Guanethidine-mediated destruction of ovarian sympathetic nerves disrupts ovarian development and function in rats

H. E. Lara, J. K. McDonald, C. E. Ahmed, Sergio Ojeda

    Research output: Contribution to journalArticle

    68 Citations (Scopus)

    Abstract

    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 β-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 β-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. The immunocytochemical appearance and distribution of hypothalamic LHRH, neuropeptide Y, and tyrosine hydroxylase-containing nerve terminals, and tubero-infundibular tyrosine hydroxylase-containing neurons was not affected by the GD treatment. The results substantiate the view that ovarian sympathetic nerves contribute to the developmental regulation of ovarian function and are important for the acquisition and maintenance of ovarian reproductive capacity. (Endocrinology 127: 2199-2209, 1990) Address all correspondence and reprint requests to: Dr. S. R. Ojeda, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. * This work was supported by the Rockefeller Foundation and NIH Grants HD-24870, HD-00727, and RR-00163, and Emory University Research Grant 2-50016. Publication No. 1734 of the Oregon Regional Primate Research Center.

    Original languageEnglish (US)
    Pages (from-to)2199-2209
    Number of pages11
    JournalEndocrinology
    Volume127
    Issue number5
    StatePublished - Nov 1990

    Fingerprint

    Guanethidine
    Ovary
    Neuropeptide Y
    Gonadotropin-Releasing Hormone
    Tyrosine 3-Monooxygenase
    Nerve Growth Factor
    Periodicity
    Ovulation
    Primates
    Research
    Neurons
    Median Eminence
    Cholinergic Neurons
    Adrenergic Antagonists
    Antibodies
    Calcitonin Gene-Related Peptide
    Organized Financing
    Granulosa Cells
    Endocrinology
    Sensory Receptor Cells

    ASJC Scopus subject areas

    • Endocrinology
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Guanethidine-mediated destruction of ovarian sympathetic nerves disrupts ovarian development and function in rats. / Lara, H. E.; McDonald, J. K.; Ahmed, C. E.; Ojeda, Sergio.

    In: Endocrinology, Vol. 127, No. 5, 11.1990, p. 2199-2209.

    Research output: Contribution to journalArticle

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    abstract = "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 β-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 β-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. The immunocytochemical appearance and distribution of hypothalamic LHRH, neuropeptide Y, and tyrosine hydroxylase-containing nerve terminals, and tubero-infundibular tyrosine hydroxylase-containing neurons was not affected by the GD treatment. The results substantiate the view that ovarian sympathetic nerves contribute to the developmental regulation of ovarian function and are important for the acquisition and maintenance of ovarian reproductive capacity. (Endocrinology 127: 2199-2209, 1990) Address all correspondence and reprint requests to: Dr. S. R. Ojeda, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. * This work was supported by the Rockefeller Foundation and NIH Grants HD-24870, HD-00727, and RR-00163, and Emory University Research Grant 2-50016. Publication No. 1734 of the Oregon Regional Primate Research Center.",
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    N2 - 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 β-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 β-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. The immunocytochemical appearance and distribution of hypothalamic LHRH, neuropeptide Y, and tyrosine hydroxylase-containing nerve terminals, and tubero-infundibular tyrosine hydroxylase-containing neurons was not affected by the GD treatment. The results substantiate the view that ovarian sympathetic nerves contribute to the developmental regulation of ovarian function and are important for the acquisition and maintenance of ovarian reproductive capacity. (Endocrinology 127: 2199-2209, 1990) Address all correspondence and reprint requests to: Dr. S. R. Ojeda, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. * This work was supported by the Rockefeller Foundation and NIH Grants HD-24870, HD-00727, and RR-00163, and Emory University Research Grant 2-50016. Publication No. 1734 of the Oregon Regional Primate Research Center.

    AB - 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 β-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 β-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. The immunocytochemical appearance and distribution of hypothalamic LHRH, neuropeptide Y, and tyrosine hydroxylase-containing nerve terminals, and tubero-infundibular tyrosine hydroxylase-containing neurons was not affected by the GD treatment. The results substantiate the view that ovarian sympathetic nerves contribute to the developmental regulation of ovarian function and are important for the acquisition and maintenance of ovarian reproductive capacity. (Endocrinology 127: 2199-2209, 1990) Address all correspondence and reprint requests to: Dr. S. R. Ojeda, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. * This work was supported by the Rockefeller Foundation and NIH Grants HD-24870, HD-00727, and RR-00163, and Emory University Research Grant 2-50016. Publication No. 1734 of the Oregon Regional Primate Research Center.

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