Hormone-replacement therapy: current thinking

Journal name:
Nature Reviews Endocrinology
Volume:
13,
Pages:
220–231
Year published:
DOI:
doi:10.1038/nrendo.2016.164
Published online
Corrected online

Abstract

For several decades, the role of hormone-replacement therapy (HRT) has been debated. Early observational data on HRT showed many benefits, including a reduction in coronary heart disease (CHD) and mortality. More recently, randomized trials, including the Women's Health Initiative (WHI), studying mostly women many years after the the onset of menopause, showed no such benefit and, indeed, an increased risk of CHD and breast cancer, which led to an abrupt decrease in the use of HRT. Subsequent reanalyzes of data from the WHI with age stratification, newer randomized and observational data and several meta-analyses now consistently show reductions in CHD and mortality when HRT is initiated soon after menopause. HRT also significantly decreases the incidence of various symptoms of menopause and the risk of osteoporotic fractures, and improves quality of life. In younger healthy women (aged 50–60 years), the risk–benefit balance is positive for using HRT, with risks considered rare. As no validated primary prevention strategies are available for younger women (<60 years of age), other than lifestyle management, some consideration might be given to HRT as a prevention strategy as treatment can reduce CHD and all-cause mortality. Although HRT should be primarily oestrogen-based, no particular HRT regimen can be advocated.

At a glance

Figures

  1. Adverse effects in women treated with HRT.
    Figure 1: Adverse effects in women treated with HRT.

    Data shown represent lifelong probability of adverse effects in 50-year-old white women; uterus status and progestogen addition have been omitted for simplicity. Effects of oestrogen (blue) versus no treatment (red). Relative risks (RR) and probabilities extracted taken from elsewhere8. HRT, hormone-replacement therapy.

  2. Coronary vessels in atherosclerosis.
    Figure 2: Coronary vessels in atherosclerosis.

    Left panel depicts coronary vessels in a young woman with early atherosclerosis. Right panel depicts coronary vessels in an older (aged >65 years) woman with established atherosclerosis. Various effects of hormone-replacement therapy (HRT) on the vessels in the two stages of atherosclerosis are shown, with benefit in young arteries and altered biology in old arteries. CAMs, cell adhesion molecules; COX2, cyclooxygenase 2; ER, oestrogen receptor; MCP1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; TNF, tumour necrosis factor; VSMC, vascular smooth muscle cell. Permission obtained from the American Association for the Advancement of Science © Mendelsohn, M. E. & Karas, R. H. Science 308, 15831587 (2005).

  3. Breast cancer risk.
    Figure 3: Breast cancer risk.

    Relative risks of breast cancer associated with treatment with conjugated equine oestrogens (CEE) alone or with medroxyprogesterone acetate (MPA), occupational exposures and endogenous risks. Data obtained from elsewhere19, 25, 81, 82.

  4. Events and symptoms associated with CEE.
    Figure 4: Events and symptoms associated with CEE.

    Absolute changes in events or symptoms (minus placebo effect) per 1,000 women aged 50–59 years who were treated for 5 years with conjugated equine oestrogens (CEE). Data obtained from elsewhere25, 89.

Change history

Corrected online 03 November 2016
In the original published article, reference 41 was incorrect. The correct reference is Carrasquilla, G. D. et al. The association between menopausal hormone therapy and coronary heart disease depends on timing of initiation in relation to menopause onset: results based on pooled individual participant data from the Combined Cohorts of Menopausal Women — Studies of Register Based Health Outcomes in Relation to Hormonal Drugs (COMPREHEND) study [abstract S17]. Menopause 22, 1373 (2015). This error has been corrected in the HTML and PDF versions of the article.

References

  1. Kling, J. The strange case of premarin. moderndrugdiscovery http://pubs.acs.org/subscribe/archive/mdd/v03/i08/html/kling.html (2000).
  2. Wilson, R. A. in Feminine forever (ed. Evans, M.) (Lippincott, 1966).
  3. Osteoporosis. National Institutes of Health Consensus Development Conference Statement, April 2–4, 1984. Department of Health & Human Services. http://consensus.nih.gov/1984/1984Osteoporosis043html.htm (1984).
  4. Stampfer, M. J. & Colditz, G. A. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev. Med. 20, 4763 (1991).
  5. Grodstein, F., Stampfer, M. J. & Colditz, G. A. Postmenopausal hormone therapy and mortality. N. Engl. J. Med. 336, 17691775 (1997).
  6. Yaffe, K., Sawaya, G., Lieberburg, I. & Grady, D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 279, 688695 (1998).
  7. Woodruff, J. D. & Pickar, J. H. The Menopause Study Group. Am. J. Obstet. Gynecol. 170, 12131223 (1994).
  8. Ross, R. K., Pike, M. C., Henderson, B. E., Mack, T. M. & Lobo, R. A. Stroke prevention and oestrogen replacement therapy. Lancet 1, 505 (1989).
  9. Henderson, B. E., Paganini-Hill, A. & Ross, R. K. Decreased mortality in users of estrogen replacement therapy. Arch. Intern. Med. 151, 7578 (1991).
  10. Grady, D. et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann. Intern. Med. 117, 10161037 (1992).
  11. Lobo, R. A. & Whitehead, M. Too much of a good thing? Use of progestogens in the menopause: an international consensus statement. Fertil. Steril. 51, 229231 (1989).
  12. Hartley, C. J. Estrogen drug beneficial, panel decides. Los Angeles Times http://articles.latimes.com/1990-06-16/news/mn-152_1_advisory-committee (1990).
  13. Hulley, S. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280, 605613 (1998).
  14. Herrington, D. M. et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N. Engl. J. Med. 343, 522529 (2000).
  15. Clarke, S. C., Kelleher, J., Lloyd-Jones, H., Slack, M. & Schofiel, P. M. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. BJOG 109, 10561062 (2002).
  16. Rossouw, J. E. 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 288, 321333 (2002).
  17. [No authors listed] NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk and lack of overall benefit. South. Med. J. 95, 795797 (2002).
  18. Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291, 17011712 (2004).
  19. Shumaker, S. A. et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289, 26512662 (2003).
  20. Shumaker, S. A. et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 291, 29472958 (2004).
  21. Stevenson, J. C., Hodis, H. N., Pickar, J. H. & Lobo, R. A. Coronary heart disease and menopause management: the swinging pendulum of HRT. Atherosclerosis 207, 336340 (2009).
  22. Anderson, G. L., Chlebowski, R. T. & Rossouw, J. E. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen and progestin. Maturitas 55, 107115 (2006).
  23. Stefanick, M. L. et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295, 16471657 (2006).
  24. Anderson, G. L. et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomized placebo-controlled trial. Lancet Oncol. 13, 476486 (2012).
  25. Hsia, J. et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch. Intern. Med. 166, 357365 (2006).
  26. Rossouw, J. E. et al. Postmenopausal hormone therapy and cardiovascular disease by age and years since menopause. JAMA 297, 14651477 (2007).
  27. Parker-Pope, T. How NIH misread hormone study in 2002. The Wall Street Journal http://www.wsj.com/articles/SB118394176612760522 (2007).
  28. Manson, J. E. et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 310, 13531368 (2013).
  29. Ettinger, B. et al. Evolution of postmenopausal hormone therapy between 2002 and 2009. Menopause 19, 610615 (2012).
  30. Sprague, B. L., Trentham-Dietz, A. & Cronin, K. A. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010. Obstet. Gynecol. 120, 595603 (2012).
  31. Islam, S., Liu, Q., Chines, A. & Hetzer, E. Trend in incidence of osteoporosis-related fractures among 40- to 69-year old women: analysis of a large insurance claims database, 2000–2005. Menopause 16, 7783 (2009).
  32. Karim, R. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause 18, 11721177 (2011).
  33. Sarrel, P., Njike, V., Vinante, V. & Katz, D. L. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59. Am. J. Pub. Health 103, 15831588 (2013).
  34. Mikkola, T. S., Tuomikoski, P. & Lyytinen, H. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J. Clin. Endocrinol. Metab. 100, 45884594 (2015).
  35. Lobo, R. A. Don't be so quick to stop hormone-replacement therapy. Nat. Rev. Endocrinol. 12, 1113 (2016).
  36. Kindig, D. A. & Cheng, E. R. Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8 percent of counties from 1992 to 2006. Health Aff. (Millwood) 32, 451458 (2013).
  37. Clarkson, T. B. The new conundrum: do estrogens have any cardiovascular benefits? Int. J. Fertil. Womens Med. 47, 6168 (2002).
  38. Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 15831587 (2005).
  39. Clarkson, T. B., Anthony, M. S. & Morgan, T. M. Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J. Clin. Endocrinol. Metab. 86, 4147 (2001).
  40. Hodis, H. N., Mack, W. J. & Henderson, V. W. Effects of early versus late postmenopausal treatment with estradiol. N. Engl. J. Med. 374, 12211231 (2016).
  41. Carrasquilla, G. D. et al. The association between menopausal hormone therapy and coronary heart disease depends on timing of initiation in relation to menopause onset: results based on pooled individual participant data from the Combined Cohorts of Menopausal Women — Studies of Register Based Health Outcomes in Relation to Hormonal Drugs (COMPREHEND) study [abstract S17]. Menopause 22, 1361 (2015).
  42. Pereira, R. I. Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. J. Clin. Endocrinol. Metab. 12, 44564462 (2015).
  43. Zhang, Q. G. C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection. Proc. Natl Acad. Sci. USA 35, E617E624 (2011).
  44. Rao, Y. S., Mott, N. N., Wang, Y., Chung, W. C. & Pak, T. R. MicroRNAs in the aging female brain: a putative mechanism for age-specific estrogen effects. Endocrinology 8, 27952806 (2013).
  45. LeBlanc, E. S., Janowsky, J., Chan, B. K. & Nelson, H. D. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285, 14891499 (2001).
  46. Zandi, P. P. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 17, 21232129 (2002).
  47. Whitmer, R. A., Quesenberry, C. P., Zhou, J. & Yaffe, K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann. Neurol. 69, 163169 (2011).
  48. Nelson, H. D. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA 13, 16101620 (2004).
  49. Haines, C. J., Xing, S. M., Park, K. H., Holinda, C. F. & Ausmanas, M. K. 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 52, 264276 (2005).
  50. Soares, C. N. Mood disorders in midlife women: understanding the critical window and its clinical implications. Menopause 21, 198206 (2014).
  51. Worsley, R., Davis, S. R. & Gavrilidis, E. Hormonal therapies for new onset and relapsed depression during perimenopause. Maturitas 73, 127133 (2012).
  52. Barnabei, V. M., Cochrane, B. B. & Aragaki, A. K. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet. Gynecol. 105, 10631073 (2005).
  53. Sturdee, D. W., Panay, N., International Menopause Society Writing Group. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 6, 509522 (2010).
  54. Zhu, L., Jiang, X., Sun, Shu, W. Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials. Menopause 4, 461470 (2015).
  55. Ettinger, B. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet. Gynecol. 104, 443451 (2004).
  56. Christiansen, C. & Riis, B. J. 17 β-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J. Clin. Endocrinol. Metab. 4, 836841 (1990).
  57. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 19, 257271 (2012).
  58. Galis, Z. S., Sukhova, G. K., Lark, M. W. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 24932503 (1994).
  59. Hu, P., Greendale, G. A. & Palla, S. L. The effects of hormone therapy on the makers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the Postmenopausal Estrogen Progestin Intervention (PIPI) trial. Atherosclerosis 185, 347352 (2006).
  60. Lobo, R. A. Evaluation of cardiovascular event rates with hormone therapy in healthy postmenopausal women: results from four large clinical trials. Arch. Intern. Med. 164, 4884 (2004).
  61. Post, W. S. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc. Res. 43, 985991 (1999).
  62. Umetani, M. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 11851192 (2007).
  63. LaCroix, A. Z., Chlebowski, R. T. & Manson, J. E. & WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 305, 13051314 (2011).
  64. Schierbeck, I. L. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 345, e6409 (2012).
  65. Salpeter, S. R., Walsh, J. M., Greyber, E. & Salpeter, E. E. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J. Gen. Intern. Med. 21, 363366 (2006).
  66. Harman, S. M. et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann. Intern. Med. 161, 249260 (2014).
  67. Tuomikoski, P., Lyytinen, H. J. & Korhonen, P. Coronary heart disease mortality and hormone therapy before and after the Women's Health Initiative. Obstet. Gynecol. 124, 947953 (2014).
  68. Mikkola, T. S., Tuomikoski, P. & Lyytinen, H. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause 22, 976983 (2015).
  69. Salpeter, S. R., Cheng, J., Thabane, L., Buckley, N. S. & Salpeter, E. E. Bayesian meta-analysis of hormone therapy and mortality in younger post-menopausal women. Am. J. Med. 122, 10161022 (2009).
  70. Boardman, H. M. et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database of Syst. Rev. 3, http://dx.doi.org/10.1002/14651858 (2015).
  71. Henderson, V. W. & Lobo, R. A. Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health Initiative trials. Climacteric 15, 229234 (2012).
  72. Grodstein, F., Manson, J. E., Stampfer, M. J. & Rexrode, K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch. Intern. Med. 168, 861866 (2008).
  73. Sare, G. M., Gray, L. J. & Bath, P. M. Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. Eur. Heart J. 29, 20312041 (2008).
  74. Lobo, R. A. & Clarkson, T. B. Different mechanisms for benefit and risk of coronary heart disease and stroke in early postmenopausal women: a hypothetical explanation. Menopause 18, 237240 (2011).
  75. Lidegaard, O., Lokkegaard, E., Jensen, A., Skovlund, C. W. & Kelding, N. Thrombotic stroke and myocardial infarction with hormonal contraception. N. Engl. J. Med. 366, 22572266 (2012).
  76. Sweetland, V., Beral, A. & Balkwill, B. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J. Thromb. Haemost. 10, 22772286 (2012).
  77. Bergendal, A., Kieler, H., Sundstrom, A., Hirschberg, A. L. & Kocoska-Maras, L. Risk of venous thromboembolism associated with local and systemic use of hormone therapy in peri- and postmenopausal women and in relation to type and route of administration. Menopause 23, 593599 (2016).
  78. Canonico, M., Plu-Bureau, G., Lowe, G. D. & Scarabin, P. Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 336, 12271231 (2008).
  79. Leading causes of death in females. Centers for Disease Control and Prevention. www.cdc.gov/women/lcod/index.htm (2015).
  80. Cancer among women. Centers for Disease Control and Prevention. www.cdc.gov/cancer/dcpc/data/women.htm (2016).
  81. Chlebowski, R. T. et al. Estrogen plus progestin and lung cancer: follow-up of the Women's Health Initiative randomized trial. Clin. Lung Cancer http://dx.doi.org/10.1016/j.cllc.2015.09.004 (2016).
  82. Grodstein, F., Newcomb, P. A. & Stampfer, M. J. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am. J. Med. 106, 574582 (1999).
  83. Prentice, R. L. et al. Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women's Health Initiative clinical trial and observational study. Cancer Epidemiol. Biomarkers Prev. 18, 15311537 (2009).
  84. Williams, C., DiLeo, A., Niv, Y. & Gustafsson, J. A. Estrogen receptor β as target for colorectal cancer prevention. Cancer Lett. 372, 4856 (2016).
  85. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalyses of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411women without breast cancer. Lancet 350, 10471059 (1997).
  86. Chen, W. Y. et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch. Intern. Med. 166, 10271032 (2006).
  87. Fournier, A., Berrino, F. & Clavel-Chapelon, F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res. Treat. 107, 103111 (2008).
  88. Santen, R. J. Yue, W. & Heitjan, D. F. Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy. Cancer Epidemiol. Biomarkers Prev. 21, 10381048 (2012).
  89. Jordan, V. C. & Ford, L. G. Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis. Cancer Prev. Res. (Phila.) 4, 633637 (2011).
  90. Gompel, A. & Santen, R. J. Hormone therapy and breast cancer risk 10 years after the WHI. Climacteric 15, 241249 (2012).
  91. Bluming, A. Z. & Tavri, C. What are the real risks for breast cancer? Climacteric 15, 133138 (2012).
  92. Ziel, H. K. & Finkle, W. D. Increased risk od endometrial carcinoma among users of conjugated estrogens. N. Engl. J. Med. 293, 11671170 (1975).
  93. Chlebowski, R. T. Continuous combined estrogen plus progestin and endometrial cancer: the Women's Health Initiative randomized trial. J. Natl Cancer Inst. 108, djv350 (2015).
  94. Beral, V., Bull, D., Reeves, G., Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 365, 15431551 (2005).
  95. Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral, V. et al. Menopausal hormone use and ovarian cancer: individual participant meta-analysis of 52 epidemiological studies. Lancet 385, 18351842 (2015).
  96. Davis, S. R. & Baber, R. Reproductive endocrinology: menopausal hormone therapy-ovarian cancer risk revisited. Nat. Rev. Endocrinol. 11, 322323 (2015).
  97. Santen, R. J., Allred, D. C. & Ardoin, S. P. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J. Clin. Endocrinol. Metab. 95 (Suppl. 1), s1s66 (2010).
  98. Salpeter, S. R., Buckley, N. S., Liu, H. & Salpeter, E. E. The cost-effectiveness of hormone therapy in younger and older postmenopausal women. Am. J. Med. 122, 4252 (2009).
  99. Baber, R. J., Panay, N., Fenton, A., and the IMS Writing Group. 2016 IMS recommendations on women's midlife health and menopause hormone therapy. Climacteric 19, 109150 (2016).
  100. Stuenkel, C. A. et al. Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 100, 39754011 (2015).
  101. Menopause: diagnosis and management, NICE guidelines [NG23]. National Institute for Care and Health Excellence. https://www.nice.org.uk/guidance/NG23 (2015).
  102. Manson, J. E. et al. Algorithm and mobile app for menopausal symptom management and hormonal/non-hormonal therapy decision making: a clinical decision-support tool from The North American Menopause Society. Menopause 22, 247253 (2015).
  103. Lobo, R. A., Davis, S. R. & De Villiers, T. J. Prevention of diseases after menopause. Climacteric 17, 540556 (2014).
  104. Maruther, N. M., Wang, N. -Y. & Appel, L. J. Lifestyle interventions to reduce coronary artery disease risk. Results from the PREMIER trial. Circulation 119, 20262031 (2009).
  105. Walsh, J. M. & Pignone, M. Drug treatment of hyperlipidemia in women. JAMA 291, 22432252 (2004).
  106. Petretta, M., Costanzo, P. & Perrone-Filardi, P. Impact of gender in primary prevention of coronary heart disease with stain therapy: a meta-analysis. Int. J. Cardiol. 138, 2531 (2010).
  107. Brugts, J. J., Yetkin, T. & Hoeks, S. E. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 338, b2376 (2009).
  108. Berger, J. S., Roncaglioni, C. & Avanzini, F. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 295, 306313 (2006).
  109. Ridker, P. M., Cook, N. R. & Lee, I. M. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 12931304 (2005).
  110. Ogawa, H., Nakayama, M. & Morimoto, T. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 300, 21342141 (2008).
  111. Kanaya, A. M. et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 138, 19 (2003).
  112. Margolis, K. L. et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 47, 11751187 (2004).
  113. Bonds, D. E., Lasser, N. & Qi, L. The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomized trial. Diabetologia 49, 459468 (2006).
  114. Sattar, N., Preiss, D. & Murray, H. M. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 375, 735742 (2010).
  115. Lobo, R. A. Where are we 10 years after the Women's Health Initiative? J. Clin. Endocrinol. Metab. 98, 17711780 (2013).
  116. Bolland, M. J., Barber, P. A. & Doughty, R. N. Vascular events in healthy older women receiving calcium supplementation: randomized controlled trial. BMJ 336, 262266 (2008).
  117. Canonico, M. et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of administration and progestogens: the ESTER study. Circulation 115, 840845 (2007).
  118. Komm, B. S., Mirkin, S. & Jenkins, S. N. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 90, 7181 (2014).
  119. Ryan, J., Canonico, M. & Carcaillon, L. Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study. PLoS ONE 7, e34112 (2012).
  120. Herrington, D. M., Howard, T. D. & Hawkins, G. A. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N. Engl. J. Med. 346, 967974 (2002).
  121. Santoro, N., Braunstein, G. D. & Butts, C. L. Compounded bioidentical hormones in endocrinology practice: an Endocrine Society Scientific Statement. J. Clin. Endocrinol. Metab. 101, 13181343 (2016).

Download references

Author information

Affiliations

  1. Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, New York 10032, USA.

    • Roger A. Lobo

Competing interests statement

R.A.L. declares that in the past 3 years he has consulted for Allergan, Pfizer and Teva, and has participated in clinical trials for TherapeuticsMD, with funds paid to Columbia University.

Corresponding author

Correspondence to:

Author details

  • Roger A. Lobo

    Roger Lobo obtained his MD in 1974 from Georgetown University, Washington D.C., USA. He is board certified in Obstetrics and Gynecology, Reproductive Endocrinology and Infertility. He has held several teaching positions including Fellowship Director and Chairman of the Department of Obstetrics and Gynecology at Columbia University in New York, where he is Professor at present. He has 480 peer-reviewed publications and several books on reproductive endocrinology and menopause. He serves on several advisory boards and conducts clinical trials in reproductive endocrinology and menopause.

Additional data