A previously uncharacterized role for estrogen receptor β: Defeminization of male brain and behavior

Abstract

Sex differences in brain and behavior are ubiquitous in sexually reproducing species. One cause of sexual dimorphisms is developmental differences in circulating concentrations of gonadal steroids. Neonatal testes produce androgens; thus, males are exposed to both testosterone and estradiol, whereas females are not exposed to high concentrations of either hormone until puberty. Classically, the development of neural sex differences is initiated by estradiol, which activates two processes in male neonates; masculinization, the development of male-type behaviors, and defeminization, the loss of the ability to display female-type behaviors. Here, we test the hypothesis that defeminization is regulated by estrogen receptor ␤ (ER␤). Adult male ER␤ knockout and WT mice were gonadectomized, treated with female priming hormones, and tested for receptive behavior. Indicative of incomplete defeminization, male ER␤ knockout mice showed significantly higher levels of female receptivity as compared with WT littermates. Testes-intact males did not differ in any aspects of their male sexual behavior, regardless of genotype. In olfactory preference tests, males of both genotypes showed equivalent preferences for female-soiled bedding. Based on these results, we hypothesize that ER␤ is involved in defeminization of brain and behavior. This aspect of ER␤ function may lead to developments in our understanding of neural-based sexually dimorphic human behaviors.developmental neurobiology ͉ neuroendocrinology ͉ sexual differentiation M ales undergo two processes during development that affect their adult behavior. Masculinization refers to the underlying neural circuitry and behavioral patterns that are exhibited to a greater degree by males than females. For example, males of many species display a set of sex specific courtship and copulatory behaviors. In addition, a separate process, defeminization, reduces the likelihood that males will display female-typical behaviors in adulthood, such as display of the receptive mating posture, lordosis. Many sexual dimorphisms in brain and behavior are caused by developmental sex differences in steroid hormones that act on nuclear receptors (1). Specifically, neonatal testes produce testosterone for a finite period beginning at the end of gestation until shortly after birth (2). Testosterone is aromatized neurally to estradiol (E2) and binds to two known estrogen receptors (ER␣ and ER␤) (3). Depriving males of their testes, or steroids produced by the testes, during this developmental period results in demasculinization and feminization (4 -6).The mechanism by which estradiol affects both masculinization and defeminization is unknown. Here, we test the hypothesis that these processes are regulated by different ERs. We hypothesize that ER␤ has a specialized function in the development of a sexually differentiated behavior and is essential for defeminization. This hypothesis is supported by the report of sex differences in ER␤ in neonatal mice; during late gestation and the first 2 weeks after ...

Sex differences and effects of neonatal aromatase inhibition on masculine and feminine copulatory potentials in prairie voles

“…Furthermore, neonatal activation of ERs, specifically ER β , has been shown to be responsible for defeminization in mice (Kudwa et al, 2005). However, our negative results and those of Peterson (1986) indicate that neonatal aromatization may not be necessary for defeminization of sexual behaviors in any Microtus species.…”

“…Indeed, treating male rats or mice with ovarian hormones rarely results in high levels of feminine sexual behaviors (Dominguez-Salazar et al, 2002;Edwards and Burge, 1971;Kudwa et al, 2005;Parsons et al, 1984;Whalen et al, 1986;Whalen and Olsen, 1981). Furthermore, although female rats treated with testosterone may mount other females, the frequency is often low compared to males, and intromissive and ejaculatory behaviors are rarely displayed in either rats or mice given testosterone Dominguez-Salazar et al, 2002;Edwards and Burge, 1971;Gladue and Clemens, 1980;Levine and Mullins, 1964;Whalen and Olsen, 1981).…”

The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior

“…Evidence suggests that the masculinization and defeminization processes, although complementary, are mediated by independent hormonal and neural mechanisms (Kudwa et al, 2005;Todd et al, 2005). It is unknown whether the female-like sexual differentiation of brain and behavior observed in GPR54 KO males represents a complete sex reversal of sexually dimorphic phenotypes (impaired masculinization and defeminization) or only a partial effect (impaired masculinization but not defeminization, or vice versa).…”

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females

“…Contrasting with an apparent minor role in sexual behavior, ERβ appeared to be a major determinant of antianxiety behaviors in female mice (11,12), and, in a transient manner, of aggressive behaviors in male mice (13). ERβ was also reported to be involved in male mouse brain defeminization (14).…”