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. Normally, the two ERs are expressed in differing levels in different tissues and selective cell types. Gene targeting allowed us to produce lines of mice with disrupted ER (ERKO) and ER genes (ERKO) as well as a compound ERKO. Unlike androgen receptor insensitivity in males, no developmental phenotypes were evident in ERKO mice indicating that ER signaling was not needed to develop the female reproductive tract. Generation of this mouse model provided evidence for identification of a patient with ER loss of function mutation. Male and female ERKO mice are infertile. Comparable levels of ER- mRNA in tissues of ERKO mice suggesting that ER- expression is not dependent on ER. Estrogen or growth factor treatments failed to induce uterine growth and DNA synthesis in ERKO uteri. ERKO females are infertile and have hypoplastic uteri and hyperemic ovaries and no corpora lutea due to persistent LH stimulation from loss of negative feedback. ERKO females show arrested folliculogenesis and subfertility. Ovarian analyses indicate differential gene expression related to ovulatory stimulation deficits including lack of LH, PR, Cyp19 and Cox2 expression. A unique ovarian phenotype is found only in ERKO females showing a transdifferentiation of granulosa cells to sertoli cells. Mammary glands of adult ERKO females showed a primitive ductal rudiment rather than the fully developed ductal tree seen in WT or ERKO mice. ERKO males are infertile, with testicular atrophy and seminiferous tubule dysmorphogenesisproducing decreased spermatogenesis and inactive sperm. Sperm transplantation of ERKO males rescues the infertility indicating the loss of ER is not necessary in the sperm but the somatic cells.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.