Cortisol이 사람 과립-황체화 세포의 스테로이드 생성과 세포자연사에 미치는 영향
Effects of Cortisol on the Steroidogenesis and the Apoptosis of Human Granulosa-Luteal Cells
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Cortisol은 난소내 다량으로 존재하며 난소 세포에 그 수용체가 있는 것으로 보고되고 있다. 또한 사람의 과립 및 황체화 세포에서 cortisol은 스테로이드 생성과 세포 대사에 영향을 미치는 것으로 알려지고 있으나, 배란 후 난포액에 높은 농도로 존재하는 cortisol이 과립-황체화 세포에 어떤 영향을 미치는 지는 정확히 밝혀져 있지 않다. 따라서 본 실험에서 과배란 유도후 획득한 사람 과립-황체화 세포를 배양하면서 5, 50, 500 ㎍/㎖ cortisol과 1 IU/㎖ FSH를 처리하고 세포의 세포자연사와 분비된 progesterone(P4)과 estradiol(E2) 양의 변화를 조사하였다. DNA 분절화 분석과 TUNEL 방법으로 세포자연사를 평가한 결과, cortisol는 농도 의존적으로 과립-황체화 세포의 세포자연사를 증가시켰고, 특히 50과 500 ng/㎖ cortisol을 처리한 군에서 유의한 차이를 보이며 세포자연사 비율을 증가시켰다. 또한 cortisol에 의한 세포자연사의 증가는 FSH에 의해 억제되지 못함을 알 수 있었다. 화학발광면역 측정법을 이용하여 배양내 P4와 E2의 양을 측정한 결과, cortisol을 처리한 후 E2의 양은 변화가 없었던 반면 P4의 양은 감소하였다. 이러한 cortisol의 P4 합성 억제 효과는 세포자연사 결과 마찬가지로 FSH에 의해 회복되지 못함을 확인할 수 있었다. 이상의 결과는 일정 농도 이상의 cortisol은 과립-황체화 세포의 세포자연사를 유발시킬 수 있으며, 또한 P4의 합성을 억제시킴으로써 난포 폐쇄를 직접적으로 유발시킬 수 있음 보여준다. 그러나 본 연구 결과들은 기존의 연구 결과와 상반된 결과를 보이고 있으며, 앞으로 과립-황체화 세포에 대한 cortisol의 생리적인 관련성을 밝혀 그 기전을 명확히 할 필요성이 있다.
Abstract
Cortisol is present in high concentration in ovary and its receptor is expressed in the ovarian cells. Moreover, cortisol is known to have a role in steroid synthesis and cell metabolism in human granulosa and lutein cells. However, little is known of the role of cortisol presenting in high concentration in the follicles after LH surge on the granulosa-lutein cells. Therefore, in the this study we evaluated the apoptosis and the production of progesterone (P4) and estradiol (E2) in the granulosa-lutein cells that are obtained during oocyte-retrieval after treatment with 5, 50, and 500 ㎍/㎖ cortisol and 1 IU/㎖ FSH. Results of DNA fragment analysis and TUNEL assay demonstrated that DNA fragmentation and the rate of apoptotic cells were increased in a dose-dependent manner showing a significant increase in 50 and 500 ㎍/㎖ cortisol treated cells. We found, however, that FSH did not suppress the apoptosis of the cells induced by cortisol. In the results of chemiluminescence assay for P4 and E2, P4 production was decreased by cortisol treatment, whereas E2 was not changed. We also got to know that FSH did not inhibit the suppressive effect of GnRH on P4 production as the result of apoptosis. The present study suggests that cortisol of high concentration could cause the apoptosis of human granulosa-lutein cells and the atresia of follicles by suppressing the production of P4. However, we need more studies to elucidate the mechanism by which cortisol induces apoptosis in human granulosa-lutein cells in view of the fact that our results are inconsistent with previous reported data.
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