The previous studies in this laboratory have shown that gonadotropin-releasing hormone (GnRH) or its agonistic analog (GnRH-Ag; WY-40972) suppresses plasma progesterone (P) levels within 24 h, which subsequently results in abortion; the treatment also suppresses nuclear estradiol receptors in the luteum (CL) and decreases the magnitude of nocturnal surges of prolactin (PRL) during this 24 h period. The primary goal of this research proposal is to determine the precise locus, or probably the loci, of the antifertility action of GnRH and to understand the mechanism by which it suppresses the luteal P synthesis and secretion during gestation. GnRH-Ag will be used in this study at the effective dose to suppress luteal P secretion within 24 h. First, it will be determined if the antigestational action of GnRH-Ag is mediated by suppressing lactogenic hormone(s) during gestation. During the first half of pregnancy, (i) PRL receptors at the level of CL will be measured; (ii) it will be determined if PRL replacement restores plasma P levels to normal in GnRH-Ag treated rats; if P or E replacement restores the magnitude of nocturnal surge of PRL to normal; (iii) the level of decidual luteotropin (a PRL-like hormone) in the decidua will be measured; (iv) pituitary PRL levels and their GnRH-receptor content will be measured, and (v) the effect of GnRH-Ag treatment in a steroidal milieu on PRL synthesis and secretion by dispersed pituitary cells will be assessed using the monolayer cell culture and perifusion systems. During the second half of pregnancy, the levels of placental lactogen in the jugular and uterine vein plasma, as well as in the trophoblastic tissue and PRL receptors in CL, will be measured. It will be determined if the replaced PRL during the first half or the replaced rat placental lactogen during the second half of pregnancy in the appropriate amounts will restore the levels of nuclear estradiol receptors and of PRL receptors in the CL to normal. Next, the involvement of GnRH over luteal P synthesis through LH will be examined by measuring luteal synthesis of testosterone, estradiol and P in response to hCG treatment in vitro. Finally, it will be determined if the luteal suppression of P by GnRH is mediated by its direct action on luteal steroidogenesis and/or the cholesterol availability for luteal P synthesis. The results will indicate the involvement of receptor bound estradiol in cholesterol transport and GnRH effect on it in the CL. These studies will increase our understanding of the mechanism of action of GnRH during pregnancy.
| Sridaran, R; Lee, M A; Haynes, L et al. (1999) GnRH action on luteal steroidogenesis during pregnancy. Steroids 64:618-23 |
