Vaginal Estrogen Not Tied to Added Heart, Cancer Risks

Use of vaginal estrogen wasn't tied to increased cardiovascular or cancer risks, according to a new study.

Looking at postmenopausal women who participated in the Nurses' Health Study, vaginal estrogen use in women with or without an intact uterus was not associated with any increased risks of several cancers or cardiovascular outcomes over an 18-year follow-up period, reported JoAnn E. Manson, MD, DrPH, of Brigham and Women's Hospital in Boston, and colleagues.

The study, published in Menopause, found that the risk for several health outcomes was not statistically higher compared with the risk in women who did not use vaginal estrogen in a fully adjusted model:

  • Myocardial infarction: HR 0.73 (95% CI 0.47-1.13)

  • Stroke: HR 0.85 (95% CI 0.56-1.29)

  • Pulmonary embolism/Deep vein thrombosis: HR 1.06 (95% CI 0.58-1.93)

  • Hip fracture: HR 0.91 (95% CI 0.60-1.38)

  • All cancers: HR 1.05 (95% CI 0.89-1.25)

Included in the assessment of all cancers was the risk for invasive breast cancer, ovarian cancer, endometrial cancer, and colorectal cancer, although the risk for endometrial cancer included only women with an intact uterus:

  • Invasive breast cancer: HR 1.07 (95% CI 0.78-1.47)

  • Ovarian cancer: HR 1.17 (95% CI 0.52-2.65)

  • Endometrial cancer: HR 1.62 (95% CI 0.88-2.97)

  • Colorectal cancer: HR 0.77 (95% CI 0.45-1.34)

"Over-the-counter vaginal lubricants and moisturizers are often used as first-line treatments for women with symptoms of [genitourinary syndrome of menopause, GSM]," said JoAnn Pinkerton, MD, executive director of the North American Menopause Society (NAMS), in a statement. "Persistent symptoms often need therapies such as local vaginal estrogen, intravaginal dehydroepiandrosterone, or oral ospemifene."

"This study adds to a growing body of data showing the long-term efficacy and safety of low-dose vaginal estrogen, which works primarily locally with minimal systemic absorption," she added.

Currently, all estrogens -- including vaginal estrogen -- carry a black-box warning issued by the FDA for a potentially increased risk for heart attacks, strokes, blood clots, GSM, and breast cancer. "Despite lack of any observational or clinical trial evidence for chronic disease risks related to vaginal estrogen use, the FDA has issued a boxed warning on the package label for low-dose vaginal estrogen," noted the study authors.

Despite this warning, low-dose vaginal estrogen is recommended for treatment of GSM by several organizations, including NAMS, the American College of Obstetricians and Gynecologists, and the Endocrine Society. Furthermore, the American Association of Clinical Endocrinologists' 2017 update to their menopause clinical practice guidelines recommended the use of transdermal estrogen compared with oral forms, stating that these preparations "may be considered less likely to produce thrombotic risk and perhaps the risk of stroke and coronary artery disease."

The prospective analysis included nearly 900 postmenopausal women currently using vaginal estrogen who were compared with approximately 53,000 non-users. Current users of systemic hormone therapy were excluded from the analysis. During the follow-up period, in which the participants completed a questionnaire every 2 years during 1982 and 2012, the average length of vaginal estrogen use was around 36 months. Neither information on the type of vaginal estrogen -- whether it be a tablet, cream, ring, or suppository -- nor the dosage of estrogen were collected, a limitation to the findings, the researchers said.

Other limitations included the observational design of the study and, in addition, at the early years of follow-up, some women potentially used higher doses of vaginal estrogen rather than low-doses that are commonly prescribed now, the team noted.

Bhupathiraju is supported by a Career Development Grant from the National Institutes of Health.

The Nurses' Health Study is supported by grants from the National Institutes of Health.

Manson and co-authors reported having no conflicts of interest.

HRT Reduced Body Fat in Menopausal Women


  • by Jeff Minerd Jeff Minerd, Contributing Writer, MedPage Today March 27, 2018
  • This article is a collaboration between MedPage Today® and:

Action Points

  • Current menopausal hormone therapy (MHT) is associated with reduced total and visceral adiposity, but the effect is small and disappears when therapy is discontinued, according to a cross-sectional study of about 1,500 postmenopausal women 50 to 80 years of age.
  • Recognize that the benefit of MHT on body composition might rapidly disappear after its withdrawal, and it is important therefore to strongly encourage women to optimize nutrition and increase physical activity when stopping MHT.

Menopausal women undergoing hormone replacement therapy tended to have less body fat, especially visceral fat, although the effect disappeared once therapy was discontinued, researchers reported from a cross-sectional study.

The mean percentage of body fat in women undergoing therapy was 34.6%, compared with 36.2% for women who had therapy in the past and 35.9% for women who never had hormone therapy (P=0.01 for trend), said Georgios Papadakis, MD, of the Lausanne University Hospital in Switzerland, and colleagues.

Mean visceral fat mass, measured as the fat deep in the abdomen around the internal organs, not subcutaneous abdominal fat, was 0.42 kg for women undergoing therapy, compared with 0.48 kg both for women with past therapy and those who never received it (P=0.01 for trend), the team reported online in the Journal of Clinical Endocrinology & Metabolism.

Similarly, the mean body-mass index (BMI) was 24.9 for current users of menopausal hormone therapy, versus 25.6 for past users and 25.8 for never users (P=0.03). All study results were adjusted for potential confounders including age, diet, physical activity, and a diagnosis of depression, Papadakis and colleagues said.

However, the benefits of therapy did not persist once it stopped. Mean visceral fat mass in women who had been off therapy for less than 2 years was 0.53 kg, and this was not significantly different in women who had been off therapy for 2-5 years (0.51 kg) or more than 5 years (0.50 kg; P=0.813). Differences in mean BMI were similarly non-significant among the three groups (P=0.985).

"In conclusion, current MHT [menopausal hormone therapy] use prevents the increase of visceral adiposity," Papadakis and colleagues said. "This finding may have important cardiovascular, metabolic, and bone implications which should be taken into account when assessing the benefit-risk ratio for MHT prescription. Nevertheless, the effect size on BMI and total fat mass is relatively small and MHT prescription cannot substitute for other interventions such as physical activity."

"Physicians should be aware that the benefit of MHT on body composition might rapidly disappear after its withdrawal and strongly encourage women to optimize nutrition and increase physical activity when stopping MHT," the study authors said.

JoAnne Pinkerton, MD, executive director of the North American Menopause Society, agreed with the authors' recommendation. "Discussions about stopping hormone therapy should include a discussion of increased gain of abdominal fat, the associated health risks, and recommendations to decrease caloric intake and increase regular physical activity to combat the weight gain seen with stopping hormone therapy," Pinkerton said in an email to MedPage Today.

The best candidates for hormone therapy are symptomatic women younger than 60 or within 10 years of menopause, Pinkerton said. "Having less increase in abdominal fat is an extra benefit beyond relief of hot flashes, night sweats, improved sleep, and less bone loss," she said.

However, "There is no one-size-fits-all approach when it comes to decisions about hormone therapy," Pinkerton added. "The risks and benefits vary depending on the woman's own characteristics as well as the type of hormone therapy, the dose used, the duration of use, type of administration -- whether it's a pill or a patch, for example – and especially age and time from menopause when therapy is initiated."

The cross-sectional, observational study included 1,053 postmenopausal women age 50-80. They were classified as current hormone therapy users (21%), past users (27%), or never users (52%). The vast majority (98%) were white. Current users had been on therapy an average of 12 years, and past users had been off therapy an average of 8.5 years. Participants were questioned about their diet, physical activity, and psychological health.

Participants underwent dual-energy X-ray absorptiometry (DXA) with body composition assessment. The main outcome was visceral adipose tissue as measured by DXA. Secondary outcomes included BMI, total fat mass, lean mass, and hand grip strength. The study found no significant differences among participants for lean mass or grip strength.

Exactly how hormone replacement therapy affects fat mass is unclear, Papadakis and colleagues said. It could have a direct effect on fat cells, or it could have behavioral effects that influence food intake and physical activity, they said.

Because the vast majority of study participants were white, the results may not be generalizable to other patient populations, they said. In addition, information on the duration of hormone therapy, as well as the type of therapy and route of administration, was self-reported, "preventing us from reliably assessing these factors," they said.