Hormone replacement therapy in young women with surgical primary ovarian insufficiency
2016; Elsevier BV; Volume: 106; Issue: 7 Linguagem: Inglês
10.1016/j.fertnstert.2016.09.018
ISSN1556-5653
AutoresPhilip M. Sarrel, Shannon D. Sullivan, Lawrence M. Nelson,
Tópico(s)Endometriosis Research and Treatment
ResumoBilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical primary ovarian insufficiency is clearly indicated. Bilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical primary ovarian insufficiency is clearly indicated. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/11945-hormone-replacement-therapy-in-young-women-with-surgical-primary-ovarian-insufficiency Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/11945-hormone-replacement-therapy-in-young-women-with-surgical-primary-ovarian-insufficiency Most bilateral oophorectomies occur at the time of hysterectomy and most hysterectomies occur between ages 35 and 45 years, with more than half of all hysterectomies in women aged 45 years or younger (1Asante A. Whiteman M.K. Kulkarni A. Cox S. Marchbanks P.A. Jamieson D.J. Elective oophorectomy in the United States: trends and in-hospital complications, 1998–2006.Obstet Gynecol. 2010; 116: 1088-1095Crossref PubMed Scopus (85) Google Scholar, 2Wright J.D. Herzog T.J. Tsui J. Ananth C.V. Lewin S.N. Lu Y.S. et al.Nationwide trends in the performance of hysterectomy in the United States.Obstet Gynecol. 2013; 122: 233-241Crossref PubMed Google Scholar). As a result, surgical primary ovarian insufficiency (POI) is the leading cause of ovarian hormone deficiency in premenopausal women. Although the number of hysterectomies has declined in recent years, there are still >200,000 women who undergo bilateral oophorectomy each year in the United States (1Asante A. Whiteman M.K. Kulkarni A. Cox S. Marchbanks P.A. Jamieson D.J. Elective oophorectomy in the United States: trends and in-hospital complications, 1998–2006.Obstet Gynecol. 2010; 116: 1088-1095Crossref PubMed Scopus (85) Google Scholar, 2Wright J.D. Herzog T.J. Tsui J. Ananth C.V. Lewin S.N. Lu Y.S. et al.Nationwide trends in the performance of hysterectomy in the United States.Obstet Gynecol. 2013; 122: 233-241Crossref PubMed Google Scholar). This is the sum of surgeries done [1] at the time of hysterectomy, [2] bilateral oophorectomy performed for treatment of ovarian pathology, and [3] “stand-alone” procedures to reduce risk in women genetically predisposed to breast and ovarian cancer. Bilateral salpingo-oophorectomy essentially eliminates ovarian cancer risk and reduces breast cancer risk in these women (3Rebbeck T.R. Kauff N.D. Domcheck S.M. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.J Natl Cancer Inst. 2009; 191: 80-87Crossref Scopus (675) Google Scholar). The adverse effects of prophylactic oophorectomy are hormone deficiency-related symptoms, increased risk of acquiring certain diseases, and increased morbidity and mortality (4Gierach G.L. Pfeiffer R.M. Patel D.A. Black A. Schairer C. Gill A. et al.Long-term overall and disease-specific ,mortality associated with benign gynecologic surgery performed at different ages.Menopause. 2014; 21: 592-601Crossref PubMed Scopus (54) Google Scholar, 5Shuster L.T. Rhodes D.J. Gostout B.S. Grosshardt B.R. Rocca W.A. Premature menopause or early menopause: long-term health consequences.Maturitas. 2010; 65: 161-166Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar). These effects are similar to women who develop POI by other mechanisms. However, in Surgical POI symptoms are more sudden in onset and consequences can be more severe. Before 2002 >90% of women used estrogen therapy (ET) after bilateral salpingo-oophorectomy. This was for good reason. ET started close to the time of surgery (6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar, 7Rossouw J.E. Prentice R.L. Manson J.E. Wu L. Barad D. Barnabei V.M. et al.Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297: 1465-1477Crossref PubMed Scopus (1448) Google Scholar) is effective in controlling symptoms, inhibiting disease processes, and reducing morbidity and mortality. At present, the figure has declined to <10%. For young women who have undergone oophorectomy, not taking E means years of loss of its protective effects. Nevertheless, fear of taking any kind of hormone therapy (HT) is pervasive despite the evidence for the safety and efficacy of ET (8Chubaty A. Shandro M.T. Schuurmans N. Yuksel N. Practice patterns with hormone therapy after surgical menopause.Maturitas. 2011; 69: 69-73Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Women undergoing natural menopause differ dramatically from women experiencing surgical menopause at a young age. In most cases women experiencing natural menopause have a gradual onset of ovarian hormone deficiency after prolonged intermittent and unpredictable ovarian function, inherent in the physiology of the process. Generally these women are treated with HT for symptoms, not as a replacement for missing ovarian hormones. This is the critical distinction for the clinician to keep in mind, and it is important to explain this to young women who will be undergoing bilateral oophorectomy. Women who develop surgical POI experience more severe and more frequent menopausal symptoms than women who experience natural menopause (9Benshushan A. Rojansky N. Chaviv M. Arbel-Alon S. Benmeir A. Imbar T. et al.Climacteric symptoms in women undergoing risk-reducing bilateral salpingo-oophorectomy.Climacteric. 2009; 12: 404-409Crossref PubMed Scopus (49) Google Scholar) (Fig. 1). These symptoms occur almost immediately and can persist for decades. Untreated, symptoms, such as hot flashes, sleep disturbance, fatigue, decreased sexual desire, anxiety and depressed mood, often have a major impact on quality of life, capacity to function, and disease risk (7Rossouw J.E. Prentice R.L. Manson J.E. Wu L. Barad D. Barnabei V.M. et al.Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297: 1465-1477Crossref PubMed Scopus (1448) Google Scholar, 9Benshushan A. Rojansky N. Chaviv M. Arbel-Alon S. Benmeir A. Imbar T. et al.Climacteric symptoms in women undergoing risk-reducing bilateral salpingo-oophorectomy.Climacteric. 2009; 12: 404-409Crossref PubMed Scopus (49) Google Scholar, 10Nachtigall L. Hot flashes: is a hot flash just a hot flash?.Menopause. 2014; 21: 1-2Crossref Scopus (1) Google Scholar, 11Thurston R.C. El Khoudary S.R. Sutton-Tyrrell K. Crandall C.J. Gold E. Sternfeld B. et al.Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation.Menopause. 2011; 18: 1044-1051Crossref PubMed Scopus (60) Google Scholar, 12Kronenberg F. Hot flashes, epidemiology and physiology.Ann N Y Acad Sci. 1990; 592: 122-133Google Scholar). Also, delay in initiation of replacement E has an adverse effect on bone health (Table 1) (13Challberg J. Ashcroft L. Lalloo F. Eckersley B. Clayton R. Hopwood P. et al.Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT.Br J Cancer. 2011; 105: 22-27Crossref PubMed Scopus (55) Google Scholar).Table 1Effect of delay in hormone replacement therapy on bone health in women undertaking bilateral risk reducing salpingo-oophorectomy.Length of estrogen deprivation, moAge (y) at BRRSPO, median (range)Age (y) at DEXA, median (range)DEXA normal, n (%)Osteopenia (DEXA T score −1.0 to −2.4), n (%)Osteoporosis (DEXA T score <−2.4), n (%)042.6 (31–48)49 (41–61)26 (84)4 (13)1 (3)1–2342.9 (34–48)50 (32–68)6 (60)3 (30)1 (10)≥2441.1 (24.9–48)50 (38–78)42 (54)26 (33)10 (13)Note: BRRSPO = bilateral risk reducing salpingo-oophorectomy; DEXA = bone density scan. Used with permission, Challberg et al. 13Challberg J. Ashcroft L. Lalloo F. Eckersley B. Clayton R. Hopwood P. et al.Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT.Br J Cancer. 2011; 105: 22-27Crossref PubMed Scopus (55) Google Scholar. Open table in a new tab Note: BRRSPO = bilateral risk reducing salpingo-oophorectomy; DEXA = bone density scan. Used with permission, Challberg et al. 13Challberg J. Ashcroft L. Lalloo F. Eckersley B. Clayton R. Hopwood P. et al.Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT.Br J Cancer. 2011; 105: 22-27Crossref PubMed Scopus (55) Google Scholar. Menopausal symptoms should be regarded as important signals of pathophysiological changes. Although androgen deficiency can contribute to these changes, most appear to be due to E2 deficiency. For example, hot flashes are a state of vasomotor instability during which arterial flow is affected by surging levels of epinephrine and norepinephrine (12Kronenberg F. Hot flashes, epidemiology and physiology.Ann N Y Acad Sci. 1990; 592: 122-133Google Scholar, 14Freedman R.R. Physiology of hot flashes.Am J Hum Biol. 2001; 13: 453-464Crossref PubMed Scopus (290) Google Scholar). Vasodilation occurs in the skin as core blood flow shunts to the periphery. Coronary artery constriction during hot flashes can occur with >30% of women experiencing chest pressure or pain during a severe episode (12Kronenberg F. Hot flashes, epidemiology and physiology.Ann N Y Acad Sci. 1990; 592: 122-133Google Scholar, 15Sarrel P.M. Lindsay D.C. Rosano G.M.C. Poole-Wilson P.A. Angina and normal coronary arteries in women: gynecologic findings.Am J Obstet Gynecol. 1992; 167: 467-472Abstract Full Text PDF PubMed Scopus (79) Google Scholar). Vaginal dryness signals decreased genital blood flow and cell loss eventuating in genital atrophy and the urogenital syndrome of menopause (16Sarrel P.M. Sexuality and menopause.Obstet Gynecol. 1990; 75: 26S-30SPubMed Google Scholar). Impaired cognition, impaired short-term memory, sleep disturbance, and vasomotor instability reflect nervous system effects, including decreased brain blood flow and degenerative changes, predisposing to functional cognitive decline and dementia (11Thurston R.C. El Khoudary S.R. Sutton-Tyrrell K. Crandall C.J. Gold E. Sternfeld B. et al.Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation.Menopause. 2011; 18: 1044-1051Crossref PubMed Scopus (60) Google Scholar, 17Thurston R.C. Aizenstein H.J. Derby C.A. Sejdic E. Maki P.M. Menopausal hot flashes and white matter hyperintensities.Menopause. 2016; 23: 27-31Crossref PubMed Scopus (38) Google Scholar, 18Bove R. Secor E. Chibnik L.B. Barnes L.L. Schneider J.A. Bennett D.A. et al.Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women.Neurology. 2014; 82: 222-229Crossref PubMed Scopus (210) Google Scholar). The impact of untreated menopausal symptoms on quality of life is seen in studies of the effects on symptomatic women in the workplace (19Sarrel P.M. Portman D. Lefebvre M.A. Lafeuille M.H. Grittner A.M. Fortier J. et al.Incremental direct and indirect costs of untreated vasomotor symptoms.Menopause. 2015; 22: 260-266Crossref PubMed Scopus (88) Google Scholar, 20Geukes M. van Aalst M.P. Rebroek S.J.W. Laven J.S.E. Oosterhof H. The impact of menopause on work ability in women with severe menopausal symptoms.Maturitas. 2016; 90: 3-8Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). For example, 252,000 working women with untreated hot flashes were compared to asymptomatic age-matched women. During a 12-month period, the women with hot flashes showed increased work-loss, 1.1 million extra medical visits, and a health insurance bill almost $400,000,000 more compared to the asymptomatic women (19Sarrel P.M. Portman D. Lefebvre M.A. Lafeuille M.H. Grittner A.M. Fortier J. et al.Incremental direct and indirect costs of untreated vasomotor symptoms.Menopause. 2015; 22: 260-266Crossref PubMed Scopus (88) Google Scholar). A study of menopause symptoms and Dutch women concluded: “Over ¾ of women with severe menopausal symptoms report a low ability to undertake work” (20Geukes M. van Aalst M.P. Rebroek S.J.W. Laven J.S.E. Oosterhof H. The impact of menopause on work ability in women with severe menopausal symptoms.Maturitas. 2016; 90: 3-8Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). After bilateral oophorectomy, >80% of untreated women report one or more sex problems, including vaginal dryness with painful intercourse, inhibited sexual response, and loss of sexual desire (21Graziottin A. Basson R. Sexual dysfunction in women with premature menopause.Menopause. 2004; 11: 766-777Crossref PubMed Google Scholar, 22Shifren J.L. Braunstein G.D. Simon J.A. Casson P.R. Buster J.E. Redmond G.P. et al.Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.N Engl J Med. 2000; 343: 682-688Crossref PubMed Scopus (783) Google Scholar, 23Tucker P.E. Bulsara M.K. Salfinger S.G. Tan J.J. Green H. Cohen P.A. The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy.Maturitas. 2016; 85: 42-48Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). The increased occurrence of sexual dysfunction after bilateral salpingo-oophorectomy is more distressing in premenopausal than in postmenopausal women (23Tucker P.E. Bulsara M.K. Salfinger S.G. Tan J.J. Green H. Cohen P.A. The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy.Maturitas. 2016; 85: 42-48Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Estrogen therapy has proved effective for restoring vaginal cytology and lubrication and, therefore, reducing the occurrence of dyspareunia (15Sarrel P.M. Lindsay D.C. Rosano G.M.C. Poole-Wilson P.A. Angina and normal coronary arteries in women: gynecologic findings.Am J Obstet Gynecol. 1992; 167: 467-472Abstract Full Text PDF PubMed Scopus (79) Google Scholar). It is also effective in restoring sex response. However, the problem of loss of sexual desire may require the addition of an androgen to achieve satisfactory results (22Shifren J.L. Braunstein G.D. Simon J.A. Casson P.R. Buster J.E. Redmond G.P. et al.Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.N Engl J Med. 2000; 343: 682-688Crossref PubMed Scopus (783) Google Scholar, 23Tucker P.E. Bulsara M.K. Salfinger S.G. Tan J.J. Green H. Cohen P.A. The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy.Maturitas. 2016; 85: 42-48Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Severe vasomotor symptoms are associated with more frequent and more severe levels of depression and anxiety. For example, Kronenberg (12Kronenberg F. Hot flashes, epidemiology and physiology.Ann N Y Acad Sci. 1990; 592: 122-133Google Scholar) reported depressed feelings during hot flashes were more common in women after surgical menopause than with natural menopause and that suicidal thoughts during hot flashes occurred almost twice as often (10%) in these women. With regard to hospitalization for attempted suicide, Rosenberg et al. (24Rosenberg L. Hennekens C.H. Rosner B. Belanger C. Rothman K.J. Speizer F.E. Early menopause and the risk of myocardial infarction.Am J Obstet Gynecol. 1981; 139: 47-51Abstract Full Text PDF PubMed Scopus (286) Google Scholar) compared women who had experienced natural menopausal to women aged 35 years and younger who had undergone bilateral oophorectomy and had not used HT. They reported a relative risk of 2.4 for hospitalization for a suicide attempt in the women with surgical POI. The pathophysiology that occurs with menopausal symptoms can contribute to subsequent disease risk. For example, The Study of Women's Health Across the Nation reported that hot flashes were associated with a higher incidence of insulin resistance and glucose levels (11Thurston R.C. El Khoudary S.R. Sutton-Tyrrell K. Crandall C.J. Gold E. Sternfeld B. et al.Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation.Menopause. 2011; 18: 1044-1051Crossref PubMed Scopus (60) Google Scholar). More recently, the investigators of the Study of Women's Health Across the Nation reported that severe hot flashes were “robustly” associated with higher intima media thickness, an important marker for subclinical cardiovascular disease (25Thurston R.C. Barinas-Mitchell E. Jennings J.R. Santoro N. von Kanel R. Chang Y. et al.Physiologically monitored hot flashes and subclinical cardiovascular disease among midlife women.Menopause. 2015; 22: 1371Crossref Scopus (22) Google Scholar). In the Women's Health Initiative (WHI) study, more frequent and more severe symptoms were associated with an increased risk of hypertension, cardiovascular disease, and stroke (7Rossouw J.E. Prentice R.L. Manson J.E. Wu L. Barad D. Barnabei V.M. et al.Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297: 1465-1477Crossref PubMed Scopus (1448) Google Scholar). With regard to cardiovascular risk, there has been a paradigm shift in thinking with regard to effects of E deficiency on young women. Menopausal symptoms should be taken seriously and considered to be “canaries in the coal mine” signaling the need for medical attention and evaluation (26Kerber I.J. Turner R.J. Eu-estrogenemia, KNDY neurons, and vasomotor symptoms.JAMA Intern Med. 2015; 175: 1586Crossref Scopus (4) Google Scholar). In the past, “symptoms” of hormonal insufficiency have been at the center of managing menopause. Evaluation and treatment focused on control of symptoms for a limited time with the expectation that once a woman passed through the menopausal transition there would be no further need for hormonal intervention. However, starting in the 1950s, as the cardiovascular and bone consequences of ovarian hormone deficiency became more apparent, the role of ovarian HT for the prevention of disease emerged. Subsequently, many cohort studies and randomized clinical trials have been carried out to determine the connection between loss of ovarian function and disease development, as well as the effects of hormone replacement in disease prevention. In this section, we describe the findings we believe are the most significant. We begin with the findings of the Mayo Clinic Cohort Study of Oophorectomy and Aging (5Shuster L.T. Rhodes D.J. Gostout B.S. Grosshardt B.R. Rocca W.A. Premature menopause or early menopause: long-term health consequences.Maturitas. 2010; 65: 161-166Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar) because it addresses our focus on women who have undergone bilateral oophorectomy, and its findings relate to most of the concerns that have been raised by other studies about the immediate and long-term effects of ovarian hormone deficiency. The Mayo Clinic Cohort Study of Oophorectomy and Aging (5Shuster L.T. Rhodes D.J. Gostout B.S. Grosshardt B.R. Rocca W.A. Premature menopause or early menopause: long-term health consequences.Maturitas. 2010; 65: 161-166Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar) reports that following bilateral oophorectomy risk is increased for all-cause mortality (28%), coronary heart disease (33%), stroke (62%), cognitive impairment (60%), parkinsonism (80%), osteoporosis and bone fractures (50%), sexual dysfunction (40%–110%), and, possibly, glaucoma. The study shows even greater risks with earlier age at the time of surgical POI. For example, all-cause mortality was increased by 67% in women who had undergone bilateral oophorectomy before age 45 years. Perhaps most important, the Mayo Clinic study indicates that starting ET at the time of oophorectomy and continuing until at least the age of natural menopause (ages 51–52 years) significantly reduces most, but not all, of the increased risks seen in untreated women. These findings support the so-called timing hypothesis that, applied to cardiovascular, bone, and nervous system protection, argues for hormone replacement as close to the onset of hormone deficiency as possible (27Hodis H.N. Mack W.J. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Parts 1 and 2.J Am Geriatr Soc. 2013; 61: 1005-1018Crossref PubMed Scopus (39) Google Scholar). Other studies besides the Mayo Clinic study, which show that starting ET as close to the time of surgery, optimizes cardiovascular protection, include the Danish Nurses Study, the WHI estrogen-only study, and the ELITE trial (6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar, 7Rossouw J.E. Prentice R.L. Manson J.E. Wu L. Barad D. Barnabei V.M. et al.Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297: 1465-1477Crossref PubMed Scopus (1448) Google Scholar, 28Hodis H.N. Mack W.J. Henderson V.W. Kono N. Stanczyk F. Selzer S. et al.Vascular effects of early vs late postmenopausal treatment with estradiol.N Engl J Med. 2016; 374: 1221-1231Crossref PubMed Scopus (422) Google Scholar, 29Lokkegaard E. Jovanovic Z. Heitmann B.L. Kelding N. Ottesen B. Pedersen A.T. The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy.Maturitas. 2006; 53: 226-233Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Most of these studies indicate the best cardiovascular results were in women who used E after oophorectomy for 10 years or more (6Faubion S.S. Kuhle C.L. Shuster L.T. Rocca W.A. Long-term health consequences of premature or early menopause and considerations for management.Climacteric. 2015; 18: 483-491Crossref PubMed Scopus (257) Google Scholar, 7Rossouw J.E. Prentice R.L. Manson J.E. Wu L. Barad D. Barnabei V.M. et al.Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause.JAMA. 2007; 297: 1465-1477Crossref PubMed Scopus (1448) Google Scholar, 28Hodis H.N. Mack W.J. Henderson V.W. Kono N. Stanczyk F. Selzer S. et al.Vascular effects of early vs late postmenopausal treatment with estradiol.N Engl J Med. 2016; 374: 1221-1231Crossref PubMed Scopus (422) Google Scholar, 29Lokkegaard E. Jovanovic Z. Heitmann B.L. Kelding N. Ottesen B. Pedersen A.T. The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy.Maturitas. 2006; 53: 226-233Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). For almost 70 years data have been accumulating that clarify the role of E2 in disease prevention. Advances in molecular biology have enabled the identification of literally thousands of cellular actions of E2 (30Carroll J.S. Meyer C.A. Song J. LI W. Geistlinger T.R. Eeckhoute J. et al.Genome-wide analysis of estrogen receptor binding sites.Nature Genet. 2006; 38: 1289-1297Crossref PubMed Scopus (1093) Google Scholar). Most of these data refer to actions that affect bone, and the circulatory, urogenital, and nervous systems. In addition, the clinical findings of E reducing risk for developing breast cancer can be explained by a variety of molecular mechanisms including E-induced apoptosis in breast cancer cells (30Carroll J.S. Meyer C.A. Song J. LI W. Geistlinger T.R. Eeckhoute J. et al.Genome-wide analysis of estrogen receptor binding sites.Nature Genet. 2006; 38: 1289-1297Crossref PubMed Scopus (1093) Google Scholar, 31Chlebowski R.T. Anderson G.L. Changing concepts: menopausal hormone therapy and breast cancer.J Natl Cancer Inst. 2012; 104: 517-527Crossref PubMed Scopus (117) Google Scholar). In 1953, a Mayo Clinic autopsy study reported that 90% of the women with prior surgical POI showed severe atherosclerosis cardiovascular disease (32Wuest J.H. Dry T.J. Edwards J.E. The degree of coronary atherosclerosis in bilaterally oophorectomized women.Circulation. 1953; 7: 801-808Crossref PubMed Scopus (105) Google Scholar). Among the women who had died before age 50 years, 50% had severe atherosclerotic disease. The youngest of the women, a 28-year-old developed surgical POI at age 23 years. The interval between oophorectomy and death averaged 11 years in the women who died before age 60 years. More than 80% of the women died before age 70 years (32Wuest J.H. Dry T.J. Edwards J.E. The degree of coronary atherosclerosis in bilaterally oophorectomized women.Circulation. 1953; 7: 801-808Crossref PubMed Scopus (105) Google Scholar). Hormone replacement therapy is not mentioned in the report but it is safe to assume that very few would have been treated hormonally during the years after their surgery. Since that initial report, multiple mechanisms have been described through which E might inhibit atherosclerosis and maintains arterial function. These mechanisms include beneficial effects on cholesterol metabolism, direct actions in the arterial wall to inhibit atherosclerosis, and control of catecholamine release (33Forte T.F. Hormonal, metabolic, and cellular influences on cardiovascular disease in women. American Heart Association Monograph Series. Futura Publishing, Armonk, NY1997Google Scholar, 34Gerhard M. Ganz P. How do we explain the clinical benefits of estrogen? From bedside to bench.Circulation. 1995; 92: 5-8Crossref PubMed Scopus (156) Google Scholar). We have already referred to the surges in catecholamine levels that occur with vasomotor symptoms and the correlation between these symptoms and risk for developing cardiovascular disease (11Thurston R.C. El Khoudary S.R. Sutton-Tyrrell K. Crandall C.J. Gold E. Sternfeld B. et al.Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation.Menopause. 2011; 18: 1044-1051Crossref PubMed Scopus (60) Google Scholar, 12Kronenberg F. Hot flashes, epidemiology and physiology.Ann N Y Acad Sci. 1990; 592: 122-133Google Sc
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