In this study, we have prospectively observed that intravaginal estrogen therapy for women taking either an AI or an SERM for treatment or prevention of breast cancer results in significantly elevated circulating E2 levels. Our data suggest that these elevations occur regardless of whether the VE preparation is by tablet or slow-release ring. We detected elevated E2 levels despite long-term VE use, which has previously been hypothesized to prevent vaginal estrogen absorption due to cornification.4,13,22
E2 levels may not be persistently elevated after VE tablet insertion, as levels appeared to return to baseline within 24 hours for one patient, and because preinsertion levels in all patients were no different than those of women not using VE. However, for women using the VE ring, we detected elevated preinsertion E2 levels (> 10 pmol/L) in all four patients taking an SERM and in two thirds of patients taking an AI, suggesting that absorption is persistent in the VE user. Tamoxifen and raloxifene are not known to have any effect on circulating levels of estrogens in postmenopausal women.25–28
Other studies have shown that estrogen is readily absorbed from the vagina. Randomized trials in postmenopausal women without breast cancer have demonstrated marginally increased, but still postmenopausal, estradiol and estrone levels in women using the estrogenic vaginal ring.17
However, there is indirect evidence of a systemic estrogenic effect in these women, which might be deleterious with regard to breast cancer recurrence.29
Our data are consistent with those from Kendall et al,8
who demonstrated an initial absorption in six of seven postmenopausal women with breast cancer using a VE (either the VE used in the current study (Vagifem) or VE cream (Premarin; Wyeth, New York, NY). However, as in our study, not all patients exhibited an increased level. In the Kendall et al study, one patient did not have any increase in E2, and in one half of the remaining six patients, E2 levels returned to baseline at 12 weeks.
The sample size of both cases and controls was small. The cases sample was limited to the number of patients receiving VEs in our practice. The number of controls was selected to roughly match the number cases. Patients were accepted as controls if they were postmenopausal, receiving an AI in the adjuvant setting without known recurrence, and completed all their local therapy. They were not matched for other possible variables such as compliance, body mass index, prior chemotherapy, or others that might influence the outcome. It is unlikely that matching such a small number of patients would give any further insight. Furthermore, our control patients' E2 levels are consistent with the literature, and each case served as their own control with a baseline E2 level.8
Taken together, these findings have immediate clinical implications. They indicate that VE therapy, although effective in treating atrophic vaginitis, may have adverse effects with regard to breast cancer treatment, as previously reported, large prospective studies have demonstrated worse cancer outcomes in the setting of estrogenic effect in women taking tamoxifen with an AI.20
It is possible that exposure of occult breast cancer to intermittent estrogens may not be detrimental. However, there is no research to substantiate this view.
Unfortunately, antiestrogenic cancer treatments do cause considerable vaginal toxicity, for which, short of estrogen treatment, there are few good alternatives. Several studies have documented that lack of adherence and/or persistence to SERMs and AI is quite high, despite their life-saving benefits, as a result of postmenopausal symptomatology, including atrophic vaginitis.30–33
Over-the-counter nonhormonal vaginal moisturizers and lubricants appear to be only modestly helpful.34–36
There is little research support for vaginal testosterone, dehydroepiandrosterone, or other hormonal interventions.37
Furthermore, these hormones serve as precursors for estrogenic compounds via aromatization. Although it is not known whether pharmacologic use of precursors increases estradiol levels, one must have some concern about this possibility.
A lower dose estradiol vaginal tablet has recently replaced the higher dose. A 17 beta-estradiol tablet formulation is now available in a 10-μg tablet. When compared with the 25-μg 17 beta-estradiol vaginal tablet used in this study, there is similar symptom relief. There is less systemic absorption after both initial and chronic use.38,39
However, the assays used in these studies may be less sensitive than the extraction radioimmunoassay in this study. This formulation has not been reported in breast cancer survivors on an AI or tamoxifen. A prospective trial of the 10-μg tablet is underway.40
In summary, our data suggest that intravaginal estrogen preparations, although attractive for the treatment of postmenopausal atrophic vaginitis, should be used with caution for women with hormone receptor–positive breast cancer taking antiestrogen therapy. For women with symptomatic vaginal atrophy, nonhormonal vaginal moisturizers and lubricants should be tried. For those without symptomatic relief who request intervention to improve their quality of life or compliance, the known risks and benefits should be discussed with their physician.