CME Author: Zeena Nackerdien
Study Authors: Shilpa N. Bhupathiraju, Francine Grodstein, et al.
Target Audience and Goal Statement: Gynecologists, endocrinologists, urologists, and primary care physicians
The goal was to explore findings from the Nurses’ Health Study, which focused on associations between vaginal estrogen use and multiple health outcomes, including cardiovascular disease, in postmenopausal women who were not current users of systemic hormone therapy at the start of the study or during follow-up.
Given the limited data regarding the benefit/risk profile of vaginal estrogen use in postmenopausal women, extracting relevant data (1982-2012) from the longest running study on health and wellness (Nurses’ Health Study), it fills an unmet treatment gap. Study investigators addressed the following questions:
- What are the prospective associations between vaginal estrogen use and chronic disease outcomes among postmenopausal women in the Nurses’ Health Study?
- Can benefits and risks be ascertained from long-term treatment among women not using systemic hormone therapy?
Synopsis and Perspective:
Hormonal fluctuations, especially reduced estrogen levels, lead to numerous changes during menopause. Estrogen deficiency results in conditions where the vaginal microbiota are disrupted, the vaginal epithelium becomes thinner, its barrier function is lost, vaginal folding, tissue elasticity, and secretion from Bartholin’s glands decrease, which can cause often-debilitating symptoms (e.g., lack of lubrication, urinary symptoms of urgency, and recurrent urinary tract infections). Unlike hot flashes, these symptoms do not resolve without treatment. Broadly speaking, genitourinary syndrome of menopause (GSM) has been defined as “a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder.” Prevalence estimates for components of GSM range from 25% to 70%.
In the absence of contrary evidence, the FDA stipulated in 2003 that all estrogen products, including vaginal estrogen products for the treatment of GSM, be regarded as having similar risks to those reported for oral conjugated equine estrogens (0.625 mg combined with medroxyprogesterone acetate 2.5 mg, per day). These risks include elevated possibilities of heart attacks/strokes, venous thrombosis, breast cancer, and dementia. Many patients have opted to “suffer” in silence rather than expose themselves to the purported risks expressed on the black box label, purely for the sake of making sex more comfortable.
Despite the black box warning, low-dose vaginal estrogen is recommended for treatment of GSM by several organizations, including the North American Menopause Society (NAMS), the American College of Obstetricians and Gynecologists, and the Endocrine Society. The American Association of Clinical Endocrinologists’ 2017 update to their menopause clinical practice guidelines recommends 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.” Furthermore, many studies have shown vaginal estrogen to be superior to non-hormone therapies and these findings also demonstrate that it provides better symptom relief than oral estrogen therapy.
There are no randomized clinical trial reports describing the effect of low-dose vaginal estrogen therapy on major health outcomes such as cardiovascular disease and cancer. Reported outcomes from population-based cohort studies have been contradictory (e.g., one study reported no association between vaginal estrogen use and risk of breast and endometrial cancer, and another study reported a higher risk of endometrial cancer).
The current prospective study by JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital in Boston, and colleagues, compared about 53,000 non-users with nearly 900 postmenopausal women currently using vaginal estrogen. Users of systemic hormone therapy were excluded from the present study. Women self-reported vaginal estrogen use on biennial questionnaires. 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.
When comparing nonusers to vaginal estrogen users in terms of the risk for major health outcomes, the latter group had a lower risk of total myocardial infarction (MI; HR 0.56, 95% CI 0.36-0.87) and a non-significant lower risk of total stroke (HR 0.71, 95% CI 0.47-1.09). No significant differences were seen between the two study arms in age-adjusted risks of other major health outcomes (e.g., pulmonary embolism/deep vein thrombosis, total invasive cancer, invasive breast cancer, ovarian cancer, endometrial cancer, and colorectal cancer).
Using the fully adjusted model, the trend for no statistically significant difference persisted between users and nonusers of vaginal estrogen for all major cardiovascular outcomes, cancer outcomes, or hip fracture. In sensitivity analyses, when researchers examined associations by hysterectomy status, stratified results were typically similar to those of the total cohort.
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 the low-doses that are commonly prescribed now, the team noted.
Source Reference: Menopause, Dec 17, 2018, DOI: 10.1097/GME.0000000000001284
Study Highlights: Explanation of Findings
This novel study that followed systemic-hormone-therapy-naïve, postmenopausal women treated with low-dose vaginal estrogen for 18 years, found that low-dose vaginal estrogen was not linked to a higher risk of cardiovascular disease, cancer, or hip fractures. The evaluated risks included risks for myocardial infarction, stroke, and pulmonary embolism, as well as breast, endometrial, ovarian, and colorectal cancers.
Warnings against the use of oral estrogen stem from evidence generated by randomized clinical trials of systemic hormone therapy. Because the pharmacokinetics of vaginal estrogen does not involve the gastrointestinal conversion of estradiol (E2) to estrone, this mode of delivery bypasses the first-pass liver metabolism associated with taking the hormone as a pill. The latter process is linked to hepatic synthesis of more thrombotic and other factors. While the use of oral equine estrogens (0.625 mg/d) was associated with an elevated risk of stroke and deep vein thrombosis in the intervention phase of the Women’s Health Initiative (WHI) Hormone Therapy (HT) trials, the authors found no evidence of these outcomes with the use of vaginal estrogen.
Finally, the authors noted that the comprehensive evaluation of the relationship between vaginal estrogen and numerous health outcomes is reassuring with respect to the safety of low-dose vaginal estrogen to treat GSM.
“Over-the-counter vaginal lubricants and moisturizers are often used as first-line treatments for women with symptoms of [GSM],” said JoAnn Pinkerton, MD, executive director of the 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.
Kristen Monaco wrote the original story for MedPage Today.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner