CardioExchange Archive

More than a decade ago, the NHLBI’s Women’s Health Initiative trials overturned the conventional wisdom that hormone therapy (HT) for menopausal women helped protect women from a broad spectrum of chronic diseases, including cardiovascular disease. The findings caused dramatic reductions in the use of HT but important questions remained, many involving the age or time since menopause of women taking HT.  Now a report published in JAMA provides for the first time a comprehensive overview of the risks and benefits of HT.

“Overall,” the authors state, “the WHI findings suggest that hormone therapy has a harmful effect on CHD risk among older women, whereas the results in younger women remain inconclusive.”

In the WHI, more than 16,000 women with an intact uterus were randomized to the combination of estrogen and progestin or placebo (median length of treatment, 5.6 years). More than 10,000 women with a prior hysterectomy were randomized to estrogen alone or placebo (median length of treatment, 7.2 years). The new report contains data on an additional 6 to 8 years of follow-up.

Women randomized to estrogen and progestin had significantly elevated risks for coronary heart disease, breast cancer, stroke, pulmonary embolism, dementia (in women aged 65 years and older), gallbladder disease, and urinary incontinence. On the other hand, they were at reduced risk for hip fractures, diabetes, and vasomotor symptoms. After discontinuation of therapy, most of the effects, both positive and negative, were no longer apparent, though a small increase in breast cancer risk remained.

For women who received estrogen alone, the findings were less certain. Estrogen therapy in this group was associated with an increased risk for stroke and venous thrombosis, and a lowered risk for hip and total fractures. After discontinuation of therapy, most of the effects were no longer evident. The investigators were surprised by — and at a loss to explain — a small, nonsignificant drop in breast cancer; following discontinuation of estrogen therapy, this decrease achieved statistical significance. Women under the age of 60 in this group also had small but significant reductions in all-cause mortality and myocardial infarction.

The authors wrote:

“Even though hormone therapy may be a reasonable option for management of moderate to severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy, in conjunction with the multiple testing limitations attending subgroup analyses, preclude a recommendation in support of CEE use for disease prevention even among younger women. Current findings also suggest caution when considering hormone therapy treatment in older age groups, even in the presence of persistent vasomotor symptoms, given the high risk of coronary heart disease and other outcomes associated with hormone therapy use in this setting.”

In a press release, the NHLBI’s Jacques Rossouw warned about the long-term use of estrogen in younger women:

“While the risk versus benefits profile for estrogen alone is positive for younger women, it’s important to note that these data only pertain to the short-term use of hormone therapy. There are no reliable data on the risks or benefits of long-term hormone therapy use for the prevention of chronic diseases.”

In the same NHLBI press release, the principal investigator for the WHI, JoAnn Manson, said:

“The combination of the six to seven years of intervention combined with the extended post-intervention follow-up make these hormone therapy medications among the best studied medications in medical history. There are very few other treatments with this much information about the balance of benefits and risks over such a long period of time that include such a long post-intervention phase. The ultimate goal of this paper and the analysis is to help women and their health care providers make informed decisions.”