Effects of experimentally induced hyperthyroidism on central hypothalamic–pituitary–adrenal axis function in rats: in vitro and in situ studies

Johnson, Elizabeth O.; Calogero, Aldo E.; Konstandi, Maria; Kamilaris, Themis C.; Vignera, Sandro La; Chrousos, George P.

doi:10.1007/s11102-012-0417-5

Cited by 9 publications

(18 citation statements)

References 32 publications

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“…Our findings that experimentally induced hyperthyroidism is associated with a time-dependent decrease in adrenocortical reserves has not only theoretical implications, but clinical implications, as well [16,17]. Thyroid storm has been associated with subclinical hypoadrenocorticism [20].…”

Section: Introductionmentioning

confidence: 75%

“…On the other hand, thyrotoxicosis in humans and experimental animals is thought to be associated with hyperactivity of the HPA axis [4,[6][7][8][9][10]. While this conclusion was initially based on the concentrations of total plasma corticosteroids [11,12], excretion of urinary 17-hydroxysteroids and assessment of the adrenocortical response to the synthetic ACTH [13][14][15], our recent in vivo and in vitro studies in hyperthyroid rats further support this hypothesis [4,6,16,17]. Despite the sustained hyperactivity of the HPA axis and the significant increase in adrenal weights, longterm hyperthyroidism appears to be associated with diminished adrenal functional reserve of corticosterone [16,17].…”

Section: Introductionmentioning

confidence: 95%

“…While this conclusion was initially based on the concentrations of total plasma corticosteroids [11,12], excretion of urinary 17-hydroxysteroids and assessment of the adrenocortical response to the synthetic ACTH [13][14][15], our recent in vivo and in vitro studies in hyperthyroid rats further support this hypothesis [4,6,16,17]. Despite the sustained hyperactivity of the HPA axis and the significant increase in adrenal weights, longterm hyperthyroidism appears to be associated with diminished adrenal functional reserve of corticosterone [16,17]. Examination of the functional integrity of each component of the HPA axis reveal abnormalities that occur either as a direct consequence of thyroid hormone excess or as a secondary change in one or more component(s) of the adrenal axis [4,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the sustained hyperactivity of the HPA axis and the significant increase in adrenal weights, longterm hyperthyroidism appears to be associated with diminished adrenal functional reserve of corticosterone [16,17]. Examination of the functional integrity of each component of the HPA axis reveal abnormalities that occur either as a direct consequence of thyroid hormone excess or as a secondary change in one or more component(s) of the adrenal axis [4,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…The available evidence strongly suggests that a central locus is principally responsible for the HPA activation observed in experimentally induced hyperthyroidism [16,17]. Circulating glucocorticoids can regulate HPA axis activity by negative feedback directly on the two central components of the HPA axis, the hypothalamus and pituitary, as well as at the level of the hippocampus and prefrontal cortex [26].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

et al. 2015

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Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [(3)H2]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

et al. 2015

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Maternal hormonal milieu influence on fetal brain development

2018

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An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high‐risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short‐term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment.

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Influence of maternal thyroid hormones during gestation on fetal brain development

et al. 2017

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Thyroid hormones (TH) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence THs synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programming of brain development, with implications for early identification of risk, primary prevention and intervention.

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Effects of experimentally induced hyperthyroidism on central hypothalamic–pituitary–adrenal axis function in rats: in vitro and in situ studies

Cited by 9 publications

References 32 publications

Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

Maternal hormonal milieu influence on fetal brain development

Influence of maternal thyroid hormones during gestation on fetal brain development

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