Adrenal Steroid Production

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Joan Keiser - One of the best experts on this subject based on the ideXlab platform.

  • torcetrapib induces aldosterone and cortisol Production by an intracellular calcium mediated mechanism independently of cholesteryl ester transfer protein inhibition
    Endocrinology, 2009
    Co-Authors: Xiao Hu, Jessica D Dietz, Delvin R Knight, William T Loging, Haodan Yuan, Andrew H Smith, David Austen Perry, Joan Keiser
    Abstract:

    ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on Adrenal Steroid Production were assessed in cell culture using the H295R as well as the newly developed HAC15 human Adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of Steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcripti...

  • Torcetrapib induces aldosterone and cortisol Production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
    Endocrinology, 2009
    Co-Authors: Jessica D Dietz, Delvin R Knight, William T Loging, Haodan Yuan, Andrew H Smith, David Austen Perry, Chunsheng Xia, Joan Keiser
    Abstract:

    ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on Adrenal Steroid Production were assessed in cell culture using the H295R as well as the newly developed HAC15 human Adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of Steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating Adrenal Steroid biosynthesis. Hormone-induced Steroid Production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib's effect in Adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and Adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.

Bjarne Styrishave - One of the best experts on this subject based on the ideXlab platform.

  • Atorvastatin decreases Steroid Production in H295R cells and in major endocrine tissues of male rats
    Archives of Toxicology, 2018
    Co-Authors: Cecilie Hurup Munkboel, Michelle L. K. Baake, Bjarne Styrishave
    Abstract:

    Obesity is increasing worldwide, and since obesity is associated with dyslipidemia, the consumption of cholesterol-lowering pharmaceuticals has increased. The aim of this study was therefore to study potential endocrine disrupting effects of one of the world’s most frequently prescribed drugs, the cholesterol-lowering drug, atorvastatin (ATO) in vitro using the H295R Steroidogenesis assay and in vivo using male Sprague–Dawley rats. We analyzed all major Steroids in the mammalian Steroidogenesis using liquid chromatography–tandem mass spectrometry (LC–MS/MS). In vitro, ATO significantly decreased all Steroids in the H295R Steroidogenesis at concentrations close to human plasma C _max values, with an IC_50 value for testosterone of 0.093 ± 0.033 µM. Additionally, we determined Steroid hormone levels in testis, Adrenals, brain and plasma from rats after 14 days of exposure to three therapeutically relevant doses of ATO and observed pronounced decreasing Steroid levels in particular in testis and Adrenals but also in brain and plasma. In testis, all major Steroidogenic enzymes were up-regulated, indicating autocrine and/or paracrine compensation for the decrease in Steroid Production by this tissue. In Adrenals, StAR and CYP11A1 gene expression were decreased, whereas little effects were observed in the brain. Furthermore, we analyzed plasma LH and ACTH levels to investigate feedback via the PT and HPA axes. No effects were observed on LH levels, indicating little compensation via the PT axis. In contrast, ACTH levels increased during ATO exposure, indicating that the HPA axis to some extend compensated for the decrease in Adrenal Steroid Production. Overall, ATO exerted pronounced effects on Steroid Production both in vitro and in vivo at therapeutically relevant doses. This clearly demonstrates the high potency of ATO to affect Steroid homeostasis during therapeutic treatment. Further clinical and epidemiological studies should be conducted to investigate the relevance of these observations in patients treated with cholesterol-lowering pharmaceuticals.

  • Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism
    Toxicological Sciences, 2018
    Co-Authors: Cecilie Hurup Munkboel, Lizette Weber Larsen, Johan Juhl Weisser, David Møbjerg Kristensen, Bjarne Styrishave
    Abstract:

    Selective serotonin reuptake inhibitors are used as first line treatment in major depressive disorder. However, selective serotonin reuptake inhibitors have also been associated with sexual disorders, abnormalities, and sexual dysfunction, although mechanisms are unclear. The aim of this project was to investigate the possible endocrine disrupting effect of sertraline (SER) on sex Steroid Production in male rats exposed to 3 therapeutically realistic doses of SER 1.25, 5, and 20 mg/kg/day. To achieve this, we analyzed all the major Steroids in testis, Adrenals, brain, and plasma using Liquid chromatography tandem mass spectrometry. Furthermore, we investigated the potential effects on gene expression on the major genes involved in testicular, Adrenal and brain Steroidogenesis using quantitative PCR. Moreover, plasma luteinizing hormone (LH) levels were analyzed. We observed significant reduction in Steroid Production, in particular on the testicular Δ-4 axis and on the Adrenal CYP17-hydroxylase axis. Effects in brain and plasma were less pronounced. Testicular gene transcription was also significantly down-regulated except for the CYP19 (aromatase) gene. In contrast, no effects on the Adrenal gene expression were observed, except for an up-regulation of the CYP17. Plasma LH and LH/TS were increased, in particular in the lowest exposure group, indicating some degree of compensatory hypogonadism. In conclusion, this study demonstrates extensive endocrine disruption during SER exposure in male rats, both directly on Steroid Production in major endocrine tissues, but also indirectly by affecting gene expression. Furthermore, increased LH levels may augment decreased sex Steroid Production, in particular testosterone Production, inducing a state of compensatory hypogonadism.

William E. Rainey - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic High-Density Lipoprotein (sHDL) Inhibits Steroid Production in HAC15 Adrenal Cells.
    Endocrinology, 2016
    Co-Authors: Matthew Taylor, Aalok R. Sanjanwala, Emily E. Morin, Elizabeth Rowland-fisher, Kyle Anderson, Anna Schwendeman, William E. Rainey
    Abstract:

    High density lipoprotein (HDL) transported cholesterol represents one of the sources of substrate for Adrenal Steroid Production. Synthetic HDL (sHDL) particles represent a new therapeutic option to reduce atherosclerotic plaque burden by increasing cholesterol efflux from macrophage cells. The effects of the sHDL particles on Steroidogenic cells have not been explored. sHDL, specifically ETC-642, was studied in HAC15 adrenocortical cells. Cells were treated with sHDL, forskolin, 22R-hydroxycholesterol, or pregnenolone. Experiments included time and concentration response curves, followed by Steroid assay. Quantitative real-time RT-PCR was used to study mRNA of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, lanosterol 14-α-methylase, cholesterol side-chain cleavage enzyme, and Steroid acute regulatory protein. Cholesterol assay was performed using cell culture media and cell lipid extracts from a dose response experiment. sHDL significantly inhibited Production of cortisol. Inhibition occurred in a con...

  • Human adrenocortical carcinoma cell lines.
    Molecular and cellular endocrinology, 2011
    Co-Authors: Tao Wang, William E. Rainey
    Abstract:

    The human Adrenal cortex secretes mineralocorticoids, glucocorticoids and Adrenal androgens. These Steroids are produced from unique cell types located within the three distinct zones of the Adrenal cortex. Disruption of Adrenal Steroid Production results in a variety of diseases that can lead to hypertension, metabolic syndrome, infertility and androgen excess. The Adrenal cortex is also a common site for the development of adenomas, and rarely the site for the development of carcinomas. The adenomas can lead to diseases associated with Adrenal Steroid excess, while the carcinomas are particularly aggressive and have a poor prognosis. In vitro cell culture models provide important tools to examine molecular and cellular mechanisms controlling both the normal and pathologic function of the Adrenal cortex. Herein, we discuss currently available human adrenocortical carcinoma cell lines and their use as model systems for Adrenal studies.

  • Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells
    Journal of molecular endocrinology, 2007
    Co-Authors: Edson F. Nogueira, Claudia A Vargas, Mélissa Otis, Nicole Gallo-payet, Wendy B. Bollag, William E. Rainey
    Abstract:

    Angiotensin-II (Ang-II) regulates Adrenal Steroid Production and gene transcription through several signaling pathways. Changes in gene transcription occur within minutes after Ang-II stimulation, causing an increase in aldosterone Production and subsequent increase in the overall capacity to produce aldosterone. Our goal was to compare the Ang-II regulation of early gene expression and confirm the up-regulation of selected genes using quantitative real-time RT-PCR (qPCR) across three species, such as, human, bovine, and rat. Microarray analyses were performed using samples from control and Ang-II (10 nM)-treated (1 h) cells from human adrenocortical tumor cell line H295R, and primary Adrenal glomerulosa cells from bovine and rat, applied respectively to human, bovine, and rat chips. qPCR was performed to confirm up-regulation of selected genes using mRNA. The microarray comparison revealed 18% similarity among the top 50 up-regulated genes, with human/rat, 20%; human/bovine, 36%; and rat/bovine, 26% similarity. The gene list generated by this comparison included: activating transcription factor 3, B-cell translocation gene (BTG2), Nuclear receptor subfamily 4, group A, member 1 (NR4A1), NR4A2, NR4A3, early growth response 1, v-fos FBJ murine osteosarcoma viral oncogene homolog (c-FOS), FOSB, and Jun family member B (JUNB). Pretreatment of H295R cells with cycloheximide had no effect on Ang-II induction of these genes, suggesting that they are direct targets of Ang-II signaling. The Ang-II gene targets have been defined in three different adrenocortical model systems. Several of the listed genes have previously been described as being key regulators of adrenocortical function. The presence of Adrenal cell common genes in such distinct cell models strengthens the hypothesis that these genes are regulators of aldosterone Production.

  • transcriptional regulation of dehydroepiandrosterone sulfotransferase sult2a1 by estrogen related receptor α
    Endocrinology, 2005
    Co-Authors: Jeremiah Seely, Bruce R. Carr, Karla Saner Amigh, Takashi Suzuki, Bobbie Mayhew, Hironobu Sasano, Vincent Giguere, Josee Laganiere, William E. Rainey
    Abstract:

    The estrogen-related receptors (ERRα, -β, and -γ) are a subfamily of orphan nuclear receptors (designated NR3B1, NR3B2, and NR3B3) that are structurally and functionally related to estrogen receptors α and β. Herein we test the hypothesis that ERRα regulates transcription of the genes encoding the enzymes involved in Adrenal Steroid Production. Real-time RT-PCR was first used to determine the levels of ERRα mRNA in various human tissues. Adult Adrenal levels of ERRα transcript were similar to that seen in heart, which is known to highly express ERRα. Expression of ERRα in the adult Adrenal was then confirmed using Western blotting and immunohistochemistry. To examine the effects of ERRα on Steroidogenic capacity we used reporter constructs with the 5′-flanking regions of Steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage (CYP11A), 3β-hydroxySteroid dehydrogenase type II (HSD3B2), 17α-hydroxylase/17,20-lyase (CYP17), and dehydroepiandrosterone sulfotransferase (SULT2A1). Cotrans...

Jessica D Dietz - One of the best experts on this subject based on the ideXlab platform.

  • torcetrapib induces aldosterone and cortisol Production by an intracellular calcium mediated mechanism independently of cholesteryl ester transfer protein inhibition
    Endocrinology, 2009
    Co-Authors: Xiao Hu, Jessica D Dietz, Delvin R Knight, William T Loging, Haodan Yuan, Andrew H Smith, David Austen Perry, Joan Keiser
    Abstract:

    ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on Adrenal Steroid Production were assessed in cell culture using the H295R as well as the newly developed HAC15 human Adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of Steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcripti...

  • Torcetrapib induces aldosterone and cortisol Production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
    Endocrinology, 2009
    Co-Authors: Jessica D Dietz, Delvin R Knight, William T Loging, Haodan Yuan, Andrew H Smith, David Austen Perry, Chunsheng Xia, Joan Keiser
    Abstract:

    ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on Adrenal Steroid Production were assessed in cell culture using the H295R as well as the newly developed HAC15 human Adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of Steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating Adrenal Steroid biosynthesis. Hormone-induced Steroid Production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib's effect in Adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and Adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.

Cecilie Hurup Munkboel - One of the best experts on this subject based on the ideXlab platform.

  • Atorvastatin decreases Steroid Production in H295R cells and in major endocrine tissues of male rats
    Archives of Toxicology, 2018
    Co-Authors: Cecilie Hurup Munkboel, Michelle L. K. Baake, Bjarne Styrishave
    Abstract:

    Obesity is increasing worldwide, and since obesity is associated with dyslipidemia, the consumption of cholesterol-lowering pharmaceuticals has increased. The aim of this study was therefore to study potential endocrine disrupting effects of one of the world’s most frequently prescribed drugs, the cholesterol-lowering drug, atorvastatin (ATO) in vitro using the H295R Steroidogenesis assay and in vivo using male Sprague–Dawley rats. We analyzed all major Steroids in the mammalian Steroidogenesis using liquid chromatography–tandem mass spectrometry (LC–MS/MS). In vitro, ATO significantly decreased all Steroids in the H295R Steroidogenesis at concentrations close to human plasma C _max values, with an IC_50 value for testosterone of 0.093 ± 0.033 µM. Additionally, we determined Steroid hormone levels in testis, Adrenals, brain and plasma from rats after 14 days of exposure to three therapeutically relevant doses of ATO and observed pronounced decreasing Steroid levels in particular in testis and Adrenals but also in brain and plasma. In testis, all major Steroidogenic enzymes were up-regulated, indicating autocrine and/or paracrine compensation for the decrease in Steroid Production by this tissue. In Adrenals, StAR and CYP11A1 gene expression were decreased, whereas little effects were observed in the brain. Furthermore, we analyzed plasma LH and ACTH levels to investigate feedback via the PT and HPA axes. No effects were observed on LH levels, indicating little compensation via the PT axis. In contrast, ACTH levels increased during ATO exposure, indicating that the HPA axis to some extend compensated for the decrease in Adrenal Steroid Production. Overall, ATO exerted pronounced effects on Steroid Production both in vitro and in vivo at therapeutically relevant doses. This clearly demonstrates the high potency of ATO to affect Steroid homeostasis during therapeutic treatment. Further clinical and epidemiological studies should be conducted to investigate the relevance of these observations in patients treated with cholesterol-lowering pharmaceuticals.

  • Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism
    Toxicological Sciences, 2018
    Co-Authors: Cecilie Hurup Munkboel, Lizette Weber Larsen, Johan Juhl Weisser, David Møbjerg Kristensen, Bjarne Styrishave
    Abstract:

    Selective serotonin reuptake inhibitors are used as first line treatment in major depressive disorder. However, selective serotonin reuptake inhibitors have also been associated with sexual disorders, abnormalities, and sexual dysfunction, although mechanisms are unclear. The aim of this project was to investigate the possible endocrine disrupting effect of sertraline (SER) on sex Steroid Production in male rats exposed to 3 therapeutically realistic doses of SER 1.25, 5, and 20 mg/kg/day. To achieve this, we analyzed all the major Steroids in testis, Adrenals, brain, and plasma using Liquid chromatography tandem mass spectrometry. Furthermore, we investigated the potential effects on gene expression on the major genes involved in testicular, Adrenal and brain Steroidogenesis using quantitative PCR. Moreover, plasma luteinizing hormone (LH) levels were analyzed. We observed significant reduction in Steroid Production, in particular on the testicular Δ-4 axis and on the Adrenal CYP17-hydroxylase axis. Effects in brain and plasma were less pronounced. Testicular gene transcription was also significantly down-regulated except for the CYP19 (aromatase) gene. In contrast, no effects on the Adrenal gene expression were observed, except for an up-regulation of the CYP17. Plasma LH and LH/TS were increased, in particular in the lowest exposure group, indicating some degree of compensatory hypogonadism. In conclusion, this study demonstrates extensive endocrine disruption during SER exposure in male rats, both directly on Steroid Production in major endocrine tissues, but also indirectly by affecting gene expression. Furthermore, increased LH levels may augment decreased sex Steroid Production, in particular testosterone Production, inducing a state of compensatory hypogonadism.