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Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats

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Abstract

Although estradiol (E2) may have some beneficial effects as a treatment for menopause symptoms, E2 also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E2 was developed. First, the effects of different duration of chronic E2 exposure (2 vs 6 months), or no such exposure, on proliferation (tumor incidence and weight, uterine weight) in adult, ovariectomized (OVX) rats was determined. Second, the effects of different dosages of E2 (0.03 or 0.09 mg/kg) compared to vehicle only on sexual behavior, and measures of proliferation of adult OVX rats treated with a chemical carcinogen (DMBA; 1.25, 12.50, or 25.00 mg), or inert vehicle, were investigated. Vehicle or E2 was administered subcutaneously (SC) to OVX rats once per week for 14 weeks. Six months of continuous E2 exposure increased tumor incidence, tumor weight, and uterine weight, compared to 2 months of E2 or no E2 exposure. Rats administered DMBA had increased incidence, number, and size of tumors compared to vehicle treatment, and this effect appeared to be augmented by E2. Compared to vehicle, E2 increased lordosis and uterine weight. Thus, E2 may have the unfavorable effect of increasing proliferation when administered in chronic situations. Studies investigating the action of E2 for these effects are ongoing.

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References

  • Aidoo A, Bishop ME, Shelton SD, Lyn-Cook LE, Chen T, Manjanatha MG (2005) Effects of daidzein, genistein, and 17beta-estradiol on 7,12-dimethylbenz[a]anthracene-induced mutagenicity and uterine dysplasia in ovariectomized rats. Nutr Cancer 53:82–90 doi:10.1207/s15327914nc5301_10

    Article  PubMed  CAS  Google Scholar 

  • Callejo J, Cano A, Medina M, Villaronga M, Gonzalez-Bosquet E, Sabria J, Lailla JM (2005) Hormonal environment in the induction of breast cancer in castrated rats using dimethylbenzanthracene: influence of the presence or absence of ovarian activity and of treatment with estradiol, tibolone, and raloxifene. Menopause 12:601–608 doi:10.1097/01.gme.0000172269.32573.34

    Article  PubMed  Google Scholar 

  • Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR (1999) Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of osteoporotic fractures research group. Ann Intern Med 130:270–277

    PubMed  CAS  Google Scholar 

  • Cheng YJ, Karavolas HJ (1973) Conversion of progesterone to 5α-pregnane-3,20-dione and 3α-hydroxy-5α-pregnan-20-one by rat medical basal hypothalami and the effects of estradiol and stage of estrous cycle on the conversion. Endocrinology 93:1157–1162

    Article  PubMed  CAS  Google Scholar 

  • Cheskis BJ, Greger JG, Nagpal S, Freedman LP (2007) Signaling by estrogens. J Cell Physiol 213:610–617 doi:10.1002/jcp.21253

    Article  PubMed  CAS  Google Scholar 

  • Cheskis BJ, Greger J, Cooch N, McNally C, Mclarney S, Lam HS, Rutledge S, Mekonnen B, Hauze D, Nagpal S, Freedman LP (2008) MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways. Steroids 73:901–905 doi:10.1016/j.steroids.2007.12.028

    Article  PubMed  CAS  Google Scholar 

  • Cheung SY, Yuen MT, Choi HL, Cheng HK, Huang Y, Chen S, Chan FL (2003) An expression study of hormone receptors in spontaneously developed, carcinogen-induced and hormone-induced mammary tumors in female Noble rats. Int J Oncol 22:1383–1395

    PubMed  CAS  Google Scholar 

  • Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285 doi:10.1056/NEJM200101253440407

    Article  PubMed  CAS  Google Scholar 

  • Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE (1995) The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332:1589–1593 doi:10.1056/NEJM199506153322401

    Article  PubMed  CAS  Google Scholar 

  • Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047–1059 doi:10.1016/S0140–6736(97)08233–0

    Article  Google Scholar 

  • Constantinou AI, Lantvit D, Hawthorne M, Xu X, van Breemen RB, Pezzuto JM (2001) Chemopreventive effects of soy protein and purified soy isoflavones on DMBA-induced mammary tumors in female Sprague-Dawley rats. Nutr Cancer 41:75–81 doi:10.1207/S15327914NC41–1&2_10

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Bayon LE, Pursnami NK, Purdy RH (1998) The neurosteroids, progesterone and 3α,5α-THP, enhance sexual motivation, receptivity, and proceptivity in female rats. Brain Res 808:72–83 doi:10.1016/S0006–8993(98)00764–1

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Rhodes ME, Petralia SM, Walf AA, Sumida K, Edinger KL (2006) 3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors. Neuroscience 138:1007–1014 doi:10.1016/j.neuroscience.2005.06.015

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Sumida K, Dudek BC, Harney JP, Lydon JP, O'Malley BW, Pfaff DW, Rhodes ME (2006) Progesterone's effects to reduce anxiety behavior of aged mice do not require actions via intracellular progestin receptors. Psychopharmacology 186:312–322 doi:10.1007/s00213–006–0309–3

    Article  PubMed  CAS  Google Scholar 

  • Gustafsson JA (2003) What pharmacologists can learn from recent advances in estrogen signaling. Trends Pharmacol Sci 24:479–485 doi:10.1016/S0165–6147(03)00229–3

    Article  PubMed  CAS  Google Scholar 

  • Hankinson SE, Willet WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90:1292–1299 doi:10.1093/jnci/90.17.1292

    Article  PubMed  CAS  Google Scholar 

  • Hardy DF, Debold JF (1971) Effects of mounts without intromission upon the behavior of female rats during the onset of estrogen-induced heat. Physiol Behav 7:643–645 doi:10.1016/0031–9384(71)90120-X

    Article  PubMed  CAS  Google Scholar 

  • Hu YK, Lau KM, Ho SM, Russo J (1998) Increased expression of estrogen receptor β in chemically transformed human breast epithelial cells. Int J Oncol 12:1225–1228

    PubMed  CAS  Google Scholar 

  • Hulka BS (1996) Epidemiology of susceptibility to breast cancer. Prog Clin Biol Res 395:159–174

    PubMed  CAS  Google Scholar 

  • Lambe M, Hsieh CC, Chan HW, Ekbom A, Trichopoulos D, Adami HO (1996) Parity, age at first and last birth, and risk of breast cancer: a population-based study in Sweden. Breast Cancer Res Treat 38:305–311 doi:10.1007/BF01806150

    Article  PubMed  CAS  Google Scholar 

  • Leung G, Tsao SW, Wong YC (2003) Sex hormone-induced mammary carcinogenesis in female Noble rats: detection of differentially expressed genes. Breast Cancer Res Treat 77:49–63 doi:10.1023/A:1021123914339

    Article  PubMed  CAS  Google Scholar 

  • Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN (1995) Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 87:1681–1685 doi:10.1093/jnci/87.22.1681

    Article  PubMed  CAS  Google Scholar 

  • Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I (1999) Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer 81:339–344 doi:10.1002/(SICI)1097–0215(19990505)81:3<339::AID-IJC5>3.0.CO;2–6

    Article  PubMed  CAS  Google Scholar 

  • Meijer WJ, van Lindert AC (1992) Prophylactic oophorectomy. Eur J Obstet Gynecol Reprod Biol 47:59–65 doi:10.1016/0028–2243(92)90215-K

    Article  PubMed  CAS  Google Scholar 

  • Minino AM, Heron MP, Murphy SL, Kochankek KD (2007) Deaths: final data for 2004. Natl Vital Stat Rep 55(19). National Center for Health Statistics, Hyattsville, MD

    Google Scholar 

  • Ramon JM, Escriba JM, Casas I, Benet J, Iglesias C, Gavalda L, Torras G, Oromi J (1996) Age at first full-term pregnancy, lactation and parity and risk of breast cancer: a case-control study in Spain. Eur J Epidemiol 12:449–453 doi:10.1007/BF00143995

    Article  PubMed  CAS  Google Scholar 

  • Rapp PR, Morrison JH, Roberts JA (2003) Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J Neurosci 23:5708–5714

    PubMed  CAS  Google Scholar 

  • Razavi D, Farvacques C, Delvaux N, Beffort T, Paesmans M, Leclercq G, Van Houtte P, Paridaens R (1990) Psychosocial correlates of oestrogen and progesterone receptors in breast cancer. Lancet 335:931–933 doi:10.1016/0140–6736(90)90996-I

    Article  PubMed  CAS  Google Scholar 

  • Rhodes ME, Frye CA (2005) Estrogen-priming can enhance progesterone's anti-seizure effects in part by increasing hippocampal levels of allopregnanolone. Pharmacol Biochem Behav 81:907–916

    PubMed  Google Scholar 

  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288:321–333 doi:10.1001/jama.288.3.321

    Article  PubMed  CAS  Google Scholar 

  • Russo J, Russo IH (1996) Experimentally induced mammary tumors in rats. Breast Cancer Res Treat 39:7–20 doi:10.1007/BF01806074

    Article  PubMed  CAS  Google Scholar 

  • Russo IH, Russo J (1998) Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia 3:49–61

    Article  PubMed  CAS  Google Scholar 

  • Russo IH, Koszalka M, Gimotty PA, Russo J (1990) Protective effect of chorionic gonadotropin on DMBA-induced mammary carcinogenesis. Br J Cancer 62:243–247

    PubMed  CAS  Google Scholar 

  • Sakamoto S, Kudo H, Suzuki S, Mitamura T, Sassa S, Kuwa K, Chun Z, Yoshimura S, Maemura M, Nakayama T, Shinoda H (1997) Additional effects of medroxyprogesterone acetate on mammary tumors in oophorectomized, estrogenized, DMBA-treated rats. Anticancer Res 17:4583–4587

    PubMed  CAS  Google Scholar 

  • Shughrue PJ, Lane MV, Merchenthaler I (1997) Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J Comp Neurol 388:507–525 doi:10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6

    Article  PubMed  CAS  Google Scholar 

  • Shughrue PJ, Scrimo PJ, Merchenthaler I (1998) Evidence for the colocalization of estrogen receptor-β mRNA and estrogen receptor-α immunoreactivity in neurons of the rat forebrain. Endocrinology 139:5267–5270 doi:10.1210/en.139.12.5267

    Article  PubMed  CAS  Google Scholar 

  • Schairer C, Persson I, Falkeborn M, Naessen T, Troisi R, Brinton LA (1997) Breast cancer risk associated with gynecologic surgery and indications for such surgery. Int J Cancer 70:150–154 doi:10.1002/(SICI)1097-0215(19970117)70:2<150::AID-IJC2>3.0.CO;2-W

    Article  PubMed  CAS  Google Scholar 

  • Shumaker SA, et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative memory study: a randomized controlled trial. JAMA 289:2651–2662

    Article  PubMed  CAS  Google Scholar 

  • Shupnik MA (2007) Estrogen receptor-β: why may it influence clinical outcome in estrogen recpeptor-α positive breast cancer? Breast Cancer Res 9:107 doi:10.1186/bcr1735

    Article  PubMed  CAS  Google Scholar 

  • Stewart SL, Querec TD, Ochman AR, Gruver BN, Bao R, Babb JS, Wong TS, Koutroukides T, Pinnola AD, Klein-Szanto A, Hamilton TC, Patriotis C (2004) Characterization of a carcinogenesis rat model of ovarian preneoplasia and neoplasia. Cancer Res 64:8177–8183 doi:10.1158/0008–5472.CAN-04–1702

    Article  PubMed  CAS  Google Scholar 

  • Sugiura H, Toyama T, Hara Y, Zhang Z, Kobayashi S, Fujii Y, Iwase H, Yamashita H (2007) Expression of estrogen receptor β wild-type and its variant ERßcs/β2 is correlated with better prognosis in breast cancer. Jpn J Clin Oncol 37:820–828 doi:10.1093/jjco/hym114

    Article  PubMed  Google Scholar 

  • Thomas HV, Key TJ, Allen DS, Moore JW, Dowsett M, Fentiman IS, Wang DY (1997) A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey. Br J Cancer 76:401–405

    PubMed  CAS  Google Scholar 

  • Ting AY, Kimler BF, Fabian CJ, Petroff BK (2007) Characterization of a preclinical model of simultaneous breast and ovarian cancer progression. Carcinogenesis 28:130–135 doi:10.1093/carcin/bgl140

    Article  PubMed  CAS  Google Scholar 

  • Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, Banerjee S, Koenig KL, Shore RE, Strax P, Pasternack BS (1995) A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87:190–197 doi:10.1093/jnci/87.3.190

    Article  PubMed  CAS  Google Scholar 

  • Vongher JM, Frye CA (1999) Progesterone in conjunction with estradiol has neuroprotective effects in an animal model of neurodegeneration. Pharmacol Biochem Behav 64:777–785 doi:10.1016/S0091–3057(99)00140–9

    Article  PubMed  CAS  Google Scholar 

  • Walf AA, Frye CA (2005a) Antianxiety and antidepressive behavior produced by physiological estradiol regimen may be modulated by hypothalamic-pituitary-adrenal axis activity. Neuropsychopharmacology 30:1288–1301 doi:10.1038/sj.npp.1300713

    Article  PubMed  CAS  Google Scholar 

  • Walf AA, Frye CA (2005b) ERβ-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats. Neuropsychopharmacology 30:1598–1609 doi:10.1038/sj.npp.1300713

    Article  PubMed  CAS  Google Scholar 

  • Walf AA, Frye CA (2006) A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology 31:1097–1111

    PubMed  CAS  Google Scholar 

  • Walf AA, Frye CA (2007) Administration of estrogen receptor β-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats. Pharmacol Biochem Behav 86:407–414 doi:10.1016/j.pbb.2006.07.003

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported, in part, by grants from the Department of Defense CDMRP Breast Cancer Research Program and National Science Foundation. Assistance, provided by Carolyn Koonce, Danielle Osborne, Mary Unger, and Allicia Ryan, is greatly appreciated.

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Authors and Affiliations

  1. Department of Psychology, The University at Albany, State University of New York (SUNY), Life Sciences Research Building 01058, 1400 Washington Avenue, Albany, NY, 12222, USA

    Alicia A. Walf & Cheryl A. Frye

  2. Department of Biological Sciences, The University at Albany (SUNY), Albany, NY, USA

    Cheryl A. Frye

  3. The Centers for Neuroscience, The University at Albany (SUNY), Albany, NY, USA

    Cheryl A. Frye

  4. Department of Life Sciences Research, The University at Albany (SUNY), Albany, NY, USA

    Cheryl A. Frye

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  1. Alicia A. Walf
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  2. Cheryl A. Frye
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Correspondence to Cheryl A. Frye.

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Walf, A.A., Frye, C.A. Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats. AGE 31, 221–229 (2009). https://doi.org/10.1007/s11357-008-9079-7

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  • DOI: https://doi.org/10.1007/s11357-008-9079-7

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