Activation of ovarian sympathetic nerves in polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is one of the most common human ovarian pathologies affecting women of reproductive age. Despite extensive investigation, the etiology of PCOS remains poorly understood. Experimentally, a PCO-like syndrome can be induced in rodents by a single dose of the long-acting estrogen, estradiol valerate (EV). We have used this model to examine the possibility that PCOS is associated with derangement of the sympathetic control of the ovary. The release of newly incorporated norepinephrine (NE) from ovarian nerve terminals in response to transmural stimulation of the gland increased significantly before the formation of cysts (30 days after EV injection) and remained elevated at the time when cysts form (60 days). The increase in evoked NE release was accompanied by an augmented NE content and enhanced incorporation of [3H]NE into ovarian tissue; both of these changes had been initiated by 30 days after EV treatment and became unambiguous at the time of cyst formation. The overall increase in ovarian sympathetic outflow suggested by these alterations in catecholamine homeostasis was accompanied by a thecal cell-interstitial tissue selective down-regulation ofβ-adrenergic receptors; theβ-adrenergic receptor concentration in these sympathetically innervated ovarian compartments was significantly lower in PCO than during the estrous phase of the estrous cycle, a time at which theβ-adrenergic receptor concentration reaches its lowest levels in normal cycling ovaries. Tyrosine hydroxylase activity was found to increase only when expressed per mg ovary, but not in absolute terms (i.e. per total ovary), suggesting regulation of enzyme activity by the enhanced catecholamine content. The results demonstrate that an activation of the sympathetic neurons innervating the ovary precedes the development of cysts in EV-induced PCOS and raise the possibility that a derangement of sympathetic inputs to the ovary contributes to the etiology of PCOS.