Inhibition of luteal steroidogenesis by two lhrh antagonists (NAL-GLU and NAL-ARG Antagonists) in the pregnant rat

Abstract

We have examined the effect of two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) on the basal progesterone (P₄), pregnenolone (P₅) and 20α-dihydroprogesterone (20α-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 μmol/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., 20α-DHP to assess whether this suppression in P₄ production is due to an enhancement in the P₄ metabolism by increasing the activity of 20α-hydroxydehydrogenase. However, instead, we observed (i) a decrease in the production of 20α-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 20α-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 3β-hydroxysteroid dehydrogenase (3β-HSD). which catalyzes the oxidation of P₅ to P₄ or due to a decrease in activity of both enzymes.