A challenging hypothesis: can a SNP changing cysteine 1 in the α inhibin pro-domain induce reproduction-linked PCOS phenotypes?

PCOS, the leading cause of female infertility, affects 4 to 21% of women in age to give birth. Despite numerous investigations aimed at understanding the syndrome, its origin(s) remains unknown. This paper reports neglected or overlooked studies and seeks to integrate them within the relevant literature. Data presented herein strongly suggests that a modified Pro-αC inhibin (featuring a deletion of the 15 N-terminal amino acids of αC domain: "Pro-▵1-15-αC inhibin") suppresses GnRH pulses ("GnRH-Statin activity") in vivo and GnRH secretion in vitro. Pro-αC inhibin, an α inhibin gene product devoid of βA/βB inhibin domains and lacking inhibin or activin activity is present in follicular fluid and serum and is strongly expressed in luteal cells. A SNP, changing cysteine at position 1 to serine in the α inhibin gene Pro-domain was identified in a human polycystic ovary, in contrast to human placenta and a human macrophage cell line. This mutation which disrupts the S-S bridge linking the Pro and αC inhibin domains of Pro-▵1-15-αC inhibin or Pro-αC inhibin, is hypothesized to induce a loss-of-function. The hypothesis proposed is the following: such a loss-of-function could induce an over-activity of GnRH neurons, that has been shown to induce PCOS-like reproductive traits in female mice. Overall, if experimentally verified, this hypothesis could constitute a breakthrough in understanding the long sought after etiology (or ethiologies) for a subset of reproductive PCOS phenotypes. Furthermore, beyond the SNP hypothesis, the paper revisits Pro-αC inhibin-related molecules and their activities.