Effects of Ospemifene on Breast Tissue Morphology and Proliferation: A Comparative Study Versus Other Selective Estrogen Receptor Modulators in Ovariectomized Rats

Abstract

Ospemifene is a tissue-selective estrogen agonist/antagonist that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy, which occurs in up to approximately 50% of postmenopausal women. The current analyses were conducted to determine whether ospemifene exhibits estrogenic activity in the mammary glands of ovariectomized rats and to compare potential estrogenic activity with selective estrogen receptor modulators (tamoxifen, raloxifene, and toremifene). Three separate studies with differing durations (6, 9, and 28 days) were conducted using similar procedures in ovariectomized Sprague-Dawley rats. Estradiol treatment and sham-treated ovariectomized rats were used as positive and negative controls, respectively. Cell proliferation was examined using labeled 5-bromo-2-deoxyuridine; cytoplasmic prolactin was characterized with antibody staining. The morphology of the mammary gland was studied by histological staining of sections from the right fourth mammary glands, and the excised gland from the left side was used for counting the lobulus number. Neither ospemifene nor selective estrogen receptor modulators substantially induced 5-bromo-2-deoxyuridine staining, altered the morphology of the mammary glands, or changed prolactin immunostaining in ovariectomized rats compared with the ovariectomized controls. With the exception of toremifene, the selective estrogen receptor modulators did not cause a substantial induction in mammary gland lobuli. Estradiol had effects opposite to those of the selective estrogen receptor modulators in these studies. Ospemifene exhibited no substantial estrogenic activity in the mammary gland of ovariectomized rats. Activity in the mammary gland of ovariectomized rats with ospemifene was comparable to raloxifene and tamoxifen.

Key words

ospemifene - selective estrogen receptor modulator - antiestrogenic effects - mammary gland - breast

• References

• 1 Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010; 85: 87-94
• 2 North American Menopause Society . Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause 2013; 20: 888-902 quiz 903–904
• 3 Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009; 6: 2133-2142
• 4 Sturdee DW, Pines A. on behalf of the International Menopause Society Writing Group . Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011; 14: 302-320
• 5 http://www.census.gov/2010census Accessed February 13, 2013
• 6 IMS Health Plan Claims (Apr 2008 – Mar 2011)
• 7 Nelson HD. Menopause. Lancet 2008; 371: 760-770
• 8 North American Menopause Society . The 2012 hormone therapy position statement of The North American Menopause Society. Menopause 2012; 19: 257-271
• 9 Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, Colditz GA. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006; 166: 1027-1032
• 10 Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT. for the WHI investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006; 295: 1647-1657
• 11 Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol 2000; 152: 950-964
• 12 OsphenaTM (ospemifene) . Full Prescribing Information. Shionogi Inc.; Florham Park, NJ: 2013
• 13 Tamoxifen (tamoxifen citrate) . Full Prescribing Information. Watson Pharmaceuticals; Corona, CA, USA: 2011
• 14 Evista (raloxifene hydrochloride) . Full Prescribing Information. Eli Lilly & Company; Indianapolis, IN, USA: 2011
• 15 Fareston (toremifene citrate) . Full Prescribing Information. GTx, Inc; Memphis, TN: 2011
• 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, Gregg JP, Beckett LA, Yu Q, Degregorio MW. Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol 2005; 97: 230-240
• 18 Qu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, Koskinen M, Hemminki K, Kangas L, Väänänen K, Härkönen P. 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
• 19 Burich RA, Mehta NR, Wurz GT, McCall JL, Greenberg BE, Bell KE, Griffey SM, DeGregorio MW. Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model. Menopause 2012; 19: 96-103
• 20 Namba R, Young LJ, Maglione JE, McGoldrick ET, Liu S, Wurz GT, DeGregorio MW, Borowsky AD, MacLeod CL, Cardiff RD, Gregg JP. Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ. Breast Cancer Res 2005; 7: R881-R889
• 21 Bernichtein S, Touraine P, Goffin V. New concepts in prolactin biology. J Endocrinol 2010; 206: 1-11
• 22 Duan R, Ginsburg E, Vonderhaar BK. Estrogen stimulates transcription from the human prolactin distal promoter through AP1 and estrogen responsive elements in T47D human breast cancer cells. Mol Cell Endocrinol 2008; 281: 9-18