Download PDF
Exp Clin Endocrinol Diabetes 2006; 114(2): 82-90
DOI: 10.1055/s-2006-923888
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Effects of Long-Term Treatment with Resveratrol and Subcutaneous and Oral Estradiol Administration on the Pituitary-Thyroid-Axis

M. Böttner[*] 1 , J. Christoffel[*] 2 , G. Rimoldi2 , W. Wuttke2
  • 1Department of Anatomy, University of Lübeck, Lübeck, Germany
  • 2Department of Clinical and Experimental Endocrinology, University of Göttingen, Göttingen, Germany
Further Information

Publication History

Received: July 12, 2005 First decision: August 28, 2005

Accepted: November 14, 2005

Publication Date:
29 March 2006 (online)

Also available at
    Permissions and Reprints

Abstract

The lack of estrogen during menopause is associated with various symptoms including osteoporosis, cardiovascular diseases, and menopausal symptoms. For many years, conventional hormone replacement therapy has been successfully used to treat these conditions. However, in light of recent studies that draw attention to potential hazards of conventional HRT, various attempts were undertaken to search for alternatives of classical HRT. Phytoestrogens are supposed to ameliorate various discomforts associated with menopause. Resveratrol (RES) is present in red wine, grapes and peanuts and has been implicated in cardioprotection and prevention of adverse side effects observed after regular HRT. As the pituitary-thyroid axis is a target of estrogen action, we first assessed the effects of E2 administration on thyroid hormone stimulating hormone releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion from pituitary cell cultures in vitro. Our data reveal that E2 treatment augments the TRH-induced TSH secretion. We furthermore designed a long-term study of three months to assess the effects of subcutaneous and oral administration of 17β-estradiol (E2), as well as the actions of RES on the pituitary-thyroid axis in ovariectomized (OVX) female rats. Our results demonstrate that serum levels of 1.0 and 8.1 µM RES lead to a significant increase in total serum trijodthyronine (T3) levels. OVX induces TSHβ mRNA in the adenohypohysis and E2 treatment attenuates this effect. Treatment of rats with subcutaneous implants of E2 does not affect the pituitary-thyroid axis, whereas orally applied E2 benzoate (E2B) increases plasma TSH and total thyroxine (T4) in OVX rats. In all animals, we could not detect changes in thyroid morphology as assessed by hematoxylin-eosin (HE) and Perjod-Acid Schiff's (PAS) staining.

Key words

Estrogen - phytoestrogen - TSH - T4 - T3

References

  • 1 Anderson J J, Garner S C. Phytoestrogens and bone.  Bailleres Clin Endocrinol Metab. 1998;  12 543-557
    PubMedGoogle Scholar
  • 2 Ashby J, Tinwell H, Pennie W, Brooks A N, Lefevre P A, Beresford N, Sumpter J P. Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF‐7 cells and its suggested cardiovascular protective effects.  J Appl Toxicol. 1999;  19 39-45
    CrossrefPubMedGoogle Scholar
  • 3 Bagchi D, Das D K, Tosaki A, Bagchi M, Kothari S C. Benefits of resveratrol in women's health.  Drugs Exp Clin Res. 2001;  27 233-248
    PubMedGoogle Scholar
  • 4 Bartalena L, Robbins J. Variations in thyroid hormone transport proteins and their clinical implications.  Thyroid. 1992;  2 237-245
    PubMedGoogle Scholar
  • 5 Baur A, Bauer K, Jarry H, Köhrle J. Effects of proinflammatory cytokines on anterior pituitary 5′-deiodinase type I and type II.  J Endocrinol. 2000;  167 505-515
    CrossrefPubMedGoogle Scholar
  • 6 Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;  362 419-427
    CrossrefPubMedGoogle Scholar
  • 7 Bhat K P, Lantvit D, Christov K, Mehta R G, Moon R C, Pezzuto J M. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models.  Cancer Res. 2001;  61 7456-7463
    PubMedGoogle Scholar
  • 8 Bhat K P, Pezzuto J M. Cancer chemopreventive activity of resveratrol.  Ann NY Acad Sci. 2002;  957 210-229
    PubMedGoogle Scholar
  • 9 Bi X L, Yang J Y, Dong Y X, Wang J M, Cui Y H, Ikeshima T, Zhao Y Q, Wu C F. Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia.  Int Immunopharmacol. 2005;  5 185-193
    CrossrefPubMedGoogle Scholar
  • 10 Böttner M, Wuttke W. Chronic treatment with low doses of estradiol affects pituitary and thyroid function in young and middle-aged ovariectomized rats.  Biogerontology. 2005;  6 261-269
    CrossrefPubMedGoogle Scholar
  • 11 Bowers J L, Tyulmenkov V V, Jernigan S C, Klinge C M. Resveratrol acts as a mixed agonist/antagonist for estrogen receptor alpha and beta.  Endocrinology. 2000;  141 3657-3667
    CrossrefPubMedGoogle Scholar
  • 12 Burger H. Hormone replacement therapy in the post-Women's Health Initiative era. Report of a meeting held in Funchal, Madeira, February 24 - 25, 2003.  Climacteric. 2003;  6 (Suppl 1) 11-36
    PubMedGoogle Scholar
  • 13 Cadenas S, Barja G. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3.  Free Radic Biol Med. 1999;  26 1531-1537
    CrossrefPubMedGoogle Scholar
  • 14 Carlson H E, Jacobs L S, Daughaday W H. Growth hormone, thyrotropin, and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pre-treatment.  J Clin Endocrinol Metab. 1973;  37 488-490
    PubMedGoogle Scholar
  • 15 Chen H J, Walfish P G. Effects of estradiol benzoate on thyroid-pituitary function in female rats.  Endocrinology. 1978;  103 1023-1030
    PubMedGoogle Scholar
  • 16 Chiechi L M. Dietary phytoestrogens in the prevention of long-term postmenopausal diseases.  Int J Gynaecol Obstet. 1999;  39-40
    PubMedGoogle Scholar
  • 17 Chiechi L M, Lobascio A, Grillo A, Valerio T. Phytoestrogen-containing food and prevention of postmenopausal osteoporosis and cardiovascular diseases.  Minerva Ginecol. 1999;  51 343-348
    PubMedGoogle Scholar
  • 18 D'Angelo S A, Fisher J S. Influence of estrogen on the pituitary-thyroid system of the female rat: mechanisms and loci of action.  Endocrinology. 1969;  84 117-122
    PubMedGoogle Scholar
  • 19 Davies P H, Sheppard M C, Franklyn J A. Inflammatory cytokines and type I 5′-deiodinase expression in phi1 rat liver cells.  Mol Cell Endocrinol. 1997;  129 191-198
    CrossrefPubMedGoogle Scholar
  • 20 De Leo, Lanzetta D, Vanni A L, D'Antona D, Severi F M. Low estrogen oral contraceptives and the hypothalamo-pituitary axis.  Contraception. 1991;  44 155-161
    CrossrefPubMedGoogle Scholar
  • 21 Donnelly L E, Newton R, Kennedy G E, Fenwick P S, Leung R H, Ito K, Russell R E, Barnes P J. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms.  Am J Physiol Lung Cell Mol Physiol. 2004;  287 L774-L783
    CrossrefPubMedGoogle Scholar
  • 22 Dubal D B, Kashon M L, Pettigrew L C, Ren J M, Finklestein S P, Rau S W, Wise P M. Estradiol protects against ischemic injury.  J Cereb Blood Flow Metab. 1998;  18 1253-1258
    PubMedGoogle Scholar
  • 23 ElAttar T M, Virji A S. Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation.  Anticancer Drugs. 1999;  10 187-193
    PubMedGoogle Scholar
  • 24 Faglia G, Beck-Peccoz P, Ferrari C, Ambrosi B, Spada A, Travaglini P. Enhanced plasma thyrotrophin response to thyrotrophin-releasing hormone following oestradiol administration in man.  Clin Endocrinol (Oxf). 1973;  2 207-210
    PubMedGoogle Scholar
  • 25 Fantz C R, Dagogo-Jack S, Ladenson J H, Gronowski A M. Thyroid function during pregnancy.  Clin Chem. 1999;  45 2250-2258
    PubMedGoogle Scholar
  • 26 Farbota L, Hofmann C, Oslapas R, Paloyan E. Sex hormone modulation of serum TSH levels.  Surgery. 1987;  102 1081-1087
    PubMedGoogle Scholar
  • 27 Fisher J S, D'Angelo S A. Stimulatory and inhibitory action of estradiol on TSH secretion.  Endocrinology. 1971;  88 687-691
    PubMedGoogle Scholar
  • 28 Foster J S, Wimalasena J. Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells.  Mol Endocrinol. 1996;  10 488-498
    CrossrefPubMedGoogle Scholar
  • 29 Freyberger A, Hartmann E, Hildebrand H, Krotlinger F. Differential response of immature rat uterine tissue to ethinylestradiol and the red wine constituent resveratrol.  Arch Toxicol. 2001;  74 709-715
    PubMedGoogle Scholar
  • 30 Fujii T, Sato K, Ozawa M, Kasono K, Imamura H, Kanaji Y, Tsushima T, Shizume K. Effect of interleukin-1 (IL‐1) on thyroid hormone metabolism in mice: stimulation by IL‐1 of iodothyronine 5′-deiodinating activity (type I) in the liver.  Endocrinology. 1989;  124 167-174
    PubMedGoogle Scholar
  • 31 Furlanetto T W, Nguyen L Q, Jameson J L. Estradiol increases proliferation and downregulates the sodium/idodide symporter gene in FRTL‐5 cells.  Endocrinology. 1999;  140 5705-5711
    CrossrefPubMedGoogle Scholar
  • 32 Gehm B D, McAndrews J M, Chien P Y, Jameson J L. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor.  Proc Natl Acad Sci USA. 1997;  94 14138-14143
    CrossrefPubMedGoogle Scholar
  • 33 Glinoer D. What happens to the normal thyroid during pregnancy?.  Thyroid. 1999;  9 631-635
    CrossrefPubMedGoogle Scholar
  • 35 Gual C, Kastin A J, Schally A V. Clinical experience with hypothalamic releasing hormones. 1. Thytrotropin-releasing hormone.  Recent Prog Horm Res. 1972;  28 173-200
    PubMedGoogle Scholar
  • 36 Hashimoto H, Igarashi N, Miyawaki T, Sato T. Effects of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 on type I iodothyronine 5′-deiodination in rat thyroid cell line, FRTL‐5.  J Interferon Cytokine Res. 1995;  15 367-375
    PubMedGoogle Scholar
  • 37 Henderson B E, Ross R K, Pike M C, Casagrande J T. Endogenous hormones as a major factor in human cancer.  Cancer Res. 1982;  42 3232-3239
    PubMedGoogle Scholar
  • 38 Herrington D M. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study.  Ann Intern Med. 1999;  131 463-466
    PubMedGoogle Scholar
  • 39 Inoue H, Oshimo K, Kawano M, Monden Y. Immunohistochemical study of estrogen receptors and the responsiveness to estrogen in papillary thyroid carcinoma.  Cancer. 1993;  72 1364-1368
    PubMedGoogle Scholar
  • 40 Jakobs T C, Mentrup B, Schmutzler C, Dreher I, Köhrle J. Proinflammatory cytokines inhibit the expression and function of human type I 5′-deiodinase in HepG2 hepatocarcinoma cells.  Eur J Endocrinol. 2002;  146 559-566
    CrossrefPubMedGoogle Scholar
  • 41 Köhrle J. Thyroid hormone deiodination in target tissues - a regulatory role for the trace element selenium?.  Exp Clin Endocrinol. 1994;  102 63-89
    PubMedGoogle Scholar
  • 42 Kuhl H, Gahn G, Romberg G, Althoff P H, Taubert H D. A randomized cross-over comparison of two low-dose oral contraceptives upon hormonal and metabolic serum parameters: II. Effects upon thyroid function, gastrin, STH, and glucose tolerance.  Contraception. 1985;  32 97-107
    CrossrefPubMedGoogle Scholar
  • 43 Leung B S, Potter A H. Mode of estrogen action on cell proliferative kinetics in CAMA‐1 cells. I. Effect of serum and estrogen.  Cancer Investigation. 1987;  5 187-194
    PubMedGoogle Scholar
  • 44 Lin J K, Tsai S H. Chemoprevention of cancer and cardiovascular disease by resveratrol.  Proc Natl Sci Counc Repub China B. 1999;  23 99-106
    PubMedGoogle Scholar
  • 45 Manole D, Schildknecht B, Gosnell B, Adams E, Derwahl M. Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms.  J Clin Endocrinol Metabol. 2001;  86 1072-1077
    CrossrefPubMedGoogle Scholar
  • 46 McElduff A. Measurement of free thyroxine (T4) levels in pregnancy.  Aust NZ J Obstet Gynaecol. 1999;  39 158-161
    PubMedGoogle Scholar
  • 47 Meng Y, Ma Q Y, Kou X P, Xu J. Effect of resveratrol on activation of nuclear factor kappa B and inflammatory factors in rat model of acute pancreatitis.  World J Gastroenterol. 2005;  11 525-528
    PubMedGoogle Scholar
  • 48 Moreira R M, Lisboa P C, Curty F H, Pazos-Moura C C. Dose-dependent effects of 17-beta-estradiol on pituitary thyrotropin content and secretion in vitro.  Braz J Med Biol Res. 1997;  30 1129-1134
    PubMedGoogle Scholar
  • 49 Mortimer C H, Besser G M, Goldie D J, Hook J, McNeilly A S. The TSH, FSH and prolactin responses to continuous infusions of TRH and the effects of oestrogen administration in normal males.  Clin Endocrinol (Oxf). 1074;  3 97-103
    PubMedGoogle Scholar
  • 50 Olas B, Wachowicz B, Saluk-Juszczak J, Zeilinski T. Effect of resveratrol, a natural polyphenolic compound, on platelet activation induced by endotoxin or thrombin.  Thromb Res. 2002;  107 141-145
    CrossrefPubMedGoogle Scholar
  • 51 Pang X P, Hershman J M, Mirell C J, Pekary A E. Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-alpha (cachectin).  Endocrinology. 1989;  125 76-84
    PubMedGoogle Scholar
  • 52 Ramey J N, Burrow G N, Polackwich R J, Donabedian R K. The effect of oral contraceptive steroids on the response of thyroid-stimulating hormone to thyrotropin-releasing hormone.  J Clin Endocrinol Metab. 1975;  40 712-714
    PubMedGoogle Scholar
  • 53 Ramsey L A, Ross B S, Fischer R G. Phytoestrogens and the management of menopause.  Adv Nurse Pract. 1999;  7 26-30
    PubMedGoogle Scholar
  • 54 Rastogi G K, Dash R J, Sinha M K. Thyrotropin releasing hormone induced thyrotropin release in euthyroid men. Effect of ethinyl oestradiol priming.  Indian J Med Sci. 1974;  28 529-531
    PubMedGoogle Scholar
  • 55 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
    CrossrefPubMedGoogle Scholar
  • 56 Sato M, Maulik N, Das D K. Cardioprotection with alcohol; role of both alcohol and polyphenolic antioxidants.  Ann NY Acad Sci. 2002;  957 122-135
    PubMedGoogle Scholar
  • 57 Sawhney R C, Rastogi I, Rastogi G K. Effect of estrogens on thyroid function. I. Alterations in rhesus plasma thyrotropin and its kinetics.  Endocrinology. 1978;  102 1310-1316
    PubMedGoogle Scholar
  • 58 Schlecht C, Klammer H, Jarry H, Wuttke W. Effects of estradiol, benzophenone-2 and benzophenone 3 on the expression pattern of the estrogen receptors (ER) alpha and beta, the estrogen receptor-related receptor 1 (ERR1) and the aryl hydrocarbon receptor (AhR) in adult ovariectomized rats.  Toxicology. 2004;  205 123-130
    CrossrefPubMedGoogle Scholar
  • 59 Sosic-Jurjevic B, Filipovic B, Milosevic V, Nestorovic N, Manojlovic-Stojanoski M, Brkic B, Sekulic M. Chronic estradiol exposure modulates thyroid structure and decreases T4 and T3 serum levels in middle-aged female rats.  Horm Res. 2005;  63 48-54
    PubMedGoogle Scholar
  • 60 Spitz I M, Zylber-Haran E A, Trestian S. The thyrotropin (TSH) profile in isolated gonadotropin deficiency: a model to evaluate the effect of sex steroids on TSH secretion.  J Clin Endocrinol Metab. 1983;  57 415-420
    PubMedGoogle Scholar
  • 61 Tang Y P, Haslam S Z, Conrad S E, Sisk C L. Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid beta scavenger protein.  J Alzheimer's Disease. 2004;  6 413-420 443-449 (discussion)
    PubMedGoogle Scholar
  • 62 Thomas D K, Storlien L H, Bellingham W P, Gillette K. Ovarian hormone effects on activity, glucoregulation and thyroid hormones in the rat.  Physiol Behav. 1986;  36 567-573
    CrossrefPubMedGoogle Scholar
  • 63 Toldy E, Locsei Z, Rigo E, Kneffel P, Szabolcs I, Kovacs G L. Comparative analytical evaluation of thyroid hormone levels in pregnancy and in women taking oral contraceptives: a study from an iodine deficient area.  Gynecol Endocrinol. 2004;  18 219-226
    PubMedGoogle Scholar
  • 64 Turner R T, Evans G L, Zhang M, Maran A, Sibonga J D. Is resveratrol an estrogen agonist in growing rats?.  Endocrinology. 1999;  140 50-54
    CrossrefPubMedGoogle Scholar
  • 65 Yane K, Kitahori Y, Konishi N, Okaichi K, Ohnishi T, Miyahara H, Matsunaga T, Lin J C, Hiasa Y. Espression of the estrogen receptor in human thyroid neoplasms.  Cancer Lett. 1994;  84 59-66
    CrossrefPubMedGoogle Scholar

1 * These two authors contributed equally to the presented work.

Martina Böttner

University of Lübeck
Department of Anatomy

Ratzeburger Allee 160

23538 Lübeck

Germany

Phone: + 49(0)4515004022

Fax: + 49 (0) 45 15 00 40 34

Email: boettner@anat.uni-luebeck.de

      >