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Hormone replacement therapy: a question of balance?

Does HRT still have a place as firstline climacteric therapy? Steve Dawber summarises expert recommendations and examines HRT prescriber confidence

Steve Dawber
BSc(Hons) MCIJ
Freelance Medical
Writer and Journalist

Hormone replacement therapy (HRT) has long been considered the most effective treatment for menopause-related symptoms.(1) It also significantly reduces the risk of osteoporosis.(2) However, in July 2002, a Women's Health Initiative (WHI) study reported that HRT increased the risk of breast cancer and cardiovascular disease in women aged between 50 and 79 years.(1) Unsurprisingly, these findings were extensively covered by medical and lay media across the world, and as a result, the safety of HRT was widely and publicly debated.
The subsequent adverse publicity resulted in a significant reduction in HRT usage, which while abating the perceived risks, culminated in a dramatic decline in the quality of life of millions of peri- and postmenopausal women worldwide.(3)
This, in turn, prompted a stringent re-evaluation of the original WHI evidence, and in 2007 renewed evidence-based guidelines were issued by some of the world's leading menopause organisations.(4-6)

The WHI HRT study: a brief summary
In July 2002, the National Heart, Lung and Blood Institute (NHLBI) prematurely stopped a large multicentre trial, which was a component of the WHI.(1,7) The aim of the 16,608-woman study was to examine the effects of oestrogen and progestogen on the prevention of heart disease and hip fracture in women aged between 50 and 79 years. It was also designed to record any associated change in breast and colon cancer risk. 
The study was discontinued after an average follow-up period of 5.2 years. This was because, when compared with placebo, the oestrogen and progestogen therapy was found to be associated with an increased risk of invasive breast cancer. Increases in coronary heart disease, stroke and pulmonary embolism were also discovered.(1,7)
Specifically, it was found that, compared with placebo, the HRT combination evoked:(1,7)

  • A 41% increase in the number of strokes.
  • A 29% increase in the number of heart attacks.
  • A doubling of venous thromboembolism rates (blood clots).
  • A 22% increase in the incidence of total cardiovascular disease.
  • A 26% increase in the incidence of breast cancer.
  • A 37% reduction in the incidence of colorectal cancer.
  • A one-third reduction in the number of hip fractures.
  • A 24% reduction in the number of total fractures.
  • No difference in total mortality (of all causes).

The investigators concluded that while there were noteworthy benefits of HRT therapy, including fewer cases of hip fracture and colon cancer, on balance, overall harm was greater than overall benefit.(1,7)

Current opinion, guidance and recommendations
The WHI study prompted statements and warnings from many health authorities, including the US Preventive Services Task Force (USPSTF) and the European Agency for the Evaluation of Medicinal Products (EMEA). Such warnings specified that: "The use of HRT is dangerous and should be avoided, unless there is a substantial reduction in menopause-related quality of life. In those cases, treatment should be given for the shortest possible duration."
This was a catalyst for negative sentiments towards HRT, and by the time more detailed subanalyses could be published, HRT use had fallen dramatically.(3)
However, according to the International Menopause Society (IMS), the WHI results were prematurely released and not properly evaluated. Therefore it is the IMS' vehement belief that the findings were too negatively slanted.(8)
It did recognise, however, that the study highlighted the vast importance of factors such as age and time since menopause as major determinants of the benefit-risk equilibrium of HRT (ie, that timely HRT employment has many clinical benefits).(8) Regrettably, these crucial clinical messages were lost in the prevailing negative aftermath, prompting the IMS to hold its "First Global Summit on Menopause-Related Issues". 
Following the Summit, the IMS released the following statement: "It is clear that the WHI showed that properly timed HRT is safe for healthy women in their early postmenopause, and that it has major preventive effects against fractures. It reduces mortality and this may be, in large part, due to the prevention of heart disease."(8)
More specific evidence-based findings of the IMS Summit are provided in Box 1.

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The most eminent current guidance agrees that there is a place for HRT as firstline climacteric therapy. 
The 2007 IMS guidance states that:(4)

  • HRT remains the most effective therapy for vasomotor and oestrogen-deficient urogenital symptoms.
  • HRT should not be recommended without a clear indication for its use.
  • Dosage should be titrated to the lowest effective dose. Lower doses of HRT than have been used routinely can maintain quality of life in a large proportion of users.
  • The safety of HRT largely depends on age. Women aged below 60 years should not be concerned about the safety profile of HRT. New data and reanalyses of older studies by women's age show that, for most women, the potential benefits of hormone therapy given for a clear indication are many and the risks are few when initiated within a few years of menopause.

Similarly, the North American Menopause Society and European Menopause and Andropause Society stipulate that:

  • Current evidence supports a consensus regarding the role of HRT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered.(5)
  • Some women may be susceptible to early thrombotic risk, but when appropriate HRT is given after individual clinical evaluation, the benefits will far outweigh any potential risks and treatment should be recommended.(6)

So, has physician confidence in HRT recovered since the WHI findings? A recent international study involving 600 experienced gynaecologists, obstetricians and general practitioners (including 150 clinicians from the UK) found that the vast majority of physicians (97% overall and 89% in the UK) believed that HRT was effective in relieving the most common menopausal symptoms of hot flushes, sleep disturbances, mood swings and vaginal dryness.3 In addition, most physicians (90% overall and 75% from the UK) believed that the benefits of HRT outweighed the risks in suitable patients, and 96% (90% from the UK) would prescribe it for themselves, their spouses or their families. 
This latter result compares very favourably with a pre-WHI physician survey (circa 1996) which showed that 86% of gynaecologists' wives and 88% of female gynaecologists had used HRT themselves.(9)

Modern HRT formulations
The current advocation of "prescribing the lowest effective dose for the shortest time" has prompted research into new ultralow-dose HRT therapies. Studies have shown that both oestrogenic side-effects (eg, nausea, bleeding, bloating, breast pain, headache) and progestogenic side-effects (eg, migraine, mood disturbance, acne, greasy skin) are reduced at these lower doses, but that clinical efficacy is fully maintained.(10-13)
For example, a recent double-blind, placebo-controlled randomised controlled trial involving 577 postmenopausal women aged between 44 and 65 years, investigated the efficacy and side-effect profile of two ultralow-dose HRT regimens: 0.5 mg 17ß-estradiol + 0.1 mg norethisterone acetate (NETA), and 0.5 mg 17ß-estradiol + 0.25 mg NETA.(13) The investigators found that when compared with placebo, both ultralow-dose regimens produced a rapid, statistically significant decrease in the frequency and severity of hot flushes which continued throughout the 24-week study. 
They concluded that the ultralow-dose combinations were a new milestone in offering postmenopausal women effective symptom relief while minimising safety concerns. It is thought that the first of these ultralow-dose HRT combinations will be available in the UK by the end of the year.

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References

  1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-3.
  2. 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.
  3. Birkhauser MH, Reinecke I. Current trends in hormone replacement therapy: perceptions and usage. Climacteric 2008;11:192-200.
  4. Pines A, Sturdee DW, Birkhauser MH, Schneider HP, et al. IMS updated recommendations on postmenopausal hormone therapy. Climacteric 2007;10:181-94.
  5. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008;15:584-602.
  6. Gompel A, Barlow D, Rozenberg S, Skouby SO. The EMAS 2006/2007 update on clinical recommendations on postmenopausal hormone therapy. Maturitas 2007;56:227-9.
  7. National Institutes of Health. NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk, lack of overall benefit [NIH news release]. 2002. Available from: http://www.nhlbi.nih.gov/new/press/02-07-09.htm
  8. International Menopause Society. HRT in the early menopause: scientific evidence and common perceptions. Summary of the first IMS Global Summit on menopause-related issues. Available from: http://www.imsociety.org/pdf_files/comments_and_press_statements/ims_pre...
  9. Andersson K, Mattsson LA, Milsom I. Use of hormone replacement therapy. Lancet 1996;348:1521.
  10. 1Bellantoni MF, Harman SM, Cullins VE, et al. Transdermal estradiol with oral progestin: biological and clinical effects in younger and older postmenopausal women. J Gerontol 1991;46:M216-22.
  11. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71.
  12. Archer DF, Dorin M, Lewis V, et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080-7.
  13. Panay N, Ylikorkala O, Archer DF, et al. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric 2007;10:120-31.
  14. Rapkin AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obstet Gynecol 2007;196:97-106.
  15. Burger H, Archer D, Barlow D, et al. Practical recommendations for hormone replacement therapy in the peri- and postmenopause. Climacteric 2004;7:210-6.