Role of macrophages in ovarian follicular development.

The effects of macrophages on granulosa cell proliferation were examined using gonadotropin-primed immature female rats and osteopetrotic (op/op) mice, a model defective in monocyte-macrophage lineage cells. Macrophages were found in the follicles at various developmental stages in rats and mice. The labeling index with [3H]thymidine of cultured rat granulosa cells was maximal when they were cultured with peritoneal macrophages at a macrophages:granulosa cell ratio of 0.01. This ratio was similar to those in rat preantral and antral follicles in vivo. In op/op mice, the number of developing follicles was markedly reduced, but increased after daily macrophage-colony-stimulating factor (M-CSF) administration. In the antral follicles of op/op mice, both granulosa cells and macrophages were significantly decreased in number but were increased after M-CSF treatment. Double immunohistochemical staining revealed that epidermal growth factor (EGF)-positive cells were macrophages in the developing rat follicles. These findings suggest that macrophages are located in the developing follicles and participate in promoting granulosa cell growth through a paracrine mechanism by secreting EGF and other cytokines.