Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo

Siiteri, Pentti K.; Wilson, Jean D.

doi:10.1210/jcem-38-1-113

Cited by 536 publications

(205 citation statements)

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“…The initiation of prostatic development is dependent upon androgens produced by the fetal testes (9) and studies with 5α reductase inhibitors have shown that dihydrotestosterone (DHT) is the active androgen required for prostate formation (13). Normal development, differentiation and onset of secretory activity requires the presence of androgens throughout the developmental process (14).…”

Section: Prostate Gland Developmentmentioning

confidence: 99%

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

Prins

Birch

Tang

et al. 2007

Reproductive Toxicology

206

162

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Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period -from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures -results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.

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Section: Prostate Gland Developmentmentioning

confidence: 99%

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

Prins

Birch

Tang

et al. 2007

Reproductive Toxicology

206

162

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“…These two ducts are related to the endodermal urogenital sinus (UGS) and to the external genitalia (Jirásek 1967). The MD in the male give rise to the epididymis, the ductus deferens, seminal vesicles and the ejaculatory ducts (Siiteri & Wilson 1974, Sadler 1995. In females, the PMD give rise to the Fallopian tubes, the uterus, the cervix and the upper part of the vagina.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical localization of androgen receptors in the urogenital tracts of human embryos

Sajjad¹,

Quenby²,

Nickson³

et al. 2004

Reproduction

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The aim of this study was to investigate androgen receptor (AR) expression in the developing human urogenital tract. The distribution of AR was examined in paraffin-embedded tissue sections of the lower urogenital tract using 55 human embryos of 8-12 weeks of gestation. Immunohistochemistry was performed for AR detection and gender was determined by polymerized chain reaction. There were no differences in the distribution of AR in male and female embryos at any stage of gestation. AR was present only in the mesenchymal tissues of the urogenital sinus at 8 weeks whilst the epithelium was negative, but after 9 weeks the epithelium also showed progressively more positive staining. In the phallus, AR staining was prominent. There was far less staining in the epithelium of the urethral groove from 8 to 10 weeks, whilst the mesenchyme of the urethral folds showed positive staining. At 11 and 12 weeks, both the urethral groove and folds showed uniform staining. The genital tubercle, genital swelling and bulbourethral gland precusors were also positively stained, although paramesonephric ducts were negative. Staining was observed in the mesonephric duct from 9 weeks. There was an absence of staining in the rectum at all stages of gestation. The expression of AR in an epithelium may be dependent upon the mesenchyme. Mesenchymal-epithelial interactions played an important role in development, as has been described in experimental animals. AR expression could play a part in the growth of the genital organs.

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“…Anti-androgen treatment consisted of finasteride (0.6 mg kg Ϫ1 daily) and flutamide (23-24 mg kg Ϫ1 daily), delivered from as early as day 21 of a 110-day gestation. The former compound, a 5α-reductase inhibitor, prevents conversion of testosterone to dihydrotestosterone, which is traditionally assumed to be the critical androgen involved in formation of male genitalia (Siiteri & Wilson 1974;Wilson et al 1981). The latter compound, an anti-androgen, blocks the actions of all active androgens at the receptor level.…”

Section: Introductionmentioning

confidence: 99%

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating

Drea¹,

Place²,

Weldele³

et al. 2002

Proc. R. Soc. Lond. B

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Among all extant mammals, only the female spotted hyena (Crocuta crocuta) mates and gives birth through the tip of a peniform clitoris. Clitoral morphology is modulated by foetal exposure to endogenous, maternal androgens. First births through this organ are prolonged and remarkably difficult, often causing death in neonates. Additionally, mating poses a mechanical challenge for males, as they must reach an anterior position on the female's abdomen and then achieve entry at the site of the retracted clitoris. Here, we report that interfering with the actions of androgens prenatally permanently modifies hyena urogenital anatomy, facilitating subsequent parturition in nulliparous females who, thereby, produce live cubs. By contrast, comparable, permanent anatomical changes in males probably preclude reproduction, as exposure to prenatal anti-androgens produces a penis that is too short and has the wrong shape necessary for insertion during copulation. These data demonstrate that the reproductive costs of clitoral delivery result from exposure of the female foetus to naturally circulating androgens. Moreover, the same androgens that render an extremely unusual and laborious process even more reproductively costly in the female are apparently essential to the male's physical ability to reproduce with a normally masculinized female.

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Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo

Cited by 536 publications

References 0 publications

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

Immunohistochemical localization of androgen receptors in the urogenital tracts of human embryos

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating

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