As circulating estrogen levels rise on the afternoon of proestrus, they stimulate the hypothalamo-pituitary axis. This estrogen positive feedback is pivotal to stimulate the luteinizing hormone (LH) surge required for ovulation and luteinization of ovarian follicles. In addition to estrogen, pre-LH surge progesterone is critical for an LH surge as was demonstrated by blocking progesterone synthesis. In ovariectomized (OVX) rats treated with trilostane, a blocker of the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) that catalyzes the conversion of pregnenolone to progesterone, estrogen did not induce an LH surge. Further, estrogen induced an LH surge in OVX and adrenalectomized (ADX) rats, indicating that the source of progesterone was neither the ovary nor adrenal gland. This estrogen-only LH surge was inhibited by pretreatment with trilostane, indicating that although the adrenal gland and ovary were not necessary for positive feedback, progesterone synthesis was critical for estrogen-induced positive feedback in an OVX/ADX rat. This suggested that the LH surge is dependent on the pre-LH surge synthesis of progesterone. Estrogen-induced progesterone receptors in the hypothalamus are vital for the LH surge, so a potential location for progesterone synthesis is the hypothalamus. OVX/ADX female rats were treated with 17β-estradiol (50 µg) and progesterone levels were assayed by RIA. Progesterone levels were elevated in hypothalamic tissue following estrogen treatment. No increases in tissue progesterone levels were found in parietal cortex, cerebellum, medulla, pituitary or plasma. Additionally, male rats that do not have an estrogen positive feedback-induced LH surge were examined. Castrated/ADX male rats had no increase in hypothalamic progesterone levels after estrogen treatment. Together, these data strongly suggest that estrogen enhances neuro progesterone synthesis in the hypothalamus that is involved in the positive feedback regulating the LH surge.

1.
Chazal G, Faudon M, Gogan F, Laplante E: Negative and positive effects of oestradiol upon luteinizing hormone secretion in the female rat. J Endocrinol 1974;61:511–512.
2.
Ferin M, Tempone A, Zimmering PE, Van de Wiele RL: Effect of antibodies to 17beta-estradiol and progesterone on the estrous cycle of the rat. Endocrinology 1969;85:1070–1078.
3.
Labhsetwar AP: Role of estrogens in ovulation: A study using the estrogen-antagonist, ICI 46,474. Endocrinology 1970;87:542–551.
4.
Brom GM, Schwartz NB: Acute changes in the estrous cycle following ovariectomy in the golden hamster. Neuroendocrinology 1968;3:366–377.
5.
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.
6.
Mahesh VB, Brann DW: Regulation of the preovulatory gonadotropin surge by endogenous steroids. Steroids 1998;63:616–629.
7.
Chappell PE, Levine JE: Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology 2000;141:1477–1485.
8.
Mahesh VB, Brann DW: Interaction between ovarian and adrenal steroids in the regulation of gonadotropin secretion. J Steroid Biochem Mol Biol 1992;41:495–513.
9.
Sanchez-Criado JE, Hernandez G, Bellido C, Gonzalez D, Tebar M, Diaz-Cruz MA, Alonso R: Periovulatory LHRH, LH and FSH secretion in cyclic rats treated with RU486: Effects of exogenous LHRH and LHRH antagonist on LH and FSH secretion at early oestrus. J Endocrinol 1994;141:7–14.
10.
Ke FC, Ramirez VD: Membrane mechanism mediates progesterone stimulatory effect on LHRH release from superfused rat hypothalami in vitro. Neuroendocrinology 1987;45:514–517.
11.
O’Malley BW, Schrader WT, Mani S, Smith C, Weigel NL, Conneely OM, Clark JH: An alternative ligand-independent pathway for activation of steroid receptors. Recent Prog Horm Res 1995;50:333–347.
12.
Chappell PE, Lee J, Levine JE: Stimulation of gonadotropin-releasing hormone surges by estrogen. II. Role of cyclic adenosine 3′5′-monophosphate. Endocrinology 2000;141:1486–1492.
13.
DePaolo LV: Attenuation of preovulatory gonadotrophin surges by epostane: A new inhibitor of 3 beta-hydroxysteroid dehydrogenase. J Endocrinol 1988;118:59–68.
14.
Nass TE, Lapolt PS, Judd HL, Lu JK: Alterations in ovarian steroid and gonadotrophin secretion preceding the cessation of regular oestrous cycles in ageing female rats. J Endocrinol 1984;100:43–50.
15.
Mahesh VB, Brann DW: Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids. Steroids 1998;63:252–256.
16.
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.
17.
Kalra SP, Kalra PS: Temporal interrelationships among circulating levels of estradiol, progesterone and LH during the rat estrous cycle: Effects of exogenous progesterone. Endocrinology 1974;95:1711–1718.
18.
Feder HH, Brown-Grant K, Corker CS: Pre-ovulatory progesterone, the adrenal cortex and the ‘critical period’ for luteinizing hormone release in rats. J Endocrinol 1971;50:29–39.
19.
Mann DR, Korowitz CD, Macfarland LA, Cost MG: Interactions of the light-dark cycle, adrenal glands and time of steroid administration in determining the temporal sequence of LH and prolactin release in female rats. Endocrinology 1976;99:1252–1262.
20.
Sridaran R, Blake CA: Effects of long-term adrenalectomy on periovulatory increases in serum gonadotrophins and ovulation in rats. J Endocrinol 1980;84:75–82.
21.
Baulieu EE: Steroid hormones in the brain: Several mechanisms?; in Fuxe K, Gustafsson JA (eds): Steroid Hormone Regulation of the Brain. Oxford, Pergamon, 1981, pp 3–14.
22.
Le Goascogne C, Robel P, Gouezou M, Sananes N, Baulieu EE, Waterman M: Neurosteroids: Cytochrome P-450scc in rat brain. Science 1987;237:1212–1215.
23.
Baulieu EE: Neurosteroids: A new function in the brain. Biol Cell 1991;71:3–10.
24.
Mellon SH: Neurosteroids: Biochemistry, modes of action, and clinical relevance. J Clin Endocrinol Metab 1994;78:1003–1008.
25.
Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, Jung-Testas I, Robel P, Akwa Y, Baulieu EE: Progesterone synthesis and myelin formation by Schwann cells. Science 1995;268:1500–1503.
26.
Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu EE: Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 1981;78:4704–4707.
27.
Sanne JL, Krueger KE: Expression of cytochrome P450 side-chain cleavage enzyme and 3-beta-hydroxysteroid dehydrogenase in the rat central nervous system: A study by polymerase chain reaction and in situ hybridization. J Neurochem 1995;65:528–536.
28.
Jung-Testas I, Hu ZY, Baulieu EE, Robel P: Neurosteroids: Biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 1989;125:2083–2091.
29.
Jung-Testas I, Alliot F, Pessac B, Robel P, Baulieu EE: Immunocytochemical localization of cytochrome P-450scc in cultured rat oligodendrocytes. C R Acad Sci III 1989;308:165–170.
30.
Mellon SH, Deschepper CF: Neurosteroid biosynthesis: Genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 1993;629:283–292.
31.
Guennoun R, Fiddes RJ, Gouezou M, Lombes M, Baulieu EE: A key enzyme in the biosynthesis of neurosteroids, 3 beta- hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in rat brain. Brain Res Mol Brain Res 1995;30:287–300.
32.
Nuti KM, Karavolas HJ: Effect of progesterone and its 5 alpha-reduced metabolites on gonadotropin levels in estrogen-primed ovariectomized rats. Endocrinology 1977;100:777–781.
33.
Sim JA, Skynner MJ, Herbison AE: Direct regulation of postnatal GnRH neurons by the progesterone derivative allopregnanolone in the mouse. Endocrinology 2001;142:4448–4453.
34.
Warner M, Tollet P, Stromstedt M, Carlstrom K, Gustafsson JA: Endocrine regulation of cytochrome P-450 in the rat brain and pituitary gland. J Endocrinol 1989;122:341–349.
35.
Corpechot C, Collins BE, Carey MP, Tsouros A, Robel P, Fry JP: Brain neurosteroids during the mouse oestrous cycle. Brain Res 1997;766:276–280.
36.
Micevych PE, Mills RH, Sinchak K, Chen J, Tao L, LaPolt P, Lu JKH: Estrogen increases progesterone expression in young but not old female rat hypothalamus. in Soc for Neurosci. 2000. New Orleans, LA, 349.316.
37.
Micevych P, Mills R, Sinchak K, Lapolt P, Chen J, Tao L, Lu J: Estrogen stimulates progesterone synthesis in rat hypothalamus. Soc Neurosci Abstr, San Diego, 2001, 631.615.
38.
Harms PG, Ojeda SR: A rapid and simple procedure for chronic cannulation of the rat jugular vein. J Appl Physiol 1974;36:391–392.
39.
Potts GO, Creange JE, Hardomg HR, Schane HP: Trilostane, an orally active inhibitor of steroid biosynthesis. Steroids 1978;32:257–267.
40.
Lu JK, Damassa DA, Gilman DP, Judd HL, Sawyer CH: Differential patterns of gonadotropin responses to ovarian steroids and to LH-releasing hormone between constant-estrous and pseudopregnant states in aging rats. Biol Reprod 1980;23:345–351.
41.
Day JR, LaPolt PS, Lu JK: Plasma patterns of prolactin, progesterone, and estradiol during early pregnancy in aging rats: Relation to embryonic development. Biol Reprod 1991;44:786–790.
42.
LaPolt PS, Matt DW, Lu JK: Progesterone implants delay age-related declines in regular estrous cyclicity and the ovarian follicular reserve in Long-Evans rats. Biol Reprod 1998;59:197–201.
43.
Power RF, Mani SK, Codina J, Conneely OM, O’Malley BW: Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 1991;254:1636–1639.
44.
Denner LA, Weigel NL, Maxwell BL, Schrader WT, O’Malley BW: Regulation of progesterone receptor-mediated transcription by phosphorylation. Science 1990;250:1740–1743.
45.
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.
46.
Levine JE: New concepts of the neuroendocrine regulation of gonadotropin surges in rats. Biol Reprod 1997;56:293–302.
47.
Sherwood NM, Fink G: Effect of ovariectomy and adrenalectomy on luteinizing hormone-releasing hormone in pituitary stalk blood from female rats. Endocrinology 1980;106:363–367.
48.
Gorski RA, Wagner JW: Gonadal activity and sexual differentiation of the hypothalamus. Endocrinology 1965;76:226–239.
49.
Cam V, Schlinger BA: Activities of aromatase and 3beta-hydroxysteroid dehydrogenase/delta4-delta5 isomerase in whole organ cultures of tissues from developing zebra finches. Horm Behav 1998;33:31–39.
50.
Akwa Y, Young J, Kabbadj K, Sancho MJ, Zucman D, Vourc’h C, Jung-Testas I, Hu ZY, Le Goascogne C, Jo DH, et al: Neurosteroids: Biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem Mol Biol 1991;40:71–81.
51.
Usui M, Yamazaki T, Kominami S, Tsutsui K: Avian neurosteroids. II. Localization of a cytochrome P450scc-like substance in the quail brain. Brain Res 1995;678:10–20.
52.
Tsutsui K, Yamazaki T: Avian neurosteroids. I. Pregnenolone biosynthesis in the quail brain. Brain Res 1995;678:1–9.
53.
Kohchi C, Ukena K, Tsutsui K: Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes p450scc, P450c17 and 3beta-HSD in the postnatal rat brain. Brain Res 1998;801:233–238.
54.
Robel PB: Neurosteroids and neuroactive steroids; in Micevych PEH (ed): Neurobiological Effects of Sex Steroid Hormones. Cambridge, Cambridge University Press, 1995, pp 281–296.
55.
Hu ZY, Bourreau E, Jung-Testas I, Robel P, Baulieu EE: Neurosteroids: Oligodendrocyte mitochondria convert cholesterol to pregnenolone. Proc Natl Acad Sci USA 1987;84:8215–8219.
56.
Zwain IH, Yen SS: Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain. Endocrinology 1999;140:3843–3852.
57.
Jung-Testas I, Renoir M, Bugnard H, Greene GL, Baulieu EE: Demonstration of steroid hormone receptors and steroid action in primary cultures of rat glial cells. J Steroid Biochem Mol Biol 1992;41:621–631.
58.
Azcoitia I, Sierra A, Garcia-Segura LM: Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain. Glia 1999;26:260–267.
59.
Sinchak K, Mills RH, Tao L, LaPolt P, Lu JKH, Micevych PE: Estrogen induces de novo progesterone synthesis in astrocytes. J Neuroscience Res 2003, in press.
60.
Yuan W, Connor ML: Protein kinase C activity and its effect on progesterone production by large and small porcine luteal cells. Proc Soc Exp Biol Med 1997;216:86–92.
61.
Toaff ME, Strauss JF, 3rd, Hammond JM: Regulation of cytochrome P-450scc in immature porcine granulosa cells by FSH and estradiol. Endocrinology 1983;112:1156–1158.
62.
Holt JA, Schreiber JR, Zirkin BR: Estradiol-induced changes in rabbit luteal cell progestin production and cholesterol and cholesterol ester content. Biochem Biophys Res Commun 1983;113:1026–1033.
63.
Endo T, Henmi H, Goto T, Kitajima Y, Kiya T, Nishikawa A, Manase K, Yamamoto H, Kudo R: Effects of estradiol and an aromatase inhibitor on progesterone production in human cultured luteal cells. Gynecol Endocrinol 1998;12:29–34.
64.
Gibori G, Chen YD, Khan I, Azhar S, Reaven GM: Regulation of luteal cell lipoprotein receptors, sterol contents, and steroidogenesis by estradiol in the pregnant rat. Endocrinology 1984;114:609–617.
65.
Rodway MR, Swan CL, Crellin NK, Gillio-Meina C, Chedrese PJ: Steroid regulation of progesterone synthesis in a stable porcine granulosa cell line: A role for progestins. J Steroid Biochem Mol Biol 1999;68:173–180.
66.
Rao MC, Palfrey HC, Nash NT, Greisman A, Jayatilak PG, Gibori G: Effects of estradiol on calcium-specific protein phosphorylation in the rat corpus luteum. Endocrinology 1987;120:1010–1018.
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.