Effects of ospemifene on the female reproductive and urinary tracts: Translation from preclinical models into clinical evidence

Menopause

Volumn 22, Issue 7, 2015, Pages 786-796

  Archer, David F ^a   Carr, Bruce R ^b   Pinkerton, JoAnn V ^c   Taylor, Hugh S ^d   Constantine, Ginger D ^e  

^a EASTERN VIRGINIA MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c UNIVERSITY OF VIRGINIA   (United States)

^d YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e Endorheum Consultants   (United States)

Author keywords

Dyspareunia; Endometrium; Estrogen receptor agonist antagonist; Selective estrogen receptor modulator; Urinary tract; Vulvar and vaginal atrophy

Indexed keywords

BAZEDOXIFENE; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; LASOFOXIFENE; OSPEMIFENE; RALOXIFENE; TAMOXIFEN; ANTIESTROGEN;

BINDING AFFINITY; BONE; BREAST; CHEMICAL STRUCTURE; DRUG ANTAGONISM; DRUG MECHANISM; DRUG RECEPTOR BINDING; DYSPAREUNIA; ENDOMETRIAL THICKNESS; ENDOMETRIUM; ENDOMETRIUM POLYP; FEMALE GENITAL SYSTEM; HISTOPATHOLOGY; HUMAN; MEDLINE; MENSTRUAL IRREGULARITY; METRORRHAGIA; POSTMENOPAUSE; REVIEW; SYSTEMATIC REVIEW; TRANSVAGINAL ECHOGRAPHY; URINARY TRACT; UTERUS WEIGHT; VAGINA; VAGINA ATROPHY; VAGINA BLEEDING; VAGINA SMEAR; ANALOGS AND DERIVATIVES; DRUG EFFECTS; FEMALE; FEMALE UROGENITAL DISEASES; MENOPAUSE; TRANSLATIONAL RESEARCH; UROGENITAL SYSTEM;

ESTROGEN ANTAGONISTS; FEMALE; FEMALE UROGENITAL DISEASES; HUMANS; MENOPAUSE; TAMOXIFEN; TRANSLATIONAL MEDICAL RESEARCH; UROGENITAL SYSTEM;

EID: 84937072759     PISSN: 10723714     EISSN: 15300374     Source Type: Journal    
DOI: 10.1097/GME.0000000000000365     Document Type: Review

References (108)

1. Clarke BL, Khosla S. Female reproductive system and bone. Arch Biochem Biophys 2010;503:118-128.
2. Raz R. Urinary tract infection in postmenopausal women. Korean J Urol 2011;52:801-808.
3. Bakos O, Smith P, Heimer G, Ulmsten U. Transvaginal sonography of the internal genital organs in postmenopausal women on low-dose estrogen treatment. Ultrasound Obstet Gynecol 1994;4:326-329.
4. Sultana CJ, Walters MD. Estrogen and urinary incontinence in women. Maturitas 1994;20:129-138.
5. Sturdee DW, Pines A, International Menopause Society Writing Group, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011;14:302-320.
6. The North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013;20:888-902.
7. Kingsberg S, Kellogg S, Krychman M. Treating dyspareunia caused by vaginal atrophy: a review of treatment options using vaginal estrogen therapy. Int J Womens Health 2009;1:105-111.
8. The North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause 2012;19:257-271.
9. Madak-Erdogan Z, Charn TH, Jiang Y, Liu ET, Katzenellenbogen JA, Katzenellenbogen BS. Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators. Mol Syst Biol 2013;9:676.
10. Leitman DC, Paruthiyil S, Vivar OI, et al. Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. Curr Opin Pharmacol 2010;10:629-636.
11. Zheng H, Kangas L, Harkonen PL. Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus. J Steroid Biochem Mol Biol 2004;88:143-156.
12. Wurz GT, Hellmann-Blumberg U, DeGregorio MW. Pharmacologic effects of ospemifene in rhesus macaques: a pilot study. Basic Clin Pharmacol Toxicol 2008;102:552-558.
13. Unkila M, Kari S, Yatkin E, Lammintausta R. Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause. J Steroid Biochem Mol Biol 2013;138:107-115.
14. Qu Q, Zheng H, Dahllund J, et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 2000;141:809-820.
15. Burich RA, Mehta NR, Wurz GT, et al. Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model. Menopause 2012;19:96-103.
16. Taras TL, Wurz GT, DeGregorio MW. In vitro and in vivo biologic effects of ospemifene (FC-1271a) in breast cancer. J Steroid Biochem Mol Biol 2001;77:271-279.
17. Wurz GT, Read KC, Marchisano-Karpman C, et al. Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol 2005;97:230-240.
18. Michael H, Ha¨rkönen PL, Kangas L, Va¨a¨na¨nen HK, Hentunen TA. Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro. Br J Pharmacol 2007;151:384-395.
19. Qu Q, Ha¨rkönen PL, Va¨a¨na¨nen HK. Comparative effects of estrogen and antiestrogens on differentiation of osteoblasts in mouse bone marrow culture. J Cell Biochem 1999;73:500-507.
20. Stygar D, Muravitskaya N, Eriksson B, Eriksson H, Sahlin L. Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus. Reprod Biol Endocrinol 2003;1:40.
21. Fitts JM, Klein RM, Powers CA. Tamoxifen regulation of bone growth and endocrine function in the ovariectomized rat: discrimination of responses involving estrogen receptor α/estrogen receptor β, G protein-coupled estrogen receptor, or estrogen-related receptor γ using fulvestrant (ICI 182780). J Pharmacol Exp Ther 2011;338:246-254.
22. Fong CJ, Burgoon LD, Williams KJ, Jones AD, Forgacs AL, Zacharewski TR. Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice. J Mol Endocrinol 2010;45:161-173.
23. Al-Jamal JH, Dubin NH. The effect of raloxifene on the uterine weight response in immature mice exposed to 17β-estradiol, 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane, and methoxychlor. Am J Obstet Gynecol 2000;182:1099-1102.
24. Kim NN, Stankovic M, Armagan A, Cushman TT, Goldstein I, Traish AM. Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat. BMC Womens Health 2006;6:14.
25. Nunez NP, Jelovac D, Macedo L, et al. Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer. Clin Cancer Res 2004;10:5375-5380.
26. Fong CJ, Burgoon LD, Williams KJ, Forgacs AL, Zacharewski TR. Comparative temporal and dose-dependent morphological and transcriptional uterine effects elicited by tamoxifen and ethynylestradiol in immature, ovariectomized mice. BMC Genomics 2007;8:151.
27. Sikoski P, Register TC, Lees CJ, et al. Effects of two novel selective estrogen receptor modulators, raloxifene, tamoxifen, and ethinyl estradiol on the uterus, vagina and breast in ovariectomized cynomolgus monkeys (Macaca fascicularis). Am J Obstet Gynecol 2007;196:75.e1-75.e7.
28. Cline JM, Soderqvist G, Register TC, Williams JK, Adams MR, Von Schoultz B. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Pathol 2001;29:84-90.
29. Carthew P, Edwards RE, Nolan BM, Tucker MJ, Smith LL. Compartmentalized uterotrophic effects of tamoxifen, toremifene, and estradiol in the ovariectomized Wistar (Han) rat. Toxicol Sci 1999;48:197-205.
30. Evans GL, Bryant HU, Magee DE, Turner RT. Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology 1996;137:4139-4144.
31. Davis AM, Ellersieck MR, Grimm KM, Rosenfeld CS. The effects of the selective estrogen receptor modulators, methyl-piperidino-pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus. Mol Reprod Dev 2006;73:1034-1044.
32. Black LJ, Sato M, Rowley ER, et al. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 1994;93:63-69.
33. Hascalik S, Celik O, Tamser M, Mizrak B. Effects of resveratrol, raloxifene, tibolone and conjugated equine estrogen on vaginal squamous cell maturation of ovariectomized rats. Gynecol Obstet Invest 2005;60:186-191.
34. Kastrati I, Edirisinghe PD, Hemachandra LP, et al. Raloxifene and desmethylarzoxifene block estrogen-induced malignant transformation of human breast epithelial cells. PLoS One 2011;6:e27876.
35. Shibata MA, Morimoto J, Shibata E, et al. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer. BMC Cancer 2010;10:566.
36. Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996;10:905-912.
37. Erlandsson MC, Jonsson CA, Lindberg MK, Ohlsson C, Carlsten H. Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice. J Endocrinol 2002;175:319-327.
38. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology 2005;146:3999-4008.
39. Ethun KF, Wood CE, Cline JM, Register TC, Appt SE, Clarkson TB. Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model. Menopause 2013;20:777-784.
40. Ethun KF, Wood CE, Register TC, Cline JM, Appt SE, Clarkson TB. Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. Menopause 2012;19:1242-1252.
41. Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 2013;19:2420-2431.
42. Kulak J Jr, Fischer C, Komm B, Taylor HS. Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Endocrinology 2011;152:3226-3232.
43. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010;17:480-486.
44. Portman DJ, Bachmann GA, Simon JA, Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013;20:623-630.
45. Portman D, Palacios S, Nappi RE, Mueck AO. Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: a randomised, placebo-controlled, phase III trial. Maturitas 2014;78:91-98.
46. Goldstein SR, Bachmann GA, Koninckx PR, et al. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric 2014;17:173-182.
47. Komi J, Lankinen KS, DeGregorio M, et al. Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women. J Bone Miner Metab 2006;24:314-318.
48. Komi J, Heikkinen J, Rutanen EM, Halonen K, Lammintausta R, Ylikorkala O. Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol 2004;18:152-158.
49. Duffy S, Jackson TL, Lansdown M, et al. The ATAC ('Arimidex,' Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment. Hum Reprod 2006;21:545-553.
50. Lindahl B, Andolf E, Ingvar C, Ranstam J, Willen R. Adjuvant tamoxifen in breast cancer patients affects the endometrium by time, an effect remaining years after end of treatment and results in an increased frequency of endometrial carcinoma. Anticancer Res 2008;28:1259-1262.
51. Cuzick J, Sestak I, Bonanni B, et al. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 2013;381:1827-1834.
52. Friedrich M, Mink D, Villena-Heinsen C, Woll-Hermann A, Schmidt W. Tamoxifen and proliferation of vaginal and cervical epithelium in postmenopausal women with breast cancer. Eur J Obstet Gynecol Reprod Biol 1998;80:221-225.
53. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852-856.
54. Komi J, Lankinen KS, Ha¨rkönen P, et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause 2005;12:202-209.
55. Cohen FJ, Watts S, Shah A, Akers R, Plouffe L Jr. Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol 2000;95:104-110.
56. Evista (Raloxifene Hydrochloride). Full Prescribing Information. Indianapolis, IN: Eli Lilly and Company; 2011.
57. Christodoulakos GE, Botsis DS, Lambrinoudaki IV, et al. A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness. Maturitas 2006;53:413-423.
58. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-1647.
59. Delmanto A, Nahas-Neto J, Nahas EA, de Oliveira ML, Fernandes CE, Traiman P. Effect of raloxifene on the vaginal epithelium of postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2008;139:187-192.
60. Meunier PJ, Vignot E, Garnero P, et al. Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group. Osteoporos Int 1999;10:330-336.
61. Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG. A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 2000;85:2197-2202.
62. Palacios S, de Villiers TJ, Nardone Fde C, et al. Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: results of a 7-year, randomized, placebo-controlled, phase 3 study. Maturitas 2013;76:81-87.
63. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause 2010;17:281-289.
64. Harvey JA, Holm MK, Ranganath R, Guse PA, Trott EA, Helzner E. The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis. Menopause 2009;16:1193-1196.
65. Pinkerton JV, Archer DF, Utian WH, et al. Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause 2009;16:1102-1108.
66. Miller PD, Chines AA, Christiansen C, et al. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 2008;23:525-535.
67. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008;23:1923-1934.
68. Silverman SL, Chines AA, Kendler DL, et al. Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 2012;23:351-363.
69. Ball LJ, Levy N, Zhao X, et al. Cell type- and estrogen receptor-subtype specific regulation of selective estrogen receptor modulator regulatory elements. Mol Cell Endocrinol 2009;299:204-211.
70. Flamini MI, Sanchez AM, Goglia L, Tosi V, Genazzani AR, Simoncini T. Differential actions of estrogen and SERMs in regulation of the actin cytoskeleton of endometrial cells. Mol Hum Reprod 2009;15:675-685.
71. Glaeser M, Niederacher D, Djahansouzi S, et al. Effects of the antiestrogens tamoxifen and raloxifene on the estrogen receptor transactivation machinery. Anticancer Res 2006;26:735-744.
72. Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004;25:45-71.
73. MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998;50:151-196.
74. Levy N, Tatomer D, Herber CB, et al. Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene. Mol Endocrinol 2008;22:287-303.
75. Kangas L, Unkila M. Tissue selectivity of ospemifene: pharmacologic profile and clinical implications. Steroids 2013;78:1273-1280.
76. Constantine G, Graham S, Portman DJ, Rosen RC, Kingsberg SA. Female sexual function improved with ospemifene in postmenopausal women with vulvar and vaginal atrophy: results of a randomized, placebo-controlled trial. [published online ahead of print September 25, 2014]. Climacteric doi:10.3109/13697137.2014.954996.
77. Bachmann G, Bobula J, Mirkin S. Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy. Climacteric 2010;13:132-140.
78. Duavee® (Conjugated Estrogens/Bazedoxifene). Full Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals; 2013.
79. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril 2009;92:1025-1038.
80. Parsons A, Merritt D, Rosen A, et al. Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy. Obstet Gynecol 2003;101:346-352.
81. Pinkerton JV, Shifren JL, La Valleur J, Rosen A, Roesinger M, Siddhanti S. Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. Menopause 2003;10:45-52.
82. Cella D, Fallowfield L, Barker P, et al. Quality of life of postmenopausal women in the ATAC ("Arimidex," tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast Cancer Res Treat 2006;100:273-284.
83. Wood CE, Kaplan JR, Fontenot MB, Williams JK, Cline JM. Endometrial profile of tamoxifen and low-dose estradiol combination therapy. Clin Cancer Res 2010;16:946-956.
84. Tsujioka S, Ban Y, Wise LD, et al. Collaborative work on evaluation of ovarian toxicity, 3: effects of 2- or 4-week repeated-dose toxicity and fertility studies with tamoxifen in female rats. J Toxicol Sci 2009;34(suppl 1):SP43-SP51.
85. Long GG, Cohen IR, Gries CL, Young JK, Francis PC, Capen CC. Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicol Pathol 2001;29:719-726.
86. Martino S, Disch D, Dowsett SA, Keech CA, Mershon JL. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin 2005;21:1441-1452.
87. Palacios S. The future of the new selective estrogen receptor modulators. Menopause Int 2007;13:27-34.
88. Cohen I, Perel E, Flex D, et al. Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients. J Clin Pathol 1999;52:278-282.
89. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila) 2010;3:696-706.
90. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996;275:370-375.
91. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975;293:1167-1170.
92. Mofrad MH, Shandiz FH, Roodsare FV, Moghiman T. Evaluation of ovarian cysts in breast cancer cases on tamoxifen. Asian Pac J Cancer Prev 2010;11:161-164.
93. Kim HS, Jeon YT, Kim YB. The effect of adjuvant hormonal therapy on the endometrium and ovary of breast cancer patients. J Gynecol Oncol 2008;19:256-260.
94. Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 2009;16:1109-1115.
95. Sharma A, Gentry-Maharaj A, Burnell M, et al. Assessing the malignant potential of ovarian inclusion cysts in postmenopausal women within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a prospective cohort study. BJOG 2012;119:207-219.
96. Breyer BN, Wang G, Lin G, et al. The effect of long-term hormonal treatment on voiding patterns during filling cystometry and on urethral histology in a postpartum, ovariectomized female rat. BJU Int 2010;106:1775-1781.
97. Tantiwongse K, Fandel TM, Wang G, et al. The potential of hormones and selective oestrogen receptor modulators in preventing voiding dysfunction in rats. BJU Int 2008;102:242-246.
98. dos Santos AR, Lopes-Costa PV, Borges CS, et al. Effects of raloxifene on the urethra of adult castrated female rats. Climacteric 2008;11:483-488.
99. Acar D, Cayan S, Aktas S, Tek M, Akbay E. The effect of tamoxifen on bladder functions and histology, and the role of estrogen receptor β in a rat chemical cystitis model. Neurourol Urodyn 2007;26:309-316.
100. Albertazzi P, Sharma S. Urogenital effects of selective estrogen receptor modulators: a systematic review. Climacteric 2005;8:214-220.
101. Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol 2013;8:135-155.
102. Goldstein SR, Nanavati N. Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol 2002;187:521-527.
103. Warming L, Christoffersen C, Riis BJ, Stakkestad JA, Delmas PD, Christiansen C. Adverse effects of a SERM (levormeloxifene). Safety parameters and bone mineral density 12 months after treatment withdrawal. Maturitas 2003;44:189-199.
104. Munster PN. Arzoxifene: the development and clinical outcome of an ideal SERM. Expert Opin Investig Drugs 2006;15:317-326.
105. Gennari L. Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother 2009;10:2209-2220.
106. Pinkerton JV, Stanczyk FZ. Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy. Menopause 2014;21:309-319.
107. Arevalo MA, Santos-Galindo M, Lagunas N, Azcoitia I, Garcia-Segura LM. Selective estrogen receptor modulators as brain therapeutic agents. J Mol Endocrinol 2011;46:R1-R9.
108. Carneiro AL, de Cassia de Maio Dardes R, Haidar MA. Estrogens plus raloxifene on endometrial safety and menopausal symptoms - semisystematic review. Menopause 2012;19:830-834.