Ovarian Pathology and High Incidence of Sex Cord Tumors in Follitropin Receptor Knockout (FORKO) Mice

Abstract

In this investigation we describe our observations of the status of the aging ovary in mice with disruption of the receptor for FSH. Knockout mice at 3–5 months of age are acyclic and sterile, with very small, underdeveloped ovaries. Thus, they exhibit hypergonadotropic-hypogonadism with high levels of circulating FSH similar to the postmenopausal state in women. By 12 months more than 92% of these animals developed various kinds of ovarian pathology, including neoplasms of sex cord-stromal type as well as cysts. Interestingly, the majority of tumors were located in the right ovary, with the contralateral ovary remaining unaffected but atrophic. The ovary from heterozygotes also showed pathology after 15 months. None of the age-matched wild-type mice that remained fertile developed any sign of ovarian tumors. Circulating LH and FSH levels were increased in follitropin receptor knockout mice and remained severalfold higher in tumor-bearing animals. The histological appearances of ovarian tumors were similar to the pathology observed in some types of sex cord-stromal neoplasms in women. The tumor burden caused weight loss and cachexia in follitropin receptor knockout mice. Based on these characteristics as well as the high incidence of ovarian pathology in the aging mutant, we propose that the loss of the FSH receptor signaling mechanisms predispose the ovary to molecular and structural changes leading to tumor formation. Hence, in the intact and fertile animal, FSH receptor signaling offers a protective mechanism that is lost upon reproductive senescence (menopause in women). Further studies are warranted in this genetic model to explore the molecular changes underlying the development of ovarian neoplasia.