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HRT in the early menopause:

scientific evidence and common perceptions

International Menopause Society

Summary of the First IMS Global Summit on menopause-related issues

March 29-30, 2008

A. Pines, D. W. Sturdee, M. H. Birkhäuser, T. de Villiers, F. Naftolin, A. Gompel, R. Farmer, D. Barlow, D. Tan, P. Maki, R. Lobo and H. Hodis, et al. on behalf of the International Menopause Society

http://www.imsociety.org/pdf_files/comments_and_press_statements/ims_press_statement_13_05_08.pdf 

(Reproduced with permission from IMS http://www.imsociety.org/)

Introduction

Hormone replacement therapy (HRT) remains the first-line and most effective treatment for menopausal symptoms. But, despite massive, good-quality clinical outcome data on efficacy and safety when HRT is begun for symptoms in the early postmenopause, many physicians and lay people believe that hormones are risky and undesired even in the most appropriate case scenarios. Many misconceptions and misperceptions play roles in this complicated situation: some are purely scientific, others are cultural or social. The importance of the media and internet as effective, but unmonitored, means for dissemination of information, interpretation and recommendations cannot be ignored. Actual scientific facts and data have become trivialized in the mass media, often receiving less editorial scrutiny than normal journalism. Furthermore, many HRT prescribers and users do not attempt to broaden their knowledge on menopause and its treatment beyond capturing headlines or short commentaries, often produced by unqualified or prejudiced sources or unprofessional people.

As a result, a gap has formed between the actual clinical evidence and the way it is perceived by all concerned.

The results of the Women's Health Initiative (WHI), a very large, government-sponsored study of hormone treatment regardless of indications (in contradistinction to normal practice that is based on clinical symptoms and signs), were prematurely released before the study was completed and before the results could be properly evaluated. As a result, the results were over-interpreted and negatively slanted. It was viewed as a negative study by its investigators and failed to emphasize the data, which pointed at the vast importance of age and time since menopause as major determinants of the benefit-risk equilibrium of HRT and the many benefits from timely employment of HRT. This was a catalyst for negative sentiments toward HRT. By the time that more detailed analyses from the WHI study could be published in the past 2 years, much ground was lost for all concerned and much remains to be set right for patients and caregivers, alike. At present, it is clear that the WHI showed that properly timed HRT is safe for healthy women in their early postmenopause and has major preventative effects against fractures. It reduces mortality and this may be, in large part, due to prevention of heart disease.

The premature evaluation of the WHI includes statements and warnings from many health authorities, such as the US Preventive Services Task Force (USPSTF) and the European Agency for the Evaluation of Medicinal Products (EMEA) that sent a message that still prevails: the use of HRT is dangerous and therefore should be avoided, unless there is a substantial reduction in quality of life because of menopausal symptoms, in which case treatment should be given for the shortest possible duration. This seems untenable in light of the presently available data, the opinion of skilled and experienced health professionals, and even some of the WHI investigators themselves.

The aim of the International Menopause Society (IMS) in developing the Zürich Summit was to openly discuss and better understand the current situation in various areas of the globe. The knowledge and perspectives of scientists, consumers and the media were sought to recommend ways to narrow the gap between the evidence and its perception by health professionals and the lay public. The forum, which included experts from the various fields of menopause medicine and representatives of 40 national and regional menopause societies, agreed that the following summary of the scientific data will be addressed as the ‘Evidence'. Each statement will quote its scientific level of evidence, and a list of the corresponding references is attached at the end of the document. Level A evidence refers to data from

randomized controlled trials, whereas Level B evidence comes from case-control/observational studies. As pointed out in the Summit's title, the focus of discussions was the effects of HRT first administered during the early postmenopausal period.

Quality Of Life And Menopause

The perception of menopause and its impact on quality of life vary in different areas of the world1-5. In some places, menopause leads to a higher social status, in others - not. The forum agreed that the issue of quality of life is pivotal for any discussion on menopause management and the evaluation of the benefits versus the risks of HRT. Quality of life may be defined in many ways, based on medical, cultural and social parameters, but is largely subjective and therefore not easy to evaluate under a global, unified scale. Some may say that menopause is just a physiological stage during a woman's life cycle and therefore its associated adverse consequences of quality of life should not be medicalized. Others may argue that the risks of HRT do not justify its use unless quality of life is substantially compromised. The negative sentiments coming from the WHI publications and the related media coverage intimidate women and health-care providers and in a way lead to confusion and to a degraded credibility of the medical profession over these issues, but the WHI Quality of Life analysis started with only 11% of subjects who had moderate or severe hot flushes and did not have the power to determine a comparative improvement in the treatment vs. placebo group6. Such a low incidence of climacteric symptoms is not representative of the healthy peri- and early postmenopausal women treated in everyday practice.

  • In symptomatic postmenopausal women, quality of life and sexuality are improved by HRT7,8 and, in the presence of symptoms of androgen deficiency, by additional androgen administration.
  • In some cultures, and for some women, vaginal bleedings are unacceptable4; if bleeding cannot be eliminated, alternatives to HRT may be used.
  • There is no evidence that so-called ‘natural' products and unregulated hormone products (compounded bio- identical) significantly improve quality of life.

Perceptions Vs. Scientific Data (The ‘Evidence')

HRT, coronary heart disease, stroke and thromboembolism

Perceptions

  • HRT increases coronary heart disease (CHD) risk throughout the whole postmenopausal period.
  • HRT causes an increase in coronary events in the first 1-2 years in all women.
  • Stroke risk is substantially increased in women receiving HRT.
  • The risk of both venous and arterial thromboembolism is increased during HRT.

The evidence

  • HRT in women aged 50-59 years does not increase CHD risk in healthy women and may even decrease the risk in this age group9. [A]
  • Estrogen-alone therapy in the age group 50-59 was associated with significantly less coronary calcification (equivalent to a smaller plaque burden), which is consistent with findings of a lower coronary intervention score in women of this age in the WHI study10. [A]
  • Early harm (more coronary events during the first 2 years of HRT) was not observed in the early postmenopausal period. The number of CHD events decreased with duration of HRT in both WHI clinical trials11. [A]
  • Data derived from randomized controlled trials in the age group 50-59 are similar to the older observational data suggesting a protective effect of HRT on coronary disease9,12. [A, B]
  • It is unclear at present whether there is a statistical increase in ischemic stoke with standard HRT in healthy women aged 50-59. The WHI data showed no statistically significant increase in risk; nevertheless, even if statistically increased, as found in the Nurses' Health Study, the low prevalence of this occurrence in this age group makes the attributable risk extremely small13,14. [A,B]
  • The risk of venous thrombosis is approximately two-fold higher with standard doses of oral HRT, but is a rare event in that the background prevalence is extremely low in a healthy woman under 60 years of age15. [A]
  • The risk of venous thrombosis is possibly less with transdermal, compared with oral estrogen therapy16. [B]

Breast

Perceptions

  • All types of HRT cause an increased risk of breast cancer within a short duration of use.
  • HRT causes an increase in mortality from breast cancer.
  • The reported decline in breast cancer rates in the US following the publication of the WHI proves that HRT causes cancer.
  • HRT causes an increase in mammographic breast density.
  • Increase in mammographic breast density is associated with an increased risk of breast cancer.

The evidence

  • There is a wide variation across the world in the incidence of breast cancer and its risk factors17.
  • There are multiple risk factors for breast cancer, including life-style factors especially alcohol intake, obesity and lack of exercise. These need to be included during counselling to put the magnitude of risk of HRT into an appropriate perspective18,19. [B]
  • After 5 years' use of combined estrogen and progestogen, there is a small increase in risk of breast cancer in North American women of about eight extra cases per 10,000 women per year. However, no significant increase was seen in women without prior use of HRT in the WHI study20. [A]
  • Estrogen-only use does not cause an increase in breast cancer for up to 7 years21. [A] In observational studies, a small increase in the risk with estrogen-alone therapy appears with long-term use22. [B]
  • Women using combined HRT before a diagnosis of breast cancer have a reduced mortality23. [B]
  • A decline in the incidence of breast cancer in the USA started before the WHI publication and can be partially related to fluctuation in screening24. There has been no decline in breast cancer registration in the UK following the Million Women Study report, nor in Norway, Canada, the Netherlands and countries with stable screening programmes25. [B]
  • Combined estrogen and progestogen therapy may cause increased breast density in up to 50% of postmenopausal women, dependent on the regimen (dosage, type of progestogen). The effect of estrogen alone is smaller26. [A]
  • The effect on breast density is dose-related. Ultra-low-dose regimens do not cause any perceptible change in density27. [A]
  • The average increase in breast density under standard-dose HRT is only about 5-10%28. [A]
  • Increased baseline breast density is a risk factor for breast cancer29. There are no data to support a direct association between HRT-induced breast density changes and the risk of developing breast cancer.
  • Many women who develop breast cancer have no known risk factors other than growing older and most women with known risk factors do not develop breast cancer.
  • Individual risk analysis for breast cancer is strongly recommended in clinical practice30.

Bone

Perceptions

  • HRT should not be used for bone protection because of its unfavorable safety profile.
  • HRT is not as effective in reducing fracture risk as other products, e.g. bisphosphonates.
  • Official recommendations by health authorities (EMEA, FDA) limit the use of HRT to a second-line alternative. HRT could only be considered when other medications failed, were contra-indicated or not tolerated or in symptomatic women.

The evidence

  • Overall, HRT is effective in the prevention of all osteoporosis-related fractures, even in patients at low risk of fracture31,32. [A]
  • Although no head-to-head studies have compared HRT to bisphosphonates in terms of fracture reduction, there is no evidence to suggest that bisphosphonates or any other antiresorptive therapy are superior to HRT.
  • It is therefore suggested that, in 50-59-year-old postmenopausal women, HRT is a cost-effective first-line treatment in the prevention of osteoporotic fractures.
  • Even lower than standard-dose preparations maintain a positive influence on bone indices such as bone mineral density33. [A]
  • HRT has a positive effect on osteoarthritis and the integrity of intervertebral disks.

Cognition

Perceptions

  • Menopause transition is associated with cognitive decline.
  • HRT increases the risk of cognitive/memory impairment and dementia at any age.
  • Progestogens counteract estrogen effects in the brain.

The evidence

  • At present, there is no evidence of substantial cognitive decline across the menopausal transition34. [A] However, many women experience cognitive difficulties in association with vasomotor symptoms, sleep disturbances and mood changes35,36.
  • Verbal memory performance relates with the objective number of hot flushes women experience but not to the number of hot flushes they report35.
  • Clinical trial findings currently find no cognitive benefit among women initiating HRT late in the postmenopausal period (i.e. after age 65)37.
  • Cognitive benefits from estrogen replacement therapy appear to depend on age of initiation38.
  • Observational studies show a decreased risk of Alzheimer's disease in hormone users and typically involve women who initiated estrogen therapy early in the menopausal transition39- 41. [B]
  • Limited data exist on the effect of progestogen added to estrogen in the early postmenopause period. Clinical trial data suggest no cognitive benefit with MPA early in the menopause42. [A]

Actions to be Taken

The forum agreed that education and dissemination of the clinical data are crucial in the process of closing the gap between the scientific evidence on HRT and its

perception. Three main targets were identified: the health-care providers, the consumers and the journalists. The forum did not believe that actions should be taken vis-à-vis the regulatory/health authorities, since the chance of changing their opinion at this moment is slim. In order to avoid any debate over the ‘Evidence', it was based entirely on high-quality information, derived from randomized clinical trials whenever possible. Through presentations from each continent, it became quite clear that menopause symptoms and the incidence of illnesses associated with menopause or HRT may vary to a large extent in different parts of the world, as well as priorities in medical care. In addition, cultural and social attitudes may have a substantial impact, all affecting perceptions and decision-making in regard to menopause management and the use of hormones. Therefore, each regional/national menopause society should adapt the general framework according to its local situation and needs. The message to be delivered should be simple and clear, stressing the benefits of HRT and relieving fears according to the best quality clinical evidence. The most frequent misperceptions should therefore be identified and balanced by the corresponding data that were published in the medical literature. The above bullet points may serve as a template to be used locally by the societies.

Disclosure of Interest

The International Menopause Society was able to hold the Global Summit Meeting with the assistance of unrestricted educational grants received from three pharmaceutical companies: Wyeth Pharmaceuticals, Bayer Schering Pharma and Novo Nordisk Femcare. The industry had no influence on the choice of speakers, the content of the meeting, the discussions or the final statement. The signatories to the summary statement have no associations or financial links with any pharmaceutical company, but have received honoraria for lecturing at scientific meetings and research grants.

References

Quality of life

1. Haines CJ, Yim SF, Chung TK, et al. A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Maturitas 2003;44:207-14

2. Haines CJ, Xing SM, Park KH, Holinka CF, Ausmanas MK. Prevalence of menopausal symptoms in different ethnic groups of Asian women and responsiveness to therapy with three doses of conjugated estrogens/medroxyprogesterone acetate: The Pan-Asia Menopause (PAM) study. Maturitas 2005;52:264- 76

3. Lock M. Ambiguity of ageing: Japanese menopause. Culture, Medicine and Psychiatry 1986;10:23-47

4. Obermeyer CM. Menopause across cultures: a review of the evidence. Menopause 2000;7:184-92

5. Tan D, Haines CJ, Limpaphayom KK, Holinka CF, Ausmanas MK. Relief of vasomotor symptoms and vaginal atrophy with three doses of conjugated estrogens and medroxyprogesterone acetate in postmenopausal Asian women from 11 countries: The Pan-Asia Menopause (PAM) study. Maturitas 2005;52:35-51

6. Hays J, Ockene JK, Brunner RL, et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839-54

7. Wiklund I, Karlberg J, Mattson L-A. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol 1993;168:824-30

8. Syrjala KL, Roth-Roemer SL, Abrams JR, et al. Prevalence and predictors of sexual dysfunction in long-term survivors of marrow transplantation. J Clin Oncol 1998;16:3148-57

HRT, coronary heart disease, stroke and thromboembolism

9. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77

10. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-602

11. Lobo R. Evaluation of cardiovascular event rates with hormone therapy in healthy, early postmenopausal women: results from 2 large clinical trials. Arch Intern Med 2004;164:482-4

12. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health 2006;15:35-44

13. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113:2425-34

14. Grodstein F, Manson JE, Stampfer J, Rexrode K. Postmenopausal hormone therapy and stroke. The role of time since menopause and age of initiation of hormone therapy. Arch Intern Med 2008;168:861-6

15. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573-80

16. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-5

Breast

17. Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer Statistics 2002. CA Cancer J Clin 2005;55:74-108

18. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001;344:276-85

19. Veronesi U, Boyle P, Goldhirsch A, et al. Breast cancer. Lancet 2005;365:1727-41

20. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. JAMA 2003;289:3243-53

21. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57

22. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-32

23. Newcomb PA, Egan KM, Trentham-Dietz A, et al. Prediagnostic use of hormone therapy and mortality after breast cancer. Cancer Epidemiol Biomarkers Prev 2008;17:864- 71

24. Li CI, Daling JR. Changes in breast cancer incidence rates in the United States by histologic subtype and race/ethnicity, 1995 to 2004. Cancer Epidemiol Biomarkers Prev 2007;16

25. Ponti A, Rosso S, Zanetti R, Ricceri F, Tomatis M, Segnan N. Re: Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 2007;99:1817-8

26. Greendale GA, Reboussin BA, Sie A, et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann Intern Med 1999;130:262-9

27. Lundström E, Bygdeson M, Svane G, Azavedo E, von Schoultz B. Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic density. Climacteric 2007;10:249-56

28. Hofling M, Lundström E, Azavedo E, et al. Testosterone addition during menopausal hormone therapy: effects on mammographic breast density. Climacteric 2007;10:155-63

29. Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005;6:798-808

30. Santen RJ, Boyd NF, Chlebowski RT, et al.; Breast Cancer Prevention Collaborative Group. Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocr Relat Cancer 2007;14:169-87

Bone

31. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized trial. J Bone Miner Res 2006;21:817-28

32. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003;290:1729-38

33. Huang AJ, Ettinger B, Vitinghoff E, et al. Endogenous estrogen levels and the effects of ultra-low-dose transdermal estradiol on bone turnover and BMD in postmenopausal women. J Bone Min Res 2007;22:1791-7

Cognition

34. Meyer PM, Powell LH, Wilson RS, et al. A population-based longitudinal study of cognitive functioning in the menopausal transition. Neurology 2003;61:801-6

35. Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause 2008;in press

36. Woods NF, Smith-Dijulio K, Percival DB, et al. Symptoms during the menopausal transition and early postmenopause and their relation to endocrine levels over time: observations from the Seattle Midlife Women's Health Study. J Womens Health 2007;16:667-77

37. Espeland MA, Rapp SR, Shumaker SA, et al. Women's Health Initiative Memory Study. Conjugated equine estrogens and global cognitive function in postmenopausal women. JAMA 2004;291:2959-68

38. Bagger YZ, Tankó LB, Alexandersen P, Qin G, Christiansen C. Early postmenopausal hormone replacement therapy may prevent cognitive impairment later in life. Menopause 2005;12:12-17

39. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 1997;48:1517-21

40. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer's disease on older women the Cache County study. JAMA 2002;288:2123-9

41. Tang M-X, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429-32

42. Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology 2007;69:1322-30

Content Updated 30 March, 2008