The nature and role of the peptidergic innervation of the ovary were examined by determining the location and function of vasoactive intestinal peptide (VIP)-containing nerve fibers in the immature rat ovary. Immunohistofluorescence analysis of prepubertal ovaries using a specific VIP antibody revealed sparse delicate VIP-immunoreactive fibers localized around veins and arterioles, in the interstitial tissue, and associated with the thecal layers of developing follicles. Radioimmunoassayable VIP content was found to be approximately 100 pg/ovary (3 nM). The VIP immunoreactivity coeluted with authentic VIP when subjected to Sephadex G-25 chromatography. VIP enhanced in vitro progesterone release from infantile (12 days old), juvenile (30 days old), and peripubertal ovaries and estradiol release during the two latter developmental periods. The maximal estradiol response to VIP occurred during the early and first proestrous phases of puberty. No response was observed during estrus or first diestrus. The progesterone response to VIP increased moderately between day 12 and first proestrus, and then strikingly at estrus and first diestrus. The stimulatory effect of VIP on ovarian steroid production was dose related, as determined in ovaries from PMSG-treated immature rats (ED50 = 215, 44, and 51 nM for estradiol, androgen, and progesterone, respectively). The specificity of the VIP effect was tested using five other gastrointestinal peptides (porcine peptide histidine isoleucine, gastric inhibitory polypeptide, secretin, motilin, and glucagon). Only peptide histidine isoleucine, which has the greatest sequence homology with VIP, enhanced ovarian steroid production at 50% of VIP effectiveness. VIPergic nerves thus appear to be involved in the developmental regulation of ovarian steroidogenesis.
Immunosympathectomy produced by treatment of newborn rats with antibodies to nerve growth factor (NGF) delays ovarian development and disrupts estrous cyclicity. While these alterations have been ascribed to loss of sympathetic neurons innervating the ovary, the treatment also causes partial loss of ovarian sensory innervation. The present experiments were undertaken to determine if selective interference with ovarian noradrenergic/sympathetic action would result in alterations of ovarian development similar to those caused by NGF antibodies (NGF Ab). We have used two approaches to disrupt catecholamine action on ovarian cells: 1) inhibition of beta-adrenoreceptors by local delivery of receptor blockers to the ovaries of juvenile rats; and 2) elimination of the sympathetic innervation by long term postnatal treatment with guanethidine (GD), an adrenergic neuron blocking agent. When GD is administered chronically it produces an autoimmune-mediated destruction of peripheral sympathetic nerves, without affecting cholinergic or sensory neurons. Of the receptor blockers tested, FM-24, a nonreversible antagonist, resulted in a sustained 70% decrease in available receptors throughout the 10-day period studied. In spite of this, the timing of puberty, assessed by the age at vaginal opening and first ovulation, was not delayed, suggesting that activation of the remaining receptors by an intact innervation suffices to maintain a normal noradrenergic influence. GD treatment initiated at the end of the first week of postnatal life and maintained for three weeks slowed the juvenile-peripubertal rate of body growth, delayed the time of vaginal opening and first ovulation, and disrupted subsequent estrous cyclicity, but did not affect the animals' fertility. The ovaries of GD-treated rats exhibited a striking loss of sympathetic (norepinephrine and neuropeptide Y) nerves but a normal sensory innervation (represented by fibers containing calcitonin gene-related peptide). The concentration of beta-adrenoreceptors in granulosa cells was reduced, suggesting follicular immaturity. Direct assessment of this inference by morphometric analysis of the ovaries revealed that follicular development was retarded. The progesterone and estrogen response of juvenile ovaries to gonadotropins in vitro were also reduced. At this time, circulating LH levels were slightly decreased, but neither LHRH content in the median eminence nor the LHRH response to prostaglandin E2 in vitro were affected.(ABSTRACT TRUNCATED AT 400 WORDS)
Neuropeptide Y (NPY)-like immunoreactivity has been found in nerves that innervate the rat ovary. In this study, we used immunohistochemical and biochemical methods to identify NPY in the prepubertal rat ovary. The normal distribution of NPY-containing nerve fibers and the route by which these nerves enter the ovary were analyzed with indirect immunofluorescence techniques. In ovaries with intact nerves, a profuse network of NPY-labeled fibers was observed surrounding blood vessels. Immunoreactive fibers were also seen in the interstitial tissue and coursing between follicles. Occasionally some fibers appeared to enter the follicles. Surgical transection of the superior ovarian nerve had no effect on NPY immunoreactivity; however, transection of the plexus nerve completely eliminated NPY-labeled nerve fibers in all ovarian compartments. The nature of this immunoreactivity was examined in extracts of pooled ovaries that were subjected to reverse phase HPLC and then analyzed by RIA. The major peak of NPY immunoreactivity in each extract eluted at the same time or slightly before synthetic porcine NPY. Two additional peaks of NPY-like immunoreactivity that eluted much earlier than porcine NPY were found in each extract. We conclude that the plexus nerve carries NPY afferents to the ovary and that the ovary contains NPY-like peptides, one of which has a retention time on reverse phase HPLC nearly identical to that of porcine NPY, whereas two others elute with earlier retention times. While the identity and composition of these substances remain to be determined, the presence of peptides that display NPY-like immunoreactivity in the ovary as well as the profuse network of NPY-containing fibers strongly imply a physiological involvement of NPY in the regulation of ovarian function.
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