Alteration in localization of steroid hormone receptors and coregulatory proteins in follicles from cows with induced ovarian follicular cysts

Abstract

Cystic ovarian disease (COD) is an important cause of infertility in cattle. The altered follicular dynamics and cellular differentiation observed in COD may be mediated through a disruption of the expression of steroid receptors and their associated transcriptional cofactors. The aim of this study was to determine the protein expression profiles of ESR1, ESR2, PGR, AR, NCOA3, NCOR2, and PHB2 (REA) in ovarian follicles in an experimental model of COD induced by the administration of ACTH. Ovaries were collected and follicles were dissected from heifers during the follicular phase (control) or from heifers treated with ACTH to induce the formation of ovarian follicular cysts. Ovaries were fixed, sectioned, and stained immunohistochemically for steroid receptors and the associated transcription factors. The relative expression of ESR1 was similar in follicular cysts and in tertiary follicles from both control and cystic cows and was significantly higher than in secondary follicles. The expression of ESR2 in the granulosa was higher in cystic follicles. No differences were seen for PGR. The expression of androgen receptor was significantly increased in tertiary follicles with lower immunostaining in cysts. The expression of NCOA3 was observed in the granulosa and theca with a significantly increased expression in the theca interna of cystic follicles. The highest levels of NCOR2 expression in granulosa, theca interna, and theca externa were observed in cysts. In granulosa cells, NCOR2 levels increase progressively as follicles mature and the treatment had no effect. In summary, ovaries from animals with induced COD exhibited altered steroid receptor expression compared with normal animals, as well as changes in the expression of their regulators. It is reasonable to suggest that in conditions characterized by altered ovulation and follicular persistence, such as COD, changes in the intra-ovarian expression of these proteins could play a role in their pathogenesis.

Molecular aspects of bovine cystic ovarian disease pathogenesis

“…In addition, studies on cows with COD induced by the administration of ACTH have evidenced changes only in the expression of ESR2 in cystic follicles compared with control follicles, partially coinciding with the findings in animals with spontaneous disease , Alfaro et al 2012. Studies have also demonstrated an increase in ESR1 expression in animals with spontaneous COD and not in the experimental model, differences that are probably due to the persistence time of the cysts (Salvetti et al 2012).…”

“…Studies have also demonstrated an increase in ESR1 expression in animals with spontaneous COD and not in the experimental model, differences that are probably due to the persistence time of the cysts (Salvetti et al 2012). Other authors have found analogous modifications in the expression of ESR2 in cysts from women with polycystic ovarian syndrome related to normal-size follicles (Jakimiuk et al 2002) and in prenatal testosterone-treated sheep characterized by an abnormal follicular persistence ).…”

“…It has been previously demonstrated that a subtle imbalance in the expression of the two subtypes of ESR in the components of the ovarian follicle could be involved in the pathogenesis of follicular cysts in cattle (Garverick 1997, Alfaro et al 2012, sheep ), humans (Shushan et al 1996, Jakimiuk et al 2002, and rodents ).…”

“…In relationship to AR, Hampton et al (2004) showed that this receptor is expressed in ovarian follicles of bovines, and that its expression is increased throughout folliculogenesis, whereas Alfaro et al (2012) found that AR mRNA expression is significantly increased in granulosa cells of bovine follicular cysts. This increase would be associated with the role of androgens in follicular differentiation and growth (Hillier & Tetsuka 1997, Vendola et al 1998, Walters et al 2008.…”

“…This increase would be associated with the role of androgens in follicular differentiation and growth (Hillier & Tetsuka 1997, Vendola et al 1998, Walters et al 2008. Furthermore, there are discrepancies between AR mRNA and protein expression, which could be explained by post-translational regulation (Sette et al 2010, Salvetti et al 2012. Finally, changes in the delicate balance between the ESR subtypes, coupled with alterations in the expression of AR, may contribute COD development especially to the maintenance over time of the cystic structures (Ortega et al 2008.…”