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 of beta-adrenergic receptors; the beta-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 the beta-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.

Norepinephrine release in the immature ovary is regulated by autoreceptors and neuropeptide-Y.

Experiments were undertaken to study the role that neuropeptide-Y (NPY) and adrenergic autoreceptors may play in the regulation of norepinephrine (NE) release from the rat ovary. Ovaries from 28- to 32-day-old rats were preincubated with [3H]NE, and the release of the recently taken up catecholamine in response to electric field stimulation was assessed. The release was strictly dependent on the presence of extracellular calcium and decreased when the frequency of stimulation was increased. This drop in [3H]NE release was significantly reversed by exposure of the ovaries during stimulation to yohimbine, a selective alpha 2-adrenoreceptor blocker. The existence of prejunctional alpha 2-adrenergic autoreceptors in ovarian nerves was further suggested by the ability of exogenous NE to mimic the inhibitory effect of high frequency stimulation. NPY inhibited by 40% the release of [3H]NE induced by electrical stimulation. The specificity of this effect and its prejunctional nature were demonstrated by the finding that avian pancreatic polypeptide, a structural homolog of NPY that is not recognized by prejunctional NPY receptors of the Y2 subtype, failed to alter the induced release of [3H]NE. Neither NPY, avian pancreatic polypeptide, nor peptide-YY, another member of the pancreatic polypeptide fold family, altered progesterone or estradiol secretion from whole ovaries or granulosa cells in culture, suggesting that NPY (and its structural homologs) does not directly affect ovarian steroidogenesis. The results suggest that 1) the release of NE from ovarian sympathetic nerves is subjected to a dual modulatory influence provided by NE itself and NPY; and 2) this regulatory effect is exerted via specific prejunctional receptors. Such NE/NPY actions are likely to regulate the availability of NE to its postsynaptic receptors during ovarian development and adult function. The fact that NPY is mostly released during high frequency stimulation raises the possibility of NPY involvement in ovarian dysfunctions associated with situations of enhanced sympathetic discharge, such as strenuous exercise and psychogenic amenorrhea.

Release of norepinephrine from the rat ovary: local modulation of gonadotropins.

Experiments were undertaken to define the role of gonadotropins in the release of norepinephrine and the relationship with beta-receptors of the ovary. Rat ovaries were removed at different stages of the estrous cycle and incubated in [3H]norepinephrine. Subsequently, ovaries were electrically stimulated and the release of [3H]norepinephrine was recorded. There were no changes in the norepinephrine content during the estrous cycle. The ovary exhibited cyclical variation in norepinephrine-induced release during the estrous cycle. The lowest release of norepinephrine was found during diestrus; there was an increase during proestrus and estrus followed by a decline during metestrus. The release of norepinephrine changed in the opposite way to the beta-receptor number, suggesting a process involving down-regulation between norepinephrine release and beta-receptors of the ovary. Norepinephrine released from the ovary was locally regulated by gonadotropins. The presence of FSH in the superfusion medium stimulated the norepinephrine-induced release from the ovaries of rats in diestrus (by 20%) and estrus (by 40%), but no effect was found during proestrus. In addition, the presence of hCG stimulated (by 40%) norepinephrine-induced release during proestrus, but no changes were apparent during the other stages of the estrous cycle. These results suggest that the local action of gonadotropins on nerve terminals of the ovary might be one of the factors governing the changes in norepinephrine release through the estrous cycle. The changes in the norepinephrine released to the synaptic cleft might exert down-regulation on the beta-adrenergic receptor content of the ovary and in this way control the ovarian steroid secretory activity.