Thyroid Axis Function Research Articles

Estrogen effects on thyroid iodide uptake and thyroperoxidase activity in normal and ovariectomized rats

Sex steroids interfere with the pituitary–thyroid axis function, although the reports have been controversial and no conclusive data is available. Some previous reports indicate that estradiol might also regulate thyroid function through a direct action on the thyrocytes. In this report, we examined the effects of low and high doses of estradiol administered to control and ovariectomized adult female rats and to pre-pubertal females. We demonstrate that estradiol administration to both intact adult and pre-pubertal females causes a significant increase in the relative thyroid weight. Serum T3 is significantly decreased in ovariectomized rats, and is normalized by estrogen replacement. Neither doses of estrogen produced a significant change in serum TSH and total T4 in ovariectomized, adult intact and pre-pubertal rats. The highest, supraphysiological, estradiol dose produced a significant increase in thyroid iodide uptake in ovariectomized and in pre-pubertal rats, but not in control adult females. Thyroperoxidase activity was significantly higher in intact adult rats treated with both estradiol doses and in ovariectomized rats treated with the highest estradiol dose. Since serum TSH levels were not significantly changed, we suggest a direct action of estradiol on the thyroid gland, which depends on the age and on the previous gonad status of the animal.

Depression and thyroid axis function in coronary artery disease: Impact of cardiac impairment and gender

Increased rates of depression are reported in coronary artery disease (CAD). In heart disease, depression increases disability, reduces quality of life, and increases mortality. The study was undertaken to examine the relationship between depression and thyroid axis function in patients with CAD. In all, 73 patients with CAD, consecutively admitted to a cardiac rehabilitation hospital, were assessed for depression using the Hospital Anxiety and Depression scale (HADS). Blood was drawn for assessment of thyroid axis hormones and the N-amino terminal fragment of the pro-B-type natriuretic peptide (NT-pro BNP). The patients with CAD with depressive symptoms had a higher prevalence of cardiac failure (p = 0.04), higher NT-pro BNP concentrations (p = 0.02), and lower free triiodothyronine (T3) concentrations (p = 0.04) than patients with CAD but without depressive symptoms. They also showed a strong trend (p = 0.058) toward a higher incidence of the low T3 syndrome. Higher NT-pro BNP concentrations were related to lower total T3 concentrations (r = -0.294, p = 0.011) and to higher reverse T3 concentrations (r = 0.353, p = 0.002). In men, higher scores of depression were related to lower total T3 concentration (r = -0.289, p = 0.034) and to higher NT-pro BNP concentration (r = 0.380, p = 0.005). These findings suggest that symptoms of depression in patients with CAD are associated with changes in thyroid axis function and with cardiac impairment, especially in men.

Disruption of neuromedin B receptor gene results in dysregulation of the pituitary–thyroid axis

The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P< 0.05), normal intra-pituitary TSH content, and no significant changes in alpha and beta TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P< 0.01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P< 0.05), while TRH receptor mRNA levels were importantly increased (78%, P< 0.05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7.1-and 4.0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P< 0.05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.

Somatostatin treatment of congenital chylothorax may induce transient hypothyroidism in newborns

Aim: To describe a group of neonates with congenital, non-traumatic chylothorax, one of whom developed transient hypothyroidism following treatment with somatostatin. Methods: The charts of seven infants with congenital chylothorax were reviewed in terms of their clinical presentation, the severity of their disease, the complications they presented and the duration of their hospitalization. Their pituitary–thyroid axis function was monitored in particular. Results: The seven infants, all preterm (32–34 wk), suffered from congenital chylothorax and hydrops fetalis diagnosed during the prenatal period. Four were treated by intrauterine drainage, and four had congenital malformations. Hospitalization lasted from 32 to 120 d. Three of the infants suffered from thrombocytopenia, three had chronic lung disease, and one suffered from Gram-negative sepsis. The infant treated with somatostatin initially had normal thyroid function, but later developed primary transient hypothyroidism and was treated with L-thyroxine. The thyroid screening tests for the infants who were not treated with somatostatin were all normal. Conclusions: Repeated doses of somatostatin were effective in reducing chylus production. Administering this treatment earlier should be considered in order to minimize known complications. The only potential side effect observed was primary transient hypothyroidism. Therefore, careful monitoring of the pituitary–thyroid axis is advised.

Adrenal and Thyroid Axis Function in Preterm Ventilated Baboons

Cortisol and thyroid hormones are critical to normal fetal development and neonatal transition, and baseline values and stimulation tests are abnormal after preterm birth. To evaluate cortisol and thyroxine (T₄) responses that are not influenced by uncontrolled antenatal events associated with human preterm labor, we measured cortisol and T₄ after standard-dose adrenocorticotropin (ACTH) and corticotropin-releasing hormone (CRH) stimulation tests, as well as high-dose CRH and thyrotropin-releasing hormone stimulation tests in baboons that were delivered for 3 separate protocols at 125 days of gestation (term is 186 days). The animals were surfactant treated and ventilated for up to 14 days. Some fetuses were exposed to fetal or maternal betamethasone, and some newborns were treated with 10 µg/kg T₄ for 9 days after birth. Baseline cortisol levels were in a stress range of 30–60 µg/dl by day 5. Cortisol did not increase consistently until day 11 in response to a high CRH dose or ACTH. T₄ treatment for 9 days after birth suppressed the cortisol responses and subsequent baseline T₄ levels. The hypothalamic-pituitary-adrenal (HPA) axis was unresponsive to standard dose stimulation tests until 11 days of age in preterm baboons, indicating HPA immaturity.

Chronic stress influences the immune system through the thyroid axis

The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T 3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T 3 and thyroxine (T 4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T 4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.

Effects of Long‐Term Phenobarbital Treatment on the Thyroid and Adrenal Axis and Adrenal Function Tests in Dogs

Phenobarbital can interfere with the thyroid axis in human beings and rats by accelerating hepatic thyroxine metabolism because of enzyme induction. In human beings, it also can interfere with the low‐dose dexamethasone suppression test (LDDST) used to assess adrenal function by accelerating dexamethasone metabolism. This effect can cause a lack of suppression of pituitary ACTH and subsequent adrenal cortisol release after dexamethasone administration. The effects of phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests were prospectively investigated in 12 normal, adult dogs. Phenobarbital was administered at 5 mg per kilogram of body weight (range, 4.8–6.6 mg/kg) PO q12h for 29 weeks, resulting in therapeutic serum concentrations (20–40 μg/mL). Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before and during phenobarbital treatment. LDDST, ACTH stimulation tests, and ultra‐sonographic evaluation of the adrenal glands were performed before and during treatment. TT4 and FT4 decreased significantly (P≤ .05), TT3 had minimal fluctuation, TSH had only a delayed compensatory increase, and cholesterol increased during phenobarbital treatment. The delayed increase in TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic thyroxine elimination may not be the only effect of phenobarbital on the thyroid axis. There was no significant effect of phenobarbital on either of the adrenal function tests. With the methods employed, we did not find any effects of the drug on the hormonal equilibrium of the adrenal axis.

Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs.

Phenobarbital can interfere with the thyroid axis in human beings and rats by accelerating hepatic thyroxine metabolism because of enzyme induction. In human beings, it also can interfere with the low-dose dexamethasone suppression test (LDDST) used to assess adrenal function by accelerating dexamethasone metabolism. This effect can cause a lack of suppression of pituitary ACTH and subsequent adrenal cortisol release after dexamethasone administration. The effects of phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests were prospectively investigated in 12 normal, adult dogs. Phenobarbital was administered at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h for 29 weeks, resulting in therapeutic serum concentrations (20-40 microg/mL). Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before and during phenobarbital treatment. LDDST, ACTH stimulation tests, and ultrasonographic evaluation of the adrenal glands were performed before and during treatment. TT4 and FT4 decreased significantly (P < or = .05), TT3 had minimal fluctuation, TSH had only a delayed compensatory increase, and cholesterol increased during phenobarbital treatment. The delayed increase in TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic thyroxine elimination may not be the only effect of phenobarbital on the thyroid axis. There was no significant effect of phenobarbital on either of the adrenal function tests. With the methods employed, we did not find any effects of the drug on the hormonal equilibrium of the adrenal axis.

Electrodermal Activity in Nonmedicated Hyperthyroid Patients Having No Depressive Symptoms

The aim of the present study was to investigate whether the alteration in hypothalamic–pituitary–thyroid axis function results in electrodermal abnormality without causing marked psychiatric manifestations or not. Electrodermal activity was recorded with the skin conductance unit and IBM-AT computer. Basal levels of electrodermal activity (EDA), as well as responsivity to repeated insignificant acoustic stimulation were studied in 24 nonmedicated hyperthyroid patients and 35 healthy controls. The outcome of psychiatric rating scores indicated that patients had low anxiety scores and normal depression scores. The basal levels of thyroid hormones were higher in patients, when compared with the control group. On the analysis of EDA, we found lower onset latency and duration of the skin conductance response and higher skin conductance level in nonmedicated patients than healthy controls. The results above provide supporting evidence that the change of hypothalamic–pituitary–thyroid axis function results in abnormal EDA, without causing marked psychiatric manifestations.

Hypothalamic–pituitary–thyroid-axis function in treatment resistant depression

Recently, there were some reports that the prevalence of various grades of hypothyroidism may be increased in patients with treatment resistant depression (TRD). The aim of the present study was to examine serum basal thyroid-stimulating hormone (TSH) and thyroxine (T4) levels in 36 major depressed subjects, of whom 27 had TRD and 15 were normal volunteers. There were no significant differences in serum basal TSH or T4 levels between major depressed subjects and normal controls, or between patients with TRD versus normal controls or subjects without TRD. There was a trend towards lower serum basal T4 concentrations in patients with TRD than in other depressed patients and normal controls. One patient with TRD had basal serum TSH levels in the hyperthyroid range. Two subjects, one with TRD and one normal control, had serum TSH values in the subclinical hypothyroid zone, but their serum T4 values were in the euthyroid range. There were no significant relationships between basal TSH or T4 and severity of illness, staging of depression based on prior treatment non-response, length of the depressive episode, duration of illness, or number of previous depressive episodes. In conclusion, the results of this study do not provide evidence that (subclinical) hypothyroidism occurs more than coincidentally in depressed patients with TRD.

Altered thyroid axis function in lewis rats with genetically defective hypothalamic CRH/VP neurosecretory cells

Lewis rats display hyporesponsive hypothalamo-pituitary-adrenocortical (HPA) axes, overproduction of cytokines, and susceptibility to inflammatory disease. The Lewis corticotropin-releasing hormone (CRH) neurosecretory system contains normal numbers of vasopressin (VP)-deficient axon varicosities, but abnormally sparse VP-containing varicosities in the external zone of the median eminence, compared to the normoresponsive Sprague Dawley (SD), Wistar and Fischer 344 strains. Since VP may act as a thyrotropinreleasing factor, we hypothesized that thyroid axis responsivity may be altered in Lewis rats. T3, T4 and TSH were measured by radioimmunoassay, and free T4 by equilibrium dialysis, in adult male Lewis and SD rats. One h cold (5°C) induced significant increases in T3, T4 and TSH levels in Lewis rats but not in SD rats. Ninety min insulininduced hypoglycemia (1 IU/kg, ip) induced a significant T3 increase in Lewis rats and a significant T4 increase in SD rats. Two h after ip LPS (0.25 or 0.75 mg/kg), T4 levels fell significantly in Lewis rats but not in SD rats. TSH decreases were significant in Lewis rats after 0.75 mg/kg and in SD rats after 0.25 mg/kg. Baseline hormone levels were generally higher in Lewis rats; the differences were significant for T3 and T4 in the insulin experiments and for T3, T4 and free T4 in the LPS experiments. The data suggest that reduced inhibition from the adrenocortical axis in Lewis rats leads to hyperresponsivity of the thyroid axis to cold, and greater LPS-induced decreases in T4 levels, probably due to an exaggerated inhibitory cytokine response.

Thyroid Disorders of Pregnancy

Practical aspects in the management of thyroid diseases in pregnancy are reviewed. Information on the hypothalamic-pituitary thyroid axis function in pregnancy and transplacental passages of thyroid hormones is discussed. Diagnosis and management of thyroid dysfunction in pregnancy are updated together with the management of women on thyroid replacement therapy at the time of conception. A practical evaluation of thyroid nodules in pregnancy is suggested. Finally, the syndrome of postpartum thyroid dysfunction is reviewed, stressing the importance of proper diagnosis and the need for long-term follow-up evaluation of these patients.

Sex differences in thyroid axis function: Relevance to affective disorder and its treatment

AbstractThroughout life the thyroid economy differs for men and women. The “set point” for TSH is higher in women, they experience more goiter and nodule formation, and autoimmune thyroid disease is greater throughout life. Excluding cancer, the lifetime prevalence of thyroid disease for women is variously estimated between 2.25‐4.0%, some 4 to 10 times the estimates for men.Contrary to earlier interpretation, maternal thyroid hormones are now thought to be important in the early life of the fetus and the development of the CNS; however, after the first trimester maternal free thyroid hormone falls to reach a nadir post partum, a fact not to be discounted in postpartum psychosis.Major depression is more common in women and approximately 5‐10% have some metabolic evidence of a diminished thyroid economy. Adjunctive tri‐iodothyronine has been shown to speed recovery from depression in women but not in men.Manic‐Depressive Illness in its classic form (Bipolar I) is approximately equal in prevalence between men and women. However, the malignant variant of treatment resistant rapid cycling (RC) is predominant in women and is significantly associated with Grade I hypothyroidism. Furthermore, the use of high dose thyroxine as an adjunct to anticycling medications such as lithium and the anticonvulsants with frequently mitigate the cycling and induce clinical remission.Studies in premenopausal women (the common sufferers of RC) suggest that this pharmacologic use of thyroxine has few side effects and is without detectable increased risk of osteoporosis.Particularly lithium, but also other clinically employed psychotropic agents, are antithyroid as well as thymoleptic injunction. The study of the interaction of lithium and thyroid metabolism at the cellular and molecular level will help inform these clinical observations. That the c‐erb‐A family of gene products share considerable homology at the DNA binding region across nuclear T3, glucocorticoid, and estrogen receptors may be of significance in this regard.Thyroid screening of women with affective disorder is recommended for those who are aged 45 years or older, have a history of postpartum thyroiditis, or a family history of thyroid disease. Depression 3:33‐42 (1995). © 1995 Wiley‐Liss, Inc.

Thyroid axis function during the menstrual cycle in women with premenstrual syndrome

Fifteen women with premenstrual syndrome (PMS) and 15 control women were tested twice for thyroid axis measures, once during the follicular and once during the luteal phase of the menstrual cycle. While PMS and control women did not differ in mean hormone values during either phase of the menstrual cycle, PMS women showed significantly greater variability in hormone measures including TSH, T3 uptake, T4, and FTI relative to controls. These findings are consistent with the conceptualization that, for a subset of women with PMS, thyroid axis abnormalities may contribute to their disorder. Additionally, when analyzed in the sample as a whole, the menstrual cycle exerted a significant effect on reverse T3 with greater levels observed in the luteal relative to the follicular phase of the cycle.

Dose response of thyrotropin-releasing hormone on pulmonary maturation in corticosteroid-treated preterm rabbits

The dose-response effect of thyrotropin-releasing hormone in enhancing pulmonary maturation was investigated with six dosing regimens. Pregnant does received thyrotropin-releasing hormone (5, 10, or 50 µg/kg every 12 hours for four doses or one dose of 20 µg/kg) in conjunction with betamethasone beginning on day 25 of gestation, with betamethasone alone or saline solution used as comparison treatment groups. Half of the newborn rabbits received supplemental surfactant therapy after delivery on day 27, and all were ventilated on a ventilator plethysmography system for 30 minutes. There were no differences among the four thyrotropin-releasing hormone doses in surfactant pool sizes, compliances, or proteins leak into or out of the air spaces. The groups that received multiple doses of thyrotropin-releasing hormone had significantly higher perinatal loss rates than the single-dose group. The lungs of the group treated with thyrotropin-releasing hormone plus steroid and the rabbits treated only with steroid were more compliant than the controls without surfactant therapy, and showed significant improvements in protein leak. The addition of thyrotropin-releasing hormone to betamethasone improved several of the protein leak measurements compared with use of betamethasone alone. These results question the necessity of multiple doses of thyrotropin-releasing hormone to induce pulmonary maturation, especially when the higher perinatal mortality and the theoretical long-term effects of fetal hyperthyroidism on thyroid axis function are considered.

Early Development of the Thyroid Axis in the Brattleboro Rat

Plasma concentrations of thyrotrophin (TSH), thyroxine (T4), and triiodothyronine (T3), and pituitary TSH concentrations were determined at weekly intervals during the first 42 days following birth in Brattleboro homozygous (DI), Brattleboro heterozygous (HZ), and Long-Evans (LE) rats. Offspring from matings of Brattleboro rats were divided into DI and HZ animal subgroups on the basis of hypothalamic vasopressin content. In control LE rats, circulating levels of TSH, T4, and T3, and pituitary TSH concentrations increased during the early postnatal period to reach relatively stable levels between 28 and 42 days of age. In DI and HZ rats, the thyroid axis developed in parallel to that of LE rats during initial postnatal weeks. However, by 42 days of age, pituitary TSH concentrations were clearly elevated in Brattleboro rats relative to levels in age-matched LE animals. These data indicate that differences in thyroid axis function between Brattleboro and LE rats occur only after the attainment of a degree of maturity.

Neuroendocrine aspects of primary endogenous depression VII. Logistic regression analysis of matched patient-control hormone data for discrimination between groups

We previously reported significant alterations in hypothalamo-pituitary-adrenal cortical (HPA) and thyroid (HPT) axis function in a group of 40 primary, RDC definite endogenous depressives compared to 40 individually matched normal control subjects. In those reports, univariate statistical tests for matched samples were used (paired t-tests). We next wished to use both the HPA and the HPT measures in a multivariate analysis to discriminate the patients from the controls, but the paired nature of the hormone data obviated the use of standard techniques. With an adaptation of the BMDP PLR statistical program, we performed a matched logistic regression analysis, in stepwise fashion, which resulted in a model incorporating two HPA variables and one HPT variable. From this model, odds ratios which associate being depressed or not with levels of the HPA and HPT measures were estimated. The median odds ratio for the 40 matched pairs was 7.8. To illustrate the model, we present graphs of estimated odds ratios of patients with selected hormone values compared to a typical normal subject with hormone values close to the median values of the 40 controls in our study.

Abnormalities in pituitary thyroid axis function tests in patients with paroxysmal supraventricular arrhythmias.

The study was carried out on 60 consecutive patients (23 males and 37 females) aged between 20 and 83 years (means +/- SD, 40.7 +/- 16) who arrived at our Cardiologic Unit with paroxysmal supraventricular arrhythmias (PSVA) including junctional paroxysmal tachycardia (n = 32), atrial fibrillation (n = 13), atrial flutter (n = 1), premature beats (n = 13) and with no obvious cardiovascular causes. Serum thyroxine and triiodothyronine were normal in all patients and thyroid scintiscan revealed normal shape and size thyroids without autonomously functioning nodule(s). Thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) was normal in 44 subjects in whom normal serum free T4 (FT4) and free T3 (FT3) levels were measured. Six patients with normal FT4 and FT3 levels did not respond to TRH. Abnormalities in thyrotropin response to TRH were observed in 10 patients all exhibiting increased FT4 or also FT3 levels. Among these, 5 patients did not respond to TRH, whereas the remaining 5 exhibited a blunted TSH response to TRH. These results suggest that only in a small proportion (5/60) of consecutive patients with PSVA it is possible to recognize a status of "occult thyrotoxicosis" on the basis of the combined evaluation of free thyroid hormones and TSH response to TRH.

Studies on Acute in Vivo Exposure of Rats to 2450-MHz Microwave Radiation: II. Effects on Thyroid and Adrenal Axes Hormones

The effects of 8 hr continuous exposure of rats to 2450-MHz (cw) microwave radiation were studied at incident power densities of 0, 2 and 10 mW/cm/sup 2/. Thyroid axis function, as measured by serum thyroxine (T/sub 4/) and triiodothyronine (T/sub 3/) as well as T/sub 3/ uptake, free thyroxine index, and adjusted-T/sub 4/ values was not altered by the experimental conditions. Adrenal axis activity was also unaffected in rats exposed to 2 mW/cm/sup 2/ microwave radiation for 8 hr. In the 10 mW/cm/sup 2/ group, the serum corticosterone levels were less than in the 0 or 2 mW/cm/sup 2/ groups (7.8 versus 9.9 ..mu..g/dl). The experimental protocol increased serum corticosterone levels (7.0 versus 9.9 ..mu..g/dl for the nonhandled and sham-exposed groups, respectively); however, the corticosterone concentration in the 10 mW/cm/sup 2/ group was similar to that in the untreated (nonhandled) controls (7.8 versus 7.0 ..mu..g/dl). This modified adrenal axis function gives further support to the concept that microwave radiation affects endocrine function.

Function of Hypothalamo-Pituitary Thyroid Axis in Depressed Patients

Nineteen out of 51 depressed patients showed abnormal TSH response to TRH in terms of exaggerated, diminished and delayed responses. The basal value of T3 and its response to TRH were significantly lower in patients with delayed or diminished response than in the normal subjects. These results indicate that the dysfunction of the hypothalamo-pituitary thyroid axis plays an important role in the pathogenesis of depression.