Functional luteolysisからstructural luteolysisへの移行のメカニズム : Matrix metalloproteinase, apoptosis, 過酸化水素の関わり(シンポジウム1 黄体機能の調節とその異常)

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The mechanisms of human luteal regession are unknown. Corpus luteum regression, or luteolysis can be divided into at least two stages, functional and structural. Functional luteolysis refers to suppression of progesterone synthesis and secretion, a process that precedes structural luteolysis. These definitions were proposed thirty years ago by Malven, based on observations in the rat. In this species, functional and structural luteolysis are clearly separate events under separate endocrine control. Functional and structural regression also appear to be separate events in the human, as corpora lutea of previous cycles are evident within the ovary. While the interval between loss of functional activity and the induction of structural involution is not known in the human, in the rat, corpora lutea are known to persist for up to four to five estrous cycles. We investigated the mechanisms of functional luteolysis and structural luteolysis Recent evidence indicates that reactive oxygen species of ovarian origin may mediate luteolysis in the rat. Hydrogen peroxide may be a mediator of luteolysis in the rat and may play a similar role in species such as the human, in wich little is known about the nature and mechanisms of action of luteolysins. We examined the effects of hydrogen peroxide on progesterone (P4) production, estradiol(E2) production and cAMP synthesis by human culoured luteinzed granulosa cells. To gain information on mechanisms of luteal involution, we developed an animal model by treatment of PMSG-hCG-treated immature female rats with gonadotropin releasing hormone agonist (GnRHa : Leuprolide). We also examined the machanisms of luteal regressin in human using corpora lutea collected in early, mid-and late luteal phases with the informed consent of patients undergoing hysterectomy. Vascular endothelial growth factor (VEGF) is reported to play an important role during luteal formation. The expression of VEGF was investigated in corpus luteum during luteal regression. We previously reported the occurrence of apoptosis in corpus luteum in luteal involution induced by prolactin (PRL) treatment follwing use of bromocryptine (Br) to suppress serum PRL. Apoptosis was determined in human corpora lutea in the late luteal phase using an in situ 3'-OH nickend-labeling method (TUNEL method) and electron microscopy. Elevation of matrix metallo-proteinase (MMP) -2, 9 activity in rat corpora lutea during structural involution induced by PRL treatment following Br was reported. We investigated the expression of MMP-2 and membrane type MMP (MT-MMP), which is reported to activate pro-MMP-2, in corpora lutea in humans and in GnRHa-treated rats. Hydrogen peroxide reduced P4, E2 and cAMP production of human cultured luteinized granulosa cells. As it did not cause cell death, it is clear that peroxide did not cause apoptosis. The most notable cells that produce reactive oxygen species are phagocytes, endothelial cells, and fibroblasts, all of which are known constituents of the human corpus luteum. Thus, peroxide may act as a mediator for functional luteolysis in humans. VEGF expression was reduced in corpus luteum of Br-treated rats. In structural luteolysis induced by RPL-or GnRHa-treatment VEGF expression in corpus luteum was extremely reduced. These data suggested that the reduction of VEGF expression may be associated with both functional luteolysis and structural luteolysis. VEGF in human corpora lutea was expressed in early and mid-luteal phases. By contrast, VEGF expression was extremely reduced in human corpora lutea in the late luteal phase. These data indicated that the reduction of VEGF expression may be also associated with human luteal regression. The percentage of apoptotic cells was approximately 3.0% in corpora lutea of structual luteolysis in the rat and human using the TUNEL method. Electron microscopic findings showed the existence of apoptotic bodies in structural luteolysis in rats and humans.These findings indicated th
社団法人日本産科婦人科学会の論文
1998-08-01

Functional luteolysisからstructural luteolysisへの移行のメカニズム : Matrix metalloproteinase, apoptosis, 過酸化水素の関わり(シンポジウム1 黄体機能の調節とその異常)

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