Follicular sterol composition in gonadotrophin stimulated women with polycystic ovarian syndrome.

This is the first study evaluating whether oocyte development and fertilization competence are related to intrafollicular concentration of cholesterol, meiosis-activating sterols and progesterone, after human chorionic gonadotrophin (HCG) administration of women with polycystic ovarian syndrome (PCOS). The concentration of follicular fluid meiosis-activating sterol (FF-MAS) significantly increased in the periovulatory period from 10-14 to 34-38 h after HCG administration, while the concentration of testis meiosis-activating sterol (T-MAS) decreased, suggesting a HCG-dependent inhibition of sterol Delta14-reductase. There was no correlation between follicular lanosterol, FF-MAS, T-MAS, and progesterone concentrations and the presence or absence of MII oocytes. Interestingly, free cholesterol level was significantly lower and FF-MAS/cholesterol and progesterone/cholesterol ratios significantly higher in follicles containing MII oocytes compared to follicles from which oocytes were not retrieved. Yet, fertilization and embryo quality did not correlate with follicular sterols. This knowledge should be beneficial for the implementation of protocols for in vitro maturation process, usually used in PCOS patients.

Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS).

Lanosterol 14alpha-demethylase (CYP51) produces follicular fluid meiosis-activating sterol (FF-MAS), which is converted further to testis meiosis-activating sterol (T-MAS). MAS are intermediates in the cholesterol biosynthetic pathway, with the ability to trigger resumption of oocyte meiosis in vitro. In contrast to the liver, where pre- and post-MAS genes are upregulated coordinately at the level of transcription by a cholesterol feedback mechanism through sterol regulatory element-binding proteins (SREBP), regulation differs in the testis. Genes encoding pre-MAS enzymes [HMG-CoA synthase (SYN), HMG-CoA reductase (RED), farnesyl diphosphate synthase (FPP), squalene synthase (SS), and CYP51] are upregulated during sexual development of the testis, although not all genes are turned on at the same time. Furthermore, two post-MAS genes, C-4 sterol methyl oxidase and sterol Delta(7)-reductase, are expressed at low levels and are not upregulated either in rat or human. This transcriptional discrepancy seems to be SREBP independent. Besides cAMP/cAMP-responsive element modulator, other unknown transcription factors control expression of individual cholesterogenic genes during spermatogenesis. HPLC analysis shows an 8-fold increase in T-MAS during development of rat testis whereas MAS is barely detectable in livers of the same animals. We propose that the lack of a coordinate transcriptional control over the cholesterol biosynthetic pathway contributes importantly to overproduction of the signaling sterol T-MAS in testis.