How women benefit from HRT
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Hormone replacement therapy – where are we now?
Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women’s Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different – the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.
自2002年在妇女健康倡议(WHI)试验的初步结果公布后, 激素替代疗法成为更年期的管理标准, 人们对于激素的看法发生了变化。该报告引发的对乳腺癌和心脏病发作的担忧没有数据支持, 尤其是对近期绝经的妇女。临床上, HRT通常在绝经前开始。WHI测试了一些不同的东西——绝经后使用激素替代治疗十年或更长时间的效果。事实证明, 开始激素替代治疗的年龄是决定效益/风险的关键。继2002年WHI风潮后, 激素替代治疗的使用量大幅下降, 并且一直保持在较低水平, 这引发了人们对替代疗法的浓厚兴趣。大多数激素都有其自身的不利影响, 没有一种药物能像雌激素那样对多器官系统产生广泛的益处。激素替代治疗可以有效缓解各种健康状况, 潜在地避免了对不同疾病的多重治疗。不幸的是, 在许多女性和临床医生避免激素的使用, 激素替代疗法的益处/风险的被扭曲了, 并且导致了不必要的痛苦。继WHI之后, 许多临床医生还没有接受足够的培训来适应使用激素替代疗法。在绝经10年内开始使用激素替代疗法降低了全因死亡率和冠心病、骨质疏松症和痴呆症的风险。
Keywords: Hormone replacement therapymenopause managementvasomotor symptomswomen’s healthcoronary heart diseaseosteoporosisgenitourinary syndrome of menopausebreast cancerPrevious articleView issue table of contentsNext article
HRT in the context of contemporary options for menopause management
For the majority of women seeking relief of menopausal symptoms, the perceived harms of hormone replacement therapy (HRT) are exaggerated, while the perceived benefits of alternative therapies are overstated, and their risks either ignored or underestimated 1 . There is robust evidence that estrogen is a highly effective treatment for menopausal vasomotor symptoms 2 and the genitourinary syndrome of menopause 3 . When initiated before the age of 60 years (or roughly within 10 years of menopause), HRT is effective in reducing all-cause mortality 4–8 . In that age range, HRT prevents coronary heart disease (CHD) 4 , 5 , 9 , 10 . Moreover, HRT prevents hip fractures 11 , an important and underappreciated cause of morbidity and mortality in postmenopausal women. Nonetheless, HRT use dropped precipitously between 2001 and 2008, following the initial publication of the Women’s Health Initiative (WHI) trial of conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) in 2002, decreasing from approximately 43% to 11% of women aged 45–74 years 12 , 13 .
Fear of HRT among women, and misunderstanding of the risk/benefit, along with lack of appropriate education among providers, has led to underutilization, unnecessary suffering, and excess chronic disease and mortality in postmenopausal women over the past two decades 14–17 . Why is this disconnect so prevalent and persistent?
Fear of breast cancer
When asked to rank health concerns, women and health-care providers consistently place breast cancer at the top of the list 18 , 19 . Use of HRT has been associated with both decreases and increases in breast cancer, with associations varying by the form of HRT, dose, and duration of use 20 . In initial reports from the largest clinical trial to address the question, the WHI, use of CEE-alone reduced the risk of breast cancer although the results were not statistically significant 21 , while use of CEE + MPA was associated with an increase in breast cancer that was also not statistically significant 22 . Subsequent analyses found significant reductions in invasive breast cancer among adherent women taking CEE-alone 23 . In the most recent reprise of those analyses by the WHI group, CEE-alone significantly reduced the risk of breast cancer by 22%, while CEE + MPA increased the risk by 28% in analyses not adjusted for covariates 24 . Notably, in the only analysis of these data including protocol-specified adjustment for covariates, the breast cancer risk for CEE + MPA was not statistically significant 25 . Even had the breast cancer association for CEE + MPA been significant, it was rare, affecting approximately one woman for every 1200 woman-years of treatment 22 . These contrasts are mirrored in reports from large observational cohorts reflecting use of estradiol and a variety of progestogens, where micronized progesterone was associated with no risk, while elevated associations for synthetic progestins varied by class 26 , 27 . These findings for breast cancer imply that the progestogen component modulates the effect of estrogens, and suggest that the breast cancer risk is dependent on the specific treatment used, with the progestogen component, used to protect the endometrium, being pivotal.
The vast majority of published reports on HRT and breast cancer come from observational studies that are subject to a variety of biases and residual confounding. Virtually all of these were combined in a collaborative publication in 2019 involving 58 observational studies with 568,859 women and 108,647 cases of invasive breast cancer. Modeling initiation at age 50 years and 5 years of use, and combining all forms of estrogens and all forms of progestogens, continuous HRT, sequential HRT, and estrogen alone were associated with, respectively, 2, 1.4, and 0.5 excess cases of breast cancer per 100 women over 20 years 28 . These numbers translate into 1.0, 0.7, and 0.25 excess cases per 1000 woman-years; a rare adverse event using World Health Organization criteria 29 . Importantly, the median year for a breast cancer diagnosis was 2005 so that the treatments evaluated have largely been replaced by newer regimens over the past two decades. Although excluded from the main paper, the Collaborative Group did report a combined analysis of results from randomized clinical trials. Aggregating data for estrogen alone from five clinical trials other than the WHI, representing approximately 2850 woman-years of use and 17,000 woman-years of follow-up, yielded a non-significant 39% reduced hazard ratio (0.61; 95% confidence interval [CI] 0.34–1.09) 28 . The parallel data from four clinical trials representing about 13,350 woman-years of exposure and 30,500 woman-years of follow-up yielded a 14%, also non-significant, increased risk of breast cancer for estrogen plus progestogen, 1.14 (95% CI 0.78–1.65). The latter is substantially lower than the pooled relative risk from the observational studies, which exceeded a hazard ratio of 2 28 . The contrasts between the results of the randomized trials and the observational data underscore the reliability issues of less rigorous study designs 20 .
Misunderstanding of the associations between age, HRT, and cardiovascular risk
The second major area of confusion is the effect of HRT on incident cardiovascular disease (CVD), particularly CHD and stroke. Again, the largest clinical trial to address this question is the WHI trial. As with breast cancer, the WHI trials of CEE-alone and CEE + MPA demonstrated different findings for CVD. Age and time since menopause when HRT was initiated emerged as an important confounding factor that was not recognized when the WHI was designed. A primary goal of the WHI was to evaluate HRT in older women well past menopause because the weight of evidence available when the study was planned strongly suggested that HRT had a favorable benefit/risk ratio when initiated near the time of menopause. Accordingly, the WHI enrolled primarily women well beyond menopause (mean age 63 years, mean time since menopause 12 years), with only 30% of the cohort <60 years of age 30–32 .
In the WHI CEE-alone trial overall, among women aged 50–79 years at baseline there were non-significant results for CHD (9% reduction) and stroke (39% increase), with a priori adjustment for multiple comparisons 21 . In contrast, among women aged 50–59 years, there was a statistically significant 40% reduction in a composite endpoint of CHD and related coronary diagnoses 9 , and there was no increase in stroke 21 . In the WHI CEE + MPA trial among women aged 50–79 years at baseline, there were non-significant results for CHD (29% increase) and stroke (41% increase) with a priori adjustment for multiple comparisons 22 . Similar to the CEE-alone trial, in women within 10 years of menopause, there was a non-significant 11% decrease in CHD, a parallel non-significant reduction in CHD in women aged 50–59 years with vasomotor symptoms 33 , and a non-significant increase in stroke in women aged 50–59 years 11 . The Danish Osteoporosis Study evaluated a composite endpoint of hospitalized heart failure, myocardial infarction, and death in 1006 women aged 45–58 years (mean 7 months postmenopausal). Women with a uterus were randomized to estradiol with norethisterone acetate or no treatment, while women with prior hysterectomy received estradiol or no treatment. After 10 years, the composite endpoint was significantly reduced by 52% with HRT and there was no effect on stroke 10 . The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized secondary prevention trial of CEE + MPA in older postmenopausal women (mean age 67 years) with pre-existing CHD. In the HERS, CEE + MPA increased myocardial infarction in the first year of treatment, suggesting that HRT increased plaque rupture. Over the subsequent 4 years, there was a statistically significant reduction in CHD with HRT relative to placebo 34 . HERS findings indicate that HRT acted early on rupture-susceptible plaque, resulting in myocardial infarction within the first year of treatment. Viewed in context with the WHI results that demonstrated opposite effects for HRT initiated within 10 years of menopause, or >10 years after, these findings imply that HRT introduced in the presence of atheroma can trigger plaque rupture 35 . These findings led to the recognition that timing of initiation relative to the health of the endothelium is key to the vascular effects of HRT, the ‘timing hypothesis’ 36 , 37 .
The 7-year Early vs. Late Intervention Trial with Estradiol (ELITE) is the only clinical trial to directly test the ‘timing hypothesis’. It tested oral micronized estradiol 1 mg daily (plus micronized progesterone vaginal gel in women with an intact uterus) versus placebo in healthy women who were <6 years or >10 years past menopause when randomized. The ELITE found reduced progression of subclinical atherosclerosis (carotid artery intima-media thickness) in women who were <6 years postmenopausal, but no benefit in women >10 years past menopause (p for interaction = 0.007) 38 . The timing hypothesis was also studied using the Finnish nationwide death registry (1994–2009) comprising 489,105 postmenopausal women with 3.3 million years of HRT exposure; CHD death was evaluated among HRT users according to age at initiation. The CHD standardized mortality ratio was lower among women who initiated estradiol alone or estradiol/progestogen therapy at age <60 years compared to those initiating at older ages. HRT reduced the risk of all-cause mortality in a nearly linear relationship with duration of exposure 7 . With this in mind, it should be noted that the WHI CEE + MPA trial included 1298 women with pre-existing CVD. The effects of HRT in women with pre-existing CVD could have confounded the CHD results, giving the impression that CEE + MPA increased CHD in primary prevention. A stratified analysis of WHI women by baseline CVD to determine the effects of HRT on CHD in women with and without pre-existing CVD is conspicuously missing from the literature.
Meta-analyses of clinical trial data stratified by either age or time since menopause show that HRT may decrease CHD and all-cause mortality by 30–48% when initiated in women <60 years of age and/or <10 years since menopause 4 , 5 , 39 , 40 . A Bayesian meta-analysis of HRT and all-cause mortality in younger postmenopausal women (mean age 55 years) showed a similar 22–27% reduction in all-cause mortality across randomized clinical trials and observational studies 40 . A Cochrane systematic review found that in women initiating HRT at <60 years old and/or <10 years since menopause, CHD risk was reduced by roughly half (relative risk [RR] 0.52; 95% CI 0.29–0.96) and all-cause mortality by 30% (RR 0.70; 95% CI 0.52–0.95) 5 . In contrast, in women initiating HRT when >60 years of age and/or >10 years since menopause, HRT had no effect on CHD or all-cause mortality. Venous thromboembolism was significantly increased, but there was no evidence of an excess risk of stroke with HRT.
Prevention of fractures
Estrogen is a potent modifier of bone metabolism and menopause is associated with a rapid loss of bone mineral density (BMD) and a downstream increase in fracture risk. Nearly all trials testing interventions to prevent osteoporotic fracture have been conducted in women with osteopenia or osteoporosis. The Postmenopausal Estrogen Progestins Interventions (PEPI) trial and the WHI are unusual in having evaluated HRT for effects on bone health in women unselected for fracture risk. The PEPI trial enrolled 875 women aged 45–64 years (mean 56 years), and within 10 years of menopause, in a 3-year trial comparing treatment with CEE-alone, CEE + MPA daily, CEE + MPA sequentially, or CEE + micronized progesterone sequentially versus placebo on a range of metabolic factors 41 . All active regimens provided increases of about 2% and 5% in BMD at the hip and spine, respectively, and there were no statistically significant differences between regimens 42 . The WHI went further in assessing not just BMD but also fracture rates. In women on average 7 years older than PEPI participants (mean age 63 years), both the WHI CEE-alone and CEE + MPA trials found a somewhat greater 3-year increase in hip BMD, approximately 3.5% versus placebo 43 , 44 . Overall, the WHI showed consistent benefits for both CEE-alone and CEE + MPA, with a 33% reduction in hip fracture, the most catastrophic outcome of osteoporosis, with either CEE-alone or CEE + MPA. Vertebral fractures were significantly reduced by 36% and 32%, respectively, in the two trials and a composite outcome of all fractures was reduced by approximately 25% 11 .
The effects of estrogen in major organ systems and contrasts with other pharmacotherapy
Estrogen has important metabolic effects in most major organ systems. It normalizes the vaginal and urethral environment 3 , positively influences arterial blood flow 45 and subclinical atherosclerosis 37 , 38 , promotes a non-atherogenic lipid profile 41 , reduces rates of incident diabetes mellitus 46 , helps to prevent bone loss and may restore lost bone 47 , limits excess osteoclastic activity 48 , and maintains neuronal health in the central nervous system and spine by promoting growth and mitigating inflammation 49 . The flight away from HRT has resulted in the increased use of individual drugs to prevent or treat the effects of decreased endogenous estrogen. For instance, statins are given for the prevention of coronary disease. Bisphosphonates, selective estrogen receptor modulators, receptor activator of nuclear factor-κΒ ligand inhibitors, and a variety of other strategies are used for bone loss, and selective serotonin reuptake inhibitors are used for hot flushes. None provide the physiologic spectrum of end organ effects delivered by estrogen. All are associated with their own adverse effect profiles.
Whereas HRT in close proximity to menopause reduces CHD and all-cause mortality, in women lipid-lowering with statin therapy has a null effect on CHD in primary prevention, and a null effect on all-cause mortality in primary and secondary prevention 50 . Unlike HRT, which reduces new-onset diabetes mellitus, statin therapy increases the risk of incident diabetes particularly among postmenopausal women 50 . Additionally, a signal for increased risk of breast cancer in women randomized to statin therapy relative to placebo has been reported in at least four randomized controlled trials 51–54 . Other cardiovascular medications are linked to breast cancer at an even greater degree than that reported for HRT. For example, calcium channel blockers used predominantly for hypertension and angina have been shown to statistically significantly increase the risk for ductal breast cancer (RR = 2.4) and lobular breast cancer (RR = 2.6), compared to risk ratios typically <1.3 reported for the association between HRT and breast cancer 55 . Unlike HRT, bisphosphonates have been associated with fractures (specifically femoral shaft atypical spiral fractures and mandibular necrosis), atrial fibrillation, and cardiovascular mortality 56–58 . While HRT is the most effective therapy for ameliorating hot flushes, selective serotonin reuptake inhibitors maximally reduce flushing up to 50% while being associated with increased fracture risk 59 , 60 .
Prior to the WHI, several large observational studies found that HRT was associated with reduced rates of Alzheimer’s disease and other dementias 61–63 . The WHI Memory Study (WHIMS) was added to address this question during the main trial with the critical caveat that only women aged 65 years and older were enrolled. The rationale was that dementia incidence rates are too low in women under 65 years old for an effect to have been detected during a primary trial period of roughly 8 years. Rather than finding benefit, the WHIMS found an increased rate of mild cognitive impairment and dementias in women over 65 years old randomized to either CEE-alone or CEE + MPA 64 , 65 . However, those findings, like the unanticipated increase in cardiovascular events in women aged >60 years when HRT was initiated in the WHI trials, may be explained by the reversal of estrogen benefits when replacement is initiated late, as described in detail earlier. In the 18-year follow-up of the WHI, considering the entire cohort with an average age of 63 years at baseline, use of CEE with or without MPA was associated with a significant reduction in mortality attributed to dementias. The association was strongest for CEE-alone 8 . In the Women’s Estrogen for Stroke Trial (WEST), after 3 years of treatment with estradiol, women with cerebrovascular disease and a normal Mini-Mental State Examination at randomization had lower rates of cognitive decline (RR = 0.46; 95% CI 0.24–0.87) relative to women with an abnormal Mini-Mental State Examination at entry 66 .
Contemporary views and knowledge of HRT
Based on the non-significant findings for increased breast cancer and CHD in the CEE + MPA arm of the WHI, the US Food and Drug Administration (FDA) placed a black-box warning on all HRT regimens in 2002 that has remained essentially unchanged despite the emergence of data to the contrary cited earlier, including the opposing findings for both outcomes in the CEE-alone parallel trial. That decision, together with the unprecedented and sustained attention to the initial WHI results in the popular press, caused a dramatic exodus away from not just the use of HRT, but from education in clinical training. The results of this cascade of events, predicated on a widely misunderstood evidence base, have led to a profoundly unscientific situation in contemporary medicine. It has led to the rise in use of unproven treatments for menopausal symptoms, many of them not regulated and carrying their own risks. It has led to a great disconnect between the evidence and beliefs among women who are potential candidates for HRT. It has also led to a generation of clinicians who are inadequately trained in evaluating a patient’s risk/benefit for HRT, or managing it. The absence of education in this area has resulted in some clinicians adopting the negative perspective of the general press and not remaining abreast of the literature. As a result, many physicians do not include it in their practice, denying the opportunity of treatment with HRT to women who would be appropriate candidates.
In the USA, the lack of accurate understanding of HRT risk/benefit has also led to pharmacy formulary decisions by insurance plans that create substantial financial barriers to treatment even for women with clinicians willing to prescribe HRT. On one of the most widely held insurance plans in the USA, a monthly course of HRT costs approximately $200 67 . In contrast, the combined cost of a monthly course of atorvastatin for coronary prevention, along with alendronate for osteopenia, is under $10 67 . Costs are similar with other major insurance plans in the USA. As documented earlier, the combined adverse effect profile of statins and bisphosphonates appears worse than that of CEE-alone, and presumably that of CEE with a metabolically mild progestogen. Thus, there is a strong incentive for the use of multiple drugs whose mechanisms are not physiological like estrogen, with increased adverse effects, for the prevention of diseases that are physiologically addressed by restoring effective levels of estrogen.
The rise in popularity of transdermal estrogens
In parallel with the increase in complementary and alternative treatments for menopause, there has been an increase in the forms and regimens available for HRT. The largest change has been the movement away from oral estrogens in favor of transdermal products. Within the category of transdermal products, there has been a rise in popularity of compounded ‘bioidentical estrogens’ that are not approved by regulatory authorities. Besides estradiol, compounded products may include estrone and estriol, as well as progestogens and androgens in combination. Medical societies have consistently advised against these products. Although marketed as ‘natural’, they are in fact synthesized in laboratories 68 . They are unregulated, the hormones delivered are not consistent, and some of the hormones included do not have an indication. The assertion by advocates that these formulations are safer is also without foundation. Indeed, there is evidence that bioidentical estrogen products have caused endometrial cancer 69 .
However, pharmaceutical-grade, FDA-approved, ‘bioidentical’ transdermal estradiol is available as a patch or gel. It is important to note that transdermal estrogens are exclusively estradiol, while there are a variety of oral preparations available, with the most data available for CEE (a mix of estrogens, dominated by estrone sulfate and equilin sulfate, with minimal estradiol content). Other commonly available oral estrogen preparations for use in menopause include estradiol, esterified estrogens, and estropipate. In contrast to estradiol, and to some degree other oral estrogen preparations, the metabolic conversion of the mixed estrogens in CEE results in the circulation of estrogens with a variety of receptor affinities, and estrogen receptor agonism and antagonism, or selective estrogen receptor modulator-like activity.
Increasing use of transdermal estrogens was driven initially by observational data suggesting a lower risk of thrombotic complications 70 . Transdermal preparations can also be more convenient for the patient in that patches are placed once or twice weekly, while oral estrogen must be taken daily. Combination patches with estrogen plus progestogen are available on some formularies. Otherwise, for women with a uterus, this advantage in convenience is reduced because a progestogen must be taken daily. Transdermal gels and creams also require daily administration and are less popular than patches. A report from the WHI Observational Study of 93,676 postmenopausal women found non-significant trends for lower rates of CHD, stroke, and cardiovascular mortality, but not all-cause mortality, for transdermal estradiol compared to oral CEE 71 . In a US matched-cohort study of health insurance claims between 1999 and 2011, transdermal estrogen preparations were associated with a lower incidence of cardiovascular complications (including CHD, angina, heart failure, stroke, transient ischemic attacks, pulmonary embolism, and other venous thromboembolisms) compared with oral estrogen preparations: incidence rate ratio 0.81 (95% CI 0.67–0.99), irrespective of the type of estrogen used 72 . Two large case–control studies in the UK found that oral HRT regimens were associated with increased venous thromboembolism while transdermal use was not. CEE was associated with a higher risk than estradiol. Within the oral regimens, CEE + MPA had the highest risk while estradiol + dydrogesterone had the lowest 73 .
Clinical trial data on transdermal estrogens are limited to relatively small studies, typically with fewer than 1000 participants. Results are available for intermediate markers rather than differences in disease rates. The Kronos Early Estrogen Prevention Study (KEEPS) evaluated progression of carotid artery intima-media thickness with transdermal estrogen (estradiol 50 μg/day), low-dose oral estrogen (CEE 0.45 mg/day), and placebo over 4 years in 727 healthy newly menopausal women. There were no significant differences in carotid artery intima-media thickness between treatment groups 74 .
An early observational report also suggested a lower risk of breast cancer with transdermal estrogen 26 . However, a later report in the same population found that estrogen alone was associated with increased risk (RR 1.29; 95% CI 1.02–1.65) and that the progestogen component modulated this risk with non-significant associations for estrogen with micronized progesterone (RR 1.00; 95% CI 0.83–1.22) and for estrogen–dydrogesterone (RR 1.16; 95% CI 0.94–1.43), but a significant association for estrogen combined with other progestogens (RR 1.69; 95% CI 1.50–1.91) 27 .
Contrasts between outcomes with various progestogens
The only role for progestogens in menopausal therapy is to protect against endometrial hyperplasia and endometrial cancer. Accordingly, progestogens are not indicated for women who have had a hysterectomy. All clinical trials and most observational studies that have evaluated multiple progestogens have found important differences in their metabolic effects and in disease outcomes. The PEPI trial found that micronized progesterone taken sequentially and MPA taken either daily or sequentially provided effective endometrial protection. CEE-alone and CEE with micronized progesterone had similar effects in raising high-density lipoprotein cholesterol that were superior to CEE + MPA. Likewise, CEE-alone and CEE with micronized progesterone had no effect on 2-h post-challenge glucose, while CEE + MPA caused a mild increase 41 . Nonetheless, in both the WHI trial and the HERS, CEE-based regimens including CEE + MPA reduced incident type 2 diabetes 11 , 75 . A meta-analysis of 107 HRT randomized controlled trials provides strong evidence that HRT statistically significantly reduces new-onset diabetes mellitus 46 .
Perhaps the most clinically important differences in progestogens are the effects in breast tissue. A clinical trial in 71 postmenopausal women evaluated sequential CEE + MPA, or transdermal estradiol with sequential micronized progesterone (TDE + MP), over two cycles. CEE + MPA significantly increased cell proliferation measured using Ki-67/MIB nuclear antigen expression compared with baseline (p = 0.003) and compared with TDE + MP (p = 0.05). TDE + MP did not significantly increase cell proliferation 76 . These data are consistent with a longer-term experiment conducted in oophorectomized cynomolgus monkeys. In this model, estradiol plus progesterone did not significantly increase proliferation in breast epithelial cells (p = 0.47 for lobular cells and p = 0.72 for ductal cells) compared with placebo, measured using Ki-67 expression. In contrast, estradiol + MPA significantly increased lobular cell proliferation by 194% (p = 0.009) and ductal proliferation by 544% (p = 0.006) versus placebo 77 .
Contemporary HRT as a therapeutic option for menopause management
Each woman must be assessed in the context of her unique presentation of concerns and physical findings. For women seeking relief of vasomotor symptoms, estrogen is the most effective treatment although other strategies may work. For a woman presenting with vasomotor symptoms plus other issues (e.g. genitourinary syndrome of menopause, osteopenia), HRT becomes increasingly more useful as a single modality that can manage multiple conditions. Even in the absence of significant vasomotor symptoms, HRT is a good option for healthy women within 10 years of menopause who may be at higher risk for chronic diseases 78 . HRT can meaningfully improve quality of life, and this contrasts sharply with other products that are not estrogen-based 79 . Contemporary options include CEE, oral estradiol, and transdermal estradiol, each in a variety of doses that can be titrated to achieve treatment goals. CEE-alone reduced breast cancer in the WHI. For women with a uterus, micronized progesterone has a more favorable metabolic profile, and a reduced proliferative effect in the breast, than MPA. Dydrogesterone, norethisterone, and drospirenone are other options, although there are no head-to-head comparative outcome data versus other progestogens.
The clinical trial data indicate that, for women starting HRT before age 60 years, or within 10 years of menopause, all-cause mortality is reduced. CHD risk may be reduced depending upon the treatment regimen, fracture risk will be reduced, and there may be protection against dementia. Some women will experience the return of vasomotor symptoms and genitourinary syndrome of menopause after stopping HRT, as well as rapid bone loss, even at ages well beyond 60 years. Risks, including those for vascular events and fracture, return when effective treatment is stopped 14 , 16 , 17 . Accordingly, there are no reasons to place mandatory limitations on the duration of MHT, conditioned upon ongoing individualized reassessment of benefit and risk for each woman using HRT 68 .
Professor Studd, one of the world’s foremost researchers and expert on hormones, wrote this excellent article on the benefits and risks of HRT. Also look in my archives for August 14th, where I outlined all the lovely things oestrogen does for women.
Ten reasons to be happy about hormone replacement therapy: a guide for patients
Professor John Studd, DSc,MD,FRCOG was Consultant Gynaecologist at the Chelsea & Westminster Hospital, London and also Professor of Gynaecology at Imperial College. He qualified in 1962 and has worked and trained in Birmingham. Zimbabwe and London. He was Consultant Gynaecologist in Salisbury, Rhodesia and Consultant and Senior Lecturer at the University of Nottingham and moved to London in 1974 as Consultant Obstetrician and Gynaecologist at King’s College Hospital. Six years ago he was invited to join the staff at the new Chelsea & Westminster Hospital, London.He is Founder and Vice-President of the National Osteoporosis Society and has been a Council Member of the Royal College of Obstetricians and Gynaecologists for 12 years and a Past-President of the Section of Obstetrics and Gynaecology at the Royal Society of Medicine. In 2005-2007 Professor Studd was Chairman of the British Menopause Society.
- London PMS and Menopause Clinic, London, UK
- Correspondence: Professor John Studd, London PMS and Menopause Clinic, 46 Wimpole Street, London W1G8SD, UK. Email: email@example.com
In spite of the negative press reports following the 2002 Women’s Health Initiative (WHI) publication, women can be reassured that in the correct circumstances, hormone replacement therapy (HRT) is beneficial and safe, particularly if treatment is started below the age of 60. Transdermal estradiol is probably safer than oral estrogens as coagulation factors are not induced in the liver and HRT is safer if a minimal duration and dose of progestogen is used. HRT is effective for the treatment of estrogen-deficiency symptoms of flushes, sweats and vaginal dryness. Estrogens prevent osteoporotic fractures and should be first-choice therapy, rather than bisphosphonates. Similarly, HRT protects the intervertebral discs in a way that non-hormonal preparations do not. Estrogens perhaps with the addition of testosterone help certain sorts of reproductive depression, as well as improving energy and libido. There is new evidence to support the previous observational studies that HRT reduces the incidence of heart attacks. Estrogen therapy has a beneficial effect upon collagen, thus improving the texture of the skin, the nails, the intervertebral discs and bone matrix. Discussion of side-effects should not be avoided, particularly the 1% extra lifetime risk of breast cancer. This should be balanced against the fewer heart attacks, fewer deaths and less osteoporotic fractures in those who start HRT below the age of 60.
(1) HRT will stop your hot flushes and sweats
Troublesome hot flushes, severe night sweats and headaches causing chronic insomnia are characteristic symptoms of the menopause. These symptoms may last for many years. Apart from being socially embarrassing they result in tiredness and depression because of lack of sleep. These symptoms can almost invariably be cured with the correct small dose of estrogen. Although selective serotonin reuptake inhibitor antidepressants have been suggested for the treatment of vasomotor symptoms, no other treatment is nearly as effective as estrogens. Women who still have a uterus should still have 7–12 days of progestogen in order to produce a withdrawal bleed and prevent endometrial hyperplasia.
(2) Estrogens will treat vaginal dryness and many causes of painful intercourse and lack of libido
Thinning of the pelvic tissues producing vaginal dryness and occasionally bleeding is another characteristic result of estrogen deficiency that occurs after the menopause. This also can be successfully treated with estrogen either by tablets or through the skin by patches or gels or implants. Transdermal estrogen therapy is probably the safest and most effective route as hepatic coagulation factors are not stimulated. Local estrogens can also be given for this symptom using local vaginal applications of weak estrogens such as oestriol that are hardly absorbed. Other related problems of painful intercourse, loss of libido and recurrent ‘cystitis’, if due to pelvic atrophy are also effectively treated by systemic or long-term local vaginal estrogens.
(3) HRT increases bone density and prevents osteoporotic fractures
Every study confirms that estrogens are the most effective way of increasing bone density and preventing osteoporotic fractures even in low-risk women. This treatment is very safe when started in women under the age of 60. It is more effective and beneficial than the bisphosphonates that are frequently used by bone physicians as first choice and by general practitioners unsure about the safety of estrogen therapy. These non-hormonal drugs with their considerable long-term complications should have no place in maintaining bone density in women under the age of 60. For the recently menopausal women receiving estrogen therapy for climacteric symptoms such as flushes, sweats or vaginal dryness, there will be a considerable increase, up to 15% in 10 years to such an extent that osteoporotic fractures 20 years later in the older women are much less likely to occur. If these women have low bone density, even without typical menopausal symptoms, estrogens must be seen as first-choice therapy. For those younger women with severe osteopenia or osteoporosis due to premature menopause, early hysterectomy and oophorectomy or anorexia with amenorrhoea, estrogens are an essential long-term treatment.
(4) HRT protects the intervertebral discs
Important recent studies from several centres have shown conclusively that estrogens prevent collagen being lost from the intervertebral discs, thus maintaining their strength and function. These discs make up one-quarter of the length of the spinal column and act as cushions preventing crush fractures of the vertebral bodies. It is these crush fractures that lead to loss of height and the lordosis of the upper spine known as the Dowager’s hump. This important protective effect of estrogens seems to be unique as bisphosphonates and the other non-hormonal treatments of low bone density do not have any beneficial effect upon the discs.
(5) HRT does reduce the number of heart attacks
There are about 30 years of evidence from many observational trials that estrogens reduce the incidence of coronary heart disease. This has subsequently been questioned by the 2002 WHI Study, which showed an increase in heart attacks. However, this study looked at patients of the wrong age and who were using the wrong dose of estrogen and progestogen. Subsequent reports from the same investigators have shown a very much reduced incidence of heart attacks in women who start HRT below the age of 60. This is particularly apparent in women who have had a hysterectomy and can have estrogens without progestogen. The view now is that HRT, particularly estrogen alone, is very safe and is associated with a reduced number of heart attacks if started below the age of 60. Thus there is primary prevention of coronary heart disease, but there is no evidence of protection in women with established coronary damage.
It would appear that the factor that is associated with the apparent increase in severe side-effects such as breast cancer and heart attacks and possibly stroke is the progestogen component of HRT. As progestogen also produces unwanted PMS-type side-effects of depression, anxiety, bloating and loss of libido in patients who are progestogen intolerant, it is sensible to keep the dose of oral gestogen to a minimum. The alternative is to insert a Mirena intrauterine system, which produces amenorrhoea and avoids the use of oral progestogen with its side-effects for five years or more.
(6) Estrogens help depression in many women
Estrogens are more effective in the treatment of depression in premenopausal or perimenopausal women than post- menopausal women. However there is no doubt that depression is helped in postmenopausal women who have been suffering from night sweats, insomnia or vaginal dryness, painful intercourse and marital problems in that most of these problems can be effectively treated and removed. However, it is true that the most impressive effect on mood is seen in younger perimenopausal women in the 2–3 years before the period cease in the menopausal transition. This cannot be diagnosed by blood tests but by a careful history. This depression often occurs in women who are sensitive to abrupt changes in their hormones, either endogenous oestradiol or progesterone. These women had previously had postnatal depression and premenstrual depression in what should be known as reproductive depression. They often also have cyclical headaches/migraines that occur with the cyclical hormonal fluctuations at menstruation. As premenstrual depression becomes worse with age, it blends into the more severe depression of the transition phase and is very effectively treated by moderately high-dose transdermal estrogens used by patches, gels or implants.
(7) HRT improves libido
HRT certainly improves libido if estrogens are used to cure vaginal dryness and painful intercourse. Even without these characteristic symptoms, estrogens can improve sexual desire. However, if necessary, the addition of testosterone has a more dramatic effect upon libido, frequency of intercourse and intensity of orgasm. Testosterone patches licensed in women after hysterectomy and testosterone gels in the appropriate dose are often and should be used ‘off license’ with full consent and explanation.
Women must be aware that testosterone is not only a male hormone but it is an essential female hormone present in women in about 10 times the blood levels as estrogen. It is an essential hormone, important for energy, mood and sexuality.
(8) HRT improves the texture of the skin
After the menopause, women lose about 25% of their body collagen, which is manifested by thin inelastic skin, brittle nails, loss of hair and loss of the collagenous bone matrix. This latter loss is an essential cause of osteoporosis and osteoporotic fractures. Estrogen therapy replaces the lost collagen in the skin and the bone. Its affect on the facial skin is a very obvious useful cosmetic effect.
(9) ‘I am a nicer person to live with’
This is a quote from a patient. Many women say that when estrogen therapy stops their depression, their loss of libido and their irritability, they become more agreeable people for their partners to live with. The depression, irritability, grumpiness and loss of energy and disinterest in sex can usually be improved considerably by the appropriate doses of the appropriate hormones that may include testosterone as well as estrogen.
(10) HRT is safe
In spite of the press reports stressing bad news, virtually all claims of major adverse effects from the WHI study have been reconsidered even by the investigators. It seems quite clear that the reported major side-effects of breast cancer, stroke and heart attacks occurred in women who started the wrong dose of HRT over the age of 60. In women who started below the age of 60 there were fewer heart attacks, fewer deaths, fewer osteoporotic fractures and even less breast cancer in this study. It is probable that the one residual side-effect is a small 1% extra lifetime risk of developing breast cancer, but this is no more than the breast cancer risk of being overweight, drinking wine, having no children or even taking statins.
- © 2010 The British Menopause Society
Professor of Gynaecology, The London PMS Menopause Centre, London.
Until recently it was believed that HRT was an extremely safe treatment for vasomotor symptoms, osteoporosis, depression and a major preventative measure for heart disease, colon cancer, Alzheimer’s disease and probably strokes. This has all been turned upside down by two greatly flawed studies, The Women’s Health Initiative, (WHI) and the Million Women Study (MWS). These will be discussed.
There is no evidence that oestradiol given in the appropriate dose in women below the age of 60 is associated with serious side effects although the addition of continuous progestogen may be the harmful factor in the causation of cardiovascular disease.
The WHI study studied a single preparation, Prempro (not available in this country), in the belief that one dose fits all patients. This is untrue because different women require different dose via a different route with different combinations of different hormones for different symptoms for different symptoms with different surgical status and for different ages. There was an added fault in that patients were recruited who were without symptoms – hence none of them needed this inappropriate therapy anyway.
This paper describes the different therapies required in women after hysterectomy and bilateral salpingo-oophorectomy, for premature menopause, for the perimenopausal patients with depression or libido problems, for women in the early post menopausal state and for older women in the late menopausal state.
Women with vasomotor symptoms or pelvic atrophy are easily treated with low dose oestradiol either by the oral route or by transdermal gel or patch. The treatment can last for the duration of the symptoms and there is no reason to limit therapy to 5 or 10 years. In patients with a uterus they will require endometrial protection with a progestogen which can be for the orthodox 14 days or continuously or, with patients with progestogen intolerance for 7 days each month.
Young women with premature ovarian failure need oestrogen therapy to protect their bones and their cardiovascular system as well as prevent symptoms until at least the age of 50 – the time of the normal menopause. If there is a suggested limit for the duration of HRT then the counting starts from the age of 50, the age of the normal menopause. It is important to check the bone density of these patients before treatment and every 3 years.
After hysterectomy and bilateral salpingo-oophorectomy, women need oestrogens, sometimes in the higher dose than for more mild symptoms. If they have lost their ovarian androgens, they benefit from the addition of testosterone. These women often suffer symptoms of the female androgen deficiency syndrome, (FADS) which is loss of energy, loss of libido and loss of self confidence, depression and headache. The ideal way to treat these patients is by implantation of oestradiol 25 mgs and testosterone 75 mgs every 6 months.
Patients with perimenopausal depression which is often linked with cyclical premenstrual depression are better treated with transdermal oestrogens in the form of oestradiol patches 100 mcgs or even 200 mcgs. This not only wipes out the cycles producing the cyclical symptoms of PMS but has a mental tonic effect for the perimenopausal women. These women of course require cyclical progestogen tablets but as these women with hormone responsive depression, (perhaps better called reproductive depression) are progestogen intolerant, a Mirena IUS should be considered.
Osteoporosis can usually be prevented by oestradiol therapy and the bone density can be increased in established osteoporosis by the use of oestrogens which produce plasma oestradiol levels of at least 300 pmol/L. This is a most effective therapy, more effective than bisphosphonates or SERMS but of course will not correct any deformity that may have occurred in established osteoporosis.
Many patients have loss of energy and loss of libido and these respond well to a higher dose of oestradiol with or without testosterone. Patients should have a clear explanation of the advantages and the putative dangers of HRT and their need for HRT assessed every year. The lowest effective dose should be used for the appropriate symptom or indication remembering that a higher dose is required for depression or correction of osteoporosis than for vasomotor symptoms.
Older post menopausal women who need oestrogens for pelvic atrophy or established osteopenia or osteoporosis should initially have a very low dose possibly with unopposed oestrogens because the major side effects of the WHI study occur in older women receiving combined oestrogen and progestogen therapy.
The strange syndrome of chronic fatigue syndrome/PMS is associated with low plasma oestradiol levels, low bone density and an excellent response to transdermal oestrogens with or without testosterone. This infrequently recognised condition needs further study.
There may be an increased risk of breast cancer after 5 or 10 years but these data are disputed and on a practical level it is very difficult to persuade women who feel well on HRT to discontinue. Until this issue is clarified, I believe patients should be advised to have a mammogram every 18 months.
Endocrine Society Statement.
Hormone Replacement Therapy or Menopausal Hormone Therapy offers significant benefits to women around the menopause suffering from moderate to severe menopausal symptoms.
The Australasian Menopause Society welcomes the publication of a complete analytic review of the evidence on the use and safety of menopausal hormone therapy. The US-based Endocrine Society has published a scientific statement “designed as a comprehensive, rigorously documented, objective, scientific analysis of existing data evaluating the benefits and risks of hormone therapy for menopausal women.”
The Review Committee consisted of a group of experts with clinical experience from across the world including three from Australia. The report outlines the risks and benefits according to their level of evidence, level A being the highest level of evidence.
The major level A conclusions were that Menopausal hormone therapy improves the symptoms of the menopause, including vaginal and bladder symptoms, prevents early postmenopausal bone loss and prevents hip and vertebral fractures. Combined oestrogen and progesterone therapy reduces colon cancer risk and oestrogen and oestrogen plus progestogen therapy increases mammographic density. The risks include a 2 fold risk of venous thrombosis with oral Menopausal Hormone Therapy, which is further increased when other factors such as weight and age are taken into account. Cancer of the uterus is a risk in women taking oestrogen alone but not with oestrogen and progestogen, but either therapy increases the risk of gallbladder disease. Stroke risk is not reduced in older women on hormone therapy. Testosterone as a patch developed for women improves sexual function whereas DHEA does not.
Other conclusions are of weaker levels of evidence.
The President of the Australasian Menopause Society, Dr Elizabeth Farrell, believes this is a very important scientific review outlining for women and health professionals information about the use of hormone replacement therapy. Many women suffer the symptoms of the menopause and should be given rational and up to date information about the safety and risks of the therapy. These women should be able to be prescribed without fear that has been relayed in the past using inaccurate levels of evidence.
The full report from the Endocrine Society can be downloaded from this site:
The statement is published in the July 2010 issue of the The Journal of Clinical Endocrinology and Metabolism.
Menopausal Hot Flushes – new report shows women don’t have to suffer, says International Menopause Society
International Menopause Society – press release
Embargoed until: 00.01, 18th October, 2011
Up to a quarter of women suffer a poorer quality of life because of hot flushes and night sweats associated with the menopause. Now the International Menopause Society (IMS) is marking World Menopause Day (18th October) with a new report* highlighting the problems associated with the menopause, and by calling for women and doctors to be more aware of the treatment possibilities for troubling menopausal symptoms.
The majority of women suffer from hot flushes or night sweats (also known as vasomotor symptoms or VMS) during the menopause. The exact numbers vary by culture, ethnic group, and individual health background, but on average 25% of women experience debilitating or distressing symptoms. These symptoms include depression, discomfort and embarrassment, causing real problems for women, their partners and their families. On average these symptoms may last 4 years, although some women are less troubled whereas some women have significant symptoms which are longer-lasting.
The IMS commissioned a multi-disciplinary comprehensive review of the evidence behind hot flushes and night sweats (published in the peer-reviewed journal Climacteric). As a result of the review, the IMS concludes that women should be less accepting of the problems caused by menopausal symptoms, and calls for women to be more proactive in asking for treatment.
women should be less accepting of the problems caused by menopausal symptoms, and calls for women to be more proactive in asking for treatment.
Hot flushes are caused by dilation of the blood vessels and increased flow of blood to the trunk, head and neck. This can cause reddening of the skin, and sweating. Night sweats are hot flushes which take place during sleep, so disrupting sleep and causing fatigue and stress.
These symptoms can lead to physical discomfort, embarrassment, fatigue, and loss of confidence, often leading women to avoid social situations. The impact of hot flushes on quality of life varies with a variety of factors, including the frequency and duration of the flushes, a woman’s lifestyle and how she views her symptoms. A woman may enter a ‘vicious cycle’, where the symptoms lead to problems in coping with her everyday life, which in turn leads to problems in coping with the symptoms.
The review concludes that Hormone Replacement Therapy (HRT) shows the best results in treating VMS, with up to 90% of symptoms being abolished within 3 months of starting the treatment. However, not all women can take HRT, and for them there may be alternatives such as SSRIs and other non hormonal medications as well as psychological methods of treatment (e.g. using cognitive behavioural therapy).
The IMS review cautions against the use of untested or unproven methods of counteracting VMS, Some techniques such as acupuncture have shown mixed results