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Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
11β HSD-I is highly expressed in the hippocampus. Studies with knockout mice demonstrate that 11β HSD-I is the enzyme that results in the activation of glucocorticoids (i.e., in mice, it converts the inactive 11-dehydrocorticosterone to corticosterone).205 Analysis of hippocampal function in 11 β HSD-I knockout mice suggests that 11 β HSD-I attenuates the deleterious effects of chronic glucocorticoid excess upon cognitive function.206 Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the water maze; this glucocorticoid-associated learning deficit was ameliorated in aged 11 β HSD-I knockout mice, despite having elevated plasma corticosterone levels throughout life. These data suggest that the lack of hippocampal 11 β HSD-I results in decreased corticosterone concentrations, which result in increases in learning and memory in aged animals. The data further suggest that local brain concentrations of steroids do not necessarily reflect plasma concentrations, and that these locally synthesized steroids have profound effects on learning and memory.
The Role of Steroid Sulfatase and Sulfotransferase Enzymes in the Metabolism of C21 and Cl9 Steroids
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The first evidence that glucocorticoid sulfates might be involved in cancer came from a study by LeBeau and Baulieu,100 who demonstrated the accumulation of these compounds in adrenal tumor homogenates. More recently, several laboratories have reported that urinary glucocorticoid sulfates (“corticosteroid sulfates”), which represent the sum of cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone sulfates, are elevated significantly in patients with breast, bronchial, and colonic cancers.129–131 Ghosh et al.129 suggested that the glucocorticoid sulfates might be of great importance in the prediction of tumor responses to adrenal ablation and other hormone manipulation. Fahl et al.130 and Rose et al.132 reported that the abnormal elevation of urinary glucocorticoid sulfate levels was more frequent in advanced breast cancer than in “early” tumors and that glucocorticoid sulfate levels do not necessarily correlate with the urinary free cortisol. These data suggest that the concentrations of glucocorticoid sulfates in biological fluids may prove to be a relevant index of the stage of development of certain tumors.
Formation and Metabolism of Steroid Conjugates: Effect of Conjugation on Excretion and Tissue Distribution
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
P. I. Musey, K. Wright, J. R. K. Preedy, D. C. Collins
Determinations of glucocorticoid sulfate in maternal and fetal blood at term, presented in Table 2, suggest that the fetus is the primary source of this conjugate.139 The urinary excretion of glucocorticoid conjugates is shown in Table 3. It is interesting that only cortisol sulfate, cortisone sulfate, corticosterone sulfate, and 11-dehydrocorticosterone sulfate are elevated in pregnancy urine.140 Luttrell and Steinbeck141,142 measured the urinary excretion of the glucosiduronates of cortisol and cortisone in normal men and women and in pregnancy. They found the excretion of cortisol glucosiduronate ranged from 16 to 100 µg/24 hr (n= 14) with a mean ± SE of 58.6 ± 6.2 in normal men and women. Cortisone glucosiduronate ranged from 55 to 120 µg/24 hr with a mean ± SE of 81.0 ± 4.8 µg/24 hr (n = 15). Both of these conjugates were elevated in Cushings syndrome and following ACTH infusion. No progressive elevation appeared in three women studied throughout pregnancy.142
Legacy environmental polychlorinated biphenyl contamination attenuates the acute stress response in a cartilaginous fish, the Round Stingray
Published in Stress, 2019
Kady Lyons, Katherine E. Wynne-Edwards
Contributions from other corticosteroids (cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-dehydrocorticosterone) were broadly excluded by mass spectrometry. At limits of detection of 0.1 or 0.05 ng/ml by liquid chromatography coupled to tandem mass spectrometry, plasma concentrations of several other corticosteroids that might cross-react with the antibody as per the kit pamphlet (corticosterone (100%), 11-dehydrocorticosterone (11%), progesterone (0.31%), cortisol (0.17%), cortisone (<0.01%)) were rarely detectable in Round Stingrays (28/420 = 6.7% of quantitations for 103 plasma samples × five steroids; Supplemental Table 1). In particular, corticosterone, which has the greatest cross-reactivity with the kit antibody, was not detected by mass spectrometry in any plasma samples. If corticosterone was present in our samples, but below the detection limit of our mass spectrometry method, the most cross-reactivity that corticosterone could contribute would be 50 pg/mL (i.e. the limit of detection). This would maximally contribute less than 20% of the mean concentrations from our samples. Thus, we assumed that the corticosterone ELISA would reflect relative 1α-OH-corticosterone measurements in response to the capture stress. For these reasons, results of the ELISA are referred to as relative 1α-OH-corticosterone concentrations.
Placental glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase-2 recruitment indicates impact of prenatal adversity upon postnatal development in mice
Published in Stress, 2018
Moshe Gross, Hava Romi, Yelena Gilimovich, Elyashiv Drori, Albert Pinhasov
GR is responsible in large part for regulation of the intrauterine environment by moderating capillary development within the placental labyrinthine layer (Alagappan et al., 2005; Hewitt, Mark, & Waddell, 2006). Furthermore, excess GR activation has been shown to impair development of the junctional zone in the mouse placenta (Cuffe, O’Sullivan, Simmons, Anderson, & Moritz, 2012), positioning placental GR as a key moderator of nutrient transfer efficiency across the placenta (Clifton et al., 2017). 11βHSD2 catalyzes the metabolism of cortisol and corticosterone to their inactive 11-keto derivatives (cortisone or 11-dehydrocorticosterone) (Mikelson et al., 2015), effectively shielding the developing fetus from elevated glucocorticoid concentrations in the mother during gestation (Harris & Seckl, 2011). A key molecular function of placental GR is the binding to a glucocorticoid response element (GRE) within the promoter of the HSD11B2 gene coding for 11βHSD2 (Hebbar & Archer, 2007), thereby aiding in the induction of transcription.
Mineralocorticoid and glucocorticoid receptor-mediated control of genomic responses to stress in the brain
Published in Stress, 2018
Karen R. Mifsud, Johannes M. H. M. Reul
HPA axis activation results in the release of corticotrophin-releasing factor (CRF) from parvocellular neurons residing in the paraventricular nucleus (PVN) of the hypothalamus, which acts on the pituitary to induce the release of adrenocorticotrophic hormone (ACTH) into the circulation. ACTH acts on the adrenal cortex to stimulate the secretion of glucocorticoid hormones (GCs) into the circulation. GCs are synthesized from cholesterol through a series of enzymatic reactions. 11β-hydroxysteroid dehydrogenases (11β-HSDs) regulate the biological activity of glucocorticoids, with 11β-HSD1 catalyzing activation of the steroid into its active forms (cortisol in humans or corticosterone (cort) in rodents). 11β-HSD2 facilitate the opposite reaction converting the active forms cortisol and cort to the inactive forms cortisone and 11-dehydrocorticosterone (Chapman, Holmes, & Seckl, 2013). The abundance of 11β-HSD1 and lack of 11β-HSD2 expression in MR-positive brain regions ensures that glucocorticoids are the primary factor driving responses in these areas (Wyrwoll, Holmes, & Seckl, 2011). Originally, it was thought that the adult brain completely lacks 11β-HSD2, but indeed more recent studies have shown low to moderate levels of 11β-HSD2 expressed in regions such as the nucleus tractus solitarus and (other) key regions linked to blood pressure control and sodium appetite (Wyrwoll et al., 2011).