Progression of tumors with development of cerebral metastases is accompanied by suppression of thyroid and glucocorticoid functions.

e14005 Background: Cutaneous melanoma (CM), breast cancer (BC) and lung cancer (LC) metastasize to the brain most frequently. Early diagnosis of cerebral metastases is challenging and requires new prognostic criteria. Imbalance of thyroid and glucocorticoid hormones changes the growth and development of malignant tumors. The purpose of the study was to identify readily available prognostic criteria for cerebral metastases in cancer patients at various stages of treatment and follow-up. Methods: Blood levels of cortisol and total triiodothyronine (tT3) were determined by RIA (Immunotech, Czech Republic) in patients with BC (n = 50), LC (n = 50) and CM (n = 50) without brain metastases and in patients with BC (n = 25), LC (n = 25) and CM (n = 25) with cerebral metastases. Results: Blood levels of cortisol in BC, LC and CM patients were normal in 63-84% and elevated on average by 1.7 times in 16-37%. Levels of tT3 in LC were normal, and in BC and CM – within the normal limits, but 1.3 times lower than the mean values. In patients with cerebral metastases, cortisol was lower than the norm by 4.9, 2.5 and 3.6 times in 36% BC, 75% LC and 45% CM cases, respectively. Levels of tT3 in all patients with cerebral metastases were lower than the norm or values in patients without metastases by 2 times and lower. Conclusions: Decreased levels of both cortisol and tT3 in patients with BC, LC and CM may serve as one of prognostic markers of possible development of cerebral metastases. The dynamic determination of levels of thyroid and glucocorticoid hormones is required in cancer patients at various stages of treatment and follow-up.

Sexual Dimorphism in Glucocorticoid Stress Response

Chronic stress is encountered in our everyday life and is thought to contribute to a number of diseases. Many of these stress-related disorders display a sex bias. Because glucocorticoid hormones are the main biological mediator of chronic stress, researchers have been interested in understanding the sexual dimorphism in glucocorticoid stress response to better explain the sex bias in stress-related diseases. Although not yet demonstrated for glucocorticoid regulation, sex chromosomes do influence sex-specific biology as soon as conception. Then a transient rise in testosterone start to shape the male brain during the prenatal period differently to the female brain. These organizational effects are completed just before puberty. The cerebral regions implicated in glucocorticoid regulation at rest and after stress are thereby impacted in a sex-specific manner. After puberty, the high levels of all gonadal hormones will interact with glucocorticoid hormones in specific crosstalk through their respective nuclear receptors. In addition, stress occurring early in life, in particular during the prenatal period and in adolescence will prime in the long-term glucocorticoid stress response through epigenetic mechanisms, again in a sex-specific manner. Altogether, various molecular mechanisms explain sex-specific glucocorticoid stress responses that do not exclude important gender effects in humans.

Influence of glucocorticoid hormones on the thyroid gland function

The injection of exogenous analogues of glucocorticoid hormones (cortisone, hydrocortisone, corticosterone, dexamethasone, betamethasone, etc.) leads to a change in thyroid function at all levels (biosynthesis and secretion of hormones by the thyroid gland, the transport, interaction with receptors in target organs, biological action, their metabolism and excretion). Glucocorticoid hormones change regulationof the thyroid function: transhypophysially (glucocorticoids block the secretion of thyroliberin, thyroid stimulating hormone, corticotropin releasing hormone, somatoliberin and the production of somatotropin under the influence of the last one) and parahypophysially (glucocorticoids stimulate formation of insulin in β-cells of the pancreas).

PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory

Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2MAPK signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition.

Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders that affects males more frequently than females. Numerous genetic and environmental risk factors have been suggested to contribute to the development of ASD. However, no one factor can adequately explain either the frequency of the disorder or the male bias in its prevalence. Gonadal, thyroid, and glucocorticoid hormones all contribute to normal development of the brain, hence perturbations in either their patterns of secretion or their actions may constitute risk factors for ASD. Environmental factors may contribute to ASD etiology by influencing the development of neuroendocrine and neuroimmune systems during early life. Emerging evidence suggests that the placenta may be particularly important as a mediator of the actions of environmental and endocrine risk factors on the developing brain, with the male being particularly sensitive to these effects. Understanding how various risk factors integrate to influence neural development may facilitate a clearer understanding of the etiology of ASD.

Glucocorticoids Influencing Wnt/β-Catenin Pathway; Multiple Sites, Heterogeneous Effects

Glucocorticoid hormones are vital; their accurate operation is a necessity at all ages and in all life situations. Glucocorticoids regulate diverse physiological processes and they use many signaling pathways to fulfill their effect. As the operation of these hormones affects many organs, the excess of glucocorticoids is actually detrimental to the whole human body. The endogenous glucocorticoid excess is a relatively rare condition, but a significant proportion of adult people uses glucocorticoid medication for the treatment of chronic illnesses, therefore they are exposed to the side effects of long-term glucocorticoid treatment. Our review summarizes the adverse effects of glucocorticoid excess affecting bones, adipose tissue, brain and skin, focusing on those effects which involve the Wnt/β-catenin pathway.