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Hormone therapy for menopausal women

David Sturdee
MD FRCOG
Consultant Gynaecologist Solihull Hospital
Senior Clinical Lecturer Birmingham University
E:david.sturdee@heartsol.wmids.nhs.uk

The series of publications from the USA, and recently the UK, concerning the risks of hormone therapy (HT) in postmenopausal women has had a devastating impact on the confidence of both women and their healthcare advisers in the merits of HT. Sales of HT products have plummeted, some pharmaceutical companies have withdrawn their HT sales forces, many women are now experiencing a deterioration in their quality of life without HT, and their healthcare advisers are uncertain how to respond and help them. Is all this an overreaction? Can HT, which has been available for over 50 years and widely prescribed from about the mid-1970s, suddenly be too dangerous? What is the truth? The response to such questions, however, will depend very much on who is asked - the menopausal woman, the menopause expert, representatives of the pharmaceutical industry, media/newspaper reporters or epidemiologists. All will look at the role of HT, and the balance of risks and benefits, from a different perspective.

Symptoms
Epidemiological studies have shown that over 80% of women in the UK will experience some symptoms considered to be due to oestrogen deficiency during the menopausal transition.(1) It is for the relief of these symptoms and for an improved quality of life that most women request HT. Many studies in the early days of HT use reported dramatic symptomatic benefits of oestrogen, but these studies were not adequately controlled for the considerable placebo response. It was not until 1975 that Jean Coope reported the first satisfactory double-blind, randomised, controlled trial,(2) which confirmed the superior benefit of oestrogen over placebo in reducing hot flushes. The effect of oestrogen on other symptoms was later demonstrated by Campbell and Whitehead in a double-blind crossover study.(3) Oestrogen was significantly better than placebo, not only in relieving hot flushes, sweats and vaginal dryness, but also in causing a significant reduction in insomnia, anxiety, irritability, urinary frequency, worry about self and age, and headaches, together with a significant improvement in memory, good spirits and optimism. The reduction of flushes and sweats and the related disturbance of sleep results in an improvement in many other symptoms, which is termed a "domino" effect.
It is regrettable that, with all the anxiety that has been generated by the recent publications, many women have abandoned HT for various nonproven therapies, which are often considered to be "natural". These include progesterone cream, oil of evening primrose, phyto- oestrogens, black cohosh, ginseng, various dietary supplements and acupuncture. A few small studies have suggested a slight benefit of some phyto-oestrogens over placebo for hot flushes, but otherwise there is no other evidence that any of these treatments is better than a placebo. There remains no comparable treatment to oestrogen for the relief from menopausal symptoms .

Cardiovascular disease
Coronary heart disease (CHD) is the largest single cause of death in women, and if HT could reduce the incidence of cardiovascular disease this would have a major impact on morbidity and mortality. For many years, various observational studies, such as the large Nurses' Health Study from California, produced a series of papers indicating a reduction in CHD in HT users of up to 50%, and that this was greatest in those who had the most risk factors.(4) Some concerns were raised about the validity of such studies because of a "healthy user" bias whose lifestyle made them less likely to develop CHD. HT users tend to be thinner, take more exercise, drink more alcohol and have higher HDL cholesterol, but also smoke more, than other women.(5) The Heart and Estrogen/progestogen Replacement Study (HERS) was the first major prospective randomised, controlled trial that addressed the subject of CHD.(6) This involved 2,763 postmenopausal women with a mean age of 67 years, all of whom had pre-existing CHD. This was therefore a secondary prevention study, with women randomised to receive either placebo or continuous combined therapy of conjugated equine oestrogens  0.625mg per day, with medroxyprogesterone acetate (MPA) 2.5mg per day. After 4 years there was no difference in the incidence of myocardial infarction or death between the two groups, but there was a significant threefold increased incidence of venous thromboembolism (VTE), which had also been reported in  previous observational studies,(7,8) and confirmed in more recent reports. For menopausal women, the prevalence of VTE is about 1 per 10,000 in those not taking HT, so this would be increased to 3 per 10,000 with HT, which is equivalent to 1 extra case per 5,000 users per year. This risk increases with advancing age and obesity. (All the data concerning VTE and HT have, until recently, been concerned with oral oestrogen preparations. However, a study comparing oral and transdermal therapy from France has shown a similar increased risk as the other studies for oral therapy, but no increased risk with transdermal oestrogen.(9) This difference is due to the lack of the first-pass effect through the liver by the transdermal route, and it is in the liver that most of the coagulation factors are produced and modified by high levels of oestrogen passing through the portal circulation). The HERS study caused much concern and disappointment and indicated that HT was of no benefit for women with existing heart disease.

Women's Health Initiative
The Women's Health Initiative (WHI) was a randomised controlled trial of 16,608 postmenopausal women who did not have evidence of CHD, although their mean age at screening was 63.2 years.(10) They received the same continuous combined therapy as in the HERS study or placebo, and those who had previously had a hysterectomy were randomised to either unopposed oestrogen or placebo. This study was stopped after 5.2 years because it was considered that the health risks for those taking the continuous combined therapy outweighed the benefits. They had found a significant increase in the risk of cardiovascular disease, stroke and VTE, as well as an increase in invasive breast cancer. On the beneficial side, however, they reported a significant decrease in hip fracture, vertebral fracture, total fractures and colorectal cancer. The media chose to highlight to the public the relative risks in percentages, which made for dramatic headlines and big impact, with a 26% increase in breast cancer, 29% in heart attacks and 41% in strokes. Inevitably these data caused great public alarm, because the concept of relative risk is not readily understood by many, including the medical and nursing professions.
However, if the figures are expressed as absolute risk the implications and true perspective are more easily appreciated (see Tables 1 and?2). Furthermore, subsequent analysis has shown that the increased risk of CHD applied to those who were more than 10 years after the menopause. The increased risk of breast cancer for those who had never taken HT before entering the study became apparent in the fourth year of the study. However, in those who had previously been taking HT, the increased risk became apparent after the second year.(11,12) Nevertheless, WHI and HERS have indicated that HT does not reduce CHD risk and should not be prescribed solely for that purpose.

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[[NIP17_table2_66]]

The unopposed oestrogen arm of WHI continued until 2 March 2004 and was only stopped as there was unlikely to be any further information gained. However, most significantly, of the 11,000 women studied, there was no evidence of an increase in breast cancer or CHD, a similar significant reduction in hip fracture and the same increased risk of stroke at 8 per 10,000 women per year as in the combined treatment arm.
The WHI Memory Study (WHIMS) has also assessed the effect of HT on older women with dementia.(18) Previous observational data had suggested that the incidence of Alzheimer's disease was reduced by HT, but WHI has not shown this and even suggests an increased risk in older women.

Million Women Study
The more recent Million Women Study (MWS) is a large observational study of women aged 50-64 years attending the UK National Breast Screening Programme.(13) It reported that all forms of HT were associated with a significant increased risk of breast cancer, with relative risks (RRs) ranging from 1.3 with oestrogen alone to 2.0 for combined oestrogen and progestogen regimens. Livial (Organon), another drug tested in the study, had an RR of 1.45, which is not significantly different from oestrogen alone. Although this is an observational and not a randomised controlled study and relies on women's recall of their HT usage, it has been given credibility because of the very large numbers analysed (n=828,923).
In the discussion of these results, the authors suggested that there would now seem "to be little advantage to using oestrogen-progestogen in preference to oestrogen-only HRT for women who still have a uterus". Progestogen is added to HT regimens to prevent endometrial cancer, and to change this practice would be unwise.

Implications for clinical management
All these reports have provoked intense debate around the world. Several consensus statements and guidelines have been produced, particularly by the British Menopause Society (BMS), the International Menopause Society (IMS) and a BMJ editorial.(14­-16) Much of the concern centres on whether it is appropriate to extrapolate data from studies of older postmenopausal women receiving a particular combination of hormones to every woman regardless of age and HT regimen: that is, is there a class effect of oestrogens and progestogens?
It is certainly well established that oestrogen has different effects depending on the route of administration. This has important implications for metabolic effects, such as those that influence the risk for cardiovascular disease, but makes no difference to the effect on bone.
The WHI report on unopposed oestrogen is reassuring about breast cancer, with no evidence of an increased risk, which contradicts the MWS. It is a much smaller study but has the merit of being a randomised controlled trial. Typically, this piece of relatively good news caused very little media response compared with the banner headlines for the previously reported adverse effects. But now our patients will be even more confused and will need well-informed advice on the implications, which can be summarised as follows:(17)

  • Loss of ovarian production of oestrogen is the basic cause of the various symptoms and physical effects attributed to the menopause.
  • Not every woman needs or will benefit from HT.
  • HT is not a panacea for all the problems of ­middle and later life.
  • HT is the most suitable and effective treatment for menopausal symptoms, which may require treatment for several years.
  • Long-term treatment (>5 years) with combined oestrogen and progestogen is associated with an increased risk of breast cancer and stroke. Absolute or excess risk is usually easier to understand than percentage increase or relative risk.
  • Unopposed oestrogen may not be associated with an increased risk of breast cancer, but risk of stroke and thromboembolism is increased.
  • Transdermal therapy is not associated with the increased risk of thromboembolism found with the oral route.
  • HT is associated with a reduction in the risk of colorectal cancer.
  • The lowest effective dose should be prescribed, ­
  • re-evaluated annually and adjusted to the woman's needs and clinical response.
  • HT does prevent osteoporosis and reduce fracture risk, but this requires long-term use.
  • Women with a premature menopause should have HT at least until the normal age of the menopause. The risks of HT do not apply to women before the age of 50.
  • To date there is no evidence that unlicensed dietary supplements have any beneficial effects that are comparable to HT.
  • There is no single preparation that is suitable for all women.
  • Data from studies of women with a mean age of 65 taking one particular combination of hormones cannot be applied to women around the time of the menopause.
  • There is no indication to prescribe HT solely for the prevention of CHD.
  • A healthy lifestyle is more important for long-term health.

References

  1. McKinley SM, Jefferys M. The menopausal syndrome. Br J Prev Soc Med 1974;28:108-15.
  2. Coope J, et al. Effects of natural oestrogen replacement therapy on menopausal symptoms and blood clotting. BMJ 1975;4:139-43.
  3. Campbell S, Whitehead M.  Oestrogen therapy and menopausal syndrome. Clin Obstet Gynaecol 1977;4:31-47.
  4. Grodstein F. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease.  N Engl J Med 1996;335:453-61.
  5. Newton JN. The epidemiology of CHD and HRT. J Br Menop Soc 1998;4:135-42.
  6. Hulley S, et al.  Randomized trial of estrogen plus progestin for secondary prevention of CHD in postmenopausal women. JAMA 1998;280:605-13.
  7. Daly E, et al. Risk of VTE in users of HRT. Lancet 1996;348:977-80.
  8. Gutthann SP, et al. HRT and risk of VTE; population-based case-controlled study. BMJ 1997;314:796-800.
  9. Scarabin P-Y, et al. Differential association of oral and transdermal estrogen-replacement therapy with VTE risk. Lancet 2003;362:428-32.
  10. Writing Group, WHI Investigators. Risks and benefits of estrogen and progestin in healthy postmenopausal women; principle results from the WHI trial. JAMA 2002;288:321-33.
  11. Manson JE, et al. Estrogen plus progestins and the risks of CHD. N Engl J Med 2003;349:523-34.
  12. Chlebowski RT, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women; WHI trial. JAMA 2003;289:3243-53.
  13. MWS Collaborators. Breast cancer and HRT in the MWS. Lancet 2003;362:419-27.
  14. BMS Consensus statement on HRT. www.the-bms.org
  15. The IMS. Guidelines for the hormone treatment of women in the menopausal transition and beyond. www.imsociety.org
  16. McPherson K.  Where are we now with HRT? BMJ 2004;328:357-8.
  17. Sturdee DW. The facts of HT for menopausal women. London: Parthenon; 2004.
  18. Shumaker SA, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: WHIMS. JAMA 2003;289:2651-62.