The mechanism of action of epidermal growth factor and transforming growth factor alpha on aromatase activity in granulosa cells from polycystic ovaries

Abstract

We investigated aromatization and the mechanism of action of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) on oestradiol biosynthesis in freshly prepared granulosa cells from polycystic ovaries. Freshly prepared granulosa cells from polycystic ovaries incubated for only 3 h under basal conditions secreted significantly (P< 0.001) greater amounts of oestradiol-17beta than that of granulosa cells from normal ovaries. 8-Bromo-cyclic adenosine monophosphate (8-Br-cAMP), but not follicle stimulating hormone (FSH) or luteinizing hormone (LH), further enhanced this activity. Both EGF and TGFalpha inhibited gonadotrophinor 8-Br-cAMP-stimulated, but not basal, oestradiol production. LH receptor (LHR) binding, estimated by immunolabelling the bound LH, was significantly (P< 0.001) reduced in granulosa cells from polycystic ovaries when compared with cells from normal ovaries. EGF or TGFalpha significantly reduced the binding in cultured cells from all patient groups (P< 0.05). More interestingly, a further increase of the inhibitory effect was seen in granulosa cells from polycystic ovaries (P < 0.001). In conclusion, granulosa cells from polycystic ovaries contain high levels of basal aromatase activity in vitro, which is probably inherited from the in-vivo condition. EGF and TGFalpha suppress oestradiol synthesis at a step beyond the production of cAMP and also LHR binding with more effect in granulosa cells from polycystic ovaries.

Interactions Between Follicle-Stimulating Hormone and Growth Factors in Modulating Secretion of Steroids and Inhibin-Related Peptides by Nonluteinized Bovine Granulosa Cells1

“…Exposure of granulosa cells to EGF/TGF␣ promotes cell proliferation [26] associated with a loss of differentiated function, exemplified by a marked reduction in E 2 production in vitro [27][28][29][30] and in vivo [31]. Theca cells have been identified as a key site of TGF␣ expression in the bovine ovary and evidence suggests that TGF␣ of thecal origin exerts a local paracrine action on neighboring granulosa cells to modulate their proliferation and responsiveness to gonadotropins and other regulatory factors [26,32].…”

Expression of mRNA and protein localization of epidermal growth factor and its receptor in goat ovaries

“…In cumulus cells, EGF promotes Ca 2+ efflux and improves their expansion during maturation (Hill et al ., 1999; O'Donnell et al ., 2004). It was furthermore reported that EGF stimulates granulosa cells proliferation in vitro (pig: May et al ., 1992) and estrogen production through aromatase activation (human: Misajon et al ., 1999; goat: Behl & Pandey, 2001). There is evidence for EGF regulating the in vitro cellular activities of granulosa cells either by inhibiting LH receptor production (Hattori et al ., 1995) or inhibin secretion (Serta & Seibel, 1993) or by stimulating FSH receptor expression (Luciano et al ., 1994) and binding affinity (May et al ., 1987).…”

“…EGF also promotes in vitro proliferation of porcine granulosa cells obtained from preantral follicles (Morbeck et al ., 1993) and growth of early follicles in cow (Gutierrez et al ., 2000), hamster (Roy, 1993), mouse (Boland & Gosden, 1994) and human (Roy & Kole, 1998). In antral follicles, EGF has been shown to stimulate in vitro oocyte maturation (mouse: Smitz et al ., 1998; De La Fuente et al ., 1999; sheep: Guler et al ., 2000; cattle: Lonergan et al ., 1996; human: Goud et al ., 1998; pig: Prochazka et al ., 2003; Li et al ., 2002), cumulus cells expansion (mouse: O'Donnell et al ., 2004), granulosa cell proliferation (pig: May et al ., 1992) and estrogen production (human: Misajon et al ., 1999).…”