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National Collaborating Centre for Women's and Children's Health (UK). Menopause: Full Guideline. London: National Institute for Health and Care Excellence (UK); 2015 Nov 12. (NICE Guideline, No. 23.)

  • December 2019: The table cited in recommendation 1.5.11 has been deleted by NICE and replaced with a link to the MHRA summary table of HRT risks and benefits. Other tables have been renumbered accordingly.

December 2019: The table cited in recommendation 1.5.11 has been deleted by NICE and replaced with a link to the MHRA summary table of HRT risks and benefits. Other tables have been renumbered accordingly.

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Menopause: Full Guideline.

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11Long-term benefits and risks of hormone replacement therapy (HRT)

11.1. Venous thromboembolism

11.1.1. Introduction

Venous thromboembolism (VTE) is a condition comprising deep vein thrombosis (DVT) and pulmonary embolism (PE) which are precipitated by conditions that cause blood flow to slow down, such as immobility, compression of the blood vessel or increased blood viscosity. This causes vascular endothelial damage, coagulation of the blood and clot formation, the last of which sometimes breaks up, resulting in clots lodging in the lung. Alterations in the constituents of the blood (which may be either inherited or acquired alterations in coagulation) also increase the chance of clot formation. The clotting mechanism is designed to stem haemorrhage from damaged vessels and functions as a fine balance between the clotting cascade and the fibrinolytic system which acts to counterbalance this, ensuring the clot remains localised and does not spread to obstruct the entire vessel. Alterations of this delicate homeostatic balance can be both inherited and acquired.

The most frequent causes of an inherited thrombophilia are known gene mutations of factor V Leiden and prothrombin, which together account for 50% of cases. Defects in the natural anticoagulants protein S, protein C, and antithrombin III account for most of the remaining cases, along with rare disorders of fibrinogen, but there may be additional causes.

Risk factors for thrombosis include increasing age, surgery, trauma, immobilisation, malignancy, pregnancy, hormone use, obesity, smoking, antiphospholipid syndrome and a number of other major medical illnesses.

Studies that have evaluated the association between hormone replacement therapy (HRT) and VTE have suggested that HRT caused an approximately 2-fold increase in VTE risk, which appeared to be greatest in the first year of treatment (Canonico 2008) as well as in those women with an increased BMI (Canonico 2006).

Oral HRT is ingested and metabolised in the liver. While undergoing first pass metabolism it affects the clotting cascade by increasing resistance to protein S and protein C (natural anticoagulants) and increasing fibrinogen, thus increasing a woman’s tendency towards thrombosis. Transdermal oestrogens are absorbed directly into the bloodstream, thus avoiding this first pass metabolism and therefore having less effect on the coagulation factors in the liver.

In addition to the type and route of oestrogen administration, the type of progestogen may also affect the risk of VTE (Canonico 2006).

11.1.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of developing venous thromboembolism (VTE)?

The aim of this review was to determine the effect of HRT on the risk of developing VTE for women in menopause. The focus population of the review was women who have started using HRT before the age of 65. Given that the risk of developing VTE may be different for women of different ages or at different menopausal stages, the Guideline Development Group decided at the protocol stage to look at subgroup analyses on age groups and user categories (ever, past and current users). The risk of developing VTE was examined in terms of different HRT types, duration and timing since discontinuation.

Randomised controlled trials (RCTs) and comparative prospective cohort studies were selected for inclusion in this review. Only comparative cohort studies that have adjusted for the most common confounders for developing VTE – such as age, BMI and family history of VTE – in their analyses were included.

Two outcomes were prioritised by the group:

  • risk of developing VTE (including DVT and PE)
  • mortality related to VTE.

For full details see the review protocol in Appendix D.

11.1.3. Description of included studies

Seven RCTs comparing some form of HRT with placebo were included in this review (Cherry 2002, Høibraaten 2000, Holmberg 2008, Manson 2013, Nachtigall 1979, Vickers 2007, Whiteman 1999).

All included RCTs assessed the effect of HRT in comparison with placebo. Two RCTs (Cherry 2002; Manson 2013) compared the effect of oestrogen alone versus placebo. Four RCTs (Høibraaten 2000, Nachtigall 1979, Manson 2013, Vickers 2007) compared oestrogen plus progestogen versus placebo.

Three of RCTs were conducted in the USA (Manson 2013, Nachtigall 1979, Whiteman 1999), 1 in the UK (Cherry 2002), 1 in Norway (Høibraaten 2000) and 1 in Sweden (Holmberg 2008). One was a multi-centre study carried out in the UK, Australia and New Zealand (Vickers 2007).

Eight comparative cohort studies were included which compared HRT with no treatment (Benson 2012, Canonico 2009, Eischer 2014, Grodstein 1996, Laliberté 2011, Ohira 2010, Olié 2011, Su 2012). They were conducted in the USA, France, UK, Austria, Canada and Taiwan. Sample sizes of the included cohort studies varied widely, ranging from 630 (Eischer 2014) to 105,825 (Benson 2012, Million Women Study).

The majority of included studies considered first incidence of VTE in HRT users. Three studies examined the risk of VTE in women at a higher risk for VTE, for example those with a previous history of VTE (Høibraaten 2000 [RCT], Eischer 2014 [prospective cohort study]) and breast cancer (Holmberg 2008 [RCT]). Most of the included studies excluded pre- or perimenopausal women.

When studies provided results by HRT type (oestrogen alone or oestrogen plus progestogen) and the associated risk of VTE for women in menopause then these are presented separately.

11.1.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (see Appendix I). See also the study selection flowchart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

11.1.5. Evidence statements

11.1.5.1. Evidence statements for RCTs

Current use of oral HRT

Moderate to very low quality of evidence from 7 RCTs including 34,379 women showed a significantly increased risk of VTE with current oral use of any HRT when compared with placebo. The same result was found when the role of either oestrogen alone or oestrogen plus progestogen was examined in comparison with placebo by 2 RCTs (total 11,756 women) and 4 RCTs (total 21,301 women), respectively.

Duration of HRT use

Findings on the risk of VTE in relation to duration of HRT use were mixed. Moderate quality evidence from a single RCT including 4385 women showed a significantly increased risk for up to 1 year duration and more than 5 years duration (evidence from 2 RCTs including more than 20,000 participants). However, low quality evidence from 4 RCTs (total 2479 women) showed no significant difference between those who were on HRT for between 1 and 5 years when compared with those on placebo.

Women aged 50–59

When the subgroup of women aged 50–59 at baseline was examined, low quality evidence based on over 5000 women from an RCT showed an increased risk in VTE for women taking oestrogen plus progestogen in comparison with those in placebo group, whereas findings based on over 3000 women from another RCT showed no significant difference in VTE risk between oestrogen alone use and placebo (very low quality evidence).

Time since menopause

One RCT with a subgroup analysis of women age 50–59 years showed that among those who have initiated oestrogen plus progestogen within 10 years since menopause, there was a significant increased risk of VTE when compared with the placebo group (moderate quality evidence). However, very low quality evidence from the same RCT showed that the risk of VTE was not significantly different between users of oestrogen alone and placebo groups.

11.1.5.2. Evidence statements for comparative cohort studies

Current HRT use

Moderate to very low quality evidence from 3 cohort studies (sample size ranged from 600 to 60,000 women with menopause) found a significantly increased risk of VTE in current HRT users compared with the no treatment group.

Past use of HRT

Moderate to very low quality evidence from 5 cohort studies (sample sizes ranged from 6,600 to more than 500,000) all showed no significant difference in the risk of VTE for past users of HRT (no information on the type of HRT administration) compared with women who had never used HRT.

Administration routes of HRT

Low quality evidence from 2 cohort studies found a significantly increased risk of VTE among oral HRT users compared with non-users, whereas low to very low quality evidence from 3 cohort studies with sample sizes up to more than 500,000 women showed no significant difference between transdermal HRT users and non-users. When oral and transdermal HRT uses were compared directly in 2 cohort studies including more than 54,000 participants, both studies showed a significantly increased risk of VTE in oral HRT use compared with transdermal use (low quality evidence).

Subgroup analysis from 1 cohort of more than 500,000 women by age distribution (women aged less than 50 years or over 50 years) showed similar results regarding the effect on VTE from oral and transdermal HRT use; more specifically, oral HRT use was found to increase the risk of VTE when compared with no treatment, whereas this was not the case for the comparison of transdermal HRT use and no treatment (moderate to low quality evidence).

Types of HRT

Low to very low quality evidence from 2 cohort studies including more than 500,000 women found a significantly increased risk of VTE among oestrogen users compared with non-users, whereas another 3 cohorts showed no significant difference between oestrogen users and non-users (very low quality evidence). However, the results from the 3 cohorts should be interpreted with caution as they had used both types of HRT administration (transdermal and oral) and the pulmonary embolism (PE) was included in their analysis. One study also presented results for the outcome of DVT and found a significantly increased risk of VTE among oestrogen users compared with non-users (moderate quality evidence).

When oestrogen plus progestogen was examined, low quality evidence from 1 cohort study (with more than 670,000 women) showed a significantly increased risk of VTE in oestrogen plus progestogen users in comparison with non-users. However, another cohort study carried out among Chinese women found no significant difference between oestrogen plus progestogen users and non-users (very low quality evidence).

Duration of HRT

Moderate quality evidence from a large cohort study (about 500,000 women) showed a significantly increased risk of VTE in oral HRT users with a duration of 2 years or less compared with non-users, but this difference was not found to be significant when transdermal HRT users were compared with non-users. Similar effect direction was found when different administration routes (oral and transdermal routes) were analysed in terms of HRT duration up to 5 years and more than 5 years compared with non-users. This evidence was of moderate to very low quality based on 2 cohort studies.

Subgroup analysis by age (less than 50 years or over 50 years) from 1 study with more than 500,000 women showed similar results regarding the effect on VTE from oral and transdermal HRT use; more specifically, oral HRT use was found to increase the risk of VTE when compared with no treatment, whereas this was not the case for the comparison of transdermal HRT use and no treatment (moderate to low quality evidence).

Recurrence of VTE among women who have had a first VTE

Very low quality evidence from a single cohort study including 630 women in menopause found no significant difference in the risk of recurrence of VTE among users of oestrogen alone who have had a first VTE compared with non-users.

Different preparations of oestrogen and progestogen in combined HRT

When different preparations of oestrogen were examined, low quality evidence from a cohort study of over 500,000 women showed a significant increase in the risk of VTE for users of conjugated equine oestrogens and oestradiol users compared with no treatment (low quality evidence).

With regards to different types of progestogen in combined HRT (oestrogen plus progestogen), mixed findings were reported across studies:

  • Very low quality evidence from 2 cohort studies showed no significant difference in the risk of VTE for current users of micronised progesterone as a component of combined HRT in comparison with non-users.
  • The same result was found for current users of pregnane derivatives as an HRT component (low quality evidence) compared with non-users
  • Moderate quality evidence from a large cohort study (more than 500,000 women) showed an increased risk of VTE for users of medroxyprogesterone acetate as a component of combined HRT when compared with non-users.

For non-testosterone derivatives as a component of combined HRT, moderate quality evidence from 1 large cohort study (more than 500,000 women) showed an increased risk of VTE associated with this type of HRT, whereas another study found no significant difference between this type of HRT and the no treatment group (very low quality evidence).

11.1.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise short-term treatment. However, the clinical evidence from this review was used to inform the model on short-term treatment where there was impact on longer term outcomes arising from short-term use.

11.1.7. Evidence to recommendations

11.1.7.1. Relative value placed on the outcomes considered

The Guideline Development Group considered VTE a critical long-term outcome for evaluating the effect of HRT on women. VTE is associated with long-term morbidity via an increase in pulmonary embolus and is also associated with increased mortality. This complication has been widely reported as being associated with use of sex steroid hormones (such as the combined oral contraceptive pill) which impact the hepatic synthesis of coagulation factors and thus increase the risk of clotting.

The group followed the principles established in the NICE guideline on patient experience in adult NHS services regarding the presentation of information to personalise risks and benefits as far as possible. For that purpose the use of absolute risk is preferred rather than relative risk. Information provision of all aspects of the benefit/risk ratio of HRT regarding both the short term and the long term is of paramount importance for women’s decision-making regarding the choice of treatment for menopausal symptoms.

11.1.7.2. Consideration of clinical benefits and harms

Overall, evidence from both RCTs and observational studies was largely consistent with regard to the increased risk of VTE associated with current oral HRT use compared with non-use for women in menopause.

The Guideline Development Group concluded that current oral HRT use was associated with a significant increase in risk of developing VTE compared with non-use. Conversely, the risk of VTE was not found to be significantly different with transdermal HRT use compared with non-use. This difference in the risk of VTE between oral and transdermal routes of HRT was supported by data from studies of both designs. In particular, subgroup analyses of observational data showed that this trend was the same whether the duration of HRT use was less than 2 years, less than 5 years or more than 5 years, and whether women started HRT use either before or after age 50 years. Furthermore, when oral and transdermal HRT were directly compared in 2 observational studies, both studies found a significantly increased risk of VTE among those taking oral HRT compared with those on transdermal HRT. Therefore, the group concluded that the information given to women prior to HRT use should explain that the risk of VTE is increased with oral HRT use whereas this is not the case for transdermal HRT. However, the group still wanted to draw attention to women’s baseline risk of VTE and the recommendation explicitly states that transdermal HRT does not not further increase the risk of VTE above the individual baseline risk. Furthermore, due to the well-known VTE risk associated with obesity, the group emphased that the use of transdermal HRT is not contraindicated for those with a high BMI (over 30 kg/m2).

The evidence showed that the increase in the VTE risk occurs rapidly after starting HRT and continues until treatment is discontinued. Evidence from randomised participants showed a significantly increased risk of VTE within the first year of HRT use, while observational data on oral HRT also reported the same effect direction for up to 2 years of HRT treatment.

For women who had experienced previous episodes of VTE, observational evidence found no significant difference between HRT users and non-users. However, the group considered that there may be special considerations for this set of menopausal women before they start HRT and concluded that a referral to a haematologist should be offered.

Findings for different types of progesterone and progestogens in combined HRT were inconclusive. Some observational studies showed an increased risk for some specific preparations of progesterone or progestogen when combined with oestrogen, while other studies found no significant difference. Therefore, the group decided not to differentiate the direction of their decision-making based on HRT type.

Besides the general inconsistency in evidence, the group also noted the large sample sizes of some included studies. For example, 1 of those studies included more than 500,000 women. The group considered that although VTE was a significant side effect, it was relatively uncommon in women of menopausal age. It was found that 9 more per 1000 women (95% confidence interval [CI] 2 to 32 more) treated with HRT (oral or transdermal) may develop VTE within the first year of use, and this absolute risk would increase to 10 more per 1000 women (95% CI 5 to 13) for the duration of 5 years of use.

11.1.7.3. Consideration of economic benefits and harms

VTE is expensive to manage and treat and is associated with significant morbidity and mortality. VTE is recognised as a potential adverse event arising from oral HRT treatment and therefore it was important to consider it as part of an overall trade-off of risks and benefits of therapy. This trade-off was done formally through an economic evaluation reported in Appendix L, although the analysis did not find that VTE outcomes were an important determinant of cost effectiveness.

11.1.7.4. Quality of evidence

Evidence from this review was assessed as being of moderate to very low quality. For the included RCTs, the main reasons leading to downgrading of evidence were the small sample size, highly-selected study populations, open-label study design, high drop-out rates and/or disproportionate drop-out rates between trial arms.

For the comparative cohort studies, although studies with very large populations (over 500,000 women) and population-based studies were included, findings from these studies were more prone to risk of bias arising from their study design. Major risks of bias were identified in the majority of included studies, such as: recall bias because of self-reported HRT use which could result in misclassification of HRT use during follow-ups; different baseline characteristics in HRT and no-treatment groups due to the ‘self-select’ effect, resulting in generally younger, healthier and lower BMI participants in HRT groups; differences in confounding adjustments (for example some studies could not adjust for some known risk factors such as family history of VTE and thrombophilia due to data availability in the analyses); different length of follow-up for HRT and no treatment groups; and high drop-out rates without further details on reasons for the drop outs.. Furthermore, many outcome data were downgraded due to the imprecision of the risk estimates.

Evidence was obtained from a large number of subgroup-analyses conducted within some of the RCTs and observational studies. These should be interpreted with caution due to the lack of precision in the effect estimates and the increased likelihood of Type I errors.

11.1.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence and the expert opinion of Guideline Development Group members.

The group discussed the importance of well-known risk factors for VTE, such as age, genetic abnormalities, obesity, smoking and the presence of an inherited thrombophilia impacting on the clotting cascade with increase in coagulation (thrombophilias). They discussed how these should be taken into consideration when a prescription of HRT is considered. They also noted that some women with risk factors for VTE may be on anticoagulant therapy which means they should only be considered for HRT following specialist advice. The group considered that a referral should be made to a haematologist for all women with a significant increase in risk of DVT, for example a previous thromboembolic episode or a hereditary thrombophilia (Factor V Leiden). The decision whether to offer HRT or not to these women is complex and therefore the group decided that the involvement of a haematologist is necessary in order to contribute expertise to a woman’s thrombophilia risk assessment before considering HRT unless she is already on anticoagulant therapy.

The group also discussed the management of women who use HRT and are considered for elective surgery. Since transdermal HRT has little or no impact on coagulation and is not associated with an increased risk of VTE, the group did not consider that there is a need for HRT to be discontinued prior to elective surgery, especially when the surgery is minor and will not involve immobility. However, the group felt that this is a discussion that should take place between the woman, her surgeon and her anaesthetist.

11.1.7.6. Key conclusions

The Guideline Development Group concluded that:

  • Oral HRT (either oestrogen alone or oestrogen plus progesterone) increases the risk of VTE and this can occur immediately after starting HRT treatment.
  • There is no significantly increased risk of VTE in women using transdermal preparations compared with non-users.
  • The risk of VTE when using progesterone and the different progestogens may differ when combined with oestrogen.
  • The background risk of VTE increases substantially with age and this should be taken into consideration when HRT use is considered for women in menopause.
  • The increased risk of VTE disappears after HRT use has been stopped.

11.1.8. Recommendations

39.

Explain to women that:

  • the risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population risk
  • the risk of VTE associated with HRT is greater for oral than transdermal preparations
  • the risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk.
40.

Consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.

41.

Consider referring menopausal women at high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT.

11.1.9. Research recommendations

Research question
3.

How does the preparation of HRT affect the risk of venous thromboembolism (VTE)?

Why this is needed
Importance to ‘patients’ or the populationAn increase in the risk of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a significant side effect of HRT, particularly bacause PEs can be fatal. This risk appears to be greater with oral than transdermal HRT. DVT risk increases with age and BMI, among other risk factors.
The progestogen component of HRT may also influence the risk of a DVT, which may be greater with androgenic synthetic progestogens than natural progesterone (but findings from observational studies need confirmation). Most women in the UK take oral HRT comprising oestrogen combined with a synthetic progestogen, and the use of progesterone is less common.
Randomised controlled trials are needed to compare oral with transdermal HRT, and HRT containing different types of progestogens. These trials should measure coagulation factors and the incidence of VTE in women at increased risk of VTE for whom transdermal oestrogen is indicated.
Relevance to NICE guidanceHigh importance. The recommendation in this guideline regarding VTE risk has been formulated using observational data from a relatively restricted population alone and this should be confirmed or amended as appropriate.
Relevance to the NHSReducing VTE risk would have a significant effect in regard to the safety of HRT overall and since there is also a suggestion that progesterone may have less impact on breast cancer risk, this could lead to a change in the type of HRT offered.
This would make a difference to clinical practice as transdermal HRT would be recommended for women with risk factors e.g. raised BMI, and postmenopausal women initiating HRT could be offered oestrogen by the transdermal route in combination with progesterone as a first line treatment.
National prioritiesN/A
Current evidence baseThere are several studies quoted in the Guideline which include large epidemiological studies undertaken mainly in France. These are observational, thus the data are not conclusive.
EqualityN/A
FeasibilityIt would be possible to conduct the study if the primary end point is an alteration in coagulation factors that provides an estimate of change in risk. A study of VTE event rate would be the “gold standard” but is likely to need inclusion of larger numbers to demonstrate a statistically significant difference.
No other ethical or technical issues were identified.
Other commentsTraditional oral HRT might be contributed by the manufacturers of appropriate HRT preparations (e.g. oestradiol combined with norethisterone) and similarly transdermal HRT. Oestradiol and progesterone cannot be given by a single patch/gel but would require a combination of the patch/gel with either oral micronised progesterone or a vaginal pessary.

11.2. Cardiovascular disease

11.2.1. Introduction

Cardiovascular disease (CVD) (including coronary heart disease [CHD] and stroke) is the most common cause of death in women worldwide (1 in 2). In certain parts of the world the rate of death due to CVD is known to be increasing.

There is a significant increase in the risk of developing CVD after the menopause, regardless of the age at which menopause occurs. Historically, there has been controversy about the possible influence of HRT on CVD risk. Epidemiological data initially suggested that there might be a reduced risk of CHD with long-term HRT usage. However, subsequent randomised controlled trials (RCTs) suggested that risk might be increased if hormone therapy is initiated at a later age. The aim of this review was to determine the precise CVD benefit/risk profile of hormonal products used during the menopause, thus empowering healthcare providers and women to make fully informed therapeutic decisions.

11.2.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of development of cardiovascular disease (CVD) (including stroke) in women at different stages of the menopause?

The focus population of the review was women who have started treatment with HRT before age 65. Given that the risk of developing CVD may be different for women of different ages or at different menopausal stages, the Guideline Development Group decided at the protocol stage to produce subgroup analyses on the following:

  • age distribution
  • user categories (ever, past and current users)
  • durations of HRT use
  • timing of HRT initiation relative to the onset of menopause
  • time since stopping HRT
  • different treatment administration routes
  • different preparations of HRT.

RCTs and comparative prospective cohort studies were selected for inclusion in this review. For comparative cohort studies, only those that have adjusted their analyses for the most common confounders, such as age, hypertension and BMI, were included.

For full details see the review protocol in Appendix D.

11.2.3. Description of included studies

Five RCTs comparing some form of HRT with control or placebo group were included):

  • 1 trial (Shierbeck 2012) conducted in Denmark examined the effect of HRT on coronary disease and stroke in comparison with the no treatment group.
  • 1 trial (the Women’s Health Initiative [WHI], which included 9 intervention or post-intervention reports conducted in the USA: Anderson 2004, Hendrix 2006, Lacroix 2009, Manson 2003, Manson 2013, Prentice 2009, Rossouw 2007, Toh 2010, Wassertheil-Smoller 2003) examined the effect of oestrogen alone and oestrogen plus progestogen on CHD and stroke in comparison with placebo groups.
  • 1 study (Cherry 2014) conducted in the UK between 2000 and 2002 examined the effect of oestrogen on ischemic heart disease (IHD) death among women with an intact uterus in comparison with placebo. The included report focused on the IHD death outcome during its post-intervention phase where HRT use or not could not be ascertained after the active intervention was finished.
  • 2 trials conducted in the USA assessed the effect of HRT on blood pressure change in comparison with placebo (Brownley 2004, The Writing Group for the PEPI Trial 1995).

During validation of the guideline, stakeholders identified a recently published Cochrane review (Boardman 2015) that assessed the effect of HRT use on cardiovascular disease in postmenopausal women. This review was not identified in our search as it was published after the date of the last update searches (22 January 2015). Although we considered this review for inclusion, it was not found eligible for inclusion due to three main differences from our protocol (see further details in Appendix D):

  • The age profile of women in our protocol was restricted to menopausal women who intiatiated HRT before the age of 65 years, whereas this review did not use any age-related restrictions.
  • One of the primary outcomes in this review was angina which was not considered a priority outcome in our protocol due to lack of precision around the assessment of CVD risk among women.
  • The Cochrane review meta-analysed data from studies looking at different types of HRT, pooling together data from studies looking at the effect of oestrogen alone and of the combination HRT treatment of oestrogen plus progestogen.
Table 16. Main characteristics of the RCTs included in the review.

Table 16

Main characteristics of the RCTs included in the review.

Eighteen cohort studies comparing HRT use with no use were included (Alexander 2001, Corrao 2007, Graff-Iversen 2004, Gast 2011, Ettinger 1996, Folsom 1995, Hedblad 2002, Hernandez 1990, Li 2006, Lokkegaard 2008, Sourander 1998, Lafferty 1994, Pentti 2006, Shlipak 2001, Stram 2011, Su 2012, The Nurses’ Health Study (The National Health Service; with 5 publications), Grodstein 1996, Grodstein 2000, Grodstein 2006, Grodstein 2008, Stampfer 1985, Weiner 2008).

The majority of the cohort studies were conducted in the USA, some in Europe (UK, Denmark, Finland, the Netherlands, Italy) and 1 in Chile and Turkey. Sample sizes varied and ranged from 157 (Lafferty 1994) to 698,098 participants (Lokkegaard 2008).

A summary of the cohort studies that were included in this review are presented in Table 17.

Table 17. Main characteristics of the comparative cohorts included in the review.

Table 17

Main characteristics of the comparative cohorts included in the review.

11.2.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles in Appendix I. See also the study selection flowchart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies list in Appendix G.

11.2.5. Evidence statements

11.2.5.1. Evidence statements for RCTs

Low to very low quality evidence from 1 RCT of over 1000 women (mixed population of women with and without a uterus) aged 45–58 years who were followed up for 10 years found that:

  • The risk of CHD is significantly lower for those women in the HRT group compared with placebo. This beneficial effect of HRT followed the same direction in the subgroup analysis for the age groups of 45–49 and 50–58 years and this effect was preserved for 6 years after HRT termination.
  • No difference was found for the outcome of stroke whereas some indication was found for reduction of systolic blood pressure with the use of HRT in a different RCT (of 42 women).

Low to very low quality evidence from over 5000 women in a RCT with post-intervention follow-up found no significant difference between oestrogen plus progestogen and placebo users in the risk of CHD or stroke among women aged between 50 and 59 years.

Low quality evidence from over 3000 women in the same RCT with post-intervention follow-up found no significant difference between oestrogen and placebo users in the risk of CHD or stroke among women aged between 50 and 59 years.

Renalysis of the same RCT found:

  • There was no significant difference in the risk of CHD or stroke when oestrogen plus progestin users or oestrogen alone users were compared with placebo users. More specifically, re-analysis by estrogen plus progestin use duration found that women treated with oestrogen plus progestogen for more or less than 2 years had no significant difference in CHD or stroke risk when compared with placebo users users (very low quality evidence).
  • Re-analysis by estrogen plus progestin initiation time since menopause showed women who initiated oestrogen plus progestogen within 2, 2–4, 5 or 10 years of menopause (with and without prior HRT use) had no significant difference in the risk of CHD or stroke when compared with placebo users (low to very low quality evidence). This finding also applied to women who initiated estrogen plus progestin within 10 years since menopause and with a duration of less or more than 2 years (very low quality evidence).
  • Re-analysis by time since oestrogen plus progestin termination found that among women aged 50–59 years at baseline there was no significant difference between those who had oestrogen plus progestogen and placebo users in the risk of CHD, stroke or total myocardial infarction (MI) after a median 8.2 years following termination of the therapy (median cumulative follow-up 13.2 years) (low quality of evidence).
  • Re-analysis by oestrogen initation time since menopause found that women who initiated oestrogen within 2, 2–4, 5 or 10 years of menopause (with and without prior HRT use) had no difference in risk of CHD or stroke compared with placebo users (low quality of evidence).
  • Re-analysis by time since oestrogen termination showed that among women aged 50–59 years at baseline there was no significant difference in the risk of stroke between those who had oestrogen compared with placebo users after a median of 5.9 or 6.6 years since the therapy’s termination (low quality of evidence). However, among women aged 50–59 at baseline, there was a significantly reduced risk of CHD or total MI after a median of 5.9 years and 6.6 years after termination of the oestrogen therapy compared with placebo users (low quality of evidence).

When the 2 clinical trials (oestrogen alone, oestrogen plus progestogen) of the same RCT were combined in another reanalysis, no significant difference was found in the risk of CHD and stroke for women aged 50–59 years at baseline compared with non-users. However, when data in this reanalysis were analysed according to time of initiating HRT after menopause had started, compared with non-users a significantly increased risk of stroke was found among women who initiated HRT use within 10 years since menopause but no significant difference was found for the risk of CHD. The quality of the evidence was very low.

A post-intervention analysis of 1 RCT which examined the effect of oestrogen on women with an intact uterus who had survived an MI found no significant difference in the risk of IHD death after a mean 10 years follow-up between women who had oestrogen and those who had no HRT (very low quality evidence).

For the outcomes of systolic and diastolic blood pressure, moderate to low quality evidence from 1 RCT found no significant difference in either systolic or diastolic pressure among HRT users of different preparations (oestrogen, oestrogen plus medroxyprogesterone acetate [MPA] cyclic, oestrogen plus MPA daily) compared with the placebo group. However, another RCT showed that there was a significant reduction in the mean systolic and diastolic pressure among HRT users of less than 5 years duration compared with the placebo group.

11.2.5.2. Evidence statements for comparative cohort studies

Risk of CHD in relation to HRT use according to user category

Very low quality evidence of a meta-analysis of 4 cohort studies with more than 70,000 participants showed a significant reduction in the risk of CHD between current HRT users and non-users.

However, a subgroup analysis of 2 cohorts of women younger than 55 years found no difference in the risk of CHD among current HRT users and non-users (very low quality evidence).

Further analysis showed that:

  • There was a significant reduction in the risk of CHD among those who have used HRT for durations of more than 2 or 5 years compared with non-users (very low quality evidence from two cohorts).
  • Moderate quality evidence from another cohort study found no difference in the risk of CHD (defined as cardiac events which was acomposite of death/MI/unstable angina [UA]) or MI in current and prior users with more than 2 years of duration.
  • No difference was found in the risk of CHD among women who had ever used HRT with or without the presence of flushing symptoms. The evidence was low to very low quality and came from 1 cohort study.
  • A significantly higher risk of CHD in current HRT users with pre-existing heart disease was found compared with non-users. The evidence was low quality and from 2 cohorts.

For the outcome of IHD 1 cohort study found no significant difference in the risk of IHD among users of any route of HRT with a duration of 7 to 12 months compared with HRT users of less than 6 months’ duration. The same direction of effect was found in users of any route of HRT with a duration of 1 to 2 years and 2 to 3 years. The quality of this evidence was low. Low to very low quality evidence that had the different routes of administration (oral, transdermal) supported the same conclusion.

For the outcome of death from IHD, CVD or CHD:

  • Very low quality evidence from single cohort studies found no difference in the risk of IHD death in former HRT users aged 36–59 years compared with non-users. The same was found in former HRT users aged 60–64 years and for HRT users who initiated the treatment at the age of 45–54 years or 55–64 years
  • Timing of initiation of HRT since menopause was not found to impact on the previous finding that there is no difference in the risk of IHD death in women who initiated HRT use within 5 or 10 years since menopause compared with non-users.
  • Meta-analysis of 4 cohort studies showed a significantly lower risk of CVD death in current HRT users compared with non-users. The quality of evidence was low.
  • Meta-analysis of 4 cohort studies showed a significantly lower risk of CHD death in current HRT users compared with non-users. The quality of evidence was very low.
  • Very low quality evidence from 2 cohort studies found no difference in the risk of CHD death in current HRT users of more than 5 years’ duration compared with non-users.

For the outcome of total stroke (generally including fatal and non-fatal, ischemic and haemorrhagic stroke in studies) low quality evidence from different cohorts comprising more than 50,000 participants showed:

  • There was a significantly increased risk of total stroke in current HRT users compared with non-users.
  • There was no difference in the risk of total stroke in current HRT users with a duration of more than 2 years (2 cohorts) or 5 years (2 cohorts) compared with non-users. The quality of evidence was very low.
  • There was no difference in the risk of stroke among users of any route of HRT and with a duration of 7 to 12 months compared with HRT users of less than 6 months’ duration. The same was found in users of any route of HRT with a duration of 1 to 2 years. However, a significantly reduced risk of stroke was found in users of any route of HRT with a duration of 2 to 3 years, and of more than 3 years when compared with HRT users of less than 6 months duration. The quality of evidence was low.
  • One cohort study found a significantly reduced risk of stroke among users of transdermal HRT with a duration of 7 to 12 months, 2 to 3 years and more than 3 years when compared with HRT users of less than 6 months duration. However, among users of transdermal HRT with a duration of 1 to 2 years, no difference was found in the risk of stroke when compared with oral HRT users of less than 6 months’ duration. The quality of evidence was low.
  • One cohort study found no difference in the risk of stroke among users of oral HRT with a duration of 7 to 12 months compared with HRT users of less than 6 months’ duration. The same was found in users of oral HRT with a duration of 1 to 2 years, 2 to 3 years and more than 3 years. The quality of evidence was low to very low.

For systolic blood pressure, very low quality evidence from 1 cohort showed that there is no significant difference in mean values between HRT users and non-users at 6-month follow-up, whereas the same evidence showed that there was a significant decrease in diastolic blood pressure for HRT users.

Low to very low quality evidence from a large prospective cohort study found:

  • significantly reduced risk for total CHD among current HRT users compared with non-users at follow-up at 4, 10, 16, and 20 years
  • no significant difference in the risk for CHD between current HRT users and non-users among women aged less than 50 years, but among women aged 50–59 years a significantly reduced risk was found among current HRT users compared with non-users
  • a significantly reduced risk for CHD among current HRT users of less than 1 year duration compared with non-users, and the same reduced risk was also shown for durations 1–2, 2– 4.9, 5–9.9 and more than 10 years
  • a significantly reduced risk for total CHD among oestrogen users compared with non-users at follow-up at 24 years, which was repeated when women with and without pre-existing heart disease were included in the analysis
  • a significantly reduced risk of total CHD among oestrogen plus progestogen users compared with non-users at follow-up at 16 and 24 years, which remained significant when women with and without pre-existing heart disease were included in the analysis at 24-year follow-up
  • no difference in the risk for total CHD between past HRT users and non-users at follow-up at 4, 10 and 16 years
  • a significantly reduced risk for CHD among past users of HRT compared with non-users at 20-year follow-up.

Subgroup analysis based on age distribution found that:

  • Among women aged 40–44 years, there was no significant difference in the risk for total CHD in either current users or those who had ever used HRT compared with non-users. However, among women aged 45–49 years, a significantly reduced risk for total CHD was found in both current users and women who had ever used HRT compared with non-users
  • Among women aged 50–55 years, the same study found no significant difference between women who had ever used HRT and non-users, while a significantly reduced risk was found among current users compared with non-users.
  • Among women aged 56 and 59 years, the same study showed no significant difference in the CHD risk between those who had ever used HRT and non-users.

Low to very low quality evidence from reanalyses of cohort studies found:

  • a significantly reduced risk of CHD among women who initiated oestrogen or oestrogen plus progestogen use within 4 years of menopause compared with non-users, but a nonsignificant difference was found between those who initiated oestrogen at least 10 years after menopause compared with non-users
  • a significantly reduced risk of non-fatal MI among current HRT users compared with non-users at 4-year follow-up but not between past and non-users
  • no difference in the risk of CVD between current or past HRT users and non-users at 10-year follow-up
  • a significantly reduced risk for CVD death in current HRT users but not in past users compared with non-users at 16-year follow-up
  • no difference in the risk of total stroke between current HRT users and non-users at follow-up at 10, 16 and 20 years: the conclusion was reached when the total stroke was broken down into ischaemic and subarachnoid stroke at 10-year follow-up
  • at 16-year follow-up, a significantly increased risk for ischemic stroke among current users compared with non-users, but no difference in subarachnoid stroke among current HRT users and non-users
  • among current HRT users of less than 1 year duration, no significant difference in the risk of stroke between current HRT users and non-users; similarly for the durations of 1–2, 2–4.9, 5–9.9 and more than 10 years
  • no difference in the risk of total stroke between current oestrogen or oestrogen plus progestogen users and non-users at 16-year follow-up
  • a significantly increased risk of stroke (including ischemic) among current oestrogen or oestrogen plus progestogen users compared with non-users at 28-year follow-up: the risk of haemorrhagic stroke was found significantly increased for current oestrogen users when compared with non-users but not for current oestrogen plus progestogen users and non-users at 28-year follow-up
  • a significantly increased risk of stroke among women who initiated oestrogen use within 4 years and at least 10 years after menopause but not for those who initiated oestrogen plus progestogen compared with non-users.
  • no significant difference between women who initiated HRT within 4 years or at least 10 years after menopause compared with non-users.
  • a significantly increased risk for stroke among women who initiated oestrogen use at age 50–59 years, but no significant difference was found among women of the same age who initiated oestrogen plus progestogen compared with non-users.
  • no difference in the risk of stroke or fatal stroke death between current or past HRT users (either oestrogen alone or oestrogen plus progestogen) and non-users at 16-year or 28 year follow-up.

11.2.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise short-term treatment. The review undertaken for this guideline of CHD related to HRT use found no convincing evidence that administration of HRT increases risk in women aged under 65 years. There was evidence that HRT increases the risk of stroke when administered orally, but the absolute risk was very small and therefore the clinical evidence from this review was not used to inform the model on short-term treatment.

11.2.7. Evidence to recommendations

11.2.7.1. Relative value placed on the outcomes considered

The Guideline Development Group considered different types of CVD, such as stroke and MI, cardiac event composite scores, change in blood pressure and mortality from CVD as the most important outcomes for this review question. The group followed the principles outlined in the NICE Patient Experience guideline regarding the presentation of information to personalise risks and benefits as far as possible. For that purpose, the use of absolute risk is preferred rather than relative risk. Information provision of all aspects of the benefit/risk ratio of HRT regarding short- and long-term consequences of treatment is of paramount importance for women’s decision-making regarding the choice of treatment for menopausal symptoms (linked to other long-term symptom reviews).

11.2.7.2. Consideration of clinical benefits and harms

The population included in this review was women who have initiated treatment with HRT before age 65 years. Randomised evidence from several thousand women aged between 45 and 58 years consistently showed that the risk of stroke and MI is not significantly different between menopausal women who received HRT (either as oestrogen alone or as a combination of oestrogen plus progestogen) and those who received no treatment and the group decided to recommend that menopausal women and healthcare professionals involved in their care understand that HRT doesn’t increase the cardiovascular disease risk when started in women aged under 60 years.

Subgroup analyses of RCT data also showed an absence of harm for those women being treated with either oestrogen alone or oestrogen plus progestogen and this was preserved independently of the timing of initiation of HRT (within 2, 4, 5 or 10 years since menopause) and duration of HRT. This result also remained 6 or 8 years after termination of HRT.

Evidence from observational studies revealed similar conclusions to those drawn from RCTs, although more information was provided for specific subgroups (for example women with pre-existing heart disease), different routes of HRT administration and different HRT durations.

The group placed importance on the following results from the observational studies when they were drafting the recommendations:

  • The risk of CHD was significantly lower for women using HRT compared with no treatment across different follow-up periods (4, 10, 16 and 20 years) and different HRT durations (1, 2, 5 or 10 years) although the risk seemed to significantly increase in current users with pre-existing heart disease.
  • Conflicting results were found as to whether the risk of CVD or CHD is reduced or is similar in current HRT users compared with non-users.
  • Some observational data found that the risk of stroke may be higher for women aged under 55 years who are on HRT compared with non-users, whereas other evidence found no difference in the outcome of stroke among users of any route of HRT with different duration of use and long-term follow-up (16, 20 years) when compared with non-users.
  • Weak data suggesting transdermal HRT administration may be associated with a lower risk of stroke than oral.

The group discussed the role of age in development of heart disease: CHD risk rises for everyone as they age, but for women, specifically, cardiovascular symptoms can become more evident after the onset of menopause. Although menopause does not cause CVD, there may be associated risk factors (such as smoking, poor diet, lack of exercise) that increase the risk of CVD around the time of menopause. The group considered in detail the synthesis of evidence and they concluded that there is no clear evidence of harm in terms of CHD or stroke in menopausal women who are taking HRT and aged under 65 years when HRT is terminated. Therefore, there is enough evidence to support healthcare professionals in advising women of the absence of or low risk in CVD outcomes associated with the use of HRT. In addition, although there were limited data indicating that there may be a significant increase in CHD found in current HRT users with pre-existing conditions compared with non-users, the group did not feel that this evidence was compelling enough to draft a negative recommendation for information giving.

Based on UK data, the baseline risk of CVD and stroke is low at 26.3 per 1000 and 11.3 per 1000 (Weiner 2008) respectively, over a period of 7.5 years (please see further details in Methods section how this risk was calculated). This increases with age but is not significantly increased by the use of HRT.

11.2.7.3. Consideration of economic benefits and harms

The evidence shows that HRT increases the risk of stroke of women who are in menopause. However, the absolute risk is very small and therefore the economic benefits and harms are limited. There is a suggestion that transdermal preparations have less impact on the risk of stroke than oral preparations.

11.2.7.4. Quality of evidence

The majority of RCT evidence was low to very low quality, largely due to high risk of bias (mainly due to unblinding of study design) and the lack of confidence in the direction of effect size (imprecision). The WHI data, which contributed substantially to the RCT evidence base, had some design limitations; namely that the study included a group of healthy menopausal women with a high baseline BMI (35–40% of this group had BMI of 30 kg/m2 or over) and was terminated earlier than expected due to high prevalence of side effects. In addition, a proportion of the women included in the trial had initiated treatment outside the study’s protocol (for example 9.1% in the placebo arm were using HRT) and 36% had previous HRT experience. Thus the greatest concern in using the WHI study was the external validity of the estimates given by the characterisation of the present study population. Furthermore, the information from the post-intervention period is unblinded. Several post-hoc analyses have been included for the presentation of the relevant evidence and the results of these analyses should be interpreted with caution due to lack of statistical power in these type of analyses. However, the sample size of this trial was sufficiently large to allow clinically relevant conclusions.

The majority of observational evidence (cohort studies) was assessed as being of very low quality. The main methodological limitations of these studies were the difference in baseline characteristics between the HRT and no treatment arms, the highly selective approach of the included population (for example the Nurse’s Health Study included only nurses (potentially a healthy cohort) and the serious heterogeneity and imprecision observed in some of the results. Given that these data were observational and the role of confounding factors is important in the estimates of effects, evidence was downgraded if the results were not adjusted for the most relevant confounders (such as age and HRT duration).

11.2.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence reviewed and on the expert opinion of the Guideline Development Group members.

The group discussed how this review did not consider any potential differences in outcome related to different types and dosage of HRT, although there was weak evidence suggesting that transdermal preparations may be associated with a lower risk of stroke than oral, consistent with the finding of lower VTE risk. The expert opinion of the group suggests that there may be differential effects and further research in this area is needed.

This review question looked at the impact on the risk of CVD of HRT use, duration, timing since stopping and age, but did not consider any potential differences in outcome related to the different formulations or the type and dosage of HRT in the preparations, although the clinical experience of the group members suggests that there may be differential effects and further research in this area is needed.

Although the group concluded that menopausal women should be informed that the risk of CHD associated with HRT use is low or minimal, they highlighted the need for all women around the age of menopause to have their personal cardiovascular risk reviewed on an ongoing basis in line with the NICE guideline on lipid modification.

11.2.7.6. Key conclusions

The Guideline Development Group concluded that:

  • There is no convincing evidence that the administration of HRT increases the risk of CVD in women aged under 65 years. This is evidenced for both oestrogen and oestrogen plus progestogen preparations and is not influenced by route of administration.
  • There is evidence to show that HRT increases the risk of stroke of women in the menopause. There is a suggestion that transdermal preparations have less impact on the risk of stroke than oral preparations.
  • There is no evidence of increased risk of haemorrhagic stroke with HRT administration.

11.2.8. Recommendations

42.

Ensure that menopausal women and healthcare professionals involved in their care understand that HRT:

  • does not increase cardiovascular disease risk when started in women aged under 60 years
  • does not affect the risk of dying from cardiovascular disease.
43.

Be aware that the presence of cardiovascular risk factors is not a contraindication to HRT as long as they are optimally managed.

44.

Using tables 1 and 2, explain to women that:

  • the baseline risk of coronary heart disease and stroke for women around menopausal age varies from one woman to another according to the presence of cardiovascular risk factors
  • HRT with oestrogen alone is associated with no, or reduced, risk of coronary heart disease
  • HRT with oestrogen and progestogen is associated with little or no increase in the risk of coronary heart disease.
45.

Explain to women that taking oral (but not transdermal) oestrogen is associated with a small increase in the risk of stroke. Also explain that the baseline population risk of stroke in women aged under 60 years is very low (see table 2).

11.3. Development of Type 2 diabetes

11.3.1. Introduction

More than 3% of the UK population have Type 2 diabetes mellitus (T2DM), with rates rising to 5–7% in areas where larger proportions of the population are of South Asian or African/Caribbean origin. In addition to genetic factors, such as family history, increasing age is an important risk factor for T2DM, as is abnormal glucose tolerance (impaired fasting glycaemia [IFG]). Rates of IFG increase from 15.3% for women aged 40–49 years to 28.1% for women aged 60–69 years, while the incidence of T2DM increases from middle-age onwards.

Insulin resistance and pancreatic beta cell depletion are common features of T2DM. Although androgens reduce peripheral insulin sensitivity, oestrogens antagonise this effect. At the menopause, reduced levels of oestrogen with relatively increased androgenic activity may result in impaired glucose tolerance and central obesity, possibly explaining the increased T2DM risk (Collins 2007).

Dyslipidaemia is an important component of T2DM and there is a 3 to 5 times greater risk of death from IHD among diabetic women. Changes in serum lipids and lipoprotein profiles are seen at the menopause, with increases in serum triglycerides and low density lipoproteins but decreasing high density lipoproteins especially HDL2 subfractions (Collins 2007)

Although women with type 1 diabetes have better lipid profiles than women with T2DM, by the age of the menopause their incidence of IHD is 9 times higher than that of non-diabetic women, probably due to endothelial dysfunction and microvascular changes.

Thus, maintaining physiological oestrogen levels in postmenopausal women could be hypothesised to decrease the incidence of abnormal glucose tolerance, T2DM and associated dyslipidaemia with the potential to improve cardio-metabolic risk.

11.3.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of developing type 2 diabetes (T2DM)?

The aim of this review was to assess the effect of HRT use on the risk of developing T2DM in menopausal women. Subgroup analyses of the age distribution of the participants or on the stage of menopause (peri- or postmenopause) were presented if data were available.

The risk of developing T2DM was examined in terms of different HRT types, current or past HRT use, duration of use and time since stopping if data were available.

Given the interventional nature of this review question, we only considered systematic reviews, RCTs and comparative cohort studies for inclusion. In order to answer this review question, only studies assessing women who started to use HRT before the age or average age of 65 years were included for consideration in this review.

For full details see review protocol in Appendix D.

11.3.3. Description of included studies

Four studies were included for this review question (Bonds 2006, de Lauzon-Guillain 2009, Manson 1992, Zhang 2002), of which 1 was a parallel RCT (Bonds 2006) and 3 were comparative cohort studies (de Lauzon-Guillain 2009, Manson 1992, Zhang 2002). Although Bonds (2006) and Manson (1992) were both WHI-related publications and some of these women were double counted in both studies, results are presented separately because subgroup analyses on duration of HRT are only provided in the publication by Manson (1992) which was considered as a cohort study.

Women included in 3 studies were postmenopausal (Bonds 2006, Manson 1992, Zhang 2002) with those in the remaining study (de Lauzon-Guillain, 2009) described only as menopausal. Participants in all studies were not diagnosed with T2DM at the baseline.

Self-reported HRT use at baseline or during follow-up was either elicited by survey questionnaire (de Lauzon-Guillain 2009, Manson 1992) or ascertained by prescriptions brought to the study visit (Zhang 2002) and was examined across the 3 cohort studies. Risk of T2DM in relation to the characteristics of HRT such as user category, formulation, duration of use and age was assessed across the 3 cohort studies, while the single RCT (Bonds 2006) examined the risk of T2DM associated with conjugated equine oestrogen compared with placebo. Follow-up time of the 3 cohort studies (de Lauzon-Guillain 2009, Manson 1992, Zhang 2002) ranged from an average of 4 years to 14 years, whereas the RCT (Bonds 2006,) lasted for on average 7 years.

Three studies were undertaken in the USA (Bonds 2006, Manson 1992, Zhang 2002), and 1 in France (de Lauzon-Guillain 2009). The RCT (Bonds 2006) included 9712 women and the sample size of the 3 cohort studies ranged from 857 (Zhang 2002) to 63,624 (de Lauzon-Guillain 2009). The majority of studies included women with an age profile between 48 and 59 years whereas 1 study (Zhang 2002), which was conducted among American Indian women recruited women with a wider age profile of between 45 and 74 years.

Results from studies that did not specify the HRT type and those reporting results for the comparison of combined equine oestrogen with placebo are presented separately.

A summary of the baseline characteristics of included studies is presented in Table 18.

Table 18. Summary characteristics of included studies.

Table 18

Summary characteristics of included studies.

11.3.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles in Appendix I. See also the study selection flowchart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

11.3.5. Evidence statements

Evidence from RCTs

Low quality RCT evidence from almost 10,000 women aged 50–59 showed that there was no significant difference in the risk of T2DM between those who were current users of conjugated equine oestrogen compared with placebo at 7 years follow-up.

Evidence from cohort studies

Low to very low quality evidence from 2 separate cohort studies (with sample sizes of 21,028 and 63,624) showed that current HRT users have a significantly lower risk of developing T2DM compared with non-users at 12 and 14 years follow-up respectively. In addition, very low quality evidence reported in subgroup analyses on different durations of treatment with HRT (less than 1 or 2 years, less than 5 years or more than 5 or 7 years) also showed that current HRT users had a significantly lower risk of developing T2DM compared with non-users, but these results should be interpreted with caution given the post hoc subgroup analyses of these observational studies.

Very low quality evidence from 2 separate cohort studies and their post hoc subgroup analyses on different durations of HRT found no significant difference in the risk of T2DM between past HRT users and non-users.

Very low quality evidence from a post hoc subgroup analysis of 20,000 postmenopausal women (cohort study) found that the protective effect of HRT use on the risk of T2DM was preserved when HRT was administered orally or transdermally.

11.3.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise short-term treatment.

11.3.7. Evidence to recommendations

11.3.7.1. Relative value placed on the outcomes considered

The Guideline Development Group decided that T2DM and mortality (either general or condition specific) are the most important outcomes for this question. However, the group discussed that T2DM may be unrecognised and this was taken into consideration at the time of developing recommendations.

11.3.7.2. Consideration of clinical benefits and harms

Although evidence from randomised studies showed no significant difference in risk of developing T2DM associated with HRT compared with placebo, evidence from large cohort studies found that current HRT users have a significantly lower risk of T2DM compared with non-users. This protective effect of HRT on the risk of developing T2DM seems to disappear when the HRT treatment stops, as was found when data were compared between past HRT users and non-users. Data from post hoc subgroup analyses of different durations of HRT consistently indicated a protective effect of HRT on T2DM risk. Route of administration also did not seem to change HRT’s protective effect against T2DM. The group discussed the contrast of this result with the data for the combined oral contraceptive which contains higher concentrations of more potent sex steroids.

Most of the women included in the studies were postmenopausal before age 65. Although the outcome of diabetes was self-reported in most of the studies and biochemical confirmation was not necessarily obtained, the results might underestimate the protective effect of HRT on the risk of T2DM given that some cases would be undiagnosed. Only 1 study used the diagnosis of diabetes based on measurement of plasma glucose levels.

11.3.7.3. Consideration of economic benefits and harms

The Guideline Development Group believe that the clinical review provided some evidence of a protective effect associated with HRT which, depending on the magnitude of the effect, potentially could save future health service costs in the treatment and management of T2DM and its complications, as well as averting losses in health related quality of life (HRQoL).

11.3.7.4. Quality of evidence

The evidence informing these recommendations included 1 RCT and 3 comparative cohort studies. One of the cohort studies was a post hoc subgroup analysis for a part of the same dataset that was used in the RCT. However, results are presented separately due to the additional information given in the cohort for some predefined subgroup analyses in the protocol. All of the subgroup analyses presented by the cohort studies should be interpreted with caution due to the risk of type II errors.

The main reasons for downgrading the quality of the studies were the high and very high risk of bias due to selection, performance and attrition bias. Quality of evidence was also downgraded due to imprecision in the estimates of relative effects.

11.3.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence reviewed and on the expert opinion of Guideline Development Group members.

This section refers only to women in menopause with no prior diagnosis of T2DM or with insulin-dependent (Type 1) diabetes.

Women with ketonuria (more than trace) were also outside the scope of this review question.

See Section 11.4 in this guideline which also refers to women with T2DM; in this case regarding the associated risk of glucose control with HRT treatment.

11.3.7.6. Key conclusions

The Guideline Development Group concluded that HRT administration is not associated with an increased risk of developing T2DM.

11.3.8. Recommendations

46.

Explain to women that taking HRT (either orally or transdermally) is not associated with an increased risk of developing type 2 diabetes.

11.4. Type 2 diabetes management – control of blood sugar

11.4.1. Introduction

Diabetes is a heterogeneous condition which presents as a syndrome of biochemical and clinical disturbances of which blood glucose levels have been adopted as the defining criteria. HRT is, however, known to affect many biochemical markers so surveillance of all these should be continued as routine.

The menopausal transition is defined as a time of irregularity in the menstrual cycle and variation in hormone levels. Changes in sex hormones can have an influence on blood sugar levels. The symptoms of flushing and night sweats can be confused by a woman with diabetes as a symptom of hypoglycaemia.

There is some evidence that oestrogens and non-androgenic progestogens do not impair glycaemic control. Current practice is to use transdermal methods of HRT delivery in women with diabetes.

There is little evidence of significant long-term changes to blood sugar levels with the administration of HRT. Normal regular assessments of diabetes control should continue with blood sugar levels being more closely monitored only at the initiation of therapy.

11.4.2. Review question

What impact does administration of HRT have on diabetes/glycaemic levels in those with T2DM?

The objective of this review was to assess the impact of HRT use on diabetes/glycaemic control in menopausal (including perimenopausal and postmenopausal) women with Type 2 diabetes mellitus (T2DM). Comparisons were presented for any type of HRT and placebo or no HRT. Subgroup analyses were only considered based on the age distribution of the included population or on the stage of menopause (peri- or postmenopausal) if data were available. Given the interventional nature of this review question only systematic reviews of RCTs, RCTs and comparative cohort studies were considered for inclusion.

For full details see the review protocol in Appendix D.

11.4.3. Description of included studies

Five RCTs, 4 of which were parallel RCTs (Darko 2001, Kernohan 2007, McKenzie 2003, Perera 2001) and 1 crossover RCT (Sutherland 2001) were included for this review question. No comparative cohort studies were found to match the protocol. However, 1 large (over 15,000 women) cross-sectional study (Ferrara 2001) from a USA Diabetes Register was identified which compared different types of HRT with placebo. After discussion with the Guideline Development Group it was decided that, given its large size, this study would be included in the review to provide supplementary evidence. Results from this study were interpreted with caution due to the limitations of the study design and the lack of confidence in the production of effect sizes.

Women included in all studies were postmenopausal women with T2DM. Some common exclusion criteria were reported across these studies, such as women taking insulin, lipid lowering therapy, HRT use prior to study entry, poor glycaemic control, other co-morbidities (such as breast cancer or endometrial cancer) and moderate to severe hypertension. The age of the population ranged from 60 to 70 years. The majority of studies were conducted in the UK, 1 study in USA and 1 study in New Zealand.

Results are presented separately by HRT type. The 2 types of HRT included were sequential and continuous combined HRT (either oral or transdermal). Evidence was only found on the outcomes of glycaemic control at 12 weeks and 6 months measured by either glycated haemoglobin (HbAl1c, %) or blood glucose levels (mmol/litre). No evidence was found for the other outcomes specified in the protocol (health related quality of life, mortality or adverse events).

Data from the cross-over RCT (Sutherland 2001) were only reported from the second arm (after wash-out to 6 months of treatment) and were presented separately.

A summary of the baseline characteristics of included studies in this review are presented in Table 19.

Table 19. Summary of included studies.

Table 19

Summary of included studies.

11.4.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (see Appendix I). See also the study selection flow chart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

Study quality was assessed using the GRADE methodology. RCTs were initially assigned high quality and prospective cohort studies assigned moderate quality, and then downgraded based on potential sources of bias.

11.4.5. Evidence statements

Very low to low quality evidence from an RCT with 24 women comparing continuous combined HRT (oral or transdermal) with placebo showed that there was no significant difference on the outcome of diabetic control as measured by either HbA1c (%) or fasting glucose levels at 3 months follow-up. The same conclusion was found from low to very low quality evidence from 4 RCTs (of 47 women or less) which looked at both diabetic control measurements for continuous combined HRT users at 3 and 6 months follow-up compared with non-users.

Very low quality evidence from an RCT with 49 women with T2DM found significantly lower levels of blood glucose at 6 months for those treated with conjugated equine oestrogen alone compared with those with placebo.

Very low quality evidence from 1 large cross-sectional study of almost 15,000 women with T2DM showed that when results were adjusted for women’s age, there was a significant difference in the decrease of HbA1c (%) during 2 years of HRT duration for those women treated with HRT use compared with those who did not take HRT.

11.4.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise outcomes from short-term treatment.

11.4.7. Evidence to recommendations

11.4.7.1. Relative value placed on the outcomes considered

Glycated haemoglobin (HbA1c, %), blood glucose concentration (mmol/litre), health related quality of life (HRQoL), mortality (overall or condition specific mortality) and adverse events (specifically complications from diabetes) were considered as the most important outcomes when considering these recommendations.

11.4.7.2. Consideration of clinical benefits and harms

The only evidence found was for the outcomes of HbA1c and blood glucose measurements and for postmenopausal women. Evidence from randomised participants was presented separately by HRT type. Weak evidence showed that although treatment with conjugated equine oestrogen alone may be linked with a significant decrease in blood glucose levels at 6 months for HRT users with T2DM, this direction of effect was not found when the impact of either sequential or continuous combined HRT on diabetic control was examined (for either 3 or 6 months outcomes). No significant change in the direction of above effects was found for either oral or transdermal HRT preparation. The Guideline Development Group discussed the interpretation of these results and concluded that the lack of any significant differences between the HRT and no HRT groups would be expected given the trials’ short duration (as it would take longer for any effect on blood glucose levels to be observed).

In addition, supplementary evidence from a large cross-sectional study showed that HRT may have a positive impact on diabetes/glycaemic control in menopausal women taking HRT for a longer duration (2 years) compared with menopausal women who did not take HRT as the percentage of HbA1c was significantly reduced. These results should be interpreted with caution given the lack of comparability of the 2 groups (only adjusted for age differences) and due to outcome reporting bias (given that the exact timing of outcome reporting was unclear).

Control of blood glucose is important to prevent the acute complications of ketosis and hyperglycaemia. In addition, long-term complications, such as retinopathy, neuropathy, nephropathy and CVD, can be minimised if blood glucose levels are effectively controlled. Therefore the subgroup of participants with T2DM who were controlling their blood glucose while receiving treatment for menopausal symptoms was considered highly important. The group discussed that the included evidence did not suggest that HRT was contraindicated for women with T2DM, but was not strong enough to indicate a clear benefit of improving blood glucose control. However, the group discussed extensively how other co-morbidities should be noted when considering the use of HRT for women with T2DM.

11.4.7.3. Consideration of economic benefits and harms

In the absence of evidence that HRT exerts either a negative or positive impact on diabetic/glucose control for women with T2DM it is not possible to state what the economic benefits and harms are, if any.

11.4.7.4. Quality of evidence

The quality of evidence included for this question was considered to be low to very low. The included trials had very small sample sizes (the largest included 50 women in total) and there were serious concerns about the risk of bias (selection, performance and attrition). Imprecision was also a quality domain commonly and negatively affected. The timing of outcomes reported (3 to 6 months) was also not long enough to allow the demonstration of an effect between the comparisons (HRT or no HRT use). Not all studies have provided information about whether the blood glucose testing was conducted under fasting conditions.

In addition, the supplementary information from the cross-sectional study gave some indication of the association between HRT use and reduction of blood glucose levels.

11.4.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence and on the expert opinion of Guideline Development Group members.

The group discussed the difference in diagnostic performance between HbA1c and blood glucose as a measure of diabetic control. Although the use of glucose has been considered the ‘gold standard’ for assessing diabetic control for many years, glucose testing suffers from several deficiencies which are difficult to overcome (for example the requirement that the subject be fasting at the time the blood is drawn and the lack of sample stability). Alternatively, measurements of HbA1c which reflect chronic blood glucose values are now routinely used in monitoring glycaemic control and guiding therapy. This is because HbA1c measured using this method has been associated with a reduction in microvascular complications.

11.4.7.6. Key conclusions

The Guideline Development Group concluded that HRT does not exert a negative or positive impact on diabetic/glucose control for women with T2DM. However, the evidence base for this topic had flaws and the generalisation of results should be interpreted with caution.

11.4.8. Recommendations

47.

Ensure that women with type 2 diabetes and all healthcare professionals involved in their care are aware that HRT is not generally associated with an adverse effect on blood glucose control.

48.

Consider HRT for menopausal symptoms in women with type 2 diabetes after taking comorbidities into account and seeking specialist advice if needed.

11.5. Breast cancer

11.5.1. Introduction

Breast cancer is the most common cancer in the UK with almost 50,000 new cases recorded in 2011 (Cancer Research, http://www.cancerresearchuk.org), representing an approximate incidence rate of 155 per 100,000 women per year. Incidence of new diagnoses reaches a peak at around age 50 to 59 years, with approximately 500 cases recorded for every 100,000 women per year in the UK (women aged 50–59 years). This peak is believed to be due in part to an age-associated increase in incidence together with an increased identification rate of early cases via the NHS mammographic screening programmes offered to women aged 50 to 69 years.

Jewish women, particularly those of Ashkenazi heritage, are considered at much higher risk than the general population of developing breast cancer, while women of black and other minority ethnic groups are generally at lower risk. South Asian women also have a lower overall risk of developing breast cancer than the general population, but those diagnosed tend to be younger and living in more deprived areas of the UK.

Survival after diagnosis is around 80% at 5 years and 70% at 20 years after treatment, and irrespective of ethnicity, poorer survival from breast cancer occurs in lower socioeconomic groups (NICE guideline on early and locally advanced breast cancer). Given that breast cancer is linked with more deaths of women around the age of 50 than CVD, many women do not realise that they are more likely to die from CVD than from breast cancer over the course of their lifetime.

Female gender and age are considered the greatest risk factors for developing breast cancer. Family history is also important as a crude marker to specific genes (NICE guideline on familial breast cancer). Evidence from randomised and observational studies has identified sex steroids (particularly oestrogen/progestogen combinations) as another potential risk factor. Breastfeeding and physical activity are considered to be protective.

In order to help a woman assess her individual risk of developing breast cancer, she must consider the population level baseline risk in conjunction with modifying risk factors associated with family history, excess weight, excess alcohol consumption, contraceptive use and previous breastfeeding. Her own view of the importance of any risk must also be understood and discussed with the healthcare professional.

It is therefore necessary to support women in coming to a decision about the use of hormonal or non-hormonal therapies for treatment of the symptoms of the menopause, and to provide information about mammographic screening and the need to be ‘breast aware’.

11.5.2. Review question

What are the effects of HRT administered for menopausal symptoms on risk of developing breast cancer?

The aim of this review is to investigate the risk of developing breast cancer associated with HRT for menopausal symptoms. The focus population of this review question is peri- and postmenopausal women up to age 65 years. Given that the risk of developing breast cancer may be different for women at different stages of menopause (perimenopause or postmenopause), just as it is with age, subgroup analysis is presented, where available, for the stage of menopause and different age profiles of women.

Both RCTs and comparative prospective cohorts were selected for inclusion in this review. As cohort studies are prone to selection bias, only those whose analyses adjusted for the most common confounders (such as family history of breast cancer, BMI and age of menopause or first birth) were selected for inclusion.

Two outcomes were prioritised by the Guideline Development Group:

  • risk of developing breast cancer
  • mortality from breast cancer.

The risk of breast cancer was investigated in relation to ever having used HRT (which included current and past users), current or past use of HRT compared with no use, duration of HRT and the timing since discontinuing HRT. Analyses on the type of HRT is presented separately, when available. Otherwise, results are presented overall for the HRT and control arms and the interpretation of these is discussed in section 11.5.7 in relation to attributing breast cancer risk to a specific type of HRT.

For full details see the review protocol in Appendix D.

11.5.3. Description of included studies

Four RCTs comparing some form of HRT with placebo were included in this review (Cherry 2014, Schierbeck 2012, Vickers 2007, Women’s Health Initiative (WHI) [Anderson 2004, Manson 2003, Manson 2013]):

  • 1 trial (Schierbeck 2012) compared HRT (17β oestradiol, 17β oestradiol+NETA for women with uterus; 17β oestradiol only for women without uterus) with no treatment
  • 2 studies (The WHI [Manson 2003, Manson 2013], Vickers 2007) compared oestrogen plus progestogen (EP) with placebo
  • 1 study (Vickers 2007) compared oestrogen plus progestogen versus oestrogen and evaluated the risk of developing breast cancer
  • 2 studies (Cherry 2014, The WHI [Anderson 2004, Manson 2013]) compared oestrogen only versus placebo.

The majority of included trials were conducted in the USA (The WHI [Anderson 2004, Manson 2003, Manson 2013]), the UK (Cherry 2014) and Denmark (Schierbeck 2012). Vickers (2007) was a multi-site study with women recruited from the UK, Australia and New Zealand. The age range of the populations was 45 to 68 years. Duration of HRT treatment ranged from 11.9 months to 14 years.

Three trials had post-intervention follow-up and reported risk estimates for breast cancer (Cherry 2014, The WHI [Manson 2003, Manson 2013], Schierbeck 2012) for both periods (intervention and post-intervention follow-up). Post-intervention follow-up ranged from 8 to 10 years which didn’t necessarily account for the same time interval of HRT exposure, given that some women had previously used HRT. Only 2 trials (Cherry 2014, Vickers 2007) reported breast cancer as a primary outcome measure whereas 1 trial (Schierbeck 2012) reported breast cancer as a secondary outcome measure. The WHI trials [Manson 2003, Manson 2013, Anderson 2004] reported breast cancer as a safety outcome measure.

Table 20 gives a summary of the main characteristics of the included RCTs.

Table 20. Main characteristics of included RCTs.

Table 20

Main characteristics of included RCTs.

A total of 22 prospective cohort studies comparing use of HRT with never having used HRT were included in the review (Jernstrom 2003, Beral 2003, Fournier 2005, Schuurman 1995, Lando 1999, Tjonneland 2004, Ewertz 2005, Stahlberg 2004, Bakken 2011, Colditz 1992, Grodstein 1997, Mills 1989, Willis 1996, Fournier 2008, Lund 2007, Saxena 2010, Schairer 2000, Folsom 1995, Bakken 2004, Hedblad 2002, Manjer 2001, Sourander 1998). The studies were conducted in the USA and several countries in Europe (UK, France, Sweden, Netherlands, Denmark, Norway and Finland). The age of women with menopause included in these studies ranged from 33 to 64 years. The variation in the sample size and follow-up period of these studies was wide: sample size of studies ranged from 454 to 828,923 and follow-up duration ranged from 2.6 to 12.7 years.

Table 21 gives a summary of the main characteristics of included cohorts.

Table 21. Main characteristics of included cohorts.

Table 21

Main characteristics of included cohorts.

11.5.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (Appendix I). See also the study selection flow chart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

Study quality was assessed using the GRADE methodology. RCTs and comparative prospective cohort studies were appropriate study designs for addressing this question, so were initially assigned high quality and downgraded based on potential sources of bias.

11.5.5. Evidence statements

11.5.5.1. Evidence statements for RCTs

Low to very low quality evidence from 4 RCTs (with sample sizes ranging from 1000 to more than 5000 postmenopausal women) showed that the risk of breast cancer was not significantly different between those who had received hormonal replacement treatment and those who had not.

However, evidence from 3 RCTs, including the post-intervention follow-up, presented mixed results. Very low quality evidence from 1 RCT with more than 1000 participants found no significant difference between any HRT use and the control group during the 16-year treatment and follow-up period. The same was found by another RCT examining the effect of oestrogen in comparison with placebo during its 12.6 years treatment and follow-up period (very low quality evidence). Low quality evidence from 1 RCT (for the subgroup of over 5000 women aged 50–59 years) found that the risk of developing breast cancer is significantly higher for women who received oestrogen plus progestogen compared with those on placebo during 13 years of treatment and follow-up but not for women on oestrogen alone.

11.5.5.2. Evidence statements for cohort studies

Type of HRT (duration not specified)

Several cohorts of over 200,000 postmenopausal women found that those who received oestrogen alone or oestrogen plus progestogen had a significantly higher risk of breast cancer compared with women who had not used either of these HRTs. The evidence was of very low quality. However, very low quality evidence from 3 cohorts using progestogen only (sample size of almost 200,000 women) did not find a difference in the risk between those women taking progestogen only compared to those who had not used progestogen.

Current or past use of HRT

Very low quality evidence from 14 prospective cohort studies of over 1.2 million postmenopausal women showed that women who had ever used HRT were significantly at higher risk of developing breast cancer compared with women on placebo. The same harmful conclusion was found by low to very low quality evidence for current HRT use (9 cohorts of over 1 million women) but not when past use of HRT (9 cohorts of over 1 million women) was compared with never using HRT.

Past HRT users were not significantly different for the outcomes of breast cancer and mortality from breast cancer compared with women who had never used HRT (low quality evidence from 2 and 4 studies of over 500,000 women).

For studies looking separately at the components of HRT, it was found that:

  • The risk of breast cancer was found to be significantly higher for women who had ever used, or currently use, oestrogen plus progestogen compared women those who had never used this type of HRT (low to very low quality evidence from 4 cohorts of over 17,000 women).
  • Among women who had ever used, or were current or past users of oestrogen alone, only current users were at a significantly higher risk of developing breast cancer compared with women using placebo (very low quality evidence from 5 prospective cohort studies of over 400 postmenopausal women).

For some of these cohorts which looked at incident cases of breast cancer, significantly more women who had ever used or were currently using HRT were found to be at higher risk compared with women who had never used HRT (very low quality evidence from pooled analyses of 7 and 4 studies respectively of over 500,000 women).

Mortality

Insufficient evidence was found for the outcome of mortality from breast cancer to demonstrate whether there is any significant difference between women who had either ever used or currently use HRT compared with those who never used HRT (very low quality evidence from 3 cohorts).

Duration of HRT use

Inconsistent results from several cohorts were found to reveal a trend regarding the impact of the duration of HRT use on the development of breast cancer. Very low quality evidence from 4 cohorts of over 100,000 women found that up to 2 years of HRT use significantly increased the risk of breast cancer compared with the group of women who never used HRT. No significant difference was found for the outcome of breast cancer between those women who used HRT up to 4 years and non-users. The risk of breast cancer was shown to increase with HRT duration of 5 to 10 years (very low quality evidence of 3 studies of 70,000 women), 10 to 14 years and 15 years or more compared with no use (moderate quality evidence of 1 study of over 10,000 women).

For the studies which only included oestrogen as a type of HRT, 3 cohorts of 140,000 women found that being treated with oestrogen alone for 5 or more years significantly increased the risk of breast cancer compared with no use (very low quality evidence). The same conclusion was shown from very low quality evidence from 2 cohorts (of over 100,000 women) for oestrogen treatment duration of 15 years or more. However, no significant difference was found for the duration of 2 years, less than 5 years, 4 to 10 years or more than 10 years when oestrogen alone was compared with no use (moderate to very low quality evidence).

The results from studies that tested the impact of oestrogen plus progestogen duration on the risk of breast cancer compared with no use of HRT consistently found that the risk of breast cancer was significantly higher when the duration of oestrogen plus progestogen was 4 years or more (low to very low quality evidence from pooled analysis of 3 to 6 studies with sample sizes ranging from several thousand women to almost 1 million women).

Time since stopping HRT

Moderate to very low quality evidence from a cohort study of over 7000 women which examined whether time elapsed since discontinuation of HRT (up to 4 years, 4 to 10 years, 10 or more years) would impact on the risk of breast cancer did not reveal a significant difference between the HRT and no use groups. The same conclusion was found from studies that only included oestrogen alone or oestrogen plus progestogen (low to moderate quality evidence from cohorts of several hundred thousand women in studies of oestrogen alone and from cohorts of less or over 100,000 women in studies of the combination of oestrogen plus progestogen).

11.5.6. Health economics profile

No health economic studies were identified for this question.

11.5.7. Evidence to recommendations

11.5.7.1. Relative value placed on the outcomes considered

The Guideline Development Group considered the risk of breast cancer and mortality from breast cancer as the most important outcomes for answering this review question. The group followed the principles set up in the NICE Patient Experience guideline regarding the presentation of information to personalise risks and benefits as far as possible. For that purpose the use of absolute risk is preferred rather than relative risk. Provision of information provision on all aspects of the benefit/risk ratio of HRT regarding short- and long-term consequences of treatment is of paramount importance for women’s decision-making regarding the choice of treatment for menopausal symptoms (see section 11 on long-term benefits and risks of HRT).

11.5.7.2. Consideration of clinical benefits and harms

The included evidence from both randomised and cohort studies showed that there may be risk of developing breast cancer during treatment associated with oestrogen plus progestogen compared with no HRT use, but this risk does not seem to be the same for those women treated with oestrogen or progestogen taken alone.

More specifically, the WHI study found that in postmenopausal women aged 50–59 years treated for around 3.2 years with oestrogen plus progestogen the absolute risk of developing breast cancer was 8 more women per 1000 (95% confidence interval [CI] 1 fewer to 17 more) compared with women on no HRT treatment. However, this higher absolute risk was not observed in the other 2 RCTs which included smaller sample sizes and longer follow-up periods. The cohort studies also found that the absolute risk of developing breast cancer was significantly higher in women who ever used oestrogen and progestogen compared with those who never used it (29 more per 1000 [95% CI 5 to 73), while the results from the current users of oestrogen plus progestogen compared with women who had never used it moved in the same direction (17 more per 1000 [95% C.I 14 to 20]).

Evidence from observational studies showed that when HRT was used for more than 5 years, the risk of breast cancer may be increased but this associated risk seems to disappear after HRT is stopped. More specifically, it was found that 23 more women per 1000 women (95% C.I 8 to 45) treated with HRT for 5 to 10 years may develop breast cancer compared with those who have never used HRT, and this absolute risk increases to 47 more per 1000 (95% C.I 20 to 91) for a duration of HRT use of 10 to 14 years. Most of the women in the included studies started HRT when aged between 50 and 59 years and the group discussed how this would represent the majority of women starting HRT in the UK, as it is unusual for women to start using HRT after age 60. The WHI study also included women with prior HRT exposure, but it was not possible to further explore a duration HRT effect on risk of breast cancer given the limited presentation of data.

For the studies which looked at specific types of HRT, results of the impact of duration of oestrogen alone on the risk of developing breast cancer showed the same pattern, although the absolute numbers were lower; for duration of treatment of 5 years or more it is 9 more per 1000 (95% C.I 2 to 18) and for duration of treatment of 15 or more years it is 4 more per 1000 (95% C.I 1 to 8) compared to non-users. For oestrogen plus progestogen, it was shown that even for a treatment duration of less than 5 years there is an increased risk of breast cancer of 12 more per 1000 (95% C.I. 6 to 19). This risk increases to 21 more per 1000 (95% C.I. 9 to 37) with a longer treatment duration of 4 to 10 years.

The evidence found for the outcome of mortality from breast cancer came only from three observational studies of several thousand menopausal women which compared women either currently using or who had ever used HRT to women who had never used HRT. Due to low event rate of this outcome, the evidence was presented as an incidence rate per 100,000 women. It was found that 29 more women who are current HRT users per 100,000 (95% confidence interval from 43 fewer to 139 more) would be at risk of dying from breast cancer compared to non users. There was insufficient evidence to demonstrate whether mortality from breast cancer was significantly different between those who currently or had ever used HRT and those women who never been treated with HRT and the GDG did not formulate a recommendation regarding this outcome.

The Guideline Development Group discussed the importance of these findings which may suggest that HRT stimulates the development of cancer from occult lesions already present and that the natural history of the disease is not changed.

The group considered that the decision to offer HRT for women in menopause should be individualised, taking into account personal (baseline) risk factors for breast cancer that include genetic predisposition and lifestyle factors, such as diet, exercise, alcohol consumption, smoking and reproductive history.

11.5.7.3. Consideration of health benefits and resource uses

Breast cancer is expensive to manage and treat and has significant morbidity and mortality associated with it. As an adverse event arising from HRT use it is part of an overall trade-off of risks and benefits. This trade-off was assessed formally through an economic evaluation reported in detail in Appendix L.

11.5.7.4. Quality of evidence

Low to very low quality evidence from both randomised and comparative cohort studies was considered for this review question and evidence was presented by HRT type when data were available. The sample size of the studies ranged from 2 to several thousand participants. Four out of 5 RCTs presented information on the different types of HRT (oestrogen only, oestrogen plus progestogen) versus placebo. The studies for the comparison of oestrogen plus progestogen also presented results for a post-intervention follow-up period and these results are presented separately from the randomised period. Due to the high heterogeneity of studies with follow-up periods (age profile of women, duration of follow-up) results were presented separately for each study. The main reasons for downgrading the quality of included evidence were due to high risk of bias and imprecision around the estimates of relative effect.

Twenty-two prospective cohort studies from a variety of settings were also included in this review. The quality of observational evidence was rated as being of low to very quality mainly because of the serious risk of bias and inconsistency in the results. Inconsistency was a serious to very serious problem in the pooled analysis of cohort studies due to differences in the study characteristics and the follow-up period. The cohort study results were adjusted for different confounders which may have contributed to the observed inconsistency of results. However, given that the direction of effect across the studies was consistent, it was decided to present pooled results to facilitate the Guideline Development Group’s decision-making. The group was advised that the precision of results should be interpreted with caution, as should the results assessing the different durations of HRT treatments on the risk of breast cancer that were based on multiple subgroup analyses (potential risk of type II statistical error).

Although the outcome of breast cancer was not the primary outcome across all studies, quality of evidence was not further downgraded based on this factor. However, the group discussed the interpretation of results and their clinical relevance based on the way these outcomes were analysed in the studies.

11.5.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence reviewed and on the expert opinion of the Guideline Development Group members.

The impact of oestrogen on breast cancer risk is currently considered to be a class effect. There are emerging but as yet insufficient data to suggest that different progestogens may impact to a different degree and therefore these have not been considered separately.

The group discussed that due to improvements made in both screening and treatment, the mortality from breast cancer in the UK has fallen substantially over the last 20 years and 5 year survival has risen from 71% to 87% (Cancer Research, breast cancer survival statistics 1991–2011). Women in the UK can access mammography every 3 years from the age of 50, which is an important way of detecting early breast cancer. There is evidence that HRT, particularly combined oestrogen and progestogen, increases the density of the breast tissue and makes the detection of small tumours more difficult. One of the outcomes of this is that women are more likely to be recalled for further evaluation with repeat mammography, ultrasound and even biopsy.

11.5.7.6. Key conclusions

HRT with oestrogen and progestogen may be associated with an increased risk of breast cancer. Any increased risk of breast cancer associated with HRT is low and should be taken in the context of the overall benefit and risk ratio in using HRT for treating menopausal symptoms. In addition, this risk seems to be lost when HRT is discontinued, as demonstrated in the studies on the low risk of breast cancer for past HRT users.

11.5.8. Recommendations

49.

Using table 3, explain to women around the age of natural menopause that:

  • the baseline risk of breast cancer for women around menopausal age varies from one woman to another according to the presence of underlying risk factors
  • HRT with oestrogen alone is associated with little or no change in the risk of breast cancer
  • HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer
  • any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT.

11.5.9. Research recommendations

Research question
4.

What is the difference in the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators?

Why this is needed
Importance to ‘patients’ or the populationFear of breast cancer deters many women from taking HRT, even in the presence of debilitating menopausal symptoms. There is a lack of evidence from randomised controlled trials directly comparing the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators. There is a need for a national registry of women with breast cancer.
Optimising the risk benefit profile of HRT will potentially reduce morbidity and mortality from breast cancer in women who need HRT over the long term because of continuing menopausal symptoms.
Relevance to NICE guidanceHigh: the research is essential to inform future updates of key recommendations in the guideline
In the absence of good quality randomised prospective data it has not been possible for the current guidance to make recommendations concerning the best HRT regimens for minimising the risk of breast cancer
Relevance to the NHSNHS costs may rise if newer, more expensive preparations are shown to have an improved safety profile and uptake is likely to increase. This may in part be offset by improvements in quality of life and economic activity in women aged 50 to 59. Reduced long-term morbidity from breast cancer will potentially reduce the burden on NHS resources
National prioritiesThis was identified as a priority area by the British Menopause Society in the recommendation paper submitted to the Department of Health as part of the consultation process initiated by the Coalition Government White Paper to modernise the National Health Service.
Current evidence baseThere is a lack of RCT evidence for risk of breast cancer in women with menopause who are taking HRT about the direct comparisons of either progesterone, progestogen or selective oestrogen receptor modulators. There is a need for a national register for women with breast cancer.
EqualitySafer treatment options should improve availability of treatment for some women for whom it is currently not indicated, for example those at higher risk of breast cancer.
FeasibilityThe study is feasible but would require a large prospective RCT with follow-up of 5 to 10 years in order to answer the question with any degree of certainty.
Other outcomes e.g. cardiovascular could be studied concomitantly to make the study more cost effective.
Are there any ethical or technical issues? No
Other commentsA PICO has already been submitted to the NIHR HTA which has got through to the second round.
Research question
5.

What is the impact of oestradiol in combination with the levonorgestrel-releasing intra-uterine system (LNG-IUS) on the risk of breast cancer and venous thromboembolism (VTE)?

Why this is needed
Importance to ‘patients’ or the populationThe type of progestogen used in HRT influences the risk of breast cancer and VTE. Many women in the UK receive the progestogenic component of HRT by the use of an intra-uterine system (the LNG-IUS) which lasts 4 years. This is a very effective means of protecting the endometrium from the effect of unopposed stimulation by oestrogen alone and has few side-effects such as those associated with standard oral or transdermal preparations. However, the risk of breast cancer is uncertain as few data are available and the risk of VTE is unknown. If the risks were similar to those of oestradiol alone, rather than the combined HRT, then this would have significant public health impact in terms of breast cancer risk. It was not possible to consider this combination in the guideline because insufficient data of sufficient quality was available.
A study should compare a standard combination of oestradiol with progestogen with a combination of transdermal oestradiol and the LNG-IUS, in order to assess changes in risk factors and event rates in women wishing to initiate HRT
Relevance to NICE guidanceHigh importance
Relevance to the NHSThis would allow women who are potentially at increased risk of developing BC or DVT to use combined HRT with no further increased risk for these outcomes. This would be an important health benefit. Cost effectiveness of LNG-IUS is unknown in this context, but after insertion, which can be undertaken in primary or secondary care, it requires no additional care over standard combined HRT and minor adverse effects are likely to be reduced
National prioritiesN/A
Current evidence baseVirtually non-existent. There is one observational study of low quality of its impact on breast cancer risk and small studies reporting efficacy. However, no significant studies have been undertaken
EqualityNo issues
FeasibilityNo ethical or technical issues in relation to this research recommendation.
Other commentsThere might be some support from the pharmaceutical industry.
Recruitment is always more difficult when different treatment modalities are compared, especially one requires an invasive procedure.

11.6. Osteoporosis

11.6.1. Introduction

Osteoporosis is a skeletal disorder characterised by compromised bone strength that predisposes a woman to an increased risk of fracture, causing substantial pain, severe disability and a reduced quality of life. Fractures of the wrist, hip and vertebral fractures are the most common in people with osteoporosis, with hip and vertebral fractures, in particular, are associated with decreased life expectancy. Approximately 80,000 hip fractures occur in the UK each year (costing almost £2 billion in hospital care alone), while a further 280,000 osteoporotic fragility fractures also occur annually.

Fragility fractures are defined as those that are associated with a fall from standing height or less. They are associated with osteoporosis and are more common in women than men at all ages. Although most osteoporotic fractures are seen in women over 60 years of age, fracture incidence increases in women at the menopause, coinciding with lower oestrogen levels, a decrease in bone mineral density (BMD) and higher rates of bone turnover. As osteoporosis is a symptomless condition its management focuses on fracture prevention, which includes strategies for case finding and prediction of fracture risk. A number of clinical risk factors for fragility fractures have been identified which include a previous fragility fracture, use of oral or systemic glucocorticoids, history of falls or family history of hip fracture, suspected secondary osteoporosis, low body mass index (BMI), smoking and a higher than average alcohol intake. The presence of these factors can act both as a prompt to consider a woman’s future risk of fracture and to contribute to the estimate of risk using a fracture risk assessment tool, such as FRAX® (World Health Organization [WHO] Fracture Risk Assessment Tool) or the QFracture® algorithm. These risk assessment tools estimate the predicted risk of major osteoporotic or hip fracture over 10 years, expressed as a percentage.

Treatment can then be targeted at the primary prevention of fractures (in women who have not previously sustained a fragility fracture) and secondary fracture prevention in cases of fragility fracture, particularly for postmenopausal women. A number of therapies are licensed for the treatment of postmenopausal osteoporosis, including bisphosphosphonates, strontium ranelate, raloxifene, denosumab, teriparatide and calcium with vitamin D. They generally increase BMD and decrease bone turnover (although teriparatide has a different mode of action). Clinical efficacy is assessed by their effect on reducing fracture incidence.

HRT containing oestrogen was identified in early clinical trials as an agent that increases BMD and decreases bone turnover at the time of the menopause. However, although some HRT products are licensed for osteoporosis prophylaxis, none are licensed in the UK for the treatment of osteoporosis, although the benefits of continued exposure to oestrogen from HRT at the menopause can be considered in the short term (benefits on fracture risk for the duration of therapy) and the longer term (delay to future fracture risk).

For further details on the treatment of osteoporosis in women with menopause, see the NICE accredited SIGN guideline on the management of osteoporosis and the prevention of fragility fractures.

11.6.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of development of osteoporosis?

The aim of this review was to identify whether HRT use modifies the risk of developing osteoporosis. Further subgroup analyses were predefined in the protocol based on the effect of different durations of HRT treatment, age of HRT initiation, different HRT treatments and the time since treatment was discontinued.

Study designs included for this question were RCTs and comparative cohort studies. Only cohort studies which included appropriate adjustment for potential confounders (as outlined in the protocol) in their analysis were included.

Different types of fractures were prioritised by the Guideline Development Group to be the focus of this review:

  • any fracture
  • any osteoporotic fracture
  • any non-vertebral fracture
  • hip fracture
  • vertebral fracture
  • wrist fracture.

For full details see the review protocol in Appendix D.

11.6.3. Description of included studies

Forty-one studies were included in this review. Of these, 20 were RCTs (Aitken 1973, Bjarnason 2000, Cauley 2003, Cherry 2001, Delmas 2000, Genant 1997, Hosking 1998, Jackson 2006, Komulainen 1998, Liu 2005, Lees 2001, Lufkin 1992, Manson 2013, Mosekilde 2000, PEPI 1996, Ravn 1999, Reid 2004, Veerus 2006, Vickers 2007, Weiss 1999, Wimalawansa 1998) and 21 were comparative cohort studies (Bagger 2004, Banks 2004, Barrett-Connor 2003, Engel 2011, Heiss 2008, Høidrup 1999, Honkanen 2000, Hundrup 2004, Huopio 2000, LaCroix 2011, Lafferty 1994, Manson 2013, Maxim 1995, Melton III 1993, Middleton 2007, Paganini-Hill 1991, Paganini-Hill 2005, Prentice 2009, Randell 2002, Tuppurainen 1995, Yates 2004).

Further unpublished data from the RCTs were included in the synthesis of evidence for this review taken from a published systematic review and meta-analysis which assessed the role of HRT on vertebral and non-vertebral fracture (Torgerson 2001a). This meta-analysis did not meet all the inclusion and exclusion criteria in our protocol and was not incorporated per se.

Of the studies included in this review 18 were conducted in the USA (Anderson 2009, Barrett-Connor 2003, Cauley 2003, Genant 1997, Heiss 2008, Jackson 2006, Lacroix 2011, Lafferty 1994, Liu 2005, Lufkin 1992, Manson 2013, Maxim 1995, Melton 1996, PEPI 1996, Paganini-Hill 1991, Paganini-Hill 2005, Weiss 1999, Yates 2004), 5 in Denmark (Bagger 2004, Bjarnason 2000, Hoidrup 1999, Hundrup 2004, Mosekilde 2000), 5 in Finland (Honkanen 2000, Huopio 2000, Komulainen 1998, Randell 2002, Tuppurainen 1995), 5 in the UK (Aitken 1974, Banks 2004, Cherry 2002, Middleton 2007, Wimalawansa 1998), 2 in France (Delmas 2000, Engel 2011) and 1 in Estonia (Veerus 2006). A number of studies were multicentre, including 2 done in the UK, USA and Denmark (Hosking 1998, Ravn 1999), 1 across the UK, Australia and New Zealand (Vickers 2007), and 1 in the UK and Canada (Lees 2001). One multicentre study was conducted at 38 different sites across Australia, Canada, Europe, South Africa and the USA (Reid 2004).

The most common type of HRT preparation in the cohort studies was any oestrogen, with no further details on whether it was oestrogen alone or in combination with progestogen. Among the RCTs, 10 included oestrogen plus progestogen preparations (Delmas 2000, Hosking 1998, Komulainen 1998, Lees 2001, Lufkin 1992, Ravn 1999, Veerus 2006, Vickers 2007, Manson 2013, Wimalawansa 1998). Five RCTs (Cherry 2001, Genant 1997, Reid 2004, Weiss 1999, Manson 2013) included oestrogen alone preparations and 1 included progestogen-only preparations (Liu 2005). The remaining RCTs included both oestrogen alone and oestrogen plus progestogen preparations in their intervention arms, and did not present subgroup analysis by HRT preparation type. Only 1 cohort study (Hundrup 2004) provided subgroup data separately for women using oestrogen alone or oestrogen plus progestogen preparations.

The number of women participating in each study ranged widely, from 36 (Wimalawansa 1998) to 140,582 (Yates 2004). The age profile of women included in each study either varied considerably or was a defined age range that was followed up for a long period of time. Therefore, the estimation of age dependent fracture risk was not possible with the available data. Two studies (Manson 2013, Jackson 2006) did carry out subgroup analysis for the risk of fracture according to the age of the participants. The majority of studies included women older than 45 or 50 years up to the age of 65 years. Only 1 study (Melton III 1996) included a younger population of menopausal women at the start of the study (median 43.8 years, range 18 to 56) who had undergone bilateral oophorectomy.

Table 22 gives a summary of the main characteristics of included studies.

Table 22. Summary characteristics of included studies.

Table 22

Summary characteristics of included studies.

11.6.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (see Appendix I). See also the study selection flow chart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

Study quality was assessed using the GRADE methodology. Because of the nature of the outcomes assessed, which developed over time, RCTs were initially assigned high quality and downgraded based on potential sources of bias.

Different comparisons of HRT use were described in the included studies: women who had ever used HRT (‘ever users’, consisted of both current and/or past users) were compared to women who had never used HRT (‘never users’); current HRT users were compares to never users; and current users were compared to women not currently using HRT (‘no current use’). Where relevant, this has been described in the GRADE tables. Similarly, where subgroup analysis was conducted regarding the age of participants, duration of use and time since stopping HRT this analysis has been presented.

11.6.5. Evidence statements

Evidence statements for RCTs

Low quality evidence from 5 RCTs that enrolled over 5000 postmenopausal women showed a significantly lower risk of any fracture for women currently using HRT use compared with no current use.

Moderate to very low quality evidence from several RCTs considering different types of fractures in women in menopause found a significantly lower risk for current users of HRT compared with non-current users for the outcomes of non-vertebral fracture and wrist fracture (the sample size of included studies for these two outcomes ranged from 36 to almost 579 women). No significant difference was found for the outcomes of vertebral and hip fracture. This was very low quality evidence.

Subgroup analysis on the duration of HRT indicated that for HRT use lasting up to 2 years, no significant difference was found for any type of fracture (and individual types) between current HRT users and non-current users (very low quality evidence from either individual or up to 5 RCTs with sample sizes ranging from 200 to over 4000 women). However, HRT duration between 2 to 5 years showed significantly lower risk of any, non-vertebral and wrist fracture (low to moderate quality evidence from 2 to 4 RCTs including over 1000 women) in women using HRT compared to those not using HRT.

Further stratified analysis by HRT type showed that for current users of oestrogen plus progestogen, there was moderate to very low quality evidence that the risk of any fracture and vertebral and non-vertebral fracture is significantly lower in women currently using HRT compared with women not currently using HRT (from a meta-analysis of RCTs with over 2000 women and 1 RCT with over 16,000 women). Inconclusive evidence of a difference between the 2 comparison groups (of low to very low quality) was found for the direction of effect for hip and osteoporotic fractures.

Within the RCTs which looked at the role of current oestrogen plus progestogen use on different types of fractures, subgroup analyses by women’s age distribution showed that the lower risk for any fracture from the HRT use was significant in women aged 50 to 54 years and over 65 years (65–69 years) but not between 50 and 59 years old (low to very low quality evidence from single trials with sample sizes ranging from over 2000 to 16,000 women). However, results should be interpreted with caution given that the subgroup analysis on different age profiles is coming from different sources.

Moderate to low quality evidence from individual RCTs (with over 10,000 women) which included oestrogen alone as the HRT type showed that the risk of any, hip, vertebral and wrist fracture may be significantly lower for current HRT users compared with non-current users but not all results were in the same direction. Further subgroup analysis on this type of HRT showed no significant differences in the risk of any and hip fracture between current and non-HRT users for women aged 50–59 years (low to very low quality evidence). For women aged 60–69 years who were current users of oestrogen alone, the risk of any fracture was found to be significantly lower when compared with non-current users (moderate quality evidence from a study of almost 5000 women) but not for the case of hip fracture (low to very low quality evidence from 2 RCTs in both interventional and post-interventional follow-up).

Evidence statements for comparative cohort studies

Moderate to very low quality evidence from 8 prospective cohort studies (with sample size ranging from over 300 to 100,000 women) showed that the risk of any, non-vertebral, vertebral and hip and wrist fracture was significantly lower for current HRT users compared with either womeon not currently using HRT or who had never used HRT.

Subgroup analysis on the duration of HRT showed that the lower risk of any fracture and osteoporotic fracture remained significantly independent of the HRT duration (less than 1 year, 1 to 4 years, 5 to 9 years or over ≥ 10 years) for current HRT users compared with women who had never used HRT (low to very low quality evidence from single RCTs). However, the lower risk of non-vertebral and hip fracture remained significantly lower in the current HRT use group compared with women who had never used HRT for those women on treatment for more than 10 years (low quality evidence from single RCTs)

Moderate to very low quality evidence from single prospective cohort studies (with sample sizes ranging from 500 to over 8000 women) did not produce consistent results for previous HRT users and women who had never used HRT in terms of the difference in the risk for different types of fractures. Subgroup analysis by HRT duration did not provide any more clarity in the direction of the results for the risk of fracture among women who had ever used HRT and womeon who had never used HRT (all low quality evidence).

When the effect of timing of stopping HRT was examined, low to very low quality evidence showed that the risk of any, non-vertebral, hip or osteoporotic fracture was not significantly different between previous HRT users and those who discontinued HRT less than 5 years ago compared with non-users (from individual cohorts with sample size ranging from over 400 to over 70,000 women).

Low to very low quality evidence from 1 cohort enrolling over 5000 women found that the risk of non-vertebral fracture was significantly lower for both women currently using oestrogen alone or using oestrogen plus progestogen compared with women who had never used HRT, whereas further analysis on the timing of stopping HRT did not show any differences in the fracture risk between these groups (low to very low quality evidence from single cohorts of several thousand women).

11.6.6. Health economics profile

No search for health economic evidence was undertaken as it was thought that relevant studies would be identified in the health economic review on short-term treatments. Three evaluations (Zethraeus 2005, Ylikangas 2007, Lekander 2009a) in this review included fractures in the analysis. Further details of these studies can be found in a literature review in Appendix L. All compared HRT with no therapy and found HRT to be cost effective. However, the potential health benefits of HRT for preventing osteoporosis must be considered within the context of overall benefits and adverse consequences of HRT.

11.6.7. Evidence to recommendations

11.6.7.1. Relative value placed on the outcomes considered

The Guideline Development Group considered different types of fragility fractures (such as any fracture, vertebral and non-vertebral, hip, wrist and osteoporotic) as the most important outcomes to answer this review question. Of the 6 outcomes, the most important for the group’s decision-making was hip fracture as this is associated with the greatest health and personal cost, particularly as it has an increased mortality in the year following fracture. The group followed the principles set up in the Patient Experience guideline regarding the presentation of information to personalise risks and benefits as far as possible. For that purpose the use of absolute risk is preferred to relative risk. Information provision of all aspects of the benefit/risk ratio of HRT regarding short- and long-term consequences of treatment is of paramount importance for women’s decision-making regarding the choice of treatment for menopausal symptoms. The group did not consider other outcomes such as BMD and bone turnover markers which are proxy markers for the risk of fracture.

11.6.7.2. Consideration of clinical benefits and harms

Consistent evidence from both randomised and cohort studies demonstrated that the risk of any fragility fracture and non-vertebral fracture was significantly lower for women currently taking HRT (either oestrogen alone or for the combination of oestrogen plus progestogen) compared with non-users. The risk of hip fracture was also found to be significantly lower for those women on HRT treatment compared with the no treatment group, but this finding was only supported by the prospective cohort studies.

The effect of duration of HRT use on the risk of fractures was investigated in both randomised and observational data. No change in the direction of observed protective effect of HRT on the risk of any fracture was found when different HRT durations (short-term duration of less than 1 year, up to 5 years, 5 to 10 years or more than 10 years) were examined in RCTs. However, the observational evidence on non-vertebral and hip fracture showed that the effect of HRT on lowering the risk of this type of fracture was only apparent for HRT durations more than 10 years.

Subgroup analysis was undertaken on the role of different age profiles when the risk of osteoporosis was examined in relation to HRT use; randomised evidence did not support any differences in the direction of effects based on age.

Evidence from cohort studies also showed that the protective effect of HRT on the risk of fractures is not influenced by the time since stopping HRT, implying that protection may be preserved after HRT is stopped. The group concluded that the evidence was robust and showed a lower risk of fracture associated with current HRT use that persists after HRT is discontinued.

The group discussed whether women should be given information about this conclusion as a long-term consequence of HRT, to be considered in the context of benefits and risks (CVD, covered in Section 11.2, and breast cancer, covered in Section 11.5).

11.6.7.3. Consideration of economic benefits and harms

There appears to be a health benefit from long-term use of HRT in preventing fractures. However, these benefits need to be considered alongside other long-term consequences of HRT use in order to determine whether taking HRT in the long term is a good use of resources.

11.6.7.4. Quality of evidence

The majority of evidence from RCTs was rated moderate to low quality with imprecision the domain mainly affected in the quality assessment. All women included in the RCTs were postmenopausal and aged 40 to 65 years old.

The risk of fragility fracture in women around the age of menopause is influenced by a number of confounding factors, such as the use of oral or systemic glucocorticoids, previous fractures, family history of osteoporosis, smoking, alcohol consumption and low BMI. Only prospective cohort studies which adjusted their analysis for some or all of the confounders set up at the protocol were considered for inclusion in this section. However, given that the included studies have adjusted for different confounders, the meta-analysis of cohorts was not considered appropriate given the heterogeneity of their data analyses. That decision led to several cases of production of individual effect estimates for the same comparison (HRT versus no treatment) but without distorting the conclusions in terms of producing benefit or harm.

In addition, the Guideline Development Group expressed some concern about the generalisation of some of the findings for the outcome of hip fracture, as most of the cohorts contributing to this evidence were studied more than 20 years ago at a time when alternative interventions to HRT for the treatment of osteoporosis were not so widely available.

11.6.7.5. Other considerations

The recommendations were based on both the interpretation of clinical evidence reviewed and on the expert opinion of Guideline Development Group members.

Hip fracture risk at the menopause is considered to be low. The group discussed that it may be that HRT has a longer term impact on hip fracture reduction (by deferred risk) in older age. However, that evidence was not available. The group also referred to NICE guideline on osteoporosis when discussed the recommendations in this section.

11.6.7.6. Key conclusions

The Guideline Development Group concluded that current use of HRT treatment compared with non-use for women in menopause is associated with a significantly lower risk of fragility fracture and this lower risk is preserved when HRT is discontinued, although magnitude of difference between groups is smaller. Age and HRT duration may not produce any change in the direction of these conclusions.

11.6.8. Recommendations

50.

Give women advice on bone health and discuss these issues at review appointments (see the NICE guideline on osteoporosis: assessing the risk of fragility fracture).

51.

Using table 4, explain to women that the baseline population risk of fragility fracture for women around menopausal age in the UK is low and varies from one woman to another.

52.

Using table 4, explain to women that their risk of fragility fracture is decreased while taking HRT and that this benefit:

  • is maintained during treatment but decreases once treatment stops
  • may continue for longer in women who take HRT for longer.

11.7. Dementia

11.7.1. Introduction

Dementia is not a normal part of ageing; instead the umbrella term ‘dementia’ describes a set of symptoms that occur when the brain is affected by certain diseases or conditions.

Experts believe that Alzheimer’s disease, which is the most common form of dementia, begins to develop in midlife, but is typically diagnosed after symptoms have progressed significantly. Dementia often starts with episodic memory decline.

Due to the ageing demographic of the UK population and improvements in other disease morbidities, 1 in 3 people over 65 will die with some form of dementia. Dementia affects between 670,000 and 820,000 people in the UK and number is increasing. About 40% of the UK population know a close friend or have a family member with dementia (Alzheimer’s Society, http://www.alzheimers.org.uk). By 2040, the number of people affected is expected to double.

Symptoms such as memory loss and aggression can dramatically alter personality and cause distress to patients and their families and additional carers, leading to requirements for long-term social care at home or in a residential institution.

Dementia costs the UK economy more than cancer and heart disease combined and the cost may be as much as £23 billion each year.

Further research into dementia is needed; there are few good studies that provide reliable information about whether a treatment will be successful in affecting the incidence or progression of established dementia. However, some studies have suggested that HRT might impact the risk of dementia so the evidence is reviewed in this guideline.

11.7.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of dementia?

The aim of this review was to determine the effect of HRT on dementia for women in the menopause. Specifically, this review question aimed to determine whether initiation or duration of HRT has a protective effect by delaying the onset of dementia. Dementia is an umbrella term which describes the symptoms that occur when the brain is affected by certain diseases or conditions and this review did not aim to investigate the different types of dementia. Subgroup analysis was prespecified if data were available for postmenopausal and perimenopausal women, and for women at different age ranges (under 50 years, 50–60 years and 60 years and older).

Both RCTs and comparative cohort studies were selected for inclusion in this review. As RCTs are the most appropriate study design for addressing the question, they were initially assessed as high quality and downgraded based on potential sources of bias. Cohort studies started as moderate quality and were then downgraded for other sources of bias if necessary.

The risk of developing dementia was examined in terms of different HRT types, duration of treatment and time since stopping treatment. Different measurements of dementia or reduced cognitive function were included and mortality overall or attributed to dementia were also selected as outcomes of interest.

For full details see the review protocol in Appendix D.

11.7.3. Description of included studies

One RCT (Rasgon 2014) and 11 cohort studies (Bove 2014, Fillenbaum 2001, Kang 2004, Kawas 1997, Khoo 2012, Mitchell 2003, Pettiti 2008, Ryan 2008, Shao 2012, Tang 1996, Whitmer 2011) were identified to match this review protocol. The majority of included studies focused on dementia as a result of Alzheimer’s disease. Results from cohort studies were not meta-analysed given the differences in population, scales used to assess dementia and timing of outcomes reported.

One RCT (Rasgon 2014) compared the impact of continued use of HRT on cerebral function versus discontinued HRT use. The RCT compared those who had taken 17βoestradiol for 10 years and then discontinued use with those who had taken combined equine oestrogen for 10 years and had continued use, with the outcome being measured at 2 years to see changes in cerebral metabolism. This trial included 64 women aged 50–65 years who have been using HRT for more than 1 year and were considered at elevated risk for dementia, as defined by having a first-degree relative with Alzheimer’s disease or personal history of major depression. Cerebral function was measured as an indication of dementia by neuroimaging techniques (positron emission tomography [PET] scans). The duration of previous HRT use was comparable in the two groups – 10.5 years (±4.9 years) in the continued HRT group and 9.4 years (±6.2 years) in the discontinued HRT group – and participants were followed up for two years.

Of the 11 cohort studies, 6 (Bove 2014, Mitchell 2003, Ryan 2008, Shao 2008, Whitmer 2011, Zandi 2002) compared any type of HRT (current and past) with no HRT use whereas 5 (Fillenbaum 2001, Kang 2004, Kawas 1997, Khoo 2012, Tang 1996) included the use of oestrogen alone (current, past, intermittent or continuous use) and 3 (Kang 2004, Khoo 2012, Pettiti 2008) compared oestrogen plus progestogen with no current use of or never used HRT.

In relation to setting of the studies, the majority of included cohort studies were conducted in the US (Bove 2014, Fillenbaum 2001, Kang 2004, Kawas 1997, Mitchell 2003, Petitti 2008, Shao 2012, Tang 1996, Whitmer 2011), with 2 studies conducted in France (Ryan 2009) and Australia (Khoo 2010). The sample sizes in the studies ranged from 410 (Khoo 2012) to 15,646 (Kang 2004) women in menopause. Duration of treatment ranged from 2 years to 10 years, with most of the studies reporting adjusted estimates for dementia risk or decline in cognitive function. Timing of initiation of HRT treatment was reported in 5 studies (Kang 2004, Khoo 2010, Petitti 2008, Shao 2012, Whitmer 2011).

No evidence was identified for the outcome of mortality from either RCTs or cohort studies.

A summary of the studies that were included in this review are presented in Table 23.

Table 23. Summary of included studies.

Table 23

Summary of included studies.

11.7.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (see Appendix I). See also the study selection flow chart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

Study quality was assessed using the GRADE methodology. RCTs and comparative cohort studies were appropriate study designs for addressing this question.

11.7.5. Evidence statements

Evidence statements for RCTs

Low to very low quality evidence from 1 RCT with 45 post-menopausal women showed that the risk of dementia (as assessed by cerebral metabolism change, medial cortical area decline or posterior cingulate decline) was not significantly different between those who had received HRT and those who had not after 2 years of follow-up.

Evidence statements for observational studies

Low to very low quality evidence from several cohort studies (prospective or retrospective study) with sample sizes ranging from almost 2000 to over 10,000 women in menopause showed that there was no significant difference in the risk of dementia (as assessed by cognitive impairment or decline with different scales) between those women who were current or past HRT users and those who had not used HRT. The same finding was found when the effect of dementia was examined for different durations of HRT or timing of HRT initiation and in a long follow-up of 5 or 9 years (low to very low quality evidence).

However, very low quality evidence was found from 1 retrospective study of over 10,000 women in menopause that the risk of dementia at 9 years follow-up was significantly lower for those who had used HRT compared with those who had not used HRT. The same conclusion was found for a subgroup analysis of the same population aged below 80 years in which the risk of dementia was significantly lower for those who had previously used HRT with 2 or more prescriptions or refills during 4 years (very low quality evidence) compared with non-users.

When the effect of different preparations of HRT (oestrogen alone, progestogen alone, oestrogen plus progesterone) was examined, no significant difference was found for any of the outcomes when the risk of dementia was compared between HRT users and no HRT users (low to very low quality evidence).

11.7.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise outcomes from short-term treatment.

11.7.7. Evidence to recommendations

11.7.7.1. Relative value placed on the outcomes considered

The Guideline Development Group discussed that dementia and mortality (either general or condition specific) are the most important outcomes for this question. However, the group noted that mild cognitive impairment, although not the same as the major cognitive decline associated with dementia but usually preceding dementia, was considered for inclusion.

11.7.7.2. Consideration of clinical benefits and harms

The only small RCT included for this topic showed that there is no significant difference in dementia as assessed by different measurements for postmenopausal women who received HRT for 2 years and those who did not. In contrast, the evidence from prospective cohort studies was not consistent, mainly due to the heterogeneity of data included. The majority of studies, which looked at different ways to assess dementia, showed no significant difference in the development of dementia between those women who had current or prior use of HRT and those who had not. The cohorts that showed a significant reduction in the risk of dementia for previous HRT users were large size studies of menopausal women without comorbidities who mainly started HRT between 45 and 50 years of age. There was also some evidence that showed that in the long-term follow-up (7–9 years) the risk of dementia may be significantly lower with HRT use compared with non use. The direction of this protective effect was not consistent across the included studies and therefore results should be interpreted with caution.

The group considered the spectrum of both randomised and cohort evidence and concluded that there was no strong evidence base to support the protective or negative effect of HRT on the risk of dementia for women experiencing a ‘normal’, as opposed to premature, menopause. There is some indication that there may a window of opportunity for lowering the risk of dementia with HRT use for women with specific preconditions, such as higher baseline risk if they have first-line relatives with dementia, or for women who have premature ovarian insufficiency (POI).

However, the group did not feel confident to extrapolate from this evidence and their clinical experience on whether a consistent direction of HRT impact on dementia exists for women going through a normal menopause.

The group concluded that it would be important to advise women in the menopause that the evidence on HRT and the risk of dementia is yet to be firmly established either way (protective or harmful effect).

11.7.7.3. Consideration of economic benefits and harms

There is no strong evidence of either a risk or benefit from HRT use on dementia and in the absence of such evidence it is not possible to conclude what the economic benefits and harms are, if any.

11.7.7.4. Quality of evidence

Both randomised and comparative cohort studies were considered appropriate to address this question. However, the randomised evidence was of low to very low quality as it included just 1 small RCT study of high risk of bias (selection and performance bias) which was also downgraded for imprecision. In addition, its population had a younger age profile (below 60 years) and the follow-up was too short (2 years) to allow any observation of the effect of HRT on the outcome of dementia.

The quality of the evidence on comparative cohort studies varied from low to very low quality. Meta-analysis was not considered appropriate due to the high heterogeneity of the population and methods of assessing dementia (from clinician’s consensus to assessment tools and imaging techniques). The majority of cohort studies employed very large sample sizes (up to 15,000 usually healthy women in menopause) controlled for the effect of confounders – such as age, years of education, medical risks (diabetes, hypertension, hyperlipidaemia or stroke), race, BMI and number of children – on their analyses which gives more confidence in the direction and precision of effect sizes.

11.7.7.5. Other considerations

The recommendation was based on both the interpretation of clinical evidence reviewed and on the expert opinion of Guideline Development Group members.

The group has discussed the paucity of good randomised data in this area that would give more precise results on the risks or benefits of HRT on dementia.

11.7.7.6. Key conclusions

The Guideline Development Group concluded that the evidence was not strong for either direction of risk or benefit for dementia when HRT is administered to naturally menopausal women commencing HRT before age 65 years. However, some large cohort studies have shown that the risk of dementia may be lower with HRT use in long follow-up.

11.7.8. Recommendations

53.

Explain to menopausal women that the likelihood of HRT affecting their risk of dementia is unknown.

11.7.9. Research recommendations

Research question
6.

What are the effects of early HRT use on the risk of dementia?

Why this is needed
Importance to ‘patients’ or the populationConcern about the prospect of dementia in older age is increasing and any beneficial effect on the future risk of dementia will be important to women who are considering using HRT. There is a need for good-quality observational studies controlling for the effect of important confounders on how early HRT use affects dementia risk in women with early natural menopause, including women with premature ovarian insufficiency.
Relevance to NICE guidanceMedium importance:
Current NICE guidance (CG42) does not recommend HRT in dementia prevention; but this is based on the absence of evidence not evidence of harm? As two NICE guidelines now fail to show such evidence, there is a clear need to come to a more definitive conclusion.
Relevance to the NHSIf a benefit of HRT on dementia were found there would be great benefits to Public Health and the NHS as well as social care, depending on the size of the effect, as the burden of dementia care would be delayed and decreased for a large proportion of the older population.
National prioritiesDementia has been identified as a Health and Social Priority with a Department of Health Policy Paper (2013) on Dementia care and support : www​.gov.uk/government​/publications/dementia-care-and-support and the Department of Health Dementia Challenge.
http:​//dementiachallenge.dh.gov.uk/
Current evidence baseGood quality observational data on how HRT use affects dementia risk in women with early natural menopause are needed.
There are too few studies of adequate quality and both ecological and intervention studies are required. For intervention studies, follow-up is generally insufficient to reach clinically relevant endpoints relating to cognition and other features of dementia. Future research relating to HRT should include long term follow-up.
EqualityNot specific equality issues.
FeasibilityTiming is always a problem with dementia research and, with regard to HRT, this problem is amplified, since the delay between HRT use and cognitive decline is decades.
This offers considerable technical issues, relating to long term follow and potential ethical issues in studying some patients with cognitive impairment who may lack the capacity to consent.
Other commentsNo other comments

11.8. Loss of muscle mass (‘sarcopenia’)

11.8.1. Introduction

Sarcopenia means loss of muscle mass and strength. It is not a disease or a syndrome but part of physiological ageing. The European Working Group on Sarcopenia in Older People has developed a clinical definition and consensus diagnostic criteria for age-related sarcopenia, using the presence of both low muscle mass and low muscle function (strength or performance).

Optimum muscle function is important: for example, hand strength is vital as it enables people to carry out their normal tasks of daily living. Loss of muscle strength contributes to the risk of falling, thus sarcopenia leads to an increased risk of fractures and other injuries. Maintaining mass and strength may therefore have a beneficial effect.

Degenerative loss of skeletal muscle mass occurs at a rate of 0.5–1% per year after the age of 25. Decrease in muscle strength is also associated with ageing and sedentary lifestyles/lack of activity. Extreme muscle loss can be the result of decreasing anabolic stimulus (for example growth hormone or testosterone) and promotion of catabolic stimulus, such as pro-inflammatory cytokines. There may also be genetic influences.

Dual energy X-ray absorptiometry (DEXA) may be used to diagnose sarcopenia. This methodology is predictive of negative outcomes and it is also a method familiar to most clinicians. It can be assessed at the same time as measuring bone density.

Interventions that slow sarcopenia (such as exercise and good nutrition) are important as they enable postmenopausal women to maintain independent living.

11.8.2. Review question

What are the effects of HRT administered for menopausal symptoms on the risk of developing sarcopenia?

The aim of this review was to investigate the risk of developing sarcopenia for menopausal women who had received HRT for treating menopausal symptoms. Subgroup analysis was specified in the protocol if data was available for postmenopausal and perimenopausal women and at different age ranges (under 50, 50–60 and 60 years and older).

Both RCTs and comparative cohort studies were selected for inclusion in this review. RCTs were the most appropriate study design for addressing this question, so were initially assessed as high quality and downgraded based on potential sources of bias. Cohort studies started as moderate evidence and were then downgraded for other sources of bias if necessary.

The risk of developing sarcopenia was examined in terms of different HRT types, duration of HRT and time since discontinuation. The clinical outcomes for this study identified by the Guideline Development Group were measures of sarcopenia such as muscle mass and strength.

For full details see the review protocol in Appendix D.

11.8.3. Description of included studies

A total of 7 studies were included in the review. Six were RCTs, of which 5 were double-blinded (Sipila 2001, Armstrong 1996, Kenny 2005, Ribom 2002, Taaffe 2005) and 1 was open-label (Skelton 1999). Only 1 prospective comparative cohort study was included (Maddalozzo 2004).

The setting of the included studies varied, with 2 carried out in the USA (Kenney 2005, Maddalozzo 2004), 2 in the UK (Armstrong 1996, Skelton 1999), 2 in Finland (Sipila 2001, Taaffe 2005) and 1 in Sweden (Ribom 2002).

All the populations in the included RCTs were postmenopausal women with the majority of them aged below 65 years. However, there was 1 trial (Kenny 2005) that only included healthy women in the community aged over 65 years who were not treated with HRT for the 6 months prior to study commencement. The duration of HRT in these studies varied considerably from 6 weeks to 1 year.

The comparators were either placebo, no treatment, exercise or dietary supplements.

The only comparative prospective study included in this review did not use an adjusted analysis (which is the most appropriate type of data analysis for cohort studies in order to remove the selection bias associated with participants’ recruitment) and therefore those results were interpreted with caution.

Evidence was found for measurements of muscle strength and muscle mass so these were considered separately. Each of these measurements was involved in a task important for daily living (such as use of the thumb).

More details on each individual study can be found in the evidence tables (see Appendix H).

11.8.4. Evidence profiles

Evidence from these studies is summarised in the clinical GRADE evidence profiles (see Appendix I). See also the study selection flow chart in Appendix F, the study evidence tables in Appendix H, the forest plots in Appendix J and the list of excluded studies in Appendix G.

11.8.5. Evidence statements

Evidence statements for RCTs

A meta-analysis of 2 studies of 40 women found a significant increase in the outcome of knee extension torque among women treated with HRT compared to those receiving placebo and 2 studies found no significant difference between women treated with HRT and those treated with placebo in any type of measurement of change in knee extension strength, flexion strength and/or handgrip strength (low quality evidence). One study of over 100 women found that there was a significantly higher increase in the change of adductor pollicis muscle strength in the HRT group compared with those who received no treatment (low quality evidence).

For the measurements of muscle mass, a meta-analysis of 2 RCTs with 80 women showed that there was a significantly higher score in the outcome of quadriceps muscle cross-sectional area for women taking HRT compared with those who had not received HRT (low quality evidence). In the same direction, moderate quality evidence from 1 RCT found that women taking HRT have significantly higher scores in the measurement of appendicular skeletal muscle mass compared with those in the non-treatment arm.

Low quality evidence found no significant differences for the other outcomes of muscle mass between the comparison groups.

Evidence statements for prospective cohort studies

Very low quality evidence from 1 prospective cohort study of 126 women found no significant difference in muscle strength, as a composite outcome, between women who received HRT and those who did not.

11.8.6. Health economics profile

No health economic search was undertaken for this guideline as the decision was made to prioritise outcomes from short-term treatment.

11.8.7. Evidence to recommendations

11.8.7.1. Relative value placed on the outcomes considered

The Guideline Development Group assessed sarcopenia as the age-related loss of lean muscle strength and muscle mass which in turn affects balance, gait and overall ability to perform tasks associated with daily living. The group considered the change in muscle strength (knee extension torque and strength, flexion, handgrip strength and adductor pollicis) to be the most important outcome for their decision-making. Change in muscle mass was assessed using either cross-sectional lean tissue area or appendicular skeletal muscle mass.

Loss of function relating to ageing was not considered for this review question.

11.8.7.2. Consideration of clinical benefits and harms

The question the Guideline Development Group considered was whether HRT when administered for other menopausal symptoms had a positive benefit on muscle mass and strength which would be translated into better support for the skeleton and enhanced ability to undertake tasks associated with normal daily living. The importance of improved strength of adductor pollicis muscle which controls thumb movements for postmenopausal women was specifically discussed. The evidence reviewed was not consistent in terms of producing benefit for improving skeletal support for women in menopause taking HRT. The only significant result from randomised evidence was for the outcomes of quadriceps muscle cross-sectional area and adductor pollicis for postmenopausal women on HRT compared with the group who had not received treatment.

The increased appendicular skeletal muscle mass, which was found to be significantly improved for women taking HRT compared with those who were not, would improve a woman’s ability to move, get up from sitting to standing, and perform the basic tasks of daily living. However, this outcome was principally found in women over 65 years, limiting its clinical relevance to the whole age range of the population of interest.

The group also discussed the role of an integrated approach to improve skeletal support for postmenopausal women, such as dietary strategies, nutritional supplementation and physical exercise; however, preventing and treating sarcopenia was not the focus of this review, although the group discussed its importance in improving women’s muscle strength outcomes.

11.8.7.3. Consideration of economic benefits and harms

Although the Guideline Development Group concluded that there was some weak evidence that HRT improves muscle mass and strength, the interpretation and generalisability of the results was not clear and therefore it is difficult to describe what the economic benefits and harms are, if any.

11.8.7.4. Quality of evidence

The quality of the randomised evidence ranged from moderate to very low due to high risk of bias of some of the included studies (due to unclear randomisation or allocation concealment) and to imprecision. All the included women were postmenopausal, with most of them aged under 65 years (only 1 study included women over 65 years). The duration of HRT varied between the included studies and no data were available relating outcomes to time since discontinuation.

11.8.7.5. Other considerations

The recommendation was based on both the interpretation of clinical evidence reviewed and on the expert opinion of the Guideline Development Group.

For this review question the group focused on the impact of HRT on the risk of developing sarcopenia and did not consider primary treatment for that condition. For this reason, exercise that increases muscle strength was not considered as a focus in this section. There is a separate section in the guideline that looked at the role of HRT on the outcome of osteoporosis (see Section 11.6). The group discussed the link between bone strength and reducing fractures and falls for women in menopause.

The group noted that that the extension in women’s expected lifespan and increasingly sedentary lifestyles raise a great challenge for the musculoskeletal system.

11.8.7.6. Key conclusions

The Guideline Development Group concluded that there was some weak evidence that HRT improves muscle mass and strength, but there is a limitation on the interpretation of generalisation of these results.

11.8.8. Recommendations

54.

Explain to women that:

  • there is limited evidence suggesting that HRT may improve muscle mass and strength
  • muscle mass and strength is maintained through, and is important for, activities of daily living.
Copyright © 2015 National Collaborating Centre for Women's and Children's Health.
Bookshelf ID: NBK343458

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