RECOMBINANT HUMAN ACTIVIN-A PROMOTES PROLIFERATION OF HUMAN LUTEINIZED PREOVULATORY GRANULOSA CELLS<i>IN VITRO</i>

Rabinovici, Jaron; Spencer, Susan J.; Jaffe, Robert B.

doi:10.1210/jcem-71-5-1396

Cited by 91 publications

(44 citation statements)

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“…We suspect that activin A may be able to facilitate cell division in luteinised cells just as it can in FSH-treated unluteinised granulosa cells (Li et al 1995, Matzuk et al 1996, Kumar et al 1997, Ogawa et al 2003. Indeed, a preliminary report suggested increased cell numbers in cultures of human luteinised granulosa cells grown in the presence of activin A (Rabinovici et al 1990), although it should be noted that this study reports only an increase in cell number and it cannot be excluded that the increase in number may be attributed to other contaminating cell types (i.e. fibroblasts, endothelial cells; Duncan et al 2005b) that are not terminally differentiated.…”

Section: Cells (G) Of An Antral (A) Follicle (A-c) and The Granulosa-mentioning

confidence: 93%

“…One molecule that may have a role in the prevention of luteinisation is activin A. Activin A, a dimeric glycoprotein and member of the transforming growth factor (TGF)-b superfamily is found in the follicular fluid and can delay granulosa cell luteinisation and/or atresia by decreasing basal and hCG-induced progesterone in human (Rabinovici et al 1990, Di Simone et al 1994, monkey (Brannian et al 1992), sheep and goat (Shidaifat 2001) granulosa cells. In addition, we have shown that activin A action may be involved in promoting luteolysis, at the end stage of the luteal phase (Myers et al 2007a).…”

Section: Introductionmentioning

confidence: 99%

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

Myers¹,

Driesche²,

McNeilly

et al. 2008

Journal of Endocrinology

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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.

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Section: Cells (G) Of An Antral (A) Follicle (A-c) and The Granulosa-mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Myers¹,

Driesche²,

McNeilly

et al. 2008

Journal of Endocrinology

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“…Furthermore, in the marmoset, addition of antibodies to the inhibin a-subunit suppressed human chorionic gonadotrophin (hCG)-induced progesterone secretion (Webley et al 1994). Conversely, activin A may delay granulosa cell luteinization and/or atresia and decrease basal and hCG-induced progesterone production in both cultured human and monkey granulosa-lutein cells (Rabinovici et al 1990, Brannian et al 1992, Di Simone et al 1994, further reinforcing a positive role for inhibin in promoting luteal formation. The effects of activin A could be reversed by its binding protein follistatin (Cataldo et al 1994), the expression of which was upregulated by hCG in granulosa-lutein cells (Tuuri et al 1994), indicating another potential component of the gonadotrophin-dependent luteal support system.…”

Section: Ovulation Luteinization and CL Formationmentioning

confidence: 97%

TGF-β superfamily members and ovarian follicle development

Knight

Glister²

2006

Reproduction

1,063

807

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In recent years, exciting progress has been made towards unravelling the complex intraovarian control mechanisms that, in concert with systemic signals, coordinate the recruitment, selection and growth of follicles from the primordial stage through to ovulation and corpus luteum formation. A plethora of growth factors, many belonging to the transforming growth factor-b (TGF-b) superfamily, are expressed by ovarian somatic cells and oocytes in a developmental, stage-related manner and function as intraovarian regulators of folliculogenesis. Two such factors, bone morphogenetic proteins, BMP-4 and BMP-7, are expressed by ovarian stromal cells and/or theca cells and have recently been implicated as positive regulators of the primordial-to-primary follicle transition. In contrast, evidence indicates a negative role for anti-Mullerian hormone (AMH, also known as Mullerianinhibiting substance) of pre-granulosa/granulosa cell origin in this key event and subsequent progression to the antral stage. Two other TGF-b superfamily members, growth and differentiation factor-9 (GDF-9) and BMP-15 (also known as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play key roles in promoting follicle growth beyond the primary stage; mice with null mutations in the gdf-9 gene or ewes with inactivating mutations in gdf-9 or bmp-15 genes are infertile with follicle development arrested at the primary stage. Studies on later stages of follicle development indicate positive roles for granulosa cell-derived activin, BMP-2, -5 and -6, theca cell-derived BMP-2, -4 and -7 and oocyte-derived BMP-6 in promoting granulosa cell proliferation, follicle survival and prevention of premature luteinization and/or atresia. Concomitantly, activin, TGF-b and several BMPs may exert paracrine actions on theca cells to attenuate LH-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection in monovular species may depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Changes in intrafollicular activins, GDF-9, AMH and several BMPs may contribute to this selection process by modulating both FSH-and IGF-dependent signalling pathways in granulosa cells. Activin may also play a positive role in oocyte maturation and acquisition of developmental competence. In addition to its endocrine role to suppress FSH secretion, increased output of inhibin by the selected dominant follicle(s) may upregulate LH-induced androgen secretion that is required to sustain a high level of oestradiol secretion during the pre-ovulatory phase. Advances in our understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.

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“…20 Kojima and Ogata 21 demonstrated that activin A acts in a tissue-and cell-specific manner to inhibit or stimulate cell growth or to induce differentiation. Activin A stimulates the growth of granulosa cells 22 and different ovarian cancer cell lines. 23 In contrast, it also exerts growth inhibitory effects in a number of cell lines, such as mammary epithelial cells, 24 28 who demonstrated that activin A-transfected oesophageal carcinoma cells showed greater proliferation.…”

Section: Discussionmentioning

confidence: 99%

Expression of Activin A and Follistatin in Glioblastoma and Their Effects on U87 In Vitro

Zhang

et al. 2010

J Int Med Res

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In some cancer cell lines, the gene encoding activin A (inhibin bA [INHBA]) is overexpressed and enhances cancer proliferation. Protein levels of activin A and follistatin were assessed in glioblastoma and normal brain tissues in this study, and the effect of activin A and follistatin treatment on the proliferation of U87 human glioblastoma cells in vitro was also studied. High levels of activin A were observed in glioblastomas compared with normal brain tissue. In contrast, follistatin levels were similar between the two tissues.

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RECOMBINANT HUMAN ACTIVIN-A PROMOTES PROLIFERATION OF HUMAN LUTEINIZED PREOVULATORY GRANULOSA CELLSIN VITRO

Cited by 91 publications

References 0 publications

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

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

TGF-β superfamily members and ovarian follicle development

Expression of Activin A and Follistatin in Glioblastoma and Their Effects on U87 In Vitro

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