Activin A reduces luteinisation of human luteinised granulosa cells and has opposing effects to human chorionic gonadotropin in vitro

Abstract

The transition of the dominant follicle into the corpus luteum is of fundamental reproductive importance. Luteinisation involves disparate changes in the gene expression of follicular granulosa cells that differentiate into the granulosa-lutein cells of the corpus luteum after the gonadotrophin surge. We have shown that activin and human chorionic gonadotropin (hCG) have opposing effects during luteolysis. Therefore, we hypothesised that activin A was an inhibitor of luteinisation that was blocked during the pre-ovulatory gonadotrophin surge. Ovarian tissue and cells were collected from women with regular cycles having hysterectomy and women undergoing oocyte retrieval for assisted conception. Genes that changes during luteinisation were investigated in primary cultures of luteinised granulosa cells exposed to activin A and hCG in vitro. hCG promotes a luteinised granulosa cell phenotype, while activin A promotes a more follicular phenotype in luteinised cells by upregulating granulosa cells markers such as FSHR, HSD11B2 and downregulating LHCGR. In addition, activin A blocked hCG upregulation of STAR, HSD3B1 and HSD11B1 and downregulation of oestrogen receptor a. Activin A antagonised hCG effects in a dose-dependent manner and could block the hCG-stimulated molecular inhibitors of activin action (inhibin a-subunit, follistatin and TGFBR3). These studies show that hCG and activin A have opposing effects on luteinised granulosa cells and some effects of activin are seen only in the presence of hCG. While hCG can inhibit activin action in granulosa cells to facilitate luteinisation, activin A can promote an unluteinised phenotype in luteinised granulosa cells. This confirms the importance of adequate activin withdrawal during luteinisation in women.

Activin A and follistatin during the oestrous cycle and early pregnancy in ewes

“…In the current study, we have shown that treatment of luteinising ovine granulosa cells with activin A reduced progesterone secretion; thus, the increased activin A concentrations observed around the time of oestrous in the reduced ES ewes may have resulted in poor luteal function in these ewes. Similar to what was observed in the current study, activin A has been shown to reduce luteinisation of granulosa cells in vitro in both humans and cattle (Myers et al 2008, Kayani et al 2009). Activin A also suppressed progesterone production in vitro from granulosa cells collected from preovulatory follicles in rats (Miro et al 1991).…”

“…The activin pathway has been postulated to be involved in regulation of multiple reproductive processes including ovarian follicular development (Knight et al 2012), luteinisation of the follicular cells (Myers et al 2008, Kayani et al 2009), early embryo development (Rajput et al 2013) and uterine function during implantation of the conceptus (Singh et al 2011). As a member of the transforming growth factor beta superfamily of growth factors, activin forms from the dimerisation of two b-subunits of inhibin (INHB), with different combinations forming functionally different isoforms (Knight 1996, Mellor et al 2003.…”

Activin A inhibits activation of human primordial follicles in vitro

“…However, inhibitory actions of Activin A on small secondary murine follicles have been reported [23]. Indeed, inhibitory roles of activin A have been documented in various cells and tissues such as CHO-K1 (Chinese hamster ovary) cell line [27], and more recently in the luteinisation of human granulosa cells [28]. The exact mechanism of Activin A's inhibitory action is not known but there is some evidence in mice that changes in intraovarian concentration of Activin affects follicle development in a stage dependent manner [23] and the data presented here agrees with that.…”

Stimulation of tube formation mediated through the prostaglandin EP2 receptor in rat luteal endothelial cells

“…The expression of 3b-HSD, a key enzyme for the synthesis of P 4 through pregnenolone, profoundly affects the level of P 4 secreted by the CL (Tuckey 2005). Two types of 11b-HSD isoforms are present in granulosa-lutein cells, and both enzymes may be upregulated by LH during luteinization (Thurton et al 2003, Myers et al 2008. The expressions of P450scc, 3b-HSD, and 11b-HSD in the luteal EC preparation were considerably lower than those in the total ovarian cell preparation that excluded ECs.…”