Health Tips

The following is a synopsis of the North American Menopause Society’s (NAMS) October 3, 2002 report on two recent studies of estrogen-progestin therapy for postmenopausal women. Even though the studies evaluated only one hormone combination, NAMS concluded that they are the first well-controlled, adequately powered reports.

The Estrogen/Progestin Replacement Study (HERS) was a 4-year randomized, blinded, placebo-controlled study of 2,763 postmenopausal women (average age 67) with documented coronary heart disease (CHD), while the Women’s Health Initiate (WHI), begun in 1993, looked at 16,608 healthy postmenopausal women aged 50 to 79.

The WHI study was divided into two sections, a continuous-combined estrogen-progestogen therapy (CCEPT) section for women with a uterus, and an estrogen-only therapy (ET) section for women who had undergone a hysterectomy. The CCEPT section of WHI was terminated in July 2002 after 5 years of follow-up, because the overall risks exceeded the benefits. The ET arm of WHI continues, as do ancillary WHI studies evaluating memory, dementia, low-fat diet, calcium, and vitamin D.

For both studies, CCEPT therapy consisted of oral estrogen plus oral progestogen, 0.625 mg/day of conjugated equine estrogens (Premarin) plus 2.5 mg/day of medroxyprogesterone acetate (Provera or Prempro).

The NAMS report listed each study’s statistical conclusions regarding estrogen-progestin therapy and common health risks, as follows.

Coronary Heart Disease

WHI—Increased risk (7 more CHD events for every 10,000 women)
HERS—Decreased risk (2 less CHD events for every 10,000 women)

Stroke

WHI—Increased risk (8 more strokes for every 10,000 women)
HERS—Increased risk (17 more strokes for every 10,000 women)

Venous Thromboembolism (blood clots)

WHI—Increased risk (18 more venous thromboembolism events for every 10,000 women)
HERS—Increased risk (31 more venous thromboembolism events for every 10,000 women)

Breast Cancer

WHI—Increased risk (8 more breast cancer events for every 10,000 women)
HERS—Increased risk (12 more breast cancer events for every 10,000 women)

Incidence of Biliary Tract Surgery

HERS—Increased incidence (62 more biliary tract surgeries for every 10,000 women)

Colon Cancer

WHI—Decreased risk (6 less colon cancer events for every 10,000 women)
HERS—Decreased risk (6 less colon cancer events for every 10,000 women)

Osteoporotic Fracture (Hip)

WHI—Decreased risk (5 less hip fractures for every 10,000 women)
HERS—Increased risk (18 more hip fractures for every 10,000 women)

Osteoporotic Fracture (Vertebral)

WHI—Decreased risk (6 less vertebral fractures for every 10,000 women)
HERS—Decreased risk (4 less vertebral fractures for every 10,000 women)

Osteoporotic Fracture (Total)

WHI—Decreased risk (44 less fractures for every 10,000 women)
HERS—Increased risk (13 more hip fractures for every 10,000 women)

These increased risks and benefits of CCEPT persisted throughout the duration of the WHI and HERS trials. Breast cancer risk was directly related to duration of therapy. Significant risk for coronary heart disease (CHD) and venous thromboembolism was observed during the first year of therapy, although CHD risk was not significantly elevated in following years.

Based on data other than WHI and HERS, the risk for breast cancer may be higher on CCEPT than on unopposed estrogen-only therapy. However, after 5 years, WHI has not reported that the ET section has shown excess risk over benefit. The risk for breast cancer while using CCEPT appears to be related to duration of use.

The NAMS panel agreed on the following:

* Treatment of menopause symptoms that do not respond to non-pharmaceutical treatment (vasomotor and urogenital) remains the primary indication for estrogen-progestin therapy (EPT) and ET.

* The only menopause-related indication for chronic progestogen use appears to be protection of the endometrium (uterine lining) from cancer, which is a risk when estrogen is used alone.

* The effect of ET on CHD is not yet clear. Until confirming data is available, ET should not be used for primary or secondary prevention of CHD.

* WHI and HERS data cannot be directly extrapolated to symptomatic perimenopausal women or to women experiencing early menopause (40-50 years of age) or premature menopause (< 40 years of age).

* Use of EPT or ET should be limited to the shortest duration consistent with treatment goals, benefits, and risks for the individual woman, taking into account issues of quality of life.

* Lower-than-standard doses of EPT and ET should be considered. The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial demonstrated equivalent symptom relief with lower doses of EPT.

* Alternative routes of EPT administration, such as transdermal (the patch), may offer advantages.

* An individual risk profile is essential for every woman contemplating any regimen of EPT or ET. Women should be informed of known risks, and made aware that some risks are unknown.

The majority of the panelists believed that extended use of EPT or ET would be acceptable under special circumstances, including:

* Any woman for whom, in her opinion, benefits of symptom relief outweigh risks.

* Women with menopause symptoms who are at high risk for osteoporosis.

* Women with increased osteoporosis risk unable to tolerate other therapeutic options.

Future research needs include investigating biologic differences between symptomatic and asymptomatic women, effects of different doses and administration routes on benefit-risk profiles, and more studies with early, premature, and highly symptomatic perimenopausal women.