Previous work by our laboratory demonstrated that activation of the progesterone receptor through exogenous administration of progesterone suppressed glutamic acid decarboxylase-67 (GAD67) mRNA in the hypothalamus of the estrogen-primed ovariectomized rat. Since GAD67 is the major synthetic enzyme for the inhibitory transmitter, γ-aminobutyric acid, the finding raised the possibility that the endogenous activation of the progesterone receptor may act to restrain GAD67 expression during the natural preovulatory gonadotropin surge during proestrus in the rat, thereby allowing GnRH secretion and the resultant LH surge. To test this hypothesis, the progesterone receptor antagonist, RU486, was administered to regularly cycling proestrous rats and the effect on GAD67 and GAD65 mRNA levels in the preoptic area (POA) and medial basal hypothalamus (MBH) was examined. Serum luteinizing hormone (LH) levels were also examined in order to identify correlations between changes in POA and MBH GAD levels and production of the LH surge. GAD67 mRNA levels in the POA were increased in the cycling rat during proestrus at 18.00 h at the peak and just preceding the termination of the LH surge. There was no change in GAD67 mRNA levels in the MBH, and GAD65 expression was also unchanged during proestrus in the POA and MBH. Treatment with the antiprogestin RU486 resulted in an increase in GAD67 mRNA levels at 12.00 and 14.00 h in the POA, and in the MBH at 14.00, 16.00, and 18.00 h during proestrus, effects which preceded and correlated with the attenuated LH surge in RU486-treated rats at 18.00 h. GAD65 mRNA levels were also elevated by RU486 at 14.00 and 16.00 h in the POA, and at 14.00 h in the MBH during proestrus. These findings suggest that the progesterone receptor plays a role in restraining GAD expression in the hypothalamus during proestrus, and that this effect may be important for the production of the GnRH and LH surge.

Terasawa E: Luteinizing hormone-releasing hormone (LHRH) neurons: Mechanisms of pulsatile LHRH release. Vitam Horm 2001;63:91–129.
Moguilevsky JA, Wuttke W: Changes in the control of gonadotropin secretion by neurotransmitters during sexual development in rats. Exp Clin Endocrinol Diabetes 2001;109:188–195.
Levine JE: New concepts of the neuroendocrine regulation of gonadotropin surges in rats. Biol Reprod 1997;56:293–302.
Brann DW, Mahesh VB: Regulation of gonadotropin secretion by steroid hormones. Front Neuroendocrinol 1991;2:165–207.
Rao IM, Mahesh VB: Role of progesterone in the modulation of the preovulatory surge of gonadotropins and ovulation in the pregnant mare’s serum gonadotropin-primed immature rat and the adult rat. Biol Reprod 1986;35:1154–1161.
DePaolo LV: Attenuation of preovulatory gonadotropin surges by epostane: A new inhibitor of 3-beta-hydroxysteroid dehydrogenase. J Endocrinol 1989;118:59–68.
Collins RL, Hodgen GD: Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU486: A progesterone antagonist or agonist? J Clin Endocrinol Metab 1986;61:484–489.
Mahesh VB, Brann DW: Interactions between ovarian and adrenal steroids in the regulation of gonadotropin secretion. J Steroid Biochem Mol Biol 1992;41:495–513.
Chappell PE, Levine JE: Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology 2000;141:1477–1485.
Freeman ME, Duke KC, Croteau CM: Extinction of the estrogen-induced daily signal for LH release in the rat: A role for the proestrous surge of progesterone. Endocrinology 1976;99:223–229.
Chappell PE, Schneider JS, Kim P, Xu M, Lydon JP, O’Malley BW, Levine JE: Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice. Endocrinology 1999;140:3653–3658.
Fox SR, Harlan R, Shivers B, Pfaff DW: Chemical characterization of neuroendocrine targets for progesterone in the female rat brain and pituitary. Neuroendocrinology 1990;51:276–283.
Skinner DC, Caraty A, Allingham R: Unmasking the progesterone receptor in the preoptic area and hypothalamus of the ewe: No colocalization with gonadotropin-releasing neurons. Endocrinology 2001;142:573–579.
Dhandapani KM, Brann DW: The role of glutamate and nitric oxide in the reproductive neuroendocrine system. Biochem Cell Biol 2000;78:165–179.
Brann DW, Mahesh VB: Endogenous excitatory amino acid involvement in the preovulatory and the steroid-induced surge of gonadotropins in the rat. Endocrinology 1991;128:1541–1547.
Unda R, Brann DW, Mahesh VB: Progesterone suppression of glutamic acid decarboxylase (GAD67) mRNA levels in the preoptic area: Correlation to the luteinizing hormone surge. Neuroendocrinology 1995;62:562–570.
Brann DW, Zamorano PL, Putnam-Roberts CD, Mahesh VB: Gamma-aminobutyric acid-opioid interactions in the regulation of gonadotropin secretion in the immature female rat. Neuroendocrinology 1992;56:445–452.
Leonhardt S, Seong JY, Kim K, Thorun Y, Wuttke W, Jarry H: Activation of central GABAA- but not GABAB-receptors rapidly reduces pituitary LH release and GnRH gene expression in the preoptic/anterior hypothalamic area of ovariectomized rats. Neuroendocrinology 1995;61:655–662.
Mosotto C, Negro-Vilar A: GABA and gonadotropin secretion: evidence from in vitro studies on regulation of LHRH secretion; in Racagni G, Donoso AO (eds): GABA and Endocrine Function. New York, Raven Press, 1986, pp 243–250.
Martinez de la Escalera G, Choi AL, Weiner RI: Biphasic GABAergic regulation of GnRH secretion in GT1 cell lines. Neuroendocrinology 1994;59:420–425.
Adler BA, Crowley WR: Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat. Endocrinology 1986;118:91–97.
Herbison AE, Dyer RG: Effect on luteinizing hormone secretion of GABA receptor modulation in the medial preoptic area at the time of proestrous luteinizing hormone surge. Neuroendocrinology 1991;53:317–320.
Funabashi T, Jinnai K, Kimura F: Bicuculline infusion advances the timing of Fos expression in LHRH neurons in the preoptic area of proestrous rats. Neuroreport 1997;8:771–774.
Kaufman DL, Houser CR, Tobin AJ: Two forms of the gamma-aminobutyric acid synthetic enzyme glutamic decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem 1991;56:720–723.
Herbison AE, Augood SJ, McGowan EM: Expression of glutamic acid decarboxylase messenger RNA in rat medial preoptic area neurons during the estrous cycle and after ovariectomy. Mol Brain Res 1992;14:310–316.
Leonhardt S, Boning B, Luft H, Wuttke W, Jarry H: Activation of gene expression of the gamma-aminobutyric acid rather than glutamatergic system in the preoptic area during the preovulatory gonadotropin surge of the rat. Neuroendocrinology 2000;71:8–15.
Peduto JC, Mahesh VB: Effects of progesterone on hypothalamic and plasma LHRH. Neuroendocrinology 1985;40:238–245.
Bilger M, Heger S, Brann DW, Paredes A, Ojeda SR: A conditional tetracycline-regulated increase in gamma amino butyric acid production near luteinizing hormone-releasing hormone nerve terminals disrupts estrous cyclicity in the rat. Endocrinology 2001;142:2102–2114.
Donoso AO, Banzan AM: Blockade of the LH surge and ovulation by GABA-T inhibitory drugs that increase brain GABA levels in rats. Psychoneuroendocrinology 1986;11:429–435.
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.
Levine JE, Chappell PE, Schneider JS, Sleiter NC, Szabo M: Progesterone receptors as neuroendocrine integrators. Front Neuroendocrinol 2001;22:69–106.
Copyright / Drug Dosage / Disclaimer
Copyright: 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.
You do not currently have access to this content.