Study strengths and limitations
To show noninferiority of vaginal laser therapy to vaginal estrogen, 196 study participants were needed. However, after 38% had been enrolled, the FDA sent a warning letter to the Foundation for Female Health Awareness, which required obtainment of an investigational device exemption for the laser and addition of a sham treatment arm.9 Instead of redesigning the trial and reconsenting the participants, the investigators closed the study, and analysis was performed only on the 62 participants who completed the study; vaginal maturation was assessed only in 34 participants.
The study lacked a placebo or sham control, which increases the risk of bias, while small numbers limit the strength of the findings. Longer-term evaluation of the effects of laser therapy beyond 6 months is needed to allow assessment of the effects of scarring on vaginal health, sexual function, and urinary issues.
Discussing therapy with patients
Despite this study’s preliminary findings, and until more robust data are available, providers should discuss the benefits and risks of all available treatment options for vaginal symptoms, including over-the-counter lubricants, vaginal moisturizers, FDA-approved vaginal hormone therapies (such as vaginal estrogen and intravaginal dehydroepiandrosterone), and systemic therapies, such as hormone therapy and ospemifene, to determine the best treatment for the individual woman with GSM.
In a healthy postmenopausal woman with bothersome GSM symptoms not responsive to lubricants and moisturizers, I recommend FDA-approved vaginal therapies as first-line treatment if there are no contraindications. For women with breast cancer, I involve their oncologist. If a patient asks about vaginal laser treatment, I share that vaginal energy-based therapies, such as the vaginal laser, have not been approved for menopausal vaginal concerns. In addition to the possibility of adverse events or unsuccessful treatment, there are significant out-of-pocket costs and the potential need for ongoing therapy after the initial 3 laser treatments.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
For GSM that does not respond to lubricants and moisturizers, many FDA-approved vaginal and systemic therapies are available to treat vaginal symptoms. Vaginal laser treatment is a promising therapy for vaginal symptoms of GSM that needs further testing to determine its efficacy, safety, and long-term effects. If discussing vaginal energy-based therapies with patients, include the current lack of FDA approval for specific vaginal indications, potential adverse effects, the need for ongoing retreatment, and out-of-pocket costs.
For GSM that does not respond to lubricants and moisturizers, many FDA-approved vaginal and systemic therapies are available to treat vaginal symptoms. Vaginal laser treatment is a promising therapy for vaginal symptoms of GSM that needs further testing to determine its efficacy, safety, and long-term effects. If discussing vaginal energy-based therapies with patients, include the current lack of FDA approval for specific vaginal indications, potential adverse effects, the need for ongoing retreatment, and out-of-pocket costs.
Evidence points to different benefit-risk profiles for vaginal estrogen and systemic estrogen therapy
JoAnn E. Manson, MD, DrPH, NCMP
Having more appropriate, evidence-based labeling of low-dose vaginal estrogen continues to be a high priority for The North American Menopause Society (NAMS), the International Society for the Study of Women’s Sexual Health (ISSWSH), and other professional societies.
NAMS and the Working Group on Women’s Health and Well-Being in Menopause had submitted a citizen’s petition to the US Food and Drug Administration (FDA) in 2016 requesting modification of the label—including removal of the “black box warning”—for low-dose vaginal estrogen products. The petition was, disappointingly, denied in 2018.1
Currently, the class labeling, which was based on the results of randomized trials with systemic hormone therapy, is not applicable to low-dose vaginal estrogen, and the inclusion of the black box warning has led to serious underutilization of an effective and safe treatment for a very common and life-altering condition, the genitourinary syndrome of menopause (GSM). This condition affects nearly half of postmenopausal women. It tends to be chronic and progressive and, unlike hot flashes and vasomotor symptoms, it does not remit or decline over time, and it affects women’s health and quality of life.
While removal of the black box warning would be appropriate, labeling should include emphatic reminders for women that if they have any bleeding or spotting they should seek medical attention immediately, and if they have a history of breast cancer or other estrogen-sensitive cancers they should talk with their oncologist prior to starting treatment with low-dose vaginal estrogen. Although the text would still inform women of research results on systemic hormone therapy, it would explain the differences between low-dose vaginal estrogen and systemic therapy.
Studies show vaginal estrogen has good safety profile
In the last several years, large, observational studies of low-dose vaginal estrogen have suggested that this treatment is not associated with an increase in cardiovascular disease, pulmonary embolism, venous thrombosis, cancer, or dementia—conditions listed in the black box warning that were linked to systemic estrogen therapy plus synthetic progestin. Recent data from the Nurses’ Health Study, for example, demonstrated that 3 years of vaginal estrogen use did not increase the risk of cardiovascular events or invasive breast cancer.
Women’s Health Initiative. In a prospective observational cohort study, Crandall and colleagues used data from participants in the Women’s Health Initiative Observational Study to determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause.2
Women were recruited from multiple clinical centers, were aged 50 to 79 years at baseline, and did not use systemic estrogen therapy during follow-up. The study included 45,663 women and median follow-up was 7.2 years. The investigators collected data on women’s self-reported use of vaginal estrogen as well as the development of the conditions defined above.
In women with a uterus, there was no significant difference between vaginal estrogen users and nonusers in the risk of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, pulmonary embolism, or deep vein thrombosis. The risks of coronary heart disease, fracture, all-cause mortality, and GIE were lower in vaginal estrogen users than in nonusers (GIE adjusted hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.55–0.86).
In women who had undergone hysterectomy, the risks of the individual GIE components and the overall GIE were not significantly different in users of vaginal estrogen compared with nonusers (GIE adjusted HR, 0.94; 95% CI, 0.70–1.26).
The investigators concluded that the risks of cardiovascular disease and cancer were not increased in postmenopausal women who used vaginal estrogen. Thus, this study offers reassurance on the treatment’s safety.2
Meta-analysis on menopausal hormone therapy and breast cancer risk. Further evidence now indicates that low-dose vaginal estrogen is not linked to chronic health conditions. In a large meta-analysis published in 2019, investigators looked at different types of hormone therapies—oral estrogen plus progestin, transdermal estrogen and progestin, estrogen alone, low-dose vaginal estrogen—and their relationship to breast cancer risk.3
Information on individual participants was obtained from 58 studies, 24 prospective and 34 retrospective. Breast cancer relative risks (RR) during years 5 to 14 of current hormone use were assessed according to the main hormonal contituents, doses, and modes of delivery of the last-used menopausal hormone therapy. For all systemic estrogen-only preparations, the RR was 1.33 (95% CI, 1.28–1.38), while for all estrogen-progestogen preparations, the RR was 2.08 (95% CI, 2.02–2.15). For transdermal estrogen, the RR was 1.35 (95% CI, 1.25–1.46). In contrast, for vaginal estrogen, the RR was 1.09 (95% CI, 0.97–1.23).3
Thus, the analysis found that in all the studies that had been done to date, there was no evidence of increased risk of breast cancer with vaginal estrogen therapy.
The evidence is growing that low-dose vaginal estrogen is different from systemic estrogen in terms of its safety profile and benefit-risk pattern. It is important for the FDA to consider these data and revise the vaginal estrogen label.
On the horizon: New estradiol reference ranges
It would be useful if we could accurately compare estradiol levels in women treated with vaginal estrogen against those of women treated with systemic estrogen therapy. In September 2019, NAMS held a workshop with the goal of establishing reference ranges for estradiol in postmenopausal women.4 It is very important to have good, reliable laboratory assays for estradiol and estrone, and to have a clear understanding of what is a reference range, that is, the range of estradiol levels in postmenopausal women who are not treated with estrogen. That way, you can observe what the estradiol blood levels are in women treated with low-dose vaginal estrogen or those treated with systemic estrogen versus the levels observed among postmenopausal women not receiving any estrogen product.
With the reference range information, we could look at data on the blood levels of estradiol with low-dose vaginal estrogen from the various studies available, as well as the increasing evidence from observational studies of the safety of low-dose vaginal estrogen to better understand its relationship with health. If these studies demonstrate that, with certain doses and formulations of low-dose vaginal estrogen, blood estradiol levels stay within the reference range of postmenopausal estradiol levels, it would inform the labeling modifications of these products. We need this information for future discussions with the FDA.
The laboratory assay technology used for such an investigation is primarily liquid chromatography with tandem mass spectrometry, the so-called LC-MS/MS assay. With use of this technology, the reference range for estradiol may be less than 10 picograms per milliliter. Previously, a very wide and inconsistent range—about 5 to 30 picograms per milliliter—was considered a “normal” range.
NAMS is championing the efforts to define a true evidence-based reference range that would represent the range of levels seen in postmenopausal women.5 This effort has been spearheaded by Dr. Richard Santen and colleagues. Using the more sensitive and specific LC-MS/MS assay will enable researchers and clinicians to better understand how levels on low-dose vaginal estrogen relate to the reference range for postmenopausal women. We are hoping to work together with researchers to establish these reference ranges, and to use that information to look at how low-dose vaginal estrogen compares to levels in untreated postmenopausal women, as well as to levels in women on systemic estrogen.
Hopefully, establishing the reference range can be done in an expeditious and timely way, with discussions with the FDA resuming shortly thereafter.
References
1.NAMS Citizen’s Petition and FDA Response, June 7, 2018. http://www.menopause.org/docs/default-source/default-document-library/fda-responseacf7fd863a01675a99cbff00005b8a07.pdf. Accessed May 21, 2020.
2. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause. 2018;25:11-20.
3. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394:1159-1168.
4. Santen RJ, Pinkerton JV, Liu JH, et al. Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois. Menopause. May 4, 2020. doi:10.1097/GME.0000000000001556.
5. Pinkerton JV, Liu JH, Santoro NF, et al. Workshop on normal reference ranges for estradiol in postmenopausal women: commentary from The North American Menopause Society on low-dose vaginal estrogen therapy. Menopause. 2020;27:611-613.