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Cited by 16Sexual Differentiation and DisordersAdrenal Hormones and DisordersHormonal Regulation and Hypertension

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

Open access
Melau, Cecilie, Nielsen, John E, Perlman, Signe, Lundvall, Lene, Langhoff Thuesen, Lea, Juul Hare, Kristine, Schou Hammerum, Mette, Frederiksen, Hanne +3 more·2021·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa852
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Abstract

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.

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AI snapshot

Written from the paper’s full text.

TL;DR

This paper establishes a hanging-drop ex vivo culture model of first-trimester human fetal adrenal tissue that preserves morphology, viability, and steroidogenic activity for up to 14 days. It further shows that steroidogenesis can be stimulated with ACTH and inhibited with ketoconazole, supporting use for studying normal and dysregulated human fetal adrenal function.

Key findings

  • Human fetal adrenal tissue from 54 first-trimester fetuses (59 adrenals; GW 8–11) cultured as ~1 mm³ fragments maintained morphology, proliferation, and low apoptosis for 7–14 days; cPARP+ cells/mm² decreased 3.8-fold (p<0.05) at 14 days versus 7 days.
  • Cultured tissue recapitulated de novo steroidogenesis: DHEAS was the most abundant measured metabolite (>20,000 nmol/L), cortisol was second highest (>1000 nmol/L), and testosterone was lowest (<5 nmol/L) but detectable in all samples, with no differences between 7- and 14-day cultures.
  • ACTH (1 nM) after 14 days increased androstenedione 10.8-fold (p<0.01), testosterone 9.4-fold (p<0.05), DHEAS 2.5-fold (p<0.01), 17-hydroxyprogesterone 4.5-fold (p<0.01), 11-deoxycortisol 12.7-fold (p<0.01), cortisol 6.9-fold (p<0.01), cortisone 1.7-fold (p<0.01), progesterone 2-fold (p<0.05), and corticosterone 4.9-fold (p<0.01); it also increased FZ area (SPARC+ and CYP17A1+, both 3.5-fold) and decreased DZ area (NCAM-1+, 1.9-fold).
  • Ketoconazole (10 µM) after 14 days decreased androstenedione 1.8-fold (p<0.05) and DHEAS 4.2-fold (p<0.01), while increasing 11-deoxycortisol 4.3-fold (p<0.01), 17-hydroxyprogesterone 2.3-fold (p<0.05), and progesterone 11.2-fold (p<0.01); no effect on FZ/DZ area or cell viability was observed.

Methods

  • Human adrenal tissue from 54 first-trimester fetuses (59 adrenals; GW 8–11) was collected after elective surgical termination; 8 intact adrenals from independent fetuses served as non-culture controls. Tissue was divided into ~1 mm³ fragments and cultured in hanging drops in 40 µL medium for 7 or 14 days, with complete medium change every 48 hours.
  • Treatments were ACTH (1 nM) or ketoconazole (10 µM) versus vehicle; each adrenal was divided so equal halves were used for vehicle and treatment.
  • Validation included immunohistochemistry for CYP17A1, SPARC, NCAM-1, SF-1, BrdU, and cPARP, plus liquid chromatography-tandem mass spectrometry (LC-MS/MS) for steroid metabolites in pooled culture media. Statistics used Mann Whitney (two-tailed) U-test for 7- vs 14-day comparisons and Wilcoxon signed rank test (two-tailed) for treatment vs vehicle.

Limitations

  • Stated: zone-specific immunohistochemistry results should be considered semi-quantitative because paraffin-embedded cultured fragments varied in orientation; a small sub-population lost FZ/DZ markers and SF-1; ketoconazole’s lack of effect on cortisol was unexpected, and the 10 µM dose is lower than expected in vivo serum concentrations; comparing effects in heterogeneous tissue to previous cell-type- and dose-specific studies is difficult.
  • Evident from the text: the model uses normal first-trimester human fetal adrenal tissue (GW 8–11), not CAH tissue or genetically manipulated tissue, so its proposed use as a human CAH ex vivo model is not directly demonstrated.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/clinem/dgaa852

Cites

65 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Cortisol was measured in the second highest concentrations among the measured metabolites, at >1000 nmol/L.

    “with cortisol (>1000 nmol/L) measured in the second highest concentrations (after DHEAS)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Ketoconazole treatment inhibited androgen secretion in ex vivo cultured human fetal adrenal tissue.

    “inhibition of androgen secretion”
    • Also stated in: § Steroidogenic activity can be both stimulated and inhibited in HFA tissue cultured ex vivo · plain
      “Treatment with ketoconazole resulted in decreased secretion of androstenedione (1.8-fold, p<0.05) and DHEAS (4.2-fold, p<0.01) after culture for 14 days”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The DMSO vehicle at 0.1% does not affect human fetal adrenal tissue steroidogenesis or viability.
  • Findingown data

    The ex vivo culture approach preserved cell populations of all fetal adrenal zones.

    “preserved cell populations of all fetal adrenal zones”
    • Also stated in: § Ex vivo culture preserves HFA tissue morphology and cell viability · plain
      “The overall morphology of the cultured HFA fragments was maintained preserving both the DZ and FZ after both culture periods”
    • Also stated in: § Steroidogenic activity is maintained after ex vivo culture of HFA tissue · plain
      “Overall, the zonation of the ex vivo cultured tissue was preserved containing both FZ cells (SPARC + , (21)) and DZ cells (NCAM-1 + , ( 45))”
    Quote in the paperSubstantial claim
  • Findingown data

    The ex vivo culture approach maintained cell viability of human fetal adrenal tissue.

    “The culture approach maintained cell viability”
    • Also stated in: § Ex vivo culture preserves HFA tissue morphology and cell viability · plain
      “Overall, only few cPARP + cells were detected in both cultured and non-culture control HFA tissue”
    Quote in the paperSubstantial claim
  • Findingown data

    The zonation of the ex vivo cultured human fetal adrenal tissue was preserved containing both fetal zone (FZ) and definitive zone (DZ) cells.

    “Overall, the zonation of the ex vivo cultured tissue was preserved containing both FZ cells (SPARC + , (21)) and DZ cells (NCAM-1 + , ( 45))”
    Quote in the paperSubstantial claim
  • May combine two claims. 13
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Ketoconazole treatment of ex vivo cultured human fetal adrenal tissue increased 11-deoxycortisol (4.3-fold, p<0.01), 17-hydroxyprogesterone (2.3-fold, p<0.05) and progesterone (11.2-fold, p<0.01).

    “Additionally, levels of 11-deoxycortisol (4.3-fold, p<0.01), 17-hydroxyprogesterone (2.3-fold, p<0.05) and progesterone (11.2-fold, p<0.01) were all increased compared with vehicle controls as a result of ketoconazole treatment”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The DMSO vehicle at 0.1% does not affect human fetal adrenal tissue steroidogenesis or viability.

  • May combine two claims.

    Findingown data

    Testosterone levels were the lowest among the measured androgens but were detectable in all samples, at <5 nmol/L.

    “testosterone (<5 nmol/L) levels were the lowest among the measured androgens but were still detectable in all samples”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The presented human fetal adrenal ex vivo culture approach preserved cell viability and an overall tissue zonation that consisted of both neuroendocrine and steroidogenic cells.

    “Overall, the presented HFA ex vivo culture approach preserved cell viability and an overall tissue zonation that consisted of both neuroendocrine and steroidogenic cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ex vivo culture approach preserved 1st trimester human fetal adrenal morphology, maintaining both fetal zone (FZ), definitive zone (DZ) and migrating neuroendocrine cells.

    “In addition to continued proliferation, the ex vivo culture approach used here preserved 1 st trimester HFA morphology maintaining both FZ, DZ and migrating neuroendocrine cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    An ex vivo culture approach for HFA tissue has been established that allows culture for two weeks with preserved adrenal morphology, cell viability, and continued high steroidogenic activity.

    “In conclusion, we have established an ex vivo culture approach for HFA tissue that allows culture for two weeks with preserved adrenal morphology, cell viability, and a continued high steroidogenic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The applied ex vivo culture approach supports HFA tissue for up to 14 days of culture with overall preserved morphology, continued cell proliferation and a low level of apoptosis.

    “Together these results suggest that the applied ex vivo culture approach supports HFA tissue for up to 14-days of culture with overall preserved morphology, continued cell proliferation and a low level of apoptosis in the tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The presented human fetal adrenal ex vivo approach maintains a high steroidogenic activity, which is a unique advance of this experimental approach, while also preserving fetal zone-specific abundant expression of steroidogenic enzymes.

    “Thus, the presented HFA ex vivo approach maintains a high steroidogenic activity which is a unique advance of this experimental approach while also preserving FZ-specific abundant expression of steroidogenic enzymes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Negative controls were included in immunohistochemistry and processed with the primary antibody replaced by the dilution buffer alone, none of which showed staining.

    “Negative controls were included and processed with the primary antibody replaced by the dilution buffer alone, none of which showed staining.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Ex vivo cultured human fetal adrenal tissue responds in a similar manner to human fetal adrenal tissue in vivo, as enlargement of the steroidogenic adrenal cortex is known to be a consequence of hyperstimulated adrenals.

    “This suggests that ex vivo cultured tissue responds in a similar manner to HFA tissue in vivo as enlargement of the steroidogenic adrenal cortex is known to be a consequence of hyperstimulated adrenals (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] White, 2000, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Endocr Rev.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The clinically validated analysis package included estrone sulfate, testosterone, androstenedione, DHEAS, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, corticosterone, and progesterone.

    “This clinically validated analysis package included estrone sulfate, testosterone, androstenedione, DHEAS, cortisone, cortisol, 11deoxycortisol, 17-hydroxyprogesterone, corticosterone, and progesterone.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To ensure an equal relative ratio of definitive zone (DZ) vs fetal zone (FZ) cells prior to the experimental vehicle vs. treatment set-up, the adrenal gland was initially divided into two halves prior to division into 1 mm3 fragments.

    “To ensure an equal relative ratio of DZ vs FZ cells were equal prior to the experimental vehicle vs. treatment set-up, the adrenal gland was initially divided into two halves prior to division into 1 mm 3 fragments.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Steroid hormone levels in culture media were measured using a method established to quantify steroid metabolites in serum by isotype-dilution TurboFlow-LC-MS/MS as previously described.

    “Steroid hormone levels were measured using a method established to quantify steroid metabolites in serum by isotype-dilution TurboFlow-LC-MS/MS as previously described (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Søeborg, 2017, Isotope-dilution TurboFlow-LC-MS/MS method for simultaneous quantification of ten steroid metabolites in serum, Clin Chim Acta. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Conserved cross-talk between the different adrenal cell-types is central in the establishment of a culture model that aims to recapitulate normal and dysregulated human fetal adrenal development and function.

    “Thus, conserved cross-talk between the different adrenal cell-types are central in the establishment of a culture model that aims to recapitulate normal and dysregulated HFA development and function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    For the four analytical batches included in this study, the relative standard deviation (RSD) was < 10% for all steroids in culture media controls spiked in low level, except for estrone sulfate and DHEAS (< 17%), and < 4.2% for all steroids in controls spiked in high level.

    “For the four analytical batches included in this study the relative standard deviation (RSD) were < 10% for all steroids in culture media controls spiked in low level, except for estrone sulfate and DHEAS (< 17%), and < 4.2% for all steroids in controls spiked in high level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The higher prevalence of 3βHSD2+ cells in 1st trimester and similar intra-adrenal corticosteroid concentrations suggest an elevated capacity for glucocorticoid synthesis and a lower sensitivity towards inhibition of corticosteroid biosynthesis in 1st trimester adrenal tissue.

    “could suggest an elevated capacity for glucocorticoid synthesis and subsequently a lower sensitivity towards inhibition of corticosteroid biosynthesis in 1 st trimester adrenal tissue.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The gestational age of HFA tissue (1st vs 2nd trimester) does not confound the effects of ketoconazole treatment.

  • Classified as probably not a substantial claim.

    Premisecitation

    Ketoconazole is normally administered in doses between 400-1200 mg/day.

    “ketoconazole normally is administrated in doses between 400-1200 mg/day (60)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Braun, 2020, What is the role of medical therapy in adrenal-dependent Cushing’s syndrome?, Best Pract Res Clin Endocrinol Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The increased 11-deoxycortisol concentration indicates that if the system had been pushed further by initial ACTH stimulation or higher ketoconazole concentrations, an effect on cortisol might have been detectable.

    “However, the increased concentration of 11-deoxycortisol indicates that if the system had been pushed further either by initial ACTH stimulation or higher ketoconazole concentrations an effect on cortisol might have been detectable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In a system where steroidogenesis is not completely inhibited, some metabolites are expected to be upregulated while metabolites downstream of enzymes with the lowest IC50 values are expected to be downregulated.

    “therefore some metabolites are expected to be upregulated while metabolites downstream of these enzymes with the lowest IC50 values are expected to be downregulated in a system where steroidogenesis is not completely inhibited.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ketoconazole concentrations below 10 μM did not reduce cell viability of human adrenal carcinoma cells.

    “This is in line with a previous study which found ketoconazole concentrations below 10 µM did not reduce cell viability of human adrenal carcinoma cells (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Sugar, 1987, Pharmacology and toxicity of high-dose ketoconazole, Antimicrob Agents Chemother. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Ketoconazole affects multiple steps of adrenal steroidogenesis.

    “Effects of the well-known inhibitor of steroidogenic enzymes, ketoconazole which affects multiple steps of adrenal steroidogenesis was also examined in the HFA ex vivo model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Fleseriu, 2016, Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies, Pituitary. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Study design and conductreasoning

    Zone-specific immunohistochemistry results should be considered as semi-quantitative.

    “Therefore, zone-specific IHC results should be considered as semi-quantitative.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The HFA ex vivo culture model may be used to study both normal and dysregulated HFA steroidogenic activity and function, which is relevant for understanding development and management of adrenal disorders in humans.

    “Therefore, this model may be used to study both normal and dysregulated HFA steroidogenic activity and function, which will be of particular relevance for understanding development and management of adrenal disorders in humans.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ex vivo HFA culture model's responses to ACTH and ketoconazole are representative of in vivo human fetal adrenal responsiveness.
22 of 22

  • The paper relies on this without support.

    Continued secretion of steroid hormones by cultured human fetal adrenal tissue over 14 days reflects de novo steroidogenesis rather than release of pre-formed steroids.

    “recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens”

  • The paper relies on this without support.

    The DMSO vehicle at 0.1% does not affect human fetal adrenal tissue steroidogenesis or viability.

    “ketoconazole dissolved in dimethyl sulfoxide vehicle (DMSO, 0.1 %)”

  • The paper relies on this without support.

    The development and endocrine function of human fetal adrenals are still relatively unexplored.

    “Despite the importance of steroids secreted by human fetal adrenals (HFA) the development and endocrine function of these organs are still relatively unexplored.”

  • The paper relies on this without support.

    The non-culture control human fetal adrenal tissue represents the normal in vivo state of human fetal adrenal tissue.

    “Additionally, 8 intact adrenals from independent fetuses were formalin fixed immediately after dissection and used as non-culture controls.”

  • The paper relies on this without support.

    The ex vivo HFA culture model's responses to ACTH and ketoconazole are representative of in vivo human fetal adrenal responsiveness.

    “This specific steroidogenic response in the presented HFA ex vivo cultured tissue suggest that this model can be used to investigate local effects of pharmaceutical exposures or emerging therapeutic treatments that may impact adrenal development or function during pregnancy.”

  • The paper relies on this without support.

    The gestational age of HFA tissue (1st vs 2nd trimester) does not confound the effects of ketoconazole treatment.

    “The higher prevalence of 3βHSD2 + cells/tissue area in 1 st trimester compared with 2 nd trimester HFA tissues and similar intra-adrenal concentrations of corticosteroids (5) could suggest an elevated capacity for glucocorticoid synthesis and subsequently a lower sensitivity towards inhibition of corticosteroid biosynthesis in 1 st trimester adrenal tissue.”

  • The paper relies on this without support.

    The measured steroid metabolite concentrations in culture media reflect adrenal steroidogenesis in the cultured tissue.

    “Secretion of adrenal steroid metabolites was measured by LC-MS/MS in the culture media collected throughout the experimental period of 7-(b,c) or 14-days (d,e).”
7 of 7

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Authors
Melau, C., Nielsen, J. E., Perlman, S., Lundvall, L., Langhoff Thuesen, L., Juul Hare, K., Schou Hammerum, M., Frederiksen, H., Mitchell, R. T., Juul, A., & Jørgensen, A.
Affiliations
  • University of Copenhagen (DK)
  • Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Hvidovre, Denmark
  • Departmet of Obstetrics and Gynaecology, Herlev University Hospital, Herlev, Denmark
  • MRC Centre for Reproductive Health (GB)
Corresponding author
Jørgensen, Anne
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-11-19
Volume
106
Issue
3
Pages
843-857
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa852
OpenAlex
W3102866752
Semantic Scholar
fb64fa90fd1502b31e21c523b57b80dd4317f81b
Cited by
16
References
65
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 2 · 2021: 4
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health
  • Lundbeck Foundation (R249-2017-1484)
  • Novo Nordic Foundation (NNF19OC0056973)
  • Aase and Ejnar Danielsen’s Fund
  • Medical Research Council (MR/N022556/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
adrenal steroidogenesis, congenital adrenal hyperplasia, ACTH, ketoconazole, androgen secretion, glucocorticoids, apoptosis, disorders of sex development, mineralocorticoids
MeSH terms
Adrenal Glands, Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Androgens, Cell Survival, Culture Media, Drug Evaluation, Preclinical, Female, Fetus, Glucocorticoids, Humans, Ketoconazole, Models, Biological, Pregnancy, Steroids, Metabolic Networks and Pathways, Primary Cell Culture

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