Action of inhibitory LH-RH analogs in rat pituitary and luteal cell cultures.
The effect of LH-RH antagonists on LH-RH stimulated LH release was studied in primary rat pituitary cell culture and the inhibition by LH-RH antagonists of HCG provoked progesterone production was investigated in primary rat luteal cell culture. Antagonists used in this study were Ac-D-Trp1, D-Phe(Cl)2, D-Lys6, D-Ala10-LH-RH(I1) and the respective D-Lys6 isophthaloyl dimer (I2). LH-RH activity was noted to be reduced to 1/12 by I1 and to 1/23 by I2 in the pituitary cell culture system. The LH-RH inhibitors did not possess intrinsic LH releasing activity up to 10(-6) mol 1(-1). Incubation of rat luteal cells with HCG in the presence of LH-RH, I1 or I2 resulted in a smaller progesterone release than that observed in the absence of the peptides. ED50 of HCG was noted to be 5.7 X 10(-13) mol 1(-1) and 10(-8) mol 1(-1) LH-RH, I1 or I2 caused a shift of ED50 to 6.3 X 10(-12) mol 1(-1), 1.2 X 10(-12) mol 1(-1) and 7.9 X 10(-13) mol 1(-1), respectively. The present investigation is the first demonstration of reduction by LH-RH antagonists of gonadal steroid production. The present results suggest the use of such inhibitory LH-RH analogs in the treatment of hormone dependent tumors such as prostatic carcinoma and would not cause a transient rise of gonadal steroids as seen by the use of LH-RH agonists.
D000818:Animals; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003338:Corpus Luteum / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008184:Luteal Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
D006063:Chorionic Gonadotropin; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D007986:Luteinizing Hormone