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The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

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Harvard

Melau, C, Riis, ML, Nielsen, JE, Perlman, S, Lundvall, L, Thuesen, LL, Hare, KJ, Hammerum, MS, Mitchell, RT, Frederiksen, H, Juul, A & Jørgensen, A 2021, 'The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions', BMC Medicine, bind 19, nr. 1, 204, s. 204. https://doi.org/10.1186/s12916-021-02080-8

APA

Melau, C., Riis, M. L., Nielsen, J. E., Perlman, S., Lundvall, L., Thuesen, L. L., Hare, K. J., Hammerum, M. S., Mitchell, R. T., Frederiksen, H., Juul, A., & Jørgensen, A. (2021). The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions. BMC Medicine, 19(1), 204. [204]. https://doi.org/10.1186/s12916-021-02080-8

CBE

Melau C, Riis ML, Nielsen JE, Perlman S, Lundvall L, Thuesen LL, Hare KJ, Hammerum MS, Mitchell RT, Frederiksen H, Juul A, Jørgensen A. 2021. The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions. BMC Medicine. 19(1):204. https://doi.org/10.1186/s12916-021-02080-8

MLA

Vancouver

Author

Melau, Cecilie ; Riis, Malene Lundgaard ; Nielsen, John E ; Perlman, Signe ; Lundvall, Lene ; Thuesen, Lea Langhoff ; Hare, Kristine Juul ; Hammerum, Mette Schou ; Mitchell, Rod T ; Frederiksen, Hanne ; Juul, Anders ; Jørgensen, Anne. / The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions. I: BMC Medicine. 2021 ; Bind 19, Nr. 1. s. 204.

Bibtex

@article{3847507f35294907a3c8290d2e286355,
title = "The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions",
abstract = "BACKGROUND: Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions.METHODS: This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8-12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey's multiple comparisons test.RESULTS: Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions.CONCLUSIONS: Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.",
keywords = "Abiraterone, ACTH, Adrenal, Efavirenz, Ex vivo, Human, Osilodrostat, Steroid hormones",
author = "Cecilie Melau and Riis, {Malene Lundgaard} and Nielsen, {John E} and Signe Perlman and Lene Lundvall and Thuesen, {Lea Langhoff} and Hare, {Kristine Juul} and Hammerum, {Mette Schou} and Mitchell, {Rod T} and Hanne Frederiksen and Anders Juul and Anne J{\o}rgensen",
note = "{\textcopyright} 2021. The Author(s).",
year = "2021",
month = sep,
day = "8",
doi = "10.1186/s12916-021-02080-8",
language = "English",
volume = "19",
pages = "204",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "BioMed Central Ltd",
number = "1",

}

RIS

TY - JOUR

T1 - The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

AU - Melau, Cecilie

AU - Riis, Malene Lundgaard

AU - Nielsen, John E

AU - Perlman, Signe

AU - Lundvall, Lene

AU - Thuesen, Lea Langhoff

AU - Hare, Kristine Juul

AU - Hammerum, Mette Schou

AU - Mitchell, Rod T

AU - Frederiksen, Hanne

AU - Juul, Anders

AU - Jørgensen, Anne

N1 - © 2021. The Author(s).

PY - 2021/9/8

Y1 - 2021/9/8

N2 - BACKGROUND: Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions.METHODS: This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8-12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey's multiple comparisons test.RESULTS: Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions.CONCLUSIONS: Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

AB - BACKGROUND: Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions.METHODS: This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8-12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey's multiple comparisons test.RESULTS: Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions.CONCLUSIONS: Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

KW - Abiraterone

KW - ACTH

KW - Adrenal

KW - Efavirenz

KW - Ex vivo

KW - Human

KW - Osilodrostat

KW - Steroid hormones

UR - http://www.scopus.com/inward/record.url?scp=85114411736&partnerID=8YFLogxK

U2 - 10.1186/s12916-021-02080-8

DO - 10.1186/s12916-021-02080-8

M3 - Journal article

C2 - 34493283

VL - 19

SP - 204

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

M1 - 204

ER -

ID: 67610730