First Global Summit on menopause-related issuesZürich, March 2008

HRT in the early menopause: scientific evidence andHRT in the early menopause: scientific evidence andcommon perceptionscommon perceptions

Aim: to bridge the gap between clinical factsand fears that are based on misperceptionsand misinformation in regard to hormone

replacement therapy, with a focus on women less than 60 years old.

(The full summary is available on www.imsociety.org)(The full summary is available on www.imsociety.org)

Evidence vs. perception

Both physicians and the lay public do not address postmenopausalhormone therapy as an ordinary medication. There is a tendency to‘judge’ hormone therapy by other standards (for example, feminismand sexism are erroneously linked to the debate).

While the benefits of hormone therapy are very subjective (vasomotor symptoms) or preventive in nature (fractures), the potential risks involve serious, frightening diseases (breast cancer, stroke). It seems difficult for most people to put on the same scale and to weigh objectively these benefits and risks. Perception-wise, in the post-WHI era, risks are over-valued and generalized to the whole postmenopausal population and to all forms of hormone therapy.

Evidence vs. perception

Vast amounts of information exist. People tend to be

selective and pick pieces of it according to their

beliefs and personal experience; thus an overall

perspective may be missing.

Quality of life

Achieving good quality of life is a prime target in menopause medicine, which is as important as prevention and treatment of diseases. There is no argument that HRT is the first choice and the best modality to improve quality of life and sexuality in symptomatic postmenopausal women.

Cardiovascular system (1)

Perception

HRT increases the risk of coronary heart disease (CHD) throughout the whole postmenopausal period.

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 group. [A]

Rossouw J. JAMA 2007;297:1465

Cardiovascular system (2)

Perception

HRT causes an increase in coronary events in the first 1–2 years in all women.

Evidence

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 trials. [A]

Lobo R. Arch Intern Med 2004;164:482

Cardiovascular system (3)

Perception

Stroke risk is substantially increased in women receiving HRT.

Evidence

It is unclear at present whether there is a statistical increase in ischemic stroke 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 small. [A,B]

Hendrix SL. Circulation 2006;113:2425Grodstein F. Arch Intern Med 2008;168:861

Cardiovascular system (4)

PerceptionThe risk of venous thromboembolism is increased during HRT.

EvidenceThe risk of venous thrombosis in the early menopause 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 age. [A]The risk of venous thrombosis is possibly less with transdermal, compared with oral estrogen therapy. [B]

Cushman M. JAMA 2004;292:1573Canonico M. Circulation 2007;115:840

Breast (1)

PerceptionAll types of HRT cause an increased risk of breast

cancer within a short duration of use.

EvidenceAfter 5 years’ use of combined estrogen and progestogen, the WHI cohort showed a small increase in risk of breast cancer of about eight extra cases per 10,000 women per year. Risk was not increased in first-time hormone users. [A]

Chlebowski RT. JAMA 2003;289:3243Stefanic ML. JAMA 2006;295:1647

Breast (1) cont.

PerceptionAll types of HRT cause an increased risk of breast

cancer within a short duration of use.

EvidenceIn the WHI estrogen-only arm, there was no increase in breast cancer risk for up to 7 years. However, the risk of invasive breast cancer was significantly lower in first-time users of estrogen. [A] In observational studies, a small increase in risk during estrogen-alone therapy was recorded only after long-term use. [B]

Anderson GL. JAMA 2004;291:1701; Stefanic ML. JAMA 2006;295:1647Chen WY. Arch Intern Med 2006;166:1027

Breast (2)

PerceptionThe reported decline in breast cancer rates in theUS following the publication of the WHI data provesthat HRT causes cancer.

EvidenceA decline in the incidence of breast cancer in the USA started before the WHI publication and can be partially related to fluctuation in screening. 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 programs. [B]

Li CI. Cancer Epidemiol Biomarkers Prev 2007;16:2773Kliewer EV. NEJM 2007;357:509; Zahl PH. NEJM 2007;357:510

Breast (3)PerceptionHRT causes an increase in mammographic breast density.Increase in mammographic breast density is associatedwith an increased risk of breast cancer.

EvidenceIncreased baseline breast density is a risk factor for breast cancer.

Boyd NF. Lancet Oncol 2005;6:798 (review)Combined E + P therapy may cause increased breast density in up to 50% of postmenopausal women, dependent on the regimen (dosage, type of progestogen. The average increase in breast density with standard dose is up to 10%). The effect of estrogen alone is smaller. [A]

Greendale GA. Ann Intern Med 1999;130:232There are no data to support a direct association between HRT-induced

breast density changes and the risk of developing breast cancer.

Bone (1)PerceptionHRT should not be used for bone protection because ofits unfavorable safety profile. Official recommendationsby health authorities (EMEA, FDA) limit the use of HRTto a second-line alternative. HRT could only be consideredwhen other medications failed, were contraindicated or nottolerated, or in the very symptomatic woman.

EvidenceFor the age group 50–59, HRT is safe and cost-effective. Overall, HRT is effective in the prevention of all osteoporosis-related fractures, even in patients at low risk of fracture. [A]

Rossouw J. JAMA 2007:297:1465; Cauley JA. JAMA 2003;290:1729

Jackson RD. J Bone Min Res 2006;21:817

Bone (2)

PerceptionHRT is not as effective in reducing fracture risk as other products (bisphosphonates, etc.).

EvidenceAlthough 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.

Cognition (1)

PerceptionMenopause transition is associated with cognitive decline.

EvidenceThere is no evidence of substantial cognitive decline across the menopausal transition. [A] However, many women experience cognitive difficulties in association with vasomotor symptoms, sleep disturbances and mood changes. [B]

Meyer PM. Neurology 2003;61:801; Maki PM. Menopause 2008 (in press)Woods NF. J Womens Health 2007;16:667

Cognition (2)PerceptionHRT increases the risk of cognitive/memory impairment and dementia at any age.

EvidenceNo cognitive benefit was found among women initiating HRT late in the postmenopausal period (after age 65). [A]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 transition. [B] Cognitive benefits from estrogen therapy appear to depend on age at initiation. [B]

Espeland MA. JAMA 2004;291:2959; Tang M-X. Lancet 1996;348:429Bager YZ. Menopause 2005;12:12

Cognition (3)

PerceptionProgestogens counteract estrogen effects in the brain.

EvidenceLimited data exist on the effect of progestogen added to estrogen in the early postmenopause period.

Conclusions

Menopause symptoms and the incidence of illnessesassociated with menopause or HRT may vary to a largeextent in different parts of the world, as well aspriorities in medical care. In addition, cultural and socialattitudes may have a substantial impact, all affectingperceptions and decision-making in regard to menopause management and the use of hormones.

Each regional/national menopause society should adaptthe general framework according to its local situationand needs.

Actions to be taken

The forum agreed that education and dissemination of theclinical data are crucial in the process of closing the gapbetween the scientific evidence on HRT and its perception.

Three main targets were identified: the health-careproviders, the consumers and the journalists.

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 have been published in the medical literature.

Take-home message

Many people read only headlines or short messages.

For these people, a short take-home message is the following:

• The target population for initiation of HRT is usually women up to age 55.• HRT initiated in the early postmenopausal period in healthy

women is safe.• Like all medicines, HRT needs to be used appropriately,

but it is essential that women in early menopause who aresuffering menopausal symptoms should have the option ofusing HRT.