madman
Super Moderator
Abstract
A large body of scientific research accumulated over the past twenty years documents the cardiovascular (CV) benefits of estradiol (E2) and progesterone (P4) in reproductive-aged women. In contrast, accelerated development of CV disease (CVD) occurs in the absence of ovarian-produced E2 and P4. Hormone replacement therapy (HRT) with E2 and P4 has been shown to cause no harm to younger menopausal women. This robust scientific data supports a reconsideration of the prescriptive use of E2 and P4 as preventative therapeutics for the reduction of CVD, even without additional large-scale studies of the magnitude of the Women’s Health Initiative (WHI). With the current expanded understanding of the critical modulatory role played by E2 on a multitude of systems and enzymes impacting CVD onset, initiation of HRT shortly after cessation of ovarian function, known as the “Timing Hypothesis”, should be considered to delay CVD in recently postmenopausal women.
Introduction
Despite the high incidence of cardiovascular (CV) complications experienced by a large portion of the aging female population, major CV societies do not currently support estradiol (E2) and progesterone (P4) use for the prevention or treatment of CV disease(CVD). There is, however, a large body of research confirming that a) loss of ovarian production of E2 and P4 is associated with detrimental vascular and myocardial changes1 and b) postmenopausal (PM) use of human bioidentical transdermal E2, as a patch or gel, and of oral P4, is safe (Figure 1).2
Prior to the Women’s Health Initiative (WHI), the results of which were published over twenty years ago, HRT was promoted by physicians, but support for HRT plummeted after the WHI results were publicized widely. Fortunately, its conclusions were reassessed and the data is now recognized as showing significant benefits to women in their 50s.3 Additionally, it is now more widely recognized that the results of the WHI cannot be applied to hormone formulations other than those used– oral-conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).3-5 An additional problem with the WHI was its inclusion of a preponderance of study subjects who were many years postmenopausal, including many with pre-existing medical conditions.6-8 Despite current understandings of the flaws of the WHI and the robust data on the many important functions of E2 supporting CV health, little interest exists for the prescriptive use of safer hormonal formulations and delivery modalities for the use as preventative medicine in cardiology. And the “Timing Hypothesis (initiation of HRT is beneficial only when begun within 10 years of last menstrual period),” though now widely acknowledged, has only resulted in the half-hearted acceptance of short-term, low-dose HRT solely for the amelioration of hot flashes and night sweats.9
In the years since the WHI, a small number of randomized, prospective, placebo-controlled trials were conducted, and the results were published. Each study adhered to the prevailing opinion that the smallest possible dose of estrogen was best. Fortunately, different forms of estrogen and progestins from those used in the WHI were included in subsequent studies, but transdermal E2 and oral micronized progesterone were not consistently the forms of hormones used. It is generally recognized now that those are the preferred forms of the hormones to be used for HRT.10 The use of various types of hormones and delivery modalities, the smaller numbers of study subjects, the shorter duration of the studies, as well as of dosing regimens used which resulted in low serum levels of E2, may all have contributed to the study outcomes that have not demonstrated CV benefits with the use of HRT.11 Although not clearly showing large CV benefits, the data from the major subsequent studies- the Kronos Early Estrogen Prevention Study (KEEPS) and Early Versus Late Intervention Trial with Estradiol (ELITE) studies, both showed no harm from HRT, with improvement in quality of life (QoL), and of vascular benefits for younger, recently PM women in the ELITE data, which similar to the WHI, was supportive of the “Timing Hypothesis.” 12, 13
Many observational studies have consistently shown the safety and health benefits of menopausal hormone use.14 A pervasive fear of HRT remains, and many patients and their physicians refrain from using HRT, when utilized, the prevalent use is for symptom reduction and not as part of a strategy for achieving healthy longevity and CV optimization, with most users choosing the smallest possible doses of E2 for the shortest possible time, and avoidance of cyclical P4 dosing.15
This review acknowledges that there are no large, prospective, placebo-controlled clinical trials utilizing physiologic and rhythmic dosing of human bioidentical hormones, designed to evaluate CVD outcomes. But as mortality and morbidity among women from CVD events remains high, practicing CVD specialists should consider the safe use of HRT, prescribing physiological doses of transdermal E2 and oral P4, as a modality to maintain a healthy, highly functional CV system for the promotion of healthy longevity. This article provides the framework to utilize human, bioidentical HRT as an integral component of preventive cardiology, including a general protocol for the prescriptive use of HRT for women.
*Overview of HRT Studies in PM
*HRT in PM Women for Prevention of CVD Revisited
*Effects of E2 in Female
Conclusions
Although there is a deficiency of prospective, placebo-controlled studies on the use of human bioidentical HRT in PM women, this should not dissuade general clinicians and specialists in CVD from recommending HRT at least to the majority of their young, recently PM women patients, for maintaining ideal long-term CV health. The robust safety data of the KEEPS and ELITE trials, as well as many observational studies, combined with the limited but definitive vascular benefits as shown in the ELITE study, and in many rodent and primate studies, in conjunction with the abundance of basic scientific data, outlining the mechanisms by which E2 protects CV structures, justifies the recommendation to provide young PM women with physiologic, rhythmic HRT. The goal is to replicate the hormonal levels and rhythms of a healthy reproductive-aged woman. A proactive, rather than a reactive, approach to CV well-being is the desired therapeutic strategy. With the prevention of CVD as a top priority, HRT is a safe and potentially highly beneficial therapeutic modality for appropriately selected women. Large-scale studies using better HRT preparations would be ideal, but these are not likely to be on the horizon anytime soon. Therefore, clinicians should consider the preponderance of evidence already available for recent PM women, based on the timing Hypothesis, and at the same time weigh the potential benefits vs risks of HRT for other PM women, using the superior, safer HRT preparations currently available.
A large body of scientific research accumulated over the past twenty years documents the cardiovascular (CV) benefits of estradiol (E2) and progesterone (P4) in reproductive-aged women. In contrast, accelerated development of CV disease (CVD) occurs in the absence of ovarian-produced E2 and P4. Hormone replacement therapy (HRT) with E2 and P4 has been shown to cause no harm to younger menopausal women. This robust scientific data supports a reconsideration of the prescriptive use of E2 and P4 as preventative therapeutics for the reduction of CVD, even without additional large-scale studies of the magnitude of the Women’s Health Initiative (WHI). With the current expanded understanding of the critical modulatory role played by E2 on a multitude of systems and enzymes impacting CVD onset, initiation of HRT shortly after cessation of ovarian function, known as the “Timing Hypothesis”, should be considered to delay CVD in recently postmenopausal women.
Introduction
Despite the high incidence of cardiovascular (CV) complications experienced by a large portion of the aging female population, major CV societies do not currently support estradiol (E2) and progesterone (P4) use for the prevention or treatment of CV disease(CVD). There is, however, a large body of research confirming that a) loss of ovarian production of E2 and P4 is associated with detrimental vascular and myocardial changes1 and b) postmenopausal (PM) use of human bioidentical transdermal E2, as a patch or gel, and of oral P4, is safe (Figure 1).2
Prior to the Women’s Health Initiative (WHI), the results of which were published over twenty years ago, HRT was promoted by physicians, but support for HRT plummeted after the WHI results were publicized widely. Fortunately, its conclusions were reassessed and the data is now recognized as showing significant benefits to women in their 50s.3 Additionally, it is now more widely recognized that the results of the WHI cannot be applied to hormone formulations other than those used– oral-conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).3-5 An additional problem with the WHI was its inclusion of a preponderance of study subjects who were many years postmenopausal, including many with pre-existing medical conditions.6-8 Despite current understandings of the flaws of the WHI and the robust data on the many important functions of E2 supporting CV health, little interest exists for the prescriptive use of safer hormonal formulations and delivery modalities for the use as preventative medicine in cardiology. And the “Timing Hypothesis (initiation of HRT is beneficial only when begun within 10 years of last menstrual period),” though now widely acknowledged, has only resulted in the half-hearted acceptance of short-term, low-dose HRT solely for the amelioration of hot flashes and night sweats.9
In the years since the WHI, a small number of randomized, prospective, placebo-controlled trials were conducted, and the results were published. Each study adhered to the prevailing opinion that the smallest possible dose of estrogen was best. Fortunately, different forms of estrogen and progestins from those used in the WHI were included in subsequent studies, but transdermal E2 and oral micronized progesterone were not consistently the forms of hormones used. It is generally recognized now that those are the preferred forms of the hormones to be used for HRT.10 The use of various types of hormones and delivery modalities, the smaller numbers of study subjects, the shorter duration of the studies, as well as of dosing regimens used which resulted in low serum levels of E2, may all have contributed to the study outcomes that have not demonstrated CV benefits with the use of HRT.11 Although not clearly showing large CV benefits, the data from the major subsequent studies- the Kronos Early Estrogen Prevention Study (KEEPS) and Early Versus Late Intervention Trial with Estradiol (ELITE) studies, both showed no harm from HRT, with improvement in quality of life (QoL), and of vascular benefits for younger, recently PM women in the ELITE data, which similar to the WHI, was supportive of the “Timing Hypothesis.” 12, 13
Many observational studies have consistently shown the safety and health benefits of menopausal hormone use.14 A pervasive fear of HRT remains, and many patients and their physicians refrain from using HRT, when utilized, the prevalent use is for symptom reduction and not as part of a strategy for achieving healthy longevity and CV optimization, with most users choosing the smallest possible doses of E2 for the shortest possible time, and avoidance of cyclical P4 dosing.15
This review acknowledges that there are no large, prospective, placebo-controlled clinical trials utilizing physiologic and rhythmic dosing of human bioidentical hormones, designed to evaluate CVD outcomes. But as mortality and morbidity among women from CVD events remains high, practicing CVD specialists should consider the safe use of HRT, prescribing physiological doses of transdermal E2 and oral P4, as a modality to maintain a healthy, highly functional CV system for the promotion of healthy longevity. This article provides the framework to utilize human, bioidentical HRT as an integral component of preventive cardiology, including a general protocol for the prescriptive use of HRT for women.
*Overview of HRT Studies in PM
*HRT in PM Women for Prevention of CVD Revisited
*Effects of E2 in Female
Conclusions
Although there is a deficiency of prospective, placebo-controlled studies on the use of human bioidentical HRT in PM women, this should not dissuade general clinicians and specialists in CVD from recommending HRT at least to the majority of their young, recently PM women patients, for maintaining ideal long-term CV health. The robust safety data of the KEEPS and ELITE trials, as well as many observational studies, combined with the limited but definitive vascular benefits as shown in the ELITE study, and in many rodent and primate studies, in conjunction with the abundance of basic scientific data, outlining the mechanisms by which E2 protects CV structures, justifies the recommendation to provide young PM women with physiologic, rhythmic HRT. The goal is to replicate the hormonal levels and rhythms of a healthy reproductive-aged woman. A proactive, rather than a reactive, approach to CV well-being is the desired therapeutic strategy. With the prevention of CVD as a top priority, HRT is a safe and potentially highly beneficial therapeutic modality for appropriately selected women. Large-scale studies using better HRT preparations would be ideal, but these are not likely to be on the horizon anytime soon. Therefore, clinicians should consider the preponderance of evidence already available for recent PM women, based on the timing Hypothesis, and at the same time weigh the potential benefits vs risks of HRT for other PM women, using the superior, safer HRT preparations currently available.
