Animal studies in the 1980s suggested the existence of an ovarian
hormone, termed
gonadotropin surge-inhibiting/attenuating factor (
GnSIF/AF), that modulates pituitary secretion of
luteinizing hormone (LH). Given the importance of identifying regulatory factors of the hypothalamic-pituitary-ovarian axis and the accumulating data suggesting its existence, we conducted a comprehensive literature search using PubMed, Web of Science, Scopus, and Embase to identify articles related to
GnSIF/AF. The search generated 161 publications, of which 97 were included in this study. Several attempts have been made to identify and characterize this
hormone and several candidates have been identified, but the
protein sequences of these putative
GnSIF/AF factors differ widely from one study to another. In addition, while the RF-
amide RFRP-3 is known foremost as a
neuropeptide, some research supports an ovarian origin for this non-steroidal
hormone, thereby suggesting a role for RFRP-3 either as a co-modulator of
GnSIF/AF or as a
gonadotropin-inhibiting factor in the hypothalamus (GnIH). Discovery of the KNDy neurons that modulate
GnRH secretion, on the other hand, further encourages the search for
substance(s) that modulate their activity and that indirectly affect LH secretion and the hypothalamic-pituitary-ovarian axis. While it has remained an elusive
hormone,
GnSIF/AF holds many potential applications for
contraception, in vitro fertilization, and/or
cancer as well as for understanding
polycystic ovary syndrome,
metabolic diseases, and/or pubertal development. In this review, we rigorously examine the available evidence regarding the existence of
GnSIF/AF, previous attempts at its identification, limitations to its discovery, future directions of research, and potential clinical applications.