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

BMC Medicine

Anne Jørgensen¹  Malene Lundgaard Riis¹  Hanne Frederiksen¹  John E. Nielsen¹  Cecilie Melau¹  Anders Juul²  Lene Lundvall³  Signe Perlman³  Mette Schou Hammerum⁴  Kristine Juul Hare⁵  Lea Langhoff Thuesen⁵  Rod T. Mitchell⁶ 

[1] Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark;International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark;Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark;International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark;Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;Department of Gynaecology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark;Department of Obstetrics and Gynaecology, Copenhagen University Hospital - Herlev and Gentofte Hospital, Herlev, Denmark;Department of Obstetrics and Gynaecology, Copenhagen University Hospital - Hvidovre and Amager Hospital, Hvidovre, Denmark;MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK;

关键词: Human;    Adrenal;    Ex vivo;    Steroid hormones;    ACTH;    Osilodrostat;    Efavirenz;    Abiraterone;   

DOI  :  10.1186/s12916-021-02080-8

来源: Springer

【 摘 要 】

BackgroundDisordered 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.MethodsThis 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.ResultsTreatment 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.ConclusionsOur 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.

【 授权许可】

CC BY