Lipoprotein-incorporated pregnenolone fatty acid esters act as substrate for ovarian progestin synthesis

Progesterone is of great importance in the normal development of the ovarian follicle and its biosynthesis has been shown to rely on plasma low-density lipoproteins for delivery of cholesterol substrate. However, the pre-ovulatory ovarian follicle has no access to plasma low-density lipoproteins suggesting that other substrates may be involved in pre-ovulatory progestin production. We show in this study using tritiated pregnenolone fatty acid esters incorporated into lipoproteins can give rise to a series of labelled progestins following lipoprotein-mediated internalization. In doing so, progestins are synthesized by shunting the accepted rate limiting step of steroidogenesis, the intracellular P450 side chain cleavage pathway. Furthermore, we demonstrate that follicular fluid high density lipoproteins contain vast endogenous concentrations of this lipoidal pregnenolone metabolite which may indeed contribute to progesterone production in the pre-ovulatory ovarian follicle.