A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. The clinical profile of a tissue selective estrogen complex will result from the blended tissue-selective activities of its components. An appropriate tissue selective estrogen complex may provide the therapeutic benefits of estrogens and selective estrogen receptor modulators with better tolerability and safety than either therapy alone. An ideal menopausal therapy would reduce the number and severity of hot flashes, effectively treat vulvar-vaginal atrophy and its symptoms, prevent and treat menopausal osteoporosis, and have favorable effects on lipoprotein profiles, while at the same time would not stimulate the endometrium, not cause uterine bleeding, not increase the risk of vascular events, not be associated with breast pain or tenderness, and potentially reduce breast cancer incidence. Here, we introduce the concept of a tissue selective estrogen complex and the rationale for its development as a next generation menopausal therapy.
World Health Organization.Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Technical report series no 843. Geneva: World Health Organization; 1994:1-129.
4.
National Osteoporosis Foundation. America's Bone Health.The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation ; 2002:1-55.
5.
Magaziner J. , Fredman L., Hawkes W., et al. Changes in functional status attributable to hip fracture: a comparison of hip fracture patients to community-dwelling aged. Am J Epidemiol. 2003;157:1023-1031.
6.
Scaf-Klomp W. , van Sonderen E., Sanderman R., Ormel J., Kempen GIRecovery of physical function after limb injuries in independent older people living at home. Age Ageing. 2001;30:213-219.
7.
Leibson CL, Tosteson AN, Gabriel SE, Ransom JE, Melton LJMortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. J Am Geriatr Soc. 2002;50:1644-1650.
8.
Kanis JA, Oden A., Johnell O., De Laet C., Jonsson B.Excess mortality after hospitalisation for vertebral fracture. Osteoporos Int. 2004;15:108-112.
9.
Johnell O., Kanis JA, Oden A., et al. Mortality after osteoporotic fractures. Osteoporos Int. 2004;15:38-42.
10.
Komm BS, Pickar JHTissue Selective Estrogen Complex (TSEC): A New Paradigm for Menopausal Therapy . In: 6th International Menopause Society Workshop Menopause and Ageing Quality of Life and Sexuality. Pisa , Italy, 2006;1-12. Available at: http://www.6thimsworkshop.com/sito/inside_pages/proceedings/pickar.pdf.
11.
Kharode Y., Bodine PVN, Miller CP, Lyttle CR, Komm BSThe pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis preventionEndocrinology. 2008; IN PRESS.
12.
Evista® (raloxifene hydrochloride) [Prescribing Information] . Eli Lilly and Company, Indianapolis, IN; 2007.
13.
Persson I., Yuen J., Bergkvist L., Schairer C.Cancer incidence and mortality in women receiving estrogen and estrogenprogestin replacement therapy-long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327-332.
14.
Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L.Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril. 2003;80:1234-1240.
Anderson GL , Judd HL, Kaunitz AM, et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003;290:1739-1748.
17.
Williams JK , Honore EK, Washburn SA, Clarkson TBEffects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Car-diol. 1994 ;24:1757-1761.
18.
Williams JK , Hall J., Anthony MS, Register TC, Reis SE, Clarkson TBA comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys. Menopause . 2002;9:41-51.
19.
Register TC , Adams MR, Golden DL, Clarkson TBConjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol. 1998;18:1164-1171.
20.
Clarkson TB, Anthony MS, Wagner JDA comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys . J Clin Endocrinol Metab. 2001;86:5396-5404.
21.
Clarkson TB, Anthony MS, Morgan TMInhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab. 2001;86:41-47.
22.
Clarkson TB, Anthony MS, Mikkola TS, St Clair RWComparison of tibolone and conjugated equine estrogens effects on carotid artery atherosclerosis of postmenopausal monkeys. Stroke. 2002;33:2700-2703.
23.
Levine RL, Chen SJ, Durand J., Chen YF, Oparil S.Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation . 1996;94:2221-2227.
24.
Budoff MJ, Chen GP, Hunter CJ, et al. Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography. J Womens Health (Larchmt). 2005;14:410-417.
25.
Writing Group for the PEPI Trial.Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199-208.
26.
Lobo RA, Bush T., Carr BR, Pickar JHEffects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril. 2001;76:13-24.
27.
Fernandes CE , Pompei LM, Machado RB, Ferreira JA, Melo NR, Peixoto S.Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow. Maturitas. 2008;59:249-258.
28.
Zegura B., Guzic-Salobir B., Sebestjen M., Keber I.The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women. Menopause. 2006;13: 643-650.
29.
Utian WH, Shoupe D., Bachmann G., Pinkerton JV, Pickar JHRelief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril . 2001;75:1065-1079.
30.
Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998 ;279:1445-1451.
Raymundo N. , Yu-cheng B., Zi-yan H., et al. Treatment of atrophic vaginitis with topical conjugated equine estrogens in postmenopausal Asian women. Climacteric. 2004;7: 312-318.
33.
Simon JA, Liu JH, Speroff L., Shumel BS, Symons JPReduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. Am J Obstet Gynecol. 2003;188:92-99.
34.
Yildirim G. , Tugrul S., Uslu H., Pekin O., Eren S.Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding. Arch Gynecol Obstet. 2007 ;273:268-273.
35.
Archer DF, Dorin M., Lewis V., Schneider DL, Pickar JHEffects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril. 2001;75:1080-1087.
36.
Wattanakumtornkul S., Chichareon S., Geater A., Suwan K.Compliance with hormone replacement therapy at Songklanagarind Hospital. J Obstet Gynaecol Res. 2003;29:380-387.
37.
Manonai J., Theppisai U., Suchartwatnachai C., Jetsawangsri T., Chittacharoen A.Compliance with hormone replacement therapy in Thai women. Maturitas. 2003;44:201-205.
38.
Shulman LP, Yankov V., Uhl K.Safety and efficacy of a continuous once-a-week 17β-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause. 2002;9:195-207.
39.
Barnabei VM , Cochrane BB, Aragaki AK, et al. Women's Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol.2005;105: 1063-1073.
40.
Cummings SR , Eckert S., Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. JAMA. 1999;281:2189-2197.
41.
Martino S., Cauley JA, Barrett-Connor E., et al. CORE Investigators. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst.2004 ;96: 1751-1761.
42.
Cauley JA, Norton L., Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat.2001;65:125-134.
43.
Stefanick ML , Anderson GL, Margolis KL, et al. WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647-1657.
44.
Komm BS, Lyttle CRDeveloping a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci. 2001;949:317-326.
45.
Bhavnani BR , Woolever CAInteraction of ring B unsaturated estrogens with estrogen receptors of human endometrium and rat uterus. Steroids. 1991;56:201-210.
46.
Bhavnani BR , Cecutti A., Gerulath A.Pharmacokinetics and pharmacodynamics of a novel estrogen delta8-estrone in postmenopausal women and men. J Steroid Biochem Mol Biol. 1998 ;67:119-131.
47.
Dey M., Lyttle CR, Pickar JHRecent insights into the varying activity of estrogens. Maturitas . 2000;34(suppl 2):S25-S33.
48.
Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CRBazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146: 3999-4008.
49.
Komm BS, Nagpal S., Chang KCN, et al. Tissue selective estrogen complexes (TSECs): optimal menopausal therapy. Paper presented at: Endocrine Society Annual Meeting; June 2-5, 2007; Toronto, Canada.
50.
Gottardis MM , Robinson SP, Jordan VCEstradiol-stimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen . J Steroid Biochem. 1988 ;30:311-314.
51.
Holinka CF, Bressler RS, Zehr DR, Gurpide E.Comparison of effects of estertrol and tamoxifen with those of estriol and estradiol on the immature rat uterus. Biol Reprod. 1980;22: 913-926.
52.
Jordan VC, Phelps E., Lindgren JUEffects of anti-estrogens on bone in castrated and intact female rats . Breast Cancer Res Treat. 1987;10:31-35.
53.
Turner RT, Wakley GK, Hannon KS, Bell NHTamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology. 1988 ;122: 1146-1150.
54.
Cuzick J., Forbes J., Edwards R., et al. IBIS Investigators.First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002 ;360:817-824.
55.
Fisher B., Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.
56.
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.
57.
Ashby J., Odum J., Foster JRActivity of raloxifene in immature and ovariectomized rat uterotrophic assays . Regul Toxicol Pharmacol. 1997;25:226-231.
58.
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.
59.
Evans GL, Bryant HU, Magee DE, Turner RTRaloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology. 1996;137:4139-4144.
60.
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.
61.
Delmas PD, Ensrud KE, Adachi JD, et al. Mulitple Outcomes of Raloxifene Evaluation Investigators.Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab.2002;87: 3609-3617.
62.
Ettinger B. , Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA . 1999;282:637-645.
63.
Checa MA, Garrirdo A., Prat M., Conangla M., Rueda C., Carreras R.A comparison of raloxifene and calcium plus vitamin D on vaginal atrophy after discontinuation of longstanding postmenopausal hormone therapy in osteoporotic women. A randomized, masked-evaluator, one-year, prospective study. Maturitas. 2005;16:70-77.
64.
Ke HZ, Paralkar VM, Grasser WA, et al. Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology. 1998;139:2068-2076.
65.
Wang X.-N, Simmons HA, Salatto CT, Cosgrove PG, Thompson DDLasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor beta and androgen receptor in rats. Menopause. 2006;13:609-620.
66.
Ke HZ, Foley GL, Simmons HA, Shen V., Thompson DDLong-term treatment of lasofoxifene preserves bone mass and bone strength and does not adversely affect the uterus in ovariectomized rats. Endocrinology. 2004;145:1996-2005.
67.
McClung MR, Siris E., Cummings S., et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause. 2006;13:377-386.
68.
Crabtree JS , Peano BJ, Zhang X., Komm BS, Winneker RC, Harris HAActivity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol. 2008;287:40-46.
69.
Ronkin S., Northington R., Baracat E., et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol. 2005;105:1397-1404.
70.
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.
71.
Roman R., Yates CH, Millar JF, Vanden Heuvel WJA.Identification of estrogens isolated from pregnant mares' urine. Can J Pharm Sci. 1975;10:8-11.
72.
Subbiah MT, Kessel B., Agrawal M., Rajan R., Abplanalp W., Rymaszewski Z.Antioxidant potential of specific estrogens on lipid peroxidation . J Clin Endocrinol Metab. 1993;77: 1095-1097.
73.
Bhavnani BR, Cecutti A., Gerulath A., Woolever CA, Berco M.Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women. Menopause. 2001;8:408-419.
74.
Mueck AO, Seeger H., Wallwiener D.Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition. Climacteric. 2003;6:221-227.
75.
Lindsay R., Gallagher JC, Kleerekoper M., Pickar JHEffect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668-2676.
76.
Lindsay R., Gallagher JC, Kleerekoper M., Pickar JHBone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women . Osteoporos Int. 2005;16:372-379.
77.
Jackson RD, Wactawski-Wende J., LaCroix AZWomen's Health Initiative Investigators.Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized trial. J Bone Miner Res.2006;21:817-828.
78.
Cauley JA, Robbins J., Chen Z., et al. Women's Health Initiative Investigators.Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA. 2003;290:1729-1738.
79.
Komm B., Chang K., Freedman L., Bodine PVN.Tissue selective estrogen complexes: a new paradigm for menopausal therapy . Paper presented at: 17th Annual Meeting of the North American Menopause Society; October 14-16, 2006 ; Nashville, TN.
80.
McDonnell DP , Clemm DL, Hermann T., Goldman ME, Pike JWAnalysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens . Mol Endocrinol. 1995;9:659-669.
81.
Paige LA, Christensen DJ, Gron H., et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc Natl Acad Sci USA. 1999;96: 3999-4004.
82.
Brzozowski AM, Pike AC, Dauter Z., et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature . 1997;389:753-758.
83.
Shiau AK, Barstad D., Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell . 1998;95:927-937.
Tzukerman MT , Esty A., Santiso-Mere D., et al. Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol . 1994;8: 21-30.
86.
Stovall DW, Utian W., Gass M., et al. The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety. Menopause. 2007;14:1-8.
87.
Davis SR, O'Neill SM, Eden J., et al. Transition from estrogen therapy to raloxifene in postmenopausal women: effects on treatment satisfaction and the endometrium-a pilot study . Menopause. 2004;11:167-175.
88.
Carranza-Lira S., Gooch AL, Saldivar N., Osterwalder MSClimacteric symptom control after the addition of low-dose esterified conjugated estrogens to raloxifene standard doses. Int J Fertil Womens Med. 2007;52:93-96.
