Aromatase is abundantly expressed by neonatal rat penis but downregulated in adulthood

Abstract

Although synthesis of estrogen by male gonads has been well documented for over half a century, it is only recently that the role of estrogen in male reproductive events has gained appreciation. We recently reported abundant expression of estrogen receptor (ER)-and -in different cell types of the rat penis, whose levels diminished with advancing age. The present study, which builds on data from the ER study, was designed to determine whether the penis is capable of generating its own local estrogen by examining evidence of the expression of aromatase, a microsomal enzymatic complex which irreversibly converts androgens to estrogens, using immunohistochemistry, Western blotting, in situ hybridization and real-time PCR analyses. Secondly, the effects of sex steroid hormones on penile aromatase were examined. Discrete aromatase immunoreactive cells were localized in primordial corpus cavernosum, corpus spongiosus and os penis, blood vessels and sensory corpuscle of glans penis. In situ hybridization signals corresponded with immunohistochemical findings. Western blot, enzyme immunoassay and real-time PCR analyses of rat penile samples revealed an age-dependent expression of aromatase and estrogen, with levels at week 1 almost resembling those of the ovary, but they decreased sharply by week 8, and decreased further by week 35. This expression pattern was strikingly similar to that of ERreported previously. Testosterone and diethylstilbesterol administered prenatally upregulate levels of aromatase mRNA and protein, and estrogen postnatally. Dihydrotestosterone upregulated aromatase mRNA and protein, but not estrogen. We conclude that estrogen acts via ER in a paracrine and/or autocrine manner to regulate penile events, particularly during development, and that estrogen synthesis is regulated by estrogen and androgens.

Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

“…Similarly, reports of fertility in ERbKO (Couse & Korach 1999) and aromatase knockout (Fisher et al 1998) male mice indicate that neither ERb nor estrogen is essential in normal penile development. This is despite the fact that ERa and ERb (Jesmin et al 2002), as well as aromatase enzyme (Jesmin et al 2004, Mowa et al 2006, are present in the neonatal rat penis. Hence, based on the available data, it appears that neither ERa nor ERb nor estrogen has a significant role in normal development of the penis.…”

“…Unlike the case with androgens, the role of estrogen in development of male reproductive organs, especially in the penis, remains largely unknown; although both estrogen receptors (ERs) and/or aromatase enzyme have been localized in the developing penis of a number of species, including humans (Crescioli et al 2003, Schultheiss et al 2003, Dietrich et al 2004) and rodents (Jesmin et al 2002(Jesmin et al , 2004, and rabbits (Srilatha & Adaikan 2004). Additionally, epidemiological studies have suggested links between inappropriate estrogen exposure and higher frequency of reproductive abnormalities in men and wild animals (Toppari et al 1996, McLachlan et al 2001, Safe et al 2001, Mosconi et al 2002, Fisher 2004, Vidaeff & Sever 2005, Storgaard et al 2006.…”

Current understanding of hypospadias: relevance of animal models

“…9,23,38,52,58,59 Likewise, oestrogen induction of hypospadias is reinforced by the presence of oestrogen receptors α and β and aromatase in the developing rodent and human penises. 10,23,28,38,[60][61][62][63][64] Human studies the case of 'Des sons' is particularly interesting. in a cohort study of 205 male infants exposed in utero to Des compared to 8,934 infants without Des exposure, the incidence of hypospadias was increased ~20-fold (prevalence ratio 21.3; 95% Ci 6.5-70.1) in infants with in utero exposure to Des, although the absolute incidence of Nature Reviews | Urology …”

“…9 this latter finding emphasizes the risks associated with exposure to 'antiandrogenic' agents. studies from the past 10 years [63][64][65][66][67][68][69] have better defined the genes associated with hypospadias. a genome-wide association study of pooled Dna samples from 436 indivi duals with hypospadias and 494 without revealed a strong association between two common variants of diacylglycerol kinase κ (DGKK; rs1934179 and rs7063116).…”

Role of estrogen in induction of penile dysmorphogenesis: a review

“…However, unlike androgens, the role of estrogen in development of male reproductive organs, especially in the penis, remains largely unknown; although both estrogen receptors (ERs) and/or aromatase enzyme have been identified in the developing penis of a number of species, including humans (Crescioli et al 2003, Schultheiss et al 2003, Dietrich et al 2004, rodents (Jesmin et al 2002(Jesmin et al , 2004, and rabbits (Srilatha & Adaikan 2004). Epidemiological studies have shown links between inappropriate estrogen exposure and higher frequency of reproductive abnormalities in men and wild animals (Toppari et al 1996, McLachlan et al 2001, Safe et al 2001, Mosconi et al 2002, Fisher 2004, Vidaeff & Sever 2005, Storgaard et al 2006.…”