Julie A.W. Stilley, Rongbin Guan, Donna A. Santillan, Bryan F. Mitchell, Kathryn G. Lamping, Deborah L. Segaloff

Previous studies from our laboratory revealed that the follicle stimulating hormone receptor (FSHR) is expressed at low levels in non-pregnant human myometrium and that it is up-regulated in pregnant term non-laboring myometrium; however, the physiological relevance of these findings was unknown. Herein, we examined signaling pathways stimulated by FSH in immortalized uterine myocytes expressing recombinant FSHR at different densities and show that cAMP accumulation is stimulated in all cases, but that inositol phosphate accumulation is stimulated only at high FSHR densities. Because an increase in cAMP quiets myometrial contractile activity but an increase in 1,4,5-triphoshoinositol stimulates contractile activity, we hypothesized that FSHR density dictates whether FSH quiets or stimulates myometrial contractility. Indeed, in human and mouse non-pregnant myometrium, which expresses low levels of FSHR, FSH application resulted in a quieting of contractile activity. In contrast, in pregnant term non-laboring myometrium, which expresses higher levels of FSHR, FSH application resulted in increased contractile activity. Examination of pregnant mouse myometrium from different stages of gestation revealed that FSHR levels remain low throughout most of pregnancy. Accordingly, through mid-gestation, the application of FSH resulted in a quieting of contractile activity. At Pregnancy Day 16.5, FSHR was up-regulated, though not yet sufficiently to mediate stimulation of contractility in response to FSH. This outcome was not observed until Pregnancy Day 19.5, when FSHR further up-regulated. Our studies describe a novel FSHR signaling pathway that regulates myometrial contractility, and suggest that myometrial FSHR levels dictate the quieting vs. stimulation of uterine contractility in response to FSH.