Elsevier

Brain Research

Volume 484, Issues 1–2, 10 April 1989, Pages 279-289
Brain Research

Suppression of spontaneous LH surges in estrogen-treated ovariectomized rats by microimplants of antiestrogens into the preoptic brain

https://doi.org/10.1016/0006-8993(89)90371-5Get rights and content

Abstract

Studies by others have shown that parenteral administration of antiestrogens blocks the positive feedback effect of estrogen on the luteinizing hormone (LH) surge mechanism. Since all estrogen-accumulating cells could be affected by this treatment, it is difficult to identify the site(s) at which this steroid acts to affect LH surges. In the present study we attempted to deprive specific hypothalamic neurons of estrogen by stereotaxically implanting antiestrogen-containing microcannulae into the brains of ovariectomized (OVX) rats which, otherwise, were completely estrogenized. The animal model used in these studies was the 14-day OVX rat into which 2 estradiol-containing Silastic capsules were inserted s.c. on day 14 (day 0). Microcannulae were placed into either the medial or lateral preoptic nuclei (MPN, LPN) on day 0 and the effects on LH release were examined 2 days later (day 2). When empty cannulae were placed into the MPN or LPN, 6 of 7 and 8 of 8 rats, respectively, had normal spontaneous LH surges. In contrast, when cannulae containing either CI-628, LY 10074 or Keoxifene were implanted into MPN only 33.3, 0, and 14.3% of the rats, respectively, had LH surges by 16.00 h on day 2 (time of LH peak). When antiestrogen-containing cannulae were placed into the LPN, all rats displayed normal LH patterns of release and concentrations. The antiestrogens did not prevent estrogen from suppressing elevated high post-ovariectomy plasma LH concentrations (negative feedback). To evaluate whether Keoxifene affected releasable luteinizing hormone-releasing hormone (LH-RH), we examined the effects of MPN-Keoxifene implants on LH sercretion evoked by electrochemical stimulation (ECS) of the MPN or the medial basal hypothalamus (MBH). In ketamine-anesthetized rats with empty cannulae, plasma LH increase significantly to reach peak concentrations 30–45 min after ECS. Similar LH concentrations and release patterns occurred in rats with the antiestrogen implant. Other studies examined the effects of MPN-Keoxifene implants on norepinephrine (NE) concentrations and rate constants following administration of α-methyl-p-tyrosine. NE concentrations and rate constants in the MPN and median eminence did not differ significantly in rats which had received empty versus Keoxifene-containing microcannulae. In the final series of studies we examined the response of LH-RH neurons to an intracerebroventricular (i.c.v.) infusion of norepinephrine (20 μg). Plasma LH peaked within 10 min after i.c.v. NE and, thereafter, declined towards baseline. Keoxifene did not affect LH-RH neuronal responsiveness to i.c.v. NE. Thus, while each of the antiestrogens studied had profound effects on spontaneous LH surges, the mechanism(s) by which these drugs exerted their effect remains unresolved. Releasable LH-RH pools were not altered and neither NE turnover rates in the MPN or median eminence nor LH-RH neuronal responsiveness to NE was affected. However, it is possible that transduction of the endogenous NE signal required for the LH surge may be affected by alterations in the activity of estrogen-containing interneurons when antiestrogens are placed in the vicinity of LH-RH perikarya.

References (35)

  • BarracloughC.A. et al.

    The role of catecholamines in the regulation of pituitary LH and FSH secretion

    Endocr. Rev.

    (1982)
  • BilliardR. et al.

    Inhibition of ovulation in the rat by intrahypothalamic implants of antiestrogen

    J. Endocrinol.

    (1973)
  • CampP. et al.

    Correlation of luteinizing hormone surges with estrogen nuclear and progestin cytosol receptors in the hypothalamus and pituitary gland. II. Temporal estradiol effects

    Neuroendocrinology

    (1985)
  • CampP. et al.

    Correlation of luteinizing hormone surges with estrogen nuclear and progestin receptors in the hypothalamus and pituitary gland. I. Estradiol dose response effects

    Neuroendocrinology

    (1985)
  • FuchsE. et al.

    Biochemical and morphological evidence for the existence of preoptic estrogen receptive neurons utilizing GABA as a neurotransmitter

    Acta Endocrinol.

    (1984)
  • GoodmanR.L.

    The site of the positive feedback action of estradiol in the rat

    Endocrinology

    (1978)
  • HeritageA.S. et al.

    3H-estradiol in catecholamine neurons of rat brain stem: combined localization by autoradiography and formaldehyde-induced fluorescence

    J. Comp. Neurol.

    (1977)
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