Mice lacking estrogen receptors α and β were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of αβ estrogen receptor knockout (αβERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult αβERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, andSox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.

Male mice with a knockout of the estrogen receptor (ER)-α gene, a ligand-activated transcription factor, showed reduced levels of intromissions and no ejaculations whereas simple mounting behavior was not affected. In contrast, all components of sexual behaviors were intact in male mice lacking the novel ER-β gene. Here we measure the extent of phenotype in mice that lack both ER-α and ER-β genes (αβERKO). αβERKO male mice did not show any components of sexual behaviors, including simple mounting behavior. Nor did they show ultrasonic vocalizations during behavioral tests with receptive female mice. On the other hand, reduced aggressive behaviors of αβERKO mice mimicked those of single knockout mice of ER-α gene (αERKO). They showed reduced levels of lunge and bite aggression, but rarely showed offensive attacks. Thus, either one of the ERs is sufficient for the expression of simple mounting in male mice, indicating a redundancy in function. Offensive attacks, on the other hand, depend specifically on the ER-α gene. Different patterns of natural behaviors require different patterns of functions by ER genes.

▪ Abstract Tremendous progress has been made in elucidating numerous critical aspects of estrogen signaling. New tools and techniques have enabled detailed molecular analysis of components that direct estrogen responses. At the other end of the spectrum, generation of a multiplicity of transgenic animals has allowed analysis of the physiological roles of the estrogen-signaling components in biologically relevant models. Here, we review the ever-increasing body of knowledge in the field of estrogen biology, especially as applied to the female reproductive processes.

ERα action in skeletal muscle is involved in the preservation of mitochondrial health and insulin sensitivity in female mice and can serve as a defense against metabolic disease in women.

In the uterus insulin-like growth factor-1 (IGF-1) signaling can be initiated by estradiol acting through its nuclear receptor (estrogen receptor (ER)) to stimulate the local synthesis of IGF-1. Conversely, in vitro studies have demonstrated that estradiol-independent ER transcriptional activity can be induced by IGF-1 signaling, providing evidence for a cross-talk mechanism between IGF-1 and ER. To investigate whether ERα is required for uterine responses to IGF-1 in vivo, both wild-type (WT) and ERα knockout (αERKO) mice were administered IGF-1, and various uterine responses to IGF-1 were compared. In both WT and αERKO mice, IGF-1 treatment resulted in phosphorylation of uterine IGF-1 receptor (IGF-1R) and formation of an IGF-1R/insulin receptor substrate-1/ phosphatidylinositol 3-kinase signaling complex. In addition, IGF-1 stimulated phosphorylation of uterine Akt and MAPK in both WT and αERKO mice. However, IGF-1 treatment stimulated BrdUrd incorporation and proliferating cell nuclear antigen expression in WT uteri only. To determine whether ERα can be activated in vivo by IGF-1 signaling, transgenic mice carrying a luciferase gene driven by two estrogen response elements (ERE-luciferase mice) were utilized. Treatment of ovariectomized ERE-luciferase mice with IGF-1 resulted in an increase in uterine luciferase activity that was attenuated in the presence of the ER antagonist ICI 182,780. Together these data demonstrate that 1) functional signaling proximal to IGF-1R is maintained in the αERKO mouse uterus, 2) ERα is necessary for IGF-1 induction of uterine nuclear proliferative responses, and 3) cross-talk between IGF-1R and ER signaling pathways exists in vivo.