Drugs & Aging

, Volume 27, Issue 7, pp 533–544 | Cite as

Tissue-Selective Estrogen Complexes

A Promising Option for the Comprehensive Management of Menopausal Symptoms
Review Article


At menopause many women experience undesired symptoms such as hot flashes and those associated with vulvovaginal atrophy, and are susceptible to loss of bone mass. Menopausal therapies to date include various estrogen and estrogen-progestin (progesterone congener) formulations. However, both physicians and women became concerned about hormone-related therapies following publication of data from the Women’s Health Initiative. Thus, the need exists for alternative therapies for postmenopausal women. Tissue-selective estrogen complexes (TSECs) are the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM). The goal of developing a TSEC is to provide the clinical benefits of each of its components with improved tolerability. This goal can potentially be achieved by the result of the different molecular and cellular activities of the treatment’s estrogen and SERM components. The therapeutic profile of a TSEC would optimally include relief of hot flashes, treatment of vulvovaginal atrophy and its symptoms, and prevention of bone loss, while providing safety for the endometrium and breast. Recent data indicate that the TSEC containing the SERM bazedoxifene and conjugated estrogens relieves hot flashes, improves vulvovaginal atrophy and its symptoms, and prevents loss of bone mass without stimulating the endometrium. This article reviews the current options for menopausal treatment as well as the environment that has driven the most recent evolution of new therapies for menopausal women, including the most recent development of the TSEC bazedoxifene and its early preclinical and clinical data.



The author appreciates the collaborative research and medical writing assistance of Kathleen Ohleth and Chastity Bradley of Precise Publications, LLC. Professor Archer is a consultant for Abbott Laboratories, Agile Therapeutics, Bayer Healthcare, ConCert Pharmaceutical, Novo Nordisk, Radius, Schering Plough, Warner Chilcott and Wyeth (acquired by Pfizer in October 2009). He has received research support from Bayer Healthcare, Duramed, Organon-Schering Plough, Solvay, Warner Chilcott and Wyeth, and has received consultant fees for speaking from Novo Nordisk, Organon-Schering Plough and Wyeth. Support for medical writing assistance was provided by Wyeth, which was acquired by Pfizer Inc. in October 2009.


  1. 1.
    McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992; 14: 103–15PubMedCrossRefGoogle Scholar
  2. 2.
    Grady D. Clinical practice: management of menopausal symptoms. N Engl J Med 2006; 355: 2338–47PubMedCrossRefGoogle Scholar
  3. 3.
    Burger GH, Teede HJ. Endocrine changes during the perimenopause. In: Lobo RA, editor. Treatment of the postmenopausal woman: basic and clinical aspects. 3rd ed. Burlington (MA): Academic Press, 2007Google Scholar
  4. 4.
    Speroff L. The menopause: a signal for the future. In: Lobo RA, editor. Treatment of the postmenopausal woman: basic and clinical aspects. 3rd ed. Burlington (MA): Academic Press, 2007Google Scholar
  5. 5.
    Bachmann GA, Ebert GA, Burd ID. Vulvovaginal complaints. In: Lobo RA, editor. Treatment of the postmenopausal woman. 2nd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 1999Google Scholar
  6. 6.
    Lindsay R, Cosman F. Pathogenesis of osteoporosis. In: Lobo RA, editor. Treatment of the postmenopausal woman: basic and clinical aspects. 3rd ed. Burlington (MA): Academic Press, 2007Google Scholar
  7. 7.
    Feldman BM, Voda A, Gronseth E. The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health 1985; 8: 261–8PubMedCrossRefGoogle Scholar
  8. 8.
    Kronenberg F. Hot flashes. In: Lobo RA, editor. Treatment of the postmenopausal woman: basic and clinical aspects. 2nd ed. Philadelphia (PA): Lippincott, Williams & Wilkins, 1999Google Scholar
  9. 9.
    Erlik Y, Tataryn IV, Meldrum DR, et al. Association of waking episodes with menopausal hot flushes. JAMA 1981; 245: 1741–4PubMedCrossRefGoogle Scholar
  10. 10.
    Rödström K, Bengtsson C, Lissner L, et al. A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause 2002; 9: 156–61PubMedCrossRefGoogle Scholar
  11. 11.
    van Geelen JM, van de Weijer PH, Arnolds HT. Urogenital symptoms and resulting discomfort in non-institutionalized Dutch women aged 50–75 years. Int Urogynecol J Pelvic Floor Dysfunct 2000; 11: 9–14PubMedCrossRefGoogle Scholar
  12. 12.
    Oskay UY, Beji NK, Yalcin O. A study on urogenital complaints of postmenopausal women aged 50 and over. Acta Obstet Gynecol Scand 2005; 84: 72–8PubMedGoogle Scholar
  13. 13.
    Haines CJ, Xing SM, Park KH, et al. Prevalence of menopausal symptoms in different ethnic groups of Asian women and responsiveness to therapy with three doses of conjugated estrogens/medroxyprogesterone acetate: the Pan-Asia menopause (PAM) study. Maturitas 2005; 52: 264–76PubMedCrossRefGoogle Scholar
  14. 14.
    Stenberg A, Heimer G, Ulmsten U, et al. Prevalence of genitourinary and other climacteric symptoms in 61-year-old women. Maturitas 1996; 24: 31–6PubMedCrossRefGoogle Scholar
  15. 15.
    Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000; 96: 351–8PubMedCrossRefGoogle Scholar
  16. 16.
    Versi E, Harvey MA, Cardozo L, et al. Urogenital prolapse and atrophy at menopause: a prevalence study. Int Urogynecol J Pelvic Floor Dysfunct 2001; 12: 107–10PubMedCrossRefGoogle Scholar
  17. 17.
    North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause 2006; 13: 340–67CrossRefGoogle Scholar
  18. 18.
    Hedlund LR, Gallagher JC. The effect of age and menopause on bone mineral density of the proximal femur. J Bone Miner Res 1989; 4: 639–42PubMedCrossRefGoogle Scholar
  19. 19.
    Bjarnason NH, Alexandersen P, Christiansen C. Number of years since menopause: spontaneous bone loss is dependent but response to hormone replacement therapy is independent. Bone 2002; 30: 637–42PubMedCrossRefGoogle Scholar
  20. 20.
    Nilas L, Christiansen C. The pathophysiology of peri- and postmenopausal bone loss. Br J Obstet Gynaecol 1989; 96: 580–7PubMedCrossRefGoogle Scholar
  21. 21.
    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: 1023–31PubMedCrossRefGoogle Scholar
  22. 22.
    Scaf-Klomp W, van Sonderen E, Sanderman R, et al. Recovery of physical function after limb injuries in independent older people living at home. Age Ageing 2001; 30: 213–9PubMedCrossRefGoogle Scholar
  23. 23.
    Leibson CL, Tosteson AN, Gabriel SE, et al. Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. J Am Geriatr Soc 2002; 50: 1644–50PubMedCrossRefGoogle Scholar
  24. 24.
    Kanis JA, Oden A, Johnell O, et al. Excess mortality after hospitalisation for vertebral fracture. Osteoporos Int 2004; 15: 108–12PubMedCrossRefGoogle Scholar
  25. 25.
    Johnell O, Kanis JA, Oden A, et al. Mortality after osteoporotic fractures. Osteoporos Int 2004; 15: 38–42PubMedCrossRefGoogle Scholar
  26. 26.
    Salaffi F, Cimmino MA, Malavolta N, et al. The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study. J Rheumatol 2007; 34: 1551–60PubMedGoogle Scholar
  27. 27.
    Oleksik A, Lips P, Dawson A, et al. Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures. J Bone Miner Res 2000; 15: 1384–92PubMedCrossRefGoogle Scholar
  28. 28.
    Randell AG, Nguyen TV, Bhalerao N, et al. Deterioration in quality of life following hip fracture: a prospective study. Osteoporos Int 2000; 11: 460–6PubMedCrossRefGoogle Scholar
  29. 29.
    North American Menopause Society. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of the North American Menopause Society. Menopause 2008; 15: 584–602CrossRefGoogle Scholar
  30. 30.
    Nolvadex® (tamoxifen citrate) [prescribing information]. Wilmington (DE): AstraZeneca, 2006 [online]. Available from URL: http://www1.astrazeneca-us.com/pi/arimidex.pdf [Accessed 2010 Apr 24]
  31. 31.
    Evista® (raloxifene hydrochloride) [prescribing information]. Indianapolis (IN): Eli Lilly and Company, 2007 [online]. Available from URL: http://pi.lilly.com/us/evista-pi.pdf [Accessed 2010 Apr 24]
  32. 32.
    Checa MA, Garrirdo A, Prat M, et al. A comparison of raloxifene and calcium plus vitamin D on vaginal atrophy after discontinuation of long-standing postmenopausal hormone therapy in osteoporotic women: a randomized, masked-evaluator, one-year, prospective study. Maturitas 2005; 16: 70–7CrossRefGoogle Scholar
  33. 33.
    Food and Drug Administration. Guidance for industry: labeling guidance for noncontraceptive estrogen drug products for the treatment of vasomotor symptoms and vulvar and vaginal atrophy symptoms-prescribing information for health care providers and patient labeling. Rockville (MD): US Department of Health and Human Services, 2003: 1–21 [online]. Available from URL: http://www.fda.gov [Accessed 2010 Apr 24]Google Scholar
  34. 34.
    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: 312–8PubMedCrossRefGoogle Scholar
  35. 35.
    Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75: 1065–79PubMedCrossRefGoogle Scholar
  36. 36.
    Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998; 92: 982–8PubMedCrossRefGoogle Scholar
  37. 37.
    Hedrick RE, Ackerman RT, Koltun WD, et al. Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women. Menopause 2009; 16: 132–40PubMedCrossRefGoogle Scholar
  38. 38.
    Simon JA, Bouchard C, Waldbaum A, et al. Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol 2007; 109: 588–96PubMedCrossRefGoogle Scholar
  39. 39.
    Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003; 44Suppl. 1: S67–77PubMedCrossRefGoogle Scholar
  40. 40.
    Odabasi AR, Yüksel H, Demircan SS, et al. A prospective randomized comparative study of the effects of intranasal and transdermal 17 beta-estradiol on postmenopausal symptoms and vaginal cytology. J Postgrad Med 2007; 53: 221–7PubMedCrossRefGoogle Scholar
  41. 41.
    Buster JE, Koltun WD, Pascual ML, et al. Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008; 111: 1343–51PubMedCrossRefGoogle Scholar
  42. 42.
    Simon J, Klaiber E, Wiita B, et al. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999; 6: 138–46PubMedCrossRefGoogle Scholar
  43. 43.
    Dobs AS, Nguyen T, Pace C, et al. Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 2002; 87: 1509–16PubMedCrossRefGoogle Scholar
  44. 44.
    Moriyama CK, Oneda B, Bernardo FR, et al. A randomized, placebo-controlled trial of the effects of physical exercises and estrogen therapy on health-related quality of life in postmenopausal women. Menopause 2008; 15: 613–8PubMedCrossRefGoogle Scholar
  45. 45.
    Al-Azzawi F, Buckler HM. Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms. Climacteric 2003; 6: 118–27PubMedGoogle Scholar
  46. 46.
    Buckler H, Al-Azzawi F. The effect of a novel vaginal ring delivering oestradiol acetate on climacteric symptoms in postmenopausal women. BJOG 2003; 110: 753–9PubMedCrossRefGoogle Scholar
  47. 47.
    Pickar JH, Yeh I, Wheeler JE, et al. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 76: 25–31PubMedCrossRefGoogle Scholar
  48. 48.
    Pickar JH, Yeh IT, Wheeler JE, et al. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril 2003; 80: 1234–40PubMedCrossRefGoogle Scholar
  49. 49.
    Lindsay R, Gallagher JC, Kleerekoper M, et al. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002; 287: 2668–76PubMedCrossRefGoogle Scholar
  50. 50.
    Archer DF, Dorin M, Lewis V, et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001; 75: 1080–7PubMedCrossRefGoogle Scholar
  51. 51.
    Lobo RA, Bush T, Carr BR, et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001; 76: 13–24PubMedCrossRefGoogle Scholar
  52. 52.
    Pornel B, Spielmann D. A study of the control of climacteric symptoms in postmenopausal women following sequential regimens of 1 mg 17beta-estradiol and trimegestone compared with a regimen containing 1 mg estradiol valerate and norethisterone over a two-year period. Gynecol Endocrinol 2005; 21: 74–81PubMedCrossRefGoogle Scholar
  53. 53.
    Gambacciani M, Spielmann D, Genazzani AR. Efficacy on climacteric symptoms of a continuous combined regimen of 1 mg 17beta-estradiol and trimegestone versus two regimens combining 1 or 2 mg 17beta-estradiol and norethisterone acetate. Gynecol Endocrinol 2005; 21: 65–73PubMedCrossRefGoogle Scholar
  54. 54.
    Bouchard P, De Cicco-Nardone F, Spielmann D, et al. Bleeding profile and endometrial safety of continuous combined regimens 1 mg 17β-estradiol/trimegestone versus 1 or 2 mg 17β-estradiol/norethisterone acetate in postmenopausal women. Gynecol Endocrinol 2005; 21: 142–8PubMedCrossRefGoogle Scholar
  55. 55.
    Koninckx PR, Spielmann D. A comparative 2-year study of the effects of sequential regimens of 1 mg 17β-estradiol and trimegestone with a regimen containing estradiol valerate and norethisterone on the bleeding profile and endometrial safety in postmenopausal women. Gynecol Endocrinol 2005; 21: 82–9PubMedCrossRefGoogle Scholar
  56. 56.
    Warming L, Ravn P, Spielman D, et al. Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women. Menopause 2004; 11: 337–42PubMedCrossRefGoogle Scholar
  57. 57.
    Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004; 7: 189–96PubMedCrossRefGoogle Scholar
  58. 58.
    Archer DF, Thorneycroft IH, Foegh M, et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005; 12: 716–27PubMedCrossRefGoogle Scholar
  59. 59.
    Activella® (estradiol/norethindrone acetate) tablets. Princeton (NJ): Novo Nordisk Inc., 2006 [online]. Available from URL: http://www.vagifemhcp.com/Content/files/activella-pi.pdf [Accessed 2010 Apr 24]
  60. 60.
    Panay N, Ylikorkala O, Archer DF, et al. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric 2007; 10: 120–31PubMedCrossRefGoogle Scholar
  61. 61.
    Sturdee DW, Archer DF, Rakov V, et al. Ultra-low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women. Climacteric 2008; 11: 63–73PubMedCrossRefGoogle Scholar
  62. 62.
    Johnson JV, Davidson M, Archer D, et al. Postmenopausal uterine bleeding profiles with two forms of continuous combined hormone replacement therapy. Menopause 2002; 9: 16–22PubMedCrossRefGoogle Scholar
  63. 63.
    Archer DF, Furst K, Tipping D, et al. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol 1999; 94: 498–503PubMedCrossRefGoogle Scholar
  64. 64.
    Samsioe G, Boschitsch E, Concin H, et al. Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study. Climacteric 2006; 9: 368–79PubMedCrossRefGoogle Scholar
  65. 65.
    Greenwald MW, Gluck OS, Lang E, et al. Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with norethindrone acetate in the prevention of bone loss in early postmenopausal women: dose-dependent effects. Menopause 2005; 12: 741–8PubMedCrossRefGoogle Scholar
  66. 66.
    Rowan JP, Simon JA, Speroff L, et al. Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials. Clin Ther 2006; 28: 921–32PubMedCrossRefGoogle Scholar
  67. 67.
    Speroff L, Symons J, Kempfert N, et al. The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (Femhrt®) on the frequency and intensity of vasomotor symptoms. Menopause 2000; 7: 383–90PubMedCrossRefGoogle Scholar
  68. 68.
    Simon JA, Symons JP. Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens. Menopause 2001; 8: 321–7PubMedCrossRefGoogle Scholar
  69. 69.
    Haas JS, Kaplan CP, Gerstenberger EP, et al. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med 2004; 140: 184–8PubMedGoogle Scholar
  70. 70.
    Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004; 291: 47–53PubMedCrossRefGoogle Scholar
  71. 71.
    Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women’s Health Initiative. JAMA 2004; 292: 1983–8PubMedCrossRefGoogle Scholar
  72. 72.
    Wattanakumtornkul S, Chichareon S, Geater A, et al. Compliance with hormone replacement therapy at Songklanagarind Hospital. J Obstet Gynaecol Res 2003; 29: 380–7PubMedCrossRefGoogle Scholar
  73. 73.
    Manonai J, Theppisai U, Suchartwatnachai C, et al. Compliance with hormone replacement therapy in Thai women. Maturitas 2003; 44: 201–5PubMedCrossRefGoogle Scholar
  74. 74.
    Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33CrossRefGoogle Scholar
  75. 75.
    Hoffmann M, Hammar M, Kjellgren KI, et al. Changes in women’s attitudes towards and use of hormone therapy after HERS and WHI. Maturitas 2005; 52: 11–7PubMedCrossRefGoogle Scholar
  76. 76.
    Helenius IM, Korenstein D, Halm EA. Changing use of hormone therapy among minority women since the Women’s Health Initiative. Menopause 2007; 14: 216–22PubMedCrossRefGoogle Scholar
  77. 77.
    Rolnick SJ, Kopher RA, DeFor TA, et al. Hormone use and patient concerns after the findings of the Women’s Health Initiative. Menopause 2005; 12: 399–404PubMedCrossRefGoogle Scholar
  78. 78.
    Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291: 1701–12CrossRefGoogle Scholar
  79. 79.
    Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349: 523–34PubMedCrossRefGoogle Scholar
  80. 80.
    Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297: 1465–77PubMedCrossRefGoogle Scholar
  81. 81.
    Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243–53PubMedCrossRefGoogle Scholar
  82. 82.
    Prentice RL, Chlebowski RT, Stefanick ML, et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2008; 167: 1207–16PubMedCrossRefGoogle Scholar
  83. 83.
    Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292: 1573–80PubMedCrossRefGoogle Scholar
  84. 84.
    Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350: 991–1004PubMedCrossRefGoogle Scholar
  85. 85.
    Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003; 290: 1729–38PubMedCrossRefGoogle Scholar
  86. 86.
    Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006; 295: 1647–57PubMedCrossRefGoogle Scholar
  87. 87.
    Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006; 166: 772–80PubMedCrossRefGoogle Scholar
  88. 88.
    Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. 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: 817–28PubMedCrossRefGoogle Scholar
  89. 89.
    Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006; 116: 561–70PubMedCrossRefGoogle Scholar
  90. 90.
    Komm BS, Kharode YP, Bodine PV, et al. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology 2005; 146: 3999–4008PubMedCrossRefGoogle Scholar
  91. 91.
    Komm BS, Lyttle CR. Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci 2001; 949: 317–26PubMedCrossRefGoogle Scholar
  92. 92.
    Crabtree JS, Peano BJ, Zhang X, et al. Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol 2008; 287: 40–6PubMedCrossRefGoogle Scholar
  93. 93.
    Kharode Y, Bodine PVN, Miller CP, et al. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology 2008; 149: 6084–91PubMedCrossRefGoogle Scholar
  94. 94.
    Peano BJ, Crabtree JS, Komm BS, et al. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology 2009; 150: 1897–903PubMedCrossRefGoogle Scholar
  95. 95.
    Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv 2005; 5: 343–57PubMedCrossRefGoogle Scholar
  96. 96.
    McDonnell DP, Clemm DL, Hermann T, et al. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995; 9: 659–69PubMedCrossRefGoogle Scholar
  97. 97.
    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: 3999–4004PubMedCrossRefGoogle Scholar
  98. 98.
    Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389: 753–8PubMedCrossRefGoogle Scholar
  99. 99.
    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: 927–37PubMedCrossRefGoogle Scholar
  100. 100.
    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: 525–35PubMedCrossRefGoogle Scholar
  101. 101.
    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: 1923–34PubMedCrossRefGoogle Scholar
  102. 102.
    Komm BS, Pickar JH. Tissue selective estrogen complex (TSEC): a new paradigm for menopausal therapy. Complete Proceedings Collection of the 6th International Menopause Society Workshop Menopause and Ageing, Quality of Life and Sexuality; 2006 Dec 1–4; Pisa. Climacteric 2007; 10: 1–12Google Scholar
  103. 103.
    Pickar JH. Tissue selective estrogen complex: a new paradigm for menopausal therapy. Menopausal Med 2008; 16: S10–3Google Scholar
  104. 104.
    Pickar JH, Yeh I-T, Bachmann G, et al. Endometrial effects of a tissue selective estrogen complex (TSEC) containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril 2009; 92: 1018–24PubMedCrossRefGoogle Scholar
  105. 105.
    Lobo RA, Pinkerton JV, Gass MLS, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic bone parameters and overall safety profile. Fertil Steril 2009; 92: 1025–38PubMedCrossRefGoogle Scholar
  106. 106.
    Lindsay R, Gallagher JC, Kagan R, et al. Efficacy of tissue-selective estrogen complex (TSEC) of bazedoxifene/conjugated estrogens (BZA/CE) for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril 2009; 92: 1045–52PubMedCrossRefGoogle Scholar
  107. 107.
    Archer DF, Lewis V, Carr BR, et al. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril 2009; 92: 1039–44PubMedCrossRefGoogle Scholar
  108. 108.
    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: 510–7PubMedCrossRefGoogle Scholar
  109. 109.
    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: 167–75PubMedCrossRefGoogle Scholar
  110. 110.
    Carranza-Lira S, Gooch AL, Saldivar N, et al. Climacteric symptom control after the addition of low-dose esterified conjugated estrogens to raloxifene standard doses. Int J Fertil Womens Med 2007; 52: 93–6PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Clinical Research Center, Jones Institute for Reproductive MedicineEastern Virginia Medical SchoolNorfolkUSA

Personalised recommendations