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

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
• 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
• 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
• 4 Bartalena L, Robbins J. Variations in thyroid hormone transport proteins and their clinical implications.  Thyroid. 1992;  2 237-245
• 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
• 6 Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;  362 419-427
• 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
• 8 Bhat K P, Pezzuto J M. Cancer chemopreventive activity of resveratrol.  Ann NY Acad Sci. 2002;  957 210-229
• 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
• 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
• 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
• 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
• 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
• 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
• 15 Chen H J, Walfish P G. Effects of estradiol benzoate on thyroid-pituitary function in female rats.  Endocrinology. 1978;  103 1023-1030
• 16 Chiechi L M. Dietary phytoestrogens in the prevention of long-term postmenopausal diseases.  Int J Gynaecol Obstet. 1999;  39-40
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 25 Fantz C R, Dagogo-Jack S, Ladenson J H, Gronowski A M. Thyroid function during pregnancy.  Clin Chem. 1999;  45 2250-2258
• 26 Farbota L, Hofmann C, Oslapas R, Paloyan E. Sex hormone modulation of serum TSH levels.  Surgery. 1987;  102 1081-1087
• 27 Fisher J S, D'Angelo S A. Stimulatory and inhibitory action of estradiol on TSH secretion.  Endocrinology. 1971;  88 687-691
• 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
• 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
• 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
• 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
• 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
• 33 Glinoer D. What happens to the normal thyroid during pregnancy?.  Thyroid. 1999;  9 631-635
• 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
• 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
• 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
• 38 Herrington D M. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study.  Ann Intern Med. 1999;  131 463-466
• 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
• 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
• 41 Köhrle J. Thyroid hormone deiodination in target tissues - a regulatory role for the trace element selenium?.  Exp Clin Endocrinol. 1994;  102 63-89
• 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
• 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
• 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
• 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
• 46 McElduff A. Measurement of free thyroxine (T4) levels in pregnancy.  Aust NZ J Obstet Gynaecol. 1999;  39 158-161
• 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
• 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
• 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
• 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
• 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
• 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
• 53 Ramsey L A, Ross B S, Fischer R G. Phytoestrogens and the management of menopause.  Adv Nurse Pract. 1999;  7 26-30
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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
• 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
• 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
• 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

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