433
Insights from the Women’s Health Initiative: Individualizing Risk Assessment for Hormone Therapy Decisions JoAnn E. Manson, MD, DrPH2
1 Department of Obstetrics and Gynecology, Biostatistics and
Epidemiology, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma 2 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Address for correspondence JoAnn E. Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215 (e-mail: [email protected]).
Semin Reprod Med 2014;32:433–437
Abstract
Keywords
► ► ► ► ►
hormone therapy risk individualizing estrogen menopause
Identifying appropriate candidates for menopausal hormone therapy (HT) is challenging given the complex profile of risks and benefits associated with treatment. Most professional societies agree that HT should not be used for chronic disease prevention. Recent findings from the Women’s Health Initiative and other randomized trials suggest that a woman’s age, proximity to menopause, underlying cardiovascular risk factor status, and various biological characteristics may modify health outcomes with HT. An emerging body of evidence suggests that it may be possible to assess individual risk and therefore better predict who is more likely to have favorable outcomes versus adverse effects when taking HT. Thus, once a woman is identified as a potential candidate for HT due to moderate-to-severe menopausal symptoms or other indications, risk stratification may be an important tool for minimizing patient risk. This individualized approach holds great promise for improving the safety of HT. We review here the evidence for this approach, focusing on vascular health because of limited data on other outcomes. The ultimate goal of this research is to develop a personalized risk/benefit prediction model to be used when a woman seeks therapy for symptom management. Patient centered outcomes including quality of life and sense of well-being should also be incorporated and will directly impact the benefit: risk ratio and compliance. Additional research on hormone dose, formulation, and route of delivery will be important for improving this model.
Background The majority of women have vasomotor symptoms as they transition through the menopause. It has been reported that approximately 15 to 20% have symptoms severe enough to interfere with their sleep and to negatively impact their quality of life.1,2 Most have some form of vaginal changes and some have severe atrophic vaginal changes.3 Hormone therapy (HT) has been historically widely used to relieve these “menopausal symptoms,” and no other available treatment has better efficacy for this purpose.4 In addition to being
Issue Theme Women’s Health Initiative: Lessons Learned 20 Plus Years After; Guest Editor, Robert Bryzski, MD
the mainstay of treatment for women with menopausal symptoms, HT was being increasingly used for chronic disease prevention in previous decades. Recent randomized clinical trials, however, have demonstrated that risks of menopausal HT may outweigh the benefits when HT is used for chronic disease prevention.5 Estrogen therapy (ET), as well as estrogen plus progestin (E þ P) therapy, has complex systemic biological effects and net outcomes may vary according to a woman’s risk factor status.1,6,7 Rates of adverse outcomes for women taking HT differ by age, time since menopause transition, baseline vascular health, risk for breast cancer,
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384626. ISSN 1526-8004.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Robert A. Wild, MD, MPH, PhD1
Insights from the Women’s Health Initiative
Wild, Manson
risk for osteoporotic fracture, genetic predisposition, and biomarker profile before and during therapy.1,5,7–12 Evidence is evolving regarding the role of HT doses, preparations and formulations, routes of delivery, and how these may interact with a woman’s clinical risk factors to modify outcomes on HT. Ultimately, a decision to provide symptom relief should be made with a patient’s full understanding of potential risks and benefits and taking into account her personal preferences. To better integrate patient values, practical considerations, and emerging clinical experience, recent research from observational studies and randomized clinical trials on HT should be considered. This article, which adapts and extends our earlier review on this topic,7 summarizes evidence on the utility of conducting a personalized risk assessment before initiating HT. Only those women with a clinical indication for HT, such as moderate-tosevere symptoms, would be candidates for this assessment. The bulk of available evidence pertinent to these issues derives from the Women’s Health Initiative (WHI). The WHI HT clinical trials studied more than 27,000 postmenopausal women ages 50 to 79 years (mean age was 63 years).13 In the EP trial, 16,608 women with a uterus were randomized to daily oral conjugated equine estrogens (CEE, 0.625 mg) combined with medroxyprogesterone (MPA, 2.5 mg) versus a placebo.14 In the estrogen (E) alone trial, 10,739 women with a hysterectomy (41% had prior bilateral oophorectomy) were given oral CEE 0.625 mg daily versus placebo.15 The main efficacy outcome of interest was coronary heart disease (CHD). A representative cohort of postmenopausal women (including women in older age groups) was targeted for enrollment. After 5.6 years of follow-up, the EP trial was terminated early because of greater frequency of CHD, stroke, and venous thromboembolism (VTE) and breast cancer in the active arm.14 The E-alone trial was terminated after 6.8 years because an increased frequency of stroke not offset by a reduced frequency of CHD in the active arm of the trial.15 Both regimens reduced the risk for osteoporotic fractures and estrogen alone was associated with reduced risk for breast cancer after extended follow-up. However, the overall risks appeared to outweigh the benefits for a large segment of the WHI study population in both trials. We focus on cardiovascular risk and parameters of quality of life in this review.
CVD Outcomes Associated with Hormone Therapy In the WHI EP clinical trial, women in the active arm were 24% more likely to have a myocardial infarction (MI) or coronary death, 30 to 40% more likely to have a stroke,14 and twice as likely to develop a pulmonary embolism.14 In the E-alone clinical trial, there was a 40% increase in stroke but a neutral effect on MI and CHD death.15,16 Subgroup analyses revealed that women who had poor cardiovascular disease (CVD) outcomes tended to have CVD risk factors, including older age, greater distance from menopause onset, elevated lowdensity lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, low HDL, or other dyslipidemias, presence of the metabolic syndrome (MetS), and, for VTE, factor V Leiden genotype.5,10,17 Seminars in Reproductive Medicine
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The Role of Age and Years since Menopause WHI analyses suggest that age or time since menopause modified the association between HT and CHD. In analyses that pooled data across both clinical trials, HT-associated relative risks (RR) for CHD were 0.76 (95% confidence interval [CI], 0.50–1.16), 1.10 (95% CI, 0.84–1.45), and 1.28 (95% CI, 1.03–1.58) among women who were < 10, 10 to 19, and 20 years past the menopausal transition at study enrollment (p, trend ¼ 0.02).8 Among women aged 50 to 59 years, CEE alone was associated with significant reductions in the secondary end point of coronary revascularization (RR ¼ 0.55; 95% CI, 0.35–0.86) and a composite end point of MI, coronary death, or coronary revascularization (RR ¼ 0.66; 95% CI, 0.44– 0.97), but CHD risk reductions were not seen for women in older age groups (60–69 or 70–79).16 Overall, HT appeared to have a beneficial or neutral effect on CHD risk for women closer to menopause (who are more likely to have healthier arteries) but a harmful effect in older women more distant from menopause, presumably due to more advanced atherosclerotic disease in the latter group.9,11,12 Analysis of the intervention plus postintervention phases of the WHI estrogen-alone clinical trial also found more favorable results for MI and CHD in younger, compared with older, women. For MI, the RRs associated with randomization to estrogen alone were 0.54 (0.34–0.86), 1.05 (0.82– 1.35), and 1.23 (0.92–1.65) for ages 50 to 59, 60 to 69, and 70 to 79 years, respectively (p, interaction ¼ 0.007).18 Results were similar for CHD.18 For stroke, no effect modification was apparent with age. Women assigned to either CEE þ MPA or CEE alone were 30 to 40% more likely to experience stroke than those assigned to placebo, irrespective of age, or time since menopause.8,14,15,19 Baseline age, time since menopause, and other examined clinical characteristics did not identify women who were at higher risk for a stroke on HT in the WHI. Women in the CEE þ MPA group in the EP clinical trial in the WHI were twice as likely as the placebo group to have a pulmonary embolism.17 Assignment to CEE alone appeared to raise the risk by 37%; this increase however was not statistically significant.20 No clear effect modification by age or time since menopause was found. Lower absolute baseline risks for CHD, stroke, VTE, and other adverse events in younger versus older women translated into lower absolute excess risks associated with HT use in younger women.
Biomarkers Higher LDL cholesterol and LDL/HDL ratios at baseline were predictive of more adverse CHD outcomes on HT. When the average LDL/HDL cholesterol ratio was > 2.5, there was a 73% greater risk of CHD with HT. Having the MetS at baseline was also predictive of greater risk when HT was used (►Table 1). The presence of the MetS was defined by having three of five characteristics including lower HDL cholesterol (< 50 mg/dL), high triglycerides ( 150 mg/dL), high baseline glucose (> 100 mg/dL), high waist circumference, and/or high blood pressure (> 135/80 mm Hg). When MetS was present, the risk
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Table 1 CHD risk in the WHI clinical trials (E þ P and E alone) by baseline biomarker level Biomarker
p value for interaction
OR (95% CI) for HT treatment effect
CHD risk in the WHI HT trials (E þ P and E alone) according to baseline levels of biomarkers LDL cholesterol (mg/dL) < 130 130
0.66 (0.34–1.27) 1.46 (1.02–2.10)
0.03
0.60 (0.34–1.06) 1.73 (1.18–2.53)
0.002
< 2.0 2.0
1.01 (0.63–1.62) 1.58 (1.05–2.39)
0.16
MetS No MetS
2.26 (1.26–4.07) 0.97 (0.58–1.61)
0.03
LDL/HDL cholesterol ratio < 2.5 2.5
Abbreviations: CHD, coronary heart disease; CI, confidence interval; E þ P, estrogen plus progestin; hs-CRP, high-sensitivity C-reactive protein; HT, hormone therapy; OR, odds ratio; LDL, low-density lipoprotein; MetS, metabolic syndrome; WHI, Women’s Health Initiative. Source: Bray et al.10 Wild RA, et al Menopause 2013;20(3):254–260.31
for a CHD event was more than double compared with those who were not taking HT in the WHI clinical trials, whereas in the absence of MetS, the HR was neutral (►Table 1). Several other biomarkers were predictive of greater CHD risk in the WHI, but did not significantly modify CHD risk on HT. These included higher levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6, matrix metalloproteinase 9, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin21 which were found in those more likely to have an event. The dyslipidemias and cardiometabolic abnormalities associated with MetS, described earlier, significantly modified the effect of HT on CHD and helped identify women more or less likely to have a CHD event on HT. Other biomarkers are currently being studied (see►Table 2) for listing of selected biomarkers under study in the WHI and other randomized trials and/or observational studies).8 These and other biomarkers may help identify women at high versus low risk of CVD and other outcomes on HT, including cancer, diabetes, and cognitive decline, among others. Whether or not these biomarkers enhance risk stratification is not yet known.
Genetic Markers Having either homozygous or heterozygous factor V Leiden was strongly predictive of pulmonary embolism and other venous thromboembolic events, and having the genetic polymorphism glycoprotein IIIa leu33pro was predictive of a CHD event in WHI.17,21 Factor V Leiden also interacted with HT to augment VTE risk.17 However, glycoprotein IIIa leu33pro was not associated with effect modification with HT as to vascular risk.21 Gene variants in ABO blood group have been linked to VTE, CHD, stroke, and other cardiovascular events, but it
Table 2 Several biomarkers under study to determine if they provide incremental risk prediction for CVD in women taking hormone therapy Biochemical markers • Lipids (serum LDL cholesterol, LDL/HDL ratios, triglyceride levels, Lp(a), 27-OH-cholesterol, apolipoprotein levels) • Inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor α, leukocyte count) • Adipokines (adiponectin, leptin, retinol-binding protein-4) • Endothelial markers (E-selectin, P-selectin, ICAM, VCAM) • Glucose tolerance markers: fasting glucose, insulin, HOMA-IR, IGF-1, and biomarkers of metabolic syndrome • Matrix metalloproteinases • Hemostatic markers (D-dimer, factor VIII, von Willebrand factor, homocysteine, fibrinogen, tissue factor pathway inhibitor, or acquired activated protein C resistance) • Sex steroid hormone levels, sex hormone–binding globulin level
Genetic markers • • • • • • • •
Factor V Leiden Glycoprotein IIIa leu33pro Gene variants in ABO blood group Estrogen and progesterone receptor polymorphisms Gene variants related to sex hormone biosynthesis Gene variants related to sex hormone metabolism Gene variants related to sex hormone signaling Genome-wide association studies and exome sequencing for gene discovery
Abbreviations: HDL, high-density lipoprotein; HOMA - IR, homeostasis model assessment of insulin resistance; ICAM, intercellular adhesion molecule; IGFI, insulin-like growth factor-I; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); VCAM, vascular cell adhesion molecule. Source: Adapted from Manson.7 Seminars in Reproductive Medicine
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hs-CRP (mg/dL)
Insights from the Women’s Health Initiative
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remains unclear whether these genetic factors interact with HT to influence risk.22 In the WHI, estrogen receptor polymorphisms were found to reduce the effect of HT on plasmin– antiplasmin, a marker of coagulation and fibrinolysis.23 Analyses of other genetic markers are under study and results are expected soon (►Table 2).
Menopausal Symptoms and Quality of Life Women who have hot flashes, night sweats, disrupted sleep, and/or vaginal or genital dryness are more likely to derive quality-of-life benefits from HT than women without such symptoms. In the WHI, among women who were symptomatic at baseline, CEE þ MPA provided significantly greater relief than placebo at 1 year: hot flashes (RR ¼ 4.40; 95% CI, 3.40–5.71), night sweats (RR ¼ 2.58; 2.04–3.26), vaginal or genital dryness (RR ¼ 2.40; 1.90–3.02), joint pain or stiffness (RR ¼ 1.43; 1.24–1.64), and general aches or pains (RR ¼ 1.25; 1.08–1.44).24–26 However, HT was also associated with more adverse effects including an increased risk of vaginal bleeding more endometrial sampling and/or hysterectomy, headaches, breast tenderness, and urinary incontinence. A similar pattern was seen for estrogen-alone users.27,28 Ongoing research is attempting to determine those clinical characteristics that best predict a net benefit for quality of life improvement when HT is used.
Dose, Formulations, and Route of Delivery of Hormone Therapy Using the lowest yet effective dose and delivering the medication transdermally may be associated with fewer adverse events than the oral route of administration.1,2,5,6 Organ symptom-related side effects may well be different depending on the preparation, dose, and route of delivery.29 Tissue effects may differ depending on whether there is a first-pass hepatic effect, as is the case with oral estrogen. With vaginal and transdermal preparations there is less effect on clotting factors, lipid metabolism, inflammatory biomarkers, and sex hormone–binding globulin synthesis. Differences in dose, route, formulations, in conjunction with genetic metabolic differences may lead to different outcomes. Observational studies, although limited in number, suggest that transdermal delivery may be associated with less risk of VTE and stroke than oral estrogen,1,2,30 but these studies do not prove a cause–effect relationship. Randomized clinical trial evidence to more definitively answer this question is lacking. We believe that it may be possible to develop individual prediction models based on a woman’s clinical characteristics, baseline biomarker status, gene variants, and pharmacoepidemiology to identify patients most likely to benefit from a specific dose, route of delivery, or a specific preparation. It may also be possible to better predict who should avoid any form of HT given personal individual risk for major adverse events.
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Conclusions Menopausal HT has a complex profile of risks and benefits that may vary according to a woman’s clinical characteristics and risk factor status. Our ability to identify women who are more likely to have favorable outcomes, and less likely to have adverse events, when HT is used has improved due to recent research findings. In the not-too-too distant future, we should be able to better individualize choice of dose, formulation, and/or route of delivery, based on a woman’s clinical characteristics, serum biomarker information, genomic data, and gene–environment interactions. Quality of life is an important outcome for HT. The goal is to reduce menopausal symptoms and improve quality of life, while minimizing risks, by integrating patient values and risk stratification. An important component of decision making is identifying women at greater risk for a CVD event, among whom HT should be avoided. The menopause transition provides an opportunity to screen for CVD risk factors, apply preventive modalities, and improve overall quality of life. HT continues to have an important role in providing symptomatic relief and improving quality of life among women with moderate-to-severe menopausal symptoms. Understanding a woman’s individual risk based on accessible clinical information and tailoring HT to appropriate candidates will allow for benefits to be achieved while minimizing the risks.
References 1 North American Menopause Society. The 2012 Hormone Therapy
2
3
4
5
6
7
8
9
10
Position Statement of the North American Menopause Society. Menopause 2012;19:257–271 Santen RJ, Allred DC, Ardoin SP, et al; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(7, Suppl 1):s1–s66 Frank SM, Ziegler C, Kokot-Kierepa M, Maamari R, Nappi RE. Vaginal Health: Insights, Views & Attitudes (VIVA) survey - Canadian cohort. Menopause Int 2012 Tan O, Bradshaw K, Carr BR. Management of vulvovaginal atrophyrelated sexual dysfunction in postmenopausal women: an up-todate review. Menopause 2012;19(1):109–117 Manson JE, Bassuk SS. The menopause transition and postmenopausal hormone therapy. In: Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo L, eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2011 Writing Group on behalf of Workshop Consensus Group. ; International Menopause Society Consensus Statement. Aging, menopause, cardiovascular disease and HRT. Climacteric 2009;12(5):368–377 Manson JE. The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. Metabolism 2013;62(Suppl 1):S15–S19 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(13):1465–1477 Manson JE, Bassuk SS. Invited commentary: hormone therapy and risk of coronary heart disease why renew the focus on the early years of menopause? Am J Epidemiol 2007;166(5): 511–517 Bray PF, Larson JC, Lacroix AZ, et al; Women’s Health Initiative Investigators. Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of
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22 Carpeggiani C, Coceani M, Landi P, Michelassi C, L’abbate A. ABO
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blood group alleles: A risk factor for coronary artery disease. An angiographic study. Atherosclerosis 2010;211(2):461–466 Rossouw J, Bray P, Liu J, et al. Estrogen receptor polymorphisms and the vascular effects of hormone therapy. Arterioscler Thromb Vasc Biol 2011;31(2):464–469 Barnabei VM, Cochrane BB, Aragaki AK, et al; Women’s Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol 2005;105(5 Pt 1): 1063–1073 Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294(2): 183–193 Hays J, Ockene JK, Brunner RL, et al; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348(19):1839–1854 Brunner RL, Gass M, Aragaki A, et al; Women’s Health Initiative Investigators. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women’s Health Initiative Randomized Clinical Trial. Arch Intern Med 2005;165(17): 1976–1986 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(5):946–954 Manson JE. The Kronos Early Estrogen Prevention Study. Womens Health (Lond Engl) 2013;9(1):9–11 Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115(7): 840–845 Wild RA, Wu C, Curb JD, Martin LW, Phillips L, Stefanick M, Trevisan M, Manson JE. Coronary heart disease events in the Women’s Health Initiative hormone trials: effect modification by metabolic syndrome: A nested case-control study within the Women’s Health Initiative randomized clinical trials. Menopause 2013; 20(3):254–260
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treatment-related coronary events. Am J Cardiol 2008;101(11): 1599–1605 Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308(5728):1583–1587 Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med 2003; 348(7):645–650 The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19(1):61–109 Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. 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):321–333 Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701–1712 Hsia J, Criqui MH, Herrington DM, et al; Women’s Health Initiative Research Group. Conjugated equine estrogens and peripheral arterial disease risk: the Women’s Health Initiative. Am Heart J 2006;152(1):170–176 Cushman M, Kuller LH, Prentice R, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292(13):1573–1580 LaCroix AZ, Chlebowski RT, Manson JE, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305(13):1305–1314 Wassertheil-Smoller S, Hendrix SL, Limacher M, et al; WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289(20):2673–2684 Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166(7):772–780 Rossouw JE, Cushman M, Greenland P, et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women’s health initiative trials of hormone therapy. Arch Intern Med 2008;168(20):2245–2253
Wild, Manson
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Insights from the Women’s Health Initiative: Individualizing Risk Assessment for Hormone Therapy Decisions JoAnn E. Manson, MD, DrPH2
1 Department of Obstetrics and Gynecology, Biostatistics and
Epidemiology, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma 2 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Address for correspondence JoAnn E. Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215 (e-mail: [email protected]).
Semin Reprod Med 2014;32:433–437
Abstract
Keywords
► ► ► ► ►
hormone therapy risk individualizing estrogen menopause
Identifying appropriate candidates for menopausal hormone therapy (HT) is challenging given the complex profile of risks and benefits associated with treatment. Most professional societies agree that HT should not be used for chronic disease prevention. Recent findings from the Women’s Health Initiative and other randomized trials suggest that a woman’s age, proximity to menopause, underlying cardiovascular risk factor status, and various biological characteristics may modify health outcomes with HT. An emerging body of evidence suggests that it may be possible to assess individual risk and therefore better predict who is more likely to have favorable outcomes versus adverse effects when taking HT. Thus, once a woman is identified as a potential candidate for HT due to moderate-to-severe menopausal symptoms or other indications, risk stratification may be an important tool for minimizing patient risk. This individualized approach holds great promise for improving the safety of HT. We review here the evidence for this approach, focusing on vascular health because of limited data on other outcomes. The ultimate goal of this research is to develop a personalized risk/benefit prediction model to be used when a woman seeks therapy for symptom management. Patient centered outcomes including quality of life and sense of well-being should also be incorporated and will directly impact the benefit: risk ratio and compliance. Additional research on hormone dose, formulation, and route of delivery will be important for improving this model.
Background The majority of women have vasomotor symptoms as they transition through the menopause. It has been reported that approximately 15 to 20% have symptoms severe enough to interfere with their sleep and to negatively impact their quality of life.1,2 Most have some form of vaginal changes and some have severe atrophic vaginal changes.3 Hormone therapy (HT) has been historically widely used to relieve these “menopausal symptoms,” and no other available treatment has better efficacy for this purpose.4 In addition to being
Issue Theme Women’s Health Initiative: Lessons Learned 20 Plus Years After; Guest Editor, Robert Bryzski, MD
the mainstay of treatment for women with menopausal symptoms, HT was being increasingly used for chronic disease prevention in previous decades. Recent randomized clinical trials, however, have demonstrated that risks of menopausal HT may outweigh the benefits when HT is used for chronic disease prevention.5 Estrogen therapy (ET), as well as estrogen plus progestin (E þ P) therapy, has complex systemic biological effects and net outcomes may vary according to a woman’s risk factor status.1,6,7 Rates of adverse outcomes for women taking HT differ by age, time since menopause transition, baseline vascular health, risk for breast cancer,
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384626. ISSN 1526-8004.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Robert A. Wild, MD, MPH, PhD1
Insights from the Women’s Health Initiative
Wild, Manson
risk for osteoporotic fracture, genetic predisposition, and biomarker profile before and during therapy.1,5,7–12 Evidence is evolving regarding the role of HT doses, preparations and formulations, routes of delivery, and how these may interact with a woman’s clinical risk factors to modify outcomes on HT. Ultimately, a decision to provide symptom relief should be made with a patient’s full understanding of potential risks and benefits and taking into account her personal preferences. To better integrate patient values, practical considerations, and emerging clinical experience, recent research from observational studies and randomized clinical trials on HT should be considered. This article, which adapts and extends our earlier review on this topic,7 summarizes evidence on the utility of conducting a personalized risk assessment before initiating HT. Only those women with a clinical indication for HT, such as moderate-tosevere symptoms, would be candidates for this assessment. The bulk of available evidence pertinent to these issues derives from the Women’s Health Initiative (WHI). The WHI HT clinical trials studied more than 27,000 postmenopausal women ages 50 to 79 years (mean age was 63 years).13 In the EP trial, 16,608 women with a uterus were randomized to daily oral conjugated equine estrogens (CEE, 0.625 mg) combined with medroxyprogesterone (MPA, 2.5 mg) versus a placebo.14 In the estrogen (E) alone trial, 10,739 women with a hysterectomy (41% had prior bilateral oophorectomy) were given oral CEE 0.625 mg daily versus placebo.15 The main efficacy outcome of interest was coronary heart disease (CHD). A representative cohort of postmenopausal women (including women in older age groups) was targeted for enrollment. After 5.6 years of follow-up, the EP trial was terminated early because of greater frequency of CHD, stroke, and venous thromboembolism (VTE) and breast cancer in the active arm.14 The E-alone trial was terminated after 6.8 years because an increased frequency of stroke not offset by a reduced frequency of CHD in the active arm of the trial.15 Both regimens reduced the risk for osteoporotic fractures and estrogen alone was associated with reduced risk for breast cancer after extended follow-up. However, the overall risks appeared to outweigh the benefits for a large segment of the WHI study population in both trials. We focus on cardiovascular risk and parameters of quality of life in this review.
CVD Outcomes Associated with Hormone Therapy In the WHI EP clinical trial, women in the active arm were 24% more likely to have a myocardial infarction (MI) or coronary death, 30 to 40% more likely to have a stroke,14 and twice as likely to develop a pulmonary embolism.14 In the E-alone clinical trial, there was a 40% increase in stroke but a neutral effect on MI and CHD death.15,16 Subgroup analyses revealed that women who had poor cardiovascular disease (CVD) outcomes tended to have CVD risk factors, including older age, greater distance from menopause onset, elevated lowdensity lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, low HDL, or other dyslipidemias, presence of the metabolic syndrome (MetS), and, for VTE, factor V Leiden genotype.5,10,17 Seminars in Reproductive Medicine
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The Role of Age and Years since Menopause WHI analyses suggest that age or time since menopause modified the association between HT and CHD. In analyses that pooled data across both clinical trials, HT-associated relative risks (RR) for CHD were 0.76 (95% confidence interval [CI], 0.50–1.16), 1.10 (95% CI, 0.84–1.45), and 1.28 (95% CI, 1.03–1.58) among women who were < 10, 10 to 19, and 20 years past the menopausal transition at study enrollment (p, trend ¼ 0.02).8 Among women aged 50 to 59 years, CEE alone was associated with significant reductions in the secondary end point of coronary revascularization (RR ¼ 0.55; 95% CI, 0.35–0.86) and a composite end point of MI, coronary death, or coronary revascularization (RR ¼ 0.66; 95% CI, 0.44– 0.97), but CHD risk reductions were not seen for women in older age groups (60–69 or 70–79).16 Overall, HT appeared to have a beneficial or neutral effect on CHD risk for women closer to menopause (who are more likely to have healthier arteries) but a harmful effect in older women more distant from menopause, presumably due to more advanced atherosclerotic disease in the latter group.9,11,12 Analysis of the intervention plus postintervention phases of the WHI estrogen-alone clinical trial also found more favorable results for MI and CHD in younger, compared with older, women. For MI, the RRs associated with randomization to estrogen alone were 0.54 (0.34–0.86), 1.05 (0.82– 1.35), and 1.23 (0.92–1.65) for ages 50 to 59, 60 to 69, and 70 to 79 years, respectively (p, interaction ¼ 0.007).18 Results were similar for CHD.18 For stroke, no effect modification was apparent with age. Women assigned to either CEE þ MPA or CEE alone were 30 to 40% more likely to experience stroke than those assigned to placebo, irrespective of age, or time since menopause.8,14,15,19 Baseline age, time since menopause, and other examined clinical characteristics did not identify women who were at higher risk for a stroke on HT in the WHI. Women in the CEE þ MPA group in the EP clinical trial in the WHI were twice as likely as the placebo group to have a pulmonary embolism.17 Assignment to CEE alone appeared to raise the risk by 37%; this increase however was not statistically significant.20 No clear effect modification by age or time since menopause was found. Lower absolute baseline risks for CHD, stroke, VTE, and other adverse events in younger versus older women translated into lower absolute excess risks associated with HT use in younger women.
Biomarkers Higher LDL cholesterol and LDL/HDL ratios at baseline were predictive of more adverse CHD outcomes on HT. When the average LDL/HDL cholesterol ratio was > 2.5, there was a 73% greater risk of CHD with HT. Having the MetS at baseline was also predictive of greater risk when HT was used (►Table 1). The presence of the MetS was defined by having three of five characteristics including lower HDL cholesterol (< 50 mg/dL), high triglycerides ( 150 mg/dL), high baseline glucose (> 100 mg/dL), high waist circumference, and/or high blood pressure (> 135/80 mm Hg). When MetS was present, the risk
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Table 1 CHD risk in the WHI clinical trials (E þ P and E alone) by baseline biomarker level Biomarker
p value for interaction
OR (95% CI) for HT treatment effect
CHD risk in the WHI HT trials (E þ P and E alone) according to baseline levels of biomarkers LDL cholesterol (mg/dL) < 130 130
0.66 (0.34–1.27) 1.46 (1.02–2.10)
0.03
0.60 (0.34–1.06) 1.73 (1.18–2.53)
0.002
< 2.0 2.0
1.01 (0.63–1.62) 1.58 (1.05–2.39)
0.16
MetS No MetS
2.26 (1.26–4.07) 0.97 (0.58–1.61)
0.03
LDL/HDL cholesterol ratio < 2.5 2.5
Abbreviations: CHD, coronary heart disease; CI, confidence interval; E þ P, estrogen plus progestin; hs-CRP, high-sensitivity C-reactive protein; HT, hormone therapy; OR, odds ratio; LDL, low-density lipoprotein; MetS, metabolic syndrome; WHI, Women’s Health Initiative. Source: Bray et al.10 Wild RA, et al Menopause 2013;20(3):254–260.31
for a CHD event was more than double compared with those who were not taking HT in the WHI clinical trials, whereas in the absence of MetS, the HR was neutral (►Table 1). Several other biomarkers were predictive of greater CHD risk in the WHI, but did not significantly modify CHD risk on HT. These included higher levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6, matrix metalloproteinase 9, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin21 which were found in those more likely to have an event. The dyslipidemias and cardiometabolic abnormalities associated with MetS, described earlier, significantly modified the effect of HT on CHD and helped identify women more or less likely to have a CHD event on HT. Other biomarkers are currently being studied (see►Table 2) for listing of selected biomarkers under study in the WHI and other randomized trials and/or observational studies).8 These and other biomarkers may help identify women at high versus low risk of CVD and other outcomes on HT, including cancer, diabetes, and cognitive decline, among others. Whether or not these biomarkers enhance risk stratification is not yet known.
Genetic Markers Having either homozygous or heterozygous factor V Leiden was strongly predictive of pulmonary embolism and other venous thromboembolic events, and having the genetic polymorphism glycoprotein IIIa leu33pro was predictive of a CHD event in WHI.17,21 Factor V Leiden also interacted with HT to augment VTE risk.17 However, glycoprotein IIIa leu33pro was not associated with effect modification with HT as to vascular risk.21 Gene variants in ABO blood group have been linked to VTE, CHD, stroke, and other cardiovascular events, but it
Table 2 Several biomarkers under study to determine if they provide incremental risk prediction for CVD in women taking hormone therapy Biochemical markers • Lipids (serum LDL cholesterol, LDL/HDL ratios, triglyceride levels, Lp(a), 27-OH-cholesterol, apolipoprotein levels) • Inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor α, leukocyte count) • Adipokines (adiponectin, leptin, retinol-binding protein-4) • Endothelial markers (E-selectin, P-selectin, ICAM, VCAM) • Glucose tolerance markers: fasting glucose, insulin, HOMA-IR, IGF-1, and biomarkers of metabolic syndrome • Matrix metalloproteinases • Hemostatic markers (D-dimer, factor VIII, von Willebrand factor, homocysteine, fibrinogen, tissue factor pathway inhibitor, or acquired activated protein C resistance) • Sex steroid hormone levels, sex hormone–binding globulin level
Genetic markers • • • • • • • •
Factor V Leiden Glycoprotein IIIa leu33pro Gene variants in ABO blood group Estrogen and progesterone receptor polymorphisms Gene variants related to sex hormone biosynthesis Gene variants related to sex hormone metabolism Gene variants related to sex hormone signaling Genome-wide association studies and exome sequencing for gene discovery
Abbreviations: HDL, high-density lipoprotein; HOMA - IR, homeostasis model assessment of insulin resistance; ICAM, intercellular adhesion molecule; IGFI, insulin-like growth factor-I; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); VCAM, vascular cell adhesion molecule. Source: Adapted from Manson.7 Seminars in Reproductive Medicine
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remains unclear whether these genetic factors interact with HT to influence risk.22 In the WHI, estrogen receptor polymorphisms were found to reduce the effect of HT on plasmin– antiplasmin, a marker of coagulation and fibrinolysis.23 Analyses of other genetic markers are under study and results are expected soon (►Table 2).
Menopausal Symptoms and Quality of Life Women who have hot flashes, night sweats, disrupted sleep, and/or vaginal or genital dryness are more likely to derive quality-of-life benefits from HT than women without such symptoms. In the WHI, among women who were symptomatic at baseline, CEE þ MPA provided significantly greater relief than placebo at 1 year: hot flashes (RR ¼ 4.40; 95% CI, 3.40–5.71), night sweats (RR ¼ 2.58; 2.04–3.26), vaginal or genital dryness (RR ¼ 2.40; 1.90–3.02), joint pain or stiffness (RR ¼ 1.43; 1.24–1.64), and general aches or pains (RR ¼ 1.25; 1.08–1.44).24–26 However, HT was also associated with more adverse effects including an increased risk of vaginal bleeding more endometrial sampling and/or hysterectomy, headaches, breast tenderness, and urinary incontinence. A similar pattern was seen for estrogen-alone users.27,28 Ongoing research is attempting to determine those clinical characteristics that best predict a net benefit for quality of life improvement when HT is used.
Dose, Formulations, and Route of Delivery of Hormone Therapy Using the lowest yet effective dose and delivering the medication transdermally may be associated with fewer adverse events than the oral route of administration.1,2,5,6 Organ symptom-related side effects may well be different depending on the preparation, dose, and route of delivery.29 Tissue effects may differ depending on whether there is a first-pass hepatic effect, as is the case with oral estrogen. With vaginal and transdermal preparations there is less effect on clotting factors, lipid metabolism, inflammatory biomarkers, and sex hormone–binding globulin synthesis. Differences in dose, route, formulations, in conjunction with genetic metabolic differences may lead to different outcomes. Observational studies, although limited in number, suggest that transdermal delivery may be associated with less risk of VTE and stroke than oral estrogen,1,2,30 but these studies do not prove a cause–effect relationship. Randomized clinical trial evidence to more definitively answer this question is lacking. We believe that it may be possible to develop individual prediction models based on a woman’s clinical characteristics, baseline biomarker status, gene variants, and pharmacoepidemiology to identify patients most likely to benefit from a specific dose, route of delivery, or a specific preparation. It may also be possible to better predict who should avoid any form of HT given personal individual risk for major adverse events.
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Conclusions Menopausal HT has a complex profile of risks and benefits that may vary according to a woman’s clinical characteristics and risk factor status. Our ability to identify women who are more likely to have favorable outcomes, and less likely to have adverse events, when HT is used has improved due to recent research findings. In the not-too-too distant future, we should be able to better individualize choice of dose, formulation, and/or route of delivery, based on a woman’s clinical characteristics, serum biomarker information, genomic data, and gene–environment interactions. Quality of life is an important outcome for HT. The goal is to reduce menopausal symptoms and improve quality of life, while minimizing risks, by integrating patient values and risk stratification. An important component of decision making is identifying women at greater risk for a CVD event, among whom HT should be avoided. The menopause transition provides an opportunity to screen for CVD risk factors, apply preventive modalities, and improve overall quality of life. HT continues to have an important role in providing symptomatic relief and improving quality of life among women with moderate-to-severe menopausal symptoms. Understanding a woman’s individual risk based on accessible clinical information and tailoring HT to appropriate candidates will allow for benefits to be achieved while minimizing the risks.
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