Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington

Dr. Brewer reports no financial relationships relevant to this field of study.

SYNOPSIS: Vaginal estrogen may improve vaginal symptoms of menopause and does not increase the risk for endometrial cancer, stroke, or cardiovascular disease.

SOURCE: 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 2017; Aug 14. doi: 10.1097/GME.0000000000000956. [Epub ahead of print.]

Since the Women’s Health Initiative (WHI) first was published in 2002, women have been reluctant to use any type of hormone replacement therapy (HRT). In my practice, women routinely refuse both systemic HRT and vaginal HRT because of their fear of cancer, primarily breast cancer. In this recent study in Menopause, Crandall et al reported that the risk of breast and endometrial cancer and cardiovascular events was not elevated in postmenopausal women using vaginal estrogen. This observational study, which was a subset of the original WHI study, ran from 1993 to 2005, and included 45,663 postmenopausal women aged 50-79 years. One-third of these women had a hysterectomy and the remainder had an intact uterus. The authors calculated the global index event (GIE), which is the time to first coronary heart disease (CHD), breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death, and the hazard ratios (HR) ranged from 0.69-0.76, depending on which confounders were included in the model (95% confidence interval [CI], 0.59-0.81, 0.64-0.91). Death, CHD, stroke, colorectal cancer, hip fracture, and pulmonary embolism/deep vein thrombosis all had HRs < 1, but CHD and hip fracture were the only two outcomes that were statistically significant, with HRs of 0.52 (95% CI, 0.31-0.85) and 0.40 (95% CI, 0.64-0.91).

When the authors analyzed based on hysterectomy status, women without a uterus had no statistically significant difference in outcomes; women with an intact uterus tended toward an increased risk of developing endometrial cancer, but this was not statistically significant. However, these women did have a statistically significant difference in GIE (HR, 0.68; 95% CI, 0.55-0.86), death (HR, 0.62; 95% CI, 0.41-0.93), CHD (HR, 0.30; 95% CI, 0.19-0.78), and hip fracture (HR, 0.40; 95% CI, 0.16-0.96). For the outcomes listed above in the women without a uterus, the number of events was so low that there was inadequate statistical power to determine definitively that the risk was lower with vaginal estrogen. However, we can conclude that the trend was lower for these outcomes except for endometrial cancer.

Several other studies have addressed the risk of cancer, CHD, and stroke with vaginal estrogen. Two studies did not find an increase in risk of endometrial hyperplasia with atypia or cancer.^1,2 However, a Danish study found a relative risk of 1.96 (95% CI, 1.77-2.17) with vaginal estrogen. It was not clear in the study if some of the women also were taking systemic estrogen or a higher dose of vaginal estrogen than was used in this study.³

COMMENTARY

So where are we with HRT? Since 2002 when the first WHI study was published, there has been a significant fear of HRT by patients.⁴ The WHI study created such controversy that most women on HRT in 2002 stopped their HRT without understanding the real findings in the study.⁵ A follow-up publication in 2013 by some of the same authors continued to support the notion that “Menopausal [hormone therapy] is not suitable for long-term prevention of CHD given risks of stroke, venous thromboembolism, and breast cancer (for estrogen plus progestin therapy) found in both clinical trials and in observational studies.”⁶ Other studies have disagreed. In a recent publication, Langer et al stated, “The WHI was not intended, and was not statistically powered, to evaluate the common clinical use of MHT (menopausal hormone therapy) initiated near menopause.” They considered that it was inappropriate to use WHI data from the 70% of the enrolled cohort that was more than 10 years postmenopausal to make decisions about HRT in younger women transitioning into menopause. In addition, their findings were not adjusted for age or risk of chronic disease. The women in the WHI trial had a mean age of 63 years, were approximately 12 years beyond menopause, and should not have been included with the younger patients who are most likely to have menopausal symptoms and require HRT. Langer et al went on to state: “Unfortunately, the USPSTF has consistently made this error in its consideration of the evidence.”⁷ Finally, the effect of the WHI study was that most women stopped using HRT because of their fears resulting from the widespread publicity of this flawed study.

So how do we counsel our patients? The use of both systemic and vaginal estrogen around the time of menopause is safe and reduces symptoms. Patients with breast cancer or a family history of breast cancer should be counseled more carefully than those without a strong personal or family history of breast cancer. However, we can counsel our patients, even those with breast cancer, that vaginal estrogen is safe and may be beneficial for more than just vaginal symptoms. Those women with an intact uterus using vaginal estrogen had a lower risk of death, cardiovascular disease, and hip fractures while those who have had a hysterectomy will not suffer harm from vaginal estrogen. However, I have many patients who are deathly afraid of any hormone and will not even use vaginal estrogen. They suffer with many quality-of-life issues and, potentially, an increased risk of CHD because of the misconceptions around hormone replacement treatment.

REFERENCES

1. Ulrich LS, Naessen T, Elia D, et al; VAG-1748 trial investigators. Endometrial safety of ultra-low-dose Vagifem 10 microg in postmenopausal women with vaginal atrophy. Climacteric 2010;13:228-237.
2. Simon J, Nachtigall L, Ulrich LG, et al. Endometrial safety of ultra-low-dose estradiol vaginal tablets. Obstet Gynecol 2010;116:876-883.
3. Morch LS, Kjaer SK, Keiding N, et al. The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study. Int J Cancer 2016;138:1506-1515.
4. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin for healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
5. Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women’s Health Initiative trials of menopausal hormone therapy. Obstet Gynecol 2013;121:172-176.
6. Ettinger B, Grady D, Tosteson AN, et al. Effect of the Women’s Health Initiative on women’s decisions to discontinue postmenopausal hormone therapy. Obstet Gynecol 2003;102:1225-1232.
7. Langer RD, Simon JA, Pines A, et al. Menopausal hormone therapy for primary prevention: Why the USPSTF is wrong. Climacteric 2017;20:402-413.