Effects of Dietary Equol on the Pituitary of the Ovariectomized Rats

Abstract

The aim of our study was to evaluate the effects of dietary equol, metabolite of a phytoestrogen daidzein, on the secretion of prolactin (PRL) and lutenizing hormone (LH), as well as the expression of estrogen receptors (ERα, ERβ and truncated estrogen receptor-1 (TERP-1) in the pituitary gland of ovariectomized (ovx) female Sprague-Dawley rats. Two doses of equol (50 mg/kg of chow and 400 mg/kg of chow) were used and the results were compared with the effects of estradiol 3-benzoate (E2B), also given at two doses (4.3 mg/kg of chow and 17.3 mg/kg of chow). Treatment period was 3 months. Dietary equol administration at the high dose increased significantly serum PRL levels. This effect was also observed in the E2B group but this difference did not reach statistical significance. Surprisingly, high dose dietary equol treatment also significantly increased serum LH levels, which was in contrast to E2B treatment where serum LH levels were significantly decreased at both doses. Serum LH levels in the equol low group were unaffected. Equol treatment had no effects on pituitary ERα or ERβ gene expression. In contrast, high dose E2B treatment increased significantly pituitary ERα mRNA levels but decreased those of ERβ. Both doses of E2B also increased significantly pituitary TERP-1 mRNA levels. This effect was also observed in the equol high group but at a much smaller magnitude. In conclusion, high dose dietary equol administration to ovx rats exerts estrogenic like effects on the lactotropes and anti-estrogenic on the gonadotropes.

phytoestrogens - equol - pituitary - prolactin - LH - estrogen receptors - TERP-1

References

• 1 Lieberman ME, Maurer RA, Claude P, Wiklund J, Wertz N, Gorski J. Regulation of pituitary growth and prolactin gene expression by estrogen.  Adv Exp Med Biol. 1981;  138 151-163
• 2 Lieberman ME, Maurer RA, Gorski J. Estrogen control of prolactin synthesis in vitro.  Proc Natl Acad Sci USA. 1978;  75 5946-5949
• 3 Nedvidkova J, Kasafirek E, Dlabac A. Effect of enkephalin analogues Tyr-D-Ala-Gly-Phe-Cys(Et) and Tyr-D-Ala-Gly-Phe-Cys(Bu) on prolactin and growth hormone release in rats.  Endocrinol Exp. 1988;  22 255-259
• 4 Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade.  Cell. 1995;  83 835-839
• 5 Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA. Mechanisms of estrogen action.  Physiol Rev. 2001;  81 1535-1565
• 6 Mitchner NA, Garlick C, Ben-Jonathan N. Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland.  Endocrinology. 1998;  139 3976-3983
• 7 Wilson ME, Price Jr RH, Handa RJ. Estrogen receptor-beta messenger ribonucleic acid expression in the pituitary gland.  Endocrinology. 1998;  139 5151-5156
• 8 Friend KE, Ang LW, Shupnik MA. Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary.  Proc Natl Acad Sci USA. 1995;  92 4367-4371
• 9 Resnick EM, Schreihofer DA, Periasamy A, Shupnik MA. Truncated estrogen receptor product-1 suppresses estrogen receptor transactivation by dimerization with estrogen receptors alpha and beta.  J Biol Chem. 2000;  275 7158-7166
• 10 Friend KE, Resnick EM, Ang LW, Shupnik MA. Specific modulation of estrogen receptor mRNA isoforms in rat pituitary throughout the estrous cycle and in response to steroid hormones.  Mol Cell Endocrinol. 1997;  131 147-155
• 11 Schreihofer DA, Resnick EM, Soh AY, Shupnik MA. Transcriptional regulation by a naturally occurring truncated rat estrogen receptor (ER), truncated ER product-1 (TERP-1).  Mol Endocrinol. 1999;  13 320-329
• 12 Wuttke W, Jarry H, Westphalen S, Christoffel V, Seidlova-Wuttke D. Phytoestrogens for hormone replacement therapy?.  J Steroid Biochem Mol Biol. 2002;  83 133-147
• 13 Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.  Endocrinology. 1998;  139 4252-4263
• 14 Miksicek RJ. Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor.  J Steroid Biochem Mol Biol. 1994;  49 153-160
• 15 Marrian G, Haslewood G. Equol, a new inactive phenol isolated from the ketohydroxyoestrin fraction of mares urine.  Biochem J. 1932;  26 1227-1232
• 16 Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG, Katzenellenbogen JA. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta.  Bioorg Med Chem. 2004;  12 1559-1567
• 17 Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora.  Nutr Cancer. 2000;  36 27-32
• 18 Setchell KD, Brown NM, Desai PB, Zimmer-Nechimias L, Wolfe B, Jakate AS, Creutzinger V, Heubi JE. Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes.  J Nutr. 2003;  133 1027-1035
• 19 Morito K, Hirose T, Kinjo J, Hirakawa T, Okawa M, Nohara T, Ogawa S, Inoue S, Muramatsu M, Masamune Y. Interaction of phytoestrogens with estrogen receptors alpha and beta.  Biol Pharm Bull. 2001;  24 351-356
• 20 Kaziro R, Kennedy JP, Cole ER, Southwell-Keely PT. The oestrogenicity of equol in sheep.  J Endocrinol. 1984;  103 395-399
• 21 Selvaraj V, Zakroczymski MA, Naaz A, Mukai M, Ju YH, Doerge DR, Katzenellenbogen JA, Helferich WG, Cooke PS. Estrogenicity of the isoflavone metabolite equol on reproductive and non-reproductive organs in mice.  Biol Reprod. 2004;  71 966-972
• 22 Rachon D, Vortherms T, Seidlova-Wuttke D, Wuttke W. Effects of dietary equol on body weight gain, intraabdominal fat accumulation, plasma lipids and glucose tolerance in ovariectomized Sprague-Dawley rats.  Menopause. 2007;  12 1-8
• 23 Roth C, Schricker M, Lakomek M, Strege A, Heiden I, Luft H, Munzel U, Wuttke W, Jarry H. Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model.  J Endocrinol. 2001;  169 361-371
• 24 Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR.  Genome Res. 1996;  6 986-994
• 25 Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta.  Eur J Endocrinol. 2003;  149 351-362
• 26 Odum J, Lefevre PA, Tittensor S, Paton D, Routledge EJ, Beresford NA, Sumpter JP, Ashby J. The rodent uterotrophic assay: critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay.  Regul Toxicol Pharmacol. 1997;  25 176-188
• 27 Tang BY, Adams NR. Effect of equol on oestrogen receptors and on synthesis of DNA and protein in the immature rat uterus.  J Endocrinol. 1980;  85 291-297
• 28 Chen HT. Postnatal development of pituitary lactotropes in the rat measured by reverse hemolytic plaque assay.  Endocrinology. 1987;  120 247-253
• 29 Dada MO, Campbell GT, Blake CA. A quantitative immunocytochemical study of the luteinizing hormone and follicle-stimulating hormone cells in the adenohypophysis of adult male rats and adult female rats throughout the estrous cycle.  Endocrinology. 1983;  113 970-984
• 30 Levine JE. New concepts of the neuroendocrine regulation of gonadotropin surges in rats.  Biol Reprod. 1997;  56 293-302
• 31 Shupnik MA, Gordon MS, Chin WW. Tissue-specific regulation of rat estrogen receptor mRNAs.  Mol Endocrinol. 1989;  3 660-665
• 32 Schreihofer DA, Stoler MH, Shupnik MA. Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness.  Endocrinology. 2000;  141 2174-2184
• 33 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
• 34 Scully KM, Gleiberman AS, Lindzey J, Lubahn DB, Korach KS, Rosenfeld MG. Role of estrogen receptor-alpha in the anterior pituitary gland.  Mol Endocrinol. 1997;  11 674-681
• 35 Arai Y, Uehara M, Sato Y, Kimira M, Eboshida A, Adlercreutz H, Watanabe S. Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake.  J Epidemiol. 2000;  10 127-135
• 36 Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study.  Menopause. 2002;  9 329-334
• 37 Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study.  Menopause. 2000;  7 236-242
• 38 Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, Swan D, Krupp KR, Miller KD, Novotny PJ. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial.  J Clin Oncol. 2000;  18 1068-1074
• 39 Davidson IW, Parker JC, Beliles RP. Biological basis for extrapolation across mammalian species.  Regul Toxicol Pharmacol. 1986;  6 211-237
• 40 Vocci F, Farber T. Extrapolation of animal toxicity data to man.  Regul Toxicol Pharmacol. 1988;  8 389-398
• 41 Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, Wolfe BE, Nechemias-Zimmer L, Brown NM, Lund TD, Handa RJ, Heubi JE. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora.  Am J Clin Nutr. 2005;  81 1072-1079

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