Inhibition of luteal steroidogenesis by two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) in the pregnant rat.
We have examined the effect of two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) on the basal progesterone (P4), pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained from day 8 pregnant rats. A dose of 0.1 mmol/l of Nal-Glu or Nal-Arg attenuated basal P4 production by luteal cells after 12, 24 or 48 h of incubation. P5, a precursor for P4 synthesis was also reduced by both doses of Nal-Glu or Nal-Arg (0.1 mmol or 0.1 mumol/l) after 24 h of incubation. A period of 12 h was not sufficient to inhibit P5 production by luteal cells incubated with both doses of Nal-Glu or with the lower dose of Nal-Arg. The higher dose of Nal-Glu and Nal-Arg remained effective in attenuating P5 production by luteal cells after 48 h of incubation. We measured the production of a metabolite of P4, i.e., 20 alpha-DHP to assess whether this suppression in P4 production is due to an enhancement in the P4 metabolism by increasing the activity of 20 alpha-hydroxydehydrogenase. However, instead, we observed (i) a decrease in the production of 20 alpha-DHP by the higher dose of Nal-Glu and Nal-Arg after 12, 24 or 48 h of incubation and (ii) a decrease or no change in the production of 20 alpha-DHP by the lower dose of Nal-Glu or Nal-Arg at all time periods of incubation. Based on these observations we conclude that LHRH antagonists exert a direct effect on the corpus luteum and suppress luteal steroidogenesis. This suppression in luteal steroidogenesis could be due to a decrease in the activity of any one of these enzymes of the steroidogenic pathway, viz., cholesterol side chain cleavage (P450scc), a rate limiting enzyme involved in the synthesis of P5 from cholesterol, or 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which catalyzes the oxidation of P5 to P4 or due to a decrease in activity of both enzymes.
Srivastava
R K
RK
Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310-1495.
Sridaran
R
R
D000818:Animals; D003338:Corpus Luteum / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006908:Hydroxyprogesterones / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000096:biosynthesis*; D013997:Time Factors
D006908:Hydroxyprogesterones; C092464:LHRH, Ac-Nal(1)-Cpa(2)-Trp(3)-Arg(6)-Ala(10)-; C057805:LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-; D013256:Steroids; C007433:17,20-dihydroxy-4-pregnen-3-one; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D011284:Pregnenolone