Adrenoceptors and nerve growth factor. Effects of electro-acupuncture and physical exercise in rats with steroid-induced polycystic ovaries

Abstract: Polycystic ovary syndrome (PCOS) is complex endocrine and metabolic disorder associated with ovulatory dysfunction, follicular cyst and hyperandrogenism. The abnormalities detected in PCOS have been attributed to primary defects in the hypothalamic-pituitary unit, the ovarian microenvironment, the adrenal gland, and the insulin/insulin-like growth factor (IGF)-1 metabolic regulatory system. Despite extensive research seeking the pathogenesis of PCOS, there is still disagreement on the underlying mechanisms. During the last decades has the hypothesis of an increased sympathetic tone to the ovaries and increased central sympathetic outflow in women with PCOS been advanced.The aim of the present thesis was first to evaluate ovarian alteration of sympathetic markers, such as alpha1- and beta2-adrenoceptors (AR), neurotrophin nerve growth factor (NGF) and its receptor system in rats with estradiol valerate (EV) induced polycystic ovaries (PCO). Second, to evaluate the effect of low frequency (2Hz) electroacupuncture (EA) and voluntary physical exercise on these sympathetic markers in the EV-induced rat PCO model.The sympathetic nerves appears distinctly involved in the regulation of ovarian function. Recent works on sympathetic-related mechanisms underlying the development of steroid-induced PCO points to an hyper-responsiveness of beta2-adrenoceptor (AR) system in mediating NE signalling to the ovaries. The present studies demonstrates that rats with EV-induced PCO has not only disturbed intra-ovarian beta2-AR, tyrosine hydroxylase (TH) and p75 neurotrophin receptor (p75NTR) expression, but also disturbances in all the alpha1-AR subtypes expression during the first 30 days (early phase) after EV-injection. These data points to a role for the sympathetic nervous system in the pathogenesis of EV-induced PCO. It has previously been demonstrated that development of ovarian follicular cysts is preceded by an increased synthesis of ovarian nerve growth factor (NGF) and p75NTR mRNA in rats with EV-induced PCO. In the present work we demonstrate, by blocking endogenous NGF action, that EV-induced changes in ovarian morphology and expression of the sympathetic markers alpha1- and beta2-AR, p75NTR, NGF-tyrosine kinase receptor (TrkA) and TH are modulated by endogenous NGF. The data obtained further confirm the role for NGF in the pathogenesis of steroid-induced PCO in rats.Low frequency EA and physical exercise, through activation of muscle-nerve afferents, may modulate disturbed activity in the ovarian peripheral sympathetic nerve fibers. In the present studies we found that though low frequency EA do not affect ovarian morphology, repeated EA treatments decreased ovarian NGF and p75NTR protein and counteracted the EV-induced changes of alpha1-AR and beta2-AR. Moreover, we demonstrated that voluntary physical exercise normalized ovarian morphology was and counteracted the EV-induced increase of ovarian NGF and p75NTR as well as the dysregulated ovarian ARs. Our data indicate the effectiveness of EA and physical exercise in the regulation of ovarian responsiveness to sympathetic inputs. Thus it is suggested that EA and/or regular exercise could be effective in the treatment of anovulation and possibly in the prevention of human PCOS.In conclusion, our studies demonstrates that the early increase of ovarian NGF most probably constitute a major pathogenetic factor of the EV-induced PCO. The pathogenetic role of NGF might be exerted through its action on ovarian ARs expression, thus on the ovarian responsiveness to sympathetic input. The efficacy of therapeutical intervention such as EA and voluntary physical exercise in the normalization of ovarian morphology and expression of NGF and NGF-receptors and alpha1- and beta2-AR has also been demonstrated.