The evolving role of oral hormonal therapies and review of conjugated estrogens/bazedoxifene for the management of menopausal symptoms

References

• Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351–358.
   PubMed Web of Science ®Google Scholar
• Williams RE, Kalilani L, DiBenedetti DB, et al. Healthcare seeking and treatment for menopausal symptoms in the United States. Maturitas. 2007;58:348–358.
   PubMed Web of Science ®Google Scholar
• Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531–539.
   PubMed Web of Science ®Google Scholar
• Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21:924–932.
   PubMed Web of Science ®Google Scholar
• Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47.
   PubMedGoogle Scholar
• Sarrel P, Portman D, Lefebvre P, et al. Incremental direct and indirect costs of untreated vasomotor symptoms. Menopause. 2015;22(3):260–266.
   Google Scholar
• Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause. 2014;21:1063–1068.
   PubMed Web of Science ®Google Scholar
• Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med. 2009;6:2133–2142.
   PubMed Web of Science ®Google Scholar
• Simon JA, Nappi RE, Kingsberg SA, et al. Clarifying Vaginal Atrophy’s Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on North American postmenopausal women and their partners. Menopause. 2014;21:137–142.
   PubMed Web of Science ®Google Scholar
• The North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20:888–902.
   PubMed Web of Science ®Google Scholar
• The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:25–54.
   PubMed Web of Science ®Google Scholar
• Shifren JL, Gass ML. The North American Menopause Society recommendations for clinical care of midlife women. Menopause. 2014;21:1038–1062.
   PubMed Web of Science ®Google Scholar
• de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2013;16:316–337.
   PubMed Web of Science ®Google Scholar
• The North American Menopause Society. The 2012 hormone therapy position statement of: the North American Menopause Society. Menopause. 2012;19:257–271.
   PubMed Web of Science ®Google Scholar
• Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 women’s health initiative randomized clinical trials. JAMA Oncol. 2015;1:296–305.
   PubMed Web of Science ®Google Scholar
• Duavee [package insert]. Philadelphia (PA): Wyeth Pharmaceuticals; 2015.
   Google Scholar
• Brisdelle [package insert]. Miami (FL): Noven Therapeutics, LLC; 2013.
   Google Scholar
• Osphena [package insert]. Florham Park (NJ): Shionogi; 2015.
   Google Scholar
• Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–1712.
   PubMed Web of Science ®Google Scholar
• Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.
   PubMed Web of Science ®Google Scholar
• Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003;348:1839–1854.
   PubMed Web of Science ®Google Scholar
• Alving B. NIH asks participants in Women’s Health Initiative estrogen-alone study to stop study pills, begin follow-up phase: national Institutes of Health. South Med J. 2004;97:425–426. [updated 2013 Oct 29]. Available from: http://www.nhlbi.nih.gov/news/press-releases/2004/nih-asks-participants-in-womens-health-initiative-estrogen-alone-study-to-stop-study-pills-begin-follow-up-phase.html
   PubMed Web of Science ®Google Scholar
• Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310:1353–1368.
   PubMed Web of Science ®Google Scholar
• 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;289:3243–3253.
   PubMed Web of Science ®Google Scholar
• Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304:1684–1692.
   PubMed Web of Science ®Google Scholar
• Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology. 2012;79:1846–1852.
   PubMed Web of Science ®Google Scholar
• Whitmer RA, Quesenberry CP, Zhou J, et al. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. 2011;69:163–169.
   PubMed Web of Science ®Google Scholar
• Kelly JP, Kaufman DW, Rosenberg L, et al. Use of postmenopausal hormone therapy since the Women’s Health Initiative findings. Pharmacoepidemiol Drug Saf. 2005;14:837–842.
   PubMed Web of Science ®Google Scholar
• Sprague BL, Trentham-Dietz A, Cronin KA. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999-2010. Obstet Gynecol. 2012;120:595–603.
   PubMed Web of Science ®Google Scholar
• Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616–621.
   PubMed Web of Science ®Google Scholar
• de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Climacteric. 2013;16:203–204.
   PubMed Web of Science ®Google Scholar
• Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol. 2005;105:1063–1073.
   PubMed Web of Science ®Google Scholar
• Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.
   PubMed Web of Science ®Google Scholar
• Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014;161:249–260.
   PubMed Web of Science ®Google Scholar
• Hodis HN, Mack WJ, Henderson VS, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221–1231.
   PubMed Web of Science ®Google Scholar
• Kling JM, Lahr BA, Bailey KR, et al. Endothelial function in women of the Kronos Early Estrogen Prevention Study. Climacteric. 2015;18:187–197.
   PubMed Web of Science ®Google Scholar
• Files JA, Miller VM, Cha SS, et al. Effects of different hormone therapies on breast pain in recently postmenopausal women: findings from the Mayo Clinic KEEPS breast pain ancillary study. J Womens Health (Larchmt). 2014;23:801–805.
   PubMed Web of Science ®Google Scholar
• Canonico M, Oger E, Plu-Bureau, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115:840–845.
   PubMed Web of Science ®Google Scholar
• Olie V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol. 2010;17:457–463.
   PubMed Web of Science ®Google Scholar
• Renoux C, Dell’aniello S, Garbe E, et al. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010;340:c2519.
   PubMed Web of Science ®Google Scholar
• Scarabin PY, Oger E. Plu-Bureau. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–432.
   PubMed Web of Science ®Google Scholar
• American College of Obstetricians and Gynecologists, Committee on Gynecologic Practice. ACOG committee opinion no. 556: postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121:887–890.
   PubMedGoogle Scholar
• Williams RE, Kalilani L, DiBenedetti DB, et al. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States. Climacteric. 2008;11:32–43.
   PubMed Web of Science ®Google Scholar
• Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013;20:1027–1035.
   PubMed Web of Science ®Google Scholar
• The North American Menopause Society. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;22:1155–1174.
   PubMed Web of Science ®Google Scholar
• Kharode Y, Bodine PV, 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;149:6084–6091.
   PubMed Web of Science ®Google Scholar
• Komm BS. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci. 2008;15:984–992.
   PubMed Web of Science ®Google Scholar
• Komm BS, Mirkin S. Evolution of the tissue selective estrogen complex (TSEC). J Cell Physiol. 2013;228:1423–1427.
   PubMed Web of Science ®Google Scholar
• Stovall DW, Utian WH, Gass ML, et al. The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety. Menopause. 2007;14:510–517.
   PubMed Web of Science ®Google Scholar
• Riggs BL, Hartmann LC. Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618–629.
   PubMed Web of Science ®Google Scholar
• 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;150:1897–1903.
   PubMed Web of Science ®Google Scholar
• Lewis-Wambi JS, Kim H, Curpan R, et al. The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor alpha and cyclin D1. Mol Pharmacol. 2011;80:610–620.
   PubMed Web of Science ®Google Scholar
• Oliva P, Roncoroni C, Radaelli E, et al. Global profiling of TSEC proliferative potential by the use of a reporter mouse for proliferation. Reprod Sci. 2013;20:119–128.
   PubMed Web of Science ®Google Scholar
• Song Y, Santen RJ, Wang JP, et al. Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice. Endocrinology. 2012;153:5706–5715.
   PubMed Web of Science ®Google Scholar
• Song Y, Santen RJ, Wang JP, et al. Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro. Endocrinology. 2013;154:656–665.
   PubMed Web of Science ®Google Scholar
• Ethun KF, Wood CE, Register TC, et al. Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. Menopause. 2012;19:1242–1252.
   PubMed Web of Science ®Google Scholar
• Chang KC, Wang Y, Bodine PV, et al. Gene expression profiling studies of three SERMs and their conjugated estrogen combinations in human breast cancer cells: insights into the unique antagonistic effects of bazedoxifene on conjugated estrogens. J Steroid Biochem Mol Biol. 2010;118:117–124.
   PubMed Web of Science ®Google Scholar
• Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527–537.
   PubMed Web of Science ®Google Scholar
• Liu S, Han SJ, Smith CL. Cooperative activation of gene expression by agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. Mol Pharmacol. 2013;83:1066–1077.
   PubMed Web of Science ®Google Scholar
• Ethun KF, Wood CE, Cline JM, et al. Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model. Menopause. 2013;20:777–784.
   PubMed Web of Science ®Google Scholar
• Wardell SE, Nelson ER, Chao CA, et al. 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.
   PubMed Web of Science ®Google Scholar
• Archer DF, Lewis V, Carr BR, et al. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92:1039–1044.
   PubMed Web of Science ®Google Scholar
• Harvey JA, Pinkerton JV, Baracat EC, et al. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20:138–145.
   PubMed Web of Science ®Google Scholar
• Lindsay R, Gallagher JC, Kagan R, et al. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92:1045–1052.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Pickar JH, Yeh IT, Bachmann G, et al. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009;92:1018–1024.
   PubMed Web of Science ®Google Scholar
• Pinkerton JV, Utian WH, Constantine GD, et al. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause. 2009;16:1116–1124.
   PubMed Web of Science ®Google Scholar
• Utian W, Yu H, Bobula J, et al. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas. 2009;63:329–335.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Kagan R, Williams RS, Pan K, et al. 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.
   PubMed Web of Science ®Google Scholar
• Mirkin S, Komm BS, Pan K, et al. Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. Climacteric. 2013;16:338–346.
   PubMed Web of Science ®Google Scholar
• Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens: a randomized controlled trial. Obstet Gynecol. 2013;121:959–968.
   PubMed Web of Science ®Google Scholar
• Pinkerton JV, Pan K, Abraham L, et al. Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial. Menopause. 2014;21:252–259.
   PubMed Web of Science ®Google Scholar
• Pinkerton JV, Harvey JA, Lindsay R, et al. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99:E189–E198.
   PubMed Web of Science ®Google Scholar
• Skouby SO, Pan K, Thompson JR, et al. Effects of conjugated estrogens/bazedoxifene on lipid and coagulation variables: a randomized, placebo- and active-controlled trial. Menopause. 2015;22:640–649.
   PubMed Web of Science ®Google Scholar
• Kagan R, Komm BS, Ryan KA, et al. Timing and persistence of effect of conjugated estrogens/bazedoxifene in postmenopausal women. Menopause. 2016;23:1204–1213.
   PubMed Web of Science ®Google Scholar
• Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective Estrogens, Menopause and Response to Therapy (SMART) Trials. J Womens Health (Larchmt). 2014;23:18–28.
   PubMed Web of Science ®Google Scholar
• Savolainen-Peltonen H, Hautamaki H, Tuomikoski P, et al. Health-related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy. Menopause. 2014;21:732–739.
   PubMed Web of Science ®Google Scholar
• Abraham L, Pinkerton JV, Messig M, et al. Menopause-specific quality of life across varying menopausal populations with conjugated estrogens/bazedoxifene. Maturitas. 2014;78:212–218.
   PubMed Web of Science ®Google Scholar
• Hilditch JR, Lewis J, Peter A, et al. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996;24:161–175.
   PubMed Web of Science ®Google Scholar
• Palacios S, Silverman SL, de Villiers TJ, et al. A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: effects on bone density and fracture. Menopause. 2015;22:806–813.
   PubMed Web of Science ®Google Scholar
• 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;287:40–46.
   PubMed Web of Science ®Google Scholar
• Guidance for Industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms - recommendaitons for clinical evaluation: food and Drug Administration; 2003. [updated 2014 Jan 6]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071643.pdf
   Google Scholar
• Mirkin S, Pinkerton JV, Kagan R, et al. Gynecologic safety of conjugated estrogens plus bazedoxifene: pooled analysis of five phase 3 trials. J Womens Health (Larchmt). 2016;25:431–442.
   PubMed Web of Science ®Google Scholar
• Study evaluating the effects of bazedoxifene/conjugated estrogens on endometrial safety and postmenopausal osteoporosis; 2014. [updated 2015 Dec 4]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT00808132
   Google Scholar
• Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med. 2003;138:168–175.
   PubMed Web of Science ®Google Scholar
• Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6:798–808.
   PubMed Web of Science ®Google Scholar
• Crandall CJ, Aragaki AK, Cauley JA, et al. Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone Women’s Health Initiative clinical trials. Breast Cancer Res Treat. 2012;132:275–285.
   PubMed Web of Science ®Google Scholar
• de Villiers TJ, Chines AA, Palacios S, et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int. 2011;22:567–576.
   PubMed Web of Science ®Google Scholar
• Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Climacteric. 2015;18:1–19.
   Web of Science ®Google Scholar
• Stevenson JC, Chines A, Pan K, et al. A pooled analysis of the effects of conjugated estrogens/bazedoxifene on lipid parameters in postmenopausal women from the Selective Estrogens, Menopause, And Response to Therapy (SMART) Trials. J Clin Endocrinol Metab. 2015;100:2329–2338.
   PubMed Web of Science ®Google Scholar
• Prempro/Premphase [package insert]. Philadelphia (PA): Wyeth Pharmaceuticals; 2012.
   Google Scholar
• Regan MM, Emond SK, Attardo MJ, et al. Why do older women discontinue hormone replacement therapy? J Womens Health Gend Based Med. 2001;10:343–350.
   PubMedGoogle Scholar
• de Medeiros SF, Yamamoto MM, Barbosa JS. Abnormal bleeding during menopause hormone therapy: insights for clinical management. Clin Med Insights Womens Health. 2013;6:13–24.
   PubMedGoogle Scholar
• Hickey M, Ameratunga D, Marino JL. Unscheduled bleeding in continuous combined hormone therapy users. Maturitas. 2011;70:400–403.
   PubMed Web of Science ®Google Scholar
• Crandall CJ, Aragaki A, Cauley JA, et al. Associations of menopausal vasomotor symptoms with fracture incidence. J Clin Endocrinol Metab. 2015;100:524–534.
   PubMed Web of Science ®Google Scholar
• Gallagher JC, Shi H, Mirkin S, et al. Changes in bone mineral density are correlated with bone markers and reductions in hot flush severity in postmenopausal women treated with bazedoxifene/conjugated estrogens. Menopause. 2013;20:1126–1132.
   PubMed Web of Science ®Google Scholar