Early studies: HT associated with CVD benefits

Initial HT studies of symptomatic, young PM women revealed positive results. In the 1980s, the Nurses’ Health Study, Lipid Research Clinics Follow-up Study, Leisure World Study and Kaiser Permanente studies all concluded that HT provided CV benefits. The Nurses’ Health Study 10-year prospective follow-up report concluded that oestrogen reduced coronary heart disease (CHD) and CVD mortality.5 Of 15 other prospective studies, 14 found decreased CVD risks.6

In 1991, a Food and Drug Administration Advisory Committee approved HT for PM CHD risk reduction. In 1992, a meta-analysis concluded that PM hormones decreased fatal CVD by 33%,7 and the American College of Physicians recommended offering HT to high-risk PM women to prevent CVD,8 a position widely adopted. Foreshadowing future findings, in 1995 the Postmenopausal Estrogen/Progestin Interventions clinical trial found that MPA, but not human-identical progesterone (P4), negated CEE benefits by reducing the high-density cholesterol levels.9

HERS and WHI: the demise of HT

In the 1990s, two prospective placebo-controlled double-blind studies were launched—HERS to evaluate secondary prevention, and the WHI to focus on primary CVD prevention.10 HERS included PM women aged 44–79 years (average 67 years) with documented pre-existing CVD. Daily oral CEE 0.625 mg with MPA 2.5 mg was given for approximately 4 years. Thromboembolic events and gallbladder disease increased, with no reduction of CHD events despite some positive lipid changes. Consequently, HT was not recommended for secondary prevention of CHD.11

WHI used the same HT combination as HERS–CEE+MPA. In a separate WHI arm, hysterectomised women received only CEE 0.625 mg/day. The subjects, aged 50–79 years (average age 63), were recruited as healthy PM women. WHI concluded of the CEE+MPA arm, ‘Overall health risks exceeded benefits from use of combined oestrogen plus progestin … among healthy PM US women …’12 but detailed analysis reveals 78% of subjects had pre-existing illness, including overweight, obesity, hypertension, diabetes mellitus (DM) and hypercholesterolaemia, disqualifying results as applicable to young healthy PM women.13

The CEE-only arm continued, but prematurely ended when harms outweighed benefits. As with HERS, CEE+MPA group experienced elevated venous thromboembolic events (VTE).^w1 WHI concluded HT did not prevent CVD death, non-fatal myocardial infarction (MI), angina or coronary revascularisation.12 A 2015 Cochrane analysis of WHI results reported six additional strokes, eight additional cases of VTE and four additional cases of pulmonary embolism per 10 000 treated women.14

WHI and HERS had similarities in design. Both studied CEE and MPA (WHI also had a CEE-only arm) in predominantly older women, many with documented CVD and/or significant risk factors. Consequently, HERS and WHI produced comparable results—increased incidence of VTE disease and CVD events in year 1, with tapering risks thereafter.15 Although applicable only to the cohort studied and hormone products used, the findings were broadly generalised to PM women of all ages and stages of menopause, and to all hormonal products, resulting in a general abandonment of HT.16

Recent research provides a more nuanced interpretation based on age, pre-existing conditions, and time in menopause. Reanalysed WHI data show no adverse events in women aged 50–54 years. Participants under 60 in the CEE-only arm, experienced lower risk of CHD events17 and benefited per the WHI Coronary Artery Calcification Study, with lower mean coronary artery calcium (CAC) scores compared with placebo group, concluding ‘Among women 50–59 years old at enrollment, … calcified-plaque burden in … coronary arteries after trial completion was lower in women assigned to oestrogen than those assigned to placebo’.18

Updated interpretations of HERS and WHI acknowledge HT initiated later in menopause offers no CVD benefit, noting MPA’s harmful effects, and HT’s possible CVD benefits with early initiation.19 The Timing Hypothesis was born—oestrogen can delay or prevent atherosclerosis and complications in newly menopausal women but is harmful or shows no benefit in older PM women with significant atherosclerotic disease and vulnerable plaques.20

Studies support the Timing Hypothesis

The Timing Hypothesis is supported by animal and human studies.21 When given immediately following ovariectomy, oestradiol (E2) produces anti-inflammatory and cardioprotective effects.22 However, following prolonged E2 deficiency, its anti-inflammatory effects are abolished. E2 treatment had opposing effects on intima/media ratios in aged (+75%) versus young (−40%) rats. Ovariectomised, aged rats lost the anti-inflammatory and vascular protective responses to exogenous E2 observed in younger, recently ovariectomised animals.23

In the Danish study, an open-label, randomised controlled trial, 1006 recently menopausal healthy women received E2 and P4 for 11 years. Compared with controls, HT users had significantly reduced all-cause mortality, heart failure and MI, with no added risk of cancer, VTE or stroke.24 A recent long-term follow-up WHI study showed reduced breast cancer incidence in CEE-only arm and higher breast cancer incidence in CEE+MPA arm, but without increased mortality.25

KEEPS, a randomised, double-blind, placebo-controlled trial, studied CV health impact of two formulations of HT on recently menopausal, healthy women; 727 participants were prescreened for subclinical coronary atherosclerosis via CAC score. All were younger than 53 years with generally healthy CV parameters and natural menopause within 6 months to 3 years. Serial carotid artery intima-media thickness (CIMT) measurements were monitored for HT effects on progression of atherosclerosis. Two regimens used low hormone doses—daily oral 0.45 mg CEE or 50 μg E2 patch, with 200 mg oral micronised progesterone 12 days each month. Matched control groups received placebo.26 After 4 years, neither hormone regimen affected CIMT; CAC measurements showed no adverse findings; CVD markers and blood pressure showed mixed results—somewhat favourable effects or none. The KEEPS study concluded hormone regimens are safe and can improve quality of life, but no CVD benefits were realised.2 A possible explanation for the unimpressive KEEPS results was its potentially subtherapeutic oestrogen dose. The average serum level of participants using the E2 patch was only 40 pg/mL, minimally above menopausal levels. Many maintained severely menopausal levels, as low as 9–11 pg/mL. Such E2 levels would not be expected to improve CV health.2

ELITE, double-blind and placebo-controlled, evaluated the differential effect of HT on slowing progression of subclinical atherosclerosis according to time-since-menopause. The women subjects, without clinical evidence of CVD or DM, were randomised based on time-since-menopause onset into two groups: <6 years since menopause onset vs 10 or more years since menopause, all given placebo or 1 mg oral oestradiol daily. Women retaining a uterus received 10 days a month of vaginal micronised progesterone gel 4% (45 mg). Primary trial end point was progression of CIMT, measured every 6 months, up to 6 years. The rate of CIMT progression was significantly reduced in the young-aged HT group (average 3.5 years since menopause onset, mean age 55.4 years) versus placebo users. However, those 10+ years since menopause onset (average 14.3 years since menopause onset, mean age 63.6 years) showed no benefits.27 The ELITE results supported the Timing Hypothesis—only hormones initiated close to menopause onset reduced CVD progression, late initiation of HT did not.

Understanding hormones for menopausal CV health

Understanding the pros and cons of various HT options facilitates optimal HT use. CEE versus E2 and MPA versus P4 have very different molecular structures and safety-efficacy profiles, producing different physiological effects. E2—the physiological hormone—provides safety benefits compared with CEE. CEE undergoes a first pass through the liver, increasing thrombotic risk^w2 and hepatic transformation to oestrone (E1), providing predominantly E1, rather than the preferred E2.

Oestrogens comprise a class of hormones. Human female oestrogens include E1, E2 and oestriol (E3), each with varied receptor binding capabilities/affinities, and biologically active metabolites. E2 is the dominant oestrogen of reproductive-aged women; E1 dominates during menopause, and E3 dominates in pregnancy. Oestrogen receptors (ER) are ER alpha, ER beta and G-protein-coupled oestrogen receptor (GPER), a membrane receptor. ERs interact in complex ways, have varying functions^w3 and are located throughout the female body (figure 2). E2 is a non-selective ER agonist, binds to all ER receptors, maintains vascular health, reduces oxidative stress and prevents oxidation of low-density lipoproteins.28 E2 diminishes vascular inflammation, the driver of CVD. Physiological levels of E2 maintain the functionality of endothelial nitric oxide synthase, promoting vascular endothelial health, while E2 deficiency results in oxidative stress and endothelial damage.29 E2 metabolites also confer CV benefits; 2-methoxyoestradiol induces favourable CV effects, including blocking abnormal cardiac remodelling and downregulating angiotensin-1 receptors.30

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Figure 2

Oestrogen receptors: located throughout the female body. E2 is important for health and function. E2 has three types of receptors distributed throughout the body—alpha, beta and G-protein-coupled oestrogen receptors (GPERs). Through its receptors, E2 modulates the immune system, promotes metabolic homeostasis and sustains cardiovascular health. GI, gastrointestinal; NS, nervous system.

CEE and E2 produce overlapping CV benefits, but CEE also produces uniquely negative effects not seen with transdermal E2. CEE comprises at least 10 unique oestrogens, several androgens, progestins and other substances with unclear vascular and procoagulatory effects. Oral CEE and oral E2 create a hormonal profile never naturally found in human females.31 Oral CEE and oral E2 enter the serum predominantly as E1, not E2. E1 preferentially binds to ER alpha, creating an imbalance of receptor binding within the CV system. E2 levels minimally rise with CEE, but to subnormal levels. CEE’s oestrogen profile produces unpredictable and potentially negative effects on oestrogen signalling pathways (figure 3).32

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Figure 3

The Rhythms of Oestradiol and Progesterone: Oestradiol is not fixed at a static low level in a healthy reproductive-aged woman, but fluctuates in a rhythmic fashion, with varying serum levels throughout the menstrual cycle. During much of the cycle the level exceeds 100 pg/mL and is generally at least 50 pg/mL. Beneficial effects of hormones relate to physiological serum levels. The ‘most efficacious dose’ rather than the ‘lowest dose’ is the goal.

Progestins are a class of hormones including human-identical P4, and MPA. HERS and WHI used MPA, which unlike P4, is both an agonist and antagonist to P4 receptors, uniquely binding to androgenic and glucocorticoid receptors.33 MPA abolishes beneficial oestrogen effects on vascular function, alters lipids and triggers coronary artery vasospasm.34 CEE+MPA induce higher rates of blood clots compared with CEE, while P4 confers CV benefits, inhibiting atherosclerotic plaque formation and downregulating ERs.35

A large meta-analysis further validates the use of HT to support cardiometabolic health, documenting a 30% reduced incidence of DM versus placebo.36 Additionally, HT is associated with lower all-cause mortality. A Cochrane Systematic Review stated, ‘Those who started hormone therapy less than 10 years after the menopause had lower mortality’.14 A WHI review of all-cause mortality and HT use concurred and documented an HR of 0.69 for women aged 50–59 years.37 Data also suggest long-term safety of HT,38 while abrupt discontinuation may predispose to potentially fatal CHD events.39 Of note, oral contraceptives contain ethinyl oestradiol and various progestins, are thrombophilic^w4 and predispose to hypertension.40 Oral contraceptives are not recommended as HT in PM women and must be used cautiously, with individualised risk management, during the menopausal transition.

Proposed hormone prescription for CV health

Prescribing human-identical hormones for CVD primary prevention in menopause is not currently recommended by any CV society, but we believe it should now be considered and discussed, based on scientific data and human studies (table 1).41–44 ^w4 All discussions concerning HT initiation should be individualised, reviewing each woman’s risk for CVD, breast cancer, dementia, mood disorders and osteoporosis. Medically indicated standard CVD risk reduction must always be included (figure 4). Following these discussions, if it is determined that HT will be prescribed, waiting to reach the arbitrary definition of menopause ‘12 months following the last menstruation’ is not necessary.

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Figure 4

Individualised decision making for the prescriptive use of HT. The decision to prescribe HT to menopausal women must be undertaken only after careful consideration of each woman’s unique set of risk factors and of the potential health benefits and contribution to quality of life derived from HT. All HT discussions should include joint decision making. Standard CV risk reduction measures should always be included in the care of PM and perimenopausal women. CV, cardiovascular; CVD, cardiovascular disease; DEXA, dual energy X-ray absorptiometry; DHEA, dehydroepiandrosterone; DVT, deep vein thrombosis; HT, hormone therapy; MI, myocardial infarction; PE, pulmonary embolism; PM, postmenopausal; TIA, transient ischaemic attack.

Numerous studies document beneficial cardiometabolic effects of endogenous E2 and P4 during the reproductive years, effects related to hormonal rhythms and serum levels. The concept of ‘the smallest dose’ solely derived from misapplied WHI results. We propose abandoning that approach, instead advocating for the ‘most efficacious dose’. Animal models of atherosclerosis demonstrating that physiological oestrogen levels attenuate atherosclerosis lesion development in newly menopausal females support this modification.45 46

Ultimately, data may show that restoring physiological hormonal rhythms best optimise cardiometabolic health. Pending studies confirming that hypothesis, we advocate applying current knowledge of CV effects of hormonal levels to guide our proposed recommendations.

Physiological serum levels of E2 attenuate oxidative stress47 and correlate with elevated glutathione and glutathione peroxidase activity.48 Lower E2 is associated with reduced serum 25 OH vitamin D levels, impacting immune system regulation.43 In one publication, PM women with higher levels of E2 had reduced CAC scores, independent of age and other CHD risk factors.44

The Danish Sex Hormone Register Study used the national registry to assess risk of MI with HT use, reviewing duration, doses, regimens and routes of administration. In all age groups, highest risk of MI occurred with continuous P4/oestrogen regimen, with no increased risk when cyclic combined therapy was used,33 supporting the premise that cyclic P4 is superior for CV health than daily, continuous P4.

After considering the entirety of data concerning human-identical hormones and CV health, we recommend using continuous transdermal E2, as a gel, cream or patch, dosed to achieve a serum level of approximately 100 pg/mL (at least 50 pg/mL), to support CV and menopausal health—improving quality of life, mood disorders, sleep quality, bone health, hot flashes, night sweats and urogenital health (online supplemental figure 1).46 Serum E2 levels should be measured to ensure proper dosing. We also recommend oral P4, dosed at 200 mg at bedtime for the first 14 days each month, approximating menstrual cycle rhythms. Vaginal bleeding may occur mid-month, following 2 weeks of P4 dosing, reflecting a physiological hormonal milieu with regular shedding of the endometrial lining. We recognise that not all women will prefer or do best on this regimen, therefore, individualisation is recommended. Oral oestrogen regimens are included for completeness but are not recommended by us (table 2).

Our recommendations and proposed future directions

Medical societies, including the American College of Cardiology (ACC),49 American Heart Association and European Society of Cardiology, modified their HT positions, shifting to individualised approaches based on CVD risk assessment and patient-specific medical situations, recommending HT initiation within 10 years of menopause or prior to age 60 years. The United Kingdom National Health Service website states, ‘… recent evidence says … risks of HT are small and … usually outweighed by the benefits’. ACC acknowledges reduced risk with transdermal E2 over oral hormonal preparations. Recommendations for ‘the lowest dose for the shortest time’ remains, without an official HT recommendation for cardioprotection. We feel these recommendations should be reconsidered (table 3).

The North American Menopause Society states that data do not support routine discontinuation of HT at age 60–65 years, with continued use based on assessing quality of life, persistent vasomotor symptoms or desire to prevent bone loss and fracture. Women using hormones long-term would continue with appropriate surveillance measures.38 We concur with this assessment, but go further.

Existing data generally support that PM HT is safe and beneficial. Approximately 1.3 million American women enter menopause every year. Based on current knowledge, E2+P4 use should be discussed with appropriately selected women to treat symptoms, strengthen bones, improve quality of life and to preserve CV health through their PM years, augmenting standard CVD risk reduction measures.

Additional references can be found in online supplemental file 1.