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.

Although almost always a benign, self-limiting disease, infectious mononucleosis accounts for considerable symptomatic illness in the young athlete and can, on occasion, be truly life-threatening. Recognition of the syndrome "glandular fever," vis-a-vis infectious mononucleosis--fever, pharyngitis, lymphadenopathy, and splenomegaly, with characteristic changes in the peripheral blood leukocytes--dates back over a half a century. However, seroepidemiologic studies have only recently established its viral causation and epidemiology. This acute infection by the Epstein-Barr virus is unique pathophysiologically--an acute, self-limiting, lymphoproliferative disorder with autoimmune features--and may well be the cause or one of the causes of several malignant neoplasms, Burkitt's lymphoma, and nasopharyngeal carcinoma. This review (1) describes infectious mononucleosis, pathophysiologically, clinically, and epidemiologically; and outlines its most frequent and serious complications; (2) discusses how to reliably diagnose infectious mononucleosis and evaluate the heterophile-negative case; and (3) addresses management, especially the thorny issues of the use of corticosteroids and restriction from athletic training and participation.

Recent studies from our laboratory corroborated the suggested role of plasminogen activation in follicular rupture at ovulation, and its involvement in the activation process of collagenolysis in the follicle. In the present study, the molecular types and cellular source of plasminogen activator (PA) were examined. Explanted preovulatory follicles produced in vitro both urokinase type and tissue type (t-PA) activators. Upon gonadotropin stimulation a highly significant increase in t-PA, but not in urokinase type, was observed. Separation of the follicle into granulosa cells and residual tissue, mainly theca, revealed that both compartments produce both types of PA. The granulosa compartment was found to produce 80-90% of the total follicular PA activity. Gonadotropins stimulated predominantly t-PA. Most of the gonadotropin-enhanced PA activity produced by granulosa cells was secreted into the culture medium, whereas that from thecal origin remained in the tissue. Likewise, in whole follicles only about 10% of PA was secreted into the medium. Gonadotropin-induced PA activity in vitro was reduced by inhibitors of steroidogenesis. This inhibition was overcome by the addition of estradiol-17 beta. The inhibition of steroidogenesis affected predominantly the t-PA type of PA. In conclusion, the granulosa cells contribute most of the follicular PA activity, and t-PA is predominantly enhanced by gonadotropin and estrogen. It seems, therefore, that t-PA is the activator involved in the processes leading to follicular rupture.

The purpose of the present study was to measure norepinephrine (NE) in Graafian follicles and correlate changes in its concentration with circulating gonadotropins secreted endogenously or administered exogenously. Graafian follicles were removed from the ovaries of adult cycling rats. The follicles were pooled in groups of 10-13, and NE was determined by high performance liquid chromatography. Follicular NE(picograms per micrograms protein) did not change between 0900 h (3.61 +/- 0.34) and 1300 h (3.12 +/- 0.25) on proestrus, but was reduced significantly to 1.45 +/- 0.16 at 2100 h, which is 4 h after the peak of the gonadotropin surge. There was a further reduction to 0.83 +/- 0.08 in fresh corpora lutea taken on estrus at 0900 h. The decrease in follicular NE was prevented in estrous rats which were either hypophysectomized 24 h previously or treated with sodium pentobarbital at 1330 h on proestrus. To determine which pituitary hormone was responsible for follicular NE depletion, rats were injected at 0900 h on proestrus with LH (5 micrograms), FSH (20 micrograms), LH plus FSH (5 and 20 micrograms, respectively), or PRL (20 micrograms), and follicular NE was determined 4 h later. FSH reduced follicular NE significantly to 1.86 +/- 0.16 compared to both the control (3.12 +/- 0.25) and the PRL-injected group (2.92 +/- 0.32), whereas LH caused a small but nonsignificant decrease (2.49 +/- 0.2). Both LH and FSH doses used resulted in ovulation, as determined by counting tubal ova 12 h after hormonal treatment. We conclude that 1) NE in Graafian follicles is markedly reduced within 4 h after the preovulatory gonadotropin surge in the normal cycling rat; this reduction is prevented when the surge is abolished; 2) the hormone responsible for follicular NE depletion is FSH rather than LH or PRL; and 3) finally, it is suggested that follicular NE may be involved with the formation and/or functioning of the corpus luteum.

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