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Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis

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CONTEXT: Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail.

OBJECTIVE: Due to significant differences in adrenal steroidogenesis between human and model species (except higher primates), we aimed to establish a human fetal adrenal model that enables examination of both de novo and manipulated adrenal steroidogenesis.

DESIGN AND SETTING: Human adrenal tissue from 54 1st trimester fetuses were cultured ex vivo as intact tissue fragments for 7 or 14 days.

MAIN OUTCOME MEASURES: Model validation included examination of postculture tissue morphology, viability, apoptosis, and quantification of steroid hormones secreted to the culture media measured by liquid chromatography-tandem mass spectrometry.

RESULTS: The culture approach maintained cell viability, preserved cell populations of all fetal adrenal zones, and recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens. Adrenocorticotropic hormone and ketoconazole treatment of ex vivo cultured human fetal adrenal tissue resulted in the stimulation of steroidogenesis and inhibition of androgen secretion, respectively, demonstrating a treatment-specific response.

CONCLUSIONS: Together, these data indicate that ex vivo culture of human fetal adrenal tissue constitutes a novel approach to investigate local effects of pharmaceutical exposures or emerging therapeutic options targeting imbalanced steroidogenesis in adrenal disorders, including CAH.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume106
Issue number3
Pages (from-to)843-857
Number of pages15
ISSN0021-972X
DOIs
Publication statusPublished - 8 Mar 2021

Bibliographical note

Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

    Research areas

  • ACTH, androgen biosynthesis, endocrine activity, ex vivo culture, ketoconazole, steroidogenesis

ID: 61288542