July 2, 2008 — The North American Menopause Society (NAMS) has updated its guidelines on postmenopausal hormone therapy (HT) and issued a position statement published in the July/August issue of Menopause. Recent data suggest that the benefit-risk ratio for HT is favorable near menopause but decreases with aging and time since menopause in previously untreated women.

"Use of HT should be consistent with treatment goals, benefits, and risks for the individual woman," write Wulf H. Utian, MD, PhD, DSc(Med), and colleagues from the NAMS Advisory Panel. "The benefit-risk ratio for an individual woman continually changes with her age and her menopause-related symptoms (eg, vasomotor symptoms, sleep disturbance, vaginal atrophy, dyspareunia, or diminished libido), any of which may have an adverse impact on quality of life (QOL). Risk factors are related to a woman's baseline disease risks; her age; age at menopause; cause of menopause; time since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and emerging medical conditions during treatment."

The goal of the revised guidelines, aimed both at clinicians and at the lay public, was to update the NAMS evidence-based position statement published in March 2007 regarding management of menopausal HT for postmenopausal women. On the basis of new evidence, the revised statement highlights the therapeutic benefit-risk ratio of HT as either estrogen therapy (ET) or combined estrogen-progestogen therapy (EPT) at times before, during, and after menopause. Treatment goals of HT may include relief of menopause-related symptoms or disease prevention at various times through menopause and beyond.

The March 2007 NAMS position statement was reviewed by an expert advisory panel of clinicians and researchers. After evaluating newly available information through an evidence-based analysis, the panel reached consensus and issued recommendations. Although there have been many observational studies, the trials within the Women's Health Initiative are for some outcomes of the only large, relatively long-term randomized controlled trials thus far of postmenopausal women. Findings from the Women's Health Initiative were therefore given prominent consideration and weighted more heavily among all the studies reviewed in developing the position statement.

These guidelines were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement, and they were subsequently endorsed by the American Medical Women's Association, the Endocrine Society, the National Association of Nurse Practitioners in Women's Health, the National Women's Health Resource Center, and the Society for Obstetricians and Gynecologists of Canada.

In addition to reiterating major topics presented in the 2007 position statement, such as the benefits and risks for HT, practical therapeutic issues, and treatment issues, the revised 2008 guidelines contain many new and expanded topics.

New areas not covered in the 2007 statement include vaginal symptoms, sexual function, urinary health, change in body weight and mass, endometrial cancer, and total mortality rates. New topics clarifying the use of HT include explaining HT risk, individualizing therapy, timing of initiation, regimens, dosages, routes of administration, duration of use, and discontinuation of therapy. A new addendum discusses risk concepts.

Topics that have been expanded or modified since the 2007 statement include cardiovascular effects, breast cancer, mood and depression, cognitive aging and decline, dementia, and use of bioidentical hormones. An addendum suggests areas for future HT research, and a suggested reading list of key references is also provided.

The primary indication for HT is still treatment of moderate to severe vasomotor symptoms; every systemic ET and EPT product has received regulatory agency approval for this indication. ET, with or without the use of a progestogen, is the most effective treatment of these symptoms (hot flashes and night sweats).

ET is the most effective treatment of moderate to severe symptoms of vulvar and vaginal atrophy, with local vaginal ET preferred when vaginal symptoms are the sole indication for ET. Although local ET may also benefit some women with urge incontinence who have vaginal atrophy, it is still unclear whether ET by any route of administration is effective in treating overactive bladder.

To date, the published evidence suggests that potential absolute risks for use of HT are low. Findings from the Women's Health Initiative ET trial suggested considerable safety for 0.625 mg/day of oral conjugated estrogen (CE), and risks in the Women's Health Initiative EPT trial were rare by the criteria of the Council for International Organizations of Medical Sciences except for stroke, which was above the rare category.

For women who are younger than 50 years or who are at low risk for coronary heart disease, stroke, osteoporosis, breast cancer, or colon cancer, the absolute risk or benefit from ET or EPT is likely to be even smaller than that shown in the Women's Health Initiative. However, the relative risk may be similar at different ages. Because of the increasing body of evidence that each type of estrogen and progestogen, route of administration, and timing of therapy have distinct beneficial and adverse effects, further research remains essential.

"Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both," the panel concludes. "The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women."

Many of the advisory panel members have disclosed financial relationships with various pharmaceutical companies manufacturing HT. A complete list of disclosures is available in the original article.

Menopause. 2008;15:584-602.

Clinical Context

Study Highlights

• ET with or without progestogen is the most effective treatment of vasomotor symptoms, and the primary indication for HT remains the need for moderate to severe symptom management.
• ET is the most effective treatment of moderate to severe vulvar and vaginal atrophy and its consequences including dyspareunia, and local ET is recommended when this is the sole indication for treatment.
• Local ET is not recommended as sole treatment of sexual dysfunction including diminished libido.
• Local ET may be helpful for urge incontinence, but use for stress incontinence and overactive bladder is controversial, and systemic HT may worsen or provoke stress incontinence.
• HT is not indicated to prevent weight gain.
• Extended use of HT is recommended to prevent bone loss and fractures when other therapies are inappropriate.
• HT may reduce cardiovascular risk when started in younger and recently menopausal women (ages 50 - 59 years) but may increase cardiovascular risk when started 10 years or more after menopause onset.
• For women initiating HT at a younger age, longer duration of use may be associated with greater benefits.
• Younger women initiating HT at younger than 60 years with HT for 7 years or more show reduced coronary artery calcium burden.
• HT is not effective to reduce the risk for recurrent stroke among women with established cardiovascular disease or for prevention of first stroke and is not recommended for primary or secondary stroke prevention.
• Women with a history of venous thromboembolism or possess factor V Leiden are at increased risk for venous thromboembolism from HT, and the risk for venous thromboembolism is highest in the first 2 years of HT initiation.
• There is inadequate evidence to recommend HT as the sole or primary indication for the prevention of diabetes mellitus.
• Use of unopposed ET at a standard dose of 0.625 mg for CE for 3 years is associated with a 5-fold increased risk for endometrial cancer, with risk up to 10 times for 10 years of use.
• Evidence suggests that ET use for less than 5 years has a limited effect on breast cancer risk, but subgroups may be affected differently.
• Use of HT in women with a history of breast cancer is unresolved; there are no completed long-term randomized clinical trials.
• Although HT may have a positive effect on mood and behavior, it is not an antidepressant and should not be used as such.
• HT cannot be recommended at any age for the sole or primary indication of preventing cognitive decline or dementia.
• HT appears to increase the incidence of dementia when initiated in women 65 years and older.
• ET and EPT may reduce mortality rate by 30% when initiated in women younger than 60 years, but the same benefit is not observed in women who initiate HT at 60 years or older.
• The lowest effective dose of estrogen or progestogen should be used as a therapeutic standard.
• However, lower daily doses (CE 0.3 mg, oral micronized 17B-estradiol 0.5 mg, and transdermal 17-B patch 0.014 - 0.025 mg) have not been tested in long-term trials.
• Nonoral routes may be advantageous in reducing risk for VTE, and local ET is preferred when treating local effects such as vaginal symptoms.
• Systemic progestogen is required for endometrial protection, and topical progestogen is not recommended.
• There are no data to guide multiple dosing regimens.
• Premature menopause and ovarian failure are associated with lower breast cancer risk and earlier onset of cardiovascular disease and osteoporosis, and HT is recommended until the typical age of menopause.

Pearls for Practice

• HT in the lowest effective dose with endometrial protection is recommended in menopausal and postmenopausal women for vasomotor symptoms and vaginal atrophy, bone loss prevention, and cardiovascular protection in younger women aged 50 to 59 years.
• HT in menopausal and postmenopausal women is not recommended for stroke prevention, cardiovascular prevention in women older than 60 years, treatment of depression, prevention of cognitive decline or dementia, or prevention of weight gain.

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