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Menopausal Hormone Therapy: a Comprehensive Review

  • Women and Ischemic Heart Disease (P. Kohli, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

For decades the medical community recommended menopausal hormone therapy (MHT) for prevention of atherosclerotic cardiovascular disease (ASCVD) and osteoporosis in addition to relieving unpleasant vasomotor and genitourinary symptoms. These recommendations were largely based on observational studies. Several large randomized placebo-controlled trials led to the surprising finding that postmenopausal women were at higher risk of cardiovascular disease (CVD) events compared with women in the placebo group. For the next decade, women were less frequently prescribed MHT and more often declined MHT.

Recent Findings

Today, there are more evidence-based guidelines utilizing sex-specific ASCVD risk factors to assess risk in women. More recent studies have shed new light on safety and potential benefits for women initiating MHT earlier with newer options for route of administration, dosing, and combinations.

Summary

Recent studies suggest MHT safety in younger women, women within 10 years of menopause, and women who use low-dose MHT for short durations for menopause symptom relief. Transdermal, newer low-dose oral therapies and SERM therapies may also have lower risk and be reasonable considerations for women. Healthcare providers need to be aware of the current options for MHT, current indications, contraindications, long-term ASCVD risks, and nonhormonal options for high-risk women.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation. 2011;123(11):1243–62.

    PubMed  PubMed Central  Google Scholar 

  2. • Bittner VA. The New 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 2019. https://doi.org/10.1161/CIRCULATIONAHA.119.040625This guideline is an excellent summary of ASCVD prevention guidelines with specific focus on the unique and more prevalent risks factors in women.

  3. The 2017 Hormone therapy position statement of the North American Menopause Society. Menopause. 2017;24(7):728–53.

  4. Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Jama. 2004;291(14):1701–12.

    CAS  PubMed  Google Scholar 

  5. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). Jama. 2002;288(1):49–57.

    PubMed  Google Scholar 

  6. Aggarwal NR, Patel HN, Mehta LS, Sanghani RM, Lundberg GP, Lewis SJ, et al. Sex differences in ischemic heart disease: advances, obstacles, and next steps. Circ Cardiovasc Qual Outcomes. 2018;11(2):e004437.

    PubMed  Google Scholar 

  7. Chester RC, Kling JM, Manson JE. What the Women's Health Initiative has taught us about menopausal hormone therapy. Clin Cardiol. 2018;41(2):247–52.

    PubMed  PubMed Central  Google Scholar 

  8. Speroff L. Postmenopausal hormone therapy and primary prevention of cardiovascular disease -- Nurses' health study 20-year follow-up. Maturitas. 2001;38(3):221–4.

    CAS  PubMed  Google Scholar 

  9. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. Jama. 1995;273(3):199–208.

  10. Rossouw JE, Anderson GL, Prentice RL, LaCroix A, Kooperberg C, Stefanick ML, 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(3):321–33.

    CAS  PubMed  Google Scholar 

  11. Hodis HN, Mack WJ. A "window of opportunity:" the reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent. Brain Res. 2011;1379:244–52.

    CAS  PubMed  Google Scholar 

  12. Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24(3):238–46.

    PubMed  PubMed Central  Google Scholar 

  13. El Khoudary SR, et al. Effects of hormone therapy on heart fat and coronary artery calcification progression: secondary analysis from the KEEPS trial. J Am Heart Assoc. 2019;8(15):e012763.

    PubMed  PubMed Central  Google Scholar 

  14. Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2015;22(4):391–401.

    PubMed  PubMed Central  Google Scholar 

  15. Collins P, Mosca L, Geiger MJ, Grady D, Kornitzer M, Amewou-Atisso MG, et al. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation. 2009;119(7):922–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Stevenson JC, Chines A, Pan K, Ryan KA, Mirkin S. 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(6):2329–38.

    CAS  PubMed  Google Scholar 

  17. Marjoribanks J, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1:Cd004143.

    PubMed  Google Scholar 

  18. Subramanya V, Zhao D, Ouyang P, Ying W, Vaidya D, Ndumele CE, et al. Association of endogenous sex hormone levels with coronary artery calcium progression among post-menopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA). J Cardiovasc Comput Tomogr. 2019;13(1):41–7.

    PubMed  Google Scholar 

  19. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on 2 Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3237–3241. https://doi.org/10.1016/j.jacc.2018.11.003.

  20. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140(11):e596–646.

    PubMed  PubMed Central  Google Scholar 

  21. Honigberg MC, et al. Association of premature natural and surgical menopause with incident cardiovascular disease. Jama. 2019.

  22. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013;62(16):e147–239.

    PubMed  Google Scholar 

  23. Sabbatini AR, Kararigas G. Menopause-related estrogen decrease and the pathogenesis of HFpEF: JACC review topic of the week. J Am Coll Cardiol. 2020;75(9):1074–82.

    CAS  PubMed  Google Scholar 

  24. Crawford SL, et al. Menopausal hormone therapy trends before versus after 2002: impact of the Women's Health Initiative study results. Menopause. 2018;26(6):588–97.

    PubMed  PubMed Central  Google Scholar 

  25. Cody JD, Jacobs ML, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev. 2012;10(10):CD001405. https://doi.org/10.1002/14651858.CD001405.pub3.

  26. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008;(2):CD005131. https://doi.org/10.1002/14651858.CD005131.pub2.

  27. Crandall CJ, Diamant A, Santoro N. Safety of vaginal estrogens: a systematic review. Menopause. 2020;27(3):339–60.

    PubMed  Google Scholar 

  28. Dam V, Dobson AJ, Onland-Moret NC, van der Schouw YT, Mishra GD. Vasomotor menopausal symptoms and cardiovascular disease risk in midlife: a longitudinal study. Maturitas. 2020;133:32–41.

    CAS  PubMed  Google Scholar 

  29. Zeleke BM, Davis SR, Fradkin P, Bell RJ. Vasomotor symptoms and urogenital atrophy in older women: a systematic review. Climacteric. 2015;18(2):112–20.

    CAS  PubMed  Google Scholar 

  30. American Geriatrics Society. Updated AGS beers criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–94.

    Google Scholar 

  31. Zhao D, Guallar E, Ouyang P, Subramanya V, Vaidya D, Ndumele CE, et al. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J Am Coll Cardiol. 2018;71(22):2555–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Benn M, Voss SS, Holmegard HN, Jensen GB, Tybjærg-Hansen A, Nordestgaard BG. Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women. Arterioscler Thromb Vasc Biol. 2015;35(2):471–7.

    CAS  PubMed  Google Scholar 

  33. Spoletini I, Vitale C, Pelliccia F, Fossati C, Rosano GMC. Androgens and cardiovascular disease in postmenopausal women: a systematic review. Climacteric. 2014;17(6):625–34.

    CAS  PubMed  Google Scholar 

  34. Schaffrath G, Kische H, Gross S, Wallaschofski H, Völzke H, Dörr M, et al. Association of sex hormones with incident 10-year cardiovascular disease and mortality in women. Maturitas. 2015;82(4):424–30.

    CAS  PubMed  Google Scholar 

  35. Scarabin-Carré V, Canonico M, Brailly-Tabard S, Trabado S, Ducimetière P, Giroud M, et al. High level of plasma estradiol as a new predictor of ischemic arterial disease in older postmenopausal women: the three-city cohort study. J Am Heart Assoc. 2012;1(3):e001388.

    PubMed  PubMed Central  Google Scholar 

  36. Meun C, Franco OH, Dhana K, Jaspers L, Muka T, Louwers Y, et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab. 2018;103(4):1622–30.

    PubMed  Google Scholar 

  37. Laughlin GA, Goodell V, Barrett-Connor E. Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. J Clin Endocrinol Metab. 2010;95(2):740–7.

    CAS  PubMed  Google Scholar 

  38. Sievers C, Klotsche J, Pieper L, Schneider HJ, März W, Wittchen HU, et al. Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients. Eur J Endocrinol. 2010;163(4):699–708.

    CAS  PubMed  Google Scholar 

  39. El Khoudary SR, et al. Endogenous sex hormones impact the progression of subclinical atherosclerosis in women during the menopausal transition. Atherosclerosis. 2012;225(1):180–6.

    PubMed  PubMed Central  Google Scholar 

  40. Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP. Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. J Clin Endocrinol Metab. 1993;77(1):56–60.

    CAS  PubMed  Google Scholar 

  41. van Staa TP, Sprafka JM. Study of adverse outcomes in women using testosterone therapy. Maturitas. 2009;62(1):76–80.

    PubMed  Google Scholar 

  42. Reis SL, Abdo CH. Benefits and risks of testosterone treatment for hypoactive sexual desire disorder in women: a critical review of studies published in the decades preceding and succeeding the advent of phosphodiesterase type 5 inhibitors. Clinics (Sao Paulo). 2014;69(4):294–303.

    Google Scholar 

  43. Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev. 2005;(4):CD004509. https://doi.org/10.1002/14651858.CD004509.pub2.

  44. Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019;7(10):754–66.

    CAS  PubMed  Google Scholar 

  45. Achilli C, et al. Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis. Fertil Steril. 2017;107(2):475–82 e15.

    CAS  PubMed  Google Scholar 

  46. Shifren JL. Overview of sexual dysfunction in women: Management. In: Post TW, editor. UpToDate. Waltham: UpToDate; 2020.

    Google Scholar 

  47. Davis SR, Baber R, Panay N, Bitzer J, Perez SC, Islam RM, et al. Global consensus position statement on the use of testosterone therapy for women. J Clin Endocrinol Metab. 2019;104(10):4660–6.

    PubMed  PubMed Central  Google Scholar 

  48. Female Sexual Dysfunction: ACOG Practice Bulletin Clinical Management Guidelines for Obstetrician-Gynecologists, Number 213. Obstet Gynecol. 2019;134(1):e1–e18.

  49. Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, et al. Clinical review: the benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(10):3543–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Davison SL, Davis SR. Androgens in women. J Steroid Biochem Mol Biol. 2003;85(2–5):363–6.

    CAS  PubMed  Google Scholar 

  51. Vegunta S, Kling JM, Kapoor E. Androgen therapy in women. J Women's Health (Larchmt). 2020;29(1):57–64.

    Google Scholar 

  52. Shufelt CL, Braunstein GD. Safety of testosterone use in women. Maturitas. 2009;63(1):63–6.

    CAS  PubMed  Google Scholar 

  53. Hofling M, Hirschberg AL, Skoog L, Tani E, Hägerström T, von Schoultz B. Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause. 2007;14(2):183–90.

    PubMed  Google Scholar 

  54. Kabat GC, Kamensky V, Heo M, Bea JW, Hou L, Lane DS, et al. Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women. Maturitas. 2014;79(1):70–6.

    CAS  PubMed  Google Scholar 

  55. • Johnson A, Roberts L, Elkins G. Complementary and alternative medicine for menopause. J Evid Based Integr Med. 2019;24:2515690x19829380 This article outlines nonhormonal therapies for women with unpleasant menopasual symptoms.

    PubMed  PubMed Central  Google Scholar 

  56. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 Position statement of the North American Menopause Society. Menopause. 2015;22(11):1155–72 quiz 1173-4.

  57. Biglia N, et al. Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update. Ecancermedicalscience. 2019;13:909.

    PubMed  PubMed Central  Google Scholar 

  58. Rana JS, Tabada GH, Solomon MD, Lo JC, Jaffe MG, Sung SH, et al. Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, Multiethnic Population. J Am Coll Cardiol. 2016;67(18):2118–30.

    PubMed  PubMed Central  Google Scholar 

  59. Brown HL, Warner JJ, Gianos E, Gulati M, Hill AJ, Hollier LM, et al. Promoting risk identification and reduction of cardiovascular disease in women through collaboration with obstetricians and gynecologists: a presidential advisory from the American Heart Association and the American College of Obstetricians and Gynecologists. Circulation. 2018;137(24):e843–52.

    PubMed  Google Scholar 

  60. •• Isakadze N, et al. Addressing the gap in physician preparedness to assess cardiovascular risk in women: a comprehensive approach to cardiovascular risk assessment in women. Curr Treat Options Cardiovasc Med. 2019;21(9):47 This is an excellent strategy for ensuring a comprehensive ASCVD risk assessment of women of all ages.

    PubMed  Google Scholar 

  61. Boardman HM, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015;3:CD002229.

    Google Scholar 

  62. NICE, The National Institute of Health and Care Excellence Guideline. Menopause: Diagnosis and Management [NG23]. 2015.

  63. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.

    PubMed  PubMed Central  Google Scholar 

  64. Manson JE, Ames JM, Shapiro M, Gass MLS, Shifren JL, Stuenkel CA, 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. 2015;22(3):247–53.

    PubMed  Google Scholar 

  65. •• Pinkerton JV. Hormone Therapy for Postmenopausal Women. N Engl J Med. 2020;382(5):446–55 This is an excellent comprehensive review of menopausal hormonal therapy for women examining the landmark studies as well as newer studies and compiling all the current professional society guidelines regarding MHT.

    PubMed  Google Scholar 

  66. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JAV, et al. Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975–4011.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Emory University School of Medicine, Emory Women’s Heart Center, Atlanta, GA, USA

    Gina Lundberg

  2. Keele Cardiovascular Research Group, Centre for Prognosis Research, School of Primary, Community and Social Care, Keele University, Stoke-on-Trent, Staffordshire, UK

    Pensee Wu

  3. Obstetrics and Gynaecology, University Hospital of North Midlands, Stoke-on-Trent, Staffordshire, UK

    Pensee Wu

  4. Emory University School of Medicine, Emory Heart and Vascular Center, Emory Women’s Heart Center, Atlanta, GA, USA

    Nanette Wenger

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  1. Gina Lundberg
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  3. Nanette Wenger
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Correspondence to Gina Lundberg.

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Lundberg, G., Wu, P. & Wenger, N. Menopausal Hormone Therapy: a Comprehensive Review. Curr Atheroscler Rep 22, 33 (2020). https://doi.org/10.1007/s11883-020-00854-8

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