Changes In Thyroid Hormone Status Research Articles

Accustomed to the heat: Temperature and thyroid hormone influences on oogenesis and gonadal steroidogenesis pathways vary among populations of Amargosa pupfish (Cyprinodon nevadensis amargosae)

Many fish experience diminished reproductive performance under atypically high or prolonged elevations of temperature. Such high temperature inhibition of reproduction comes about in part from altered stimulation of gametogenesis by the hypothalamic-pituitary-gonadal (HPG) endocrine axis. Elevated temperatures have also been shown to affect thyroid hormone (TH) signaling, and altered TH status under high temperatures may impact gametogenesis via crosstalk with HPG axis pathways. Here, we examined effects of temperature and 3′-triiodo-L-thyronine (T3) on pathways for gonadal steroidogenesis and gametogenesis in Amargosa pupfish (Cyprinodon nevadensis amargosae) from two allopatric populations: 1) the Amargosa River – a highly variable temperature habitat, and 2) Tecopa Bore – an invariably warm groundwater-fed marsh. These populations were previously shown to differ in TH signaling profiles both in the wild and under common laboratory conditions. Sexually-mature pupfish from each population were maintained at 24 °C or 34 °C for 88 days, after which a subset of fish was treated with T3 for 18–24 h. In both populations, mRNA abundances for follicle-stimulating hormone receptor and luteinizing hormone receptor were higher in the ovary and testis at 24 °C compared to 34 °C. Females from Tecopa Bore – but not from the Amargosa River – also had greater ovarian transcript abundances for steroidogenic enzymes cytochrome P450 aromatase, 3β-hydroxysteroid dehydrogenase, and 17β-hydroxysteroid dehydrogenase at 24 °C compared to 34 °C, as well as higher liver mRNA levels of vitellogenins and choriogenins at cooler temperature. Transcript abundances for estrogen receptors esr1, esr2a, and esr2b were reduced at 34 °C in Amargosa River females, but not in Tecopa Bore females. T3 augmented gonadal gene transcript levels for steroid acute regulatory protein (StAR) transporter in both sexes and populations. T3 also downregulated liver estrogen receptor mRNAs in females from the warmer Tecopa Bore habitat only, suggesting T3 modulation of liver E2 sensitivity as a possible mechanism whereby temperature-induced changes in TH status may contribute to shifts in thermal sensitivity for oogenesis.

Altered thyroid hormone levels affect the capacity for temperature-induced developmental plasticity in larvae of Rana temporaria and Xenopus laevis.

Anuran larvae show phenotypic plasticity in age and size at metamorphosis as a response to temperature variation. The capacity for temperature-induced developmental plasticity is determined by the thermal adaptation of a population. Multiple factors such as physiological responses to changing environmental conditions, however, might influence this capacity as well. In anuran larvae, thyroid hormone (TH) levels control growth and developmental rate and changes in TH status are a well-known stress response to sub-optimal environmental conditions. We investigated how chemically altered TH levels affect the capacity to exhibit temperature-induced developmental plasticity in larvae of the African clawed frog (Xenopus laevis) and the common frog (Rana temporaria). In both species, TH level influenced growth and developmental rate and modified the capacity for temperature-induced developmental plasticity. High TH levels reduced thermal sensitivity of metamorphic traits up to 57% (R. temporaria) and 36% (X. laevis). Rates of growth and development were more plastic in response to temperature in X. laevis (+30%) than in R. temporaria (+6%). Plasticity in rates of growth and development is beneficial to larvae in heterogeneous habitats as it allows a more rapid transition into the juvenile stage where rates of mortality are lower. Therefore, environmental stressors that increase endogenous TH levels and reduce temperature-dependent plasticity may increase risks and the vulnerability of anuran larvae. As TH status also influences metabolism, future studies should investigate whether reductions in physiological plasticity also increases the vulnerability of tadpoles to global change.

Former Very Preterm Infants Show Alterations in Thyroid Function at a Preschool Age.

Preterm birth is frequently associated with altered thyroid hormone levels in the newborn period. Recent data suggest a role of prematurity independent of birth size also in childhood thyroid dysfunction. Whether the high-risk population of former very preterm infants (VPI) is particularly susceptible to thyroid hormone alterations is currently unknown. The aim of the present study was to assess whether former VPI display changes in thyroid hormone status in comparison to term-born controls at a preschool age. Free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) concentrations were determined in former VPI and same-aged children born at term at five to seven years of age. 31 former term infants and 82 former VPI were included in the study. In comparison to children born at term, former VPI had lower fT4 (16.1 ± 1.8 versus 17.0 ± 2.1 pmol/l), higher fT3 (6.8 ± 0.7 versus 6.5 pmol/l), and higher TSH levels (3.0 ± 1.4 versus 2.3 ± 1.0 μU/l), independent of major neonatal morbidities. As subclinical changes in thyroid hormone status are potentially associated with adverse health profiles, close follow-up of these children is warranted.

Hyperthyroidism and thyroid autoimmunity induced by sorafenib in metastatic renal cell cancer

Dear Editor, Tyrosine kinase inhibitors (TKIs) are novel moleculartargeted agents used in the treatment of various cancers. Treatment with TKIs has been associated with changes in thyroid hormone status. While hypothyroidism had frequently been reported with the use of TKIs, thyroid-stimulating hormone (TSH) suppressing effect of TKIs is rare [1]. Here, we describe a case with metastatic renal cell cancer (RCC), who initially became hyperthyroid under sorafenib treatment and later long-term hypothyroid under sunitinib treatment. A 58-year-old male with metastatic RCC presented with the complaints of weakness, palpitations, restlessness, and trembling in his hands for 4 weeks after starting his new cancer treatment using sorafenib. He did not have any other medication or recent iodinated-contrast exposure. On examination, he had tachycardia, fine tremor, hyperactive deep tendon reflexes, and a smooth, non-tender, slightly enlarged thyroid gland. His test results were compatible with overt hyperthyroidism [TSH: 0.011 lIU/ml (0.55–4.78); free thyroxine (fT4): 8.14 ng/dl (0.89–1.76); and free triiodothyronine (fT3): 17.3 pg/dl (2.3–4.2)], and he had high titers of thyroglobulin (anti-TG) (2,500 U/ml; normal \60), thyroid peroxidase (anti-TPO) (2,723 U/ml; normal \60), and TSH-receptor (TRAb) [24.6 U/L (0–14) antibodies; however, thyroglobulin levels were not elevated [4.76 (1.6–59.9 ng/mL)]. Thyroid function tests, anti-TG and anti-TPO, were normal before sorafenib treatment. His family history was negative for Graves disease. The ultrasonography revealed heterogeneous enlargement of the thyroid gland and the Tc-99 scintigraphy showed a homogeneously increased absorption; 4 and 24 h I uptakes were 49.5 % (15–25 %) and 70.1 % (25–35 %), respectively. Graves disease, induced by sorafenib, was diagnosed based on positivity of anti-TSH receptor antibodies and high radio-iodine thyroid uptake and methimazole (20 mg/dl) and propranolol were prescribed. Completing his first cycle of sorafenib, the patient was switched to sunitinib. He had substantial improvement 1 month after the onset of antithyroid medication. Three months after starting methimazole, he developed features of hypothyroidism with low levels of fT4 (0.59 ng/dl) and fT3 (2.36 pg/dl) despite a sustained suppression of TSH (0.026 lIU/ml). Methimazole was stopped. Four weeks after, TSH increased to 11 lIU/ml and fT4 decreased to 0.47 ng/dl. Levothyroxine treatment was initiated and the patient achieved euthyroidism in 2 months. Currently, he is on follow-up with 150 mcg/day levothyroxine for the last 7 months without significant symptoms. Few cases of thyroid hormone excess have been reported with sunitinib; however, they were whether mild and self-limiting or if overt, was associated with low uptake in thyroid scan and elevated thyroglobulins suggesting destructive thyroiditis [1]. There is even fewer data on the TSH-suppressing effect of sorafenib. Miyake et al. [2] reported that 23.9 % of patients with metastatic RCC receiving sorafenib had TSH suppression before the development of hypothyroidism. One case with overt hyperthyroidism was reported after sorafenib treatment in a C. Konca Degertekin (&) F. Balos Toruner M. Akturk Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Gazi Universitesi Hastanesi, Endokrinoloji ve Metabolizma BD, 06100 Besevler, Ankara, Turkey e-mail: ceylakonca@hotmail.com

Basal Thyrotropin and Major Depression: Relation to Clinical Variables and Treatment Outcome

There is a current argument in thyroidology about whether the normal range for basal thyrotropin (TSH) is too broad. Some groups suggest that a TSH of less than 2.5 mIU/L is a better cut-off for euthyroidism. Because major depression is associated with changes in thyroid hormone status and thyroid hormones may be an effective treatment for major depression, we examined whether TSH levels above or below 2.5 mIU/L were related to clinical variables or treatment outcome in euthyroid patients with major depression. Outpatients with major depression (n =166) were assigned to high-normal and low-normal TSH groups based on their basal TSH levels. The 2 groups were compared along clinical variables and treatment outcome. The low-normal TSH group was significantly more depressed, as measured by Hamilton Depression Rating Scale scores, and had more anxiety symptoms and suicidal tendencies than the high-normal group. There was no difference in treatment response between the groups. A comparison of low-normal and high-normal basal TSH groups with major depression revealed significant differences in severity and symptoms of depression but no difference in treatment outcome. These data are preliminary and require replication in a larger sample.

352 Serum Thyroid Hormones in Preterm Infants and Relationships to Indices of Severity of Intercurrent Illness

Introduction: In adults a decrease in serum T3 and an increase in rT3 are the most common changes in thyroid hormone levels in response to a variety of acute and chronic illnesses. With more severe illnesses serum T4 levels also decrease and this is associated with a worse prognosis. Thyroid hormone levels in infants are crucially determined by the inter-relationship between gestational and postnatal age but it remains unclear whether changes in thyroid hormone status in response to illness are similar across the wide gestational age range of prematurity. Aim: The purpose of this study was to relate severity of illness at 1, 7, 14 and 28 postnatal days in preterm infant groups 23–27 (n=73), 28–30 (n=160) and 31–34 (n=208) weeks gestation, to the corresponding sera levels of T4, FT4, TBG, TSH, T3, rT3 and T4S. Methods: The British Association of Perinatal Medicine and Neonatal Nurses Association 1992 scoring categories (Arch Dis Child; 67: 868–9) were used as an index of illness severity: Level 1 (maximal intensive care) was compared with Level 2 (high dependency intensive care) combined with Level 3 (special care); infants were scored on 1, 7, 14 and 28 postnatal days. Results: In Level 1 infants there were significant reductions in: T3 at 7 days (28–30 weeks), 14 and 28 days (23–27 and 28–30 weeks); T4 at 7, 14 and 28 days (23–27 weeks), at 14 and 28 days (28–30 weeks), and at day 7 (31–34 weeks); FT4 at 14 days (23–27 weeks). TSH was unchanged in all groups at all ages. Conclusion: The clear message from our data is that T4 and T3 are substantially reduced in infants with severe illness, irrespective of gestational age, yet TSH remains unchanged.

Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Role of thyroid hormones in hepatic effects of peroxisome proliferators.

Peroxisome proliferators are endocrine disrupting chemicals that cause liver tumors in rodents but not humans. Although the receptor that mediates key hepatic effects, the peroxisome proliferator-activated receptor alpha (PPAR-alpha), and its endogenous ligands have been identified, the mechanism whereby these commonly used chemicals cause liver tumors in rodents has yet to be elucidated. Species differences in PPAR-alpha and DNA response elements may explain some of the variability in response upon exposure to peroxisome proliferators. The possibility that thyroid-modulating effects of peroxisome proliferators may contribute to the hepatic effects of peroxisome proliferators has yet to be fully explored. When the potent peroxisome proliferator, WY-14,643, was given to hypothyroid rats, there was a blunting of the hepatomegaly and hepatocyte proliferative responses seen in thyroid-intact animals. Acyl-CoA oxidase activity was unaltered by changes in thyroid hormone status. In addition, preliminary evidence indicates that peroxisome proliferators increased hepatic thyroid receptor (TRalpha1) expression, but TRalpha1 levels in liver tumors were similar to those in unexposed animals. Significant differences between humans and rodents with respect to thyroid hormone physiology and metabolism, in conjunction with the results of these studies, may be indicative of yet another mechanism to explain differential sensitivity to hepatic effects of peroxisome proliferators.

Serum cytokines in thyrotoxicosis.

Overproduction of thyroid hormones promotes bone resorption in vivo and in vitro, and we have evaluated whether mediators of such effects could include the osteotropic cytokines. Previous studies have demonstrated raised serum interleukin (IL)-6 in thyrotoxic patients, but differentiating the contribution of the elevated thyroid hormones from that of the autoimmune inflammation present in Graves' disease (GD) has been difficult. We undertook a longitudinal study of 34 patients (19-45 yr old) with GD, toxic nodular goiter (TNG), or a history of thyroid carcinoma but no evidence of disease recurrence, receiving sufficient T4 to suppress TSH. Controls were 12 euthyroid females. The following measurements were made basally and for 6 months after carbimazole treatment: serum free T4, T3, bone-specific alkaline phosphatase (b-ALP), IL-6, IL-8, IL-1beta, tumor necrosis factor-alpha, IL-11, and urinary deoxypyridinoline (Udpd). Compared with controls (IL-6, 1.1 +/- 0.3 ng/L; IL-8, 3.2 +/- 0.8 ng/L), untreated patients with GD and TNG had elevated IL-6 (GD, 7.11 +/- 0.88 ng/L; TNG, 7.30 +/- 0.77 ng/L; P < 0.001) and IL-8 (GD, 10.3 +/- 1.23 ng/L; TNG, 9.81 +/- 1.27 ng/L; P < 0.001). These levels fell after treatment and were then indistinguishable from those in control subjects. Thyroid carcinoma patients on TSH suppressive therapy also had significantly raised levels of IL-6 (2.5 +/- 0.42 ng/L) and IL-8 (4.4 +/- 0.63 ng/L). When data from all the patients were pooled, the levels of IL-6 and IL-8 correlated with serum T3 and free T4 but not with Udpd or b-ALP. IL-1beta, IL-11, and tumor necrosis factor-alpha were not raised in any patient. The elevations in serum IL-6 and -8 that occur in hyperthyroidism seem to result from the chronic effects of thyroid hormone excess rather than the accompanying autoimmune inflammatory condition produced by Graves' thyroid or eye disease. The site of the presumed increased production of IL-6 and -8 is most likely from bone osteoblasts, despite the inability of bone markers (such as Udpd and b-ALP) to correlate with acute changes in thyroid hormone status produced by antithyroid therapy.

Thyroid hormones in grey seal pups ( Halichoerus grypus)

The aim of the present study was to describe the changes in thyroid hormone status in grey seal ( Halichoerus grypus) pups from birth to weaning and moulting. Plasma concentrations of total thyroxine (tT 4) were highest the first two days after birth, thereafter dropping to a lower, but stable level. This pattern may reflect a high transfer rate of maternal thyroxine prepartum, prior to parturition, or postpartum via colostrum, or it may be caused by active secretory thyrocytes in late foetal stage. Total triiodothyronine (tT 3) concentrations were lowest in neonatal pups, and increased as a function of age, indicating that deiodination of T 4 to T 3 increases as a function of age. Plasma concentrations of free thyroxine (fT 4) did not vary as a function of age. All hormone concentrations were higher than previously reported in adults, probably reflecting the important role of these hormones in regulating their high rates of metabolism and tissue synthesis and the growth of their juvenile pelage. Since polychlorinated biphenyls (PCBs) have been reported to affect plasma concentrations of thyroid hormones in seals, the information on thyroid hormone concentrations and dynamics reported in grey seal pups from a pristine Norwegian coastal environment provide valuable reference material for future studies on pups from more polluted areas.

Liver energy metabolism during hibernation in the golden-mantled ground squirrel,Spermophilus lateralis

Large changes in ATP production capacities and rates have been reported in mammalian hibernators throughout the different stages of the hibernation cycle. In this study we showed that total extractable liver [ATP], [ADP], and [ATP]/[ADP] do not differ among summer normothermic, hibernating, and aroused golden-mantled ground squirrels, Spermophilus lateralis, indicating that metabolism remains well balanced throughout the hibernation cycle. This implies that rates of ATP consumption must be down-regulated during deep hibernation in order to maintain this balance. Despite this, basal oxygen-consumption rates [Formula: see text] of hepatocytes isolated from hibernating, aroused, and summer cold-acclimated ground squirrels were 22.4–35.1% higher than those from ground squirrels in the summer normothermic condition when measured at 37 °C. The relatively high hepatocyte [Formula: see text] may help to minimize interbout arousal times, reducing energy demands during the hibernation season. At 7 °C, hepatocyte [Formula: see text] values do not differ among the four groups; however, the Q10for hepatocyte [Formula: see text] is significantly lower for the summer group, suggesting lower temperature sensitivity. Despite the seasonal changes in thyroid hormone status known to occur in scuirid hibernators, the proportion of hepatocyte [Formula: see text] attributed to Na+,K+-ATPase, estimated by inhibition with 1 mM ouabain, is only around 15% and does not differ among hibernation/seasonal conditions.

Expression of prepro-VIP derived peptides in the gastrointestinal tract of normal, hypothyroid and hyperthyroid rats

Vasoactive intestinal polypeptide (VIP) is a widespread neuropeptide involved in the autonomic nervous control of smooth muscle activity, blood flow and secretion. To study the biosynthetic processing of the VIP precursor in the gut of normal, hypo- and hyperthyroid rats we used antisera against the five functional domains of the precursor molecule, prepro-VIP 22–79, peptide histidine isoleucine (PHI), prepro-VIP 111–122, VIP and prepro-VIP 156–170, to quantify and characterize VIP precursor peptides by radioimmunoassay and chromatography and examine their cellular localization and co-localization by immunohistochemistry. All five peptides were expressed in the gut but not in equimolar amounts as expected from the structure of the VIP precursor. A high concentration of PHV, the C-terminally extended form of PHI which includes prepro-VIP 111–122, was found in the small intestine. Immunohistochemically the prepro-VIP derived peptides were shown to coexist in neuronal elements. Changes in thyroid hormone status induced moderate changes in peptide expression in the gut, the most prominent being a 2-fold increase in all prepro-VIP derived peptides in the gastric fundus of hypothyroid rats. The findings indicate that differences in the post-translational processing of prepro-VIP exist in neurons of the rat gut and that hypo- and hyperthyroidism induce differential changes in peptide expression.

'Low T3syndrome' in a pig model of cardiopulmonary resuscitation - the time-course of changes in thyroid hormones and plasma catecholamines

Objective: To investigate the time-course of changes in thyroid hormone and plasma catecholamine levels after administration of epinephrine, norepinephrine or vasopressin in a pig model of cardiopulmonary resuscitation (CPR). Design: Prospective, randomised controlled study. Setting: Animal care facility, Department of Experimental Anaesthesia. Subjects: A total of 21 pigs. Interventions: The pigs were randomly allocated to receive either 45 μg/kg epinephrine (epi, n=7), 45 μg/kg norepinephrine (norepi, n=7), or 0.8 IU/kg vasopressin (vaso, n=7) after 4 minutes of ventricular fibrillation and 3 minutes of open chest CPR. Measurements and main results: Arterial blood samples were obtained before CPR (pre-arrest), during mechanical CPR, ie before drug administration (DA), 5 minutes after DA and 60 and 180 minutes after restoration of spontaneous circulation (ROSC) for radioimmunological detection of iodothyronine serum concentration (total triiodothyronine TT3 ng/dl, thyroxine TT4 μg/dl, reverse triiodothyronine rT3 ng/dl, free unbound thyroxine fT4 ng/dl [equilibrium dialysis]). At the same time-points plasma catecholamine levels were measured by high pressure liquid chromatography (HPLC). Short-term ROSC was accomplished with epinephrine, norepinephrine or vasopressin in all animals. Even during CPR, all animals exhibited a rapid decrease of TT3. Irrespective of the drug given for CPR, the animals demonstrated a significant and sustained disappearance of TT3 180 minutes after ROSC (pre-arrest: epi group 55±10.7, norepi group 67±14.6, vaso group 42±6.4; 180 minutes after ROSC: epi group 14±3.4*, norepi group 18±5.6*, vaso group 14±3.4* ng/dl, *p&lt;0.05). This was accompanied by a significant increase of rT3 180 minutes after ROSC (pre-arrest: epi group 22.5±2.2, norepi group 24±5.0, vaso group 23±1.7; 180 minutes after ROSC: epi group 52±7.3*, norepi group 45±8.8*, vaso group 43±5.8* ng/dl, *p&lt;0.05). Vasopressin-treated animals exhibited significantly lower plasma levels of epinephrine and norepinephrine after drug administration. However, these differences in plasma catecholamines during CPR influenced neither the time-course nor the extent of change in thyroid hormone indices during and after CPR. Conclusions: Our data demonstrate the rapid development of a low T3 and high rT3 syndrome in a pig model of CPR within 3 hours following cardiac arrest and successful ROSC. Thyroid hormone metabolism is rapidly involved in the endocrine response to maximal stress during and after cardiac arrest. Neither the drug treatment during CPR nor the different plasma catecholamines concentrations affected the time-course and extent of changes in thyroid hormone status in this animal model.

Effects of gestational and lactational exposure to coplanar polychlorinated biphenyl (PCB) congeners or 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) on thyroid hormone concentrations in weanling rats

Perinatal exposure to polychlorinated biphenyl (PCB) mixtures or to certain ortho-substituted PCB congeners dramatically reduces circulating thyroxine (T4) concentrations. It is not clear whether perinatal exposure to coplanar PCBs or2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) has a similar effect. In this study, time-mated Sprague-Dawley rats were dosed with 2 or 8 mg/kg/day PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 0.25 or 1.00 μ/kg/day PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.025 or 0.10 μg/kg/day TCDD, or corn oil vehicle orally on gestation days 10–16. At weaning, plasma total T4 concentrations in PCB 77 and TCDD high-dose female pups were significantly depressed, but the changes were modest (84.4 and 79.6% of control, respectively). T4 concentrations in PCB 126 high-dose females and all high-dose males were also depressed slightly, but the changes were not statistically significant. UDP-Glucuronosyl transferase (UDP-GT) activity towards 4-nitrophenol was increased in all high-dose groups. Thus, the modest decreases in T4 could be due in part to increased T4 glucuronidation by UDP-GT. Triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations were unchanged in all groups. In contrast to the minor changes in thyroid hormone status, liver microsomal ethoxyresorufin-O-deethylase (EROD) was markedly induced in all exposure groups and thymus weights were depressed in the high-dose groups. Because doses of coplanar PCBs or TCDD that caused marked induction of EROD activity had only minor effects on T4, we conclude that changes in thyroid hormone status at weaning are not among the more sensitive effects of perinatal exposure to these compounds.

Borderline-low serum thyrotropin level is correlated with increased fasting urinary hydroxyproline excretion

Recent studies suggest that even mildly supraphysiologic thyroid hormonal status accelerates bone loss. In hyperthyroidism, increased bone resorption is the predominant mechanism for bone loss. We postulated that the changes in thyroid hormone status as reflected by low-normal and minimally subnormal serum thyrotropin level would have an effect on bone turnover and could be detected by a simple, noninvasive marker of bone resorption, fasting urinary total hydroxyproline-creatinine excretion (THP/Cr). We retrospectively identified ambulatory patients with a restricted range of diagnoses who had had measurements of thyrotropin and THP/Cr performed within +/- 21 days. Of the 86 patients, 47 had thyrotropin levels greater than 1.0 mU/L. In these patients, no correlation was evident for thyrotropin and THP/Cr. Of the other 39 patients, 11 had suppressed thyrotropin levels (less than 0.1 mU/L) and showed clearly elevated values for THP/Cr, as expected from previous studies of hyperthyroidism. For 28 patients with thyrotropin in the borderline and low-normal range of 0.1 to 1.0 mU/L, a significant negative correlation with THP/Cr was found. The THP/Cr was positively correlated with serum alkaline phosphatase level, as expected with increased bone turnover. These results add further support to the hypothesis that even a minimal excess of thyroid hormones increases bone turnover and may contribute to accelerated bone loss.

Borderline-Low Serum Thyrotropin Level Is Correlated With Increased Fasting Urinary Hydroxyproline Excretion

• Background. — Recent studies suggest that even mildly supraphysiologic thyroid hormonal status accelerates bone loss. In hyperthyroidism, increased bone resorption is the predominant mechanism for bone loss. We postulated that the changes in thyroid hormone status as reflected by lownormal and minimally subnormal serum thyrotropin level would have an effect on bone turnover and could be detected by a simple, noninvasive marker of bone resorption, fasting urinary total hydroxyproline-cretinine excretion (THP/Cr). Methods.— We retrospectively identified ambulatory patients with a restricted range of diagnoses who had had measurements of thyrotropin and THP/Cr performed within ±21 days. Results.— Of the 86 patients, 47 had thyrotropin levels greater than 1.0 mU/L. In these patients, no correlation was evident for thyrotropin and THP/Cr. Of the other 39 patients, 11 had suppressed thyrotropin levels (l0.1 mU/L) and showed clearly elevated values for THP/Cr, as expected from previous studies of hyperthyroidism. For 28 patients with thyrotropin in the borderline and low-normal range of 0.1 to 1.0 mU/L, a significant negative correlation with THP/Cr was found. The THP/Cr was positively correlated with serum alkaline phosphatase level, as expected with increased bone turnover. Conclusions.— These results add further support to the hypothesis that even a minimal excess of thyroid hormones increases bone turnover and may contribute to accelerated bone loss. ( Arch Intern Med. 1992;152:360-364)

The effect of thyroxine on small intestinal motility in the elderly

To study the effects of thyroxine on orocaecal transit time in a group of elderly hypothyroid patients on long-term thyroxine replacement therapy. Measurement of the effect of withdrawal and subsequent replacement of thyroxine replacement therapy on orocaecal transit time. Fifteen elderly, previously hypothyroid patients on full replacement therapy with oral thyroxine were studied. There were 11 females and four males, aged 60-94 years (median 78 years) receiving initially 50-200 micrograms of oral thyroxine daily (median 100 micrograms). Serum TSH and FT4 were measured by radioimmunoassay and orocaecal transit time assessed using a lactulose hydrogen breath test. These tests were repeated 7 days after withdrawal of thyroxine replacement and again 7 days after subsequent reinstatement of therapy. On withdrawal of therapy, the median transit time increased from 75.0 to 135 minutes (P less than 0.01), the median TSH increased from 1.8 to 2.3 mU/l (P = NS) and the median FT4 decreased from 13.7 to 10.6 pmol/l (P less than 0.01). On reinstatement of therapy, the median transit time decreased to 95 minutes (P = NS), the median TSH decreased to 1.1 mU/l (P = NS) and the median FT4 increased to 14.1 pmol/l (P less than 0.01). These findings demonstrate the sensitivity of the small bowel to changes in thyroid hormone status and suggest that constipation arising as a result of this hypomotility may well be an early physical manifestation of hypothyroidism.