In the intervening years, the advent of molecular biology, genetic engineering, and new pharmacological tools have provided insight into many of Espey’s original questions, such as the importance of steroids and prostaglandins in the ovulatory process, the follicular concentrations of other inflammatory eicosanoids such as leukotrienes, and the distribution of immune cells in the follicle wall during ovulation. For example, while recognizing the critical actions of the LH surge and resulting steroid hormone synthesis in the ovulatory follicle, Espey proposed that prostaglandins also participate in the control of ovulation. Central to this hypothesis is the role of prostaglandins as mediators of the inflammatory process and the relationship between prostaglandins and ovarian proteolytic activity. Throughout his review, Espey posed numerous thought-provoking questions about the parallels between inflammation and ovulation, as there is a high degree of analogy between many of these routine inflammatory processes and the ovulatory events that the ovary undergoes in response to an ovulatory LH stimulus. This inflammatory response involves chemokine and cytokine release, blood vessel dilation, immune cell infiltration, and localized production of molecular mediators that abrogate the inflammatory stimulus ( 3). Classically defined, inflammation is a protective response of a tissue to a harmful stimulus such as irritants, pathogens, or cellular damage ( 3). In his landmark paper in 1980, Espey ( 2) put forth the hypothesis of ovulation as an inflammatory reaction and outlined the similarities in inflammatory processes and ovulation. Nearly 40 years ago Bukovsky and Presl ( 1) proposed that the immune system regulated ovulatory ovarian function. Several disorders of ovulation share common features with dysregulated inflammatory responses Granulosa and theca cells of the follicle cooperate with resident and infiltrating immune cells to produce paracrine mediators of ovulation, many of which are also common to inflammatory responsesĪngiogenesis, increased vascular permeability, both vasodilation and vasoconstriction, and edema are essential features of both ovulation and inflammationĮxtensive remodeling of the extracellular matrix is stimulated by inflammatory mediators such as steroids, prostaglandins, and cytokinesĬoordinated control over proteolysis facilitates follicle rupture and oocyte release while also permitting rapid healing after ovulation and transformation of the ruptured follicle into the corpus luteum The process of ovulation shares many features with inflammatory responses This review focuses on the commonalities between inflammatory responses and the process of ovulation. However, ovulation includes processes that are distinct from inflammation, such as regulation of steroid action, oocyte maturation, and the eventual release of the oocyte. Throughout the ovulatory process, the importance of inflammatory responses is highlighted by the commonalities and similarities between many of these events associated with ovulation and inflammation. Ultimately, these functional and structural changes culminate in follicular rupture and oocyte release. The remainder of the follicle undergoes rapid angiogenesis and functional differentiation of granulosa and theca cells. LH-induced mediators initiate cumulus expansion and cumulus oocyte complex detachment, whereas the follicular apex undergoes extensive extracellular matrix remodeling and a loss of the surface epithelium. Collectively, these cells regulate proteolytic pathways to reorganize the follicular stroma, disrupt the granulosa cell basal lamina, and facilitate invasion of vascular endothelial cells. These mediators, in turn, activate both nonimmune ovarian cells as well as resident immune cells within the ovary additional immune cells are also attracted to the ovary. First responders to the LH surge are granulosa and theca cells, which produce steroids, prostaglandins, chemokines, and cytokines, which are also mediators of inflammatory processes. Many mediators of these LH-induced signaling cascades are associated with inflammation, leading to the postulate that ovulation is similar to an inflammatory response. The midcycle surge of LH sets in motion interconnected networks of signaling cascades to bring about rupture of the follicle and release of the oocyte during ovulation.
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