Molecular aspects of mammalian ovulation.

Ovulation, recurring every reproductive cycle of the mammalian female and triggered by a surge of luteinizing hormone (LH) released from the pituitary is an essential prerequisite for fertilization and subsequent embryonic development. Here we shall review two of the biological responses leading to follicle rupture -- vascular changes and proteolysis. Naturally, our present knowledge is based mainly on work in a few species, such as the rat, the mouse and, to lesser extent the pig and monkeys and observations in the human. Therefore any generalizations to other mammals, should be considered as a working hypothesis yet to be confirmed. The LH surge stimulates, in the preovulatory follicles, a cascade of proteolytic enzymes, including plasminogen activator (PA), plasmin and matrix metalloproteinases (MMPs). These enzymes bring about the degradation of perifollicular matrix and, most notably, the decomposition of the meshwork of collagen fibers which provides the strength to follicular wall. Pharmacological blockage of any of these enzymes resulted in the reduction of ovulation rate. The increased ovarian proteolytic activity associated with ovulation is controlled by locally produced specific inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1). The increased synthesis of these two specific proteinase inhibitors in the theca of growing follicles ensures their development by protecting them from enzymes diffusing from ovulatory follicles. The stimulation of ovulation by the gonadotropin results in an increase in follicular blood flow, hyperemia, increase in vascular permeability and a marked increase in follicular volume. These vascular changes and the proteolytic activity are triggered either directly by LH or by local mediators and factors produced in response to the gonadotropic stimulus. These mediators allow the tight coordination of these two cascades culminating in the rupture of follicle wall. We shall review here, briefly, the various mediatory systems that have been implicated in follicle rupture. These include steroids, vascular endothelial growth factor (VEGF), cytokines, eicosanoids, platelet activating factor (PAF), nitric oxide and nitric oxide synthase (NO/NOS), kinins and oxygen radicals.