Apoptosis of human ovary and uterine endometrium during the menstrual cycle

To investigate apoptotic changes in the ovary or uterine endometrium, we studied the cleavage of DNA in these tissues obtained from regularly cycling women by in situ analysis of DNA integrity and quantitative end labeling of DNA gel fractionation. In situ analysis of several sized atretic follicles of ovaries revealed that granulosa cells showed positive staining to some extent, however, these methods do not discriminate between cells undergoing apoptosis and those undergoing necrosis. Total DNA extracted from human corpora lutea (CL) of the early luteal phase contained predominantly high molecular weight DNA, whereas CL of the midluteal phase exhibited the appearance of DNA cleavage into low molecular weight ladders characteristic of apoptosis. Although apoptotic DNA cleavage of human CL increased from the midluteal phase to the late luteal phase, CL of early pregnancy did not exhibit apoptotic DNA fragmentation. Both large and small luteal cells were the primary cell type exhibiting DNA cleavage in human CL of the midluteal and late luteal phases and in regressive CL. Biochemical analysis of human endometrium revealed that the ladder pattern cleavage of DNA was identified at three different phases of the menstrual cycle, namely the early proliferative, late secretory, and menstrual phases. Cells undergoing apoptosis were scattered in the functional layer of the early proliferative endometrium, but not in the late proliferative phase to midsecretory phase: At the beginning of the late secretory phase, apoptosis reappeared in the stromal cells and spread gradually to almost all components of the functional layer. By contrast, cells in the basal layer showed no evidence of apoptosis throughout the menstrual cycle. The present findings suggest that: (1) human luteal regression may be mediated by apoptosis; (2) CL of early pregnancy may be rescued from luteolysis through inhibition of the occurrence of apoptotic luteal cell death, and (3) apoptosis occurs in specific populations of endometrial cells during the human endometrial cycle. In conclusion, apoptosis might play an important role in the regulation of the menstrual cycle in women.