Management of Menopausal Symptoms in a General Female Population

Management of menopausal symptoms in a general female population

Supplementary evidence review

March 2016

Management of menopausal symptoms in a general female population: Supplementary evidence review was prepared and produced by:

Cancer Australia
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© Cancer Australia 2016.

ISBN Online: 978-1-74127-317-5

Recommended citation

Cancer Australia, 2016.Management of menopausal symptoms in a general female population: Supplementary evidence review, Cancer Australia, Surry Hills, NSW.

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Contents

Contents

Tables

List of Abbreviations

Executive summary

1Introduction

2Methods

2.1Inclusion criteria

2.2Literature search

2.3Data extraction

2.4Risk of bias

3Results

3.1Included studies

3.2Extracted data

3.3Vasomotor symptoms

3.4Sleep disturbance

3.5Vulvovaginal symptoms and Sexual function

3.6Breast cancer occurrence

3.7Adverse events

4Discussion

4.1Vasomotor symptoms

4.2Sleep disorders

4.3Vulvovaginal symptoms and sexual function

4.4Safety and adverse events

4.5Conclusions

5Appendix A: Literature databases searched

6Appendix B: Search strategy

7Appendix C: Inclusion and exclusion criteria

8Appendix D: Flowchart for inclusion-exclusion of articles

9References

10Acknowledgements

Tables

Table 1 Key menopausal symptoms reported in the included reviews

Table 2 Key menopausal symptoms reported in the included reviews, by intervention

Table 3 Key menopausal symptoms reported in the MsFLASH RCTs, by intervention

Table 4 Summary of the characteristics and results of the included systematic reviews

Table 5 Summary of the characteristics and results of Guthrie 2015 and the MsFLASH 01, 02, 03 studies

Table 6 Summary of adverse events, by intervention

List of Abbreviations

AE
AEMD
CBT
CCTR
CEE
CEBM
CI / adverse event
allied and complementary medicine database
cognitive behavioural therapy
Cochrane controlled trials register
conjugated equine oestrogen
Centre for evidence-base medicine
confidence interval
d
E2
EB
EE
FA
GCS / day
low-dose oestradiol
evidence base
esterified oestrogen
fatty acid
Greene Climacteric Scale
h
HDL / hours
high-density lipoprotein
HRT
HT
MA / hormone replacement therapy
hormone therapy
meta-analysis
MD / mean difference
MHT / menopause hormone therapy
MsFLASH
mT
NHMRC / Menopause Strategies Finding Lasting Answers for Symptoms and Health
methyl testosterone
National Health and Medical Research Council
N / number of people
OR / odds ratio
PICO / population, intervention, comparator, outcomes
RCTs / randomised controlled trials
RR / relative risk
SMD / standardised mean difference
SR
SSRIs / systematic review
selective serotonin reuptake inhibitors
SUI
TGA / stress urinary incontinence
therapeutic good administration
UTI
UUI
w
WMD
XR
y / urinary infection
urgency urinary incontinence
weeks
weighted mean difference
extended release
year

Management of menopausal symptoms in a general female population: Supplementary evidence review 1

Executive summary

Cancer Australia has undertaken a comprehensive systematic review (SR) to support the development of clinical practice guidelines for the management of menopausal symptoms in women who have received breast cancer treatment.1 The evidence identified in the Primary Systematic Review (SR), “Management of menopausal symptoms in women with a history of breast cancer treatment”, was of variable quality, and there were many interventions of interest where the evidence base was limited or nonexistent. While women experiencing menopausal symptoms after breast cancer treatment are the population targeted by the guidelines, it was recognised that clinical trial evidence from a general female menopausal population is generalisable to a breast cancer population. Consequently the current evidence review includes studies of women experiencing menopausal symptoms in the general population treated with the same interventions considered in the Primary SR. The current review supplements the evidence found in review of evidence from the breast cancer population.Both of these reviews will support and inform the development of clinical practice guidelines.

The current evidence review identified 23 SRs (Level I evidence), and the MsFLASH studies (Level II evidence),published between January 2001 and November 2015. The MsFLASH studies were included in the review due to high quality study design and low risk of bias. In total, the current review includes 30studies (the ‘supplementary evidence base’).

The interventions identified in this review included pharmaceutical treatments (hormonal therapies, hormone receptor modulators and anti-depressants), and complementary medicine and therapies (cognitive behavioural therapy, acupuncture, yoga, physical exercise, relaxation therapy, black cohosh, phytoestrogens, omega-3 supplements, and bioidentical hormones). The main outcomes extracted from these studies were vasomotor symptoms (hot flushes and night sweats), vulvovaginal issues (vaginal dryness, loss of libido, dyspareunia), and disrupted sleep. Not all outcomes were available for all interventions.

Summary of results

Efficacy

Vasomotor symptoms

From the supplementary evidence base, 22 systematic reviews and five RCTs reported on the effect of one or more interventions on vasomotor symptoms (hot flushes and night sweats), in peri- and post-menopausal women.

Three systematic reviews and the MsFLASH studies reported that oral hormone therapies significantly reduced vasomotor symptoms frequency, bother and severity when compared with placebo, tibolone and venlafaxine. 2-6

One systematic review reported that hormone receptor modulators significantly increased the incidence of hot flushes compared to placebo.7

Two systematic reviews reported that transdermal hormonal preparations significantly reduced the frequency and severity of hot flushes, and found low-dose transdermal oestradiol to be more effective than placebo at decreasing the frequency of hot flushes.8, 9

Four systematic reviews and the MsFLASH studies found that non-hormonal pharmaceuticals including escitalopram, venlafaxine, desvenlafaxine, fluoxetine, paroxetine sertraline, and citalopram were associated with a significant to moderate decrease in hot flush frequency compared to placebo. One systematic review reported escitalopram as the most effective selective serotonin reuptake inhibitors (SSRIs) in reducing hot flush frequency when compared to placebo, but noted that the quality of the overall evidence was low due to a lack of comparative data.2, 3, 10-13

Two systematic reviews and the MsFLASH studies found that exercise and / or yoga, did not improve vasomotor symptom frequency or bother compared to baseline or placebo.2, 14-17 One study found that exercise significantly reduced hot flushes compared to control.15 Overall, the authors concluded that trials with larger numbers of participants are required to assess the effectiveness of exercise and yoga at reducing the symptoms of menopause.

One systematic review reported that cognitive behavioural therapy significantly reduced hot flushes and night sweats compared to control.18

Two systematic reviews found relaxation therapy to be ineffective in reducing hot flushes compared to control, acupuncture, or oestradiol.15, 19The authors concluded that there was insufficient evidence to draw firm conclusions regarding the effectiveness of relaxation therapy.

One systematic review reported on the effect of acupuncture on vasomotor symptoms, and found that acupuncture significantly reduced hot flush severity but not frequency compared to sham acupuncture. Acupuncture was found to be no different to relaxation, but both interventions were less effective than menopause hormone therapy. The authors concluded that there was insufficient evidence to determine whether acupuncture is effective in improving vasomotor symptoms.20

One systematic review showed that phytoestrogens are associated with some improvement in hot flushes, showing significant reductions in co-occurring symptoms.14Another systematic review found no conclusive evidence that phytoestrogens reduce the frequency or severity of hot flushes or night sweats in postmenopausal women.21

One systematic review and the MsFLASH studies reported on other complementary therapies (bioidentical hormones, black cohosh, and omega-3 fatty acid supplements), and found contradictory results. Whereas one study found bioidentical progesterone cream to significantly improve vasomotor symptom severity compared to placebo, another two studies found that manufactured progesterone cream did not significantly improve vasomotor symptoms compared to placebo.22 Thirteen of sixteen studies found that black cohosh and omega-3 fatty acid supplements did not significantly improve frequency or severity of hot flushes or night sweats. The authors concluded that the findings must be interpreted with caution due to the heterogeneity of the studies.2, 23, 24

Sleep disturbance

From the supplementary evidence base, 5 systematic reviews and three RCTs reported on the effect of one or more interventions on sleep disturbance (insomnia, sleep quality, sleep disorders), in peri- and post-menopausal women. Most of the systematic reviews reported on sleep disturbance as secondary outcome, with some of them having low quality of reporting, and therefore high to moderate risk of bias.

One systematic review reported on the effect of oral hormone therapies on sleep disturbance and found that tibolone did not reduce the frequency of insomnia compared to placebo.5

One systematic review and the MsFLASH studies reported on the effect of physical activities (exercise, yoga) on sleep disturbance, and found that exercise training and yoga improve insomnia and sleep quality. Another systematic review reported on the effects of physical activity/exercise on sleep, and found no significant effect on sleep symptoms compared to control. One of the RCTs compared yoga with exercise and found a significant treatment effect for yoga on sleep symptoms compared to baseline, but no difference between the two groups2, 15, 17

One systematic review reported that relaxation therapy significantly improved sleep symptoms compared to waitlist control.15

One systematic review reported that phytoestrogens did not significantly reduce sleep symptoms compared to placebo; but one study which used a combination of isoflavones, magnolia bark extract, magnesium, lactobacillus, calcium and vitamin D3 found that the combination therapy significantly reduced insomnia compared to placebo.14

One MsFLASH study reported that omega-3 fatty acid supplements did not improve sleep quality or insomnia compared to placebo.24

Vulvovaginal symptoms and sexual function

From the supplementary evidence base, 8 systematic reviews and one RCT reported on the effect of one or more interventions on vulvovaginal symptoms and sexual function (vaginal dryness, dyspareunia, sexual function scores, female sexual function index, vaginal atrophy, incontinence, loss of libido, vaginitis, vaginal health, maturation value, vaginal pH, itching, burning/soreness, discharge, irritation, and painful intercourse), in peri- and post-menopausal women.

Four systematic reviews, reported on the effect of different oral hormone therapies (tibolone, testosterone, oestrogen with or without progestogens, SERMS, oestradiol) on the treatment of vulvovaginal symptoms and sexual function. One systematic review found that tibolone did not reduce vaginal dryness or dyspareunia compared with placebo.5 One systematic review reported that testosterone therapy in women taking menopause hormone therapy was found to improve sexual function scores and the number of satisfying sexual episodes compared to menopause therapy alone.6 One systematic review reported on the effects of oestrogen alone and oestrogen in combination with progestogens, synthetic steroids, and SERMS. These studies found that oestrogen alone was shown to moderately improve sexual function in the hormonal therapy group compared to control in early postmenopausal women, but not in a general population of postmenopausal women. They also reported that tibolone did not significantly benefit sexual function in the hormonal group compared to control. Moreover it was reported that SERMS showed a small benefit in sexual function compared to control.25 One MsFLASH study reported that low-dose oestradiol did not significantly improve sexual function from baseline or compared to placebo.26

One systematic review reported on the efficacy of the hormone receptor modulator ospemifene, and found that compared to placebo, ospemifene significantly alleviated the dyspareunia associated with vulval and vaginal atrophy. 7

One systematic review determined the efficacy of vaginal oestrogen (cream, tablet, suppository, and ring) in women with a genitourinary syndrome of menopause. The authors concluded that all commercially available vaginal oestrogens are more effective than placebo in the relief of common vulvovaginal atrophy, such as dyspareunia and vaginal dryness, itching and burning.27 Another systematic review reported that the different variants of vaginal oestrogens were equally effective in managing the symptoms of vaginal atrophy, although vaginal oestrogen rings were found to significantly decrease dyspareunia compared to placebo and other vaginal oestrogen (tablets), as well as being the treatment of choice by patients.28

One systematic review reported on non-hormonal pharmaceuticals and showed that SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline) had no significant effect on libido compared to placebo.10

One RCT (with a low risk of bias) in menopause transition and postmenopausal womenfound that venlafaxine did not significantly alter sexual function compared to placebo; but venlafaxine did significantly improve vaginal dryness compared to placebo.3

One systematic review reported on phytoestrogens, and found evidence that soy isoflavones may relieve vaginal symptoms, compared to the control groups. However, the authors concluded that the beneficial effects remain uncertain and further studies are warranted.29

Safety

Breast cancer recurrence

Two systematic reviews specifically examined the effect of treatment on breast cancer recurrence in relation to the use of tibolone to treat vulvovaginal symptoms and sexual function in postmenopausal women. One systematic review investigated the risk of breast cancer in postmenopausal women taking testosterone with menopause hormone therapy, but none of the included RCTs reported this data. The second systematic review reported that long term safety of tibolone is concerning because of the increase risk of breast cancer in women who had already suffered from breast cancer. Moreover, they concluded that similar risks may exist for oestroprogestins, but that their overall benefit-risk profile is better known and it relates more to women with menopausal symptoms. Although one RCT reported in the systematic review found that tibolone significantly reduced the new onset of breast cancer, this must be interpreted with caution, since the population was of low-risk and the number of events was low.5

Adverse events

Adverse events varied across studies, according to intervention as well as dosage and duration of treatment. The adverse events of escitalopram, desvenlafaxine and vaginal oestrogen range from mild to severe. The adverse effects of testosterone may vary depending on mode of administration and concurrent use of oestrogen. Testosterone may increase the incidence of acne and hirsutism in women, long term effects have not been stablished. The safety of bioidentical hormones has not been established, and at present its use is not approved by the Therapeutic Goods Administrations (TGA). For a list of all adverse events reported in this systematic review by intervention please refer to Table 6.

Conclusion

This evidence review has identified evidence for the treatment of vasomotor symptoms (hot flushes and night sweats), sleep disorders, vulvovaginal symptoms and sexual function, in women with peri- and postmenopausal symptoms.

There is level I and selected level II evidence for the efficacy of: menopause hormone therapy, tibolone, hormone receptor modulators, escitalopram, desvenlafaxine, cognitive behavioural therapy (CBT), and acupuncture in treating vasomotor symptoms. Inconsistent effects on vasomotor symptoms were reported for bioidentical hormones. Relaxation therapy, exercise, yoga, isoflavones, omega-3 fatty acid supplements and black cohosh were found to be ineffective.

Therapies that may be effective for managing sleep disturbance are desvenlafaxine, exercise, and relaxation therapy. Therapies that are likely to be ineffective for managing sleep disturbance are tibolone, escitalopram, and isoflavones.

Of the treatments assessed for their effects on vulvovaginal symptoms, only vaginal oestrogen and testosterone were found to be effective. There was limited evidence that SERMs may reduce dyspareunia, but not improve sexual function overall. Menopause hormone therapy, tibolone, escitalopram, venlafaxine and isoflavones were all ineffective for managing vulvovaginal symptoms.

For many of the therapies identified in this review there is little or no evidence for their long-term safety in peri- and postmenopausal women. In particular, the use of testosterone, SERMs and bioidentical hormones in this population is not informed by long-term studies. In addition, all of the therapies included in this review, both pharmacological and non-pharmacological, have specific contraindications and adverse event profiles that should inform the consideration of their benefits and harms for individual women.

Management of menopausal symptoms in a general female population: Supplementary evidence review 1

1Introduction

A comprehensive systematic review (SR) was conducted by Cancer Australia on the management of menopausal symptoms in women who have received breast cancer treatment.1This is referred to as the ‘Primary Systematic Review (SR)’. The Primary SR included a total of 49 RCTS across 22 out of 27 interventions of interest. However, many of the RCTs included in the Primary SR are limited by small size, use of non-validated symptoms measures, and poor reporting. The consensus of the Management of Menopausal Symptoms in Women who have received Breast Cancer Treatment, Guidelines Working Group was that efficacy information from studies in a general menopausal population is accepted to be generalisable to a breast cancer population. Consequently, a supplementary evidence review has been undertaken by Cancer Australia to identify relevant level I evidence (i.e., published systematic reviews, meta-analyses, or pooled analyses) of the 27 interventions of interest in a general female menopausal population.