Expression of Functional Estrogen Receptors in Human Fetal Male External Genitalia

Abstract

It is generally assumed that male genital development is determined by androgens on a default program leading to female genitalia. Female genitalia virilization is due to high levels of androgens, whereas feminization is linked to reduction or lack of fetal androgen. Excess androgen determines sex reversion in female, whereas excess estrogen does not cause male feminization. In the present study, we investigate the presence of androgen receptors (AR) and estrogen receptors (ER) in human fetal penile tissue and in a cellular model of human fetal penile smooth muscle cells (hfPSMC). By immunohistochemistry, we showed the presence of ER and AR in the developing penile tissue of male fetuses. Besides the presence of AR, hfPSMC showed ERalpha/beta as demonstrated by RT-PCR, Western blot, and binding techniques. These receptors are functionally active because cell stimulation with 17beta-estradiol increased progesterone receptor B expression and inhibited hfPSMC growth, both effects being reversed by tamoxifen. Conversely, cell proliferation was stimulated by R1881 and testosterone, an effect enhanced by letrozole. These findings are the first demonstration of the presence of functional ER in differentiating male external genitalia and indicate a possible novel inhibitory role of estrogens in the regulation of the development of these sex structures.

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

“…On the other hand, the importance of estrogens in male reproductive tract development has been increasingly acknowledged. Functional Estrogen Receptors (ESR)s were detected in differentiating male external genitalia localized at the same structures as the androgen receptors, indicating interactions between effects exerted by the two steroid hormones (7,8); and an excess of estrogens in the developing murine urethra results in an inhibition of the cell proliferation in a dose-dependent manner (9). Moreover, hypospadias has been induced in a mice model by maternal exposure to synthetic estrogens during pregnancy (10).…”

Expression of Estrogen and Androgen Receptors in Children with Hypospadias: Preliminary Report

“…We also found that estrogen and androgen receptors did not have a special side of expression among the prepuce, glans and, urethral plate. Estrogen and androgen receptors are present in developing human fetal penile tissue and both are localized in the same structures of male external genitalia [1,2,4,7,9]. There is also a hormonal balance between androgen and estrogen which exists during the formation of the genital tubercle [1,4,8].…”

“…Estrogen and androgen receptors are present in developing human fetal penile tissue and both are localized in the same structures of male external genitalia [1,2,4,7,9]. There is also a hormonal balance between androgen and estrogen which exists during the formation of the genital tubercle [1,4,8]. Therefore, dominant expression of estrogen receptors (42%) when compared to androgen receptors (21%) in penile tissues of children with hypospadias may be the postnatal finding of disrupted estrogen and androgen receptor interaction during the intrauterine development of external genitalia.…”

“…They play an important role during urethral formation of the penile shaft [4,8]. There was expression of estrogen and androgen receptors in the male external genitalia and in developing human fetal penile tissue [1,2,4,7,9]. A higher incidences of hypospadias in the last decade and the demonstration of increased risk of hypospadias in the sons of women exposed to diethylstilbestrol raised questions of the effects of estrogen in the etiology of this defect [5,6].…”

Fine mapping analysis confirms and strengthens linkage of four chromosomal regions in familial hypospadias

“…[20][21][22][23] The finding of estrogen receptors in the male reproductive tract during development raises the possibility that estrogens may also influence the risk for hypospadias. 24 Currently, four hypospadias genes have been identified, namely the Mastermind-like Domain-containing 1 gene (MAMLD1/CXorf6), the Activating Transcription Factor 3 (ATF3) gene, the Diacylglycerol kinase kappa (DGKK) gene and most recently the basonuclin 2 (BNC2) gene. [25][26][27][28] In our search for hypospadias candidate genes, we previously performed a genome-wide linkage scan in 69 families with at least two affected family members.…”