A recent study calls into question the need for a "black-box" warning on this formulation.
A new prospective analysis from the Nurses’ Health Study (NHS) indicates that, despite its “black box” warning, low-dose vaginal estrogen does not pose an increased risk of cardiovascular disease (CVD) or cancer.
“There have been very few large-scale prospective studies of vaginal estrogen and risk of CVD and cancer,” said JoAnn Manson, MD, DrPH, a professor of medicine at Harvard Medical School and one of the lead investigators of the NHS. “Most of the studies have evaluated systemic hormone therapy.”
The earlier results of the Women’s Health Initiative (WHI) randomized trials, which tested systemic hormone therapy, have been extrapolated to low-dose vaginal therapy, resulting in a black box warning on these products for an increased risk of heart attacks, strokes, venous thromboembolism (VTE), breast cancer, endometrial cancer and dementia.
“These are all outcomes that have never previously been linked to low-dose vaginal estrogen, which has minimal if any systemic absorption,” Dr. Manson told Contemporary OB/GYN. “It is systemic hormone therapy, primarily with an oral route of delivery, that has been linked to thrombotic events.”
The large-scale, prospective cohort of 53,000 nurses, with a mean age of 54 years, was followed for up to 18 years, starting in 1982. The nurses self-reported their use of hormone therapy products, including vaginal estrogen. Endpoints were confirmed with medical records.
Women who were users of systemic hormone therapy (either oral or transdermal) were excluded from the study to avoid contamination of the results.
“We found no significant excess risk of heart disease, stroke, VTE, breast cancer, endometrial cancer, other cancers, or all-cause mortality with vaginal estrogen use,” said Dr. Manson about the study that appears in the journal Menopause. “This is in contrast to systemic hormone therapy, which has been linked to an increased risk of stroke, VTE, and breast cancer, even in the observational NHS.”
Users of vaginal estrogen had a lower risk of total myocardial infarction (MI) (HR 0.56, 95% CI 0.36 – 0.87) than nonusers and a marginally but nonsignificant lower risk of total stroke (HR 0.71, 95% CI 0.47– 1.09).
Invasive breast cancer among vaginal estrogen users also remained unchanged (HR 1.07, 95% CI 0.77 – 1.47), when excluding past systemic hormone therapy users at entry and follow-up.
For endometrial cancer (with follow-up starting in 1992 instead of 1982), results remained null and nonsignificant (HR = 1.52, 95% CI 0.78 – 2.98). In additional analysis, in which women with past systemic estrogen use were excluded and data adjusted for past systemic estrogen plus progestin or progestin alone use, the HR for endometrial cancer among vaginal estrogen users was attenuated and remained nonsignificant (HR = 1.24, 95% CI 0.64 – 2.41).
Dr. Manson said it would be expected that low-dose vaginal estrogen would not increase risk of heart attack, stroke, VTE or cancer, given the extremely low systemic exposure.
“What is surprising is that there is a black box warning on low-dose vaginal estrogen that claims that these products, based on class labeling with all other hormone therapy products, increase the risk of heart attack, stroke, blood clots and cancer,” Dr. Manson said. “This has discouraged clinicians from prescribing low-dose vaginal estrogen products, which are very effective for genitourinary syndrome of menopause (GSM). In addition, the boxed warning has scared women from taking these medications, even after purchase.”
The black box warning does not square with the evidence, according to Dr. Manson. “Ours is the second large-scale, prospective observational study of vaginal estrogen and cardiovascular disease and cancer that shows no excess risk,” she said. “Similar results were found previously in the observational component of the WHI, as well as in other smaller studies.”
The current study provides further reassurance that low-dose vaginal estrogen is safe with respect to cardiovascular events and cancer. “Thus, clinicians should not be discouraged from prescribing these products for patients with GSM,” Dr. Manson said.
However, Dr. Manson said the US Food and Drug Administration has made no commitment to remove the boxed warning, despite the lack of evidence for it – and growing evidence that refutes it.
“The FDA should revisit its decision about the product labeling and undertake a comprehensive assessment of the evidence, given the importance of this issue for women’s health and well-being,” she said.