Men with human immunodeficiency virus (HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome (AIDS) (HANA) conditions that impair overall health status. No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men. This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients' overall health status and serum T. Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone. Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density. The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism (p < 0.001) and hypogonadism is associated with several comorbidities. The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities. Frailty index is inversely related to serum total T (age-adjusted r = 0.298, r(2) = 0.089, p < 0.0001). Serum fT3 levels are significantly lower in hypogonadal than eugonadal men (p = 0.022). This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal. This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment. In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional. Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail.

Organochlorine (OC) pesticides are endocrine disruptors altering the thyroid hormonal system. The aim of this study is to investigate the relationship between exposure to OC pesticides and thyroid status in adults from a rural area in Rio de Janeiro, Brazil, heavily contaminated with OC pesticides. A cross-sectional study was carried out in 303 men and 305 women >14 years old. Concentrations of 19 OC pesticides and levels of free thyroxine (T4), total triiodothyronine (T3), thyroid-stimulating hormone (TSH), anti-thyroperoxidase (TPOAb) and anti-thyroglobulin (TgAg) antibodies were analyzed in serum samples. Associations between OC pesticides concentrations and values of biochemical thyroid parameters were determined using multivariate regression models stratified by gender. Prevalence of subclinical hyperthyroidism and the presence of TPOAb antibodies were higher than those described for euthyroid populations elsewhere. After adjusting for confounders, total T3 levels were associated with lower concentrations of endosulphan 2 in men and with higher alpha-chlordane, p,p'-dichlorodiphenyltrichloroethane (DDT), endosulphan 2, and methoxychlor in women. Levels of free T4 showed inverse association with beta-hexachlorocyclohexane (HCH) and p,p'-DDT in men, and were positively associated with hexachlorobenzene (HCB), heptachlor, o,p'-DDT, and p,p'-DDT in women. TSH levels were associated with higher beta-HCH in men. A positive association was observed between exposure methoxychlor in males and presence of TPOAb, but no association with TPOAb was found in women. These results suggest that OC pesticides can affect the thyroid system through gender-specific mechanisms that may differ among compounds. Further detailed investigations and health monitoring should be warranted for this population.

The massive meat production of broiler chickens make them continuously exposed to potential stressors that stimulate releasing of stress-related hormones like corticosterone (CORT) which is responsible for specific pathways in biological mechanisms and physiological activities. Therefore, this research was conducted to evaluate a wide range of responses related to broiler performance, immune function, plasma biochemistry, related gene expressions and cell death morphology during and after a 7-day course of CORT injection. A total number of 200 one-day-old commercial Cobb broiler chicks were used in this study. From 21 to 28 d of age, broilers were randomly assigned to one of 2 groups with 5 replicates of 20 birds each; the first group received a daily intramuscular injection of 5 mg/kg BW corticosterone dissolved in 0.5 ml ethanol:saline solution (CORT group), while the second group received a daily intramuscular injection of 0.5 ml ethanol:saline only (CONT group). Growth performance, including body weight (BW), daily weight gain (DG), feed intake (FI) and feed conversion ratio (FC), were calculated at 0, 3 and 7 d after the start of the CORT injections. At the same times, blood samples were collected in each group for hematological (TWBC's and H/L ratio), T- and B-lymphocytes proliferation and plasma biochemical assays (total protein, TP; free triiodothyronine hormone, fT3; aspartate amino transaminase, AST; and alanine amino transaminase, ALT). The liver, thymus, bursa of Fabricius and spleen were dissected and weighed, and the mRNA expression of insulin-like growth factor 1 gene (IGF-1) in liver and cell-death-program gene (caspase-9) in bursa were analyzed for each group and time; while the apoptotic/necrotic cells were morphologically detected in the spleen. From 28 to 35 d of age, broilers were kept for recovery period without CORT injection and the same sampling and parameters were repeated at the end (at 14 d after initiation of the CORT injection). In general, all parameters of broiler performance were negatively affected by the CORT injection. In addition, CORT treatment decreased the plasma concentration of fT3 and the mRNA expression of hepatic IGF-1. A significant increase in liver weight accompanied by an increase in plasma TP, AST and ALT was observed with CORT treatment, indicating an incidence of liver malfunction by CORT. Moreover, the relative weights of thymus, bursa and spleen decreased by the CORT treatment with low counts of TWBC's and low stimulation of T & B cells while the H/L ratio increased; indicating immunosuppressive effect for CORT treatment. Furthermore, high expression of caspase-9 gene occurred in the bursa of CORT-treated chickens, however, it was associated with a high necrotic vs. low apoptotic cell death pathway in the spleen. Seven days after termination of the CORT treatment in broilers, most of these aspects remained negatively affected by CORT and did not recover to its normal status. The current study provides a comprehensive view of different physiological modulations in broiler chickens by CORT treatment and may set the potential means to mount a successful defense against stress in broilers and other animals as well.

BACKGROUND

Postpartum thyroid dysfunction occurs in approximately 5-10% of women in the general population within one year of delivery. Differentiation of postpartum Graves' thyrotoxicosis (PPGr) from postpartum destructive thyrotoxicosis (PPDT) is essential because of the difference in treatment measures between the two. However, it is sometimes difficult because radioactive iodine uptake is contraindicated when patients are lactating. We examined the usefulness of determining the time of onset postpartum and measurement of antithyrotropin (anti-TSH) receptor antibodies and thyroid blood flow.

METHODS

Forty-two patients with newly developed thyrotoxicosis after delivery were examined: 18 had Graves' disease and 24 had destructive thyrotoxicosis. Serum free thyroxine (fT4), free triiodothyronine (fT3), and TSH were measured by chemiluminescent immunoassays. Anti-TSH receptor antibodies (TRAb), antithyroglobulin antibodies (TgAb), and antithyroid peroxidase antibodies (TPOAb) were measured by the Elecsys electrochemiluminescence immunoassay. Thyroid volume and blood flow (TBF) were measured quantitatively by color flow Doppler ultrasonography.

RESULTS

Onset of thyrotoxicosis was distributed from 2 to 12 months postpartum. Twelve (85.7%) of 14 patients who developed thyrotoxicosis at three months or earlier after delivery had PPDT. On the other hand, all 11 patients who developed thyrotoxicosis at 6.5 months or later had PPGr. All patients with PPGr had positive TRAb (14.9±14.9 IU/L, mean±standard deviation (SD)) and all patients with PPDT had negative TRAb (0.1±0.3 IU/L, p<0.0001). Fifteen (83.3%) of 18 PPGr patients had high TBF of more than 4.0% (8.9±4.4), and all PPDT patients had low TBF of <4.0% (1.6±1.0, p<0.0001). The fT3/fT4 ratio was higher in PPGr (64.0±23.9) than in PPDT (38.9±13.1, p<0.0002), but absolute values overlapped between the two.

CONCLUSIONS

Early onset of thyrotoxicosis postpartum was associated mainly with PPDT, and a late onset was suggestive of PPGr. Positive TRAb and high TBF >4.0% are indicators of postpartum onset of Graves' disease.

OBJECTIVE

To test whether selenium administration affects autoantibodies to thyroid peroxidase (anti-TPO) and thyroglobulin (anti-TG) titres in chronic autoimmune (Hashimoto's - HT) thyroiditis.

METHODS

A prospective, open-label, quasi-randomised study in 86 HT patients (n = 86) assigned to either selenomethionine (Seme) 200μg daily for 3 months (Se3, n = 15) or 6 months (Se6, n = 46) or placebo (Control, n = 25). Serum Se, anti-TPO, anti-TG and thyroid hormones were measured in all patients at baseline, 3 and 6 months. A subgroup of 18 patients (twelve on Se6 and six controls) were subjected in thyroid fine-needle biopsy at baseline and 6 months to detect changes in lymphocyte infiltration.

RESULTS

No significant difference in anti-TPO levels was recorded after 3 (p = 0.88) or 6 months (p = 0.62) on Seme. Anti-TG levels decreased both at 3 months (p = 0.001) and 6 months (p = 0.001). No significant changes in thyroid stimulating hormone, free thyroxine and free triiodothyronine levels or in the lymphocytes' number in thyroid cytology specimens were detected. Age, gender, duration of disease, baseline anti-TPO levels and per cent change in Se levels could not predict the response of anti-TPO levels to Seme administration.

CONCLUSIONS

Our data suggest that Seme administration in pharmacological doses for a period of 6 months seems to have no significant effect on serum thyroid auto-antibodies' levels or lymphocyte infiltration of the thyroid gland.

A low resting metabolic rate (RMR) for a given body composition has been identified as a risk factor for weight gain and obesity, and has also been reported in formerly obese individuals with the genetic predisposition for obesity. The possible role of thyroid hormone in low RMR was studied in a large sample of postobese women. RMR was measured by indirect calorimetry in 28 weight-stable postobese women with a family history of obesity (PO group) and in a control group of 28 nonobese women closely matched for age, fat mass, and fat-free mass. RMR was 8% lower in the PO than in the control group [[symbol: see text]; 95% Cl:5856 (5520, 6214) compared with 6408 kJ/d (6096, 6768 kJ/d), P < 0.02], and the group difference remained unchanged after fat-free mass and fat mass were adjusted for (552 kJ/d, P < 0.015). The PO group had lower plasma free triiodothyronine [2.4 (1.9, 3.0) compared with 3.4 pmol/L (2.9, 3.9 pmol/L), P < 0.01], whereas plasma androstenedione only tended to be lower in the PO than in the control group. Adjustment for differences in androstenedione did not reduce the difference in RMR, whereas adjustment for differences in plasma free triiodothyronine eliminated the group difference (96 kJ/d, P = 0.59). The present study shows that RMR for a given body composition is lower among postobese than among matched never-obese control subjects. Statistically, the lower plasma free triiodothyronine concentrations of the postobese subjects could explain their lower RMRs, but it remains to be established whether these findings are causally related.

Estimation and interpretation of thyroid function tests in pregnant women is of utmost importance for maternal, fetal and neonatal health. Our objective was to calculate laboratory- and geography-specific reference intervals for thyroid hormones during pregnancy in an iodine-sufficient area of the Mediterranean, Crete, Greece. This project was performed in the context of "Rhea" mother-child cohort. Fulfillment of extensive questionnaires and estimation of free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and antithyroid antibodies were performed. The reference population was defined using inclusion criteria regarding thyroidal, obstetric, and general medical status of women. Reference interval for TSH was 0.05-2.53 μIU/mL for the first and 0.18-2.73 μIU/mL for the second trimester. 6,8% and 5,9% of women in the first and second trimester, respectively, had TSH higher than the upper reference limit. These trimester-specific population-based reference ranges are essential in everyday clinical practice for the correct interpretation of thyroid hormone values and accurate classification of thyroid disorders.

BACKGROUND

Recent literature describing the effect of gastric acid suppression on levothyroxine absorption has been inconsistent. Also, ezetimibe, a lipid-lowering compound that inhibits intestinal absorption of cholesterol, may interfere with levothyroxine absorption. The objective of this study was to measure changes in levothyroxine absorption before and after famotidine, esomeprazole or single-dose ezetimibe."

METHODS

We conducted levothyroxine absorption testing on 30 healthy volunteers, excluding those with thyroid disease. Subjects were randomized to receive one of three regimens: 1 week of either famotidine or esomeprazole, or a single dose of ezetimibe administered simultaneously with levothyroxine (n = 10 in each group). Baseline levothyroxine absorption testing was performed on all subjects using 600 mcg of Synthroid with thyroid hormone levels checked at 0, 2, 4, 6, and 8 hours after administration, and then repeated 6 weeks later, after administration of one of the three study drug regimens. The area under the curve (AUC) over 8 hours for serum thyroxine (T4), triiodothyronine (T3), and free T4 index, and the mean peak hormone levels achieved during levothyroxine absorption testing at baseline and following administration of one of the three study medications were compared using paired t-tests.

RESULTS

Peak mean hormone levels and AUCs of T4, T3, and free T4 index during absorption testing before and after each of three study medications did not differ. Results for differences before and after study medication did not reach significance even when using the subtractive correction method of AUC calculation.

CONCLUSIONS

No differences were noted in levothyroxine absorption after gastric acid suppression with 1 week of famotidine or esomeprazole. A simultaneously administered dose of ezetimibe did not significantly change levothyroxine absorption.

BACKGROUND

The New Zealand population has both marginal selenium status and mild iodine deficiency. Adequate intakes of iodine and selenium are required for optimal thyroid function.

OBJECTIVE

The aim of the study was to determine whether low selenium and iodine status compromises thyroid function in an older New Zealand population.

METHODS

We investigated the effects of selenium and iodine supplementation in a double-blind, randomized, placebo-controlled trial in 100 Dunedin volunteers aged 60-80 y. Participants received 100 microg Se/d as l-selenomethionine, 80 microg I, 100 microg Se + 80 microg I, or placebo for 3 mo. Thyroid-stimulating hormone (TSH), free triiodothyronine (T(3)), free thyroxine (T(4)), thyroglobulin, plasma selenium, whole-blood glutathione peroxidase (GPx) activity, and urinary iodine concentrations (UICs) were measured.

RESULTS

Plasma selenium (P < 0.0001) and whole-blood GPx activity (P<0.0001) increased from baseline to week 12 in the selenium and selenium plus iodine groups in comparison with the placebo group. Median UIC at baseline was 48 microg/L (interquartile range: 31-79 microg/L), which is indicative of moderate iodine deficiency. UIC increased in the iodine and selenium plus iodine groups and was significant only for the iodine group (P = 0.0014). Thyroglobulin concentration decreased by 24% and 13% of baseline in the iodine and selenium plus iodine groups in comparison with the placebo group (P = 0.009 and P = 0.108, respectively). No significant treatment effects were found for TSH, free T(3), free T(4), or ratio of T(3) to T(4).

CONCLUSIONS

Additional selenium improved GPx activity but not the thyroid hormone status of older New Zealanders. Iodine supplementation alleviated the moderate iodine deficiency and reduced elevated thyroglobulin concentrations. No synergistic action of selenium and iodine was observed. The trial was registered at www.anzctr.org.au/registry/ as ACTRN012605000368639.

Brominated flame retardants (BFRs) released from e-waste related activities may affect the health of local people. Assessing the impact of e-waste exposure during recycling and dismantling activities on local people's thyroid hormone levels is an area of ongoing research. During November and December 2008, the process of e-waste recycling and dismantling was investigated, and 236 occupation-exposed people and 89 non-occupation-exposed people approximate to the e-waste recycling sites were surveyed; their thyroid hormone levels (THs), thyrotropins (TSH) and BFRs levels in serum were assayed. Multiple regression models were constructed to analyze the changes of serum THs and TSH in the people living in the exposure area (exposure group) and the people in the control group. Covariates known to be or likely to be associated with THs, TSH and BFRs levels were analyzed. Lower level of Triiodothyronine (T(3)) in both occupation-exposed and non-occupation-exposed group were observed (p<0.01), when compared with the control group, and the same trend was obtained for free triiodothyronine (fT(3)) and free thyroxine (fT4) (p<0.01). However, no significant difference in thyroxine (T(4)) was found between the two groups. The level of TSH in the e-waste recycling occupational-exposed group ranged from 0.00 to 5.00microIU/ml with a mean of 1.26microIU/ml, whereas the level of TSH in the control group was from 0.03 to 5.54microIU/ml with a mean of 1.57microIU/ml. This study revealed that people having worked on e-waste recycling and dismantling had significantly lower TSH compared with the control group (p<0.01). Moreover, the level of BDE-205 is positively associated with the level of T4, as confirmed by the linear regression model (unstandardized regression coefficient, beta=0.25, rho=0.001) and a weaker positive relation was also found between the levels of BDE-126 and T4. Meanwhile, a weak negative relation was found between the levels of PBB 103 and T3, and between the levels of fT3 and fT4. These results suggest that exposure to BFRs released from primitive e-waste handling may contribute to the changes of THs and TSH levels.

We studied the incidence of thyroid function abnormalities observed soon after allogeneic bone marrow transplantations (BMT) and their predictive value on the overall prognosis. Free serum thyroxine, free serum triiodothyronine, total serum reverse triiodothyronine and serum thyrotropin levels were systematically measured in 78 patients before and 3 months after BMT. 41 (52%) had normal hormone levels and 37 (48%) had abnormal ones, among whom four (5%) had peripheral compensated hypothyroidism and 33 (43%) were described as having 'euthyroid sick syndrome' (low thyroxine state, or low T3 syndrome). Two factors strongly influenced the appearance of thyroid abnormalities: steroid dose at the time of thyroid function testing, and age (< or = 16 years/>> 16 years). Among the younger patients, 21 had no thyroid abnormalities, while five did. Among the older patients, 20 had no thyroid abnormalities, while 32 did (P < 0.001). The occurrence of thyroid abnormalities seemed to influence survival strongly, since the 30-month projected survival time was 83% for patients without abnormalities whereas it was 49% for patients with an abnormal profile (P < 0.001). In conclusion, evidence obtained among our population reveals that euthyroid sick syndrome indicates a poor prognosis and that it is very important to monitor thyroid hormone levels (particularly free hormones) soon after allogeneic BMT and regularly thereafter.

BACKGROUND

Thyroid dysfunction after bone marrow transplantation (BMT) has been investigated in many studies, and most posttransplant thyroid disorders are now recognized as a late complication of transplantation. However, these studies mainly focused on late thyroid function after BMT, and we have little information on early changes of thyroid function after BMT.

METHODS

We prospectively investigated thyroid function in 57 patients receiving BMT. Serum thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels were determined at least monthly in the first 3 months, once between 3 and 12 months and once in the second year after BMT.

RESULTS

During the first 6 months after BMT, 24 and 7 patients were diagnosed as having euthyroid sick syndrome (ETS) and thyrotoxicosis, respectively. Of the 52 patients alive 1 year after transplantation, 9 patients were still diagnosed as having ETS, and 8 patients developed hypothyroidism. Patients with thyrotoxicosis showed similar characteristics, and the high incidence of thyrotoxicosis after BMT is a novel finding. The median for the onset of thyrotoxicosis was day 111 after transplantation. Thyrotoxicosis was transient in all of the patients, but in seven patients hypothyroidism followed, the median onset at 12 months after BMT. Serum thyroglobulin levels were elevated in five patients, and antibodies autoreactive to the thyroid gland were detected in seven patients.

CONCLUSIONS

Thyrotoxicosis may be a distinct clinical entity of thyroid dysfunction after BMT and may serve to predict the development of hypothyroidism. Immune-mediated thyroid injury may contribute to the development of posttransplant hypothyroidism.

The mechanism by which glucocorticoids induce GH expression between embryonic days 18 and 19 (E18-19) in the fetal rat pituitary gland was examined with an in vitro organ culture system. Twenty-four hour incubation of E18 pituitary glands in serum-free medium containing either dexamethasone (DEX, 5-50 nM) or corticosterone (0.55 microM) resulted in a conspicuous accumulation of GH messenger RNA (mRNA), whereas no spontaneous expression of GH mRNA was noted without glucocorticoid. Triiodothyronine (1 nM) alone weakly induced GH mRNA but increased the effect of DEX 2-fold. The GH mRNA accumulation was not observed after 5 or 10 h incubation with DEX. However, a 10-h incubation with DEX followed by 14 h chase incubation without DEX resulted in apparent induction of GH mRNA. The induction of GH mRNA by DEX was completely inhibited by puromycin. These data, taken as a whole, suggest that the induction of GH mRNA by DEX in the fetal pituitary gland is not a direct effect of DEX on the GH gene but is mediated by a factor that is synthesized in the pituitary gland in response to DEX. Both immunoblot and RNase protection assays suggested that this factor is not pit-1, which is known to be required for GH mRNA expression.

In order to evaluate the effects of climatic factors on the secretion of thyroid hormones and TSH in a high latitude population, we have taken serum and urine samples from 20 healthy men from northern Finland (67 degrees -68 degrees N) every 2 months for a period of 14 months. Serum free triiodothyronine (T(3)) levels were lower in February than in August (3.9 vs 4.4 pmol/l, P<0.05) and TSH levels were higher in December than during other months (2.1 vs 1.5-1.7 mU/l, P<0.01). Serum total and free thyroxine (T(4)), total T(3) and reverse T(3) levels and urinary T(4) levels were unchanged. Urinary T(3) levels were significantly higher in winter than in summer. Serum free T(3) correlated highly significantly with the outdoor temperature integrated backwards weekly for 7-56 days (r=0.26 for 1-56 days) from the day when the blood samples were taken. Serum TSH did not show any significant correlation with the thyroid hormones or with the integrated temperature of the previous days, but it did show an inverse and significant correlation (r=-0.31) with the ambient luminosity integrated backwards for 7 days from the day when the blood sample was taken. The gradually increasing correlation between outdoor temperatures and serum free T(3) suggests that the disposal of thyroid hormones is accelerated in winter, leading to low serum free T(3) levels and a high urinary free T(3) excretion. Since there was no correlation between thyroid hormones and serum TSH, the feedback mechanism between TSH and thyroid hormones may not be the only contributing factor, and other factors such as ambient luminosity may at least partly determine serum TSH in these conditions. Also urinary free T(3) appears to be a novel and non-invasive indicator for thyroid physiology.

The influence of triiodothyronine (T3) on right ventricular functional parameters was tested and compared to the alterations induced in the left ventricle. Female Sprague-Dawley rats received daily injections of T3 (0.2 mg/kg s.c.) for 3 days and a constant i.v. infusion of 0.9% NaCl or the beta 1-receptor blocker metoprolol (1 mg/kg/h). The hyperthyroid state after 3 days administration of T3 was characterized by an increase in heart rate and cardiac output and a decrease in the systemic peripheral resistance. However, pulmonary vascular resistance was unchanged. Beta-Receptor blockade reduced heart rate to the control level without affecting the elevation in cardiac output. The T3 group showed a marked increase in right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure, whereas left ventricular systolic pressure (LVSP) and mean aortic pressure were not significantly changed. Metoprolol had no effect on LVSP, and attenuated the increase in RVSP. Furthermore, T3 induced a considerable increase in dP/dtmax in both ventricles, which was reduced nearly to control level by concomitant metoprolol infusion. The T3-induced percentage weight gain of the right ventricular free wall (RV) was more pronounced than that of the left ventricle (LV) as indicated by the significant increase in the RV/LV weight and the RNA/DNA ratios. Metoprolol did not affect significantly the T3-induced left and right ventricular hypertrophy, but attenuated slightly the elevated RV/LV weight ratio. Our results indicate a different action of T3 on systemic and pulmonary circulation.

Marked alterations in levels of circulating thyroid hormone were found in patients undergoing cardiopulmonary bypass with a rise in the free thyroxine and a fall in the free triiodothyronine levels. Studies using thyrotropin-releasing hormone during bypass demonstrated a blunted response to this stimulus. This reduced response is related to changes in thyroid hormone levels and it is suggested that bypass surgery may have a direct inhibitory action on thyroid-stimulating hormone release at the hypothalamo-pituitary level. The potential significance of these hormonal changes is discussed.

OBJECTIVE

Correct interpretation of thyroid status during pregnancy is vital to secure fetal development. Pregnancy-related changes in maternal thyroid status necessitate the use of gestational age-specific reference ranges. In this study, we investigated between-laboratory reproducibility of thyroid reference ranges in pregnant women.

METHODS

Comparison of two longitudinal prospective cohort studies including 255 (cohort 1) and 101 (cohort 2) healthy antibody-negative Danish pregnant women attending prenatal care at Copenhagen University Hospital.

METHODS

Different immunoassays were used to measure thyroid hormone levels in the two cohorts. Thyroid hormone reference ranges were established for every 5 weeks of gestation. Differences between cohorts were explored through mixed-model repeated measures regression analyses. By applying reference ranges from one cohort to the other, the proportion of women who would be misclassified by doing so was investigated.

RESULTS

TSH increased and free thyroxine (FT4) decreased as pregnancy progressed. Results indicated highly significant differences between cohorts in free triiodothyronine (F=21.3, P<0.001) and FT4 (F=941, P<0.001). TSH levels were comparable (P=0.09). Up to 90.3% of the women had FT4 levels outside their laboratory's nonpregnant reference range, and up to 100% outside the other cohort's gestational-age-specific reference ranges. Z-score-based reference ranges markedly improved comparison between cohorts.

CONCLUSIONS

Even in the same region, the use of gestational-age-specific reference ranges from different laboratories led to misclassification. Up to 100% of maternal FT4 levels fell outside the other cohort's reference range despite similar TSH levels. In clinical practice, thyroid testing of pregnant women without adding method specificity to gestational age-dependent reference ranges will compromise patient safety.

Total body and regional bone mineral density (BMD) levels were determined in 26 premenopausal women with Hashimoto's thyroiditis receiving long-term physiological doses of levothyroxine sodium replacement therapy. The BMD levels of each patient were compared with the mean of the BMD levels of age-matched normal controls. The mean levothyroxine sodium dose was 111 +/- 6 micrograms/d, and the mean duration of treatment was 7.5 +/- 5.3 years (range, 1 to 24 years). Dietary calcium intake was similar in both groups, as were serum thyroxine, triiodothyronine, free thyroxine index, and thyrotropin levels. Women receiving the levothyroxine treatment had normal total body BMD levels but had significantly lower BMD levels at the femoral neck (-5.7%), femoral trochanter (-7.0%), Ward's triangle (-10.6%), both arms (right, -7.8%; left, -8.9%), and pelvis (-4.9%). In contrast, lumbar spine BMD levels were similar in the two groups. There was no correlation between the total body or different regional BMD levels and the duration or dosage of levothyroxine treatment or thyroid function test results. However, the z score of the femoral neck of these patients showed a significant negative correlation with their serum free thyroxine index levels. We conclude that patients receiving physiological doses of levothyroxine may have decreased bone density. Thyroid functions in patients receiving long-term levothyroxine treatment should be closely monitored and bone densitometry should be performed in patients at risk for osteoporosis.

OBJECTIVE

To characterize the time course of recovery of the hypothalamic-pituitary-thyroid (HPT) axis by determining the frequency, onset, duration, and clinical attributes of the central hypothyroid phase following 131I therapy for Graves' disease and to examine whether the central hypothyroid phase is due to direct pituitary thyrotroph suppression or to hypothalamic thyrotropin-releasing hormone (TRH) deficiency.

METHODS

Twenty-one hyperthyroid patients with Graves' disease evaluated at a university endocrine clinic and treated with radioactive iodine were prospectively studied. Serial thyroid function levels (serum thyroxine [T4], free thyroxine [free T4], triiodothyronine [T3], and thyroid-stimulating hormone [TSH]) were measured and TRH stimulation tests were performed at 2 to 4 week intervals for all subjects following 131I treatment. None of the patients was treated with thionamides after receiving 131I therapy.

RESULTS

Nineteen (90%) of the patients with Graves' disease experienced a transient central hypothyroid phase defined as the presence of a suppressed or inappropriately normal TSH level despite a low free T4 level following 131I treatment. This phase occurred a mean of 62.8 +/- 5.1 days following 131I treatment, persisted for an average of 24.7 +/- 2.4 days, and was not predictive of eventual treatment outcome. All patients had concordantly low T4 and T3 levels during this period and exhibited a blunted TSH response to TRH compared to 29 euthyroid control subjects, suggesting primary feedback suppression at the level of the pituitary thyrotrophs. The suppressed thyrotrophs required a minimum of 2 weeks to recover once patients became hypothyroid. The length of preexisting hyperthyroidism, basal free T4 elevation, and administered dose of 131I failed to predict the duration of the central hypothyroid phase, although a higher dose of 131I was associated with an earlier onset of central hypothyroidism (r = -.51, P < 0.05).

CONCLUSIONS

Clinicians should be aware of the delay in the recovery of the HPT axis that occurs in the majority of patients with Graves' disease treated with 131I and is manifested by a transient central hypothyroid phase. The blunted TSH response to TRH stimulation during this period suggests that suppression occurs primarily at the level of the pituitary thyrotrophs. The use of sensitive TSH measurements alone to monitor these patients during this period is not helpful and may be misleading.

Acute critically ill patients experience a rapid decline in plasma free thyroid hormone levels (free triiodothyronine (FT3) and free levothyroxine (FT4)), with a marked elevation of reverse T3, recognized as the euthyroid sick syndrome (ESS) or low-T3 syndrome. The ESS is also often associated with depressed myocardial function, sometimes referred to as the 'stunned myocardium'. Its clinical effects may vary from minimal hemodynamic impairment to cardiogenic shock. Medical management may range from aspirin alone to placement of a left ventricular assist device. With adequate supportive therapy, recovery usually occurs within days or weeks. The effect of T3/T4 therapy has been studied in three conditions in which the ESS and myocardial functional depression have been documented - i) transient regional myocardial ischemia and reperfusion, ii) transient global myocardial ischemia in patients undergoing cardiac surgery on cardiopulmonary bypass, and iii) transient inadequate global myocardial perfusion in brain-dead potential organ donors. Under all three conditions, myocardial ischemia leads to rapid loss of high-energy phosphates, accumulation of myocardial tissue lactate, and probably loss of homeostasis of cytosolic calcium, which may further increase cell injury. There is an inability to generate ATP through the Krebs cycle, which reduces the high-energy phosphate pool essential for all cell ATPases. Under all three conditions, following administration of T3/T4, the myocardial dysfunction was rapidly reversed. We, therefore, cautiously advocate the use of thyroid hormonal therapy to any patient with the ESS and/or a stunned myocardium.

Growth of the MCF-7, T47D, and ZR-75-1 human breast cancer cells was established in a serum-free defined medium (MOM-1) composed of a 1:1 (vol/vol) mixture of Ham's F12 medium and Dulbecco's modified Eagle's medium containing 15 mM HEPES (pH 7.2), 2 mM 1-glutamine, 20 micrograms/ml glutathione, 10 micrograms/ml insulin, 10 micrograms/ml transferrin (Tf), 10 ng/ml selenous acid, 0.3 nM triiodothyronine, 50 micrograms/ml ethanolamine, 20 ng/ml epidermal growth factor, 2.0 nM 17 beta-estradiol, and 1.0 mg/ml bovine serum albumin (BSA). Proliferation in MOM-1 was 50 to 70% of the serum stimulated rate. Deletion of components from MOM-1 gave a medium (Tf-BSA) containing only HEPES, 10 micrograms/ml Tf, and 200 micrograms/ml BSA, which sustained MCF-7 and T47D cells in a slowly dividing and mitogen responsive state; ZR-75-1 cells required Tf plus 1.0 mg/ml BSA. In Tf-BSA, insulin and insulin-like growth factor I (IGF-I) were mitogenic with ED50 values of 2 to 3 ng/ml and 30 to 150 pg/ml, respectively, with MCF-7 cells. The T47D cells were responsive to these factors in Tf-BSA but required 10-fold higher concentrations for ED50. At saturating concentrations, insulin and IGF-I promoted 1.5 to 3.5 cell population doublings over controls in 8 d. At less than or equal to ng/ml concentrations, epidermal growth factor, insulin-like growth factor II, and basic fibroblast growth factor were mitogenic for human breast cancer cells in Tf-BSA. Mitogen activities in uterus and pituitary extracts were assayed readily in Tf-BSA. This new method offers a convenient means of comparing the potencies of growth-promoting factors on human breast cancer cells without interfering activities known to be present in serum.

Hypothyroidism is associated with profound left ventricular dysfunction. Brain-dead organ donors and patients undergoing cardiopulmonary bypass are chemically hypothyroid with significantly reduced circulating free triiodothyronine (T3). To test the hypothesis that T3 enhances left ventricular function in a hormonally deficient environment, a total of 36 healthy New Zealand White rabbit hearts were studied using a modified Langendorff preparation with Krebs-Henseleit perfusate and intra-ventricular balloon. In 9 normal rabbit hearts a cumulative dose-response curve with logarithmically increasing doses of T3 was obtained. The vehicle solution for T3 dissolution served as control (n = 9). Left ventricular function was assessed from peak developed pressure at baseline and after T3 administration. Triiodothyronine had no effect in normal hearts on peak developed pressure or end-diastolic pressure. In 18 rabbits, the acute effect of T3 administration after ischemia was investigated. Preischemic left ventricular function was measured to serve as baseline, and hearts were subjected to 37 degrees C global ischemia. Triiodothyronine (n = 9) or vehicle (n = 9) was infused during reperfusion, and left ventricular peak developed pressure was measured at 30 and 60 minutes of reperfusion. Recovery of function (expressed as percent return of left ventricular peak developed pressure) was significantly improved within 15 minutes of reperfusion (65.0% +/- 2.1% versus 80.2% +/- 4.1%) and remained significantly improved throughout the reperfusion period (p less than 0.05 by analysis of variance). These data suggest that although T3 possesses no inotropic properties, it significantly improves postischemic left ventricular function. The rapidity of the functional improvement suggests that these effects may be due to plasma membrane-mediated mechanisms.

We have investigated the modulation of apolipoprotein B gene expression in HepG2 cells by thyroid hormone. ApoB secretion rate in serum-free media was found to be significantly increased in the presence of the hormone in long-term cultures (48 h, 37%). This stimulatory effect was dose-dependent. The mechanisms underlying the stimulatory effect of triiodothyronine on apoB production were investigated. Triiodothyronine increased apoB mRNA levels by about 25-36% as determined by slot- and Northern-blot analysis of total RNA. ApoB synthesis rate was also found to be increased both in in vivo pulse-chase experiments (61%) and in in vitro translation studies (54.5%). Despite the 54.5-61% increase in apoB synthesis with triiodothyronine, only a 30% increase in apoB secretion was noted suggesting that part of the increase in the intracellular apoB pool may be lost by degradation. Overall, apoB gene expression appears to be modulated by thyroid hormone at both transcriptional and posttranscriptional levels.