Hormone therapy’s unanswered questions

Earlier this year, the Women’s Health Initiative (WHI) trial of estrogen-only hormone therapy (Premarin) was halted due to an increase in stroke risk. It was the second time WHI participants were told to stop taking their pills. In 2002, the combined hormone trial ended early after Prempro (Premarin plus a progestin) prompted an unacceptable risk for breast cancer, heart attack, and stroke. Once considered a panacea for many postmenopausal ills, hormone therapy is now generally prescribed only for treating hot flashes and vaginal dryness — and only at the lowest dose, for the shortest period of time.

But several questions have arisen in the wake of the WHI’s landmark effort to ascertain hormone therapy’s long-term risks and benefits, and its role in disease prevention. For example, the WHI tested hormone therapy mostly in women who began taking it long after the start of menopause. If the women had started taking hormones earlier, would the results have been different?

Why there are believers

Before the WHI, scientists consistently observed that hormone therapy lowered heart disease risk by 35%–50% in populations of postmenopausal women. Clinical studies found good effects on cholesterol levels and improved blood vessel function — so-called surrogate evidence of heart benefits. Also, laboratory animals undergoing experimentally induced menopause that were treated with estrogen had less atherosclerosis than those that got no estrogen. That’s why, until 2002, many physicians encouraged women 50 and older to take hormone therapy to prevent heart disease.

Interestingly, in most of the animal experiments, the estrogen used was estradiol, not Premarin (a brew that contains many forms of estrogens and other compounds). This also raises the question, what if women in the WHI had taken estradiol, or another estrogen, rather than Premarin-based hormone therapy?

Long-term estrogen: Down, but not out?

After the hazards of long-term combined hormone therapy became known, attention focused on the estrogen-only trial, which included more than 10,000 postmenopausal women, average age 63, who had all had hysterectomies. The trial ended because of a nearly 40% increased stroke risk in estrogen takers, compared to those getting a placebo. Estrogen had no effect on coronary heart disease risk, slightly decreased breast cancer risk, and significantly lowered the chances of hip fracture.

Some experts contend that the increased stroke risk reflects possible underlying disease in the WHI subjects, who, on average, started hormone therapy later than most women do. Also, it may be harmful to boost estrogen in women whose bodies have grown accustomed to making do with less of it. In both WHI trials, the women who began hormone therapy closer to menopause had fewer cardiovascular events than those who started it later.

More questions, more research

Premarin and Prempro at specific doses were the only hormone drugs studied in the WHI. Might other preparations and doses have different effects? Is patch estrogen better than oral estrogen? Would starting sooner, during perimenopause, offer greater benefits and fewer risks? Although women 60 and older shouldn’t start hormone therapy for disease prevention, we have no idea if that’s good advice for women approaching menopause.

Researchers are gearing up to answer these questions with studies that address the issues raised by the WHI (see box below).