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Menopausal hormone therapy: where are we now?

Menopausal hormone therapy (MHT) is an effective treatment for symptoms associated with menopause, such as hot flushes, night sweats, mood changes, sleep disturbances and changes in sexual function. While the evidence around MHT has changed over the years, there is now international consensus that the benefits of MHT are likely to outweigh the risks for most women aged < 60 years or within ten years of menopause, for whom menopausal symptoms are affecting their quality of life.

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Published: 16 December 2019


Key practice points:

  • Every woman’s experience of menopause is different, and perceptions of menopause vary across cultures. Most women will experience some menopause symptoms, however, only some will seek treatment.
  • Menopausal hormone therapy (MHT) is likely to offer overall benefit to women with menopausal symptoms affecting their quality of life if they are aged < 60 years or within ten years of menopause
  • Adverse outcomes associated with MHT include breast cancer, stroke and venous thromboembolism (VTE). However, the risk of these outcomes depends on factors such as the age or time since menopause when MHT is initiated, MHT type, dose, duration of use,* route of administration, and whether a progestogen is used.
  • Women prescribed MHT who have a uterus must take progestogen in addition to oestrogen to avoid an increased risk of endometrial cancer; women who have had a hysterectomy can take oestrogen alone
  • Among the oestrogen and progestogen formulations available, transdermal oestrogen (funded) and micronised progesterone (not funded) are associated with the lowest risk of adverse effects
  • There is no specific recommended duration for MHT. The decision to continue treatment should be reviewed on an annual basis, taking into account any changes in the patient’s risk factors, adverse effects and extent of benefit.
  • If women primarily seek assistance for urogenital symptoms of menopause, vaginal products are recommended instead of MHT. This includes moisturisers, lubricants or a vaginal oestrogen cream or pessary.

* Stroke and VTE risk do not appear to be affected by duration of treatment, but are influenced by the woman’s age.1
Unless they are taking oestrogen + bazedoxifene (not funded)

Menopause is associated with a range of symptoms including hot flushes and night sweats (vasomotor symptoms), vaginal dryness, itching or pain during intercourse, changes in mood or sleep patterns, and joint or musculoskeletal discomfort. Most women close to the age of menopause in New Zealand report they have menopausal symptoms when asked, but little data is available on ethnic or cultural differences or preferred treatment approaches.2 Many women will not find their symptoms troublesome enough to seek assistance, but some women may experience symptoms which significantly affect their quality of life.

MHT* is the most effective treatment for the vasomotor symptoms and urogenital atrophy associated with menopause.1 However, MHT use has been controversial, largely due to early research findings from the Women’s Health Initiative trials that raised concerns about the safety of this treatment. Evidence from longer-term follow-ups of these trials, as well as from other RCTs and observational studies, has led to international consensus that the benefits of MHT are likely to outweigh the risks in most women with menopause symptoms affecting their quality of life if they are aged < 60 years or within ten years of menopause.1, 3, 4

* Hormone replacement therapy for peri- or postmenopausal women is now referred to as MHT to differentiate it from hormone replacement for other endocrine conditions, e.g. growth hormone replacement.

The Women’s Health Initiative trials investigated whether MHT would reduce the incidence of heart disease, cancer and fractures in postmenopausal women.5 The trials were stopped early due to increased risks of breast cancer, stroke, coronary heart disease and pulmonary embolism. It should be noted that these trials included few women aged < 60 years or within ten years of menopause with menopausal symptoms (the group that MHT is primarily indicated for), and only one route of administration (oral) and only one formulation and dose of oestrogen and progestogen.1

What are the current recommendations for prescribing MHT?

Initiate MHT in women who experience symptoms that affect their quality of life

The primary reason to initiate MHT should be to treat menopause symptoms or replace a hormone deficiency, e.g. due to primary ovarian insufficiency.1, 3 Some women may experience additional benefits, such as reduced risks of fracture, type 2 diabetes or cardiovascular disease, however, these should not be the primary reason for initiating MHT.1

For information on the use of MHT for women with primary ovarian insufficiency, see: www.bpac.org.nz/2019/ovarian.aspx

MHT is safest in women closer to the natural age of menopause

The decision to initiate MHT should be guided by the woman’s age or the time since her final menstrual period (see: “What do the current data say about the safety of MHT?”).1 The benefit-risk ratio is most favourable for women aged < 60 years or within ten years of menopause, provided they have no contraindications.1 For women aged > 60 years or more than ten years since menopause, the benefit-risk ratio is less favourable due to the greater absolute risks of stroke, venous thromboembolism and dementia. The overall risk of coronary heart disease is not increased, but there may be some increased risk in women who initiate combined oestrogen + progestogen MHT > 20 years since menopause.1

There is no upper limit on the duration of MHT use

The average duration of vasomotor symptoms of menopause is 7.4 years and some women may experience symptoms for more than ten years.1 Guidelines do not recommend an upper limit to how long women should use MHT; provided new contraindications do not develop, e.g. a new onset hormone-dependent cancer, MHT can be continued if it is beneficial.1

The main points to consider when deciding whether to prescribe MHT and what regimen to use include (see Figure 1 for examples):

  • The woman’s age or time since her final menstrual period
  • Any contraindications (see Figure 1) or cautions to MHT use (see below)
  • Whether she has an intact uterus; MHT regimens must include oestrogen + progestogen* in women with a uterus as oestrogen alone can cause endometrial hyperplasia and increase the risk of endometrial cancer

* Except if oestrogen + bazedoxifene is chosen as this combination provides endometrial protection without need for a progestogen.1 Bazedoxifene is a selective estrogen receptor modulator. This form of MHT is indicated for the treatment of menopausal symptoms in women with a uterus who had their last menstrual period > 12 months ago for whom progestogen treatment is not appropriate or tolerated.18

Caution is recommended when prescribing MHT to women with:17

  • An increased risk of breast cancer
  • A strong family history of venous thromboembolism or inherited thrombophilia – discussion with a haematologist is recommended
  • Increased risk of cardiovascular disease or venous thromboembolism (caution with oral oestrogen)
  • Hypertriglyceridaemia (> 400 mg/d) (caution with oral oestrogen)

When discussing menopausal symptoms, ensure that women who are sexually active are prescribed an appropriate contraceptive, as this is still required until women are postmenopausal (see: “Contraceptive needs for perimenopausal women”).

* Continuous use of progestogen can result in irregular bleeding

Extending the use of a cyclic progestogen regimen for an additional year after the last menstrual period may provide better control of bleeding

Micronised progesterone (not funded) may be preferable if cost is not a barrier. Evidence suggests that this formulation has less effect on markers of cardiovascular and thrombotic risk.17 N.B. This formulation must be used for a minimum of 12 days per cycle to provide effective endometrial protection.

Figure 1. Prescribing algorithm for initiating MHT in women with menopause symptoms affecting their quality of life1

A range of fully funded, partly funded and non-funded MHT options are available

Table 1 shows the MHT options available in New Zealand. Refer to the NZF for dosing information: www.nzf.org.nz/nzf_3855 and to Figure 1 for examples.

Choosing an oestrogen: Oestrogen should be initiated at the lowest dose. Transdermal estradiol is likely to be the most practical option due to the difficulty of dividing tablets to achieve a low dose, and the cost to the patient of other formulations that are not funded. Transdermal oestradiol also has a more favourable safety profile in terms of cardiovascular risk than oral oestradiol, particularly in older women.

Options for women beginning treatment with oestrogen include:

  • 25 micrograms estradiol transdermal patch applied twice weekly, e.g. Monday and Thursday, (fully funded)
  • 500 micrograms estradiol oral tablet, daily. This equates to half a tablet of the lowest strength available for many formulations and some tablets cannot be cut in half. Estradiol valerate (Progynova) 1 mg tablets are fully funded but efficacy is lost if they are divided. Estradiol 1 mg tablets (Estrofem) can be divided and are partly funded.
  • 300 micrograms conjugated equine oestrogens oral tablet, daily, e.g. Premarin, partly funded

Choosing a progestogen: For women requiring combined oestrogen + progesterone MHT, this can be prescribed as:

  • An oestrogen tablet or patch with a separate formulation of oral progestogen – provides greater dose control than combination formulations (fully funded options available). The oral progestogen may be taken cyclically* or continuously (Figure 1).
  • An oestrogen tablet or patch with a levonorgestrel intrauterine system (Mirena – fully funded) – provides progestogen without having to use an oral formulation; this option also provides contraception for women who may still become pregnant
  • A combination oestrogen + progesterone formulation; cyclical and continuous formulations available (partly funded)

* A withdrawal bleed occurs towards the end of, or after, the progestogen treatment cycle. N.B Up to 25% of women will not have a withdrawal bleed.

Suitable for five years’ use when prescribed for endometrial protection as part of an MHT regimen19

A guide is available from the Australasian Menopause Society to assist with changing doses or formulations of MHT: https://www.menopause.org.au/images/stories/infosheets/docs/AMS_Guide_to_Equivalent_MHT-HRT_NZ.pdf

Table 1: MHT formulations available in New Zealand18

Route of delivery Funding status* Dose forms
(refer to NZF for dosing regimens)
Oestrogen only products
Estradiol patch Transdermal 25, 50, 75 or 100 micrograms/24 hours (applied twice weekly)
Estradiol valerate tablets Oral 1 mg, 2 mg
Estradiol tablets 1 mg, 2 mg
Estriol 2 mg
Ethinylestradiol 10 micrograms
Conjugated equine oestrogens 300, 625 micrograms
Progestogen only products
Medroxyprogesterone acetate Oral 2.5 mg, 5 mg, 10 mg
Norethisterone tablets
(unapproved indication)
Oral 350 micrograms (Noriday),
5 mg (Primolut N)
52 mg levonorgestrel IUD (Mirena) Intrauterine 20 micrograms/day
Progesterone capsule
(micronised – Utrogestan)
Oral ** 100 mg
Combination products
Estradiol + norethisterone tablets Oral 2 mg estradiol + 1 mg norethisterone
1 mg estradiol + 0.5 mg norethisterone
Cyclical (three doses):
  • 2 mg oestradiol
  • 2 mg oestradiol + 1 mg norethisterone
  • 1 mg oestradiol
Conjugated equine oestrogens + bazedoxifene Oral 450 micrograms conjugated equine oestrogens + 20 mg bazedoxifene

* Funding status: Fully funded, Partly funded, Not funded

Women with a uterus must also be prescribed a progestogen unless using the combination of oestrogen + bazedoxifene

A 13.5 mg levonorgestrel IUD (Jaydess) is also available, however, this is not approved for providing endometrial protection as part of an MHT regimen

** Unsubsidised for use as MHT

Transdermal oestrogen is associated with a lower risk of adverse effects

Transdermal application avoids first-pass metabolism and results in fewer effects on markers of cardiovascular risk than other formulations of oestrogen. Transdermal oestrogen should be considered first-line, particularly for women with:17

  • Increased cardiovascular risk
  • Increased risk of venous thromboembolism
  • Hypertension
  • Type 2 diabetes
  • Obesity
  • Hypertriglyceridaemia
  • Migraine

Schedule a follow-up appointment after initiation of a MHT regimen, e.g. in one month, to assess treatment effect. Adverse effects of MHT include bloating, breast tenderness, increased blood pressure, headaches, fluid retention and urinary incontinence.17 Changes in the dose or formulation of MHT may improve these symptoms (Table 2).

A guide is available from the Australasian Menopause Society to assist with changing doses or formulations of MHT: https://www.menopause.org.au/images/stories/infosheets/docs/AMS_Guide_to_Equivalent_MHT-HRT_NZ.pdf

Unscheduled, heavy or irregular bleeding is common in the first three months of use of a continuous progestogen regimen, however, if it occurs after three to six months of use of any MHT regimen, consider endometrial cancer and perform or refer for pipelle biopsy and refer for ultrasound if appropriate.20 If endometrial cancer is diagnosed, MHT must be stopped as this is a contraindication.17

If women develop urinary incontinence or have worsening symptoms while taking MHT but do not wish to discontinue treatment, pelvic floor muscle training may improve symptoms.3 For women with primarily urogenital symptoms, switching to vaginal oestrogen treatments may improve urinary incontinence.3

Continued use of MHT should be reviewed at least annually. Discuss menopausal symptoms and reassess whether continuing use is appropriate, or dose adjustments need to be made. Update any new family history, e.g. breast cancer, as this can influence the benefit-risk ratio.4 Ensure women are having regular mammograms; screening for breast cancer with mammography is recommended every two years for females aged 45–69 years.10


Table 2: Suggested options for reducing adverse effects or improving the effectiveness of MHT.17, 20

Symptom or adverse effect Suggested course of action

Persistent vasomotor symptoms

Increase MHT doses or trial another formulation

Breast tenderness

Reduce the dose of oestrogen or switch to another progestogen. If tenderness remains on further follow-up, consider discontinuing MHT, switching patients to tibolone, or prescribing conjugated equine oestrogens + bazedoxifene (not funded).

Unscheduled bleeding within the first three months

Within the first three months of MHT:

  • Consider continuing treatment unless there is a high suspicion of endometrial cancer as bleeding may settle with time
  • Other options include:
    • Switching to cyclical progestogen for patients taking continuous progestogen
    • Increasing the dose of progestogen
    • Switching from oral progestogen to a levonorgestrel IUD

After the first three to six months of MHT:

  • Organise further investigations for endometrial cancer
  • If no endometrial pathology is detected, consider increasing oestrogen dose

Discontinuing MHT

Gradually taper the dose when MHT is withdrawn, e.g. by changing to a lower dose formulation or to alternate day dosing, as this can reduce the short term incidence of menopausal symptoms and may be better tolerated by patients.21 Remind women of sleep hygiene approaches to minimise any sleep disturbances associated with MHT withdrawal.

Women who require fracture prevention should switch to another treatment, e.g. a bisphosphonate, as the protective effect of MHT on bone mineral density declines after treatment is stopped.3

Acknowledgement

Thank you to Dr Anna Fenton, Gynaecological Endocrinologist, Canterbury DHB for expert review of this article.

N.B. Expert reviewers do not write the articles and are not responsible for the final content.


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