First, in the early 1970s, hormone replacement therapy for women was celebrated as the fountain of youth. Then, just a few years later, it was shunned for causing endometrial cancer. In the 1990s, it was embraced by more than 40% of menopausal women, who believed it could prevent heart attacks, osteoporosis and cognitive decline in addition to relieving hot flashes. The pendulum swung again in 2002 when the Women’s Health Initiative (WHI), the largest ever randomized trial of hormone therapy, halted both arms of the trial as participants suffered higher rates of stroke, blood clots and other adverse events. Now, again, views on hormone therapy have shifted toward a much more nuanced approval.

“We waited a decade to find out that, for women ages 50 to 59, the results of taking hormone therapy aren’t as bad as the WHI originally reported,” says Isaac Schiff, chief of the Vincent OB/GYN Service at Massachusetts General Hospital and editor of the journal Menopause.

As Proto reported in Spring 2009 (“Yes. No. Maybe.”), the WHI, which studied 27,000 women ages 50 to 79, found that combination estrogen plus progestin therapy increased the risk of blood clots by 106%, stroke by 31%, breast cancer by 24%, and heart disease by 20%, and that estrogen alone also increased the risk of stroke and blood clots. Yet, swayed by dozens of observational studies that showed that estrogen reduced women’s heart disease by as much as 50%, kept bones stronger and contributed to longer lives, many researchers remained convinced that hormone therapy staved off heart disease and other disorders.

Now, after publication of 116 journal articles on various trial results, the WHI last October released its most comprehensive findings, which tell a complex story. WHI investigators say no woman should take hormones solely to prevent chronic diseases, such as cardiovascular disease, because of the serious risks associated with the medication. “Women of all ages on hormone therapy had an increased risk of stroke, blood clots in the legs and gallbladder disease,” says JoAnn Manson, chief of preventive medicine at Brigham and Women’s Hospital in Boston. Women on combination therapy had more breast cancers, dementia (in women 65 and older), coronary heart disease and pulmonary embolisms than women who had taken a placebo. However, younger women in early menopause had much lower rates of adverse events than older women.

Hormone therapy was very effective at reducing or improving symptoms of menopause as well as reducing hip and other fractures by a third. So healthy women ages 50 to 59 who are more likely to have hot flashes and night sweats than older women may benefit if their menopausal symptoms are moderate to severe, say WHI investigators. “In many cases, the benefits of hormone therapy will outweigh the risks for younger women,” says Manson. “Now the $64,000 question is whether it’s safe for women who begin hormone therapy early in menopause to stay on it for more than five years.”

There may be compelling reasons for some women to stay on the therapy; all participants in the WHI had lower rates of both fractures and diabetes. But once women stopped taking hormone therapy, those benefits—as well as most of the accompanying risks—lessened. The risk of breast cancer in women on estrogen and progestin did remain slightly elevated after they stopped hormone therapy. But women on estrogen alone, after ceasing to take the hormone, had a significantly lower risk of breast cancer than women who had taken a placebo, a finding that bears further study, says Manson.

Although new research results will continue to shift the thinking about hormone therapy, Manson predicts that there may soon be an algorithm that will assess a woman’s personal risk profile to give a clearer answer to the question: Yes or no to hormone therapy?