Hypothalamic and Pituitary Actions of Gonadal Steroids
Direct Actions of Estradiol on the Anterior Pituitary Gland Are Required for Hypothalamus-Dependent Lactotrope Proliferation and Secretory Surges of Luteinizing Hormone but Not of Prolactin in Female RatsYin P. · Kawashima K. · Arita J.
Department of Physiology, Yamanashi Medical University, Yamanashi, Japan
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Estradiol induces surges of prolactin (PRL) and luteinizing hormone (LH) secretion as well as lactotrope proliferation in female rats. We examined whether these hypothalamus-dependent events require the direct action of estradiol on the anterior pituitary gland by selective blockade of its peripheral actions, using ICI182,780 (ICI), an antiestrogen that cannot cross the blood-brain barrier. Injection of ICI into ovariectomized rats, at a dose of 250 µg/day for 4 days, almost completely inhibited estradiol-induced growth of the uterus, proliferation of lactotropes as determined by bromodeoxyuridine incorporation, and afternoon surges of LH secretion. However, ICI only partially inhibited estradiol-induced surges of PRL secretion and had no effect on estradiol-induced tonic inhibition of LH secretion even at the highest dose of 1,000 µg/day. The inhibitory effects of ICI found at 250 µg/day were attributable to its selective peripheral, but not central actions since ICI did not alter hypothalamic expression of progesterone receptors, an estradiol-dependent brain process. Estradiol-induced increases in the number of progesterone receptor-immunoreactive cells in the hypothalamic ventromedial nucleus and the medial preoptic area were not inhibited by this dose of ICI but were inhibited by 500 µg/day tamoxifen, an antiestrogen that can cross the blood-brain barrier. Treatment of cycling female rats with 250 µg/day ICI beginning from diestrus day 2 was also effective in blocking estrous lactotrope proliferation and preovulatory surges of LH secretion but not PRL secretion. Finally, in ovariectomized estradiol-treated pup-deprived lactating rats, ICI did not affect suckling-induced PRL secretion but completely blocked lactotrope proliferation. These results suggest that a direct estradiol action on the anterior pituitary gland is required for lactotrope proliferation and the positive feedback action on LH secretion but not for the secretory surges of PRL or for negative feedback.
© 2002 S. Karger AG, Basel
- Butcher RL, Collins WE, Fugo NW: Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17β throughout the 4-day estrous cycle of the rat. Endocrinology 1974;94:1704–1708.
- Smith MS, Freeman ME, Neill JD: The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: Prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 1975;96:219–226.
- Hashi A, Mazawa S, Kato J, Arita J: Pentobarbital anesthesia during the proestrous afternoon blocks lactotroph proliferation occurring on estrus in female rats. Endocrinology 1995;136:4665–4671.
- Neill JD, Freeman ME, Tillson SA: Control of the proestrus surge of prolactin and luteinizing hormone secretion by estrogens in the rat. Endocrinology 1971;89:1448–1453.
- De Paolo LV: Dose-dependent inhibition of the preovulatory surges of gonadotropins and prolactin by the antiestrogen CI-628: Possible sites of action. Biol Reprod 1985;32:745–752.
- Takahashi S, Okazaki K, Kawashima S: Mitotic activity of prolactin cells in the pituitary glands of male and female rats of different ages. Cell Tissue Res 1984;235:497–502.
- Goodman RL, Knobil E: The sites of action of ovarian steroids in the regulation of LH secretion. Neuroendocrinology 1981;32:57–63.
Freeman ME: The neuroendocrine control of the ovarian cycle of the rat; in Knobil E, Neill JD (eds): The Physiology of Reproduction, ed 2. New York, Raven Press, 1994, pp 613–658.
- Wiklund J, Wertz N, Gorski J: A comparison of estrogen effects on uterine and pituitary growth and prolactin synthesis in F344 and Holtzman rats. Endocrinology 1981;109:1700–1707.
- Lieberman ME, Maurer RA, Claude P, Gorski J: Prolactin synthesis in primary cultures of pituitary cells: regulation by estradiol. Mol Cell Endocrinol 1982;25:277–294.
- Sarkar DK, Gottschall PE, Meites J: Damage to hypothalamic dopaminergic neurons is associated with development of prolactin-secreting pituitary tumors. Science 1982;218:684–686.
- Arita J, Kimura F: Direct inhibitory effect of long term estradiol treatment on dopamine synthesis in tuberoinfundibular dopaminergic neurons: In vitro studies using hypothalamic slices. Endocrinology 1987;121:692–698.
- Song J, Jin L, Lloyd RV: Effects of estradiol on prolactin and growth hormone messenger RNAs in cultured normal and neoplastic (MtT/W15 and GH3) rat pituitary cells. Cancer Res 1989;49:1247–1253.
- Wuttke W, Meites J: Effects of ether and pentobarbital on serum prolactin and LH levels in proestrous rats. Proc Soc Exp Biol Med 1970;135:648–652.
Butcher RL, Collins WE, Fugo NW: Altered secretion of gonadotropins and steroids resulting from delayed ovulation in the rat. Endocrinology 1974;96:576–586.
- Yin P, Arita J: Differential regulation of prolactin release and lactotrope proliferation during pregnancy, lactation and the estrous cycle. Neuroendocrinology 2000;72:72–79.
- Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–3873.
- Aiyer MS, Fink G, Greig F: Changes in the sensitivity of the pituitary gland to leuteinizing hormone releasing factor during the oestrous cycle of the rat. J Endocrinol 1974:60:47–64.
- Debeljuk L, Vilchez-Martinez JA, Arimura A, Schally AV: Effect of gonadal steroids on the response to LH-RH in intact and castrated male rats. Endocrinology 1974;94:1519–1524.
- Libertun C, Cooper KJ, Fawcett CP, McCann SM: Effects of ovariectomy and steroid treatment on hypophyseal sensitivity to purified LH-releasing factor (LRF). Endocrinology 1974;94:518–525.
- Hashi A, Mazawa S, Chen SY, Yamakawa K, Kato J, Arita J: Estradiol-induced diurnal changes in lactotroph proliferation and their hypothalamic regulation in ovariectomized rats. Endocrinology 1996;137:3246–3252.
- Auger AP, Moffatt CA, Blaustein JD: Reproductively-relevant stimuli induce Fos-immunoreactivity within progestin receptor-containing neurons in localized regions of female rat forebrain. J Neuroendocrinol 1996;8:831–838.
Paxinos G, Watson C: The Rat Brain, ed 3. New York, Academic Press, 1997.
Watson RE, Wiegand SJ, Clough RW, Hoffman GE: Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology. Peptides 1986;7:155–159.
- Moffatt CA, Rissman EF, Shupnik MA, Blaustein JD: Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-α gene-disrupted mice. J Neurosci 1998;18:9556–9563.
- Neill JD: Sexual differences in the hypothalamic regulation of prolactin secretion. Endocrinology 1972;90:1154–1159.
- Legan SJ, Coon GA, Karsch FJ: Role of estrogen as initiator of daily LH surges in the ovariectomized rat. Endocrinology 1975;96:50–56.
- Wade GN, Blaustein JD, Gray JM, Meredith JM: ICI182,780: A pure antiestrogen that effects behaviors and energy balance in rats without acting in the brain. Am J Physiol 1993;265:R1392–R1398.
- MacLusky NJ, McEwen BS: Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others. Nature 1978;274:276–278.
Hunt TE: Mitotic activity in the hypophysis of the rat during pregnancy and lactation. Anat Rec 1949:105:361–373.
Neill JD, Nagy GM: Prolactin secretion and its control; in Knobil E, Neill JD (eds): The Physiology of Reproduction, ed 2. New York, Raven Press, 1994, pp 1833–1860.
Stratmann IE, Ezrin C, Kovacs K, Sellers EA: Effect of TRH (thyrotropin-releasing hormone) on the fine structure and replication of TSH and prolactin cells in the rat. Z Zellforsch 1973;145:23–37.
Lloyd HM, Meares JD, Jacobi J: Effects of oestrogen and bromocryptine on in vivo secretion and mitosis in prolactin cells. Nature 1975;225:497–498.
- Hayashi I, Sato GH: Replacement of serum by hormones permits growth of cells in a defined medium. Nature 1976;259:132–134.
- Prysor-Jones RA, Silverlight JJ, Jenkins JS: Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumor cells in vitro. J Endocrinol 1989;120:171–177.
- Arita J, Hashi A, Hoshi K, Mazawa S, Suzuki S: D2-dopamine-receptor-mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape. Neuroendocrinology 1998;68:163–171.
- Sakai T, Inoue K, Hasegawa Y, Kurosumi K: Effect of passive immunization to gonadotropin-releasing hormone (GnRH) using GnRH antiserum on the mitotic activity of gonadotropes in castrated male rats. Endocrinology 1988;122:2803–2808.
- Billestrup N, Swanson LW, Vale W: Growth hormone-releasing factor stimulates proliferation of somatotropins in vitro. Proc Natl Acad Sci USA 1986;83:6854–6857.
- Childs GV, Rougeau D, Unabia G: Corticotropin-releasing hormone and epidermal growth factor: mitogens for anterior pituitary corticotropes. Endocrinology 1995;136:1595–1602.
- Sarkar DK, Kim KH, Minami S: Transforming growth factor-β1 messenger RNA and protein expression in the pituitary gland: its action on prolactin secretion and lactotropic growth. Mol Endocrinol 1992;6:1825–1833.
- Kawashima K, Yamakawa K, Arita J: Involvement of phosphoinositide-3-kinase and p70 S6 kinase in regulation of proliferation of rat lactotrophs in culture. Endocrine 2000;13:385–392.
- Suzuki S, Yamamoto I, Arita J: Mitogen-activated protein kinase-dependent stimulation of proliferation of rat lactotrophs in culture by 3′,5′-cyclic adenosine monophosphate. Endocrinology 1999;140:2850–2858.
- Löfström A: Catecholamine turnover alterations in discrete areas of the median eminence of the 4- and 5-day cyclic rat. Brain Res 1977;120:113–131.
- Rance N, Wise PM, Selmanoff MK, Barraclough CA: Catecholamine turnover rates in discrete hypothalamic areas and associated changes in median eminence luteinizing hormone-releasing hormone and serum gonadotropins on proestrus and diestrous day 1. Endocrinology 1981;108:1795–1802.
- Donath J, Nishino Y: Effects of partial versus pure antiestrogens on ovulation and the pituitary-ovarian axis in the rat. J Steroid Biochem Mol Biol 1998;66:247–254.
- Döcke F, Dörner G: The mechanism of the induction of ovulation by oestrogens. J Endocrinol 1965;33:491–499.
- Weick RF, Smith ER, Dominguez R, Dhariwal APS, Davidson JM: Mechanism of stimulatory feedback effect of estradiol benzoate on the pituitary. Endocrinology 1971;88:293–301.
- Sarkar DK, Fink G: Luteinizing hormone releasing factor in pituitary stalk plasma from long-term ovariectomized rats: Effects of steroids. J Endocrinol 1980;86:511–524.
- Akema T, Tadokoro Y, Kimura F: Regional specificity in the effect of estrogen implantation within the forebrain on the frequency of pulsatile luteinizing hormone secretion in the ovariectomized rat. Neuroendocrinology 1984;39:517–523.
- Dluzen DE, Ramirez VD: In vivo activity of the LHRH pulse generator as determined with push-pull perfusion of the anterior pituitary gland of unrestrained intact and castrate male rats. Neuroendocrinology 1987;45:328–332.
- Kato A, Hiruma H, Kimura F: Acute estradiol modulation of electrical activity of the LHRH pulse generator in the ovariectomized rat: Restoration by naloxone. Neuroendocrinology 1994;59:426–431.
- McLean BK, Chang N, Nikitovitch-Winer MB: Ovarian steroids directly alter luteinizing hormone (LH) release by pituitary homografts. Endocrinology 1975;97:196–201.
- Strobl FJ, Levine JE: Estrogen inhibits luteinizing hormone (LH), but not follicle-stimulating hormone secretion in hypophysectomized pituitary-grafted rats receiving pulsatile LH-releasing hormone infusions. Endocrinology 1988;123:622–630.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.