Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research?

Abstract

When gonadotrophin-stimulated IVF methods were being developed in the 1970s and 1980s, understanding of the physiology of FSH improved. In addition to its classic actions of stimulating aromatase activity and oestradiol secretion by ovarian granulosa cells, FSH was found to stimulate the ovarian production of an uncharacterized hormone known by its specific effect of reducing pituitary responsiveness to GnRH. This hormone has been called gonadotrophin surge-attenuating factor (GnSAF), gonadotropin surge-inhibiting factor (GnSIF), various abbreviations (GnSAF/IF, GnSIF/AF) and also attenuin. Although first described in the 1980s, GnSAF has still not been convincingly characterized and no published candidate amino acid sequences conclusively relate to GnSAF bioactivity. On the basis of superovulation studies and in vitro experimentation into the roles of steroids in regulating LH, GnRH and GnRH self-priming, the concept that GnSAF has a role in the regulation of LH secretion, the timing of the LH surge and the prevention of premature luteinization developed. For at least a decade, understanding of the specific GnSAF effects of reducing pituitary sensitivity to GnRH, especially GnRH self-priming and antagonizing the stimulatory effects of oestradiol on GnRH-induced LH secretion, supported this concept. However, improved knowledge of the changes in GnSAF bioactivity in follicular fluid and serum in women requires revision of this concept. The present authors propose that the main role of GnSAF is probably the negative regulation of pulsatile LH secretion, mainly during the first half of the follicular phase, indicating a critical role in the regulation of folliculogenesis and oestradiol secretion.