Circulating thyroid hormones in primates with mild or severe hepatitis following liver transplantation

In order to study the effects of acute immunologically mediated liver disease on circulating thyroid hormones, serum levels of thyroxine (T4, total and free) and triiodothyronine (T3) were measured in 8 baboons before and for 60 days after allogeneic liver transplantation. In 3 animals early rejection and jaundice developed; T4 levels declined as liver function deteriorated. In the 5 tolerant animals liver function was only temporarily deranged without jaundice and there was a consistent early rise in T4 (P less than 0.01) followed by a later fall. T3 concentrations were relatively normal in both groups. The T3 resin uptake test remained virtually unchanged in all animals. Serum T4 and T3 responses to exogenously administered bovine thyrotropin (TSH) were similar in the jaundiced and anicteric animals. We conclude that the early rise in T4 in the tolerant animals was caused by transient increases in thyroid binding globulin in (TBG) while the fall in thyroid hormones in these and in the jaundiced animals was related to a decline in TBG levels. Thyroid responsiveness to TSH is not disturbed by moderately deranged liver function.     

Response of the interrenal to adrenocorticotropic hormone after short-term thyroxine treatment of coho salmon (Oncorhynchus kisutch)

The effects of experimentally elevated plasma thyroxine levels on the subsequent response of interrenals of coho salmon (Oncorhynchus kisutch) to adrenocorticotropic hormone (ACTH) in vitro were examined. Animals were treated with thyroxine by immersion (200 micrograms/L) for 3 days, which resulted in physiological elevations in circulating thyroxine. In animals treated before the parr-smolt transformation was completed (early smolts), thyroxine had no effect on plasma cortisol levels but significantly enhanced the sensitivity of the interrenal to ACTH in vitro. In animals treated after the period of smoltification (postsmolts), plasma cortisol levels were significantly higher than those of controls; both experimental and control animals had plasma cortisol levels higher than normally observed at this stage of development. The response of the interrenals of thyroxine-treated postsmolts to ACTH in vitro was significantly lower than that of controls. Results from the experiments using early smolts are in agreement with studies in other vertebrates showing that thyroid hormones are involved in maintaining the normal functioning of corticosteroidogenic tissue and suggest that thyroid hormones may be involved in the activation of the interrenal that occurs during smoltification. The results obtained using postsmolts are more difficult to interpret because of the possibility that these animals were physiologically stressed by the treatment. Increased ACTH release in vivo resulting from stress may have led to a depression of interrenal sensitivity to ACTH in vitro and may have masked a refractoriness of the pituitary-interrenal axis to thyroxine.     

Maturation of the pituitary-thyroid axis during the perinatal period.

To clarify the maturation process of the pituitary-thyroid axis during the perinatal period, thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) and serum thyroid hormone levels were examined in 26 healthy infants of 30 to 40 weeks gestation. A TRH stimulation test was performed on 10 to 20 postnatal days. Basal concentrations of serum thyroxine (T4), free thyroxine (free T4) and triiodothyronine (T3) were positively correlated to gestational age and birth weight (p less than 0.001-0.01). Seven infants of 30 to 35 gestational weeks demonstrated an exaggerated TSH response to TRH (49.7 +/- 6.7 microU/ml versus 22.1 +/- 4.8 microU/ml, p less than 0.001), which was gradually reduced with gestational age and normalized after 37 weeks gestation. A similar decrease in TSH responsiveness to TRH was also observed longitudinally in all of 5 high responders repeatedly examined. There was a negative correlation between basal or peak TSH concentrations and postconceptional age in high responders (r = -0.59 p less than 0.05, r = -0.66 p less than 0.01), whereas in the normal responders TSH response, remained at a constant level during 31 to 43 postconceptional weeks. On the other hand, there was no correlation between basal or peak TSH levels and serum thyroid hormones. These results indicate that (1) maturation of the pituitary-thyroid axis is intrinsically controlled by gestational age rather than by serum thyroid hormone levels, (2) hypersecretion of TSH in preterm infants induces a progressive increase in serum thyroid hormones, and (3) although there is individual variation in the maturation process, the feedback regulation of the pituitary-thyroid axis matures by approximately the 37th gestational week.     

Postnatal maturation patterns of serum corticosterone and growth hormone in rats: effect of chronic thyroxine administration.

The effects of chronic neonatal hyperthyroidism in rats on the ontogenic pattern of serum corticosterone and growth hormone (GH) were studied. Thyroxine (T4) treated and saline injected rat pups were sacrificed under basal and stress conditions. In comparison to saline control animals, daily T4 administration (0.4 micrograms/gram body weight) produced a sustained elevation in basal corticosterone levels by day 12 and a significant elevation of serum corticosterone in response to stress by day 4. The serum GH levels in non-stressed animals were moderately decreased in response to T4 administration as compared to saline injected animals with a greater reduction in GH measured in samples obtained from stressed animals. The results indicate that chronic T4 administration influences the developmental pattern of serum corticosterone and GH under both non-stress and stress conditions.     

Retracted: Advanced glycation end-products induce oxidative stress through the Sirt1/Nrf2 axis by interacting with the receptor of AGEs under diabetic conditions

Despite the administration of exogenous insulin and other medications used to control many aspects of diabetes mellitus (DM), increased oxidative stress has been increasingly acknowledged in DM development and complications. Therefore, this study aims to investigate the role of advanced glycation end-products (AGEs) in oxidative stress (OS) of thyroid cells in patients with DM. Patients with DM with or without thyroid dysfunction (TD) were enrolled. Thyroid toxic damage was induced by adding AGE-modified bovine serum albumin (AGE-BSA) to normal human thyroid follicular epithelial cells. The cell viability, cell cycle, and cell apoptosis, as well as the content of reactive oxygen species (ROS), catalase (CAT), and malondialdehyde (MDA) in cells were measured. Thyroid hormones, T3, T4, FT3, and FT4 levels were measured by enzyme-linked immunosorbent assay. Receptor for advanced glycation end products (RAGE), sirtuin1 ( Sirt1), and NF-E2-related factor 2 ( Nrf2) expressions were detected, and the mitochondrial membrane potential was measured. We found increased AGEs in the serum of DM patients with TD. By increasing AGE-BSA concentration, cell viability; the thyroid hormones T3, T4, FT3, and FT4 levels; and mitochondrial membrane potential all significantly decreased. However, the increase in AGE-BSA concentration led to an increase in cell apoptosis, RAGE, and nuclear factor-κB expressions but produced the opposite effect on Sirt1, Nrf2, and heme oxygenase-1 expressions, as well as a decrease in antioxidant response element protein levels. The AGE-BSA increased ROS and MDA levels and reduced CAT level in normal human thyroid follicular epithelial cells on a dose independence basis. Our results demonstrated that AGEs-mediated direct increase of RAGE produced OS in thyroid cells of DM by inactivating the Sirt1/Nrf2 axis.     

Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring

The effect of prenatal stress on the time course of the corticosterone response to acute and chronic stress and on hematological and immunological parameters in the offspring were analized in the present study. Pregnant Sprague-Dawley rats were stressed daily for 2 hours during the last week of gestation, and female and male off-spring were studied during adulthood. Corticosterone response to acute immobilization stress was not significantly different in either control or prenatally stressed rats. However, after 10 days of immobilization stress the corticosterone response completely disappeared in the control animals but not in the prenatally stressed group: high levels of corticosterone were found during the first hour of stress, although they were lower than those found in acutely stressed rats. Adrenal hypertrophy in response to prenatal stress was observed in females but not in male offspring, and chronic stress only increased adrenal weights in the male control group. Prenatal stress decreased the total peripheral leukocyte count, altered its diferential count decreasing lymphocytes and increasing neutrophil and eosinhophil counts, and significantly reduced the percentage of peripheral lymphocyte T CD8+ subset in male offspring. Chronic stress also reduced the percentage of the peripheral T CD8+ lymphocyte subset in the control group but not in the prenatally stressed group. These results suggest that the exposure to stress during pregnancy alters the adaptative response of the hypothalamus-pituitary-adrenocortical axis to chronic stress and presumably the immune competence in the offspring.     

Prenatal exposure of the fetal rat to excessive L-thyroxine or 3,5-dimethyl-3'-isopropyl-thyronine produces persistent changes in the thyroid control system

Studies were conducted to determine if brief exposure, in utero, to high levels of T4 or to the synthetic thyromimetic agent 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) can produce permanent disruption of the thyroid control system in a manner analogous to the changes in the "set point" reported to occur due to neonatal T4 exposure in the "neo-T4 syndrome". If such a change were to occur, it could explain the persistent thyroid disturbances seen in the progeny of hypothyroid mother rats. These latter progeny are exposed in utero to both low and high serum T4 levels. Maternal T4 treatment produced a 4-fold elevation in fetal serum T4 accompanied by a large decrease in serum TSH levels. The brief treatment in utero with high doses of T4 or of DIMIT resulted in higher neonatal mortality and the T4-treatment produce subsequent growth stunting. These treatments resulted in suppression of the fetal/neonatal thyroid which was very apparent at 5 days of age. At 30 days post-partum, the thyroid control system of the progeny of the T4 and DIMIT-treated animals was still abnormal with low serum T4 levels accompanied with normal serum TSH and T3 levels. At 60 days of age, serum T4 levels remained low in the progeny of the T4-treated animals and the TSH response to TRH was subnormal in both the progeny of the T4-treated and the DIMIT-treated animals. However, serum and pituitary TSH and serum T3 were normal. The thyroid control system of the rat is sensitive to prenatal exposure to hyperthyroxinemia as it is to postnatal exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxoplasma gondii: cold stress-induced modulation of antibody responses.

Physical or psychological stressors have been shown to have significant consequences in the immune function and the outcome of disease in human and animal models. Recent work has demonstrated that products released during stress, such as glucocorticoids and catecholamines, can profoundly influence the in vitro growth of pathogens by modulating immune responses. The present study examined the effects of a physical stressor (cold stress) on antigens of Toxoplasma gondii that elicits an antibody-mediated immune response during the acute and chronic phases of infection. Sera obtained from different groups of mice subjected to cold stress during the acute and chronic phases of T. gondii infection were used to measure the levels of antibodies and to localize by Western blot the dominant antigens eliciting IgG and IgM antibody responses. Serum antibodies collected from stressed and infected mice recognized antigens different from those recognized by infected mice without stress. During the acute phase, a stronger IgM antibody response against antigens of 30, 42, 54, and 60 kDa was detected in stressed animals at 3 weeks postinfection. In addition, a 5-kDa antigen was specifically detected in mice subjected to stress during the acute and chronic phases of infection. Levels of specific IgG were increased in infected and in infected and stressed animals that underwent stress in the chronic phase. IgM production did not increase following cold stress in the chronic phase. These results suggest that the strong antibody response in stressed animals is associated with longer parasite persistence in circulation. Stress modulated not only the host immune response but also the ability of parasite antigens to elicit specific antibody responses by the host.     

Pituitary-thyroid axis reactivity to hyper- and hypothyroidism in the perinatal period: ontogeny of regulation of regulation and long-term programming of responses.

To evaluate the role of perinatal thyroid status in the development of pituitary-thyroid axis regulation, we administered triiodothyronine to newborn rats for the first five days postpartum to achieve hyperthyroidism, or propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5 to achieve hypothyroidism. Plasma T4, T3, and TSH levels were determined from birth through 50 days postpartum. Administration of exogenous T3 produced the expected immediate suppression of plasma T4 and TSH, with recovery toward normal values beginning within days of discontinuing the T3 regimen. Plasma T3 values were markedly elevated during the period in which T3 was being given, but subsequently became subnormal, with deficits persisting into young adulthood. With the PTU regimen, plasma T4 and T3 levels were markedly suppressed through postnatal day 10, rose over the ensuing two weeks, but nevertheless showed significant deficits into adulthood. TSH levels in the immediate neonatal period were subnormal in the PTU group, despite the marked lowering of circulating thyroid hormones; TSH then rose dramatically to levels four times normal, subsiding to control values by the end of the first month. These results suggest that a critical period exists in which regulation of pituitary-thyroid axis function is programmed. During this phase, TSH secretion can be suppressed by excess thyroid hormones, but cannot be increased by hormone deficiencies. Perhaps more importantly, perinatal thyroid status "programs" its own future reactivity, so that early hypothyroidism results in reduced T4 and T3 levels in adulthood, despite normal levels of TSH.     

Adaptation of male and female rats to iodine deficiency

The response of the hypothalamic pituitary axis to chronic iodine deficiency was compared in male and female Sprague-Dawley rats. The animals were kept on a low iodine diet for 12 weeks. Blood samples as well as thyroid and pituitary weights were obtained every two weeks. Baseline values of thyroid weight and serum thyroxine (T4) were similar in both sexes. However, females had lower serum TSH and higher serum triiodothyronine (T3), pituitary weight and pituitary TSH content. After initiation of the low iodine diet, both sexes showed similar decreases in serum T4 and similar increases of serum TSH and thyroid weight. Serum T3, pituitary weight and TSH content remained higher in females throughout the study. Pituitary TSH was directly correlated with serum TSH in both sexes. When adjusted for pituitary TSH and analyzed by a stepwise regression analysis, serum TSH was lower in females suggesting a difference in TSH secretion between males and females. Our studies demonstrate significant sex differences in the regulation of TSH secretion and maintenance of serum T3 level in response to a chronic stimulus.     

Thyroid hormone regulation by stress and behavioral differences in adult male rats

Thyroid hormones are essential regulators of growth, development and normal bodily function and their release is coordinated by the hypothalamic-pituitary-thyroid (HPT) axis. While the HPT axis has been established as an acutely stress-responsive neuroendocrine system, relatively little is known about the mechanisms of its stress regulation. The present study examined acute stress-induced changes in peripheral hormone levels [triiodothyronine (T3); thyroxine (T4), thyroid-stimulating hormone (TSH), reverse triiodothyronine (rT3)] and central mRNA levels of regulators of the HPT axis [thyrotropin-releasing hormone (TRH), somatostatin (SST), type II deiodinase (D2)] in response to an inescapable tail-shock, a rodent model of stress. Additionally, we examined whether individual differences in spontaneous exploratory behavior in an open field test predicted basal levels of TH or differential susceptibility to the effects of stress. The stress condition was associated with decreases in peripheral T3, T4 and TSH, but not rT3, when compared with controls. No changes were observed in TRH or SST mRNA levels, but there was a trend suggesting stress-related increases in D2 mRNA. We also found that an animal's exploratory behavior in an unfamiliar open field arena was positively related to peripheral thyroid hormone levels and predicted the magnitude of stress-induced changes.In conclusion, we found suggestive evidence for stress-induced decrease in central drive HPT axis, but the central mechanisms of its stress regulation remain to be elucidated. Additionally, we found that individual differences in animals' exploratory behavior were correlated with peripheral TH levels.     

Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients

Context

Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

Objective

To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

Design

Retrospective study.

Setting

Academic hospital.

Patients

1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.

Measurements

TSH, FT4 and FT3 concentrations by immunoassays.

Results

FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.

Conclusions

Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.     

Relationship of iodide-induced increase in TSH response to TRH to changes in serum thyroid hormones.

Large doses of iodide (500 mg three times a day) administered to normal men for 10--12 days caused a rise in basal serum TSH and a concomitant rise in the peak TSH response to TRH. The basal and peak levels of TSH were highly correlated (p less than 0.001). However, the iodide-induced rise in the peak TSH after TRH was poorly correlated with concomitant changes in serum thyroid hormones. Serum T3 wa not lower after iodide and, while serum T4 was somewhat lower, the fall in serum T4 was unexpectedly inversely rather than directly correlated with the rise in the peak TSH response to TRH. Thus, increased TSH secretion after iodide need not always be directly correlated with decreased concentrations of circulating thyroid hormones even when large doses of iodide are used. Clinically, a patient taking iodide may have an increased TSH response in a TRH stimulation test even though there is little or no change in the serum level of T3 or T4.     

Nongenomic effects of thyroid hormones on the immune system cells: New targets, old players

It is now widely accepted that thyroid hormones, l-thyroxine (T(4)) and 3,3',5-triiodo-l-thyronine (T(3)), act as modulators of the immune response. Immune functions such as chemotaxis, phagocytosis, generation of reactive oxygen species, and cytokine synthesis and release, are altered in hypo- and hyper-thyroid conditions, even though for many immune cells no clear correlation has been found between altered levels of T(3) or T(4) and effects on the immune responses. Integrins are extracellular matrix proteins that are important modulators of many cellular responses, and the integrin αvβ3 has been identified as a cell surface receptor for thyroid hormones. Rapid signaling via this plasma membrane binding site appears to be responsible for many nongenomic effects of thyroid hormones, independent of the classic nuclear receptors. Through the integrin αvβ3 receptor the hormone can activate both the ERK1/2 and phosphatidylinositol 3-kinase pathways, with downstream effects including intracellular protein trafficking, angiogenesis and tumor cell proliferation. It has recently become clear that an important downstream target of the thyroid hormone nongenomic pathway may be the mammalian target of rapamycin, mTOR. New results demonstrate the capability of T(3) or T(4) to induce in the short time range important responses related to the immune function, such as reactive oxygen species production and cell migration in THP-1 monocytes. Thus thyroid hormones seem to be able to modulate the immune system by a combination of rapid nongenomic responses interacting with the classical nuclear response.     

Acute and transient activation of pituitary-thyroid axis during unforced restriction in rats: component of nonshivering thermogenesis in conscious animals?

Groups of 6-8 male Wistar Olac SPF rats weighing about 300 g were subjected to unforced restriction (UR) in small cages with a metallic bottom and a Plexiglas cover for various intervals from 2 min to 72 h. An acute activation of the pituitary-thyroid axis was found which was manifested by an increase of thyrotropin (TSH) and thyroxine (T4) levels at 2-5 min of UR. This was presumably due to the emotional effect of a rapid transfer and to the placing of the animals into restriction cages. Later, between 3 and 6 h of UR, another, and more pronounced period of activation of the pituitary-thyroid axis and of the peripheral thyroid hormone metabolism was repeatedly observed which lasted until about 36-48 h and was manifested by a highly significant increase of TSH, T4, 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) levels. It was concluded that this phenomenon presumably may be a component of nonshivering thermogenesis resulting from a decreased muscular activity and resembling the conditions occurring under cold stress. Such a view was supported by findings of highly increased nonesterified fatty acid levels in plasma in restricted animals, by unchanged levels of TSH and thyroid hormones found in unrestricted animals kept individually in regular group cages and, finally, by a preventive effect of ambient temperature of 32 degrees C on the pituitary-thyroid activation at 6 h of UR. In some experiments, no substantial differences in hormone levels were found between the animals kept in Plexiglas or stainless wire-mesh restriction cages. Finally, a multifold increase of prolactin level in plasma was found as early as 2 min of UR, the peak being observed between 5 and 20 min and a decrease to about the initial level at about 360 min.     

Immunomodulatory role of thyroid hormones: effect on humoral immune response to Salmonella typhi O antigen

Effect of long term administration of thyroid hormones and the removal of thyroid on humoral antibody response to S. typhi O antigen was studied in male albino rats of HM strain. Humoral antibody response to S. typhi O antigen was enhanced in animals pretreated with T3 or T4 at a dose of 10 micrograms daily for 15 days. Administration of thyroid hormones simultaneously along with antigen, resulted in suppression of antibody response. In thyroidectomized animals, the antibody titer to S. typhi O antigen was decreased; this decrease in antibody titer was restored to normal level following hormone supplementation. Thyroidectomy significantly depressed TLC as well. Total leucocyte count and absolute lymphocyte count were increased following hormone treatment. Present findings, thus show the lymphoproliferative response of thyroid hormones and their effect on antibody response suggesting the immunomodulatory role of thyroid hormones.     

Activity of the hypothalamo-pituitary ovarian axis in hypothyroid rats with or without triiodothyronine replacement

The hypothalamic pituitary ovarian axis in adult female rats with 131-I induced hypothyroidism was studied before and after triiodothyronine (T3) replacement. Forty days after 131-I, hypothyroid (H) rats showed irregular cycles with predominantly diestrous vaginal smears, atrophied and underweight ovaries, and decreased serum T3, T4, LH and estradiol (E2). T3 replacement restored normal cycles and ovary weight and increased serum E2 levels above control values, while LH levels remained below the limit of detection of the RIA. The GnRH stimulation test performed on the day that the rats exhibited diestrous vaginal smears elicited a greater increase in FSH than in LH in H rats and a greater increase in LH than in FSH in both H-T3 treated and control rats. The data suggest that the lack of thyroid hormones in adult female rats seems to produce a reversion of sexual hormones to a prepubertal pattern, while T3 treatment restored normal estrous cycles and ovarian function.     

Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming: implications for functional collaboration between dendritic cells and thyroid.

The thyroid hormones T(3) (tri-iodothyronine) and T(4) (thyroxine) are disseminated throughout the body via the circulation and are maintained across a range of physiological concentrations under the control of thyroid-stimulating hormone (TSH). T(3) (and T(4) after conversion to T(3)) influences many biological activities, including gene expression and protein synthesis, though little is known about the nature of pituitary-thyroid immune interactions. In the present study we show that serum T(3) and T(4) levels are sharply but transiently reduced during the first 24 h of systemic antigen exposure and that this is followed by suppressed levels of free T(4), after which there is rapid recovery to normal levels. Splenic dendritic cells, depending upon the stage of maturation/activation, were found to be a rich source of TSH, and CD11c(+) cells with dendritic cell morphology were present in the thyroid 1-3 days after antigen exposure. Moreover, antigen priming of hypophysectomized mice that are unable to make pituitary-derived TSH resulted in significant increases in circulating T(4), implying that compensation in the drop in thyroid hormones can be regulated from extrapituitary sources. These findings thus identify a novel set of immune-endocrine interactions that transpire during the early phase of antigen exposure, and they suggest that under appropriate conditions the immune system directly participates in the process of maintaining physiological homeostasis by contributing to the regulatory control of thyroid hormone activity.     

Assessment of the relationship between serum thyroid hormone levels and peripheral metabolism in patients with anorexia nervosa

It has been observed that basal and/or TRH-stimulated serum TSH levels occasionally conflict with the actual values of circulating thyroid hormones in patients with anorexia nervosa. In the present study sixteen female patients with anorexia nervosa during self-induced starvation displayed clinical findings suggesting hypothyroidism, e.g., cold intolerance, constipation, bradycardia, hypothermia and hypercholesterolemia in association with decreased serum total T3 (62.8 +/- 5.2 ng/dl) and T4 (6.6 +/- 0.3 micrograms/dl). Markedly decreased T3 correlated positively with average heart rate (r = 0.5655, P less than 0.025) and negatively with total cholesterol (r = -0.7413, P less than 0.005). This result may suggest that peripheral metabolic state of the underweight anorexics depends considerably upon the serum T3 concentration. Despite decreased total thyroid hormones, free T4 assayed by radioimmunoassay was normal in all five cases examined (1.4 +/- 0.2 ng/dl) and the free T4 index in fifteen cases was normal except in one case. Basal TSH was not increased and TSH response to exogenous TRH was not exaggerated in any. These results may be compatible with a theory that free T4 has a dominant influence on pituitary TSH secretion. Furthermore, glucocorticoids may also have some influence on depressed TSH response, because an inverse correlation between increased plasma cortisol and the sum of net TSH increase after TRH was observed in twelve cases examined. In conclusion, it is suggested that normal sensitivity of peripheral tissues and pituitary thyrotroph to different circulating thyroid hormones is maintained in anorexia nervosa patients even during severe self-induced starvation, and that the metabolic state in these patients is considerably under the influence of circulating T3.