Reply to Flück et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency

Reisch, Nicole; Auchus, Richard J.; Shackleton, Cedric; Arlt, Wiebke

doi:10.1073/pnas.2007695117

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…1), contributing to the prenatal female virilization (69,(78)(79)(80). Second, as placental CYP19 (aromatase) requires POR, pregnant women carrying a fetus with the POR mutation R457H (but not POR A287P) may experience virilization during pregnancy (66-68), similarly to women carrying an aromatase-deficient fetus (81,82). The POR polymorphism A503V, which mildly affects many P450 activities, is found commonly -from 19% among African Americans to 37% of Chinese Americans (83), but does not affect the presentation of 21OHD (84).…”

Section: P450 Oxidoreductasementioning

confidence: 99%

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

et al. 2021

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Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

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Section: P450 Oxidoreductasementioning

confidence: 99%

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

et al. 2021

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“…We also investigated the brain cortex expression of enzymes involved in "classic" and "nonclassic/backdoor" pathways for DHT generation [19][20][21] (Supplementary Figures 11 & 12). Very low expression of SRD5A2 was seen, the enzyme in the classic pathway that generally coverts testosterone to DHT in reproductive tissues (e.g.…”

Section: Sex Hormone Effects On Global Early Human Brain Developmentmentioning

confidence: 99%

Sex differences in early human fetal brain development

Buonocore,

Suntharalingham,

Ogunbiyi

et al. 2024

Preprint

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The influence of sex chromosomes and sex hormones on early human brain development is poorly understood. We therefore undertook transcriptomic analysis of 46,XY and 46,XX human brain cortex samples (n=64) at four different time points between 7.5 and 17 weeks post conception (wpc), in two independent studies. This developmental period encompasses the onset of testicular testosterone secretion in the 46,XY fetus (8wpc). Differences in sex chromosome gene expression included X-inactivation genes (XIST,TSIX) in 46,XX samples; core Y chromosome genes (n=18) in 46,XY samples; and two Y chromosome brain specific genes,PCDH11YandRP11-424G14.1.PCDH11Y(protocadherin11 Y-linked)regulates excitatory neurons; this gene is unique to humans and is implicated in language development.RP11-424G14.1is a novel long non-coding RNA. Fewer differences in sex hormone pathway-related genes were seen. The androgen receptor (AR, NR4A2) showed cortex expression in both sexes, which decreased with age. Global cortical sex hormone effects were not seen, but more localized AR mechanisms may be important with time (e.g., hypothalamus). Taken together, our data suggest that limited but potentially important sex differences occur during early human fetal brain development.

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“…In the infant raised as a boy, application of topical DHT may be a method of assessing the potential of the genitalia to virilise over the longer term. With the discovery of the alternative ‘back door’ pathway to DHT synthesis, there is a possibility that defects in the aldoketo reductase pathway may also lead to XY DSD 97 but the clinical significance of this defect in the presence of normal 5α‐reductase remains debatable 98 …”

Section: Xy Dsd With Normal Testosterone Normal Precursors and Low Dhtmentioning

confidence: 99%

Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021)

Ahmed

Achermann

Alderson

et al. 2021

Clinical Endocrinology

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It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.

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Reply to Flück et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency

Cited by 5 publications

References 12 publications

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

Sex differences in early human fetal brain development

Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021)

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