Role of meiosis activating sterols, MAS, in induced oocyte maturation.

Meiosis of follicle enclosed oocytes is maintained in the prophase of the first meiotic division and oocytes do not spontaneously resume meiosis during oocyte growth and follicle development. Arrest of the meiotic process is most likely secured by the presence of follicular purines, e.g. hypoxanthine, which maintain high levels of cAMP in the oocyte and which also in vitro prevent oocytes from resuming meiosis. Only in response to the mid-cycle surge of gonadotropins will oocytes of preovulatory follicles overcome the meiosis arresting effect of hypoxanthine and resume meiosis proceeding to the metaphase of the second meiotic division. Morphologically, resumption of meiosis is observed by the disappearance of the oocyte's nuclear membrane (germinal vesicle), a process called germinal vesicle breakdown (GVB). The molecular mechanism down-stream to receptor activation by which the mid-cycle surge of gonadotropins induces oocytes to resume meiosis is, however, only partly understood. The oocyte itself lacks gonadotropin receptors and its action is mediated through the attached cumulus cells. In vitro it has been shown that FSH induces synthesis of a signal in the cumulus cells, which overcomes the meiosis arresting effect of hypoxanthine. We have shown that a group of sterols, meiosis activating sterols (MAS), induces oocyte maturation in vitro even in oocytes depleted of cumulus cells. MAS were identified as intermediates in the cholesterol biosynthesis between lanosterol and cholesterol. The two best characterized members of the MAS family are FF-MAS purified from human follicular fluid (4,4-dimethyl-5alpha-cholest-8,14,24-triene-3beta-ol) and T-MAS purified from bull testicular tissue (4,4-dimethyl-5alpha-cholest-8,24-diene-3beta-ol). The synthesis, quantification, localization and tissue-accumulation of MAS are reviewed. Several publications have documented the pharmacological effect of MAS in different species, including oocytes from mouse, rat and human. Conflicting results obtained by the use of sterol synthesis inhibitors, which prevent MAS-accumulation, are also discussed. Whether FSH actually uses MAS as a signal transduction molecule for inducing oocyte maturation and the mechanism by which MAS induce resumption of meiosis is currently unknown, but data to support that MAS is part of the FSH induced signal transduction pathway are presented.