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Programmed cell death or apoptosis plays an important role in normal reproductive function. Since apoptosis attributes to the exhaustion of the oocyte/follicle reserve, either directly through germ cell death or indirectly through follicular atresia, this process has been proposed to be the major mechanism that determines the female reproductive lifespan. Moreover, an imbalance between proliferation and apoptosis in the ovary may promote unwanted tissue growth, resulting in ovarian cancer development. A better understanding of programmed cell death in the ovary may help to develop novel therapies to treat females with ovarian disorders, such as premature ovarian failure and ovarian cancer. In this thesis, the function of several hormones on the process of apoptosis in the ovary is investigated. Furthermore, the expression of several apoptotic regulators has been investigated in a variety of ovarian cell types under physiological normal and pathological conditions. To gain more insight in the proteins involved in ovarian apoptosis under normal physiological conditions, we have investigated the localization and distribution of the Fas system and its related proteins in the ovary throughout the estrous cycle in the rat. The results of this study are described and discussed in chapter 2. In chapter 3 we examined the effect of loss of growth hormone (GH) signaling on follicular recruitment, development and atresia by using GH receptor null mice and investigated whether IGF-1 administration could antagonize the absence of GH actions. In chapter 4, the effect of hypothyroidism on follicular development and atresia was investigated in the rat ovary. The ovarian surface epithelium, which covers the ovary, is the source of a frequent and often lethal form of cancer in females. To gain more insight in the proteins that determine the fate of OSE cells and their relation with ovarian cancer, we examined the expression of components of the Fas signaling pathway in relation to apoptosis in human OSE cells at the human ovarian surface, in inclusion cysts, borderline tumors and carcinomas (chapter 5). As described above, gonadotropins, including luteinizing hormone (LH), have been suggested to play an important role in the etiology of epithelial ovarian cancers. Therefore, we examined the effect of LH on the occurrence of Fas-induced apoptosis in human OSE cancer cell lines and determined whether signaling occurs through the activation of protein kinase A (PKA) and/or protein kinase C (PKC) (chapter 6). In the summarizing discussion, the mechanisms by which hormones regulate apoptosis in the ovary are discussed. In addition, the potential means of manipulating apoptosis and its clinical relevance are discussed (chapter 7). |
