Updated Statement on Hormone Therapy  CME/CE 
News Author: Lisa Nainggolan
CME Author: Désirée Lie, MD, MSEd 
Disclosures
Release Date: February 1, 2007; Valid for credit through February 1, 2008 Credits Available  
 
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians;
Nurses - 0.25 nursing contact hours (0.25 contact hours are in the area of pharmacology)  
 


from Heartwire — a professional news service of WebMD
February 1, 2007 — A scientific advisory panel to the North American Menopause Society has issued a position statement on the use of hormone therapy (HT), which softens its previous stance on the issue. The statement was published in the February 25 Ahead of Print issue of Menopause.
"For women with severe menopausal symptoms, within a few years of their last period, hormone therapy shouldn't be as scary as it has been made out to be," director of the North American Menopause Society and panel chair Wulf Utian, MD, PhD, of Case Western Reserve University in Cleveland, Ohio, told heartwire.
For older women, the decision is more difficult, he says. Although there are fewer women of this age who will require HT, some have menopausal symptoms for many years or have experienced symptoms after stopping HT in the past few years, and this group wants to know whether they can restart therapy. But older women are at higher absolute risk for cancer and heart disease, so "it has to be a personal decision, our panel is stating that very clearly. An older woman must consider all the risks and benefits."
Initially, woman should start on the lowest dose of therapy possible and increase the dose only if relief of symptoms is not obtained, Dr. Utian says. The panel decided not to make recommendations on the duration of HT; rather, it should be used "for a time consistent with the patient's needs and goals and based on her risk profile," he says.
No Indication for CVD Prevention, Fear of MI "Overestimated"
Dr. Utian explained that the North American Menopause Society was the first professional body to respond with a formalized statement after the termination of the estrogen/progesterone group of the Women's Health Initiative study in 2002, and that it also issued updated guidelines in 2003 and 2004. "But a lot of stuff has happened in the past two years," he notes.
Based on the scientific evidence to date, Dr. Utian says, "There is no indication for HRT [hormone replacement therapy] for the sole purpose of preventing cardiovascular disease [CVD], either for primary or for secondary prevention."
However, the evidence for an increase in early myocardial infarction (MI) "is weak for women close to menopause, and the fear of a heart attack has been overestimated," he notes.
The same applies to breast cancer and venous thromboembolism, the risks for which are "rare" as defined by the World Health Organization (WHO) standards (= 10 cases per 10,000 per year), Dr. Utian notes. The risk for stroke, however, does seem to be "slightly higher, especially for older women," he added.
And, he notes that there are benefits of HT. "It is the only drug to have shown a reduction in fractures in women who have not yet developed osteoporosis," Dr. Utian says, stating that the data on this came from the Women's Health Initiative. Also, in that trial, the estrogen/progesterone HT product showed a significant reduction in colon cancer, although the estrogen-only group showed a null effect.
Is Progesterone the Culprit? "We Don't Know"
"Now doctors can give their patients numbers to indicate risks and benefits, they can advise them to start on the lowest dose of HRT available, and tell them to try to reduce their exposure to progesterone."
He explained that the question of whether progesterone in combined products — used to protect against endometrial cancer in women who still have a uterus — is responsible for the adverse breast cancer and cardiovascular outcomes in the Women's Health Initiative study and the Heart and Estrogen/Progestin Replacement Study (HERS) remains contentious.
"We think this is the case, but the data are not strong enough," he said. Hence, the panel failed to reach a consensus on this issue, and it is 1 of more than 30 recommended areas of future research.
HT Will Never Be Used for CHD Prevention
Dr. Utian says his own personal feeling is that HT will never be used for coronary heart disease (CHD) prevention, even if ongoing studies are positive. These include the Kronos Early Estrogen Protection Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE).
The KEEPS trial will include only women in early menopause who are treated with lower-dose conjugate equine estrogen. ELITE will contrast the effects of oral estradiol with intravaginal progesterone given to women less than 6 years past menopause vs women 10 years or more postmenopausal.
For both KEEPS and ELITE, the primary endpoint will be change in carotid artery intima-media thickness. Another trial, in Finland — SYMPTOM — will compare vascular and cardiac function in recently menopausal women with or without severe vasomotor symptoms and will also look at vascular response to oral and transdermal HT.
"But even if these come out with positive makers, we would have to do endpoint studies, but this can't be done in this population of younger women (those within 10 years of menopause) because the prevalence of CHD is so low you would need thousands and thousands of subjects. That is why WHI [the Women's Health Initiative] ran into problems," Dr. Utian says. However, one advantage of positive outcomes from studies such as these would be "some relief of apprehension," he notes.
Diabetes Effect Intriguing
One issue raised in the position statement is the suggestion from the Women's Health Initiative that HT might reduce the risk for new-onset diabetes mellitus. Women in the estrogen/progesterone group had a 21% risk reduction in incident-treated diabetes mellitus, or 15 fewer cases per 10,000 women per year of therapy, and in the estrogen-only group, there was a 12% reduction, or 14 fewer cases per 10,000 women per year.
The mechanism for this benefit is thought to be via lesser centripetal weight gain and/or reduced insulin resistance in women receiving HT, but the panel concluded that there is "insufficient evidence to recommend combined HRT for a sole indication of the prevention of diabetes mellitus in perimenopausal women." However, they note, "This is a promising area for future research."
The panel also cited several other recommendations for future research, including:
Timing of initiation of HT relative to menopause with regard to cardiovascular, cognitive, and other health outcomes.


Cause of the increase in stroke with HT and of increased CHD and breast cancer with combined products to better understand the pathophysiology of these events.


Effects of HT on risk for Alzheimer's disease and other forms of dementia and on neuropsychiatric disorders.


Determination of how women at risk for deep vein thrombosis and venous thromboembolism (VTE) can best be identified.
Who Takes HT for Menopausal Symptoms and for How Long?
Dr. Utian explained to heartwire that of women entering menopause, one third will have no symptoms, one third will experience mild to moderate symptoms that can be treated without HT, and the remaining third will have very severe symptoms — such as hot flashes and disturbed sleep — requiring therapy.
When women taking HT decide to stop, 50% of them will have a recurrence of symptoms, half of whom will not need therapy, but the remainder will need to begin HT again. This is acceptable "provided the woman has no major risk factors," says Dr. Utian. But some women continue to have symptoms for years, in some cases into their 80s, he notes.
Menopause. Published online in the February 25, 2007, Ahead of Print issue.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
The North American Menopause Society published position statements on perimenopausal and postmenopausal HT in 2002, 2003, and 2004. The current statement is an update of the 2004 position statement approved by the Board of Trustees, with the goal of evaluating the risk-benefit ratio of estrogen therapy and estrogen-progestogen therapy (EPT), beginning with a MEDLINE search of research literature not covered by the 2004 position statement. Advisory panelists were given the articles to review and consensus, defined by two-thirds agreement, was derived by independent review by each panelist. The clinical recommendations represent items for which consensus was achieved and for which opinions differed and further research was recommended.
This 2007 position statement focused on the use of prescription estrogen and EPT products available in the United States and Canada, and excluded selective estrogen-receptor modulators or hormones available without prescription (such as phytoestrogens). The panel stressed the importance of individual risk profiles of women considering HT and acknowledged the small magnitude of risks described by the Women's Health Initiative studies using 0.625-mg equivalents of continuous estrogen therapy daily.
Early was defined as soon after menopause, early menopause as premature menopause, and timing of initiation as timing of HT initiation relative to the last menstrual period. The panel noted a scarcity of randomized prospective data addressing consequences of long-term HT when it was used for symptomatic management.
Study Highlights
Agreement was reached on the following issues: 
All women should receive a comprehensive assessment before HT, including mammography and bone densitometry, according to clinical guidelines. 
The primary indication remains the treatment of vasomotor symptoms, and systemic estrogen and EPT are approved for this indication. 
When estrogen therapy is considered solely for vaginal dryness, topical (not systemic) therapy should be considered first-line therapy. 
Women without a uterus should not be prescribed a progestogen with estrogen, and progestogen is not generally indicated for low-dose estrogen therapy administered locally for vaginal atrophy. 
There is insufficient evidence regarding the off-label use of long-cycle progestogen (eg, every 3 - 6 months for 12 - 14 days) and vaginal or intrauterine administration as an alternative to EPT. 
Estrogen/EPT use for primary prevention in relation to timing of menopause needs further evaluation, and disparities about CHD prevention exist in relation to the proximity of menopause. 
Data do not currently support EPT use for secondary CHD prevention. 
The data show a reduction in CHD in women 50 to 59 years old who initiate EPT within 10 years of menopause, and an increased risk in women who initiate after 10 years. 
The attributable risk for CHD remains very low in younger postmenopausal women. 
The risk for VTE is highest within 1 to 2 years after initiation of systemic HT, and VTE risk is estimated at 11 additional cases for EPT and 2 additional cases per 10,000 per year for estrogen therapy in women 50 to 59 years old. 
Both estrogen and EPT increase stroke risk, with 8 additional strokes for EPT and 12 additional cases per 10,000 per year for estrogen therapy. 
Large randomized trials suggest a reduction of diabetes risk with HT, with a 21% to 35% relative risk reduction (RRR) for EPT (15 fewer cases per 10,000 per year) and a 12% RRR (14 fewer cases per 10,000 per year) for estrogen therapy. 
Breast cancer risk is slightly increased with EPT use beyond 5 years for 4 to 6 additional invasive cases per 10,000 per year. 
Estrogen and EPT reduce risk for osteoporotic fractures and should be considered an option for women at high risk for fractures within 5 to 10 years. 
Evidence is insufficient to support the use of estrogen/EPT for depression. 
Initiating EPT after age 65 years is not recommended for the primary prevention of dementia or cognitive decline because risk can be increased during the ensuing 5 years. 
Lower than standard doses of estrogen/EPT should be considered, such as 0.3 mg of oral conjugated estrogens or 0.25 to 0.5 µg of poral micronized ß-estradiol, but these have not been tested in long-term trials. 
The long-term risk-benefit ratio for nonoral administration has not been tested. 
Extended use of the lowest effective dose is acceptable, provided the benefits of relief outweigh the risks in those at high risk for osteoporotic fractures and for further prevention of bone loss when alternative therapies are not available. 
"Bioidentical" hormones should be used with caution in absence of regulatory oversight and batch-to-batch variation in quality and purity. 
The panel could not reach consensus on the following: 
Whether cessation of HT should be abrupt or tapered. 
Whether there is a difference in breast cancer risk for continuous vs sequential progestogens. 
Pearls for Practice
The North American Menopause Society advisory panel recommends comprehensive assessment of the risks and benefits in women considering HT; depression and dementia are not indications for use. 
Consensus was not reached on the mode of discontinuation of HT or breast cancer risk for different progestogen regimens.