Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene

Abstract

It is well established that spermatogenesis is controlled by gonadotrophins and testosterone. However, a role for estrogens in male reproduction recently was suggested in adult mice deficient in estrogen receptor ␣. . Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell development is unknown. We have investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene (ArKO). Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotrophins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells. In addition, Leydig cell hyperplasia͞hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. Our findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development and thus fertility.

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…Many studies have underlined the importance of estrogens in male fertility [5,[32][33][34], as demonstrated by the expression of ERs and aromatase in the testis and by the fact that mice lacking either ERa [5] or aromatase [6] show altered spermatogenesis and infertility. However, evidence for a direct action of E 2 on the seminiferous epithelium is still missing, and remarkably genes that are regulated by E 2 through classical ERE sequences remain unknown in the testis.…”

“…Growing interest in the effects of E 2 in male reproduction is linked to the observation that ERs knockout [5] or disruption of E 2 synthesis [6] impair male fertility. Although some putative direct target genes of E 2 have been found in the testis [7][8][9], up to now the identification of a testicular cell-specific ER responsive promoter has not been reported.…”

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…In knockout models, removing the ERα (αERKO) or the aromatase genes (ArKO) showed deficiency in the process of spermatogenesis and subsequently, reduced epididymal sperm count, sperm motility and fertilizing ability [99]. Recently, the genetic screening of the ERα gene locus has revealed the existence of several polymorphic sites including the PvuII (T397C) and XbaI restriction fragment length polymorphisms (RFLPs) in intron I and the (TA)n variable number of tandem repeats (VNTR) within the promoter region of the gene [21].…”

Circulating estradiol in men is inversely related to urinary metabolites of nonpersistent insecticides

“…Estradiol has recently been reported to play an important role in male reproductive health. Studies of estrogen receptor α (ERα) knockout and aromatase knockout mice first suggested an indirect role of estrogens in male fertility (3)(4)(5). Male ERα knockout mice were infertile, with post-pubertal degeneration of the testes and disrupted spermatogenesis (3,4).…”

“…Male ERα knockout mice were infertile, with post-pubertal degeneration of the testes and disrupted spermatogenesis (3,4). Estradiol is produced in the testes from aromatized testosterone, and progressive disruption of spermatogenesis and infertility was also observed among aromatase knockout mice (5). A direct role of estradiol as a germ cell survival factor was then demonstrated in the human testis in vitro, where estradiol was shown to inhibit testicular apoptosis much more effectively than testosterone (2).…”