Our data suggest that surface epithelium may be involved in the formation of some primordial follicles in adult ovaries. This process, and further follicular fate, may require a precise interplay of immune system related morphoregulatory molecules and macrophages.

This study supports the concept that endometriosis is associated with activation of peritoneal macrophages, and a higher concentration of these cells. This activation is reflected by the increased levels of cytokines found in macrophage conditioned media. The absence of significant changes in peritoneal fluid cytokine levels would seen to indicate that the above derangements are not responsible for the development or progression of endometriosis.

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Factors determining the life span of the human corpus luteum (CL) are not known. In addition to being determined by hormonal factors, such as hCG, the life of luteal cells may be determined by the preservation of luteal vascularization. Furthermore, the CL represents an immunologically unique tissue, as it is formed after menarche, long after adaptation of the immune system toward self. Thus, CL regression may be immunologically mediated. To determine what role the vasculature and immune system play in human CL development and regression, we examined immunohistochemically 1) the expression of Thy-1 differentiation protein by vascular pericytes, 2) the expression of major histocompatibility complex (MHC) class I and class II molecules in granulosa lutein cells (GLC), and 3) infiltration of the CL by macrophages and T lymphocytes. LH receptor (LHR) and cytokeratin 18 expression were also studied. In developing CL, the pericytes of luteal microvasculature released Thy-1 differentiation protein among the endothelial cells of proliferating vessels. In mature CL, Thy-1 released from vascular pericytes accumulated on the surface of GLC, and these cells exhibited LHR immunoreactivity (LHRI). Overall LHRI increased during the luteal phase and was strongest at the beginning of the late luteal phase. Although vascular pericytes showed strong LHRI, no staining of endothelium was detected during the luteal phase. GLC exhibited strong cytokeratin staining and moderate staining for MHC class I and MHC class II antigens; numerous macrophages were detected in luteal tissue. During pregnancy, the staining pattern was similar to that seen in the mature CL at the end of the midluteal phase. During the late luteal phase, surface expression of MHC class I and MHC class II antigens by GLC was substantially enhanced, and some T cells invaded among luteal cells. By the end of the cycle, an acute regression of vasculature and luteal tissue was observed along the fibrous septa. The remaining GLC showed only surface and no cytoplasmic LHRI. During the subsequent cycle, in the presence of numerous T cells, regressing GLC exhibited strong surface expression of various macrophage markers, such as CD4, CD14, CD68, and leukocyte common antigen, a feature not detected in the CL during the luteal phase nor described in other tissues. A complete loss of cytokeratin staining in GLC was observed. In regressing CL, strong LHRI was present in the endothelium of small and large luteal vessels. In conclusion, vascular pericytes and macrophages may stimulate the development and senescence of luteal tissue. The senescence of GLC may be inconsistent with preservation of luteal vasculature, and T lymphocytes appear to participate in terminal regression of the CL. Regression of luteal tissue therefore resembles immunologic rejection of a transplant. During pregnancy, the aging process of GLC appears to be interrupted, possibly due to the temporary acceptance of the CL "graft."

Peritoneal macrophage IL-6 secretion is increased in women with endometriosis, and appears to correlate with disease stage. IFN-gamma does not appear to be responsible for the activation of macrophages in women with endometriosis.

Ovarian follicular development is dependent on growth and differentiation of the oocyte, as well as the granulosa and theca cell layers. The majority of primary follicles in the adult human ovary are not growing, and most antral follicles undergo atresia. The mechanisms regulating follicular growth and differentiation are poorly understood. Expression of key regulatory proteins in cells of certain follicles may be involved. We have studied the distribution of retinoblastoma protein (pRb), a key cell cycle regulator, in human follicles and CL by quantitative immunohistochemistry. Recent studies suggest that high nuclear concentrations of pRb are associated with the arrest of cell proliferation and the beginning of differentiation; during advanced differentiation of cells pRb is markedly depleted or absent. We also studied follicular distribution of Thy-1 differentiation protein, a morpho-regulatory molecule associated with cell differentiation, and the presence of macrophages. Macrophages have been shown to stimulate steroidogenesis in granulosa cells in vitro, and they are required for release of Thy-1 differentiation protein from vascular pericytes among granulosa cells in vivo. Our results indicate that oocytes in resting follicles exhibit pRb in the nucleoli. During initiation of follicular growth, the pRb expression first extends over the oocyte nuclei and then diminishes from both nuclei and nucleoli in preantral follicles. When the oocytes reach maximum size in small antral follicles, the pRb expression is reestablished in oocyte nucleoli. In differentiating granulosa and theca cell layers of preantral and small antral follicles, pRb expression is high, but it is low in growing large antral follicles. During CL development and regression, pRb expression in the nuclei of granulosa lutein cells first increases and then decreases. Follicular development is accompanied by the presence of Thy-1 differentiation protein and macrophages under the follicular basement membrane. In growing large antral follicles, during the mid-follicular phase, larger macrophages exhibit physical contacts with granulosa cells through the follicular basement membrane, and, during the late follicular phase, small dendritic macrophages can be detected among granulosa cells, but not within the follicular antrum. Large antral follicles undergoing atresia exhibit strong pRb expression in granulosa cells. This is accompanied by a lack of Thy-1 differentiation protein among granulosa cells and the occurrence of large phagocytic macrophages in the follicular antrum. This is the first report of pRb expression in the human ovary.(ABSTRACT TRUNCATED AT 400 WORDS)

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