Tibolone Induces Serotonin, Estrogen, and Progesterone Receptor Expression but not Contractile Response to Serotonin in the Rat Uterus

Abstract

Most studies on the effect of tibolone on the uterus have focused on the endometrium dismissing the importance of the myometrium. The aim of the present study was to investigate some estrogen-like actions of tibolone in the uterus assessed by: 1) the expression of estrogen, progesterone, and serotonin receptors, and 2) the myometrial contraction induced by serotonin. Estradiol (250 μg), progesterone (50 mg), or testosterone (25 mg) pellets were implanted to ovariectomized rats. Tibolone (0.5 mg/day) was orally administered. An implanted pellet containing vehicle or an equivalent volume of water p.o., were used as controls. Sixty days after beginning the treatments, rats were killed and uterus removed. One horn was processed to evaluate estrogen-alpha, progesterone A and B, and serotonin-2A receptors expression, and the other one was used for studying contraction to serotonin and 60 mM potassium solution. The present data showed that tibolone-induced expression of estrogen, progesterone, and serotonin receptors, but did not induce uterine contractile response to either serotonin or potassium solution. These findings suggest that, in the uterus, tibolone may exert molecular estrogenic actions such as the induction of receptor expression, but not a physiological response as the estrogen-dependent contraction to serotonin.

Key words

tibolone - serotonin - estrogenic actions - myometrial response - receptor expression

*

^* These authors contributed equally to this work.

• References

• 1 Ettinger B. Overview of estrogen replacement therapy: a historical perspective. Proc Soc Exp Biol Med 1998; 217: 2-5
• 2 Lindsay R, Hart DM, Kraszewski A. Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis. Br Med J 1980; 280: 1207-1209
• 3 Van der Vies J. Pharmacological studies with (7alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14). Maturitas 1987; Suppl 1: 15-24
• 4 Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites in human endometrium. J Steroid Biochem 1990; 35: 535-541
• 5 Blok LJ, DeRuiter PE, Kühne ECM, Hanekamp EE, Grootegoed JA, Smid-Koopman E, Gielen SCJP, DeGooyer ME, Kloosterboer HJ, Burger CW. Progestagenic effects of tibolone on human endometrial cancer cells. J Clin Endocrinol Metab 2003; 88: 2327-2334
• 6 Kloosterboer HJ. Tissue-selective effects of tibolone on the breast. Maturitas 2004; 49: S5-S15
• 7 Beral V, Bull D, Reeves G. Million Women Study Collaborators . Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005; 365: 1543-1551
• 8 Sadarangani A, Salgado AM, Kato S, Pinto M, Carvajal A, Monso C, Owen GI, Vigil P. In vivo and in vitro estrogenic and progestagenic actions of Tibolone. Biol Res 2005; 38: 245-258
• 9 Hanifi-Moghaddam P, Boers-Sijmons B, Klaassens AHA, Van Wijk FH, Van Ijcken WF, Van der Spek P, Verheul HAM, Kloosterboer HJ, Burger CW, Blok LJ. Difference in signaling between various hormone therapies in endometrium, myometrium and upper part of the vagina. Hum Reprod 2008; 23: 298-305
• 10 Ichida S, Oda Y, Tokunaga H, Hayashi T, Murakami T, Kita T. Mechanisms of specific change by estradiol in sensitivity of rat uterus to seotonin. J Pharmacol Exp Ther 1984; 229: 244-249
• 11 Campos-Lara G, Caracheo F, Valencia-Sánchez A, Ponce-Monter H. The sensitivity of rat uterus to serotonin in vitro is a late estrogenic response. Arch Invest Med (Mex) 1990; 21: 71-75
• 12 National Research Council . Guide for the Care and Use of Laboratory Animals. Eighth Edition. The National Academies Press; Washington DC, USA: 2011
• 13 Pantaleão JA, Henriques HN, de Carvalho AC, Pollastri CE, Soares Filho PJ, Guzmán-Silva MA. Effect of tibolone on endometrium of castrated rats. Rev Bras Ginecol Obstet 2009; 31: 124-130
• 14 Henriques HN, de Carvalho AC, Pantaleão JA, Guzmán-Silva MA. Effect of long-time administration of tibolone on vaginal cytology of castrated rats. Clin Exp Obstet Gynecol 2010; 37: 123-126
• 15 Blom MJ, Wassink MG, DeGooyer ME, Ederveen AG, Kloosterboer HJ, Lange JG, Goos HJ. Metabolism of tibolone and its metabolites in uterine and vaginal tissue of rat and human origin. J Steroid Biochem Mol Biol 2006; 101: 42-49
• 16 Verhoeven CH, Vos RM, Delbressine LP. The in vivo metabolism of tibolone in animal species. Eur J Drug Pharmacokinet 2002; 27: 1-10
• 17 Sandker GW, Vos RM, Delbressine LP, Slooff MJ, Meijer DK, Groothuis GM. Metabolism of three pharmacologically active drugs in isolated human and rat hepatocytes: analysis of interspecies variability and comparison with metabolism in vivo. Xenobiotica 1994; 24: 143-155
• 18 Oropeza MV, Ponce-Monter H, Villanueva-Tello T, Palma-Aguirre JA, Campos MG. Anatomical differences in uterine sensitivity to prostaglandin F_2α and serotonin in non-pregnant rats. Eur J Pharmacol 2002; 446: 161-166
• 19 Zhang W, Mazella J, Kloosterboer HJ, Tseng L. Effects of tibolone on nuclear receptors in human endometrial cells. Am J Obstet Gynecol 2006; 195: 97-102
• 20 Hulchiy M, Zhang H, Cline JM, Hirschberg AL, Sahlin L. Effects of long-term tibolone treatment on nuclear sex steroid hormone receptors and G-protein-coupled estrogen receptor-1 expression in the macaque uterus. Menopause 2012; 19: 332-338
• 21 Verheul HA, Blok LJ, Burger CW, Hanifi-Moghaddam P, Kloosterboer HJ. Levels of tibolone and estradiol and their nonsulfated and sulfated metabolites in serum, myometrium, and vagina of postmenopausal women following treatment for 21 days with tibolone, estradiol, or estradiol plus medroxyprogesterone acetate. Reprod Sci 2007; 14: 160-168
• 22 Nakamura T, Kitazawa T, Cao J, Iwamoto T, Teraoka H, Kadota K, Taneike T. Excitatory and inhibitory 5-hydroxytryptamine (5-HT) receptors expressed in the isolated porcine uterine muscles. Eur J Pharmacol 2008; 600: 123-129
• 23 Sanborn BM. Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics. Semin Cell Dev Biol 2007; 18: 305-314
• 24 Ononiwu IM, Allagoa DO, Nwangwu JE, Ebong OO. Some studies on the 5-hydroxytryptamine receptors in the isolated rat uterus. Afr J Med Med Sci 2002; 31: 361-365
• 25 Perusquia M, García-Yañez E, Ibañez R, Kubli-Garfias C. Non-genomic mechanism of action of delta-4 and 5-reduced androgens and progestins on the contractility of the isolated rat myometrium. Life Sci 1990; 47: 1547-1553
• 26 Perusquia M, Navarrete E, Jasso-Kamel J, Montaño LM. Androgens induce relaxation of contractile activity in pregnant human myometrium at term: A nongenomic action on L-type calcium channels. Biol Reprod 2005; 73: 214-221
• 27 Thieulant ML, Samperez S, Jouan P. Evidence for 5alpha-androstane-3 beta,17 beta-diol binding to the estrogen receptor in the cytosol from male rat pituitary. Endocrinology 1981; 108: 1552-1560
• 28 Kloosterboer HJ. Tibolone: a steroid with tissue-specific mode of action. J Steroid Biochem Mol Biol 2001; 76: 231-238
• 29 Klaassens AHA, van Wijk FH, Hanifi-Moghaddam P, Sijmons B, Ewing PC, Ten MJ, Kooi S, Kloosterboer HJ, Blok LJ, Burger GW. Histological and immunohistological evaluation of postmenopausal endometrium after 3 weeks of treatment with tibolone, estrogen only, or estrogen plus progestagen. Fert Steril 2006; 86: 352-361
• 30 Ettinger B, Kenemans P, Johnson SR, Mol-Arts M, Van Os S, Verweij PJ, Cummings SR. Endometrial effects of tibolone in elderly, osteoporotic women. Obstet Gynecol 2008; 112: 653-659
• 31 Notelovitz M. Postmenopausal tibolone therapy: Biologic principles and applied clinical practice. Med Gen Med 2007; 9: 2