Macrophages, Cell Proliferation, and Cell Death in the Human Menstrual Corpus Luteum1

Abstract

We studied the presence and numbers of macrophages in the different compartments of the human menstrual corpus luteum (CL) in relation to the proliferative activity and apoptosis in luteal cells. Macrophages were recognized by immunohistochemical demonstration of the lysosome-associated glycoprotein CD68, and proliferating cells by immunohistochemical detection of the cell cycle-related protein Ki67 and by counting mitotic cells. In general, changes in the number of macrophages were parallel to the functional activity of the CL. Macrophage numbers increased up to the end of the early luteal phase, remained relatively unchanged during the midluteal phase, and decreased at the late luteal phase. Furthermore, macrophages showed prominent morphological changes during the cycle. They showed round or elongated cytoplasm during the early and late luteal phases, and dendritic features in the midluteal phase. Proliferating cells were very abundant on Days 15-16 and showed a significant decrease thereafter. Most proliferating cells corresponded to stromal (mainly vascular) cells. However, about 5% of granulosa-lutein cells and about 15% of theca-lutein cells were proliferating during the early and midluteal phases. Regression of the CL at the late luteal phase was associated with both a decrease in the number of proliferating cells and an increase in the number of apoptotic cells, which were highly increased on Days 25-27 of the cycle. The number of macrophages was not related to cell proliferation nor to cell death during the luteal phase. The observed changes in both macrophage number and morphology suggest the existence of a bidirectional communication between macrophages and steroidogenic cells in the human CL, or regulation of both cell populations by similar mechanisms.

Species-Related Differences in the Mechanism of Apoptosis During Structural Luteolysis

“…DNA ladder formation and apoptotic cells are detected in the mid-luteal phase corpus luteum and apparently increase in the regressing corpus luteum, whereas they are not detected in the corpus luteum of pregnancy [47][48][49]. It is generally agreed that apoptotic cells remarkably increase in number in the corpus luteum during the late luteal phase [50,51]. On the other hand, Fraser et al [52] report that autophagocytosis may be a main mechanism for natural structural luteolysis rather than apoptosis in primates because electron microscopic analysis revealed that natural luteolysis was associated with luteal cell atrophy, condensation of cytoplasmic inclusions and organelles and accumulation of lipids, but was not associated with the ultrastructural criteria for apoptosis in marmosets.…”

Significance of ovarian macrophages in the follicular aspirates from ART patients

“…Hyporesponders, also exhibited a lower concentration of IL-1β and VEGF in the culture supernatants, compared to hyper-responder patients, emphasizing that in hyporesponders the primary function of macrophages is to eliminate the apoptotic bodies, as was previously reported [9,10]. In a recent article by Balasch et al [4] it was shown that macrophages do release VEGF, but whether these macrophages are able to release cytokines while they are phagocytosing is still a matter of controversy.…”

“…Also, ovarian macrophages use phagocytosis to remove apoptotic granulosa cells and apoptotic luteal cells [9,10], thereby contributing to the processes of follicular atresia and luteolysis.…”

Effects of Melatonin on Ischemia-Reperfusion Injury in Rat Ovary: Histopathologic and Immunohistochemical Study

“…Macrophages are major secretory cells capable of releasing cytokines, chemokines and growth factors that function in normal, inflammatory and disease processes of most tissues [10]. CD68 positive cells are localized in human ovaries primarily to the vascular connective tissue and theca-lutein areas of the corpus luteum, although some are found in the granulose-lutein cell layer [11]. After ischemia reperfusion, impaired ovarian tissue melatonin effect was characterized by vascular injury and inflammation and the prevention of CD31 and CD68 markers.…”