There are risks and benefits associated with the use of estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) in perimenopausal and postmenopausal women. For this reason, the North American Menopause Society (NAMS) evaluated the latest evidence and created the following recommendations and guidelines to update its 2004 position statement.

Recommendations

PRETREATMENT

Before initiation of treatment, a thorough history should be obtained and a complete physical examination performed, including mammography in accordance with national guidelines.

VASOMOTOR SYMPTOMS

All ET and EPT products are approved for use in treating vasomotor symptoms, such as night sweats or hot flashes. Treatment of these symptoms is the main reason for systemic ET and EPT use.

VAGINAL SYMPTOMS

Nearly all systemic and vaginal ET and EPT products are approved for the treatment of symptoms of vulvar and vaginal atrophy (e.g., dryness, dyspareunia); however, local vaginal ET is typically recommended only when needed solely for this purpose.

PROGESTOGEN INDICATION AND REGIMEN

In women with intact uteruses, unopposed ET can increase the risk of endometrial cancer; progestogen is primarily used for protection against this. Physicians should provide continuous-combined EPT or continuous-sequential EPT for women with intact uteruses who are taking ET. EPT should not be prescribed for postmenopausal women without uteruses who are taking systemic estrogen.

Progestogen may have adverse effects in some women who take EPT. There is insufficient evidence to recommend alternative options, such as off-label use of long-cycle progestogen, vaginal administration, the use of the levonorgestrel-releasing intrauterine system (Mirena), or the use of low-dose estrogen without progestogen.

CORONARY HEART DISEASE

ET and EPT are not recommended for use as coronary protection in women. One arm of the Women's Health Initiative (WHI) study showed a significant association between time since start of EPT and coronary heart disease (CHD) risk, with an increased risk in the first year and a decreased risk in later years. It is important to note that the WHI study population did not include enough younger, symptomatic, newly postmenopausal women to determine if there are similar CHD risk patterns in that population.

Observational data have shown a pattern of reduced CHD events in women who started hormone therapy within the first 10 years of menopause, and a pattern of greater CHD risk if therapy was started more than 10 years after the start of menopause. The risk of early CHD is lower in the younger cohort of newly postmenopausal women compared with the older women studied in the WHI trial.

VENOUS THROMBOEMBOLISM

Studies have shown that women have a significantly increased risk of venous thromboembolism if they are using systemic ET and EPT. This risk appears within the first two years after starting therapy, but it decreases over time. In the WHI study, excess risk was low overall and lower still in women younger than 60 years who were randomized to ET and EPT. There were few data available regarding differences in venous thromboembolism risk in transdermal 17 beta-estradiol (Estrace) and oral therapies.

STROKE

ET and EPT both seem to increase ischemic stroke risk in postmenopausal women. Although some large trials have shown no increased risk, the ET arm of the WHI study had eight additional strokes per 10,000 women, and the EPT arm had 12. For this reason, it is recommended that ET and EPT should not be used for primary or secondary prevention of stroke, and they should not be prescribed to women who are already at increased risk.

DIABETES

Randomized controlled trials (RCTs) have shown that ET and EPT lower the risk of new-onset diabetes. Women taking EPT in the WHI study had a 0.61 percent annual incidence of diabetes requiring treatment compared with 0.76 percent in women taking placebo (number needed to treat to prevent one case of diabetes = 670 per year of EPT). Women receiving ET in the WHI study had a similarly small reduction. EPT is not recommended for preventing diabetes in postmenopausal women.

BREAST CANCER

EPT use beyond five years is associated with increased breast cancer risk. Evidence shows that ET alone has little or no impact; however, some limited observational data have suggested that if ET lasts longer than 15 years, risk may increase. There are few data showing any change in breast cancer mortality with ET or EPT. Both therapies increase breast cell proliferation, breast pain, and mammographic density, and EPT can obstruct the diagnostic reading of mammograms.

OSTEOPOROSIS

Evidence has shown that ET and EPT reduce osteoporotic fracture risk in postmenopausal women; many of these products are approved for this use.

DEPRESSION

Studies have shown an increased risk of onset of major depression in perimenopausal versus premenopausal women without a history of depression, and an increased risk of major and minor depression in early postmenopause versus premenopause. Effectiveness of ET as an antidepressant in perimenopausal women has been demonstrated in two RCTs, whereas one RCT did not demonstrate effectiveness in older postmenopausal women. There is insufficient evidence to recommend using ET or EPT to treat depression.

PREMATURE MENOPAUSE OR OVARIAN FAILURE

Premature menopause and ovarian failure are linked to a lower risk of breast cancer, early osteoporosis, and CHD; it is unknown if ET or EPT affect morbidity and mortality rates from these conditions. It also is unknown if the risk/benefit ratio may be favorable for younger women who start ET or EPT at an earlier age.

RISK/BENEFIT RATIO

ET and EPT use should be consistent with treatment goals, benefits, and risks. It also should take into account factors such as the cause of menopause; time since menopause; symptoms; and other issues that could affect quality of life or risk of cardiovascular disease, stroke, venous thrombosis, or other conditions.

LOWER DOSES

Studies have shown similar relief of vasomotor or vulvovaginal symptoms and maintenance of bone mineral density with lower-dose ET or EPT (e.g., 0.3 mg of oral conjugated estrogen daily, 0.25 to 0.50 mcg of oral micronized 17 beta-estradiol) compared with standard doses. These lower doses appear to better tolerated and have a better risk/benefit ratio; however, lower doses have not been evaluated in long-term studies.

NONORAL THERAPY

The risk/benefit ratio of nonoral EPT or ET administration is unknown. Differences between oral and nonoral administration are related to the role of first-pass hepatic effect, hormone concentrations in the blood by the given administration option, and biologic activity of active ingredients. Some evidence exists regarding an association between 17 beta-estradiol and a lower risk of deep venous thrombosis compared with oral ET.

LONG-TERM THERAPY IN SYMPTOMATIC WOMEN

Although RCTs in symptomatic perimenopausal women have not been performed, results of the WHI suggest that physicians should use caution in prescribing long-term therapy for these patients.

Extended use of ET or EPT in women who are aware of the risks and benefits and are under physician supervision is acceptable under certain circumstances: (1) the patient feels that the benefit of relief from menopause outweighs the risk of extended use; (2) the patient has moderate or severe menopausal symptoms and is at high risk of osteoporotic fracture; or (3) the patient has reduced bone mass and wants to prevent future bone loss, and alternative therapies are inappropriate (e.g., cause adverse effects, have unknown outcomes).

SYMPTOM RECURRENCE

If ET or EPT is discontinued, symptoms have a 50 percent chance of returning. Decisions about whether or not to continue therapy should be based on symptom severity and the current risk/benefit ratio.

QUALITY OF LIFE

Because ET and EPT improve menopausal symptoms, there typically is an associated increase in health-related quality of life. However, there is disagreement about whether this is true in asymptomatic women as well. Validated instruments should be incorporated into future studies to help determine the effects of ET and EPT on quality of life.

CLASS VS. PRODUCT EFFECT

RCTs are the only way to determine the different outcomes of various therapies. It is not possible to extrapolate the results of one study to another. However, if data specific to a certain agent are lacking, results from one trial can be generalized to other agents within the same family if they are given in equivalent dosages.

BIOIDENTICAL HORMONES

Safety concerns about ET and EPT products have prompted an increase in the use of alternative dose forms (e.g., gels, suppositories) that are not commercially available. Because there are no safety or effectiveness data for these forms, a generalized risk/benefit ratio based on commercially available products can be used instead. However, it is recommended that these alternative dose forms be used cautiously in case of possible lack of quality or purity or batch-to-batch ingredient inconsistencies.

Discussion

NAMS found insufficient or inconsistent evidence regarding several major factors of ET and EPT. There was disagreement over the best way to discontinue therapy, such as whether it should be abruptly discontinued or gradually tapered off. There also was insufficient evidence to determine if continuous-combined EPT has a different effect than continuous ET with continuous-sequential EPT. Lastly, there was conflicting evidence regarding signs that some continuous progestogen doses could be linked to adverse breast cancer or cardiovascular outcomes.

NAMS recognizes that each woman's willingness to accept risks associated with ET or EPT varies, and that disease outcomes are dependent on age and time since start of menopause. It cannot be assumed that the risks and benefits of ET and EPT apply to all ages and therapy durations. It is important to understand that even if ET and EPT are not being used, there is still a risk of developing all diseases under consideration in this statement, an idea that is demonstrated in the rates of disease seen in the RCT placebo groups. NAMS concludes that there are still many areas needing further research (e.g., timing of starting therapy, comparison of different formulations, long-term risks and benefits) with regard to ET and EPT in perimenopausal and postmenopausal women.