Endocrine Abstracts

Estrogen receptors (ER) play a crucial role in development, reproduction and normal physiology. Even though the concept of ER gene mutations was thought to be lethal. Gene targeting allowed us to produce lines of mice with disrupted ER-alpha (alpha-ERKO) and ER-beta genes (beta-ERKO) as well as a compound alpha/beta-ERKO. Comparable levels of ER-beta mRNA in tissues of alpha-ERKO mice suggesting that ER-beta expression is not dependent on ER-alpha. Estrogen, EGF or IGF-1 treatments failed to induce DNA synthesis in alpha-ERKO uteri, even though EGF and IGF-1 signaling was intact by stimulation of c-fos, or IRS-1 protein phosphorylation. Progesterone receptor mRNA was detected in alpha-ERKO mice, but not stimulated by estrogen indicating an estrogen dependent and independent gene regulation. alpha-ERKO females are infertile and have hypoplastic uteri and hyperemic ovaries and no corpora lutea. beta-ERKO females show arrested folliculogenesis and subfertility. Ovarian analyses indicate differential gene expression related to ovulatory stimulation. Mammary glands of adult alpha-ERKO females showed a primitive ductal rudiment rather than the fully developed ductal tree seen in WT or beta-ERKO mice. alpha-ERKO males are infertile, with testicular atrophy and seminiferous tubule dysmorphogenesis producing decreased spermatogenesis and inactive sperm. Sperm transplantation of alpha-ERKO males rescues the infertility. Males have reduced bone density and alterations in cardiovascular function. These phenotypes are consistent with the only male patient with estrogen insensitivity harboring a mutation in the human ER-alpha gene. Most significant of the clinical findings are decreased skeletal bone density and retarded bone age, as well as cardiovascular phenotypes. Findings from the patient and mice suggest that the absence of estrogen and functional ER is not lethal and results in significant skeletal effects and altered physiological processes, requiring more understanding of the specific roles of the two different forms of ER.