Menopausal hormone therapy: where are we now?

In 2017, the North American Menopause Society (NAMS) released a comprehensive summary of the evidence on the benefits and risks of MHT.^{1 *} The risks associated with MHT depend on the woman’s age or time since menopause, whether oestrogen + progestogen or oestrogen alone is used, the formulation, dose, duration of use,^† route of administration, and personal and family risks of breast cancer, cardiovascular disease, stroke and venous thromboembolism.¹

^* The recommendations made by NAMS take into consideration findings from the Women’s Health Initiative trials, other RCTs, meta-analyses of RCTs and observational studies. This does not include additional analyses to provide overall risk estimates.

^† Stroke and VTE risk do not appear to be affected by duration of treatment, but are influenced by the woman’s age.¹

No differences in all-cause mortality with MHT

An 18-year cumulative follow-up of the Women’s Health Initiative trials, which included over 27,000 women, found no difference in all-cause, cardiovascular or total cancer mortality with either oestrogen + progestogen or oestrogen alone MHT.⁶

N.B. These data were published after the 2017 NAMS guidance.

Breast cancer

Key points about breast cancer risk and MHT:¹

• The Women’s Health Initiative trial found that oestrogen + progestogen MHT increased the risk of breast cancer (an absolute increase of < 1 case per 1,000 woman-years). Further analysis showed that this increased risk was only in women who had previously used MHT.
• Oestrogen-only MHT does not appear to increase breast cancer risk and some analyses have found possible reductions in risk
• The risks of breast cancer may be increased with longer durations, e.g. more than seven years, and higher doses of MHT.⁷ The risk decreases after stopping MHT.³
• There is some evidence that the breast cancer risk may be higher with continuous progestogen use than with cyclical use⁸
• Micronised progesterone may be associated with a lower breast cancer risk than medroxyprogesterone
• The limited data available suggest that MHT does not further increase breast cancer risk in women at high risk, e.g. due to family history or BRCA mutations
• Prior COC does not appear to increase the risk of breast cancer in women using MHT ⁹
• Other factors such as alcohol use and physical activity levels have also been shown to influence the risk of breast cancer, and ways to reduce risk can be discussed with women⁴

Undergoing screening for breast cancer with mammography is recommended every two years for females aged 45–69 years.¹⁰

N.B. The International Menopause Society (IMS) released a statement regarding a 2019 analysis on the association between MHT and increased breast cancer risk. The IMS noted that the analysis included primarily observational studies using older MHT regimens that do not reflect current recommendations and therefore have limited applicability to current practice. The statement is available here: www.imsociety.org/manage/images/pdf/5054afeb9b1bc763032333443f1c0bed.pdf

Cardiovascular disease

Coronary heart disease (CHD):^* The effects of MHT on CHD vary depending on the woman’s age or time since menopause when treatment was initiated.¹ For women aged < 60 years or fewer than 10 years since menopause, MHT may reduce the risk of CHD.¹ A Cochrane review found a 30% relative risk reduction in all-cause mortality and a nearly 50% relative risk reduction in CHD with MHT use when treatment was initiated within ten years of menopause.¹¹ Oestrogen alone appears to offer greater benefit than oestrogen + progestogen.³ These treatment effects are no longer present when MHT is initiated more than ten years from menopause.¹¹ For women initiating MHT > 20 years since menopause, CHD risk may be increased, however, only in women taking combined oestrogen + progestogen MHT.¹

^* Composite of death from cardiovascular causes and non-fatal myocardial infarction

Stroke: The risk of stroke associated with MHT depends on the woman’s age or time since menopause when treatment was initiated.¹ RCTs have shown no increased risk of stroke in women who start MHT aged < 60 years or within ten years of menopause, but an increased risk if initiated after age 60 years or more than ten years from menopause.¹ The Women’s Health Initiative trial found an absolute risk of stroke of < 1 per 1,000 woman-years in women aged < 60 years when they initiated MHT.¹

Venous thromboembolism (VTE): Both oestrogen alone and oestrogen + progestogen MHT have been associated with a higher VTE risk across all ages, however, the absolute risk of VTE in women aged < 60 years is small (approximately 1 per 1,000 women per year, increased to 2 per 1,000 women per year when using oral MHT).^{1, 12} Transdermal oestrogen, as well as lower doses of oral or transdermal oestrogen, are associated with lower VTE risk.¹ The absolute risk of VTE increases with increasing age; other factors such as smoking and obesity also increase VTE risk.¹

Bone fracture

The use of MHT is associated with small reduction in fracture risk (all fractures combined), with 44 and 53 fewer fractures per 10,000 woman-years with oestrogen + progestogen and oestrogen alone, respectively, compared to placebo.¹³ This reduced risk begins within the first few years of treatment.^{14, 15} However, women at high risk of fracture should be prescribed bisphosphonates as a first-line treatment option, i.e. women with a previous fracture, a 10-year risk of hip fracture ≥ 3% or T-score of ≤ –2.5 from a dual energy X-ray absorptiometry (DEXA) scan.¹⁶

N.B. Participants in the Women’s Health Initiative trials were not selected on the basis of having low bone density or osteoporosis. MHT lowered fracture risk in women with normal or low bone mineral density, not just in those with osteoporosis.

Information to help patients to consider the risks and benefits of MHT is available from:

• Videos from the Australasian Menopause Society
• PDF fact sheets and infographic print outs

Contraception should be continued in sexually active women until one to two years after the last menstrual period or at age 55 years when a natural loss of fertility can be assumed (Table 3).¹⁹

The 52 mg levonorgestrel IUD (Mirena) can be used both as a contraceptive and to provide endometrial protection as part of a MHT regimen. When prescribed for endometrial protection, the IUD should be replaced after five years. If used solely for contraception, a 52mg levonorgestrel IUD can be left in place until the age of 55 years if it was inserted at age 45 years or over.¹⁹ Extended use of the smaller 13.5mg levonorgestrel IUD (Jaydess) is not recommended due to a lack of data on effectiveness as a contraceptive beyond the approved duration of use.¹⁹

Table 3: Guidance on the choice of contraceptive for females approaching menopause. Adapted from the Faculty of Sexual and Reproductive Healthcare.¹⁹

^* A copper IUD inserted after the age of 40 years can be used until contraception is no longer required

^** FSH: follicular stimulating hormone. For patients with FSH levels of ≥ 30 IU/L, progestogen-only methods should be used for one more year and then can be discontinued

Other pharmacological treatment options may be considered for women with contraindications to MHT or those who do not wish to use it. Lifestyle changes to manage menopause symptoms should be discussed with all women.

Lifestyle changes

Lifestyle changes, e.g. avoiding triggering foods or drinks, smoking cessation, weight loss and exercise, are a low risk approach that may help menopausal symptoms and reduce risks of chronic disease. Psychological techniques such as cognitive behavioural therapy, mindfulness and hypnosis have been shown to improve vasomotor symptoms of menopause.²²

Vaginal treatments are effective for urogenital symptoms

For women who principally have urogenital symptoms, non-hormonal vaginal moisturisers (e.g. Replens) and lubricants can assist with vaginal dryness, itching or pain during intercourse. These are available over-the-counter (not funded). If non-hormonal options do not provide adequate symptom relief, a 0.1% estriol cream or 500 microgram estriol pessary are available fully funded.¹⁸ These have fewer risks than systemic hormone treatment and can be prescribed without the addition of a progestogen in females with a uterus.^{17, 21}

Vaginal oestrogen formulations may be prescribed with caution to patients with a history of hormone-dependent cancer, e.g. breast or endometrial cancer, as they do not increase serum oestrogen levels beyond the normal menopausal range. However, they should only be used if patients have trialled other non-hormonal approaches and consultation with the patient’s oncologist may be appropriate.²³

Other pharmaceutical options

Various other pharmacological treatments options are available to help manage the vasomotor symptoms of menopause, with varying levels of evidence supporting their effectiveness. This includes:²⁴

• Selective serotonin or serotonin-noradrenaline reuptake inhibitors, e.g. paroxetine,^* citalopram, escitalopram and venlafaxine
• Tibolone (not funded)
• Clonidine
• Gabapentin or pregabalin^†
• Oxybutynin^†

^* Avoid in women using tamoxifen as it may affect the conversion of tamoxifen to its active metabolites²⁵

^† Unapproved indication

Complementary and alternative medicines

A range of over-the-counter supplements, remedies or alternative medicines are marketed for the treatment of menopausal symptoms, e.g. St. John’s Wort, maca, phytoestrogens. However, none of these are as effective as oestrogen treatment for menopausal symptoms.²⁶ If women enquire about non-pharmacological options, consider whether there is any evidence of effectiveness, safety, contraindications and potential for medicines interactions.

“Bioidentical” hormones are not recommended

“Bioidentical” hormones are synthesised to have the same chemical composition as hormones produced by the body. These are prepared by a compounding pharmacist as creams or troches (dissolvable lozenge), and are often marketed as “natural” and “safer” alternatives to “synthetic” hormones.²⁷ However, these products are unregulated; there is no requirement for the same testing and safety data as for conventional MHT medicines, and there is no consistency of dosing.⁴ There is also little evidence to show that these are effective. For example, transdermal wild yam creams are promoted as a natural source of progesterone. They contain diosgenin, a steroid with no hormonal activity, which can be synthesised into progesterone in a laboratory setting. However, the human body is unable to do this and the cream can therefore have no beneficial effect on menopause symptoms.