Gonadotropin-positive pituitary tumors accompanied by ovarian tumors in aging female ERβ−/− mice

At 2 years of age, 100% (23/23) of ERβ−/− female mice have developed large pituitary and ovarian tumors. The pituitary tumors are gonadotropin-positive and the ovarian tumors are sex cord (less differentiated) and granulosa cell tumors (differentiated and estrogen secreting). No male mice had pituitary tumors and no pituitary or ovarian tumors developed in ERα−/− mice or in ERαβ−/− double knockout mice. The tumors have high proliferation indices, are ERα-positive, ERβ-negative, and express high levels of nuclear phospho-SMAD3. Mice with granulosa cell tumors also had hyperproliferative endometria. The cause of the pituitary tumors appeared to be excessive secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus resulting from high expression of NPY. The ovarian phenotype is similar to that seen in mice where inhibin is ablated. The data indicate that ERβ plays an important role in regulating GnRH secretion. We suggest that in the absence of ERβ, the proliferative action of FSH/SMAD3 is unopposed and the high proliferation leads to the development of ovarian tumors. The absence of tumors in the ERαβ−/− mice suggests that tumor development requires the presence of ERα.