The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index.
In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development
Open accessAbstract
In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3beta-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.
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“Following the ninth week after conception, expression of 3HSD2 and synthesis of cortisol wane; 3HSD2 is barely detectable at 10 -11 wk and is absent at 14 wk (334).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Low 3HSD and high 17,20-lyase activity account for the abundant production of DHEA and DHEAS by the fetal adrenal, which are converted to estrogens by the placenta.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The fetal adrenal transiently produces cortisol during the first trimester, apparently minimizing adrenal synthesis of androgen precursors (334).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
The cited source says what the claim attributes to it.
In the citing paper
“Nevertheless, 17HSD5/ AKR1C3 is more highly expressed in the human fetal adrenal during the time of sexual differentiation than 17HSD3 (334) and may participate in adrenal testosterone production, particularly in virilizing CAHs.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
The cited source says what the claim attributes to it.
In the citing paper
“Nevertheless, 17HSD5/ AKR1C3 is more highly expressed in the human fetal adrenal during the time of sexual differentiation than 17HSD3 (334) and may participate in adrenal testosterone production, particularly in virilizing CAHs.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
The cited source says what the claim attributes to it.
In the citing paper
“Steroidogenic enzymes are immunocytochemically detectable in the fetal zone at 50 -52 d after conception, and by 8 wk the adrenal contains cortisol and responds to ACTH in primary culture systems (334).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
The cited source says what the claim attributes to it.
In the citing paper
“Human fetal glucocorticoids may be needed to suppress the virilization of female fetuses at about 8 -12 wk (334), but it appears that glucocorticoids are not needed thereafter (329,637,712,713).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
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In the citing paper
“( I172N)(154) reduces enzymatic activity to <5% of normal and is associated with the SV form of the disorder (mutation Group B)(107,109,221).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [154]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Accumulating evidence suggests that 5␣-reductases are at least sometimes expressed in human adrenal (334) and possibly gonads, but their function(s) in normal physiology or in pathological states is not known.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [334]
Experimental — accuracy not yet measuredIn the citing paper
“In normal, untreated pregnancies, fetal cortisol levels are low in very early gestation and rise during weeks 8 to 12, while the external genitalia are differentiating (100); fetal cortisol is only ;10% of maternal levels during midgestation (101) and then increases during the third trimester.”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [100]
In the citing paper
“In addition, HSD3B2 activity is likely to be relatively low compared with CYP17A1 in both tissues, based on transcript levels (this study and [28–30]).”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [29]
In the citing paper
“ACTH stimulated the secretion of all measured metabolites, which is in accordance with previous studies showing a stimulating effect on both cortisol, DHEAS, androstenedione and testosterone (9,30,31,39).”
From Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis (2021) · cites this paper as [9]
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Citations
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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Metadata
- Authors
- Goto, M.
- Affiliations
- University of Southampton (GB)
- Corresponding author
- Goto, M.
- ORCID
- Goto, M.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-03-23
- Volume
- 116
- Issue
- 4
- Pages
- 953-960
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1421344
- OpenAlex
- W2115432253
- Cited by
- 284
- References
- 43
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 11 · 2023: 17 · 2022: 16 · 2021: 17 · 2020: 15 · 2019: 21 · 2018: 21 · 2017: 14 · 2016: 18 · 2015: 11 · 2014: 13 · 2013: 12 · 2012: 8
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- University of Southampton
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- fetal adrenal cortex, cortisol production, external genitalia development, Nur77, HSD3B2, ACTH, negative feedback, androgen production, androstenedione, testosterone, congenital adrenal hyperplasia, masculinization
- MeSH terms
- Adrenal Cortex, Androgens, DNA-Binding Proteins, Female, Gene Expression Regulation, Gestational Age, Humans, Hydrocortisone, Models, Biological, Pituitary Gland, Anterior, Receptors, Steroid, Sex Differentiation, Transcription Factors, 3-Hydroxysteroid Dehydrogenases, Receptors, Cytoplasmic and Nuclear, Sexual Development, Nuclear Receptor Subfamily 4, Group A, Member 1
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