IS IRREGULAR REGRESSION OF CORPORA-LUTEA IN CLIMACTERIC WOMEN CAUSED BY AGE-INDUCED ALTERATIONS IN THE TISSUE CONTROL-SYSTEM

PROBLEM: We have recently observed that the regression of corpora lute a (CL) in women during the reproductive period of life is accompanied by a diminution of Thy-1 differentiation protein release from Vascular pericytes and an accumulation of T lymphocytes and activated macropha ges among both degenerating granulosa lutein cells (GLC) and theca lut ein cells. These data suggest that the immune system and other stromal factors, representing components of the ''tissue control system,'' ma y play a role in regression of the CL. We investigated degenerating CL from climacteric women to address the possibility that the decline of immune functions with advancing age may result in incomplete regressi on of luteal tissue. This could contribute to the altered hormonal pro files and abnormal uterine bleeding that frequently occur during the c limacteric. METHOD: Immunoperoxidase staining and image analysis were used to localize Thy-1 differentiation protein of vascular pericytes, cytokeratin staining of GLC, neural cell adhesion molecule expression by theca lutein cells, CD15 of neutrophils, CD4, CD14, CD68, and leuko cyte common antigens of macrophages, and CD3 and CD8 determinants of T lymphocytes. We also investigated the expression of luteinizing hormo ne receptor (LH receptor) and mitogen activated protein kinases (MAP k inases) in luteal cells. Samples of regressing luteal tissue were obta ined during the follicular phase from perimenopausal women (age 45-50) who exhibited prolonged or irregular cycles. For comparison, luteal t issues from women with regular cycles (age 29-45) and CL of pregnancy were also investigated. RESULTS: Corpora lutea of the climacteric wome n exhibited irregular regression of luteal tissue characterized by a l ack of cytoplasmic vacuolization and nuclear pyknosis in GLC, and by a persistence of theca lutein cells exhibiting hyperplasia and adjacent theca externa layers. This was accompanied by a continuing release of Thy-1 differentiation protein from vascular pericytes. Persisting GLC lacked surface expression of macrophage markers (CD4, CD14, CD68 and leukocyte common antigen) as well as nuclear granules exhibiting CD15 of neutrophils, detected in regularly regressing GLC. In addition, suc h persisting GLC showed weak or no LH receptor expression, and retaine d the expression of cytokeratin. They also exhibited enhanced staining for MAP kinases. Strong cytoplasmic MAP kinase expression with occasi onal nuclear translocation was also detected in persisting theca lutei n cells, indicating high metabolic activity of these cells. T lymphocy tes, although occasionally present in luteal stroma within luteal conv olutions, did not invade among persisting GLC and were virtually absen t from layers of theca externa and theca lutein cells. CONCLUSIONS: Th ese data indicate that the regressing CL in climacteric women may exhi bit persistence of luteal cells, perhaps because of age-induced altera tions of the immune system and other local stromal homeostatic mechani sms involved in the elimination of luteal cells. Persisting GLC and/or theca lutein cells may exhibit abnormal hormonal secretion that contr ibutes to the alteration of target tissues, such as the endometrium, r esulting in abnormal uterine bleeding, hyperplasia, and neoplasia.