Emily Banks1
(1)
National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, 0200, Australia
Emily Banks
Email: Emily.Banks@anu.edu.au
Introduction
Menopausal hormone therapy (MHT) comprises the use of oestrogen(s), with or without progestagens (progestins), or related compounds, predominantly for the treatment of the symptoms of the menopause (International Agency for Research on Cancer 1999). It is often referred to as hormone replacement therapy or HRT; the term MHT is used here because it avoids the implicit assumption that postmenopausal women have a hormone deficiency that requires “replacement”.
MHT has been commercially available since around the 1930s, with use of oestrogen-only products becoming common in the United States by the late 1960s (Beral et al. 1999). Findings of an elevated risk of endometrial cancer with use of oestrogen-only MHT led to a drop in use in the mid-1970s, along with the increasing addition of progestagens to oestrogen (known as ‘combined oestrogen-progestagen MHT’), which had been shown to reduce the excess endometrial cancer risk. Use of MHT increased relatively rapidly in many industrialised countries during the 1980s and 1990s, largely due to the impression that MHT could improve quality of life and reduce the risk of disease in older women. Despite the uncertainties about its risks and benefits, in the late 1990s around half of women aged 50–64 in the UK had ever used MHT and one-third of women in this age group were current users (Million Women Study Collaborators 2002).
In 2002 the oestrogen-progestagen arm of the Women’s Health Initiative Randomised Controlled Trial of MHT was stopped 3 years early, due to evidence of global harm in terms of the risks of serious disease, particularly breast cancer (Writing Group for the Women’s Health Initiative Investigators 2002). In 2003, the UK Million Women Study results on breast cancer were published, providing large-scale evidence on the increased risk of breast cancer in women currently using MHT, compared to women who had never used it, with substantially greater risks in users of oestrogen-progestagen compared to oestrogen-only MHT (Million Women Study Collaborators 2003).
These results led to changes in prescribing policy and practice, with rapid and substantial declines in the use of MHT in many countries. The fall in MHT use has been shown in several settings to be followed by a decline in breast cancer incidence, consistent with evidence from observational studies that MHT-associated risks are rapidly reversible after MHT use ceases (Million Women Study Collaborators 2003; Collaborative Group on Hormonal Factors in Breast Cancer 1997). In the US, a 66 % reduction in use of MHT was followed by a significant 11 % reduction in breast cancer incidence from 2001 to 2004 among women aged 50 or more years, but not in younger women (Ravdin et al. 2007). Similarly, in Australia, a 40 % reduction in MHT use was followed by a significant 7 % reduction in breast cancer incidence from 2001 to 2003 in women aged 50 and over, but no significant change in breast cancer incidence in younger women (Canfell et al. 2008).
These reductions in breast cancer incidence demonstrate that more judicious, evidence-based prescribing of MHT can reduce the harms related to it, for both individuals and the population. However, use of MHT is still common, and strategies to minimise harm, while maintaining selective access to MHT for those in whom it is likely to have the best balance of safety and efficacy, remain important.
World-Wide Evidence to Date on Menopausal Hormone Therapy
A key principle of evidence-based medicine is that clinical practice is guided by the quantitative sum total of the appropriate evidence to date, not the results of single studies or subgroups of single studies. It is particularly important that reviews of the evidence are independently conducted. For cancer outcomes, where the disease event is unpredictable and other risk factors can be reasonably accounted for, data from observational studies are often reliable (Vandenbroucke 2004) and need to be combined with data from randomised controlled trials to summarise the current relevant evidence. Since MHT tends to be preferentially prescribed to healthier women, with fewer risk factors for cardiovascular disease (Million Women Study Collaborators 2002), in a way that cannot necessarily be fully accounted for by adjustment, observational data cannot be assumed to be reliable for assessing the effects of MHT on coronary heart disease and stroke. Randomised data are therefore emphasised for these outcomes.
This chapter predominantly uses data from the UK Public Assessment Report (Medicines and Healthcare products Regulatory Agency 2007), the most recent independent quantitative review of the effect of MHT on serious disease, supplemented by data from other large scale studies.
Efficacy
MHT is an effective treatment for vasomotor symptoms (hot flushes/flashes, night sweats) and vaginal dryness/atrophy associated with the menopause (MacLennan et al. 2004). These benefits occur rapidly after commencing therapy, but cease with cessation of therapy, if the underlying symptoms persist.
For less specific symptoms that are often attributed to the menopause (e.g. irritability, mood swings), the efficacy of MHT is less established. Women included in the Women’s Health Initiative trials had an average age of 63 years; 12–17 % had moderate to severe menopausal symptoms at baseline. Health-related quality of life did not differ meaningfully between those randomised to MHT (oestrogen-only or oestrogen-progestagen) and placebo in the trials (Hays et al. 2003; Brunner et al. 2005). Bone mineral density is increased and the risk of fracture, including waist, hip and vertebral fractures, is reduced substantially among women currently using MHT (Banks et al. 2004a; Cauley et al. 2003). However, this protection wears off rapidly following cessation of use, and returns to that of a woman who has never used MHT within 5 years after stopping (Banks et al. 2004a). Hence, to reduce the risk of hip fracture at the age when it becomes a common health issue (i.e. when women are in their 70s and older), women must be currently using MHT.
Risks
The evidence to date shows that the risk of breast cancer is increased in current users of MHT, and that relative risks increase with increasing duration of use. Risks are also greater with use of oestrogen-progestagen versus oestrogen-only MHT. Current users of oestrogen-only MHT with around 5 years of use have a 20 % increase in the risk of developing breast cancer; use for around 10 years leads to a 30 % increase in risk (Medicines and Healthcare products Regulatory Agency 2007). The corresponding 5 and 10 year risks for current users of oestrogen-progestagen MHT are 60 % and 120 % (Medicines and Healthcare products Regulatory Agency 2007; Million Women Study Collaborators 2003; Collaborative Group on Hormonal Factors in Breast Cancer 1997). The risk does not appear to vary meaningfully according to the type of oestrogen or progestagen and whether the MHT is administered orally or transdermally (Medicines and Healthcare products Regulatory Agency 2007). The risk of death from breast cancer is elevated in women who are currently using MHT (Million Women Study Collaborators 2003; Banks et al. 2004b) and use of MHT by women with a previous diagnosis of breast cancer increases the risk of recurrence (Holmberg and Anderson 2004).
The evidence indicates that an elevated risk of breast cancer is present relatively soon after commencing use, and increases with increasing duration of use. For example, in the Million Women Study, the relative risk of breast cancer was 1 · 45 (1 · 19–1 · 78) among women reporting <1 year of use of oestrogen-progestagen MHT at baseline (Million Women Study Collaborators 2003), compared to women who had never used MHT. The equivalent relative risk for <1 year of oestrogen-only MHT was 0 · 81 (0 · 55–1 · 20). It is not possible to estimate the likely effect of breast cancer for use of a few months for treatment of menopausal symptoms however most biological effects are on a continuum so it seems reasonable to assume some increase in risk, which will be smaller the shorter the duration of use.
The only personal characteristic found to significantly modify the effect of MHT on breast cancer is body size; MHT results in a larger increase in the risk of breast cancer in women who have a lower compared to a higher Body Mass Index (BMI), i.e. in thinner women. Consistent with this is the finding that the effect of MHT on breast cancer is greater in Europe than in North America (where average BMI levels are higher) (Medicines and Healthcare products Regulatory Agency 2007).
In women with a uterus, the risk of endometrial cancer is increased around 3 times with 5 years of use of oestrogen-only MHT and 9 times with 10 years of use. Risks with oestrogen-progestagen MHT where progestagens are added for 10 or more days per 28 day cycle do not differ significantly from those of women who have never used MHT. The risk of ovarian cancer is increased by around 20 % among current users of oestrogen-only and oestrogen-progestagen MHT, and increases with increasing duration of use (Medicines and Healthcare products Regulatory Agency 2007; Million Women Study Collaborators 2007).
The risk of stroke is increased by around 30 % in current users of oestrogen-progestagen and oestrogen-only MHT. The risk of venous thromboembolism is increased in current users of oral MHT, with a 30 % increase in risk among women using oral oestrogen-only MHT and a 130 % increase in risk among those using oral oestrogen-progestagen MHT (Medicines and Healthcare products Regulatory Agency 2007). Risks are greater in the first 2 years after starting use than in subsequent years (Sweetland et al. 2012). The risk of venous thromboembolism does not appear to be significantly elevated in women using transdermal oestrogen-only MHT (Sweetland et al. 2012; Olie et al. 2010); there are insufficient data on transdermal oestrogen-progestagen MHT for firm conclusions to be reached (Sweetland et al. 2012). Venous thromboembolism risks are greater for women using medroxyprogesterone acetate than for those using norethisterone or norgestrel as progestagens (Sweetland et al. 2012).
The current evidence is that the MHT-associated risks identified here generally wear off within a few years of ceasing use; the Million Women Study found that no significant difference in breast cancer risks between women who had ceased use of MHT within the 5 years prior to baseline and women who had never used HRT (Million Women Study Collaborators 2003; Collaborative Group on Hormonal Factors in Breast Cancer 1997; Medicines and Healthcare products Regulatory Agency 2007).
Coronary Heart Disease and Colorectal Cancer
The main rationale for the Women’s Health Initiative Trials was the possibility that MHT might reduce the risk of coronary heart disease. This was because previous observational studies had found that women using MHT had a lower risk of coronary heart disease than non-users and other studies had indicated beneficial effects on intermediate markers of coronary heart disease risk, including LDL and HDL cholesterol levels (Barrett-Connor and Stuenkel 2001; The writing group for the PEPI trial 1995). However, since MHT tends to be prescribed to healthier women, this lower risk is not necessarily because MHT causes a reduction in risk (Million Women Study Collaborators 2002). Meta-analyses of data from relevant randomised controlled trials, which are the most appropriate study design for examining coronary heart disease risks, including the Women’s Health Initiative have not found any significant beneficial or adverse effect of MHT on coronary heart disease (Medicines and Healthcare products Regulatory Agency 2007).
The UK Public Assessment Report also found no significant effect of MHT on colorectal cancer (Medicines and Healthcare products Regulatory Agency 2007).
Balancing the Risks and Benefits
When quantitatively weighing up the risks and benefits of MHT it is important to compare like with like; hence robust analyses examine the absolute risk of potentially life threatening diseases significantly increased or reduced by MHT and estimate a quotient for its net effect. In these terms, MHT significantly increases the risk of breast cancer, stroke, ovarian cancer and venous thromboembolism and reduces the risk of fracture (Medicines and Healthcare products Regulatory Agency 2007; Banks et al. 2004a, c). Use of oestrogen-only MHT increases the risk of endometrial cancer in women with a uterus (Medicines and Healthcare products Regulatory Agency 2007).
When the major potentially life threatening conditions affected by MHT are considered together, the risk of overall harm is greater than the benefits, for both oestrogen-only and oestrogen-progestagen MHT (Medicines and Healthcare products Regulatory Agency 2007). However, the net adverse effects of oestrogen-progestagen MHT are greater than those for oestrogen-only MHT. The risks related to MHT increase with increasing duration of use; this relates not only to the fact that women are exposed to MHT-related risks for longer, but also because the relative risk of breast cancer increases with increasing duration of use (Medicines and Healthcare products Regulatory Agency 2007). The risks of venous thromboembolism and stroke are elevated shortly after use commences.
The UK Public Assessment Report weighed up the absolute risks of breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, stroke, coronary heart disease, venous thromboembolism and hip fracture and estimated the following:
· 5 years of use of oestrogen-only MHT results in:
· a net excess of potentially life threatening events affecting 5 per 1,000 users aged 50–59 [number-needed-to-harm = 200 (95 % CI 100–500)], or affecting 6 per 1,000 users aged 60–69 [number-needed-to-harm = 167 (67–∞)] among women without a uterus (Medicines and Healthcare products Regulatory Agency 2007).
· a net excess of potentially life threatening events affecting 9 per 1,000 users aged 50–59 [number-needed-to-harm = 111 (67–200)], or affecting 12 per 1,000 users aged 60–69 [number-needed-to-harm = 83 (34–200)] among women with a uterus (Medicines and Healthcare products Regulatory Agency 2007).
· 10 years of use of oestrogen-only MHT results in:
· a net excess of potentially life threatening events affecting 12 per 1,000 users aged 50–59 [number-needed-to-harm = 83 (45–200)], or affecting 17 per 1,000 users aged 60–69 [number-needed-to-harm = 59 (29–500)] among women without a uterus (Medicines and Healthcare products Regulatory Agency 2007).
· a net excess of potentially life threatening events affecting 44 per 1,000 users aged 50–59 [number-needed-to-harm = 23 (14–38)], or affecting 65 per 1,000 users aged 60–69 [number-needed-to-harm = 15 (9–29)] among women with a uterus (Medicines and Healthcare products Regulatory Agency 2007).
· 5 years of use of oestrogen-progestagen MHT results in:
· a net excess of potentially life threatening events affecting 14 per 1,000 users aged 50–59 [number-needed-to-harm = 71 (53–91)], or affecting 22 per 1,000 users aged 60–69 [number-needed-to-harm = 45 (32–63)] among women with a uterus (Medicines and Healthcare products Regulatory Agency 2007).
· 10 years of use of oestrogen-progestagen MHT results in:
· a net excess of potentially life threatening events affecting 40 per 1,000 users aged 50–59 [number-needed-to-harm = 25 (19–33)], or affecting 64 per 1,000 users aged 60–69 [number-needed-to-harm = 16 (12–22)] among women with a uterus (Medicines and Healthcare products Regulatory Agency 2007). The numbers above relate to European rates of disease and show that among women aged 50–59, one potentially life-threatening adverse event is estimated to occur for every 200 women aged 50–59 using oestrogen-only MHT for 5 years and for every 110 women using oestrogen-progestagen MHT for 5 years, that is not outweighed by a beneficial effect (i.e. the number-needed-to-harm).
MHT is highly effective in the treatment of hot flushes, night sweats and vaginal dryness related to the menopause (MacLennan et al. 2004). As difficult as it may seem, it is the severity of these symptoms that women must balance against the risk of serious disease attributable to use of MHT.
The risk-benefit calculations have been done for 5 and 10 years duration of use. Use for shorter periods of time will be accompanied by lesser increases in risk, as outlined above. It is not possible to know exactly what risks accompany use for months or less than 1 year, except to say that risk exists on a continuum. Hence, it is likely to be elevated but to a lesser extent than long-duration use.
MHT effects on other non-life-threatening conditions such as increased risk of incontinence (Hendrix et al. 2005) and gallbladder disease (Simon et al. 2001; Liu et al. 2008) and reduced peripheral fractures (Cauley et al. 2003) should also be considered.
Does the Effect of MHT Differ According to a Woman’s Age, How Long It Has Been Since Menopause, or the Dose?
A common misperception is that MHT has significantly different effects in younger compared to older women. Unfortunately, the available randomised controlled trials are too small to give reliable evidence about the effects of MHT in women of different ages or according to many attributes of MHT use, and a finding of “no significant effect” within specific groups is not meaningful evidence of safety. Examination of subgroups in trials is highly problematic and must include testing for “statistical interaction” or “effect modification”, according to pre-defined stringent levels of significance. If no significant difference in the effect is detected, the effect of MHT in this subgroup must be considered to be same as the overall effect in the whole group. Moreover, even subgroup analyses which yield marginally significant findings must be viewed with caution if they were not specified prior to analysis, or make up one of many such comparisons.
According to the current evidence, the relative risks of the conditions examined here (i.e. the percentage increase in risk) associated with MHT use do not vary significantly according to a woman’s age. However, as outlined above, the background absolute risk of all of these conditions does vary substantially with age. This difference in background rates means that the same duration of use of MHT at an older age will result in a greater number of excess cases of serious disease than use at a younger age, all other things being equal.
It has also been speculated that MHT initiated soon after menopause might prevent coronary heart disease, while therapy started later will have a null or adverse effect (the “timing hypothesis”) (Banks and Canfell 2009). This hypothesis arose because the null coronary heart disease findings of the Women’s Health Initiative trials differed from the expectation of many researchers and clinicians, that hormone therapy would be cardio-protective; the timing hypothesis was one attempt to explain this difference.
Detailed analyses of Women’s Health Initiative data designed specifically to address the timing hypothesis demonstrate:
· similar null or adverse effects of hormone therapy on coronary heart disease;
· similar adverse effects on stroke and venous thrombosis
· possibly greater adverse effects on breast cancer
with hormone therapy initiated soon after menopause compared to use starting later (Prentice et al. 2009)
Hence the overall findings regarding the risks and benefits of MHT should also apply to women initiating hormone therapy soon after menopause, with the caveat that relative risks of breast cancer may be greater.
Oestrogen-Only Versus Oestrogen-Progestagen MHT, Transdermal Versus Oral MHT, Use of Norethisterone/Norgestrel MHT
For women who have had a hysterectomy and require treatment, as has been outlined above, oestrogen-only MHT is the most appropriate in terms of minimising risk. Although it is less widely recognised, use of oestrogen-only MHT is also likely to minimise excess potentially life-threatening adverse events in women with a uterus, compared to use of oestrogen-progestagen MHT.
Use of oestrogen-progestagen MHT leads to greater relative risks of breast cancer, ovarian cancer and venous thromboembolism than oestrogen-only MHT, but leads to lesser or no increases in the risk of endometrial cancer for women with a uterus (Fig. 11.1)
Fig. 11.1
Standardised incidence rates (95 % CI) for ovarian, endometrial and breast cancer per 1,000 women in the study cohort over a 5-year period, for current users of various types of MHT and for never users* (Reproduced from Million Women Study Collaborators 2007, with permission)
*Incidence rates are standardised by age, region of residence, socioeconomic status, time since menopause, parity, use of oral contraceptives, body-mass index, and alcohol consumption. Rates apply to women with a uterus and ovaries
.
The background incidence of breast cancer (in European women) is around five times that of endometrial cancer (10 vs. 2 per 1,000 women aged 50–59 over a 5 year period, respectively); the incidence of venous thromboembolism is around 2.5 times that of endometrial cancer (5 per 1,000 women aged 50–59 over a 5-year period) (Medicines and Healthcare products Regulatory Agency 2007). Because of this difference in absolute rates, the excess breast cancers and venous thromboembolisms in users of oestrogen-progestagen MHT exceeds the increased risk of endometrial cancer. For example, in 1,000 women with a uterus aged 50–59 years, 5 years of oestrogen-progestagen MHT is estimated to result in six additional cases of breast cancer, seven additional cases of venous thromboembolism and no additional cases of endometrial cancer (Medicines and Healthcare products Regulatory Agency 2007). Five years of use of oestrogen-only MHT in an equivalent population would lead to two additional cases of breast cancer, two additional venous thromboembolisms and four additional endometrial cancers (Medicines and Healthcare products Regulatory Agency 2007). Hence, the estimated net excess of potentially life-threatening events with 5 years use of oestrogen-progestagen MHT is greater than the net excess with use of oestrogen-only MHT, for women with and without a uterus (see above) (Medicines and Healthcare products Regulatory Agency 2007; Million Women Study Collaborators 2005, 2007).
If use is prolonged, which is not generally recommended but may be required if symptoms remain problematic, the high relative risk of endometrial cancer begins to have an impact on the overall safety profile, despite the low background risk. Ten years use of oestrogen-progestagen MHT for 100 women aged 50–59 is estimated to lead to 24 (20–28) excess breast cancers, 13 (8–20) additional VTEs and no additional cases of endometrial cancer. Ten years of oestrogen-only MHT in the same age group is estimated to lead to 6 (4–10) additional breast cancers, 3 (0–7) additional VTEs and 32 (21–48) additional endometrial cancers. Hence, the net excess in risk is high and broadly comparable between oestrogen-progestagen and oestrogen-only (40 (30–53) excess potentially life-threatening events per 1,000 users of oestrogen-progestagen MHT versus 44 (26–70) per 1,000 users of oestrogen-progestagen MHT).
In summary, the current evidence indicates that, in terms of the overall risk of potentially life-threatening disease, use of oestrogen-only MHT carries fewer risks than use of oestrogen-progestagen MHT, for around 5 years for women with and without a uterus. In women with a uterus, more prolonged use carries substantially greater overall risks (due to the increased risk of endometrial cancer); the current estimates suggest that absolute excess risks with 10 years of use are similar for oestrogen-progestagen and oestrogen-only MHT.
It should be noted that in many countries, particularly parts of Europe and Australia, prescription of oestrogen-only MHT to women with a uterus is not accepted clinical practice, due to issues with uterine bleeding, endometrial hyperplasia and cancer. However, in other places, such as the US, such use, along with management of endometrial changes is more common.
The current evidence indicates that use of transdermal oestrogen-only MHT is likely to minimise the risk of venous thrombosis, compared to oral MHT (Sweetland et al. 2012; Olie et al. 2010). There is also initial evidence that oral preparations containing medroxyprogesterone acetate carry greater risks of venous thromboembolism than norethisterone and norgestrel containing preparations (Sweetland et al. 2012).
Strategies to Minimize Risk, Consistent with Guidance from Drug Regulatory Authorities
Increasing availability and consistency of data on the risks and benefits of MHT has been accompanied by agreement between key drug regulatory authorities that use should be targeted for moderate to severe menopausal symptoms only, and not for the prevention of disease. The US Food and Drug Administration (United States Department of Health and Human Services Food and Drug Administration 2005), the UK Medicines and Healthcare Products Regulatory Agency (2007), the Australian Therapeutic Goods Administration (Australian Drug Evaluation Committee 2004) and many other drug regulatory agencies world-wide are in agreement that:
· MHT should be used for the short term treatment of menopausal symptoms (e.g. hot flushes, night sweats, vaginal dryness) only;
· Women considering use of MHT should be informed of its risks and benefits;
· MHT should not be used for the prevention of disease, or (in Europe and Australia) as first line treatment for osteoporosis;
· MHT should be used for as short a period of time as possible and the need for continuing use should be reviewed six-monthly (Australian Drug Evaluation Committee 2004) or annually (Medicines and Healthcare products Regulatory Agency 2007).
Unfortunately, there is no period of use of MHT that is not accompanied by risk and, since risks increase with increasing duration of use, minimising duration is important. As can be seen from the information above, 5 years of use carries considerable risk. As has been stated above, use for shorter periods of time, particularly use for less than 1 year will be accompanied by lesser increases in risk, although precise quantification of this risk is not possible with the current data.
The main strategies for minimising the risks relating to use of MHT, generally consistent with this guidance, are summarised in Table 11.1. There are additional strategies relating to preferential use of oestrogen-only MHT and transdermal oestrogen-only MHT that require consideration.
Table 11.1
Evidence on certain risks related to menopausal hormone therapy (MHT) and related therapeutic approaches to minimise risk
|
Evidence on safety |
Therapeutic approach to minimise risk |
|
The older a woman is when she uses MHT, the greater the absolute risks related to use |
Avoid MHT in older women, where possible The need for MHT should be reviewed regularly |
|
Evidence of global harm and/or lack of overall benefit for prevention of disease Lack of long term benefits for fracture |
MHT should be used for the treatment of moderate to severe menopausal symptoms and not for the long term prevention of disease |
|
Evidence of global harm and/or lack of overall benefit for prevention of disease The relative risk of breast cancer increases with increasing duration of use |
Use MHT for as short a period as possible The need for MHT should be reviewed regularly |
|
The net average harms of combined oestrogen-progestagen MHT are greater than those of oestrogen alone, within the usual durations of use |
Where possible, avoid combined oestrogen-progestagen MHT |
|
There is an increased risk of venous thromboembolism with oral oestrogen-only and oestrogen-progestagen MHT but not transdermal oestrogen-only MHT |
Use transdermal oestrogen-only MHT, where possible |
Conclusions
Menopausal hormone therapy (MHT) is an effective treatment for menopausal symptoms and reduces the risk of fracture. However, use results in a net increase in the risk of certain potentially life-threatening conditions including breast cancer, stroke, ovarian cancer and venous thromboembolism, and use of oestrogen-only MHT increases the risk of endometrial cancer in women with a uterus. Overall risks increase with increasing duration of use and with age and are greater for oestrogen-progestagen MHT than for oestrogen-only MHT.
Increasing availability and consistency of data on the risks and benefits of MHT has been accompanied by agreement between key drug regulatory authorities that use should be targeted for moderate to severe menopausal symptoms only, and not for the prevention of disease. Key strategies for minimising MHT-associated risks are consistent with advice from drug regulatory agencies and include the following: MHT should be used for the short term treatment of menopausal symptoms (e.g. hot flushes, night sweats, vaginal dryness) only; women considering use of MHT should be informed of its risks and benefits; MHT should not be used for the prevention of disease, or (e.g. in Europe and Australia) as first line treatment for osteoporosis; MHT should be used for as short a period of time as possible and the need for continuing use should be reviewed six-monthly or annually. Preferential use of oestrogen-only MHT and transdermal oestrogen-only MHT, including in women with a uterus, are also likely to reduce MHT-associated risks, compared to use of oestrogen-progestagen MHT and oral MHT.
Take Home Messages
· Large-scale data and guidance from drug regulatory authorities on MHT support targeted use of MHT;
· MHT should be used for the short term treatment of menopausal symptoms (e.g. hot flushes, night sweats, vaginal dryness) only;
· Women considering use of MHT should be informed of its risks and benefits;
· MHT should not generally be used for the prevention of disease, or as first line treatment for osteoporosis;
· The risks related to oestrogen-progestagen MHT are generally substantially greater than those related to use of oestrogen-only MHT;
· MHT should be used for as short a period of time as possible and the need for continuing use should be reviewed six-monthly or annually.
References
Australian Drug Evaluation Committee (2004) ADEC summary statement on HRT. Australian Government Department of Health and Ageing, Therapeutic Goods Administration, Canberra
Banks E, Canfell K (2009) Invited commentary: hormone therapy risks and benefits – the women’s health initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 174:24–28CrossRef
Banks E, Beral V, Reeves G, Balkwill A, Barnes I, for the Million Women Study Collaborators (2004a) Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 291:2212–2220PubMedCrossRef
Banks E, Beral V, Reeves G, for the Million Women Study Collaborators (2004b) Published results on breast cancer and hormone replacement therapy in the Million Women Study are correct. Climacteric 7:415–416PubMedCrossRef
Banks E, Reeves G, Evans S (2004c) Disease incidence associated with long-term use of hormone replacement therapy. In: Critchley HOD, Beral V, Gebbie A (eds) Menopause and hormone replacement, Proceedings of the forty seventh study group of the Royal College of Obstetricians and Gynaecologists. Royal College of Obstetricians and Gynaecologists, London, pp 241–254
Barrett-Connor E, Stuenkel CA (2001) Hormone replacement therapy (HRT) – risks and benefits. Int J Epidemiol 30(3):423–426PubMedCrossRef
Beral V, Banks E, Reeves G, Appleby PN (1999) Use of HRT and the subsequent risk of cancer. J Epidemiol Biostatistics 4:191–215
Brunner RL, Gass M, Aragaki AK, Hays J, Granek IA, Woods NF, Mason E, Brzyski RG, Ockene JK, Assaf AR, LaCroix AZ, Matthews KA, Wallace R, Women’s Health Investigators (2005) Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy. Arch Intern Med 165:1976–1986PubMedCrossRef
Canfell K, Banks E, Moa A, Beral V (2008) Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia. Med J Aust 188:641–644PubMed
Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick M, Wactawski-Wende J, Watts NB, Investigators ftWsHI (2003) Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative Randomised Trial. JAMA 290:1729–1738PubMedCrossRef
Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 350:1047–1059CrossRef
Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG, Investigators ftWsHI (2003) Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 348:1839–1854PubMedCrossRef
Hendrix S, Cochrane B, Nygaard I, Handa VL, Barnabei V, Iglesia C, Aragaki AK, Naughton M, Wallace R, McNeeley SG (2005) Effects of estrogen with and without progestin on urinary incontinence. JAMA 293:935–948PubMedCrossRef
Holmberg L, Anderson H (2004) HABITS (hormonal replacement therapy after breast cancer – is it safe?), a randomised comparison: trial stopped. Lancet 363:453–455PubMedCrossRef
International Agency for Research on Cancer (1999) Hormonal contraception and post-menopausal hormonal therapy, vol 72. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. International Agency for Research on Cancer, Lyon
Liu B, Beral V, Balkwill A, Green J, Sweetland S, Reeves G, for the Million Women Study Collaborators (2008) Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ 337:a3.86. doi:310.1136/bmj.a1386
MacLennan A, Broadbent J, Lester S, Moore V (2004) Oral oestrogen and combined oestrogen/progestagen therapy versus placebo for hot flushes. Cochrane Database Syst Rev (4):CD002978. doi:002910.001002/14651858.CD14002978.pub14651852
Medicines and Healthcare products Regulatory Agency (2007) UK public assessment report. Hormone-replacement therapy: safety update. MHRA. http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdf. Accessed January 2009
Million Women Study Collaborators (2002) Patterns of use of hormone replacement therapy in one million women in Britain, 1996–2000. Br J Obstet Gynaecol 109:1319–1330CrossRef
Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427CrossRef
Million Women Study Collaborators (2005) Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 365:1543–1551CrossRef
Million Women Study Collaborators (2007) Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 369:1703–1710CrossRef
Olie V, Canonico M, Scarabin PY (2010) Risk of venous thrombosis with oral vs. transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol 17:457–463PubMedCrossRef
Prentice R, Manson JE, Langer R, Anderson G, Pettinger M, Jackson R, Johnson K, Kuller LH, Lane D, Wactawski-Wende J, Brzyski RG, Ockene JK, Sarto G, Rossouw J (2009) Benefits and risks of postmenopausal hormone therapy when initiated soon after then menopause. Am J Epidemiol 170:12–23PubMedCentralPubMedCrossRef
Ravdin PM, Cronin KA, Howlander N, Berg CD, Chlebowski R, Fueur EJ, Edwards BK, Berry DA (2007) The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356:1670–1674PubMedCrossRef
Simon JA, Hunninghake D, Agarwel SK, Lin F, Cauley JA, Ireland CC, Pickar JH (2001) Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. Ann Intern Med 135:493–501PubMedCrossRef
Sweetland S, Beral V, Balkwill A, Liu B, Benson VS, Canonico M, Green J, Reeves G, Collaborators MWS (2012) Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 10:2277–2286PubMedCrossRef
The Writing Group for the PEPI Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273(3):199–208CrossRef
United States Department of Health and Human Services Food and Drug Administration (2005) Guidance for industry noncontraceptive estrogen drug products for the treatment of vasomotor symptoms and vulvar and vaginal atrophy symptoms – recommended prescribing information for health care providers and patient labeling. Draft guidelines. Revision 4. http://www.fda.gov/cder/guidance/6932dft.pdf. Accessed January 2009
Vandenbroucke JP (2004) When are observational studies as credible as randomised trials? Lancet 363(9422):1728–1731PubMedCrossRef
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288:321–333CrossRef