Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle. This process is initiated by the pituitary surge of luteinizing hormone (LH), is temporally associated with transcriptional regulation of numerous genes, and is presumed to involve the synthesis and͞or activation of specific proteases that degrade the follicle wall. The progesterone receptor (PR), a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, we show that the matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation.
Ovulation is a complex process that is initiated by the lutenizing hormone surge and is controlled by the temporal and spatial expression of specific genes. This review focuses on recent endocrine, biochemical, and genetic information that has been derived largely from the identification of new genes that are expressed in the ovary, and from knowledge gained by the targeted deletion of genes that appear to impact the ovulation process. Two main areas are described in most detail. First, because mutant mouse models indicate that appropriate formation of the cumulus matrix is essential for successful ovulation, genes expressed in the cumulus cells and those that control cumulus expansion are discussed. Second, because mice null for the progesterone receptor fail to ovulate and are ideal models for dissecting the critical events downstream of progesterone receptor, genes expressed in mural granulosa cells that regulate the expression of novel proteases are described.
This presentation reviews current information on the events that lead to rupture of an ovarian follicle. It contains a summary of the morphological changes that occur at the apex of a follicle wall during ovulation. Existing information shows that the tenacious connective tissue layers of the tunica albuginea and theca externa must be weakened before the follicle wall can dissociate and break open under the force of a modest intrafollicular pressure. These changes are probably dependent on transformation of quiescent thecal fibroblasts into proliferating cells in a manner that is characteristic of tissue responses to inflammatory reactions. The metabolic factors that initiate transformation of the fibroblasts are uncertain, but they are probably generated by gonadotropin-induced changes in the theca interna and granulosa of a follicle as these layers begin to luteinize during the ovulatory process.
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