Merits and risks of postmenopausal hormone therapy

The past decade has seen marked fluctuations in opinions concerning the merits and risks of postmenopausal hormone therapy.

In July 2002, menopause management faced a major turning point when the first data from the Women's Health Initiative (WHI) trial were released. The study was categorized as a primary prevention trial for coronary heart disease, although the fact that mean age at recruitment was 63 years was not given enough importance at that time. WHI investigators concluded that hormone therapy (HT) was not cardioprotective, and, in fact, its riskbenefit ratio did not favor the use of postmenopausal hormones for prevention of chronic diseases. As a result, there was a dramatic change in prescription habits following recommendations to reserve HT for very symptomatic women, and to limit its use to the 'shortest duration needed and to the lowest effective dosage. This was the atmosphere in which the International Menopause Society (IMS) initiated the IMS Workshop held in Vienna (December 2003) and the IMS Position Paper that was based on the Workshop discussions. Looking at global perspectives, and being independent of local or regional constraints imposed by official health authorities, this IMS Statement called for a more balanced approach in the interpretation of the scientific data on hormone use that were available in 2003. Since then, additional information has been accumulated from both arms of the WHI study, observational trials and from other studies, allowing a more comprehensive review on all issues related to the use of hormones in the postmenopausal period. In view of the above, the IMS Board decided that it is time to update the 2004 Statement and to enlarge its scope to menopause management and adult women's health in general. More than 30 experts from the various fields of menopause medicine reviewed the latest information in a Workshop held in Budapest in February 2007.

The following Recommendations express the views of the IMS on the principles of hormone therapy in the peri- and postmenopausal periods. Throughout the Recommendations, the term HT will be used to cover all therapies including estrogens, progestogens, combined therapies and tibolone.

The previous IMS Statement in 2004 is still valid and serves as a basis for the current Updated Recommendations.

We are aware of the geographical variations related to different priorities of medical care, different prevalence of diseases, and country-specific attitudes of the public, the medical community and the health authorities toward menopause management, which may all impact on hormone therapy. The following recommendations, therefore, give a global and simple overview that serves as a common platform on issues related to the various aspects of hormone treatment. These Recommendations were reviewed and discussed by representatives of more than 60 National and Regional Menopause Societies from all continents. These Recommendations can be easily adapted and modified according to local needs.

Hormone therapy should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking and alcohol for maintaining the health of postmenopausal women. HT must be individualized and tailored according to symptoms and the need for prevention, as well as personal and family history, results of relevant investigations, the woman's preferences and expectations. The risks and benefits of HT differ for women around the time of menopause compared to those for older women.

HT includes a wide range of hormonal products and routes of administration, with potentially different risks and benefits. Thus, the term class effect is confusing and inappropriate.

Women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and particularly before 40 are at higher risk for cardiovascular disease and osteoporosis. They will benefit from hormone replacement, which should be given at least until the normal age of menopause.

Counselling should convey the benefits and risks of HT in simple terms, e.g. absolute numbers rather than as percentage changes from baseline expressed as a relative risk. This allows a woman and her physician to make a well-informed decision about HT.

HT should not be recommended without a clear indication for its use.

Women taking HT should have at least an annual consultation to include a physical examination, update of medical history, relevant laboratory and imaging investigations and a discussion on lifestyle.

There are no reasons to place mandatory limitations on the length of treatment. Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and risks.

Dosage should be titrated to the lowest effective dose. Lower doses of HT than have been used routinely can maintain quality of life in a large proportion of users. Long-term data on lower doses regarding fracture risk and cardiovascular implications are still lacking.

In general, progestogen should be added to systemic estrogen for all women with a uterus to prevent endometrial hyperplasia and cancer. However, natural progesterone and some progestogens have specific beneficial effects that could justify their use besides the expected actions on the endometrium. Low-dose vaginal estrogens administered for the relief of urogenital atrophy do not require progestogen co-medication. Direct delivery of progestogen to the endometrial cavity from the vagina or by an intrauterine system is logical and may minimize systemic effects.

Androgen replacement should be reserved for women with clinical signs and symptoms of androgen insufficiency. In women with bilateral oophorectomy or adrenal failure, androgen replacement has significant beneficial effects, in particular on health-related quality of life and sexual function.

HT remains the most effective therapy for vasomotor and estrogen-deficient urogenital symptoms. Other menopause-related complaints, such as joint and muscle pains, mood swings, sleep disturbances and sexual dysfunction (including reduced libido) may improve during HT. Quality of life and sexuality are key factors to be considered in the management of the aging individual. The administration of individualized HT (including androgenic preparations when appropriate) improves both sexuality and overall quality of life.

HT is effective in preventing the bone loss associated with the menopause and decreases the incidence of all osteoporosis-related fractures, including vertebral and hip, even in patients at low risk. Although the magnitude of decline in bone turnover correlates with estrogen dosage, even lower than standard-dose preparations maintain a positive influence on bone indices in most women. Based on updated evidence on effectiveness, cost and safety, HT is an appropriate first-line therapy in postmenopausal women presenting with an increased risk for fracture, particularly under the age of 60 years and for the prevention of bone loss in women with premature menopause. The protective effect of HT on bone mineral density declines after cessation of therapy at an unpredictable rate, although some degree of fracture protection may remain after cessation of HT.

The initiation of standard-dose HT is not recommended for the sole purpose of the prevention of fractures after the age of 60 years. Continuation of HT after the age of 60 years for the sole purpose of the prevention of fractures should take into account the possible long-term effects of the specific dose and method of administration of HT, compared to other proven therapies.

Cardiovascular disease is the principal cause of morbidity and mortality in postmenopausal women. Major primary prevention measures (besides smoking cessation and diet control) are weight loss, blood pressure reduction, and diabetes and lipid control. There is evidence that HT may be cardioprotective if started around the time of menopause and continued long-term (often referred to as the window of opportunity concept). HT markedly reduces the risk of diabetes and, through improved insulin resistance, it has positive effects on other related risk factors for cardiovascular disease such as the lipid profile and metabolic syndrome.

In women less than 60 years old, recently menopausal and without prevalent cardiovascular disease, the initiation of HT does not cause early harm and in fact reduces cardiovascular morbidity and mortality. Continuation of HT beyond the age of 60 should be decided as a part of the overall riskbenefit analysis.

HT has benefits for connective tissue, skin, joints and intervertebral disks. HT may reduce the risk of colon cancer. HT initiated around the time of menopause or by younger postmenopausal women is associated with a reduced risk of Alzheimer's disease.

Studies on the risks of postmenopausal hormone use have mainly focused on breast and endometrial cancer, venous thromboembolism (pulmonary embolism or deep vein thrombosis), stroke and coronary events.

The incidence of breast cancer varies in different countries. Therefore, currently available data cannot necessarily be generalized. The degree of association between breast cancer and postmenopausal HT remains controversial.

Women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum). For combined HT, observational data from the Million Women Study suggested that breast cancer risk was increased as early as the first year, raising serious reservations on possible methodologic flaws. On the contrary, randomized controlled data from the Women's Health Initiative (WHI) study indicate that no increased risk is observed in women initiating HT, for up to 7 years. It should be noted that the majority of subjects in the WHI study were overweight or obese.

Data from the WHI and Nurses Health Study suggest that long-term estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in American women. Recent European observational studies suggest that risk may increase after 5 years.

There are insufficient data to evaluate the possible differences in the incidence of breast cancer using different types and routes of estrogen, natural progesterone and progestogens, and androgen administration. Baseline mammographic density correlates with breast cancer risk. This does not necessarily apply to the increase in mammographic density induced by HT.

The combined estrogenprogestogen therapy-related increase in mammographic density may impede the diagnostic interpretation of mammograms.

Unopposed estrogen administration induces a dose-related stimulation of the endometrium. Women with a uterus should have progestogen supplementation.

Continuous combined estrogenprogestogen regimens are associated with a lower incidence of endometrial hyperplasia and cancer than occurs in the normal population.

Direct intrauterine delivery systems may have advantages. Regimens containing low-/ultra-low-dose estrogen and progestogen cause less endometrial stimulation and less bleeding.

The HT-related risk for serious venous thromboembolic events increases with age (although .minimal until age 60), and is also positively associated with obesity and thrombophilia. By avoiding first-pass hepatic metabolism, transdermal estrogen may avert the risk associated with oral HT. The impact on the risk of a thromboembolic event may also be affected by progestogen, depending on the type. Late starters of standard-dose HT may have a transient slightly increased risk for coronary events. The risk of stroke is correlated with age. HT may increase the risk of stroke after the age of 60.

Safety data from studies of low-dose and ultra-low-dose regimens of estrogen and progestogen are encouraging.

The efficacy and safety of complementary alternative medicines have not been demonstrated and further studies are required.

Selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors and gabapentin are effective in reducing vasomotor symptoms in short-term studies. Their long-term safety needs further evaluation.

There are no medical or scientific reasons to recommend unregistered bioidentical hormones. The measurement of hormone levels in the saliva is not clinically useful. These customized hormonal preparations have not been tested in studies and their purity and risks are unknown.

There is urgent need for further research especially into the relative merits of lower doses, regimens and routes of administration.

The safety of HT largely depends on age. Women younger than 60 years old should not be concerned about the safety profile of HT. New data and re-analyses 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. In view of the new data, Regulatory Authorities should review their current recommendations as a priority.