| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 102 === Progesterone (P4) is required for the support of successful pregnancy including preparation of implantation and placentation. Inadequate P4 secretion is related to recurrent pregnancy loss (RPL). P450scc, encoded by CYP11A1, catalyzes the first step of P4 biosynthesis in coupus lutem. The development and maintenance of corpora lutea during pregnancy, however, are less understood. CYP11A1 overexpression is associated with reproductive problem such as polycystic ovary syndrome (PCOS), an etiological factor of RPL. To characterize the defects caused by Cyp11a1 overexpression, I examined Cyp11a1 transgenic mice that recapitulated the endogenous expression of Cyp11a1 gene. Cyp11a1 transgenic females displayed reduced pregnancy rate, impaired implantation and placentation, leading decreased litter size in utero, although they generated comparable numbers of blastocysts. The progesterone levels were insufficient during early pregnancy then returned to normal afterwards, but its withdrawal at term was delayed and there was no live birth. The transgenic luteal cells had differentiation problem during early pregnancy such as accumulation of lipid droplets, defective mitochondrial dynamics and angiogenesis. P4 supplement rescued the implantation rates but not the ovarian defects. The genes associated with steroidogenesis, cholesterol availability and lipid metabolism were diminished in transgenic ovaries at 0 h, 4 h and 24 h post-human chorionic gonadotropin (hCG) treatment, as well as on gestation day 1 (GD1) and day 4 (GD4). Trib3 was up-regulated 3-4 folds in all five stages. Overespression of TRIB3 transduced by Lentivirus in human luteinized granulosa cells (HLGCs) decreased the P4 production after cAMP stimulation. Taken together, overexpression of Cyp11a1 disrupted the development of corpus luteum, leading to progesterone insufficiency during early pregnancy. The mis-regulation of the progesterone production in Cyp11a1-transgenic mice during pregnancy resulted in aberrant implantation, anomalous placentation and delayed parturition.
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