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Hormone Therapy in Menopause

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1242)

Abstract

As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).

Local vulvovaginal and urinary symptoms, now termed genitourinary syndrome of menopause (GSM), are seen in 50% of postmenopausal women, and it negatively impacts quality of life. Estrogen remains the most effective treatment for both VMS and GSM, for osteoporosis prevention, and for symptom relief as well as chronic disease prevention in women who experience premature menopause whether from primary ovarian insufficiency (POI) or iatrogenic etiologies. For women who have contraindications to estrogen therapy or who personally object, a panoply of nonhormonal modalities can be offered to treat both systemic and local menopausal symptoms. A historical review of estrogen studies reveals why its persona has vacillated from hero to villain (after the WHI) and back to hero. The “timing hypothesis” and its underlying mechanism shed light on the pleiotropic nature of estrogen. Finally reviewed is the compelling argument from notable thought-leaders that estrogen, in those without contraindications, should be considered for primary prevention of cardiovascular disease as well as the prevention of chronic disease.

Keywords

Vasomotor symptoms (VMS) Premature ovarian insufficiency (POI) Conjugated equine estrogens (CEE) Women’s Health Initiative study (WHI) Medroxyprogesterone acetate (MPA) Transdermal estrogen Micronized progesterone Kisspeptine 

References

  1. 1.
    Menopause practice: a clinician’s guide. North American Menopause Society; 2014.Google Scholar
  2. 2.
    Murphy SL, Xu J, Kockanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 2013;61(4):1–117.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Pinkerton JV, Aguirre FS, Blake J, Hodis H, et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause. 24(7):728–53.Google Scholar
  4. 4.
    Stuenkel C, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2015;100:3975–4011.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Sayegh R, Awwad JT. Five decades of hormone therapy research: the long, the short, and the inconclusive. In: Essentials of menopause management. Springer; 2017.Google Scholar
  6. 6.
    Bush TL, et al. Estrogen use and all cause mortality: preliminary results from the lipid research clinics program follow-up study. JAMA. 1983;249:903–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Ross RK, et al. Menopausal oestrogen therapy and protection from death from ischemic heart disease. Lancet. 1981;1:858–60.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Pfeffer RI, et al. Coronary risk and estrogen use in postmenopausal women. Am. J Epidemiol. 1978;107:479–87.CrossRefGoogle Scholar
  9. 9.
    Bain C, et al. Use of postmenopausal hormones and risk of myocardial infarction. Circulation. 1981;64:42–6.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016;254:296–304.CrossRefGoogle Scholar
  11. 11.
    Stampfer MJ, et al. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Grodstein F, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–75.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Yaffe K, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998;279:688–95.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Henderson BE, et al. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–8.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Grady D, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–37.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Stampfer MJ, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med. 1985;313:1044–9.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Bush TL, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics follow-up study. Circulation. 1987;75:1102–9.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol. 1988;159:312–7.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    American College of Physicians. Guidelines for counselling postmenopausal women about preventive hormone therapy. Ann Intern Med. 1992;117:1038–41.CrossRefGoogle Scholar
  20. 20.
    Greendale GA. Symptom relief and side effects of postmenopausal hormones: results from the PEPI trial Obstet. Gynecologie. 1998;92:982–8.Google Scholar
  21. 21.
    Writing Group for the PEPI trial. Effects of hormone therapy on bone mineral density: results from the PEPI tria. JAMA. 1996;276:1389–96.CrossRefGoogle Scholar
  22. 22.
    Hully S. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605.CrossRefGoogle Scholar
  23. 23.
    Miller V, Clarkson T. Women, hormones and clinical trials: a beginning, not an end. J Appl Physiol. 2005;99:381.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Langer RD. The evidence base for HRT: what can we believe. Climacteric. 2017;20:91–6.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Lobo R. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13:220.Google Scholar
  26. 26.
    Sprague BL, et al. Sustained decline in postmenopausal use: results from the National Health and Nutrition Examination Survey. Obstet Gynecol. 2012;120:595–603.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Karim R, et al. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study from a large HMO. Menopause. 2011;18:1172–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Islam S, et al. Trend in incidence of osteoporosis-related fractures among 40-69 year-old women: analysis of claims database, 2000-2005. Menopause. 2009;16:77–83.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Mikkola TS, Tuomikowski P, Lyytinen H, et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocrinol Metab. 2015;100(12):4588–94.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Sarrel P, et al. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50-59 years. Am J Public Health. 2013;103:1583–8.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lacroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305:1305–14.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Burger HG, et al. Evidence-based assessment of the impact of the WHI on women’s health. Climacteric. 2012;15:281–7.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Marko K, Simon JA. Clinical trials in menopause. Menopause. 2018;25:217.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–77.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Salpeter SR, Walsh JM, Grayber E, Salpeter EE. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363–6.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Clarkson TB, Mehaffey M. Coronary heart disease of females: lessons learned from nonhuman primates. Am J Primatol. 2009;71:785–93.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Clarkson TB, Melendez GC, Appt SE. Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future. Menopause. 2013;20(3):342–53.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science. 2005;308:1583–7.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    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;161:249–60.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Miller VM, Naftolin F, Asthana S, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019;26(9):1–14.Google Scholar
  41. 41.
    Taylor HS, Tal A, Pal L, et al. Effects of oral versus transdermal estrogen therapy on sexual function in early post-menopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017;177:1471–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the early versus late intervention trial with estradiol testing the menopausal hormone timing hypothesis. Menopause. 2014;22(4):391–401.CrossRefGoogle Scholar
  43. 43.
    Sriprasert I, Hodis HN, Karim R, Stancyk FZ, Shoupe D, Henderson VW, Mack W. Differential effect of plasma estradiol on subclinical atherosclerosis progression in early vs late postmenopause. J Clin Endocrinol Metab. 2019;104(2):2930300.CrossRefGoogle Scholar
  44. 44.
    Sturdee DW, Hunter MS, Maki PM, et al. The menopausal hot flush: a review. Climacteric. 2017;20(4):296–305.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Thurston RC. Vasomotor symptoms: natural history, physiology, and links with cardiovascular health. Climacteric. 2018;21(2):96–100.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Smith RL, Gallicchio LM, Flaws JA. Understanding the complex relationships underlying hot flashes: a Bayesian network approach. Menopause. 2018;25(2):182–90.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Carson MY, Thurston RC. Childhood abuse and vasomotor symptoms among midlife women. Menopause. 2019;26(10):1–7.CrossRefGoogle Scholar
  48. 48.
    Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115–20.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Rance NE, Dacks PA, Mittleman-Smith M, et al. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B, and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34:211–27.Google Scholar
  50. 50.
    Casper RF, Yen SSC. Menopausal flushes: effect of pituitary gonadotropin desensitization by a potent luteinizing hormone-releasing factor agonist. J Clin Endocrinol Metab. 1981;53:1056–8.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Gambone J, Meldrum DR, Laufer L, et al. Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes. J Clin Endocrinol Metab. 1984;59:1097–102.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Szeliga A, Czyzk A, Podfigurna A, Genazzani AD, Meczelalski B. The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications. Gynecol Endocrinol. 2018;34(11):913–9.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Skorupskaite K, George J, Anderson R. The Kisspeptin-GNRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485–500.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Padilla S, Johnson C, Barker F, Patterson M, Palmiter R. A neural circuit underlying the generation of hot flushes. Cell Rep. 2018;24:271–7.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Prague J, Roberts R, Dhillo W. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018;25(8):862–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Crandall CJ, Manson J, Hohensee C, et al. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women’s Health Initiative study. Menopause. 2017;24:252–61.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10081):1809–20.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database System Rev. 2004;4:CD002978.Google Scholar
  59. 59.
    Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294:183–93.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Brunner RL, Aragaki A, Barnabei V, et al. Menopausal symptom experience before and after stopping estrogen therapy in the Women’s Health Initiative randomized, placebo-controlled trial. Menopause. 2010;17:946–54.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Carpenter J, Gass M, Maki PM. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of the North American Menopause Society. Menopause. 2015;22(11):1155–74.CrossRefGoogle Scholar
  62. 62.
    Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal VMS: two randomized controlled trials. Menopause. 2013;20:1027–35.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Reddy SY, Warner H, Guttoso T Jr, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol. 2006;108:41–8.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–71.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Nappi RE, Palacios S, Particco M, Panay N. The REVIVE (real Women’s views of treatment options for menopausal vaginal changes) survey in Europe: country-specific comparisons of postmenopausal women’s perceptions, experiences, and needs. Maturitas. 2016;91:81–90.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views, and Attitudes (VIVA)—results from an international survey. Climacteric. 2012;15:36–44.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Nappi RE, Palacios S, Bruyniks N, et al. The burden of vulvovaginal atrophy on women’s daily living: implications on quality of life from a face-to-face real-life survey. Menopause. 2019;26(5):485–91.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Cook E, Iglehart E, Baum G, et al. Missing documentation in breast cancer survivors: genitourinary syndrome of menopause. Menopause. 2017;24(12):1360–4.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20(9):888–902.Google Scholar
  70. 70.
    Santen RJ. Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. Climacteric. 2015;18:121–34.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Rahn DD, Carberry C, Sanses TV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol. 2015;124:1147–56.CrossRefGoogle Scholar
  72. 72.
    Soe LH, Wurz GT, Koa CJ, et al. Ospemiphene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: potential benefits in bone and breast Int. J Women's Health. 2013;5:605–11.Google Scholar
  73. 73.
    Labrie F, Archer D, Koltun W, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and the genitourinary syndrome of menopause. Menopause. 2016;25(11):1339–53.CrossRefGoogle Scholar
  74. 74.
    Labrie F, Belanger A, Pellitier G, Martel C, Archer D, Utian W. Science of intracrinology in postmenopausal women. Menopause. 2017;24(6):702–12.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Faubion S, Stuenkel C, Chism L, Kaunitz AM, Parish SJ, Pinkerton JV, Shapiro M, Simon JA, Kingsberg SA. Management of genitourinary syndrome of menopause in women with or at high risk for breast cancer: consensus recommendations from the North American Menopause Society and the International Society for the Study of Women’s Sexual Health. Menopause. 2018;25(6):596–608.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Martel C, Labrie F, Archer DF, et al. Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5 mg intravaginal prasterone for 12 weeks. J Steroid Biochem Mol Biol. 2016;159:142–53.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Hodgins M, Spike R, Mackie R, MacLean A. An immunohistochemical study of androgen, oestrogen, and progesterone receptors in the vulva and vagina. Br J Obstet Gynaecol. 1998;105:216–22.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Melisko M, Goldman M, Hwang J, et al. Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial. JAMA Oncol. 2017l;3:313–9.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Salvatore S, Maggiore ULR, Athanasiou S, et al. Histological study on the effects of micro-ablative fractional CO2 laser on atrophic vaginal tissue: an ex vivo study. Menopause. 2015;22(8):845–9.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Pagano T, De Rosa P, Vallone R, et al. Fractional micro-ablative CO2 laser in breast cancer survivors affected by iatrogenic vulvovaginal atrophy after failure of non-estrogenic treatments: a retrospective study. Menopause. 2018;25:657–62.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    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. 2008;300:2134–41.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375:725–42.Google Scholar
  83. 83.
    Mikkola TS, Tuomikoski P, Lyytinen H, et al. Estradiol-based post-menopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause. 2015;22:976–83.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab. 2012;23(11):576–81.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Savolainen-Peltonen H, Tuomikoski P, Korhonen P, et al. Cardiac death risk in relation to the age at initiation or the progestin component of hormone therapies. J Clin Endocrin Metab. 2016;101:2794–801.CrossRefGoogle Scholar
  86. 86.
    Nelson LM. Primary ovarian insufficiency. NEJM. 2009;360(6):606–14.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril. 2016;106(7):1588–99.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–32.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Popat VB, Calis KA, Kalantaridou SN, et al. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab. 2014;99:3148–26.CrossRefGoogle Scholar
  90. 90.
    Stanczyk FZ, Hapgood JP, Winer D, Mishell D Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34(2):171–208.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Gompel A. Micronized progesterone and its impact on the endometrium and breast vs. progestogens. Climacteric. 2012;15(1):18–25.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Mann E, Singer D, Pitkin J, Panay N, Hunter MS. Psychosocial adjustment in women with premature menopause: a cross-sectional survey. Climacteric. 2012;15:481–9.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Thurston RC, El Khoudary SR, Tepper PG, et al. Trajectories of vasomotor symptoms and carotid intima media thickness in the study of Women’s health across the nation. Stroke. 2016;47:12–7.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    L’Hermite M. HRT optimization using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013;6(1):44–53.CrossRefGoogle Scholar
  95. 95.
    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. 2008;107:103–11.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol. 2009;113:65–73.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Schnatz P, Pinkerton J, Utian W, Appt S, de Villiers T, Henderson V, Hodis H, Kaunitz A, Maki P, Manson J, Richard-Davis G, Santoro N, Sarrel P, Shifren J, Simon J, Stuenkel C. NAMS translational science symposium report a conversation about hormone therapy: is there an appropriate dose, route, and duration of use. Menopause. 2017;24(11):1221–35.CrossRefGoogle Scholar
  98. 98.
    Kaunitz A, Manson J. Management of Menopausal Symptoms. Obstet Gynecol. 2015;126(4):859–76.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Chen W, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306:1184–890.Google Scholar
  100. 100.
    US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: USPSTF Recommendation Statement. JAMA. 2017;318:2224–33.CrossRefGoogle Scholar
  101. 101.
    Langer R, Simon J, Pines A, Lobo R, Hodis H, Pickar J, Archer D, Sarrel P, Utian W. Menopausal hormone therapy for primary prevention: why the USPSTF is wrong. Menopause. 2017;24(10):1101–12.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Lobo R, Davis S, De Villiers T, et al. Prevention of diseases after menopause. Climacteric. 2014;17:540–56.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA. 2004;291:2243–52.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Petretta M, Costanzo P, Perrone-Filardi P. Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int J Cardiol. 2010;138:25–31.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Brughts JJ, Yetkin T, Hoeks SE. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ. 2009;338:b2376.CrossRefGoogle Scholar
  106. 106.
    Berger JS, 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. 2006;295:306–13.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Ridker PM, Cook NR, Lee IM. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. NEJM. 2005;352:1293–304.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3(47):1–10.Google Scholar
  109. 109.
    Miller VM, Mitchell Harman S. An update on hormone therapy in postmenopausal women: mini-review for the basic scientist. Am J Physiol Heart Circ Physiol. 2017;313(5):H1013–21.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Hodis HN, Mack WJ. Cardiovascular risk after withdrawal of hormone therapy. Menopause. 2018;25(4):365–7.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Tepper P, Randolph J, Jones B, et al. Trajectory patterns of vasomotor symptoms over the menopausal transition in the study of women’s health across the nation. Menopause. 2013;20:1356.Google Scholar
  112. 112.
    Labrie F. Intracrinology and menopause: the science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their strictly local action and inactivation in peripheral tissues. Menopause. 2018;26(2):220–4.CrossRefGoogle Scholar
  113. 113.
    Modi M, Dhillo W. Neurokinin 3 receptor antagonism: a novel treatment for menopausal hot flushes. Neuroendocrinology. 2018;109(3):242–8.  https://doi.org/10.1159/000495889.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Thurston RC, Johnson BD, Shufelt CL, Braunstein GD, Berga SL, Stanczyk FZ, Pepine CJ, Bittner V, Reis SE, Thompson DV, Kelsey SF, Sopko G, Merz CN. Menopausal symptoms and cardiovascular disease mortality in the Women’s Ischemia Syndrome Evaluation (WISE). Menopause. 2017;24(2):126–32.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Thurston RC, Chang Y, Barinas-Mitchell E, et al. Menopausal hot flashes and carotid intima media thickness among midlife women. Stroke. 2016;47:2910–5.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. NEJM. 1999;340(23):1801–11.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. NEJM. 2016;374(13):1221–31.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Baber RJ, Panay N, Fenton A, the IMS Writing Group. 2016 IMS recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109–50.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Lenox Hill Hospital, Mount Sinai HospitalNew YorkUSA

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