Ovarian wedge resection restores fertility in estrogen receptor β knockout (ERβ^-/-) mice

Ovulation rarely occurs in mice in which the estrogen receptor β (ERβ) gene has been inactivated (ERβ^-/- mice). Here, we investigated whether this subfertility is due to a defect in the ovary itself or to more general endocrine changes in ERβ^-/- mice. We transplanted ERβ^-/- ovaries into WT mice and WT ovaries into ERβ^-/- mice. Upon mating with ERβ^-/- males, fertility increased from 20% in control intact ERβ^-/- group to 40% in the WT recipients with ERβ^-/- ovaries. The transplantation procedure was not efficient, and when WT ovaries were transplanted into WT mice, fertility was only 36%. Surgical ovarian wedge resection, a procedure which induces ovulation in anovulatory women with polycystic ovarian syndrome, resulted in 100% fertility of ERβ ^-/- mice. In ERβ^-/- mice, as the follicles enlarged, the thecal layer remained very compact (revealed by H&E and collagen staining), and there was no increase in vascularization (measured as smooth muscle actin). In addition, there was an increase in PDGF receptor α (PDGFRα) and a decrease in PDGFβ expression in the granulosa cells, similar to what has been found in follitropin receptor knockout mice. After wedge resection, expression of both smooth muscle actin and PDGFRs was normalized. During normal follicular development, increased vascularization of the thecal layer is a prerequisite for further follicular growth. We suggest that the defect in ERβ^-/- mouse ovaries is a failure of communication between the granulosa and thecal layers. The follicles do not mature because of insufficient blood supply. This problem is overcome by stimulating neovascularization by simple wedge resection of the ovaries.