Hormonal Products for Vaginal Atrophy on AI: 'Murky Waters'

Kate Johnson

March 16, 2017

Postmenopausal women taking aromatase inhibitors (AIs) for their early-stage, hormone receptor–positive breast cancer can safely use vaginal estrogen or testosterone to relieve urogenital atrophy, according to the authors of a new study published in JAMA Oncology.

But these study authors are venturing into "already somewhat murky waters," suggested the coauthor of an accompanying editorial.

"I don't know if their definition of safety is correct," commented Hyman B. Muss, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, in an interview with Medscape Medical News. "I'm still worried about the safety of both of these approaches."

"I think it's a small study with short follow-up. I suspect it will turn out to be safe, but I'm not sure," he continued. "It's likely to turn out to be a minimal risk, but it's going to take a huge number of patients with long-term follow-up to know that, and I doubt we'll see anything convincing for many years."

The randomized, noncomparative, single-institution, phase 2 trial included just 76 postmenopausal women with stage I to III hormone receptor–positive breast cancer.

All had been treated for at least 30 days with AIs and had reported vaginal dryness, dyspareunia, or decreased libido.

To treat these symptoms, the patients were randomly assigned to an intravaginal testosterone cream (IVT) compounded to 1% concentration or to an estradiol-releasing vaginal ring (Estring, Pfizer).

Determining the safety of both treatments was the primary objective of the study, and they were considered unsafe if more than 25% of patients had persistent elevations in estradiol (E2) during the 12-week study period.

A persistent elevation was defined as a level greater than 10 pg/mL and at least 10 pg/mL above baseline on 2 consecutive tests performed at least 2 weeks apart.

Because this elevation was not observed in any women using the vaginal ring and in just 12% of women using IVT (range, 16 to 45 pg/mL), the study's safety objective was met.

Transient E2 elevations were seen in 11% of women with the vaginal ring and 12% of the IVT group (ranges, 11 to 29 pg/mL and 11 to 113 pg/mL, respectively).

Estrogen E2 levels were measured at baseline and weeks 4 and 12 by using both laboratory-based radioimmunoassays and commercially available liquid chromatography/tandem mass spectrometry assays for comparison. Patients whose levels were elevated were informed of this and were offered the option to withdraw from the study, although none chose to do so.

As might be expected, the authors report that "both the vaginal ring and IVT improved vaginal atrophy, sexual interest, and desire," but they add that "only the vaginal ring improved sexual satisfaction."

"For patients who experience symptomatic improvement on either an estradiol-releasing vaginal ring or IVT, our current standard clinical practice is to continue on therapy with measurements of serum E2 every few months depending on patient preferences," they comment. But they add that the development of sustained E2 elevations and high testosterone levels in a small number of patients in the IVT group suggests "that lower-dose testosterone may be warranted."  

However, in the editorial, Dr Muss and coauthor Katherine Reeder-Hayes, MD, MBA, also from the University of North Carolina, write that "we must ask ourselves, 'How safe is safe enough?' Evidence on the risks of vaginal hormonal interventions remains extremely limited."

Sexual function is a "woefully neglected" problem among patients with breast cancer, Dr Muss acknowledged. "It makes some women and their partners' lives miserable. It's not just sexual function; they have recurrent urinary tract infections, they have bleeding — it's a very major symptom."

Initially, nonhormonal approaches should be tried, the editorialists advise. "Water-based vaginal lubricants (eg, Astroglide, Biofilm, and others), as well as nonhormonal moisturizing gels (eg, Replens, Wellspring Pharmaceuticals) can be helpful in women with mild or moderate dryness," they write. "Anecdotally, vitamin E orally or locally may also be helpful," they add, but they urge caution with herbal preparations.

However, in nonresponders, rather than moving on to vaginal hormones, Dr Muss suggested that the more prudent next step might be to switch the patient off AIs and onto tamoxifen.

"If you look at these large analyses of survival on AIs vs tamoxifen, they're very similar, so if a woman's life and sexual function are being destroyed by her AI therapy, changing her over to a drug like tamoxifen would mean vaginal estrogens or androgens are likely to be safe," he explained.

Failing that, if the patient wishes to try a vaginal hormone while continuing on AI therapy, it would be reasonable after "a frank discussion and shared decision making," the editorial authors write.

"But I think you can't look that patient in the eye and say I think that's fine — there would be some uncertainty," Dr Muss told Medscape Medical News. He also added that regular monitoring would also be prudent "to check levels — just to be on the safe side — but we're not totally certain what they mean."

The study authors acknowledge that "defining the effect of E2 fluctuation on outcome would be worthwhile" in future studies, and they point out that a surprise finding in their investigation was the elevated baseline E2 levels (above the postmenopausal range of >10 pg/mL) in 37% of patients.

"Additionally, the conclusion that these interventions are safe based on lack of sustained E2 elevation may be considered arbitrary because there was no nonhormonal intervention for comparison and the study did not have statistical power or a long-term follow-up to explore whether there was a higher rate of recurrences in our study population vs historical controls," the study authors acknowledge.  

The study was funded by AstraZeneca. The authors of the study and of the editorial have disclosed no relevant financial relationships

JAMA Oncol. 2017;3:313-319, 305-306. Abstract, Editorial

Follow Medscape Oncology on Twitter: @MedscapeOnc