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 3βHSD2 and synthesis of cortisol wane; 3βHSD2 is barely detectable at 10-11 wk and is absent at 14 wk.
“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]
The Results report that HSD3B immunoreactivity, identified as HSD3B2, was abundant at 8–9 weeks, declined thereafter, and was undetectable at 14 weeks. They also report lower cortisol content and secretion at 10 weeks. The copy does not specifically say that HSD3B2 was barely detectable at 10–11 weeks. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLow 3βHSD 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.
“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]
The Discussion (page unavailable) mentions fetal adrenal DHEA biosynthesis in mid- and late gestation, and the Results (page unavailable) report that HSD3B protein was undetectable at 14 weeks. Our copy does not establish that low 3βHSD together with high 17,20-lyase activity accounts for abundant DHEA and DHEAS production, or state that the placenta converts them to estrogens. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe fetal adrenal transiently produces cortisol during the first trimester, apparently minimizing adrenal synthesis of androgen precursors.
“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]
17βHSD5 may participate in adrenal testosterone production, particularly in virilizing CAHs.
“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]
17βHSD5/AKR1C3 is more highly expressed in the human fetal adrenal during sexual differentiation than 17βHSD3.
“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]
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.
“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]
Human fetal glucocorticoids may be needed to suppress the virilization of female fetuses at about 8-12 wk, but it appears that glucocorticoids are not needed thereafter.
“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]
I172N reduces enzymatic activity to <5% of normal and is associated with the SV form of the disorder (mutation Group B).
“( 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]
The Results (page unavailable) discuss steroidogenic enzyme expression in the developing adrenal gland, while the Discussion (page unavailable) mentions CYP21 deficiency and virilization. Searches for I172N, residual activity below 5%, the simple-virilizing form, and mutation Group B found no passage addressing the claimed variant-specific relationship. (LLM, conf=0.76)
Experimental — accuracy not yet measured5α-reductases are at least sometimes expressed in human adrenal and possibly gonads, but their function(s) in normal physiology or in pathological states is not known.
“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]
The citation is attached to the claim that 5α-reductases are expressed in the human adrenal. The Results and Discussion passages describe adrenal androgen production and HSD17B enzymes, but do not address adrenal 5α-reductase expression; searches for 5α-reductase and its proposed function found no decisive passage in our copy. No page numbers were provided for these passages. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIn normal untreated pregnancies, fetal cortisol levels are low in very early gestation and rise during weeks 8 to 12 while external genitalia differentiate; fetal cortisol is about 10% of maternal levels during midgestation and increases in the third trimester.
“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]
HSD3B2 activity is likely to be relatively low compared with CYP17A1 in both adrenal and testis, based on transcript levels.
“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]
ACTH stimulated the secretion of all measured metabolites in ex vivo cultured human fetal adrenal tissue.
“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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- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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