MECHANISM OF ACTION OF DIHYDROTESTOSTERONE IN LUTEOLYSIS DURING PREGNANCY

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The findings from this laboratory so far suggest that dihydrotestosterone (DHT) inhibits luteal progesterone (P) synthesis and release in pregnant rats. In vivo treatment of DHT increased the number of lipid droplets within the luteal cells without having any effect on tubular cristae within the mitochondria or on plasma pregnenolone levels, indicating that the decrease in plasma P may be due to decreased cholesterol transport to the mitochondria or to decreased esterase activity. The lower P levels, in turn, may lead to inhibition of the nocturnal prolactin (PRL) surge and the lesion may be at the level of 3beta-hydroxy-steroid dehydrogenase (3beta-HSD) resulting in decreased plasma P levels. In vivo administration of DHT has no effect on pituitary luteinizing hormone (LH) release. Furthermore, in vivo studies also suggest that this inhibitory effect of DHT may be mediated by prostaglandin F2alpha (PGF2alpha). The current proposal extends these studies to further investigate these observations so as to understand the precise locus or loci of antifertility action of DHT during gestation and the intracellular mechanisms by which it inhibits luteal P synthesis. In the present proposal, it will be first determined whether in vivo administration of DHT causes morphological and hormonal changes in the corpus luteum (CL) within 24 h due to the effect of treatment on pituitary and CL or due to the direct effect of treatment on CL. Subsequent experiments will attempt to define precisely the intracellular events that lead to decreased luteal P production with 24 h after in vivo DHT treatment. The luteal content of free cholesterol, cholesterol ester, ACAT and cholesteryl esterase activity will be measured. The effects of DHT treatment on luteal enzymes, P450scc and 3beta-HSD, will be quantitated by northern and immunoblot analyses throughout the study. Several hormonal end points will be measured by RIA. Next, it will be determined if the contragestational effect of DHT is mediated by PGF2alpha. The findings from this proposed study could provide an insight into the physiological role of this naturally secreting substance, DHT, in the control of luteal steroidogenesis during pregnancy.