Clinical Endocrinology

INVITED REVIEW
Reproduction

Update on Menopause Hormone Therapy; Current

Indications and Unanswered Questions
Annice Mukherjee1,2 | Susan R. Davis3,4
1
Centre for Intelligent Healthcare, Coventry University, Priory St, Coventry CV1 5FB, UK | 2Dept of Endocrinology, Spire Manchester Hospital, 170 Barlow
Moor Rd, Manchester M20 2AF, UK | 3Women's Health Research Program, School of Public Health and Preventive Medicine, Monash University, Melbourne,
VIC 3004, Australia | 4Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC 3004, Australia

Correspondence: Annice Mukherjee ([email protected])

Received: 6 November 2024 | Accepted: 19 January 2025

Keywords: hormone replacement therapy | menopause | menopause hormone therapy | menopause transition | perimenopause

ABSTRACT
Objective: To provide clinicians involved in managing menopause with a summary of current evidence surrounding meno-
pause hormone therapy (MHT).
Design: The authors evaluate and synthesize existing pooled evidence relating to MHT's clinical indications, efficacy, and safety
and explore the limitations of existing data.
Patients: The review focuses on MHT‐related outcomes in women with natural‐timed menopause captured within observa-
tional studies, RCTs, and pooled data from pivotal meta‐analyses and reviews.
Measurements: Available published data are scrutinized. Available evidence and notably lacking data from women not
adequately represented in published MHT trials, such as those with socioeconomic adversity, significant comorbidities, and
minority ethnic backgrounds, are highlighted and deliberated.
Results: The impact of MHT differs significantly between demographics. Current consensus recommendations for MHT
emphasize the importance of tailoring type, route, dose, and duration of therapy to individual needs and risk/benefit ratio
through shared decision‐making. MHT impact can change over time. Current MHT data support its benefits for treating
menopause symptoms and a potential window of opportunity in midlife to benefit skeletal health. Limitations of current
evidence highlight menopause health inequalities and underscores the need for further research.
Conclusions: This review recommends tailored use of MHT for well‐defined indications, recognizing its value for menopause
symptom relief and skeletal benefits for many midlife women. MHT may be used as long as benefits outweigh risks, through
shared decision‐making. There is insufficient clinical evidence to support the long‐term use of MHT in some contemporary
cohorts of women accessing MHT in clinical practice.

1 | Introduction their healthy counterparts, such as women with premature

ovarian insufficiency (POI) [1]. Pragmatically, the two terms are
Menopause hormone therapy (MHT) is a broad term encom- commonly used interchangeably. For this review, which focuses
passing an array of hormone treatments primarily used to on managing natural timed menopause, the term MHT has
alleviate symptoms associated with a naturally timed meno- been adopted.
pause transition. In contrast, the term hormone replacement
therapy is a more appropriate term for the replacement of In this review the term MHT refers to regulator‐approved sys-
hormones for women with hormone insufficiency relative to temic estrogenic therapy, and estrogenic‐progestogenic treatment

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly
cited.

© 2025 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.

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combinations and considers the changing landscape of MHT and fracture risk has been observed in women using MHT before
its users in recent years and the rationale for using preparations the age of 60. There is some attenuation of protection following
commonly favored today. Subcutaneous estrogen implants are cessation of MHT; however, importantly, there is no evidence of
unlicensed and are not discussed. Estrogen, DHEA and proges- increased risk of rebound fractures on discontinuation of ther-
terone used by the vaginal route and transdermal testosterone apy [25]. As such, MHT is now recognized in postmenopausal
are also sometimes described as MHT, even though their indi- osteoporosis guidelines [19, 26, 27]. Although not universally
cations, bioavailability, clinical effects and risks differ from approved for bone protection in the UK, MHT should be con-
conventional systemic MHT. Research evidence for some of these sidered as a first option for bone protection in women with early
hormone‐based preparations is limited. These therapies are or natural menopause over antiresorptive or osteoanabolic
touched on briefly. therapies, unless there are over‐riding reasons for bone‐specific
therapy use such as glucocorticoid associated bone loss. Fur-
Oral conjugated equine estrogens (CEE), and medrox- thermore, MHT may be continued long‐term if the benefits for
yprogesterone acetate (MPA), which were the predominant bone health and menopause symptoms continue to outweigh
hormones in the early years of MHT prescribing, and in the the side effects and risks.
large pioneering trials of MHT [2–5], have been largely super-
seded in the last 20 years by regulator approved formulations of A summary of MHT indications and benefits in women with
estradiol, along with various later generation progestogens and low overall rates of comorbidity and in the absence of a diag-
progesterone [6, 7]. Non‐oral MHT preparations have lower nosis of hormone related cancer or other contraindications is
side‐effect profiles at recommended doses [8]. Nonetheless, the provided in Box 1.
benefits, risks, and side effects of different MHT combinations
vary [7]. Some cohorts of women, such as those with complex co-
morbidities are not well represented in MHT research, and
The limitations of the principle findings of the Women's Health therefore there are uncertainties, due to lacking data in such
Initiative (WHI) [2], the Million Women Study [3] and other ex- women [28]. These women may still benefit from MHT and will
tensive pioneering studies of MHT [4, 5] are now well recognized be discussed in Section 5.5.
[9]. Emergent differences in outcomes according to age, dose,
route and type of MHT used have enabled better stratification of
risks and benefits of different formulations of MHT to facilitate 2.3 | MHT and Cardiovascular Health
individualized treatments, which are embedded into current
international consensus recommendations [7, 10, 11] [9, 12–19]. MHT is only recommended for cardiovascular disease (CVD)
protection in the context of POI based on available observa-
tional data [29, 30]. There is however insufficient evidence to
2 | Indications and Health Benefits of MHT
BOX 1 | Summary of MHT indications and benefits in women
2.1 | MHT for Menopause Symptoms in Healthy
with low rates of comorbidity and in the absence of a diagnosis of
Women
hormone‐related cancer or other strong contraindications.

The cardinal symptoms causally associated with menopause are

vasomotor symptoms (VMS), menstrual changes, disrupted MHT benefits
sleep, and genitourinary symptoms [20–22]. Muscle and joint
First line treatment for symptoms causally linked with
aches may predominate, particularly in Asian women [23]. In
menopause: VMS & related fatigue, sleep & mood
addition, many women describe new onset mood and cognitive
changes. Urogenital atrophy related symptoms.
symptoms, fatigue, palpitations, changes in body habitus, and
sexual dysfunction [20]. The menopause transition can last for Estrogen therapy in regulator approved MHT doses
several years, with most women experiencing symptoms, and considerably lowers the risk of hip, vertebral and other
for 25% of women, symptoms are clinically severe [20]. fractures in women with normal bone density,
osteopenia and osteoporosis & improves bone density.
MHT is considered the most effective currently available Cardiovascular protection in healthy younger & midlife
treatment for menopause symptoms with strong international women.
consensus [19]. MHT in healthy symptomatic women during a Transdermal estrogen, micronized progesterone and
natural timed menopause transition is associated with symp- levonorgestrel IUS do not appear to increase VTE risk.
tomatic benefits, and low risks.
Transdermal estrogen & micronized progesterone
appear favorable to blood pressure in normotensive
women and neutral to blood pressure in hypertensive
2.2 | MHT and Bone Health women.
Oral estrogen appears neutral to blood pressure in
A meta‐analysis of RCTs assessing fracture risk in women using
hypertensive women.
oral and transdermal estrogens (with or without the addition of
a progestogen) reported a 20% to 37% reduced risk of hip, ver- Abbreviations: VMS, vasomotor symptoms; VTE, venous
thromboembolism; IUS, intrauterine system
tebral, and total fracture [24]. A more pronounced reduced

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support the use of MHT for primary cardiovascular prevention if used in women with fluctuating endogenous estrogen during
in postmenopausal women [31]. perimenopause, may result in erratic and unpredictable bleed-
ing. As perimenopausal women may still require contraception,
While some guidelines recommend that MHT is not com- the progestogen‐only contraceptive containing drospirenone
menced after the age of 60 years or ten years beyond men- (where it is available) can be used with “add‐back” transdermal
opause, the evidence to support this merits review [32]. After estradiol. This may be particularly useful for women with cat-
18 years of follow up, all‐cause, CVD, and cancer mortality amenial migraine who need ovulation suppression but for
did not differ between the hormone therapy and placebo whom the COC is contraindicated.
arms in both WHI studies [33]. Furthermore, the WHI data
pertains specifically to oral estrogen therapy, with or without Women more than 1 year beyond their final menstrual period
MPA, in predominantly asymptomatic women [2, 34]. with an intact uterus usually use a continuous combined MHT
Evidence to justify applying these age and years‐since‐ regimen of systemic estrogen and continuous systemic proges-
menopause limits to the initiation of non‐oral estrogen togen. Advice should be given that breakthrough bleeding is
therapy for symptomatic women is lacking. These blanket common in the first 3–6 months.
recommendations therefore urgently need review. Otherwise
healthy women beyond 60 years or more than 10 years from Another MHT option for women 12 months post menopause is
final menstrual period who may benefit from MHT for tibolone [38], a compound that has estrogenic, progestogenic,
symptoms relief, may have an increased background risk of and androgenic actions Tibolone has a single oral dosing
venous thromboembolism (VTE) or stroke with oral estro- schedule, alleviates menopause symptoms and reduces bone
gen, but data do not support putative increased risk with loss and fracture [39]. A combination of CEE plus bazedoxifene
transdermal estrogen based regimens. acetate, a selective estrogen receptor modulator [40] may be
suitable for women in whom treatment with progestogen‐
containing therapy is not appropriate and who do not have
3 | Contemporary Systemic MHT Regimens increased vascular risks.

The principal aim of MHT is to relieve menopause‐related In women without a uterus, estrogen‐only MHT can be prescribed
symptoms with systemic estrogen. Concurrent progestogen ther- where indicated, other than following subtotal hysterectomy or in
apy is required to protect the endometrium in people with a the context of severe active endometriosis. Endometriosis is a
uterus. Much of the efficacy and safety data relating to MHT relate hormone‐dependent disease, and estrogen replacement has been
to oral estradiol and progestogen preparations [2–4]. However, associated with a risk of recurrence or malignant transformation.
some data relates to licensed doses of transdermal estradiol, non‐ In this situation, progestogen treatment may be recommended
oral progestogens and oral micronised progesterone [20, 35]. post‐hysterectomy [41]. It is noteworthy that estrogen‐only therapy
will not suppress perimenopausal ovulation (where ovaries are
In healthy, non‐hysterectomised women who are menstruating intact after hysterectomy), so may not alleviate ovulatory symp-
and within 12 months from the final menstrual period, a toms during this phase.
sequential MHT regimen may be commenced. This aims to
provide continuous systemic estrogen delivery with added luteal If higher than approved doses of estrogen are prescribed, a
phase progestogen. Sequential MHT ideally results in a sched- proportionate increase in progestogen has recently been rec-
uled withdrawal bleed and may usually be continued for up to ommended in the UK to reduce the risk of endometrial thick-
5 years or up to the age of 55 years. However, as these regimens ening and hyperplasia [16]. There are, however, no long‐term
do not suppress ovulation, women may experience symptoms safety data for doses of estrogen plus progestogen above the
due to their underlying fluctuating ovarian function including regulator‐approved doses. Intuitively, higher doses of any
unscheduled bleeding. This might partly explain why use of estrogen‐progestogen combination may be associated with fur-
sequential MHT for over 5 years has been reported to be asso- ther future increased breast cancer risks [3, 42]. Furthermore
ciated with endometrial thickening [36]. In perimenopausal optimized endometrial protection with effective progestogen
women, continuous systemic estrogen may be used with an administration, and screening where appropriate, is vital for
intrauterine device, which delivers progestin continuously into women with metabolic problems, including obesity and diabe-
the uterus for endometrial protection. While this provides tes, which increase the risk of endometrial hyperplasia [16].
contraception and usually results in minimal or no vaginal This is also crucial if MHT is considered in women with uterine
bleeding, women may still have the adverse effects of fluctuat- leiomyomas [43], which are more prevalent in black women
ing ovarian function. [44], but in whom data for efficacy and safety of MHT regimens
is lacking. MHT regimens currently commonly used and
Combined oral contraceptives (COCs) previously considered available are summarized in Table 1.
suitable for some women during natural timed menopause have
inherent risks, including VTE risk. However, estradiol‐ The choice of MHT regimen is individual and nuanced, with
containing COCs can be used in women who would be candi- patient preference a key consideration. It is usual to require
dates for oral estradiol therapy, to suppress ovulation and early MHT dose adjustments, and self‐limiting unscheduled
alleviate symptoms. These may be used continuously to elim- bleeding is not uncommon in the weeks after treatment initia-
inate cyclical bleeding. Emerging and promising data relating to tion [16]. To minimize MHT‐related side effects, a sagacious
an estetrol containing COC may allow this to be used more and commonly adopted strategy is to start with a low to mid‐
safely during perimenopause in the future [37]. MHT regimens, range licensed dose and up‐titrate the dose to symptoms or

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TABLE 1 | Summary of commonly used MHT regimens.

Sequential MHT regimens Continuous combined MHT regimens

Fixed dose regimens
Sequential oral Daily continuous oral
• Estradiol/Estradiol+Dydrogesterone • Estradiol/Dydrogesterone 0.5 mg/2.5 mg
1 mg/1 mg+10 mg • Estradiol/Dydrogesterone 1 mg/5 mg
• Estradiol/Estradiol+Dydrogesterone • Estradiol/Norethisterone acetate 2 mg/1 mg
2 mg/2 mg +10 mg • Estradiol/Norethisterone acetate 1 mg/0.5 mg
• Estradiol/Medroxyprogesterone 1 mg/2.5 mg
• Estradiol/Estradiol+Norethisterone acetate • Estradiol/Medroxyprogesterone 1 mg/5 mg
2 mg/2 mg/1 mg+1 mg (Triphasic)
• Estradiol/Estradiol+Norethisterone 1 mg/1 mg • Estradiol/Medroxyprogesterone 2 mg/5 mg
+1 mg (triphasic) • Estradiol/Progesterone 1 mg/100 mg
• Tibolone 2.5 mg
• Conjugated Equine Estrogens/Basedoxifene0.45 mg/20 mg
Sequential Transdermal Continuous Transdermal
• Estradiol/Estradiol+Norethisterone acetate twice • Estradiol/Norethisterone acetate twice weekly patch
weekly patch 3.2 mg/3.2+11.2 mg 3.2+11.2 mg
• Estradiol/Estradiol+Levonorgestrel once weekly • Estradiol/Levonorgestrel once weekly patch 1.5+0.525 mg
patch 1.5 mg/1.5+1.5 mg
Estrogen/progestogen separate dosing regimens
Continuous oral or transdermal estrogen;
• Estradiol tablets 1 mg/2 mg
• Estradiol patch doses range from 25 μg to 100 μg/24 h
• Estradiol gel pump (750 μg/actuation) 1–4 pumps daily
• Estradiol gel sachets 0.5–1.5 g daily
• Estradiol spray (1.53 mg/spray) dose ranges from 1 to 3 sprays daily
If endometrial protection required add luteal If endometrial protection required add continuous daily
phase (12–14 days) progestogen; oral progestogen;
• Micronized progesterone 200 mg • Micronized progesterone 100 mg
• Provera 10 mg • Provera 2.5–5 mg
• Norethisterone 5 mg • Norethisterone 5 mg (0.5–1 mg is sufficient but not available in
stand‐alone preparation
• Dydrogesterone 10 mg • Dydrogesterone 2.5–5 mg PO daily
• 52 mg Levonorgestrel IUD • 52 mg Levonorgestrel IUD
Footnote: This is not an exhaustive list. Where non‐fixed dose regimens are used, higher doses of estrogen are likely to require proportionate increases in progestogen
dosing for endometrial protection. For regulator‐approved dose ranges see the summary of product characteristics. Where above‐licensed doses are used, appropriate
informed consent, should be obtained to facilitate shared decision‐making regarding treatment effect uncertainties.

down‐titrate to side effects. Most side effects can be mitigated the UK, has led to concerns around tachyphylaxis [45] and
with dose or route adjustments and will often resolve with unscheduled vaginal bleeding [16, 46]. Nonresponse to higher
ongoing treatment. Table 2 summarizes common MHT side estrogen doses may indicate other potential contributors to
effects and options to address them. symptoms. Some women choose to discontinue treatment due
to lack of benefit or side effects; the experience of these women
MHT dosing is usually based on symptom response to is not currently well captured.
regulator‐approved regimens. Measurement of estradiol levels is
not routinely recommended. Estrogen levels may be useful in
some women with persistent symptoms using transdermal es- 3.1 | MHT Duration of Treatment
tradiol. A change in route of delivery may alleviate symptoms.
Not all women tolerate standard MHT regimens, and some do There is no arbitrary time limit for MHT use and continuation
not achieve symptom relief. An observed recent increased use of or discontinuation is guided by shared decision‐making, with
transdermal estrogen dosing, outside regular approved doses in the prescriber responsible for ensuring the patient is fully

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TABLE 2 | Summary of common side effects, with mitigation options.

Estrogen related side‐effects Mitigation of estrogen‐related side‐effects

Fluid retention, bloating, weight gain Dose reduction, change delivery route, change preparation, exclude other
causes for symptoms
Nausea/dyspepsia
Headaches
Breast discomfort
Anxiety
Progestogen‐related side effects Mitigation of progestogen related side‐effects
Fluid retention, bloating, weight gain Change delivery route or pattern, change preparation, exclude other
causes of symptoms
Cyclical mood symptoms
Headaches
Breast discomfort
Drowsiness (progesterone)

informed. If symptoms recur following treatment cessation option for suitable postmenopausal breast cancer survivors and
resumption or use of non‐estrogen options can be considered. should be made available where appropriate and considered safe.
There is evidence of an increased breast cancer risk with longer
durations of therapy in otherwise healthy postmenopausal There are inadequate data relating to vaginal dehydroepi-
women, possibly increased endometrial cancer risk with some androsterone in cancer survivors to guide recommendations.
MHT regimens [42, 47] and adverse vascular outcomes in older Oral ospemifene is likely to be safe in breast cancer survivors
women with established vascular disease [48]. This nuance without contraindications to its use [55].
should be shared with women where relevant.

4.2 | Testosterone Therapy

4 | Hormone Treatments Beyond Systemic MHT
Testosterone may be prescribed for postmenopausal women
4.1 | Treatment of Genitourinary Symptoms Due with low sexual desire after a biopsychosocial approach has
to Menopause excluded other causes of symptoms, such as relationship diffi-
culties and psychological and medication‐related causes. Com-
Local vaginal therapy may be used alone or in combination with bined testosterone therapy and psychosexual approaches may
systemic MHT for genitourinary symptoms, including symp- be beneficial in cases with mixed aetiologies. The NICE Men-
toms of vulvovaginal atrophy (VVA), urinary urgency and opause Guideline (NG23) [56] recommends that a trial of con-
recurrent urinary tract infections. Local therapy comprises low‐ ventional MHT is given before testosterone supplementation is
dose topical vaginal estrogen administered twice weekly or considered. However, postmenopausal women not requiring
vaginal dehydroepiandrosterone [49]. Topical vaginal therapies MHT can be given a trial of testosterone for low desire with
have an overall superior safety and side effect profile compared associated distress. A global consensus on testosterone for
to systemic MHT [7, 20, 50]. Systemic progestogen is not women published in 2019 provides more detailed guidance
required with regulator‐approved doses of vaginal estrogen based on the best available evidence and expert consensus [57].
therapy. Oral ospemifene is a selective estrogen receptor mod-
ulator that can also be used to alleviate VVA symptoms [51].
5 | MHT Risks and Cautions

4.1.1 | Vaginal Therapy Use in Breast Cancer Survivors Based on current pooled evidence, risks with MHT differ by age
of initiation, type, route of administration, dose, duration, time
Several cohort studies have shown reassuring results with since menopause onset, type of progestogen, if used, and pat-
vaginal estrogen therapy concerning recurrence risk among tern of prescription [7, 58]. Personalized approaches facilitate
many women with a personal history of breast cancer [52–54]. tailoring of MHT to individual needs and risk‐benefit ratio.
However, data relating to the use of vaginal estrogen in breast There is no universally optimal regimen.
cancer survivors treated with aromatase inhibitors have not
been definitively reassuring [54].
5.1 | CVD Risk
Given genitourinary symptoms associated with menopause are
prevalent in postmenopausal women and topical vaginal estrogen is The legacy of the WHI study is well documented, with many
an effective treatment, recent data generally endorse this treatment lessons learned [9]. Its primary aim was to evaluate

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cardiovascular disease prevention with estrogen, guided by embolism are not considered an association with transdermal
previous observational study results. The simple outcomes were estrogen‐based MHT [72–75].
a small but statistically significant reduced CVD risk in post-
menopausal women aged 50–59 years with estrogen only ther- In a recent study assessing the effects of different progestogens
apy but no benefit for any other group studied. Sub‐group on VTE risk in reproductive‐age women, use of norethindrone
analysis from WHI [59], confirmed low CVD risks in younger acetate and medroxyprogesterone acetate, (considered higher‐
healthy postmenopausal women without established vascular dose progestogens), were significantly associated with increased
disease. odds of incident acute VTE [76]. This was not the case for
standard dose systemic or intrauterine progestogen systems. In
A Cochrane database systematic review published in 2015 sug- general, higher dose systemic progestogens are not used as part
gested that there is strong evidence that treatment with MHT in of MHT in post‐menopausal women.
postmenopausal women, for either primary or secondary pre-
vention of CVD events, neither increased no decreased CVD Although there is no robust RCT evidence available for the risk
events overall. Nonetheless, subgroup analysis from this sys- of VTE comparing the route of MHT administration in specific
tematic review demonstrated that MHT started, or used by populations (such as women with thrombophilia), there is high‐
women before the age of 60 years or within 10 years of meno- quality, large‐scale epidemiological evidence demonstrating
pause was associated with a lower mortality, although they were that transdermal estrogen, combined with oral micronised
still at increased risk of venous thromboembolism [60]. progesterone or synthetic progestogens in standard MHT doses,
do not appear to be associated with an increased VTE risk [77].
The discrepancy in cardiovascular‐related MHT effects in dif-
ferent cohorts has been attributed to a hypothesis of the timing of Oral estrogen therapy is associated with a slight increase in the
initiation of MHT. The timing hypothesis suggests that estrogen‐ risk of stroke. Transdermal estrogen at a dose equivalent to a
mediated vascular benefits require initiation of estrogen therapy 50 μg/day patch does not appear to increase the risk of stroke
before the detrimental effects of vascular ageing are established above a woman's own background risk, however doses above
[61], and following prolonged estrogen deprivation, any cardio- this have been associated with an increased stroke risk [78].
protective effects of estrogen may be lost. This assumption is Therefore, transdermal estrogen at the lowest effective dose is
reasonable in healthy women who reflect the relevant clinical the preferred for women at increased stroke risk. Modifiable
trial participants. Nonetheless, no prospective trials exist that factors that can contribute to the absolute risk of stroke,
define the optimal duration or type of MHT. Therefore, such including smoking, hypertension, hyperlipidaemia, obesity and
recommendations are based on extrapolation [7, 62]. diabetes, should be addressed in all women.

Women with multiple CVD risk factors have generally been

excluded from MHT RCTs [63] and are underrepresented in
5.2 | Dementia Risk with MHT
observational studies, which carry healthy‐user bias [64]. Where
high‐risk women have been included, results with earlier gen-
The currently available, pooled overall data on dementia risk
eration combined MHT preparations have not demonstrated
with MHT shows a null effect. Due to the heterogeneity of the
meaningful benefits for chronic disease outcomes, some have
populations studied and the MHT regimens used, no conclu-
shown increased morbidity [4, 5]. Furthermore, biological vas-
sions can be drawn [8].
cular ageing is complex and not exclusively dependent on es-
trogen. Women with significant risk factors may develop
progressive vascular disease in the presence of estrogen, an
observation exemplified by the known existence of CVD in 5.3 | Endometrial Risk With MHT
premenopausal women [65, 66].
Unscheduled bleeding on MHT is well recognized and can
In the absence of clear‐cut evidence, clinicians should exercise affect up to 40% of users [79]. In England, estradiol gel and
caution in extrapolating favorable CVD data from clinical micronised progesterone were the top two prescribed MHT
trials with stringent inclusion criteria to high‐risk cohorts items in 2022. In parallel with this increase in prescribing, there
receiving MHT in clinical practice, such as those with multiple has been a rapid rise in unscheduled bleeding on MHT, of
comorbidities. around 43% in the UK between 2021 and 2024 and a corre-
sponding increase in referrals to the urgent suspicion of cancer
Women using oral MHT (estrogen alone and estrogen with pathway for unscheduled bleeding. This has necessitated a
progestogen) are exposed to a 2–4 fold increased risk of VTE formal consensus guidance to support clinicians [16]. Over the
compared to non‐users [67, 68], and the risk of VTE with CEE‐ same interval, the rate of endometrial cancer diagnoses rose
is nearly twice as high as that of estradiol‐containing MHT [69]. by 2%.
This is not true for transdermal estrogen‐based MHT [70, 71].
This difference is now understood to relate to oral estrogens The increased uptake of MHT outside clinical trials may be
undergoing first‐pass hepatic metabolism, activating the coag- linked to the unexpected rise in unscheduled bleeding in UK
ulation system, and increasing liver biosynthesis of procoagu- women utilizing MHT in recent years. The characteristics of
lant factors. In contrast, the effects of transdermal estrogen on women accessing MHT in clinical practice differ from those of
the liver proteins are neutral [72]. Based on these observations clinical trial participants, with a higher occurrence of co-
and much‐accumulated data, the risk of venous thrombosis and morbidities. Micronised progesterone may be considered a

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preferred progestogen for MHT in the context of, for example, Sixty to 70% of breast cancers express testosterone receptors
obesity due to its favorable VTE, stroke and breast cancer risk [92]. However, these are not routinely screened for in clinical
profile. However, these women have an increased risk of en- practice. The observations that testosterone therapy may
dometrial cancer [80]. Furthermore, some data suggest that increase [93] or decrease [94] breast cancer risk inform the
licensed doses of cyclical micronised progesterone, used in unmet need for data collection in women treated with testos-
combined MHT, may be inadequate for preventing estrogen‐ terone therapy outside clinical trials.
induced endometrial hyperplasia [47].
A large body of data now suggests that topical vaginal estrogen
Given the current high rates of obesity globally [81], the pres- does not increase the risk of primary breast cancer [42, 84].
ence of obesity in women seeking MHT should warrant a
careful discussion regarding the choice of progestogen for en- A summary of MHT risks in women with low rates of
dometrial protection. comorbidity and in the absence of a diagnosis of hormone‐
related cancer or other strong contraindications is provided
in Box 2.
5.4 | Primary Breast Cancer Risk Associated
With MHT
5.5 | MHT Use in Women With Cardiometabolic
Breast cancer risks associated with MHT vary by type, timing,
Comorbidities, Increased Hormone Related
and duration of treatment [42, 82–84]. Breast density, an
Cancers Risks and Other Medical Problems Where
independent risk factor for breast cancer [85], has been
There Are Uncertainties Due to Lack of Evidence
observed to increase with regimens containing estradiol and
CEE [86]. Individual risk is also influenced by background
MHT may benefit women with multiple cardiometabolic risk
breast cancer‐associated genetic, environmental, and lifestyle
factors and higher hormone related cancer risks, experiencing
factors [87].
intrusive menopause symptoms. Recognizing, candidly dis-
cussing and addressing underlying risk factors should be
MHT‐associated breast cancer risks appear lower with estrogen‐
prioritized if MHT is to be deployed in such women [95]. MHT‐
only therapy [42, 83], with the most favorable data relating to
specific risks should be identified to inform the judicious use of
the use of CEE [83]. CEE formulations contain more than ten
tailored MHT regimens. Different hormone therapy doses, for-
estrogens that bind with a differential affinity for the two es-
mulations, and routes of administration have different effects
trogen receptor types (ERα and ERβ) and also have differential
on target organs, allowing many options to minimize individual
actions on the target tissue, similar to selective estrogen
risks. For example, transdermal estrogen is neutral to VTE and
receptor modulators (SERMs). The SERM‐like activity of CEE
stroke risk [77, 96]; the transdermal estrogen route is therefore
may confer superior breast protection compared with other
favored in women with increased vascular risk.
estrogen plus progestogen combinations [7, 83, 88]. There
appear to be further differences based on the progestogen used.
Micronised progesterone and dydrogesterone MHT combina-
tions have been found to confer lower risks than other pro- BOX 2 | Summary of MHT risks in women with no or minor
gestogen combinations when used at the recommended dose, comorbidity and in the absence of a diagnosis of hormone related
with licensed doses of estrogen [6]. However, the data are cancer or other strong contraindications.
limited, and larger studies are needed to better characterize the
risks of progesterone and dysdrogesterone. Tibolone has been
associated with a lower risk of primary breast cancer than MHT related risks
standard combined MHT in some studies [39]. Oral estrogen increases VTE & stroke risk.

The overall MHT‐associated breast cancer risk during the early High dose transdermal estradiol may increase stroke risk.
post‐menopause, for 5 years of therapy, in otherwise healthy Some high dose systemic progestogens used at
women appears small. There are additive breast cancer risks contraceptive doses (norethindrone acetate and
with each five additional years of MHT [42]. WHI RCT data and medroxyprogesterone acetate) may increase VTE risk.
observational data from the Million women study indicate that Increased risk of endometrial hyperplasia and cancer risk
MHT has the least impact on breast cancer risk in women with with inadequate progestogen dosing for endometrial
overweight/obesity and the greatest impact on breast cancer protection.
risk in normal weight women [2, 3]. Data on MHT‐associated
Small increased risk of new breast cancer diagnosis
primary breast cancer risk in generally healthy cohorts of
evident after 5 years of treatment of naturally timed
women, including those with overweight and obesity may not
menopause. Relative risk relates to type of MHT
be directly transferable to women with additional breast cancer
regimen:
risk factors.
Estrogen only < Sequential MHT < Continuous
Postmenopausal obesity, high alcohol intake, and smoking combined MHT.
independently increase breast cancer risk, and regular physical Risk increases with duration of therapy.
activity reduces risk [89]. Whether or not multiple risk factors
Footnote: VTE, venous thromboembolism
have additive effects on risk is unknown [90, 91].

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Women with diabetes are at increased risk of breast and en- individually determined risks and benefits, may justify MHT
dometrial cancers, dementia, and vascular disease [80, 97, 98]. after breast cancer in some clinical scenarios, in conjunction
These women are not well represented in MHT research; with the breast oncology team.
therefore, the longer‐term effects of modern MHT formulations
on such women are unknown. These considerations should be Triple‐negative breast cancer (TNBC) is currently also con-
shared with women to inform decision‐making. sidered a contraindication to MHT. Any assumption that
TNBC is completely hormone‐insensitive is incorrect [109].
Addressing chronic disease burden through risk‐reducing However, nuanced individual assessment of TNBC is needed
strategies is an essential consideration in high‐risk women in the clinical setting because many such women are pre-
treated with MHT and embodies good clinical practice. Ex- menopausal at diagnosis and may be rendered post-
amples include offering women with pre‐diabetes enrollment menopausal prematurely by their treatment. After 5 years of
into a diabetes prevention program [99] and ensuring those disease‐free survival, the recurrence risk for TNBC falls sig-
with diabetes receive appropriate support to optimize diabetes nificantly compared with ER‐positive disease [110]. Where
control [98]. Women at increased risk of primary breast cancer BRCA risk genes are identified, many such women will also
should be counseled about risks if MHT is deemed necessary, have risk‐reducing surgery. In some clinical scenarios after
with consideration given to using regimens with lower breast TNBC treatment, the risks of MHT may be significantly
cancer‐associated risk. Depending on specific symptoms and reduced, and benefits deemed justified, after careful consid-
patient preference, non‐hormone treatment options may also be eration, shared decision making and informed consent, in
considered. For several medical conditions, data are absent to conjunction with the breast oncology team.
guide risk/benefit ratio with MHT.

A summary of MHT risk/side effect amelioration in women

5.7 | MHT After Other Estrogen Sensitive
with common comorbidities and long‐term conditions, where
Cancers
there is currently limited or absent clinical evidence for MHT,
and therefore uncertainties, is provided in Table 3.
In women with a prior history of early‐stage and surgically
treated endometrial cancer, combined estrogen plus progesto-
gen MHT may be considered if the clinical scenario suggests
5.6 | MHT Use After a Breast Cancer Diagnosis
that it is justified, with shared decision‐making in conjunction
with the patient's oncology team. There are no data to guide
Breast cancer is the most frequently diagnosed neoplastic disease
recommendations for MHT use in advanced‐stage endometrial
in women [100], and survival rates have improved over recent
cancers and other rare estrogen‐sensitive tumors.
decades. Around three in four women diagnosed with breast
cancer in England are expected to survive the next 10 years.

Chemotherapy is frequently integral to breast cancer treatment 6 | MHT Uncertainties and Unknowns
in premenopausal women and can induce early menopause,
which may cause debilitating symptoms. Hormone receptor‐ Where there are uncertainties or absent data, cooperation and
positive breast cancers are also usually treated with adjuvant collaboration between stakeholders can help to inform shared
endocrine therapies to block natural estrogen, and these decision‐making. Relevant factors to be considered include
unequivocally improve disease‐free and overall survival [101, those relating to the underlying comorbidity or long‐term
102]. They can, however, result in side effects, including men- condition, the type of MHT used, and patient preference
opause symptoms. (Table 3).

A history of breast cancer is generally considered a major The majority of published MHT research includes a predomi-
contraindicated to MHT. Three significant studies have previ- nance of white, socially advantaged women with overall low
ously investigated the use of MHT after a breast cancer diag- rates of underlying disease. Extrapolating data from historical
nosis. The first two studies, Stockholm and HABITS [103–105], research trials to fundamentally different demographics may
both found a higher risk of breast cancer recurrence with MHT. not be accurate, and some evidence suggests that selective
The LIBERATE trial [106] studied tibolone treatment after a interpretation of research data is facilitating misinformation
breast cancer diagnosis and was also stopped prematurely after about menopause outcomes with MHT [111–114].
an increased risk of recurrence was identified.
Comorbidities may influence risks with MHT and these tend to
Based on various criticisms of these studies there are some increase with age. Women from minority ethnic and socio-
schools of thought suggesting further MHT trials are warranted economically disadvantaged backgrounds may have differing
in breast cancer survivors [107]. However, highly effective risk profiles, but data are lacking due to their under-
nonhormonal therapies are now available to treat severe vaso- representation in MHT research.
motor symptoms [108]. Although not yet approved specifically
for women post‐breast cancer, these should be considered Where data are lacking, the collection of real‐world evidence is
before initiation of estrogen therapy. Outside clinical trials, it is crucially needed to identify and address health inequalities [115].
generally agreed that patient choice, based on assiduous in- This is a pressing issue because women with complex comorbid-
formed consent and shared decision‐making relating to ities and those from minority ethnic and socioeconomically

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TABLE 3 | MHT risk/side effect amelioration in women with common comorbidities and long‐term conditions, where there is currently limited
evidence for MHT and therefore uncertainties. Counseling regarding MHT risk uncertainties is recommended to aid informed consent for all
patients in these categories.

Comorbidity/long‐term condition General action MHT specific risk amelioration

Class 2/3 obesity Optimize management of underlying Transdermal estrogen is vascular
Class 1 obesity/overweight with condition/refer/signpost to relevant risk neutral. Avoid oral route
comorbidities services estrogen.
Prediabetes with comorbidities Micronised progesterone and
Poorly controlled diabetes levonorgestrel IUS are preferred
Poorly controlled hypertension progestogen options where there is
Established active cardio/cerebrovascular increased vascular risk as vascular
disease risk neutral
Current smoker Depending on bleeding history
Alcohol excess consider assessing endometrial
thickness to guide progestogen
Multiple Sclerosis As row 1
Chronic liver disease (MHT is Assess severity and identify underlying As row 1
contraindicated in acute severe/ diagnosis.
undiagnosed liver disease)
Advances chronic kidney disease stage 4/5 Specialist collaboration Multiple risks As row 1
including bone loss, renal bone disease,
hypertension, vascular disease need
careful consideration.
Migraine Assess and address triggers. As row 1.
Aim to optimize management with High estrogen doses may trigger
treatment according to national migraines. If this occurs, it may
migraine guidelines. resolve with dose reduction
Specialist referral may be indicated Consider drospirenone for
ovulation suppression in
perimenopause
Severe hyperlipidaemia Determine QRISK3 score, discuss As row 1
overall risk and management including Oral estrogen will increase HDL
lipid lowering therapy cholesterol and lower LDL
cholesterol
MPA and norethisterone will
lower lipoprotein(a)
Transdermal estrogen is more lipid
neutral
History or high risk of VTE Identify and address ongoing risk As row 1
factors. Hematology referral in complex Oral estrogen is contraindicated
cases
Epilepsy Specialist collaboration to optimize As row 1
disease control. Liver enzyme inducing
Antiepileptic enzyme inducing drugs antiepileptic drugs may be
promote bone loss. Identify/address impacted by oral Estrogen. Oral
associated increased risk of osteoporosis MHT may increase seizure
frequency.
History of endometriosis/uterine Assess symptom contribution from Gynecological history/symptoms to
leiomyomas/adenomyosis/polyps/ gynecological problem: anemia/pain/ guide MHT regimen Follow recent
endometrial thickening/unscheduled/ pressure effects. Identify/address UK consensus guidance pathway for
undiagnosed bleeding associated risk factors. Specialist unscheduled bleeding on MHT
gynecology referral/assessment/
investigations may be indicated

(Continues)

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TABLE 3 | (Continued)

Comorbidity/long‐term condition General action MHT specific risk amelioration

Gut absorption problems Identify and treat underlying diagnosis Transdermal estrogen preferred.
Transdermal or IUS progestogen
preferred. Oral micronised
progesterone may still be an option
Lupus Specialist collaboration to optimize Estrogen increases the
control. susceptibility to lupus through
Identify/address associated increase risk uncertain mechanisms.
of osteoporosis. If MHT is indicated the
Patients treated with transdermal estrogen route & oral
immunosuppressive agents have an micronized progesterone may be
increased risk of non‐Hodgkin's preferred. Cases with high VTE
lymphoma and breast cancer risk, should be discussed with
hematologist.
Porphyria Regional specialist input required. Expert opinion suggests some types
Postmenopause is associated with a of acute porphyria's may be
reduction in acute porphyria attacks triggered by progestogens and oral
estrogens.
Abbreviations: IUS, intrauterine system; VTE, venousthromboembolism

disadvantaged women are increasingly accessing MHT in clinical

practice.
Conflicts of Interest
While women may consider MHT in older age, clear and valid A.M.: honoraria from Astellas, Novartis, Lilly.
indications for treatment should be identified and documented.
Longer durations of MHT may be associated with a cumulative Unpaid Steering Group Chair, Society for Endocrinology Real World
increased background breast cancer risk, even in otherwise Data Registry.
healthy women [3, 42]. MHT in this context should be used for
S.R.D.: honoraria from Abbott Laboratories, Astellas, Bayer, Besins
clearcut evidenced indications such as persistent VMS, with
Healthcare, and Mayne Pharma, has served on Advisory Boards for Mayne
shared decision‐making and periodic re‐evaluation. Pharma, Astellas Pharmaceuticals, Gedeon Richter, Theramex and Besins
Healthcare, and has been an institutional investigator for OvocaBio.

7 | Conclusions and Future Directions

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