Applicability of results to younger women

Over 5,000 women in the WHI trial were between the ages of 50 and 59, and about 2,000 had moderate to severe vasomotor symptoms. In the group of women 50 to 59 years of age, the increase in mammogram abnormalities was the same as for the overall group. The WHI trial raises questions about the short-term use of menopausal hormone therapy, because it identifies an important side effect.

If a woman has moderate to mild estrogen-deficiency symptoms, she must now decide whether 80-90 percent suppression of those symptoms for a year or two is worth a 1-in-25 or 1-in-10 chance of having an abnormal mammogram. This is a new thought process for women considering menopausal hormone therapy.

For the woman with severe disabling symptoms, the chance of having an abnormal mammogram, which doesn't necessarily mean she's going to have breast cancer, is probably going to be a small consideration.

The actual chronic-disease risk associated with one, two or three years of therapy for a woman 49 or 50 years of age is going to be a very small number. The breast cancer risk for the overall population involved eight additional breast cancers per year for every 10,000 women receiving menopausal hormone therapy.

There were 19 avoidable life-threatening conditions (including coronary heart disease and stroke) per 10,000 women per year of estrogen plus progestin use. For women meeting the study criteria, one in a hundred would have an otherwise avoidable life-threatening event after five years of estrogen plus progestin use. The absolute risk would be lower for 50-year-old women, but that is a statement about the population, not the individual patient.

Influence of menopausal hormone therapy on dementia

There was a 180-degree turnaround associated with the ancillary study results on dementia (see below). The prestudy assumption was that we would see a substantial reduction in dementia. In actuality, the subset of women 65 years of age and older had over a doubling of dementia cases - from 21 to 40 cases -after five years of therapy.

We speculate that the arteriovascular effects, such as subclinical stroke, may have raised the threshold so that the natural course of dementia was evident sooner. The implication for women with breast cancer is that other agents that cause arteriovascular events, like chemotherapy or tamoxifen, may be associated with the same increase in dementia. This phenomenon has not been carefully studied with these other agents in the kind of detailed analysis that was done in the WHI trial.

Selection of the estrogen and progestin

The WHI trial evaluated the estrogen and progestin type, dose and schedule used by 85 percent of postmenopausal women with a uterus until two years ago. They weren't natural estrogens and progestins, even though there are some natural estrogens in conjugated equine estrogens.

The Europeans use more estradiol and micronized progestin or natural progestin. Whether those are going to be safer, we don't know. The FDA made all combined estrogen and progestin products include the same black-box warning that it required for conjugated equine estrogens and medroxyprogesterone acetate.

Estrogen-alone arm in women with a prior hysterectomy

A separate WHI trial in just over 10,000 women with a prior hysterectomy is evaluating an estrogen-alone arm. The data safety monitoring board looks at that data twice a year. There is a little over six years of follow-up, and by design, the trial results will be reported at 8.5 years or in about two years. As of May 30, 2002, there was no excess in breast cancer risk.

For several reasons, we can't be sure that it's just the progestin causing the difference. First, women who have had a hysterectomy are substantially different from women who have a uterus, in terms of their medical history characteristics. Second, this trial is smaller, and it may take longer to generate an equivalent number of events. There are also biologic reasons to believe that we might see something different in terms of breast cancer.

Dr Norman Boyd in Toronto has shown that breast density - especially inherited breast density - is associated with an increased risk of breast cancer. However, we don't know whether a short-term change in breast density is associated with breast cancer risk.

It's intriguing that estrogen plus progestin substantially increases breast density, whereas estrogen alone increases it much less. That suggests there may be a difference. Based on the more recent epidemiological data, one would think there would be less breast cancer risk associated with estrogen alone, but we don't know.

Indications for menopausal hormone therapy

Menopausal hormone therapy is almost exclusively indicated for the amelioration of hot flashes and vaginal symptoms. The FDA recommends the use of the lowest possible dose and duration, although we don't have information about the safety of those lower-dose schedules.

The FDA will hold hearings on the osteoporosis indication for estrogen plus progestin combinations, which certainly are effective in reducing the risk of hip fractures. However, since there are alternatives available to reduce the risk of hip fractures, I'm not sure an estrogen plus progestin combination is safe enough for this indication.

Trends in menopausal hormone therapy use

The use of menopausal hormone therapy was increasing and then leveled off after the Heart and Estrogen/Progestin Replacement Study (HERS) reported no coronary heart disease benefits in women with existing heart disease. At that time, there were about six million women in the United States on an estrogen plus progestin combination.

After the WHI report, the use of menopausal hormone therapy went down significantly. Less than three million women are currently using some kind of combined estrogen plus progestin therapy. Most of the three million women who stopped taking an estrogen plus progestin combination did so because they decided to stop, rather than because their gynecologist told them to stop.

Over 80 percent of estrogen plus progestin use is short term in perimenopausal women. A number of women, maybe one-fifth, are still taking it for long-term chronic use. We'll see how those numbers change after this most recent WHI trial report.

A decision-making approach to menopausal hormone therapy

This situation appears analogous to the situation we commonly face in a woman with an ER-negative tumor measuring less than one centimeter, who is deciding whether to take chemotherapy for a very small absolute benefit. I routinely try to project five years into the future.

Will it be intolerable if she doesn't take the chemotherapy and the tumor recurs? If she couldn't tolerate that and would say, "I missed my chance," then she should take the chemotherapy. Alternatively, if she projects herself five years from now and says, "I took the chemotherapy and the tumor didn't recur - that was a bad decision," then maybe she shouldn't take the chemotherapy. So, I give patients those two future scenarios.

In a woman with mild or moderate menopausal symptoms, I would say, "You may reduce the symptoms by 80 percent to 90 percent with hormones, but you will have to deal with a 1-in-25 or 1-in-10 chance of an abnormal mammogram. If you don't want to deal with an abnormal mammogram, then don't start menopausal hormone therapy and see what happens after a few months of just watching." If the patient says, "I can deal with an abnormal mammogram," which almost certainly is not going to be related to breast cancer, she should consider taking the menopausal hormone therapy for a year or two.

Managing menopausal symptoms in patients with breast cancer

I question some of the treatments we are using in breast cancer patients with menopausal symptoms. For example, low-dose progestins are effective in reducing symptoms. Medroxyprogesterone acetate, interestingly, was found to be effective in women with resected breast cancer; however, this is the same agent used in the WHI trial. I would be very concerned about using progestins, especially since many are pointing a finger at the progestin in this estrogen and progestin mix.

The estradiol vaginal ring (Estring®) is a locally released product that treats vaginal symptoms and atrophy. A study in the Journal of Clinical Endocrinology and Metabolism demonstrated that the estradiol vaginal ring use for one year increased HDL cholesterol and decreased LDL cholesterol, the same as full-dose estrogen and progestins.

If there is adequate absorption to change the lipid profile, it's difficult to be completely sanguine about breast safety. In terms of how to treat the patient with breast cancer and with menopausal symptoms, we've identified a problem that will require more attention.

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