Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration

Thyroid hormone is one of several factors that modulate the level of sex hormone-binding globulin (SHBG) in serum. SHBG levels are usually elevated in thyrotoxicosis and have been reported to be normal in a few patients with generalized resistance to thyroid hormone (GRTH). This study was designed to determine whether basal serum SHBG levels or the SHBG response to short term T3 administration could be used as an index of thyroid hormone action and thus serve as a test for the evaluation of patients suspected of having peripheral tissue resistance to thyroid hormone. Serum SHBG, total T4, free T4 index (FT4I), total T3, and TSH levels were measured in 21 normal subjects, 28 hypothyroid patients, 20 thyrotoxic patients, and 10 patients with GRTH. Excluding patients with GRTH, serum basal SHBG values were correlated with FT4I values (r = 0.66; P less than 0.0001). Mean SHBG levels in the patients with GRTH [37.6 +/- 16.2 (+/- SD) nmol/L] were not significantly different from those in the normal subjects (35.1 +/- 19.3 nmol/L) or hypothyroid patients (26.3 +/- 17.1 nmol/L), but were significantly lower than those in the thyrotoxic group (64.7 +/- 19.2 nmol/L; P less than 0.001). All 10 patients with GRTH had basal SHBG values in the normal range, but 7 of 20 (35%) thyrotoxic patients also had normal basal SHBG values. T3 was given orally for three sequential 3-day periods at doses of 50, 100, and 200 micrograms daily to 7 normal subjects, 11 hypothyroid and 3 thyrotoxic patients, and all 10 patients with GRTH. The serum SHBG concentration was measured on the last day at each dosage level. During T3 administration, SHBG levels increased in all individuals with normal tissue responsiveness. The increase above the basal value (delta SHBG) at each T3 dose was similar in normal, hypothyroid, and thyrotoxic individuals (non-resistant subjects). After administration of 50 micrograms T3 daily, the mean delta SHBG level was decreased [-2.9 +/- 5.3 (+/- SD) nmol/L] in the resistant patients and increased (4.0 +/- 4.9 nmol/L; P less than 0.005) in the nonresistant subjects. After administration of 100 micrograms T3 daily, the mean delta SHBG was -4.5 +/- 6.8 nmol/L in the resistant patients and 8.6 +/- 5.1 nmol/L (P less than 0.0001) in the nonresistant subjects. Serum SHBG decreased by more than 2 nmol/L in 6 of 10 (60%) resistant patients, but in no nonresistant subject.(ABSTRACT TRUNCATED AT 400 WORDS)     

Decreased thyroid gland volume in alcoholic cirrhosis of the liver

Thyroid function and thyroid gland volume were studied in 40 consecutive alcoholic patients with histologically proven cirrhosis of the liver, and compared with data obtained from 40 sex-, age-, and weight-matched normal subjects. Thyroid volume, measured ultrasonically, was significantly decreased in the patients with cirrhosis: median, 11 ml (range, 6-16 ml); compared to normal subjects: median, 20 ml (range, 10-31 ml) (P less than 0.001). Serum T3 concentrations were significantly reduced: median, 1.5 nmol/liter (range, 0.1-2.5 nmol/liter); compared to normal subjects: median, 2.2 nmol/liter (range, 1.5-2.8 nmol/liter) (P less than 0.001). The free T3 index was reduced accordingly. Serum TSH levels were significantly increased in cirrhosis: median, 2.1 microU/ml (range, 0.4-5.3 microU/ml); compared to normal subjects: median, 1.1 microU/ml (range, 0.3-3.8 microU/ml) (P less than 0.05). No significant differences were found in T3 resin uptake, free T4 index, or serum T4 levels between the two groups. No significant correlations could be demonstrated between thyroid gland volume and biochemical indices of liver function or thyroid function tests. It is suggested that alcohol might have a direct effect on the thyroid gland.     

Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST

The differential diagnosis of the various forms of inappropriate secretion of TSH (IST), i.e. generalized thyroid hormone resistance (GRTH), selective pituitary resistance [non-neoplastic IST (nnIST)], and tumoral pituitary TSH hypersecretion [neoplastic IST (nIST)], mainly rests on clinical observation, skull imaging, and measurement of several parameters assessing peripheral thyroid hormone effects. Clinically, patients with GRTH usually display compensated hypothyroidism, while those with nnIST or nIST are hyperthyroid. Since sex hormone-binding globulin (SHBG) measurement has been shown to be a reliable parameter in distinguishing between euthyroid and hyperthyroid states, we evaluated serum SHBG levels in 39 patients with IST (7 with GRTH, 15 with nnIST, and 17 with nIST). The results were compared to those in 68 normal subjects, 76 hyperthyroid patients, and 31 hypothyroid patients. SHBG levels in patients with either GRTH or nnIST were similar to those in controls or hypothyroid patients [GRTH, 40.5 +/- 11.8 (+/- SD) nmol/L (range, 26.4-57.5); nnIST, 29.7 +/- 12.8 nmol/L (range, 6.8-46.8); controls, 36.7 +/- 21.7 nmol/L (range, 5.4-96.5); hypothyroid, 30.8 +/- 14.4 nmol/L (range, 10.4-63.3)]. On the contrary, SHBG levels in patients with either overt hyperthyroidism or nIST were significantly higher than those in the above groups [hyperthyroid, 149 +/- 111 nmol/L (range, 48-557); nIST, 99.5 +/- 54.7 nmol/L (range, 21.6-259)]. The apparent overlap of SHBG values between hyperthyroid patients and controls almost completely disappeared when comparisons were made with control groups matched for age and sex. Additional indices of peripheral thyroid hormone action (basal metabolic rate, cardiac systolic time intervals, and Achilles' reflex time) were normal in patients with GRTH, while they were in the hyperthyroid range in patients with nnIST and nIST. After successful treatment of hyperthyroidism, SHBG levels normalized in patients with nIST, but they did not change in patients with nnIST. In conclusion, the measurement of SHBG in patients with IST is useful in differentiating the neoplastic form from that due to thyroid hormone resistance, but it fails to distinguish between generalized and pituitary resistance to thyroid hormone action. Moreover, the present data suggest that the resistance to thyroid hormone action in patients with nnIST is not selective at the thyrotroph cell level, but also involves the hepatic SHBG-synthesizing cells, thus supporting the view that the various forms of thyroid hormone resistance could represent a continuum of the same defect with variable expression in different tissues.     

Bone Gla protein and sex hormone-binding globulin in nontoxic goiter: parameters for metabolic status at the tissue level

Several patients with nontoxic goiter have reduced serum TSH levels, as measured with new sensitive assays. Whether this is a sign of subclinical hyperthyroidism, thus having the potential of adverse effects on different organs with time, is not known. We have measured serum levels of 2 markers of thyrometabolic status at the tissue level, bone gamma-carboxyglutamic acid-containing protein (BGP), reflecting the function of osteoblasts, and sex hormone-binding globulin (SHBG), reflecting the function of hepatocytes, in 44 patients (41 women and 3 men) with nontoxic goiter (11 diffuse and 33 nodular goiters; serum T4, T3, free T4, and free T3 levels had been normal and stable for at least 0.5 yr). Serum TSH levels ranged from normal to unmeasurably low values (less than 0.05 mU/L). Serum TSH levels correlated negatively to serum BGP levels (r = -0.60; P less than 0.001). Due to the postmenopausal surge in serum BGP levels, premenopausal women (n = 21) were tested separately without changing the significance (r = -0.53; P less than 0.02). Expressing serum BGP values as a percentage of the mean value in control subjects of the same age and sex did not change the correlation (r = -0.63; P less than 0.001). Six patients had serum BGP levels above the normal range, and patients with reduced serum TSH levels (less than 0.45 mU/L; n = 12) had significantly enhanced serum BGP levels [median, 1.53 nmol/L (range, 1.02-4.24) vs. 1.23 nmol/L (0.62-3.71); P less than 0.05]. Serum TSH also correlated negatively to serum SHBG levels (r = -0.56; P less than 0.001; women alone: r = -0.58; P less than 0.001). Eight patients had serum SHBG levels above the normal range, and patients with reduced serum TSH levels had significantly enhanced serum SHBG levels, expressed as a percentage of the mean control value for the relevant sex [203% (range, 75-288) vs. 120% (42-317); P less than 0.01]. It is concluded that the lower serum TSH levels in patients with nontoxic goiter, the higher are serum BGP and SHBG levels. This suggests a progressively generalized (not only pituitary) tissue overexposure to thyroid hormones, the lower the serum TSH levels. Therefore, the finding of a reduced serum TSH level in patients with nontoxic goiter might reflect supraphysiological levels of T4 and/or T3, which could possibly be harmful.     

Interpretation of sex hormone-binding globulin levels in thyroid disorders.

Sex hormone-binding globulin (SHBG) levels were followed in three groups of female subjects to evaluate interrelationships between its levels and parameters characterizing thyroid function. In the first part of the study the data from 201 patients with thyroid and other endocrine dysfunctions were grouped according to SHBG or basic laboratory parameters of thyroid function (thyrotropin, free thyroxine). Particular attention was paid to the presence of antithyroid antibodies (against thyroglobulin or thyroid peroxidase). Analysis of covariance revealed that SHBG changes were significant only in hyperthyroidism, and were not influenced by the presence of antibodies. Age was a minor factor influencing SHBG levels, in contrast to thyroid status. In a well-defined group of 16 females with severe hypothyroidism after total thyroidectomy because of thyroid cancer the low SHBG levels increased significantly to physiologic values after reaching normal thyroid function, irrespective of contraceptive use. In the final part of the study SHBG levels were correlated with the basic laboratory data, reflecting thyroid function in a sample of normal female population (129 subjects) screened for iodine deficiency in one region of the Czech Republic. After adjustment for age, the only significant positive correlation was between SHBG and free triiodothyronine.     

SEX HORMONE BINDING GLOBULIN IN WOMEN WITH ANOREXIA NERVOSA

In 29 women with anorexia nervosa, on a blood sample withdrawn at 0900 h before and during weight gain, the binding parameters of serum sex hormone binding globulin (SHBG) were measured by a solid phase method and the levels of testosterone, oestradiol and thyroid hormones were measured by radioimmunoassay. The binding capacity of SHBG was higher than the upper limit for normally menstruating women in 23 patients whilst its affinity for binding testosterone at 37 degrees C was normal (0.32-0.53 X 10(-9) mol/l). The mean levels of testosterone, oestradiol and free thyroxine were normal and the mean level of triiodothyronine was significantly (P less than 0.005) decreased. The binding capacity of SHBG did not correlate significantly with body mass index, percent weight lost, thyroid hormone or sex hormone levels. In 9 patients, an i.v. infusion providing 1200-1400 calories daily was given for 1 week. In these patients a significant decrease (P less than 0.005) in the binding capacity of SHBG (from 74.7 +/- 26.7 to 52.9 +/- 21.8 nmol/l) and a significant increase (P less than 0.001) in T3 levels (from 0.69 +/- 0.21 to 0.95 +/- 0.13 nmol/l) was observed. In 14 patients, when a weight gain of at least 5% was obtained, the binding capacity of SHBG fell into the normal range (25.6-62.9 nmol/l) while T3 levels rose to normal (0.85-2.30 nmol/l). These findings suggested that variations of calorie intake and/or body weight may influence the binding capacity of SHBG in the human.     

First trimester insulin resistance and subsequent preeclampsia: a prospective study

Insulin resistance is implicated in the pathogenesis of preeclampsia, but prospective data are limited. SHBG, a marker of insulin resistance among nonpregnant individuals, has not been studied in detail during pregnancy. We conducted a prospective, nested, case-control study to test the hypothesis that increased insulin resistance, marked by reduced first trimester SHBG levels, is associated with increased risk of subsequent preeclampsia. First trimester SHBG levels were measured in 45 nulliparous women who subsequently developed preeclampsia (blood pressure, > or =140/90 mm Hg; proteinuria, either > or =2+ by dipstick or > or =300 mg/24 h, after 20 wk gestation) and in 90 randomly selected normotensive nulliparous controls. Compared with controls, women who developed preeclampsia had significantly reduced first trimester SHBG levels (302 +/- 130 vs. 396 +/- 186 nmol/liter; P < 0.01). Every 100 nmol/liter increase in SHBG was associated with a 31% reduced risk of preeclampsia [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.55, 0.88; P < 0.01]. After adjusting for covariates in a multiple logistic regression model, the association between first trimester SHBG and preeclampsia remained significant (per 100 nmol/liter increase; OR, 0.66; 95% CI, 0.47, 0.92; P = 0.01). When subjects were stratified by body mass index (lean: body mass index, < 25 kg/m(2); overweight: body mass index, > or =25 kg/m(2)), overweight women had lower SHBG levels than lean women (286 +/- 156 vs. 410 +/- 166 nmol/liter; P < 0.01), and within each stratum, women with preeclampsia had lower SHBG levels than their respective controls. In a multivariable analysis, the association between SHBG and preeclampsia strengthened among lean women, such that every 100 nmol/liter increase in serum SHBG was associated with a 55% reduction in the risk of preeclampsia (OR, 0.45; 95% CI, 0.27, 0.77; P < 0.01), whereas in overweight women, the association was mitigated (OR, 1.02; 95% CI, 0.62, 1.69; P = 0.9). We conclude that increased early pregnancy insulin resistance is independently associated with subsequent preeclampsia. First trimester SHBG levels may be a useful biomarker for preeclampsia, especially among lean women who otherwise would be perceived to be at low risk.     

Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease

High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range.     

Thyroxine uptake by human hepatoma cells from serum of patients submitted to long-term thyroxine suppressive therapy

The significance of thyroxine (T4) uptake from serum in the assessment of thyroid status was evaluated, using human hepatoma (Hep G2) cells, in 30 euthyroid subjects, 6 hypothyroid and 19 hyperthyroid patients, and in 23 athyreotic cancer patients under T4 suppressive therapy. Cellular thyroxine (CT4) was determined according to Sarne and Refetoff, J. Clin. Endocrinol. Metab. 61: 1046, 1985. CT4 averaged 9.9 +/- 2.8 pg/well (mean +/- SD, range 5.7-15.3) in euthyroid subjects, 1.5 +/- 1.0 pg/well (range 0.05-4.2) in hypothyroid patients, 40.5 +/- 18.8 pg/well (range 18.3 +/- 104.7) in hyperthyroid patients, and 23.7 +/- 7.2 pg/well (range 14.2-40.2) in T4-treated patients. In eu-, hypo- and hyperthyroid patients, a significant correlation was observed between CT4 and free T4 index (FT4I), free T4 (FT4) or Sex Hormone Binding Globulin (SHBG) values. In T4-treated patients, CT4 values were correlated with FT4I values, but not with FT4 or SHBG levels. All T4-treated patients with elevated SHBG levels had elevated FT4, FT4I and CT4 values. In contrast, of the 16 T4-treated subjects with normal serum SHBG concentrations, all but one had normal FT3, 3 (19%) had elevated FT4, 10 (62%) elevated FT4I and 13 (81%) elevated CT4, but all (100%) had undetectable TSH levels. Thus, considering serum SHBG concentrations as a parameter of hepatic tissue response to thyroid hormone, CT4 values, at least in T4-treated patients, do not accurately reflect the liver responsiveness to thyroid hormone action.     

Racial differences in serum creatine kinase levels

Total creatine kinase was measured in serum samples obtained from 307 asymptomatic healthy subjects, 112 men and 195 women, during screening visits to the Yale University Hypertension Clinic or the Yale-New Haven Hospital Primary Care Center or during pre-employment physical examinations at the Yale-New Haven Hospital Personnel Health Clinic. The group consisted of 147 blacks, 132 whites, and 28 Hispanics. Blood pressure was measured in all patients, and weight, height, and serum potassium and creatinine levels were determined in most. Any subject who had engaged in any vigorous exercise in the 12 hours prior to the visit was excluded. The mean total creatine kinase level for black men was 146.5 +/- 136.9 units/liter (median, 108 units/liter), the mean level for white men was 60.8 +/- 26.1 units/liter (median, 51 units/liter), and the mean level for Hispanic men was 84.5 +/- 70.6 units/liter (median, 57 units/liter). The mean level for black women was 66.4 +/- 50.0 units/liter (median, 53 units/liter), the mean level for white women was 37.0 +/- 18.2 units/liter (median, 32 units/liter), and the mean level for Hispanic women was 41.5 +/- 36.0 units/liter (median, 30 units/liter). Using the testing laboratory's normal values for total creatine kinase (8 to 80 units/liter for men and 5 to 50 units/liter for women), 37 black men (64.9 percent) and 49 black women (54.4 percent) had abnormal values for total creatine kinase. Although sex, race, diastolic blood pressure, serum creatinine level, and presence of hypertension correlated significantly with total creatine kinase levels in the entire population, only sex did so in blacks. Multivariate analysis using linear regression techniques clearly demonstrated that sex and race were the only variables that independently predicted the total creatine kinase level. These findings show that healthy asymptomatic blacks have higher total creatine kinase levels than whites or Hispanics, with the majority having values in the abnormal range. Thus, different normal values should be used for blacks, just as they are for men and women, and elevated total creatine kinase levels should be interpreted with considerable caution.     

Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne

Reduced circulating sex hormone binding globulin (SHBG) levels were found in 54% of a group of women with moderate to severe acne and in 60% of another group of twenty-three women who had acne complicated by hirsutism and/or irregular menstrual cycles. The concentrations of SHBG for the women with acne alone (mean 48 ± 24 nmol/l) and for those with acne and hirsutes (mean 39 ± 18 nmol/l) were compared with the SHBG concentrations of fifteen unaffected women with normal menstrual cycles (mean 70 ± 19 nmol/l). The differences in mean SHBG values for both groups of women with acne were significant ( P < 0·001) on comparison with the mean for the unaffected women.
Twenty-nine per cent of the women with acne had elevated testosterone values (mean testosterone concentration for the group 1·5 ± 0·3 nmol/l) and 41% had elevated'derived'free testosterone levels (mean 21 ± 6 pmol/l). Of the women with acne and hirsutes 65% had elevated plasma testosterone levels (mean 2·1 ± 0·6 nmol/l) and 89% had elevated free testosterone concentrations (mean 31 ± 10 pmol/l). The mean values for testosterone and free testosterone in the plasma of unaffected women (mean testosterone concentration 1·1 ± 0·3 nmol/l and free testosterone 13 ± 4 pmol/l) were significantly lower than in women with acne alone ( P < 0·01 and P < 0·001) and in women with acne and hirsutism ( P < 0·001).
This study indicates that a deficiency in SHBG and an elevation in'derived'free testosterone is a frequent finding in women with severe acne and may be a significant factor in the aetiology and/or perpetuation of this condition.     

Common genetic variation in the sex steroid hormone-binding globulin (SHBG) gene and circulating shbg levels among postmenopausal women: the Multiethnic Cohort

SHBG transports sex steroid hormones in the blood, and levels in humans are thought to partially be genetically determined. Recently, studies have found a pentanucleotide (TAAAA)n repeat polymorphism in the promoter of the SHBG gene and a missense polymorphism in exon 6 (Asp327Asn) to predict circulating SHBG levels. Based on the potential role of common genetic variation in SHBG to serve as a marker of SHBG levels in the general population, we evaluated the association between the (TAAAA)n repeat polymorphism, Asp327Asn polymorphism, and SHBG levels in a population of African-American, Native Hawaiian, Japanese, Latina, and white healthy postmenopausal women from the Multiethnic Cohort Study (n = 372). Mean SHBG levels were not significantly different between carriers and noncarriers of the Asn327 allele [minor allele frequency range across ethnic groups, 0.02-0.14; Asp/Asn and Asn/Asn genotypes, 33.6 mol/liter; 95% confidence interval (CI), 28.2-40.0; n = 49; Asp/Asp genotype, 30.8 mol/liter (95% CI, 28.7-33.1; n = 296); P = 0.37]. For the repeat polymorphism, we observed six different SHBG repeat alleles segregating in the population (TAAAA6-11), and the distribution of these alleles varied widely across populations. We found suggestive evidence of linkage disequilibrium between the Asn327 allele and the eight-repeat allele in all populations except African-Americans (P > or = 0.08). In analysis of the repeat polymorphism, SHBG levels among carriers of two short alleles (seven or fewer repeats; 31.2 nmol/liter; 95% CI, 27.3-35.6; n = 82) were not statistically different from those of carriers of two long alleles (more than seven repeats; 32.7 nmol/liter; 95% CI, 29.4-36.3; n = 124; P = 0.59). We did, however, observe individual genotypic classes (n = 16) to contribute modestly to the overall prediction of SHBG levels (by analysis of covariance, P = 0.03). Carriers of the six-repeat allele (27.9 nmol/liter; 95% CI, 25.2-30.8; n = 147) were found to have nominally significantly lower SHBG levels than noncarriers (32.4 nmol/liter; 95% CI, 29.7-35.2; n = 202; P = 0.03). This effect was stronger among the subset of women who also carried the Asn327 allele (interaction, P = 0.006). In summary, these results suggest that genetic variation at the SHBG locus may contribute to modest differences in SHBG levels among healthy postmenopausal women, and that much larger studies will be needed to better comprehend the effects of common variations at this locus in predicting circulating SHBG levels.     

Iron deficiency predicts poor maternal thyroid status during pregnancy

CONTEXT: Pregnant women are often iron deficient, and iron deficiency has adverse effects on thyroid metabolism. Impaired maternal thyroid function during pregnancy may cause neurodevelopmental delays in the offspring. OBJECTIVE: Our objective was to investigate whether maternal iron status is a determinant of TSH and/or total T(4) (TT4) concentrations during pregnancy. DESIGN AND OUTCOME MEASURES: In a representative national sample of Swiss pregnant women (n = 365) in the second and third trimester, samples of urine and blood were collected, and data on maternal characteristics and supplement use were recorded. Concentrations of TSH, TT4, hemoglobin, mean corpuscular volume, serum ferritin, transferrin receptor, and urinary iodine were measured. Body iron stores were calculated and stepwise regressions performed to look for associations. RESULTS: Median urinary iodine was 139 mug/liter (range 30-433). In the third trimester, nearly 40% of women had negative body iron stores, 16% had a TT4 less than 100 nmol/liter, and 6% had a TSH more than 4.0 mU/liter. Compared with the women with positive body iron stores, the relative risk of a TT4 less than 100 nmol/liter in the group with negative body iron stores was 7.8 (95% confidence interval 4.1; 14.9). Of the 12 women with TSH more than 4.0 mU/liter, 10 had negative body iron stores. Serum ferritin, transferrin receptor, and body iron stores were highly significant predictors of TSH (standardized beta: -0.506, 0.602, and -0.589, respectively; all P < 0.0001) and TT4 (standardized beta: 0.679, -0.589, and 0.659, respectively; all P < 0.0001). CONCLUSION: Poor maternal iron status predicts both higher TSH and lower TT4 concentrations during pregnancy in an area of borderline iodine deficiency.     

Thyroid hormones influences sex steroid binding protein levels in infancy: study in congenital hypothyroidism

In order to test the hypothesis of a role of thyroid hormones on the circulating levels of sex steroid binding protein (SHBG) in children, SHBG levels were determined in 15 infants with congenital hypothyroidism at diagnosis and during the first 18 months of T4 therapy and in a separate group of 13 children with congenital hypothyroidism (7.1 +/- 0.5 yr, mean +/- SD), treated before 1 month of age, both during adequate L-T4 therapy and 4 weeks after withdrawing therapy. SHBG levels were significantly lower in hypothyroid infants than in controls (48.2 +/- 6.5 vs. 77.8 +/- 7.9 nmol/L; P less than 0.01), and significantly lower in infants with athyreosis compared to those with ectopic or eutopic glands (P less than 0.05). In patients with low values at diagnosis, SHBG increased rapidly and remained normal during LT4 therapy. After 1.5-18 months of treatment, a positive correlation (P less than 0.01) was found between SHBG, FT4, and FT3 levels. In older hypothyroid children, 4 weeks after withdrawal of therapy a significant (P less than 0.05) decrease in SHBG concentrations was observed. Analysis of these results as well as previous reports in adults, indicates that thyroid hormones influence SHBG concentrations in infants and children. This study also indicates that thyroid hormones may play a role in the physiological postnatal increase of SHBG.     

FAMILIAL DYSALBUMINAEMIC HYPERTHYROXINAEMIA: STUDIES OF ALBUMIN BINDING AND IMPLICATIONS FOR HORMONE ACTION

The abnormal intermediate-affinity T4 binding to albumin which is characteristic of familial dysalbuminaemic hyperthyroxinaemia (FDH) is dependent on buffer, temperature, and ionic composition. Scatchard analysis of T4-binding to isolated albumin preparations from FDH subjects showed that half the circulating albumin showed the higher-affinity T4 binding site, assuming one site per molecule. Using dextran-charcoal separation at 4 degrees C the T4 affinity (Kd) of purified albumin from FDH subjects was 7.5 nmol/l in phosphate and 17 nmol/l in Tris-Cl- buffer. T4 binding to FDH albumin was inhibited by a range of substances in the order: 8-anilino-1-naphthalene sulphonic acid greater than merthiolate greater than propylthiouracil greater than methyl-thiouracil greater than carbimazole greater than salicylate greater than barbitone. Binding of T4 was competitively inhibited by low concentrations of dithiothreitol (DTT). The effect of DTT 0.1-0.5 nmol/l was reversed by removal of DTT by dialysis. Competition with a range of iodothyronines indicated that the 3', 5'-iodine atoms are most important for binding to this site. Serum binding of salicylate, frusemide, fenclofenac and barbituric acid, and a range of steroid hormones was similar in FDH and normal sera. Serum levels of sex hormone binding globulin (SHBG), were not significantly different from sex-matched controls. Nuclear [125I]-T3 binding sites in circulating lymphocytes from two FDH subjects showed affinities (Kd) of 59 and 79 pmol/l (normal 67 +/- 7 pmol/l, n = 6). These findings suggest that the highly specific binding anomaly of FDH is due to a disulphide-dependent structural change in albumin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Freeze fracture morphology of thyroid tight junctions in goats with different thyrotropin stimulation

In the thyroid follicles and blood of goats with congenital hypothyroidism and goiter, abnormal iodoproteins (e.g. iodoalbumin) are found. To study the mechanism involved in the passage of these proteins between the follicles and the blood, the morphology of tight junctions in goiters and normal thyroids of goats was studied by means of freeze fracturing. The T4 and TSH levels of 16 goats were measured by RIA. Based on the TSH levels, the goats could be divided into three groups: a euthyroid group of eight goats with TSH levels between 28 and 55 mU/liter, a hypothyroid group of six goats with TSH levels higher than 199 mU/liter, and an intermediary group of two goats with TSH levels of 120 and 124 mU/liter, respectively. The euthyroid and intermediate animals had normal T4 levels (less than 49 nmol/liter), except for three newborn goats, which had T4 levels above 250 nmol/liter. The hypothyroid goats had T4 levels below 43 nmol/liter. The mean numbers of strands composing the tight junctions were negatively correlated with TSH levels. Hence, the tight junctions of the glands of hypothyroid goats are narrower and are composed of fewer strands than those of normal thyroids. This reduction in tight junction complexity may provide an explanation for the leakage of proteins into the follicles of goitrous glands.     

Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men

Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 +/- 152 ng/dl (18.6 +/- 5.26 nmol/liter), mean +/- sd]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (beta) after adjustment for age and body mass index, 286 +/- 15.8; P < 0.001] and total E2 (beta = 4.47 +/- 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (beta = -1.78 +/- 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (beta = 32.0 +/- 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (beta = -0.016 +/- 0.002; P < 0.001) or non-SHBG-bound (beta = -0.011 +/- 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.     

Effects of oral administration of androstenedione on plasma androgens in young women using hormonal contraception

Androstenedione as a dietary supplement has been targeted at the sporting community, but there are limited data regarding its effects on plasma androgens in young women. A double-blind, cross-over study was undertaken involving 10 women (20-32 yr) using hormonal contraception. Because contamination of supplements has been reported, an in-house oral formulation was prepared containing purified androstenedione, the control being lactose only. After oral administration of a single dose of androstenedione (100 mg), blood was collected frequently up to 8 h and at 24 h. Maximum plasma androgen concentrations observed between volunteers were well above the upper limit of reference ranges for women, being 121-346 nmol/liter for androstenedione, 14-54 nmol/liter for testosterone (T), 11-32 nmol/liter for 5alpha-dihydrotestosterone, and 23-90 nmol/liter for 3alpha-androstanediol glucuronide. The free androgen index and T concentration changed in a similar manner. The mean change in area under the plasma concentration-time curve (0-24 h), compared with control data were: androstenedione approximately 7-fold, T approximately 16-fold, 5alpha-dihydrotestosterone approximately 9-fold, and 3alpha-androstanediol glucuronide approximately 5-fold; the mean conversion ratio of androstenedione to T was 12.5% (range 7.8-21.6%). Increases in T area under the plasma concentration-time curve were correlated with SHBG concentration (r = 0.80; P = 0.005). Formulation characteristics and SHBG levels appear to be important factors when considering plasma androgen increases after acute androstenedione administration.     

Estrogen effects on neuronal morphology

Assocation of low sex hormone-binding globulin (SHBG) level with the risk of the metabolic syndrome (MetS) in men has previously been reported. A proline to alanine substitution in codon 12 of the peroxisome proliferator activated receptor gamma 2 (PPARγ2) gene has been shown to be related to high insulin sensitivity. The relationship of SHBG levels with the Pro12Ala polymorphism of PPARγ2 in men has not been previously studied. Therefore, we investigated the effect of the Pro12Ala polymorphism of PPARγ2 on SHBG levels in 202 young Finnish men. The range of SHBG was from 3.30 to 73 nmol/L (geometric mean=17.90; 95% Cl=16.62–19.25 nmol/L). Baseline SHBG levels tended to be lower in men who developed the MetS (n=11) compared to men who did not develop the MetS (n=169) (22.85 vs 17.26 nmol/L) on a high-caloric diet during their 6 mo military service. SHBG levels tended to be higher among the subjects with the Al12Ala genotype compared to subjects with the Pro12Pro or Pro12Ala genotypes of the PPARγ gene (27.7 vs 21.7 and 22.7 nmol/L). Among the carriers of the Pro12Pro genotype, those who developed the MetS (n=8) had significantly lower levels of SHBG compared to men who did not develop the MetS (n=93) (13.23 vs 24.22 nmol/L, p=0.027). Among the subjects who developed the MetS those with the Pro12Pro genotype (n=3) had significantly lower levels of SHBG compared to subjects with X12Ala (n=8) (13.23 vs 28 nmol/L, p=0.025). We conclude that the 12Ala allele of PPARγ2, may influence SHBG levels in young Finnish men.