key: cord-0036750-waisatga authors: Ragaz, Joseph; Budlovsky, Joshua title: Hormone Replacement Therapy: A Critical Review date: 2010-02-24 journal: Management of Breast Diseases DOI: 10.1007/978-3-540-69743-5_24 sha: 090d17f77880602fcae81dcf93e72970c42b508d doc_id: 36750 cord_uid: waisatga The aim of this chapter is to review the most recent aspects of hormone replacement therapy (HRT), and to clarify its impact on associated health conditions amidst growing uncertainties. Special emphasis has been placed on its effect on cardiovascular conditions and breast cancer, the two most important outcomes affected by HRT, and on identifying ideal candidates for HRT as well as defining the optimum new HRT regimens. The aim of this chapter is to review the most recent aspects of hormone replacement therapy (HRT), and to clarify its impact on associated health conditions amidst growing uncertainties. Special emphasis has been placed on its effect on cardiovascular conditions and breast cancer, the two most important outcomes affected by HRT, and on identifying ideal candidates for HRT as well as defi ning the optimum new HRT regimens. Until the publication in 2002 of the fi rst Women's Health Initiative (WHI) randomized trial [1] , HRT was increasingly used to treat the variety of symptoms attributed to menopause, as well as to prevent most menopause-associated medical conditions. These policies were based largely on observational and casecontrol studies, providing evidence that HRT, besides providing control of menopausal symptoms, is also associated with cardiovascular, colon cancer, and bone fracture benefi ts. Most intriguing were data associating HRT with a signifi cant all-cause mortality reduction [2] [3] [4] [5] , and paradoxically, despite increased breast cancer incidence rates, with improved rates of breast cancer mortality [5] . In 2002, the fi rst WHI controlled randomized trial of HRT using estrogen plus progestin reported increased hazard rates from HRT for coronary heart disease (CHD) and strokes, as well as adverse effects on breast cancer and thromboembolism. While the previously seen HRT benefi ts for bones and against colon cancer were confi rmed, the WHI group concluded that increased hazards outweighed the HRT benefi ts. The fi rst goal of this review is to identify the strengths and weaknesses of the published HRT data and especially to put into perspective all WHI HRT analyses. Special emphasis is placed on HRT indications for women who become menopausal as a result of a natural or iatrogenically-induced ovarian suppression, and who suffer with postmenopausal symptoms. These are mostly women aged 50-59 and/or <10 years from menopause. The second objective of this review is to defi ne the new generation of HRT regimens -agents of the lowest active dose that will palliate vasomotor and other menopausal symptoms effectively. This issue is important as the "classical" estrogen, the Premarin 0.625 tablets and Provera 2.5 mg used in most observational and in the WHI HRT trials, are considered more toxic, and thus likely associated with substantially more hazards. The Women's Health Initiative (WHI) is perhaps the most extensive population research investigation undertaken in recent decades [6] . The WHI program also includes an observational study (ObSt) that comprised 93,676 postmenopausal women recruited from the same population base as the randomized trials. The ObSt is intended to provide additional knowledge about risk factors for a range of diseases, including cancer, cardiovascular disease, and fractures. It has an emphasis on biological markers of disease risk and on risk-factor changes as risk modifi ers. Table 24 .1 provides information on enrollment by age-group in the various WHI components. The estrogen plus progestin trial ended early on July 8, 2002, when evidence had accumulated that the health risks exceeded the benefi ts for this study population, according to predefi ned WHI planning committee criteria. The second HRT trial in the estrogen-alone component was also halted early, on February 29, 2004 , because of increased risks of stroke. The Dietary and Ca-D-Vitamin trials ended as planned on March 31, 2005 . The follow-up of participating women is planned through 2010, which will give an average follow-up duration of 13 years in the four randomized trials and 12 years in the observational study. With both WHI HRT trials ending prematurely, women already enrolled in the trials were asked to stop the allocated therapy. Soon afterwards, women worldwide were told to discontinue or to never start the HRT. The WHI HRT trials were planned because of rising concerns that past HRT observational and case-controlled studies were based on small patient sample size or on study results with preselected participants who were in a better state of health than women who were not eligible for HRT. Thus, the objectives of the WHI studies were to determine, from large randomized trials, the individual HRT-related outcomes, in order to infl uence the clinical practice, whereby HRT was increasingly prescribed not only for the palliation of postmenopausal symptoms, but also for reduction of heart disease morbidity, cardiac mortality, and in general, to slow down the chronic degenerative conditions related to aging. Rossouw et al. [104] The July 17, 02 JAMA article reported the results of the fi rst of the two trials -the Estrogen plus Progestin (E2 + Prog) vs. placebo. Between 1993-1998, the WHI enrolled 16,608 women aged 50-79 with an intact uterus into the fi rst HRT study, and randomized them into: A "Global index" summarized the balance of the seven incidence events, as well as the "death due to other causes" and was defi ned as the defi nitive marker of benefi t or hazard. Each event as well as the Global index were expressed as absolute numbers/10,000 person-years, and as Hazard rates (with increased hazards defi ned as HR = 1.0; and benefi ts as HR = 1.0), with appropriate 95% confi dence intervals (CI). Over 25% of cases were past or current HRT users, with over 30% of those having had HRT use of >5 years duration prior to randomization. Median age was 63.1 years, with only one third (33%) of the participants being less than 60 years of age. The fi rst WHI HRT trial with Premarin + Provera versus Placebo was terminated on the advice of the independent Data and Safety Monitoring Board after a mean 5.2 years of follow-up because of an increased risk of breast cancer and an overall assessment of harms exceeding benefi ts for chronic disease prevention. A summary of the most complete trial results published (Table 24 cancer incidence, 29% increase of CHD, 41% increase in risk of stroke, and a doubling of the rates of thromboembolism. None of these hazards, with the exception of thromboembolism, were increased with statistical signifi cance. There was also a signifi cant 25% reduction of skeletal fracture rates, a 37% reduction of colorectal cancer, a 17% reduction of endometrial cancer, and a 2% reduction of deaths from any cause. However, despite these benefi ts, the Global index was increased (HR = 1.15, 95%CI: 0.95-1.39). In absolute terms, the results of the fi rst WHI HRT trial confi rmed in the estrogen plus progestin arm excess of CHD (excess of 0.07%); breast cancer (excess of 0.08%), stroke (excess of 0.08%), pulmonary embolism (excess of 0.08%); but reduced events of skeletal fractures (reduction by 0.44%); colorectal cancer (reduction by 0.06%); endometrial cancer (reduction by 0.01%); and of total deaths (reduced by 0.01%/ year). Blood lipid levels showed favorable profi le, with reductions in low-density lipoprotein cholesterol (−12.7%) and increases in high-density lipoprotein cholesterol (+7.3%) and triglycerides (+6.9%). Thus, authors concluded that for an average 5.2 years follow time: 1. Overall health risks of combined estrogen plus progestin exceeded benefi ts among healthy postmenopausal U.S. women. 2. All-cause mortality was not different between the two groups. 3. The risk-benefi t profi le is not consistent with the requirements for an intervention for primary prevention of chronic diseases such as CHD. The Data and Safety Monitoring Board (DSMB) reviewing the interim May 31, 2002 analyses found adverse effects in cardiovascular disease within the monitoring boundaries (i.e., not requiring the stopping of the trial). However, the increased risks for invasive breast cancer necessitated a premature termination of the trial. All investigators, trial participants, and public at large were informed about these results and their interpretation, and trial participants randomized to the HRT were asked to stop their allocated hormones. Of all participants, only less than one third (30.8%) were <60 years of age; and over 47% were past or current HRT users before enrollment. Approximately, 40% of all participants had oophorectomy with hysterectomy (39.5 vs. 42% in arm of CEE vs. Placebo, respectively). Forty eight percent of women in the trial had been treated for hypertension and 15% had therapy for elevated cholesterol. Overall, 86% of all patients had no fi rst-degree relative with breast cancer, and 74.5% had no benign breast disease in the past. Estimated hazard ratios (with adjusted 95% confidence intervals) for CEE vs. placebo for the major clinical outcomes available through February 29, 2004 are shown in Table 24 .5 . Overall, there was a 9% reduction of CHD, a 33% (nonsignifi cant) increase in thromboembolism, a 39% increase in strokes, and an 8% increase in colorectal cancer; reduced were rates of breast cancer, by 23%; overall skeletal fractures by a signifi cant 30%, and signifi cant 39% reduction of hip fractures. Total death rate was increased nonsignificantly, by 4%; and so was the global index, by 1%. For the outcomes signifi cantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of six fewer hip fractures per 10,000 personyears. The estimated risk for all monitored events in the global index was a nonsignifi cant excess of two events per 10,000 person-years. On account of these results, the second WHI trial on CEE alone vs. placebo concluded that the use of CEE, in women after hysterectomy, after follow-up of 6.8 years: a. Increases the risk of strokes. b. Decreases the risk of hip fracture. c. Does not affect the CHD incidence. d. With a possible reduction in breast cancer risk requiring further investigation . e. The sum of combined events was equivalent in the CEE and placebo groups, indicating no overall benefi t and no hazards. f. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women. As a result of these data, after reviewing data through November 30, 2003 , the National Institutes of Health (NIH) decided in February 2004 to end the intervention phase of the second WHI HRT trial early, with results published in the April 14, 2004 issue of the Journal of American Medical Association [89] . Consequences of the WHI reports. The recommendations to stop HRT resulted, in subsequent years, in millions of women in the Western world discontinuing HRT, even if they were in the age-group of 50-59, and suffering with vasomotor symptoms. By then, approximately 38% of postmenopausal women in the United States used HRT. In the year 2000 alone, just prior to the WHI HRT trial publication, 46 million prescriptions were written for Premarin (conjugated estrogens), making it the second most frequently prescribed medication in the United States and accounting for more than $1 billion U.S. in sales [90] . By the end of 2002, the use of hormone-replacement therapy had decreased by 38% in the United States, with approximately 20 million fewer prescriptions written in 2003 than in 2002. By the year 2005, the decrease was by 71%, and the drop continues [16] . This move represents one of the most dramatic health policy shifts registered in the recent medical history. HRT benefi ts from most past case-control and observational studies were in question, and most publications of the WHI trials and editorials universally agreed on more harm than benefi ts of HRT. Thus, at the start of the critique, we ask several questions, specifi cally about the age of participants as over 2/3rd were >age 60; also questioned is the possible adverse impact of HRT using progestins, as estrogen alone had more benefi cial breast cancer profi le. Lastly, questioned is appropriateness of HRT agentsin the era when high-dose Premarin and Provera both used in WHI HRT trials are agents considered more toxic than the newer regimens based on lower hormone dose or nonoral use. Overall, when all women are analyzed, the WHI fi rst HRT trials showed more CHD, strokes, and thromboembolism. Also, higher breast cancer incidence rates were seen in the fi rst WHI HRT trial but not in the second trial. These hazards were highlighted in most WHI publications since 2002. However, if one takes the results for younger women -those aged 50-60 or those <10 years since menopause -the results look different (Table 24.3 ) . Table 24 .3 shows that relative risks for total mortality of women aged 50-59 at the time of enrollment to the fi rst WHI HRT trial is substantially reduced, with a statistically signifi cant 30% reduction of all-cause mortality (HR = 0.70 ; 95% CI : 0.51-0.96). Similarly, CHD for women aged 50-59 was not adversely affected (HR = 0.93, 95% CI : 0.65-1.33), and for women <10 years since menopause, the CHD showed a nonsignifi cant reduction, by 24% (HR = 0.76 , 95% CI: 0.50-1.16). Importantly, incidence rates of strokes were also not affected in the younger women, with hazards moderately elevated but without statistical signifi cance (HR = 1.13, 95% CI: 0.73-1.76). It was only in the older age-groups, age 60+, that stroke hazards were increased more substantially (Table 24. 3 ). However, even in the elderly agegroup, the absolute rates of strokes in association with HRT are considerably lower than the risks due to potentially avoidable life style factors such as smoking, lack of exercise, overweight, and/or alcohol consumption. Specifi cally, the actual rates of strokes taking women of all ages from the fi rst WHI trial -fi gures which do matter when individual decisions are made for a given woman suffering with menopausal symptoms -were 0.19% in the HRT group vs. 0.11% for women in the placebo group, for an absolute increase of +0.08% of stroke incidence. The corresponding increase in women in 50-59 age-group is +0.02%. Taking all participants in the fi rst WHI HRT trial, breast cancer incidence rates were increased nonsignifi cantly (when HR = 1.26 , 95% adjusted CI: 0.83-1.92). However, Table 24 .4 shows that 74.1% of all women who were without the past HRT use prior to the study enrolment had no increase of invasive breast cancer (HR = 1.06). It was only in women with past hormone intake and in particular for those with >5 years that the HRT was associated with a signifi cant increase in breast cancer rate (Table 24 .4 ). With the follow-up duration of patients enrolled in the fi rst WHI HRT trials, further interesting observations were noted for CHD [91] . While in the fi rst years of the trial there was a fl uctuation of cardiac hazards (ranges 0.99-1.78), in the subsequent follow-up (years of 6-8+), the hazard rates were reduced, with CHD reduced by 22% (HR = 0.78). Similarly, for strokes, in years 1-3, the hazard rates fl uctuated between 0.99-1.79; however in years 6-8+, the stoke rates were reduced by 34% (HR = 0.66) [1, 73, 76] . The second WHI trial was halted in 2004, due to the perceived excess of overall hazards over benefi ts. However, the analysis restricted to the age-group 50-69 (Table 24 .5 ) showed a 44% reduction of CHD events approaching statistical signifi cance ( HR = 0.56, 0.30-1.03). This compares, also in this trial, to much less CHD protection of HRT for women aged 60-69 (HR = 0.92) and basically no effect among women aged 70-79 (HR = 1.04). A nonsignifi cant increase of thromboembolism was seen, with HR = 1.22, 1.31 and 1.44, respectively, for ages 50-59, 60-69, and 70-79. As with the fi rst WHI trial, strokes were also not increased among young women aged 50-69 (HR = 1.08, 95% CI: 0.57-2.04), although the rates were increased nonsignifi cantly among participants aged 60-69 and 70-79 (HR = 1.65 and 1.25, respectively, Table 24.5 ) . Surprisingly, and in contrast to the fi rst WHI trial, breast cancer rates after CEE alone were not increased, and (Table 24 .6 a-c ) outlines that most subsets of the second WHI trial actually experienced a substantial reduction of invasive breast cancers in association with CEE. That reduction reached statistical signifi cance in the sizable subset of women without underlying breast cancer risk factors (see below). Also confi rmed in this trial were reductions of colorectal cancer, with the rates reduced more so in younger women aged 50-59 (HR = 0.59), with less CRC benefi t with increasing age (HR = 0.88 and 2.09, respectively for age-groups 60-69 and 70-79, respectively). Bone fractures, among all participants (except the women 60-years old, many over the age of 70. These more elderly women are therefore poor candidates to initiate HRT. Second, that women without a history of signifi cant risk factors for breast cancer may have a signifi cant protection for subsequent incidence of invasive breast cancer using estrogen alone, without progestin. Third, this review based on the WHI HRT trials shows that in younger women the decision-generating algorithm for HRT use will be substantially different than in more elderly postmenopausal women, not only as the intensity of menopausal symptoms is typically more severe, but also as most HRT-associated hazards are substantially lower, and benefi ts higher. Thus, as identifi ed in this chapter, the WHI trial data when applied to appropriate candidates , do confi rm some of the conclusions generated in the past decades of large observational studies with long follow-up: that HRT will improve the quality of life in most women entering menopause, and in addition may have allcause mortality benefi ts most evident among younger women aged 50-69. After estrogen alone, HRT may be associated with reduced breast cancer rates. Thus, in well selected candidates, HRT-associated hazards are small, and have to be viewed in perspective with quality of life benefi ts of HRT due to reduction of menopausal symptoms for women suffering these symptoms, and in view of other avoidable risk factors. There is no doubt that HRT issues remain complex, even after a thorough research as demonstrated in this chapter. Our knowledge of hormones and their impact on benefi t and hazard in humans continues to evolve. It would be fair to conclude that the WHI trials, as did the prior observational studies, contributed greatly by generating large amounts of essential data. These indicate that no single answer with regard to HRT recommendations do exist for all women. When considering HRT, individual heterogeneity based on age and the known risk factors for each condition affected by HRT will need to be taken into consideration. To add to the complexity and thus challenges of clinicians and women dealing with HRT, these factors are infl uenced by an array of largely unknown genetic predispositions affecting most HRT-associated conditions. It is very likely, as with most therapies of human conditions, that some women will derive a great deal of benefi t from HRT with few hazards; some will have some benefi t, and some none. Some even in the younger age category, if genetically predisposed, may suffer more hazards than benefi ts -the inevitable outcome of most classes of medications for some individuals. It remains without saying that all HRT benefi ts and hazards will have be to monitored on an on-going basis, with women and their practitioners kept fully informed at all times about the complex HRT therapy as its research continues to evolve. This issue is important, primarily in view of the fact that the WHI trial reanalyses as illustrated in our review confi rm that the perception of the HRT facts and the recommendations of today may not necessarily apply to tomorrow. Accepting an HRT program is ultimately the decision of each individual woman, who should make the fi nal decision, at times accepting small hazards for a substantial improvement in the quality of her life. The important condition in this decision process, however, is a full knowledge of all facts -those fully emphasized as well as those in small print. This is the goal of this review. The collaborative Group on Hormonal Factors in Breast Cancer collected and reanalyzed individual data on over 50,000 breast cancer cases and over 100,000 healthy women, as seen from 51 different epidemiological studies OG HRT [7] . It thus represented, until the year 2002, the most comprehensive overview of HRT ever published. The results of this meta-analysis were that for current or recent HRT users, when compared to nonusers, the relative risk for breast cancer was increased, with Hazards rates (HR) = 1.023/year, translating into a 2.3% increase of annual incidence of breast cancer. The overall risk increased with the duration of HRT use, so that in users of over 15 years, cumulative Hazard rates (HR) of 1.3 for incidence was observed. A 2002 review on the subject [8] , summarized these results and indicated that while a breast cancer risk increase has been observed, it should be assessed in relation to other epidemiological causes for breast cancer risk increase [9] . For instance, much higher rates in the range of 40-60% (HR = 1.4-1.6) have been reported due to other conditions such as moderate alcohol consumption [10] , absence of exercise [11, 12] , nulliparity, or high caloric intake [13] . The past HRT policies are also to be viewed in conjunction with data showing that in the population of women at large, up to 45% mortality is from cardiovascular disease and less than 5% from breast cancer. Thus, the moderate increase of breast cancer rates related to HRT will result in lesser absolute added risk than the cardiovascular mortality -considered in the years before 2002 to benefi t from HRT. Thus, the breast cancer hazards were acceptable for those women who suffer with severe menopausal symptoms, as in absolute terms, a small increase in the risk of breast cancer would be tolerable because the overall risk benefi t ratio would favor HRT. Indeed, all-cause mortality was improved by HRT, shifting the HRT equation in favor of overall benefi ts [3, 14] . The surprisingly short time period of recorded breast cancer events in relation to HRT -i.e., fl uctuations of breast cancer rates are seen within 1-2 years of HRT start or discontinuation -negate the HRT effect on carcinogenesi s and shift the emphasis to tumor promotion . These data are obtained not only from the past observational trials [15] , but also from the recent WHI HRT analyses [1] and related epidemiology reports [16, 17] . The promotional rather than carcinogenic mechanisms would implicate the HRT effect primarily on the preformed malignant lesions, with resulting increased cell division of hormone sensitive clones. The accelerated formation of microcalcifi cations, and subsequently, earlier diagnosis through mammogram or physical examination would follow. In those women, however, the carcinogenic events presumably had occurred earlier and most likely with no connection with HRT. Thus, the promotional effect of HRT should be distinguished from any causative role. These data also indicate a possibility that in the absence of HRT, the same tumor could develop later in time, but would present with a biologically more aggressive disease, and at a more advanced stage clinically. The data from the old literature described in either bacteria [18] or in cancer clones [19] indicate that with time, as a result of random ongoing mutations during cellular divisions in either bacteria or malignant tumor clones, there will be an exponential increase of mutants with aggressive, therapy-resistant phenotypes. Thus, tumors diagnosed later in their history would be more aggressive and less sensitive to hormonal, chemotherapy, or radiation treatments [19] . Several large observational studies indeed confi rmed lower tumor aggressiveness in HRT users [5, [20] [21] [22] [23] [24] [25] [26] , which may explain the observations of reduced breast cancer mortality in HRT users compared to nonusers, despite increased incidence [5, 21, 22, 24] . For instance, Grodstein et al. reported in the update of Nurse's health study [5] a signifi cant reduction of breast cancer mortality (adjusted RR > 0.76) in women taking HRT for less than 10 years, despite the moderately increased breast cancer incidence rates (RR > 1.09-1.4). In addition, the HRT users in this study had a signifi cant reduction of overall all-cause mortality (adjusted RR > 0.63), with a similar survival improvement in cases with a strong family history of breast cancer (RR > 0.65) or in cases who had HRT after oophorectomy (RR > 0.71). Chlebowski et al. however were unable to confi rm these observations from the recent WHI trial [27] . Estrogen plus progestin increased the rates of total and invasive breast cancers compared with placebo (199 vs. 150 cases; HR, 1.24, P > 0.003). The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean 1.7 cm vs. 1.5 cm, respectively; P > 0.04) and were at more advanced stage (regional/metastatic 25.4 vs. 16.0%, respectively; P > 0.04) compared with those diagnosed in the placebo group. In favor of Nurse's health study results, however, are data from the second WHI trial showing overall, reduced breast cancer incidence rates, after the use of HRT with estrogen alone (Tables 24. 2 -24.4 ) . In this trial, women were randomized to estrogen (conjugated equine estrogen, CEE) without progestin, vs. placebo. In women with CEE, the incidence rates of invasive breast cancer were signifi cantly reduced in the majority of participants (80%) without the past history of benign breast disease or without a fi rst-degree relative with breast cancer, or similarly, signifi cantly reduced were the breast cancer rates in participants without the past use of estrogens or progestins [28] . In view of these new data, the HRT association with breast carcinogenesis and biology is becoming more complex. The long-term follow-up outcomes of the WHI HRT trials with emphasis for a possible protective role of estrogen-alone on the rates of both breast cancer incidence and mortality . Ravdin et al. recently reported a possible link between decreasing breast cancer incidence rates -as documented in U.S. -and reduced HRT use after the year 2002 -the year when the fi rst results of the WHI HRT were published indicating excess of hazards over benefi ts. While comments regarding this association have been raised [29] , a careful evaluation of not only incidence but also of mortality rates will be required, in order to clarify the important interactions of HRT use and breast cancer outcome. Several longitudinal studies of postmenopausal women have shown a strong effect of estrogen on lipid metabolism [30] , resulting in reduction of the plasma low density lipoproteins (LDL) and an increase in the high density lipoproteins (HDL). As the HDL/LDL ratio is one of the best predictors of future cardiovascular outcomes [31] , it is plausible that in the long-term there could be signifi cant benefi t of estrogen use due to reduced atherogenesis. This mechanism may explain the long-term HRT benefi ts in the primary prevention of cardiac events [32] [33] [34] , which exceeds its shortterm hazards attributed, in all likelihood, to the HRTassociated increase in the rates of thromboembolism. The most convincing evidence for the benefi cial effects of HRT on lipid metabolism comes from the Postmenopasual Estrogen/Progestin Interventions, the PEPI trial [15] , showing a signifi cant reduction, at 3 years follow-up, of LDL-cholesterol (LDL-C) in HRT users, with HDL-cholesterol (HDL-C) levels increased compared to pretreatment levels. The PEPI trial is the fi rst placebo controlled randomized study to document that estrogen either alone or in combination with progestin signifi cantly improves the serum lipid profi le, thus confi rming number of reports from nonrandomized studies. The results of the study also suggest that the effect on lipids may be comparable between estrogen alone and estrogen/progestin combination, particularly, using the newly available micronized progestin. The signifi cance of these data for prevention of cardiac mortality is yet to be determined. The long-term followup of the ongoing randomized WHI trial [35] will provide a defi nitive answer to this issue. The PEPI trial is particularly important in view of other studies in which a modest incremental HDL-C increase (4-5 mg/dL) was associated with a 20-25% reduction of CHD. These fi ndings are in line with the long-term follow-up of the observational HRT studies. More recently, Darling et al. studied HRT and simvastatin in comparative lipid analyses [36] documenting that while the effect of simvastatin was greater than that of hormone therapy with regard to LDL-C reduction, the plasma concentration of Lp(a) lipoprotein -a known risk factor for CHDdecreased with hormone therapy (mean decrease, 27%; 95% confi dence interval, 20-34%), but not with simvastatin [36] . Other mechanisms indicate possible favorable vascular effect of estrogen. Thus, uptake of LDL is reduced by coronary arteries of monkeys fed with atherogenic diets randomized to estrogens [37, 38] . Also, estrogens are known to modulate the prostacycline-mediated vasodilating effect [39] and interact with calcium channel blockers [40] and Lp(a) [30, [41] [42] [43] [44] . Furthermore, estrogen therapy signifi cantly increased the catabolism of LDL [45] ; estrogens also lowered the tissue concentration of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1, yet another mechanism that may be known to reduce atherogenesis [46] . Another line of evidence suggestive of a protective effect of estrogens involves studies of direct effects of HRT on vessel walls. Estrogen receptors (ER) are present in the muscularis layer of arteries, and improved blood fl ow through the coronaries, documented upon estrogen exposure, is probably ER mediated [47, 48] . Consistent with these observations is the fi nding that in ovariectomized female monkeys, estrogen protected vessels from vasoconstriction after exposure to acetylcholine [49] . In other trials estrogen exposure led to a reduction of systemic vascular resistance [47, 49, 50] . Similar observations were also subsequently made in postmenopausal women [51, 52] , where in one study estrogen reduced arterial impedance and vascular tone after 6 weeks of treatment [53] . Other investigators confi rmed increased hyperemic response and vasodilatation after estrogen administration [54] . Pines et al. found improved fl ow velocity and improvement of the mean cardiac ejection fraction in estrogen users, as measured by aortic sonograms [55] . Finally, estrogen was found, in a placebo-controlled trial [55] , to improve performance of women on a treadmill and to decrease symptoms of coronary artery disease [56] -effects which may be explained by the above-outlined estrogen effects on vessel vasculature. Most population-based studies examining HRT in the primary prevention of cardiac events have shown a strong risk reduction in users with cardiac mortality rates reduced between 20-60% [52, [57] [58] [59] [60] [61] [62] . The magnitude of the HRT effect is similar between case-control and cross sectional studies [50] . While several hypotheses were offered to explain these observations, the most favored concern the favorable effects of estrogen on lipid metabolism [32, 38, 56, [63] [64] [65] and endothelial function [40, 47, 51, 53, 66, 67] . There is a possible bias due to the participation in the HRT cohort of healthier women, who may also undergo cardiac screening more effectively [60] as none of these studies were randomized . While these biases may exist, they do not fully account for the strong association of HRT with improved lipid profi le and estrogen favorable vessel effect, both emerging as long-term surrogates for improved cardiac outcomes [32, 57, 62, 68] . Once the atherosclerotic plaques and/or coronary occlusions produce clinical symptoms, therapy is usually not curative. Indeed, most interventions for the secondary prevention are expected to relieve symptoms, slow down progression, but not to completely reverse the lesions. Although the favorable lipid changes are seen early, the effects of HRT on the cardiovascular outcomes may take decades. It has also been predicted that, compared to its effect in primary prevention, hormonal therapy will have lower impact once the process of atherosclerosis has already advanced. Indeed, the only randomized trial of secondary prevention, the HERs study, showed little cardiovascular protection. HERS trial was fi rst published in the late 1990s [69] and updated recently [70] . A total of 2,763 women, 65 years or older (mean age: 66.7 years), with a history of myocardial infarction, were randomized in a double-blind placebo-controlled design, to be treated with either HRT (conjugated equine estrogen, CEE, 0.635 mg, plus daily medroxyprogesterone acetate, MPA, 2.5 mg/day) or placebo. At 4 years of follow-up, the authors reported no signifi cant differences in deaths from CHD or myocardial infarction between the two arms (RR > 0.99, 95% CI: 0. 80-1.22) . The lack of an overall effect was seen despite a reduction of LDL levels and increase of HDL levels. More women in the HRT group had thromboembolic events (TEs) (RR > 2.89, 95% CI 1. 50-5.58 ) and gallbladder disease (RR > 1.38, CI 1.00-1.92). There was no difference in cancer rates or overall mortality. For the latter two parameters, however, the power of the study was greatly limited. The authors' conclusion was that HRT does not reduce the overall rate of CHD in postmenopausal women with established coronary disease, and that the risk of thromboembolism and of gall stones is increased. Examining the interaction of relative risk over time, interesting trends were observed. In the fi rst year of the study, more cardiac events were seen in the users (RR > 1.52). In the second year, however, that increase was not seen any more, with the incidence of cardiac mortality or of the nonfatal infarctions among users vs. nonusers being equal (RR > 1.0). Subsequently, in years three and four, the risk of these events in HRT users was actually reduced (RR of 0.87 and 0.67, respectively), consistent with the degree of risk reduction seen in long-term follow-up observational primary prevention studies. The updated 2002 study showed, after the follow-up ranging 4-8 years, overall, no effect (RR > 0.99-1.0). However, the proportions of patients with at least 80% adherence to HRT declined from 81% in the fi rst years, to only 45% in the year 6 [70] . Overall, these data indicate that in women with advanced atherosclerosis, the HRT may temporarily increase the morbidity, or even mortality, but in longterm, HRT plays no role in improving cardiac outcome once arterial occlusions occur. However, even in this population, HRT showed favorable effects on serum lipids, similar to the results of the primary prevention trials. The increased event rate in the fi rst years in the cohort of elderly women with established atherosclerosis exposed to HRT could be due to initial precipitating events such as thromboembolism or minor blood pressure fl uctuations, not uncommon in the population of patients with advanced vessel disease. These complications would be, however, of lesser consequence in younger women without coronary disease. In these women, not only substantial improvements in the quality of life, but in long-term follow-up, also benefi cial effect on lipid metabolism, and thus cardiac disease prevention, can be anticipated. The analyses of the WHI HRT trials mirror these observations. Manson et al. [71] reported in the WHI ancillary substudy of 1,064 women aged 50-59 years at randomization of the second HRT trial (women with hysterectomy) results of estrogen (0.625 mg/day) impact on coronary-artery calcium scores as measured by computed tomography. The CT scans were carried out at 8.7 years after randomization, with the coronaryartery calcium scores measured at a central reading center without knowledge of randomization status. The results showed the mean coronary-artery calcium score after trial completion to be signifi cantly lower among the women aged 50-59 receiving estrogen than among those receiving placebo ( P > 0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores in the group with at least 80% adherence to the study (estrogen or placebo) were reduced by 36% (HR = 0.64, P > 0.01). Authors concluded that among women 50-59 years old at enrollment, the calcifi ed-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. Our review of the WHI data [72] in women below age 60 shows early trends toward reduced CHD hazards (Table 24. 3 ), with a signifi cant all-cause mortality reduction in women aged 50-59. It is only among women over 60 and in particular in those over 70 that a nonsignifi cant trend is seen for increased CHD events. These data mirror the HERs trial: HRT has no impact on cardiac events in elderly women and failure of HRT in secondary prevention -yet they attest to the HRT potential benefi t in primary prevention in women <60. Clarkson et al. published a series of analyses where they tested in primates the impact of immediate vs. delayed administration of estrogen in conjunction with atherosclerogenic diet [33] . Compared to controls, HRT showed a substantial reduction of the atherosclerotic plaques at the time of autopsy -but only if administered at the same time as atherogenic diet. Delayed HRT administration, late into starting the high-fat diet, had outcomes similar to animals who never received HRT. More recently, Grodstein et al. [74] have prospectively examined the relation of HRT to CHD, according to the timing of hormone initiation, relative to age and time since menopause. Participants were postmenopausal women in the Nurses' Health Study, with follow-up extending from 1976 to 2000. The study showed that women beginning HRT near menopause had a signifi cantly reduced risk of CHD -by 36% for estrogen alone (RR > 0.66, 95% CI: 0.54-0.80), and 28% for estrogen with progestin (RR > 0.72, 95% CI: 0.56-0.92). On the other hand, in the elderly women, at least 10 years after menopause -a subgroup demographically similar to those in the WHI -they found no signifi cant relation between HRT and CHD among women who initiated therapy (HR = 0.87, 95% CI: 0.69-1.10 for estrogen alone; RR > 0.90, 95% CI: 0.62-1.29 for estrogen with progestin). These data, same as the HERs trial [70, 75] confi rm that no cardio-protective HRT effects are demonstrated when HRT is delivered after a more prolonged exposure of estrogen defi cit state, and after the atherosclerotic plaques have formed. Willet and Colditz, the principal authors of the Nurse's Health Study (NHS) -which showed substantial and signifi cant cardioprotection by HRT -summarized the differences between the two trials recently [76] . In the WHI trial, women were eligible up to the age of 79 years, whereas in the NHS -and most observational studies showing cardiac benefi ts -more than 80% of the women initiated HRT use within 10 years of menopause. Second, the NHS included women with much longer follow-up who had already been using hormone therapy for years. Thus, the effect mediated by improved lipid profi le could have emerged in the NHS, but less likely in the WHI trial, with much shorter time of both HRT exposure, and follow-up duration. Third, as in the HERS trial [69] where a transient risk elevation soon after HRT start is followed by risk reduction, the increased CHD risk is limited to the short interval soon after the initiation of HRT even in the WHI trials: For estrogen plus progestin, the relative risks for CHD were 1.68 for <2 years, 1.25 for 2-5 years, and 0.66 for 5 or more years [1, 76] . Prentice et al in the commentary on the WHI HRT trial [77] confi rmed that when stratifi ed by year from initiation of hormone therapy, the fi ndings for CHD from the Nurses' Health and the WHI trials did not differ appreciably. Hence the reanalysis of the WHI data according to age of participants -refl ecting the "timing" of HRT start -and length of follow-up, may after all support the decades-long HRT research, which confi rms both biochemical and lipid surrogate protection, but also a reduction of cardiac events in association with HRT. Estrogens are known to increase blood clotting, due to their effects on several clotting factors including fi brinogen, factors VII, X, and antithrombin III [78] . As a result, HRT is known to moderately increase the incidence of thromboembolism with HR ranging from 1.1-4.00 [3, 58, 69, [79] [80] [81] . However, despite these trends, no increase in mortality with HRT has been reported [82] . Abnormalities of clotting factors, however, may contribute to the HRT-associated complications [83] [84] [85] [86] [87] . It has been shown that a genetic variant of Factor V Leiden (especially the Factor V G1691A variant) is responsible for the majority of TEs in users of birth control pills [84] . In women with established coronary disease, as reported in two clinical trials, the Leiden mutation was present in 8 (16.7%) of 48 cases with TEs compared with only 7 (6.3%) of 112 without TEs. In women with the factor V Leiden mutation who were treated with HRT, the estimated absolute incidence of TEs was 15.4 in 1,000 per year compared with 2.0 in 1,000 per year in women without the mutation who were taking a placebo (HR = 7.7) [87] . Van de Water [85] confi rmed that in patients with myocardial infarction, the frequency of factor V Leiden mutation was 14.6% in patients <50 years old in the study group compared with 3.6% in patients in the control group [83] . With regard to strokes, a meta-analysis of 3,399 patients with stroke [86] showed a statistically signifi cant association with factor VG 1691A variant (Leiden) [86] . The problem of thrombembolism in HRT users may be further complicated by other confounding factors, especially smoking. In a group with high Factor V or high Factor VII levels, smoking or high blood pressure increased the relative risk for myocardial infarction up to 50-fold [88] . Thus thromboembolism in the fi rst years of HRT exposure could be responsible for vascular events leading to strokes and CHD, with genetic factors affecting coagulation in the fi rst time exposure raising the risk. The fi rst exposure to hormones will thus select the individuals prone on genetic grounds to thromboembolism, increased by other risk factors such as age, smoking, or hypertension. Subsequently, women continuing on HRT would experience fewer TEs, and may benefi t, in long-term, from HRT. The "timing" hypothesis (see below) suggests that more adverse CVS events are related to thromboembolism in the fi rst years of HRT exposure, followed by reduced hazard rates. This is confi rmed in most observational trials by the dynamics of the HERs study, which is now also emerging in the WHI reports [1, 73, 76] . These data indicate that preventative measures in individuals prone to TE selected for HRT have to be considered. These should include interventions ranging from life style changes (i.e., emphasis on regular exercise, less sedentary activities, smoking cessation, reduced alcohol intake), to more targeted anti-TE interventions such as regular dose ASA (aspirin) -or in extreme cases where HRT is clearly required due to severity of menopausal symptoms, low doses of warfarin. This study confi rmed that intranasal administration of 300 m g/day estradiol was at least as effective as oral administration of 2 mg/day estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the fi rst-pass effect. Intranasal and transdermal 17 b -estradiol combined with vaginal progesterone gel as a continuous HRT caused a similar decrease in vasomotor symptoms and did not have any signifi cant effect on vaginal maturation index after 12 weeks of treatment in this study population. Results of this study have shown that intranasal administration of 17 b -estradiol (E2) is at least as effective as oral administration of 2 mg/day E2 in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the fi rst-pass effect. Also, it is well-tolerated and provides a reproducible, easily adjustable dosing mechanism. Sustained-release vaginal progesterone gel ensures high endometrial protection and avoids the side-effects and possible risks linked to oral progesterones. A third study documenting that intranasally administered 17 b -oestradiol is signifi cantly better than placebo in reducing menopausal symptoms, and is similar to that of oral oestradiol. It was well-tolerated. Intranasal administration avoids fi rst-pass metabolism and provides a reproducible, easily adjustable dosing mechanism that represents a new option for HRT. Pulsed estrogen therapy, achieved by intranasal estradiol 150 m g/day and 300 m g/day, signifi cantly reduced the incidence of moderate to severe vasomotor symptoms, compared with placebo. The 300-m g/day dose demonstrated a greater and more rapid therapeutic effect, with no clinically signifi cant difference in tolerability, compared with the 150-m g/day dose, and therefore offers the best effi cacy/safety ratio when initiating treatment with intranasal estradiol. Transdermal estradiol and a twice-weekly administration of the vaginal progesterone gel Crinone constitutes a new, viable HRT regimen. It represents a practical option for a no-bleed treatment, ensuring both high endometrial protection and the inherent safety linked to administrating physiologic hormones nonorally. This study also shows that vaginal progesterone can be used to maintain normal uterine morphology with a decrease in systemic side effects and when used in combination with estrogen without bleeding. Women using unopposed estrogen replacement therapy (ERT) (exclusive ERT use), even for 25 years or longer, had no appreciable increase in risk of breast cancer. Ever users of HRT (includes HRT users who also had used ERT) had a 1.7-fold increased risk of breast cancer, including a 2.7-fold increased risk of invasive lobular carcinoma. Risks and benefi ts of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial Estrogen use and all-cause mortality. Preliminary results from the Lipid Research Clinics Program Follow-Up Study Hormone therapy to prevent disease and prolong life in postmenopausal women Age-matched all-cause mortality impact of hormone replacement therapy: applicability to breast cancer survivors Postmenopausal hormone therapy and mortality The Women's Health Initiative: lessons learned Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer Hormone replacement therapy in patients with a prior breast cancer history: a critical review Rating the risk factors for breaat cancer A metaanalysis of alcohol consumption in relation to risk of breast cancer Physical exercise and reduced risk of breast cancer in young women A prospective study of recreational physical activity and breast cancer risk Relationship between hormone replacement therapy, socioeconomic status, and coronary heart disease Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial The decrease in breast-cancer incidence in 2003 in the United States Breast cancer after use of estrogen plus progestin in postmenopausal women Mutations of bacteria from virus sensitivity to virus resistance A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate Prognostic characteristics in breast cancers after hormone replacement therapy Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients Low biologic aggressiveness in breast cancer in women using hormone replacement therapy Estrogen replacement therapy and breast cancer survival in a large screening study Postmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study Infl uence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy A decline in breast-cancer incidence Benefi cial effects of hormone replacement on lipoprotein(a) levels in postmenopausal women Treatment of dyslipidemia: room for improvement? Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study Experimental effects of estrogens and progestins on the coronary artery wall Rationale for hormone replacement therapy in atherosclerosis prevention Commentary on the Women's Health Initiative Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys Decreased in vitro production of 6-keto-prostaglandin F1 alpha by uterine arteries from postmenopausal women Cardiovascular protection by oestrogen-a calcium antagonist effect? Oral 17b-estradiol continuously combined with dydrogeterone lowers serum lipoprotein(a) concentrations in healthy postmenopausal women Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection Guide to preventive cardiology for women. AHA/ACC Scientifi c Statement Consensus panel statement Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause High-density lipoprotein-2 and hepatic lipase:reciprocal changes produced by estrogens and norgestrel Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease Sex steroid hormone receptors in the cardiovascular system Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women Estrogen modulates responses of atherosclerotic coronary arteries The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies arterial status, and postmenopausal women Angina and normal coronary arteries in women: gynecologic fi ndings The effects of hormone replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic fl ow Oestrogens and the heart Postmenopausal estrogen therapy and cardiovascular disease Estrogen and coronary heart disease in women Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators Postmenopausal estrogen and progestin use and the risk of cardiovascular disease Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women The role of hormone replacement therapy in the prevention of postmenopausal heart disease Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, highdensity lipoprotein subfractions, and apolipoprotein A-I Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins Cardiovascular pharmacology of hormone replacement therapy Estrogen receptors and effects of estrogen on membrane electrical properties of coronary vascular smooth muscle Benefi cial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease Menopause and heart disease. A review Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/ progestin Replacement Study (HERS) Research Group Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II) Estrogen therapy and coronary-artery calcifi cation Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Estrogen replacement in menopausal women: recent and current prospective studies, the WHI and the KEEPS Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation Estrogens should not be initiated for the secondary prevention of coronary artery disease: a debate Re: combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease Haemostatic function and ischaemic heart disease Oral contraceptives, smoking, and other factors in relation to risk of venous thromboembolic disease Hormone replacement and cancer Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study Estrogen replacement therapy and the risk of venous thrombosis HT and WHI: The Baby and The Bathwater. Personal communications Effects of oral contraceptives on hemostasis and thrombosis Prevalence of factor V Leiden and prothrombin variant G20210A in patients age <50 years with no signifi cant stenosi at angiography three ot four weeks after myocardial infarction Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease Coagulations factors I, V, VII, and X, prothrombin gene 20210G-A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial Failure of estrogen plus progestin therapy for prevention Risks and benefi ts of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial Shifting breast cancer trends in the United States A decline in breast cancer incidence A decline in breast-cancer incidence Incidence of breast cancer in Norway and Sweden during introduction of nationwide screening: prospective cohort study Breast cancer (BrCa) mortality reduction in the western world: therapeutic versus diagnostic interventions. Implications for cancer care organization processes Clinical equivalence of intranasal and oral 17beta-estradiol for postmenopausal symptoms A prospective randomized comparative study of the effects of intranasal and transdermal 17 betaestradiol on postmenopausal symptoms and vaginal cytology Effi cacy and acceptability of intranasal 17 beta-oestradiol for menopausal symptoms: randomised dose-response study Effi cacy and tolerability of pulsed estrogen therapy: a 12-week double-blind placebo-controlled study in highly symptomatic postmenopausal women Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens Relationship between long durations and different regimens of hormone therapy and risk of breast cancer Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women UK and USA breast cancer deaths down 25% Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population Low-dose esterifi ed estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women et al A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease The Kronos Early Estrogen Prevention Study