Summary of evidence for 2019 surveillance of menopause (2015) NICE guideline NG23

Vasomotor symptoms

Vasomotor and general menopausal symptoms, including quality of life were assessed in 8 RCTs (1–8) and 2 Cochrane reviews (9,10) (table 1 in the data tables appendix). The included studies assessed a variety of different HRT strategies including oestrogen only and combined HRT in a range of formulations including oral, transdermal and intravaginal preparations.

Vaginal symptoms

Vaginal symptoms and sexual function were assessed in 7 RCTs (11–17) and 1 Cochrane review (18) (table 2 in the data tables appendix). Most studies assessed intravaginal preparations of HRT compared with placebo or another active treatment, usually HRT. HRT improved vaginal symptoms in 7 of the 9 comparisons against placebo and showed no effect in the other two comparisons. All 5 of the comparisons of HRT against another active treatment showed no difference between the groups.

Depression

In 2 RCTs (19,20) HRT was associated with improvements in symptoms of depression compared with placebo (table 3 in the data tables appendix).

Other outcomes

In 2 RCTs (3,21) comparing different preparations of HRT, oestrogen may be more effective than progestogen or conjugated equine oestrogen for improving hormone levels and acceptance by patients. In 1 RCT (17) patients using vaginal oestrogen may be more likely to use the product again when compared with placebo (table 4 in the data tables appendix).

Adverse effects

Adverse effects of HRT were reported in 3 Cochrane reviews (9,10,18) and 1 RCT (3) (table 5 in the data tables appendix). A range of preparations of oestrogen-only HRT, including oral, transdermal, and intranasal showed worse or no effects on adverse events compared with placebo (6 comparisons), or other preparations of HRT (1 comparison). Oestrogen tablets had no effect on endometrial thickness compared with placebo, but an oestrogen ring preparation increased endometrial thickness compared with oestrogen cream. Tibolone was associated with more bleeding than placebo but less than combined HRT.

Vasomotor symptoms

Topic expert feedback noted that the terminology around 'bioidentical hormones' is confusing because it can be used to mean chemically identical to the hormones produced by the human body (such preparations are regulated), and preparations of different hormones in ratios produced in the body (which are not regulated). The study of 'bioidentical' oestrogen (9) included regulated products.

Topic experts also suggested that recommendations for women with breast cancer (and other hormone-dependent cancers) should be expanded, for example how treatments for vaginal atrophy might differ for women on tamoxifen and those on aromatase inhibitors.

Vasomotor symptoms

The guideline recommends offering HRT for vasomotor symptoms after discussing the risks and benefits. The new evidence indicating that HRT improves vasomotor symptoms and quality of life is consistent with current recommendations.

The guideline does not currently recommend tibolone because it was associated with reduced quality of life compared with no treatment, and thus was not cost effective. The finding that tibolone was associated with worse vasomotor symptoms compared with conjugated equine oestrogens is therefore consistent with evidence considered during guideline development.

The guideline additionally noted that 'the efficacy and safety of unregulated compounded bioidentical hormones are unknown'. One study assessed 'bioidentical' hormones but referred to regulated products rather than unregulated compounded bioidentical hormones are unknown'. However, new evidence suggested no difference in hot flushes between regulated bioidentical hormones and conjugated equine oestrogens, so no update to consider these treatments separately is necessary.

There is some overlap in recommendations on treatment of menopausal symptoms in women with or at high risk of breast cancer across NICE guidelines, particularly in the guidelines on early and locally advanced breast cancer and familial breast cancer. The guideline on menopause already has cross-references to the breast cancer guidelines. These guidelines have more detailed recommendations for women with or at risk of breast cancer who have treatment-related menopausal symptoms. We did not find sufficient new evidence to support an update of the menopause guideline in this area.

Vaginal symptoms

The guideline recommends offering vaginal oestrogen to women with urogenital atrophy, including those already on systemic HRT. The new evidence that vaginal oestrogen improves vaginal symptoms and sexual function is consistent with current recommendations.

Depression

The guideline found evidence suggesting that HRT improved symptoms of depression, and recommends considering HRT to alleviate low mood, which is consistent with the new evidence identified in surveillance.

Other outcomes

New evidence indicated that HRT, particularly vaginal oestrogen, was acceptable and satisfactory for patients, and improved hormone levels. The guideline did not address these aspects of HRT use in depth, but the new evidence provides support for the current recommendation to offer intravaginal HRT for women with vaginal symptoms.

New evidence indicated that different hormone preparations may improve levels of follicle stimulating hormone, luteinising hormone and oestrogen. However, these physiological outcomes were not considered by the guideline and the new evidence does not indicate that changes in hormone levels are directly related to changes in symptoms. Therefore, an update to consider these outcomes is not necessary.

Adverse effects

The guideline notes that unscheduled vaginal bleeding is a common side effect of HRT in the first 3 months of treatment. Although study abstracts often did not define what adverse events were included, the new evidence did not highlight any unexpected adverse events. Prescribers should consult the summary of product characteristics for information on possible adverse effects associated with individual HRT products. The guideline should not be updated to consider additional adverse events of HRT at this time.

New evidence is unlikely to change guideline recommendations.

Drug treatments

We identified 11 RCTs of non-HRT drug treatments for menopausal symptoms (table 6 in the data tables appendix). All drugs were compared against placebo, except for 1 study that used a non-active control (vaginal moisturiser).

Physical and psychological therapies

We identified 9 RCTs that assessed the effects of physical and psychological treatments for menopause (table 7 in the data tables appendix).

Cognitive behavioural therapy (CBT) was assessed in 3 studies (31–33) with wait list and menopause education acting as controls. Self-managed, therapist-based and telephone-based CBT were associated with improvements in night sweats and insomnia, but inconsistent effects were seen on hot flushes with effects seen in one study (composite outcome of hot flushes and night sweats), but no effect was seen in another study.

New evidence for other physical and psychological therapies indicated that:

Alternative medicine and complementary therapies

We identified 10 RCTs that assessed a variety of herbal remedies (14,41–51) such as extracts from lavender (and lavender aromatherapy), bitter orange, hops, soy, and homeopathic and ayurvedic preparations compared against mostly placebo controls (table 8 in the data tables appendix).

The trials assessed a range of outcomes including vasomotor symptoms, hot flushes, sleep quality and anxiety and depression. Most studies indicated a significant effect of the herbal remedy; however, the homeopathic remedy had no effect on hot flushes or quality of life compared with placebo.

Chinese herbal medicine

In 1 Cochrane review (52) and 1 RCT (53), Chinese herbal medicine compared with HRT, other drug treatments or placebo, had no effects on menopausal or vasomotor symptoms including hot flushes and night sweats or adverse events (table 9 in the data tables appendix).

Acupuncture

We identified 6 RCTs of acupuncture (table 10 in the data tables appendix) (54–59), 4 of which used a non-sham acupuncture control group (for example, self-care, wait list, or alprazolam).

The studies found improvements in sleep quality, vasomotor symptoms, and oestrogen levels, but no effect on luteinising hormone or follicle stimulating hormone levels. However, these studies may be at risk of bias because the control group was aware that they were not receiving acupuncture.

In 2 RCTs comparing acupuncture with sham acupuncture, inconsistent results were seen for hot flushes. Hot flushes were statistically significantly improved in 1 study, but the result was noted to be less than the minimum clinical difference. There was no effect on hot flushes in the other study. The study finding improved hot flushes also reported improved menopausal symptoms and menopause-related quality of life. However, these measures could be driven by effects on hot flushes to some degree, so they do not indicate a clear clinically important effect.

Drug treatments

The guideline did not consider melatonin, oxybutynin or oxytocin. The clinical importance of the results reported in the abstracts was unclear and the studies were generally conducted in small numbers of people. Larger studies are needed to clarify the role of these treatments in menopause. Therefore, the guideline should not include these treatments in an update.

The guideline assessed venlafaxine but made no recommendations on this drug. The authors of the study of venlafaxine noted that the effects on sleep were 'modest', and the change in quality of life was small and of borderline statistical significance. Overall, the clinical significance of the findings is unclear. Therefore, there is no clear indication that an update to the guideline to consider venlafaxine is needed.

The guideline did not consider prasterone although it was available as a supplement in some countries when the guideline was developed. A preparation of prasterone is now available (costing £15.94 for 28 pessaries) for treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe symptoms in the UK. New evidence suggests that prasterone may reduce vaginal symptoms of menopause and improve sexual function over 3 months of treatment. One of the studies identified in surveillance was also highlighted by topic experts. However, the evidence suggested that prasterone was no more effective than vaginal moisturiser for vaginal dryness and dyspareunia. Further evidence on the effects with prasterone treatment longer than 3 months and longer-term safety data is needed before considering an update of the guideline to evaluate the role of prasterone for treating vaginal symptoms of the menopause.

The guideline assessed ospemifene but made no recommendations on this drug. At the time of guideline development, ospemifene had recently received marketing authorisation in the UK, but its cost was unknown, so it could not be considered alongside vaginal oestrogen in the evidence review. However, it is now available in the UK (costing £39.50 for 28 tablets) and is licensed for use in postmenopausal women who are not candidates for local vaginal oestrogen therapy.

The evidence on ospemifene reviewed during guideline development included 7 studies, with analyses of the various outcomes including 331 to 1971 women. The quality of these studies ranged from very low to moderate quality. The evidence indicated that ospemifene improved dyspareunia and vaginal dryness. Ospemifene also affected several physiological outcomes, such as reducing parabasal and intermediate cells, increasing superficial cells, and reducing vaginal pH. Ospemifene treatment for up to a year was not associated with endometrial hyperplasia, but endometrial thickness was increased. It was associated with more adverse events than placebo, but women were not more likely to stop treatment over 12 weeks. The new evidence was consistent with these findings and indicated improvements in sexual function. However, the new evidence did not report on adverse events associated with ospemifene. It was not possible to tell from the abstracts whether the effects were clinically meaningful, or durable.

The cost of prasterone is comparable with available intravaginal oestrogen pessaries, and although ospemifene is more expensive, its use is restricted to a smaller group of women for whom intravaginal oestrogen is not suitable. Therefore, we do not expect these treatments to have a substantial impact on NHS resources. Additionally, we are not aware of any new safety issues relating to other treatments for vaginal symptoms of menopause. For these reasons, we decided that an update was not necessary at this time.

New evidence is unlikely to change guideline recommendations.

Physical and psychological therapies

The guideline recommended considering CBT to alleviate low mood or anxiety that arise as a result of the menopause. The new evidence suggests that CBT may be useful for coping with other menopausal symptoms. Additionally, topic experts indicated that an update should look at CBT. However, because of heterogeneity in the type of CBT intervention, and the lack of information on the clinical importance of the effects sizes reported in the abstracts, the evidence base for CBT does not appear to have advanced sufficiently to indicate a need to update the guideline at this time.

Similarly, the evidence did not show a clear effect of device-guided slow-paced breathing health coaching and exercise interventions and foot reflexology and self-directed learning were each assessed in a single small trial. A larger body of evidence is needed to support considering these treatments in a guideline update.

New evidence is unlikely to change guideline recommendations.

Alternative medicine and complementary remedies

The guideline does not recommend the herbal remedies identified in the new surveillance evidence. However, it recommends explaining to women who wish to try complementary therapies that the quality, purity and constituents of products may be unknown. The new evidence consisted of relatively small RCTs (100–200 participants). Larger studies evaluating complementary therapies in preparations with standardised quality, purity and constituents are needed before considering an update in this area.

New evidence is unlikely to change guideline recommendations.

Chinese herbal medicine

The guideline does not have recommendations on Chinese herbal medicine. The new evidence found no effect of this treatment on any relevant outcomes, indicating that an update in this area is not necessary.

New evidence is unlikely to change guideline recommendations.

Acupuncture

The guideline does not recommend acupuncture and the new evidence, showing little clinically important effect of this treatment, indicates that an update to include acupuncture is not necessary.

New evidence is unlikely to change guideline recommendations.