All those women on hormone treatment should read this very thorough up[date on where we are now as regards HRT. Note that there are many misconceptions and ill-informed people (unfortunately doctors as well) about these developments. I sometimes feel like an old time prophet, because all the things I have said about menopausal treatment of women have now come to pass. It is just unfortunate that so many women had to suffer needlessly, and some still do today, due to this incorrect understanding of the benefits and safety of HRT. Please read this, and pass on to your doctors if they are unaware of the contents of this article.

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Reviews

Hormone replacement therapy – where are we now?

R. D. Langer , H. N. Hodis , R. A. Lobo & M. A. Allison Pages 3-10 | Received 17 Sep 2020, Accepted 04 Nov 2020, Published online: 06 Jan 2021

Abstract

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.

摘要

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} .

Dementia

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 .