis. This is the first clinical trial including only patients with multinodular goitre, normal TSH values and negative anti-thyroid auto-antibodies at baseline. Eighty consecutive patients were randomised to receive (131)I plus lithium (group I+L) or (131)I alone (group I). Thyroid ultrasonography and biochemical analyses were performed at baseline and at 1, 3, 6, 12 and 24 months after treatment. At 1-4 weeks after treatment, (131)I-induced hyperthyroidism was observed in 58.8% of patients and was prevented by lithium administration. A low incidence of hypothyroidism (19%) was recorded at 24 months, whereas up to 44% of patients developed anti-thyroid antibodies. A significant reduction in thyroid volume was observed after (131)I, with a mean decrease of 47.2% (median 48.2%) at 24 months, without differences between the groups. Moreover, it was shown that the decrease in thyroid volume after (131)I was also due to the significant shrinkage of thyroid nodules. This demonstrates that adjunctive lithium is able to reduce radioiodine-induced hyperthyroidism. Therefore, such treatment appears to be safe in older patients and those with underlying cardiovascular disease. In the present large series, (131)I therapy was demonstrated to be highly effective in reducing thyroid and nodular volume even in patients treated with low (131)I doses (2.5 MBq/ml of thyroid tissue), further supporting the view that radioiodine therapy represents a real alternative to surgery.

Subclinical Hypothyroidism and Pregnancy Outcomes

Clinical thyroid dysfunction has been associated with pregnancy complications such as hypertension, preterm birth, low birth weight, placental abruption, and fetal death. The relationship between subclinical hypothyroidism and pregnancy outcomes has not been well studied. We undertook this prospective thyroid screening study to evaluate pregnancy outcomes in women with elevated thyrotropin (thyroid-stimulating hormone, TSH) and normal free thyroxine levels. All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than 0.680 ng/dL were retrospectively identified with subclinical hypothyroidism. Pregnancy outcomes were compared with those in pregnant women with normal TSH values between the 5th and 95th percentiles. A total of 25,756 women underwent thyroid screening and were delivered of a singleton infant. There were 17,298 (67%) women enrolled for prenatal care at 20 weeks of gestation or less, and 404 (2.3%) of these were considered to have subclinical hypothyroidism. Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1-8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1-2.9). We speculate that the previously reported reduction in intelligence quotient of offspring of women with subclinical hypothyroidism may be related to the effects of prematurity. II-2.

Reversible Weight Gain and Prolactin Levels - Long-term Follow-up in Childhood

In adult patients weight gain is a frequent complaint of hyperprolactinaemia and it has been associated with a high prevalence of obesity. Normalization of prolactin (PRL) levels result in weight loss. The nature of this link is poorly defined. In this report we describe a 14 year-old female with primary amenorrhea and persistent progressive weight gain. The patient's height, weight and BMI were 152 cm, 70 kg, and 30.3 kg/m2, respectively. Basal hormonal investigation showed normal free thyroxin, TSH, IGF-I, cortisol and ACTH values. Serum PRL level was very high (16,278 mIU/l; normal range 63-426 mIU/l). Magnetic resonance imaging scan showed the presence of a pituitary microadenoma. Treatment with the non-selective dopamine agonist pergolide caused a significant reduction of serum PRL concentration with a remarkable decrease of body weight. During follow-up, repeat MRI scan revealed disappearance of the microadenoma. The reduction of the daily dose of pergolide was associated with an increase of serum PRL with significant weight gain. A further reduction of body weight was subsequently observed with an increase of pergolide dosage. Serum PRL measurement may be useful as part of the endocrine work-up of obese children with a history of unexplained recent weight gain, especially if associated with pituitary-gonadal axis dysfunction. The relationship between PRL secretion and weight change needs to be examined in prospective larger studies.

Desenvolvimento de ensaio imunofluorométrico para a medida da globulina ligadora de tiroxina (thyroxine-binding globulin, TBG) e sua aplicação em casos de deficiência desta proteína

A globulina ligadora de tiroxina (thyroxine-binding globulin, TBG) é a principal transportadora de hormônios tiroidianos no soro. Variações na concentração sérica de TBG determinam variações proporcionais nas concentrações séricas totais de T4 e T3, sem implicar alterações de função, desde que a fração livre permaneça normal. Várias condições clínicas comuns levam a alterações significativas nos níveis de TBG, sendo as variações mais importantes devidas a defeitos genéticos. Como a TBG é codificada por gene localizado no cromossomo X, os defeitos se manifestam mais facilmente no sexo masculino. Descrevemos o desenvolvimento de ensaio imunofluorométrico para a medida de TBG com base em anticorpos monoclonais, sendo um desenvolvido em nosso laboratório e outro comercial. O método apresenta sensibilidade de 0,8mg/l e coeficientes de variação intra e interensaio inferiores a 10%. O estudo comparativo com método comercial mostrou alta correlação (r = 0,93; n = 48), sendo os valores normais obtidos de 10mg/l a 29mg/l. Estudamos também 20 indivíduos portadores de deficiência congênita de TBG, 19 homens e uma mulher, que apresentavam valores normais de TSH e baixos de T4 total; em todos eles os níveis de TBG foram indetectáveis. Já os níveis de T4 livre medidos por método indireto em 16 desses indivíduos mostraram-se elevados em todos, ao passo que, quando medidos por método direto pós-diálise nos quatro restantes, mostraram-se normais. Nossos resultados reforçam a necessidade prática da disponibilidade de ensaio para a medida de TBG para esclarecimento e definição diagnóstica de alguns casos especiais, principalmente quando o ensaio de T4 livre direto, pós-diálise, não é disponível.

Thyroid axis activity and serotonin function in major depressive episode.

Recent studies in depression have reported alterations in both hypothalamic-pituitary-thyroid (HPT) axis activity and serotonin (5-HT) function; however, the functional relationships between the two systems have not been well defined in patients with major depressive episode. Thyrotropin (TSH) response to 0800 and 2300 h protirelin (TRH) challenges, and adrenocorticotropic hormone (ACTH), cortisol, and prolactin (PRL) responses to D-fenfluramine (D-FEN), a specific 5-HT releasing/uptake-inhibiting agent, were examined in 60 drug-free DSM-IV major depressed inpatients and 20 hospitalized controls. Compared with controls, patients showed lower basal serum 2300 h TSH, 2300 h maximum increment in serum TSH above baseline (delta TSH) and difference between 2300 h delta TSH and 0800 h delta TSH (delta delta TSH) levels. The hormonal responses to D-FEN (i.e. delta ACTH, delta cortisol and delta PRL) were interrelated. No significant difference in basal and post-D-FEN ACTH, cortisol or PRL values were found between controls and patients. A negative relationship between hormonal responses to D-FEN and 2300 h delta TSH and delta delta TSH values was observed in the depressed group. When patients were classified on the basis of their delta TSH test status, patients with reduced delta delta TSH values (i.e. with HPT axis abnormality) had hormonal D-FEN responses comparable to those of controls. Patients with normal delta delta TSH values (i.e. without HPT axis abnormality) showed lower ACTH, cortisol and PRL responses to D-FEN than controls and patients with abnormal delta delta TSH values. These results suggest that: (1) pathophysiological mechanisms other than 5-HT dysregulation may be involved in TSH blunting in major depressed patients; (2) 5-HT function is reduced in some depressed patients, especially those without HPT axis abnormality; and (3) HPT dysregulation may be regarded as a compensatory mechanism for diminished central 5-HT activity.

Pattern of Development of Hyperprolactinemia After Initiation of Haloperidol Therapy

Objective: To determine the time it takes for prolactin (PRL) levels to increase after initiation of therapy with haloperidol (a neuroleptic medication) and the pattern and extent of the increase. Methods: Seventeen individuals scheduled to be given treatment with neuroleptic drugs were enrolled. Baseline blood specimens were collected for PRL and TSH levels. Follow-up samples for PRL determinations were obtained every 3 days for 18 days after initiation of haloperidol therapy. Results: There were 17 subjects: 14 women and three men. Two of the subjects were found to have hyperprolactinemia due to hypothyroidism and were excluded from the basic study. The 15 remaining subjects all had normal baseline PRL levels and normal TSH values. The PRL levels in all 15 showed a similar pattern: a rapid increase in PRL levels in the first 6–9 days, followed by a plateau that remained, with minor fluctuations, throughout the study. The highest mean peak level of PRL was 37.4 ng/mL and the maximum was 77 ng/mL. The two individuals with hypothyroidism had somewhat elevated baseline PRL levels; although they showed the same initial pattern of increase after haloperidol administration, their PRL levels reached values well above 100 ng/mL. Conclusion: There is a distinct pattern of response of PRL to haloperidol. The PRL level increases for 6–9 days, then plateaus, the peak being between 30 and 50 ng/mL, and always remains below 77 ng/mL. In our study, levels that continued to increase, or increased above 77 ng/mL, indicated the presence of hypothyroidism. The patterns and levels of the increase were uninfluenced by the therapeutic dose of the medication given. Given that the patients in our study with elevated levels of TSH had such high levels of PRL, all patients should have TSH determinations at the initiation of therapy with neuroleptic medications such as haloperidol.

Prevalence and significance of antibodies reactive with eye muscle membrane antigens in sera from patients with Graves' ophthalmopathy and other thyroid and nonthyroid diseases.

We have investigated the antibody responses made to porcine eye muscle antigens by sera from patients with Graves' disease and ophthalmopathy (GO) on Western blotting in a retrospective cross sectional study. Reactivity to several different eye muscle antigens was observed; however, antibodies to two antigens of 64 and 95 kd were found predominantly in sera with a prevalence of 63.6% (14/22) and 50.0% (11/22), respectively. In Graves' patients without GO the levels dropped to 18.2% (6/33) and 9.1% (3/33), and to 10.0% (2/20) and 20.0% (4/20) in patients with other thyroid diseases, and 0% (0/29) and 20.7% (6/29) in patients with nonthyroid diseases. Healthy control subjects gave positive responses in 8.0% (2/25) and 12.0% (3/25) of sera tested against the two antigens. The prevalence of the responses in patients with GO was significantly different when compared with normals and other patient groups (p < 0.05 and p < 0.01). All patients with ophthalmopathy graded class 3 or 4 and most of the patients with GO and a suppressed thyrotropin (TSH) value at the time of investigation reacted with one or other of the two antigens. Similar prevalences of response were found to the 64 and 95 antigens in those patients with GO whether they were thyrotropin receptor antibodies (TSHR-Ab) positive or negative (p > 0.05). However, the prevalence of the response to the 64 kd antigen in the TSHR-Ab positive group of patients without GO (31.3%) was significantly higher than that found in the TSHR-Ab negative (5.9%, p < 0.05) group. 81.8% (9/11) of patients with GO and a suppressed TSH recognized the 64 kd antigen compared with 45.5% with a normal TSH value (p < 0.05) and 16.7% without GO and a normal TSH (p < 0.01). In additional studies we have shown that a mouse monoclonal antibody (3B12) raised to the extracellular domain of the human TSH receptor also reacted with a 55 kd antigen in pig eye muscle but was not inhibited from its binding to either pig eye antigen or human TSH receptor antigen (3A1) by any of our patients' sera. These data suggest that serum antibodies reactive with porcine eye muscle antigens are potentially useful markers of ophthalmopathy in Graves' patients and should be further evaluated in longitudinal studies to see if they can predict the onset or regression of Graves' ophthalmopathy.

Interlaboratory/intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentrations of TSH

Clinically relevant interassay precision profiles for thyrotropin (thyroid-stimulating hormone; TSH) were constructed with human serum pools measured over 4-8 weeks by six immunometric assays, in at least two different reagent lots. Functional sensitivities (the concentration at which the interassay CV is < or = 20%) were determined in four to eight clinical laboratories plus the respective manufacturer's laboratory. These studies revealed that the manufacturer's stated functional sensitivity limit is rarely duplicated in clinical practice. Loss of specificity (indicated by artifactually high values) was seen with some methods when used to measure certain unrefrigerated low-TSH sera. Measurement of TSH in four human serum pools (TSH < 0.05-0.25 mIU/L) by 16 different methods (each in at least eight UK or US laboratories) showed that some methods could not reliably distinguish subnormal from normal TSH values. Better pool rankings and fewer misclassifications of low-TSH sera as "normal" were seen with use of assays capable of "third-generation" functional sensitivity (0.01-0.02 mIU/L) than with assays with "second-generation" functional sensitivity (0.1-0.2 mIU/L). Because inter- and intramethod differences in functional sensitivity negatively impact the diagnostic accuracy and cost-effectiveness of a TSH-centered thyroid-testing strategy, laboratories should independently establish an assay's functional sensitivity by a clinically relevant protocol. Moreover, manufacturers should assess functional sensitivity more realistically and improve the robustness of assays to ensure that their performance potential is consistently met in clinical practice.

Familial Dysalbuminemic Hyperthyroxinemia: Cumulative Experience in 29 Consecutive Patients

The syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality characterized by the presence of a variant serum albumin with preferential affinity for T4, is recognized with increasing frequency as a cause of elevated total and free T4 serum values in clinically euthyroid patients with normal TSH levels. Hyperthyroxinemia caused by this syndrome is occasionally confused with hyperthyroidism or thyroid hormone resistance syndromes, which may prompt unnecessary treatment. To better define the clinical and biochemical characteristics of patients with FDH, we undertook a retrospective analysis of the experience at our institution with this condition. We reviewed our cumulative experience in 29 consecutive patients with FDH diagnosed between 1970 and 1991. FDH was diagnosed in 18 males and 11 females (mean age, 42.7 years) on the basis of clinical euthyroidism, increased total T4 and increased/normal free T4 serum values, normal T3 and TSH serum values, increased T4 binding to serum albumin, and low/normal T4 binding to T4-binding globulin and serum prealbumin. Clinical thyroid examination revealed no abnormalities except for goitre in five patients, and the results of radioiodine uptake studies were normal. Patients with subsequently documented FDH were referred for evaluation of "unusual" findings on thyroid function tests or FDH was detected on routine thyroid function tests or identified on family screening. Euthyroid hyperthyroxinemia in combination with a family history compatible with FDH correctly suggested FDH in seven patients. Clinical euthyroidism in conjunction with a normal basal sensitive TSH value in a hyperthyroxinemic patient differentiates euthyroid hyperthyroxinemia from thyrotoxicosis, obviating unnecessary therapy. Detection of excessive thyroxine binding to serum albumin establishes the diagnosis of FDH and allows it to be differentiated from thyroid hormone resistance syndromes. After a diagnosis of FDH has been established, family screening is advisable. Hyperthyroxinemia in clinically euthyroid patients ("euthyroid hyperthyroxinemia") is recognized with increasing frequency and should prompt a careful diagnostic evaluation. The differential diagnosis of this condition may be difficult because it includes various common and unusual syndromes, including quantitative or qualitative changes in thyroid hormone-binding proteins, circulating antibodies against thyroid hormones, resistance to thyroid hormones, influences from drugs, and acute somatic or psychiatric illness (1). The recently recognized syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality with autosomal dominant transmission, is characterized by the presence of a variant serum albumin with preferential affinity for T4 (2-4). Typically, FDH is detected incidentally or patients are referred to endocrinologists on the basis of "unusual" results on routine thyroid function testing, revealing consistently elevated total T4 and elevated or normal free T4 values in a clinically euthyroid patient with normal TSH levels (1,5). Unfortunately, hyperthyroxinemia due to FDH may be confused with hyperthyroidism or thyroid hormone resistance syndromes, prompting repeated unnecessary laboratory testing and possibly even inappropriate treatment (1,3,6,7). Herein, we describe the clinical and biochemical characteristics of 29 consecutive patients with documented FDH.

Screening for thyroid diseases in an iodine sufficient area with sensitive thyrotrophin assays, and serum thyroid autoantibody and urinary iodide determinations.

The present study was designed to investigate the prevalence of thyroid dysfunction and its relation to thyroid autoantibodies and urine iodide concentration in apparently healthy people residing in Sapporo, a city of northern Japan, where the iodine intake is high. Serum TSH and thyroid autoantibodies, and urine iodide were measured in 4110 people (2931 men and 1179 women) (age 45.6 +/- 10.3 years (mean +/- SD)) who were recruited at the hospital for medical examinations. The thyroid autoantibodies were positive in 6.4% of males and 13.8% of females with an age-related increase. Of the people with positive antibodies, 87.2% had normal TSH values (0.15-5.0 mU/l) as measured by a sensitive assay. The prevalence of unsuspected hyperthyroidism as defined by suppressed TSH values was 0.61%, of which 64% was diagnosed as Graves' disease based on positive thyrotrophin receptor antibody results. The prevalence of unsuspected hypothyroidism, as evidenced by supranormal TSH, was 0.68% for males and 3.13% for females with an age-related increase. Of those with hypothyroidism, 45.5% were autoantibody positive. The overall prevalence of Hashimoto's thyroiditis was 13.11% for females and 6.15% for males. The urine iodide levels of hypothyroidism with a positive autoantibody of 38.5 (17.7-83.9) mumol/l and a negative autoantibody of 34.9 (17.9-67.9) mumol/l were both significantly higher than that of normal subjects (26.9 (14.6-49.6) mumol/l) (P < 0.01). When iodine intake was restricted for 6-8 weeks for hypothyroid subjects, the elevated TSH and thyroglobulin and low free T4 levels were reversed in the autoantibody negative but not in the positive group. This study provides further information on the prevalence of thyroid dysfunction and autoimmune thyroid diseases in an iodine sufficient area. In addition, it suggests that more than half of the patients with unsuspected hypothyroidism were negative for autoantibodies and that the excessive iodine intake may be involved in causing latent hypothyroidism.

Traitement et surveillance de l'hypothyroïdie primitive

Treatment of primary hypothyroidism requires a long-term hormonal therapy with levothyroxine which restores a normal TSH value. In a series of 192 patients followed up for at least 3 years we tried to evaluate the variability of maintenance dosage and to analyse the factors predictive of replacement dosage. The L-T4 dosage varied from one individual to the other, from 0.6 to 3.2 micrograms/kg. The mean maintenance dosage (118 +/- 38 micrograms/day) was similar in men and women weight for weight, but it was higher in subjects aged under 60 and in those with Hashimoto's or congenital hypothyroidism. There is a positive linear relation between the equilibrium dose and the TSH value (n = 0.84; p < 0.001) and a negative relation with the L-T4 concentration (n = 0.71; p < 0.001). The yearly variation of dosage in each individual was small (about 3.5%) and of the same order as the variation of weight. We conclude that the L-T4 maintenance dosage depends on the cause of hypothyroidism, on the importance of biochemical abnormalities and on the patient's age, sex and weight. In practice, however, the necessary dosage is difficult to predict. In the equilibrium phase the need for replacements is remarkably stable. A yearly assay of baseline TSH seems to be sufficient to evaluate the quality of hormonal compensation in the absence of intercurrent events.

Monitoring thyroxine treatment during pregnancy.

Data were analyzed from 77 pregnancies in 65 hypothyroid women treated with levothyroxine (T4) to determine (a) how often, how severely, and when serum thyrotropin (TSH) and free T4 concentrations become abnormal during pregnancy in women taking constant T4 doses and (b) how much to increase T4 doses to normalize elevated serum TSH levels. Group I consisted of 36 women with previous thyroid ablation. Group II consisted of 29 women with Hashimoto's thyroiditis. Serum TSH levels rose above normal (greater than 4 microU/mL) during pregnancy more often in Group I (76%) than in Group II (47%) during treatment with constant T4 doses, and mean serum free T4 levels decreased significantly in both groups, by 47% in Group I and by 35% in Group II, compared to preconception values. Serum TSH concentrations rose above 20 microU/mL in 22% of the women, and serum free T4 concentrations fell below normal in 13%. Elevated serum TSH levels usually were detected by the first TSH test during pregnancy, as early as 4 weeks gestation. Of those women tested after an initial normal serum TSH value during pregnancy, 30% had an elevated serum TSH concentration later in the pregnancy. Of 12 women followed through two pregnancies, 10 had elevated serum TSH values in both pregnancies, 1 had normal serum TSH values in both, and 1 had discordant serum TSH values.(ABSTRACT TRUNCATED AT 250 WORDS)

10 Years of Successful Treatment with Dextrothyroxine in a Girl with TSH-Induced Hyperthyroidism

14 years ago, a 5.7-year-old healthy girl was treated with desiccated thyroid for a goiter and elevated TSH levels. The goiter disappeared and TSH levels were normalized. However, hyperthyroidism appeared. Without therapy, the goiter reappeared and hyperthyroidism aggravated. Based on hormone values, TSH-induced hyperthyroidism was diagnosed. After exclusion of neoplastic TSH secretion, treatment with dextrothyroxine (DT4) was initiated at age of 10 years and continued during the last 10 years (except for short periods). The girl became euthyroid, has no goiter and normal TSH values. Since thyrotrophs and peripheral tissues are probably normally sensitive to T4, we postulate that her hypothalamopituitary-thyroid control is operating on a higher set point level for T4.

Nocturnal Serum Thyrotropin (TSH) Surge and the TSH Response to TSH-Releasing Hormone: Dissociated Behavior in Untreated Depressives*

TSH secretion, with particular regard to the nocturnal surge of the hormone, was evaluated in 15 women (age range, 35-66 yr; mean, 50 yr) with untreated major endogenous depression and 15 healthy women (age range, 32-67 yr; mean, 53 yr) using an ultrasensitive assay. Mean morning (0830 h) TSH values did not differ in the 2 groups (1.3 +/- 02 mU/L in depressives and 1.4 +/- 0.1 mU/L in controls), whereas mean nighttime (2400-0200 h) values were significantly reduced in depressives (1.5 +/- 0.3 vs. 3.1 +/- 0.3 mU/L; P less than 0.0005). At variance with the control group, morning and nighttime TSH values did not differ in the depressives. The nocturnal serum TSH surge was abolished in 14 of 15 depressed patients. The mean peak TSH value after TRH was slightly yet significantly lower in the depressives. Patients with subnormal (less than 0.4 mU/L) TSH values in the morning had a serum TSH increase after TRH less than 2 mU/L in 5 of 6 cases and a lack of the nocturnal TSH surge in 6 of 6. Among the 9 patients with normal TSH values in the morning, the nocturnal serum TSH surge was lost in 8 of 9, whereas the response to TRH was normal in all. The depressives, at variance with other reports, showed significantly lower values of total and free thyroid hormones. Mean serum sex hormone-binding globulin (SHBG) and ferritin were also significantly reduced. In conclusion, major endogenous depression is associated with a major impairment of TSH secretion, which baseline TSH measurements in the morning and the evaluation of the TSH response to TRH may not reveal. In this regard, the loss of the nocturnal serum TSH rise would appear to be a more sensitive indicator of hypothalamus-pituitary-thyroid axis alterations in depressives than the TRH test, which is commonly used in the evaluation of these patients. The lack of the nocturnal TSH surge may be responsible for the reduced thyroid hormone secretion and supports the case for some degree of central hypothyroidism in endogenous depression.

Applications of a New Chemiluminometric Thyrotropin Assay to Subnormal Measurement*

A new immunochemiluminometric TSH assay (ICMA) was shown to offer improved analytical (+2 SD of zero) and functional (20% interassay coefficient of variation) sensitivity [0.003 vs 0.045 +/- 0.005 (+/- SE; range, 0.01-0.07); 0.018 vs. 0.23 +/- 0.02 (range, 0.10-0.35, mU/L); analytical vs. functional sensitivity limit for the ICMA vs. 10 other TSH immunometric assays, respectively]. The ICMA was used to study the physiological relationship between serum TSH and free T4 [as reflected by free T4 index (FT4I)] values at both steady state and 14 days after acute pharmacological T4 administration (3 mg oral T4 load plus 0.3 mg daily). At steady state, an inverse log/linear relationship was found between serum TSH and FT4I values (log TSH = 2.56 - 0.022 FT4I; r = 0.84; P less than 0.001). Ten to 14 days after acute T4 suppression in 5 euthyroid subjects, serum TSH/FT4I levels had plateaued after decreasing in parallel to the slope of the steady state relationship, suggesting that the degree of T4 suppression of TSH can be predicted from an individual's pituitary TSH/free T4 set-point and the magnitude of the serum T4 elevation achieved. Ambulatory and hospitalized patient sera, previously identified as having low (less than 0.1 mU/L) TSH levels by a less sensitive assay, were restudied by the TSH ICMA. Normal TSH values ranged from 0.39-4.6 mU/L, whereas the majority of hyperthyroid patients [52 of 54 (96% ambulatory) and 22 of 23 (96%, hospitalized)] had undetectable (less than 0.005 mU/L), basal TSH levels and absent TRH stimulated TSH responses. In contrast, most (32 of 37; 86%) of hospitalized nonhyperthyroid patients with low (less than 0.1 mU/L) TSH values due to nonthyroidal illness or glucocorticoid treatment had detectable (greater than 0.01 mU/L) basal and TRH stimulated TSH levels. The positive relationship between basal and TRH-stimulated TSH levels was shown to extend down to the detectability limit of the assay (0.005 mU/L), which further supported the authenticity of the subnormal TSH ICMA measurements. The new TSH ICMA is considered to represent the first of a third generation of clinical TSH assays, since it has a functional (interassay) sensitivity that is 2 orders of magnitude greater than that of typical first generation TSH RIAs and 1 order of magnitude greater than current second generation TSH immunometric methods. Such third generation TSH assays will facilitate both the optimization of T4 therapy as well as the diagnosis of hyperthyroidism in hospitalized patients with nonthyroidal illness.

Effect of congenital renal disease and neonatal thyroid status on urinary human epidermal growth factor concentrations.

We have previously demonstrated that changes in urinary epidermal growth factor/creatinine ratios relate to gestational age and gender. It is unclear what controls this developmental pattern although chronic renal disease and thyroid aberrations have significant effects on epidermal growth factor and creatinine excretion in childhood and in adults. Therefore, we chose to explore the effects of these disease states on epidermal growth factor excretion during the perinatal time period. We collected urine samples from 8 infants with congenital renal disease and 45 infants with low T4 and normal TSH values who 'failed' the newborn screen. In addition, 2 infants with hypothyroidism and 2 infants with neonatal Grave's disease had urine samples examined. Values were compared with the epidermal growth factor and creatinine excretion from 190 infants. We demonstrated that epidermal growth factor excretion increased earlier in gestation than does creatinine excretion. In infants with renal disease or hypothyroidism, epidermal growth factor excretion was decreased while hyperthyroidism enhanced excretion. Epidermal growth factor excretion increased with relief of an obstruction but still remained low and creatinine excretion was unchanged. We confirm that in preterm infants as in childhood there are similar effects of thyroid and renal diseases on epidermal growth factor excretion.

Growth studies in infants and children with Down's syndrome and elevated levels of thyrotropin.

A retrospective survey of 147 patients with Down's syndrome (age range, 4 months to 27 years) showed that 60% had a thyrotropin (TSH) level higher than 5.7 mU/L in the presence of high or normal thyroxine levels. The remaining 40% of the group had low to normal TSH values. High TSH levels were predominant in patients under 4 years of age (94 children), ie, during the phase of active growth, and showed a declining trend with increasing age. All 94 infants had delayed growth of all parameters including head circumference, height, and weight, as compared with normal infants, and growth was particularly retarded in patients with TSH levels greater than 5.7 mU/L. Thyroid dysfunction, expressed as a high TSH concentration, is associated with growth retardation in children with Down's syndrome who are younger than 4 years.