N. Danilovich et al., Ovarian pathology and high incidence of sex cord tumors in follitropin receptor knockout (FORKO) mice, ENDOCRINOL, 142(8), 2001, pp. 3673-3684
In this investigation we describe our observations of the status of the agi
ng 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 mon
ths more than 92% of these animals developed various kinds of ovarian patho
logy, including neoplasms of sex cord-stromal type as well as cysts. Intere
stingly, the majority of tumors were located in the right ovary, with the c
ontralateral ovary remaining unaffected but atrophic. The ovary from hetero
zygotes also showed pathology after 15 months. None of the age-matched wild
-type mice that remained fertile developed any sign of ovarian tumors. Circ
ulating LH and FSH levels were increased in follitropin receptor knockout m
ice and remained severalfold higher in tumor-bearing animals. The histologi
cal 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 t
hese characteristics as well as the high incidence of ovarian pathology in
the aging mutant, we propose that the loss of the FSH receptor signaling me
chanisms predispose the ovary to molecular and structural changes leading t
o tumor formation. Hence, in the intact and fertile animal, FSH receptor si
gnaling offers a protective mechanism that is lost upon reproductive senesc
ence (menopause in women). Further studies are warranted in this genetic mo
del to explore the molecular changes underlying the development of ovarian
neoplasia.