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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism
Open accessAbstract
Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.
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“Originating from the embryonic yolk sac, microglia migrate and colonize the brain during early development, around embryonic day (E)9.5 in mice.”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [31]
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“This precedes a hormonal surge in the brain, with androgens and estrogens peaking at around E17.5–18 [29–34].”
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“Normal masculinization of the fetus is dependent upon androgen secretion by the testis, and androgens act initially during a critical masculinization programming window to ensure normal male reproductive development [3–5].”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [5]
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Metadata
- Authors
- Welsh, M., Saunders, P. T. K., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., & Sharpe, R. M.
- Affiliations
- The Queen's Medical Research Institute (GB)
- Corresponding author
- Welsh, Michelle
- Venue
- Journal of Clinical Investigation
- Published
- 2008-04-01
- Volume
- 118
- Issue
- 4
- Pages
- 1479-1490
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2267017
- OpenAlex
- W2003163696
- Cited by
- 781
- References
- 61
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 27 · 2023: 54 · 2022: 58 · 2021: 43 · 2020: 54 · 2019: 47 · 2018: 49 · 2017: 38 · 2016: 45 · 2015: 48 · 2014: 45 · 2013: 42 · 2012: 39
- FWCI
- 17.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Napier Research Repository (Edinburgh Napier University) (submittedVersion, cc-by-nc)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Urology › Urological Disorders and Treatments
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- fetal programming, hypospadias, cryptorchidism, testicular dysgenesis, androgen action, androgen receptor antagonists, androgens, anogenital distance, penile length, fetal development, pregnancy timing
- MeSH terms
- Androgens, Animals, Cryptorchidism, Embryo, Mammalian, Female, Gonads, Hypospadias, Male, Receptors, Androgen, Sex Characteristics, Sex Differentiation, Testosterone, Rats, Wistar, Rats
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