transforming-growth-factor-alpha and Polycystic-Ovary-Syndrome

Knowledgement on ovary function regulation is advancing. Classic concept about endocrine regulation by sexual hormones and gonadotrophin has turning to an hypothesis: autocrine and paracrine factors as intra-ovarian regulators. Follicular growth and steroidogenesis are mainly driven by follicle stimulating hormone (FSH), luteine hormone (LH) and steroids. On the other hand, the presence of intra-ovarian growth factors have an important role in modulation of gonadotrophin effects on ovarian functions. The influence of this factors on follicle growth are described.

Topics: Apoptosis; Epidermal Growth Factor; Female; Humans; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor alpha

The etiology of polycystic ovary syndrome (PCOS) has not yet been fully elucidated but involves a disruption of normal ovarian function and multisystem sequelae. A combination of abnormally functioning genes whose expression is influenced by environmental, extra-ovarian factors determines the symptoms. Growth factors are heavily involved in the pathophysiology, either contributing to or as a consequence of the arrested development of follicles, abnormal steroidogenesis and hyperinsulinemia. Hyperactivity of a--transforming growth factor (TGFa) and epidermal growth factor (EGF) may block stimulation of aromatase and attenuate apoptosis of follicles and other factors may interface with the insulin-like growth factor (IGF) system preventing arrested follicles from becoming atretic and preventing the selection of a dominant follicle. IGF-binding protein concentrations are decreased by insulin, freeing biologically active IGF-I which augments the action of luteinizing hormone (LH) by inducing LH receptors, hyperactivating the enzymes P450c17a and 17,20 lyase resulting in hyperandrogenism. Growth hormone itself may be involved in the pathophysiology, as in normoinsulinemic PCOS patients it is hypersecreted and its actions on growth factors and their binding proteins are similar to those of insulin.

Topics: Androgens; Epidermal Growth Factor; Female; Growth Substances; Humans; Insulin Resistance; Ovarian Follicle; Polycystic Ovary Syndrome; Somatomedins; Transforming Growth Factor alpha

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.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adult; Aromatase; Cells, Cultured; Epidermal Growth Factor; Estradiol; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Luteinizing Hormone; Polycystic Ovary Syndrome; Receptors, LH; Transforming Growth Factor alpha

The mechanism of anovulation in polycystic ovary (PCO) syndrome remains unknown. As circulating concentrations of FSH are apparently normal, and in vivo, granulosa cells from anovulatory PCO are hyperresponsive to FSH, it has been suggested that the lack of follicular development in anovulatory PCO is caused by overexpression of a paracrine growth factor that inhibits steroidogenesis. Epidermal growth factor and the structurally homologous transforming growth factor-alpha (TGF alpha) are suitable candidates for this role, but although the production of the latter has been demonstrated in the ovary, no comparison has been performed between the levels in normal ovaries and PCO. We compared the levels of TGF alpha in follicular fluid and in granulosa cell- and theca- and stroma-conditioned media from normal ovaries and PCO. TGF alpha was present in the range of 0.2-200 ng/mL in follicular fluid. There was a significant inverse correlation of TGF alpha with follicle size, with no differences between follicles from normal ovaries and PCO. Granulosa cell-conditioned medium contained concentrations of TGF alpha ranging from 0.1-200 ng/1000 cells. There was a wide range of concentrations in theca- and stroma-conditioned media, with levels varying from 0.2-100 ng/mg tissue and no consistent effect of LH. There were no significant differences between the levels from normal ovaries or PCO in medium conditioned by any compartment of the ovary. We conclude that the failure of folliculogenesis in PCO syndrome is not likely to be due to overproduction of TGF alpha by the ovary.

Topics: Anovulation; Female; Follicular Fluid; Humans; Menstrual Cycle; Ovarian Follicle; Ovariectomy; Ovary; Polycystic Ovary Syndrome; Reference Values; Transforming Growth Factor alpha