Adrenoceptor and Nerve Growth Factor: Effect of electroacupunture and physical excercise in rats with steroid-induced polycystic ovaries. 2005,

Polycystic ovary syndrome (PCOS) is a 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 the pathogenesis of PCOS is still unknown. During the last decade the hypothesis of an increased sympathetic tone to the ovaries and central sympathetic outflow in women with PCOS has gained support. The aim of the present thesis was first to evaluate ovarian alteration of the sympathetic markers: ?1- and??2-adrenoceptors (AR), 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) electro-acupuncture (EA) and voluntary physical exercise on these sympathetic markers in the EV-induced rat PCO model. The sympathetic nerves appear to be involved in the regulation of ovarian function. Recent work on sympathetic-related mechanisms underlying the development of steroid-induced PCO points to a hyper-responsiveness of ?2-AR system in mediating norepinephrine (NE) signalling to the ovaries. Our studies demonstrates that rats with EV-induced PCO has not only deregulated intra-ovarian ?2-AR, tyrosine hydroxylase (TH) and p75 neurotrophin receptor (p75NTR) expression, but also deregulated expression of all ?1-AR subtypes during the first 30 days (early phase) after EV-injection. It has previously been demonstrated that the development of ovarian follicular cysts is preceded by an increased synthesis of ovarian NGF and p75NTR mRNA in rats with steroid induced PCO. Blockade of endogenous NGF action restore the EV-induced changes in ovarian morphology and expression of the sympathetic markers ?1- and ?2-AR, p75NTR, NGF-tyrosine kinase receptor (TrkA) and TH. These data further confirm that there is a close interaction between NGF and the sympathetic nervous system 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 fibres. 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 ?1-AR and ?2-AR. Moreover, ovarian morphology was almost normalized and the EV-induced increase of ovarian NGF and p75NTR as well as the deregulated ovarian ARs was counteracted by physical exercise. Taken together our results suggest that EA and/or exercise could be effective in the treatment of anovulation and possibly in the prevention of human PCOS. In conclusion, our studies suggest that the early increase of ovarian NGF may 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, i.e. on the ovarian responsiveness to sympathetic input. Physical exercise almost normalized ovarian morphology and both EA and physical exercise normalize the expression of NGF and NGF-receptors, as well as ?1- and ?2-AR, suggesting that these interventions may have a therapeutical effect.