Estrogen modulates myometrium-induced sympathetic neurite formation through actions on target and ganglion

doi:10.1016/S0306-4522(02)00262-2

Neuroscience

Volume 114, Issue 2, 1 October 2002, Pages 339-347

https://doi.org/10.1016/S0306-4522(02)00262-2 Get rights and content

Abstract

Estrogen induces rapid and extensive degeneration of rodent uterine myometrial sympathetic innervation. To clarify the underlying mechanisms, we used explant cultures to assess whether estrogen affects the myometrium’s ability to induce sympathetic neuritogenesis and the sympathetic neuron’s ability to respond. Superior cervical ganglion explants from ovariectomized adult donors extended neurites when cultured alone in serum-free medium, and their numbers increased 2.3-fold in the presence of myometrial explants from ovariectomized adult rats. The myometrium’s ability to induce neuritogenesis was abolished by injection of myometrium donors with 17β-estradiol 24 h prior to tissue harvest. Myometrial neurite-promoting effects were also abolished by adding 2×10⁻⁸M estradiol to the culture medium. Because outgrowth from ganglia of ovariectomized rats cultured alone was not affected by estrogen in the culture medium, this indicates that estrogen acts directly on myometrium to abrogate its neurite-promoting effects. However, estrogen injection of ganglion donor rats also inhibited neurite extension toward ovariectomized myometrium, suggesting that some factor in ovariectomized rats normally acts on the ganglion to prevent estrogen from inhibiting neurite outgrowth. When ganglia from hypophysectomized ovariectomized donors were cultured alone, neuritogenesis was normal but estrogen added to the culture medium now attenuated outgrowth. Prolactin but not other pituitary-derived hormones reversed the suppression of neuritogenesis induced by estrogen.

We conclude that estrogen acts directly on myometrium to inhibit its neuritogenic effects on sympathetic neurons. Estrogen can also attenuate neurite formation by acting directly on the ganglion; this effect normally is not apparent at low estrogen levels because a pituitary hormone (possibly prolactin) prevents the ganglion from responding fully to estrogen. With high in vivo estrogen, this pituitary hormone’s effects are abated, possibly through diminished release, and estrogen directly reduces ganglion neuritogenesis. Thus, estrogen regulates uterine sympathetic nerve remodeling through actions on myometrium, ganglion, and intermediary pituitary factors.

Section snippets

Experimental preparations

Experiments were conducted on female Sprague–Dawley rats aged 60–90 days purchased from Harlan Laboratories. Thirty-six rats were obtained intact and 22 rats were hypophysectomized (HYPOX) by the supplier prior to shipment; completeness of HYPOX was confirmed by post-mortem examination. All rats were anesthetized (27.5 mg/kg ketamine, 25 mg/kg xylazine, and 0.24 mg/kg atropine sulfate, i.p. injection) and OVX aseptically via bilateral dorsal incisions as described previously (Zoubina et al.,

Ganglion explants grow neurites in the absence or presence of myometrium

SCG explants from adult OVX, vehicle-injected donors cultured alone, showed appreciable neurite outgrowth at 3 days in culture (Fig. 1, Fig. 2). Outgrowth consisted of extensions from one or several regions of the explant, and these extensions appeared to be either single axons or axon fascicles, referred to here collectively as neurites.

The addition of myometrial smooth muscle from untreated OVX rats to cultures containing SCG explants from OVX donors resulted in a 232% increase in the numbers

Estrogen suppresses ganglion neuritogenesis by acting directly on the myometrium

When cultured alone, SCG explants extended neurite fascicles into the surrounding collagen matrix. Previous studies have shown neurite formation by adult sympathetic ganglia when cultured alone in serum-containing NGF-supplemented media, and have noted that this is less rapid and aggressive than that of perinatal ganglia (Argiro and Johnson, 1982, Roufa et al., 1983). While fiber outgrowth from the adult SCGs used in the present study is unlikely to have been optimal, ganglia from

Conclusions

These explant studies provide evidence that in vivo uterine sympathetic nerve remodeling following E₂ administration is due, in part, to direct effects of E₂ acting on the myometrium to render it inhospitable to sympathetic innervation. Estrogen also acts upon the sympathetic ganglion to alter outgrowth properties. Under conditions of high E₂, this hormone acts directly on the sympathetic ganglion to suppress neurite outgrowth, an effect that may act in concert with myometrial actions to

Acknowledgements

Supported by NIH Grant NS39570 with core facilities provided by Center Grant HD02528 from the NICHD. The authors are indebted to Dr. Walter Imagawa for his instruction and assistance in preparing the collagen gel cultures, and Dr. Don Johnson for helpful discussions.

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Estrogen modulates myometrium-induced sympathetic neurite formation through actions on target and ganglion

Abstract

Section snippets

Experimental preparations

Ganglion explants grow neurites in the absence or presence of myometrium

Estrogen suppresses ganglion neuritogenesis by acting directly on the myometrium

Conclusions

Acknowledgements

Brain Res.

Int. J. Dev. Neurosci.

Int. J. Dev. Neurosci.

Dev. Biol.

Steroids

Mol. Cell. Endocrinol.

Dev. Brain Res.

Dev. Brain Res.

Dev. Biol.

J. Auton. Nerv. Syst.

Brain Res.

J. Steroid Biochem. Mol. Biol.

Life Sci.

Auton. Neurosci.

Neuroscience

The cerebrospinal fluid from patients with prolactinoma promotes neurite growth of sensory neurones

NeuroReport

Roles of inhibin and estradiol in the regulation of follicle-stimulating hormone and luteinizing hormone secretion during the estrous cycle of the rat

Biol. Reprod.

Patterns and kinetics of neurite extension from sympathetic neurons in culture are age dependent

J. Neurosci.

Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture

Proc. Natl. Acad. Sci. USA

Effects of estrogen and/or progesterone on serum and pituitary gonadotropin levels in ovariectomized rats

Proc. Soc. Exp. Biol. Med.

Regulation of somatic growth and the somatotropic axis by gonadal steroids: primary effect on insulin-like growth factor I gene expression and secretion

Endocrinology

Effects of chronic oestrogen treatment are not selective for uterine noradrenaline-containing sympathetic nerves: a transplantation study

J. Anat.

Postnatal development of noradrenaline-containing nerves of the rat uterus

J. Auton. Nerv. Syst.

17beta-Estradiol enhances the outgrowth and survival of neocortical neurons in culture

Neurochem. Res.

The stimulating effect of prolactin on the neurite growth of sensory neurons in an organotypic culture

Tsitologiya

Estrogen-enhanced neurite growth: evidence for a selective induction of Tau and stable microtubules

J. Neurosci.