ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

Abstract

Kisspeptin (KISS1) signaling in the hypothalamic-pituitary (H-P) axis plays essential role in regulating gonadotropin secretion. KISS1 and KISS1 receptor (KISS1R) are also expressed in the ovary; however, the role of intraovarian KISS1 signaling remains largely unclear. Granulosa cell (GC)-specific expression of KISS1, and oocyte-specific expression of KISS1R indicate that GC-derived KISS1 may act on oocytes. Expression of KISS1 in GCs is induced by gonadotropins but it is absent in estrogen receptor β knockout (Erβnull) rats. We also observed that gonadotropin stimulation failed to induce maturation of Erβnull oocytes. Interestingly, KISS1 treatment of cumulus oocyte complexes (COCs) isolated from antral follicles promotes in vitro maturation of oocytes. Treatment of oocytes with KISS1 induced intracellular Ca2+ release, and increased activation of MAP kinase ERK1/2. KISS1 treatment also induced the expression of oocyte genes that are crucial for differentiation of GCs, and maturation of oocytes. Our findings suggest that ovarian KISS1-signaling plays an important role in gonadotropin induced follicle development and oocyte maturation.

ERβ Regulation of Gonadotropin Responses during Folliculogenesis

“…Despite an increased expression of FSHR, administration of PMSG fails to induce the genes required for an effective LH response [ 101 , 128 ]. Although there was no change in FSH-induced genes such as Star , expression of Lhcgr , Cyp11a1 , Cyp19a1 , Gata4 , and Npr2 failed to upregulate in Erβ KO GCs [ 10 , 100 , 101 , 129 ] ( Figure 5 ). These findings suggest that expression of a subset of FSH-induced genes is dependent on the presence of ERβ in GCs [ 101 ].…”

“…However, the molecular mechanism underlying such reduced cAMP production in GCs remains unclear [ 79 ]. In vitro and in vivo studies have also demonstrated defective antrum formation, associated with decreased cumulus expansion after FSH treatment [ 120 , 129 , 130 ]. Due to the reduced levels of Cyp11a1 and Cyp19a1 , GCs in Erβ KO preovulatory follicles exhibit significantly lower levels of FSH-induced estrogen synthesis [ 120 , 130 ].…”

“…We previously demonstrated that loss of ERβ results in failure of LH-induced Kiss1 gene expression in Erβ KO rat GCs [ 100 , 101 ]. Our recent findings suggest that ERβ-regulated ovarian kisspeptin may play an important role in preovulatory maturation of oocytes [ 129 ]. However, it remains unknown if ovarian kisspeptin has any role in regulating GnRH neurons.…”

“…Our studies have shown that ERβ plays a major role in regulating the GC-genes that are important for oocyte maturation and induction of ovulation [ 10 , 100 , 101 , 129 ]. Administration of gonadotropins for ovarian stimulation is a common practice in assisted reproductive technologies [ 174 , 175 ].…”