Age-specific changes in sex steroid biosynthesis and sex development
Abstract
Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.
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Fetal testicular T is essential for the development of the male internal genitalia, while the local conversion of testicular T to DHT is essential for the development of external genitalia taking place between 8 and 12 weeks of gestation.
“Fetal testicular T is essential for the development of the male internal genitalia, while the local conversion of testicular T to DHT is essential for the development of external genitalia taking place between 8 and 12 weeks of gestation (Krone et al., 2007, Sobel et al., 2004).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Krone et al., 2007
Androgen intracrinology plays a crucial role for the physiology of peripheral tissues in both sexes.
“Besides its essential function for normal male sexual development (Auchus and Miller, 2012, Krone et al., 2007), androgen intracrinology plays a crucial role for physiology of peripheral tissues in both sexes.”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Krone et al., 2007
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- Authors
- Krone, N., Hanley, N. A., & Arlt, W.
- Affiliations
- University of Birmingham (GB)
- University of Southampton (GB)
- Corresponding author
- Arlt, Wiebke
- Venue
- Best Practice & Research Clinical Endocrinology & Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 21
- Issue
- 3
- Pages
- 393-401
- ISSN
- 1521-690X (ISSN-L)
- OpenAlex
- W1992571492
- Cited by
- 36
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 1 · 2012: 2
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Best Practice & Research Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- 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 › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- sex steroid biosynthesis, sexual development, sexual differentiation, congenital adrenal hyperplasia, 21-hydroxylase deficiency, P450 oxidoreductase deficiency, 46,XX disorders of sex development, ACTH receptor, anti-Müllerian hormone, SRY gene, 5α-reductase, dihydrotestosterone, Leydig cells, masculinization
- MeSH terms
- Adrenal Hyperplasia, Congenital, Aging, Animals, Female, Humans, Hypothalamo-Hypophyseal System, Male, NADPH-Ferrihemoprotein Reductase, Pituitary-Adrenal System, Gonadal Steroid Hormones, Steroid 21-Hydroxylase, Gonadal Dysgenesis, 46,XX, Feedback, Physiological, Sexual Development
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