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Vaginal ring, intravaginal testosterone cream appear safe, improve sexual dysfunction in postmenopausal women
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Postmenopausal women receiving aromatase inhibitors for early-stage breast cancer experienced improvements in vaginal dryness, sexual interest and sexual dysfunction when treated with a vaginal ring or intravaginal testosterone cream, according to results of a randomized noncomparative clinical trial published in JAMA Oncology.
Estradiol levels were elevated at baseline in 37% of the women in the trial, but persistent estradiol elevation levels were low enough to meet the study’s safety endpoint.
“These results are intriguing, particularly given that 21% with elevated baseline estradiol had undergone oophorectomy, and most had postmenopausal folic-stimulating hormone levels,” Michelle E. Melisko, MD, associate clinical professor in the department of medicine (hematology/oncology) at University of California San Francisco Hellen Diller Family Comprehensive Cancer Center, and colleagues wrote.
Vaginal dryness and decreased libido may cause noncompliance of aromatase inhibitors among women with early-stage breast cancer. Data have shown up to 50% of women on aromatase inhibitors report low sexual interest and 74% report insufficient lubrication.
Although vaginal estrogens effectively treat urogenital atrophy, they may be unsafe in women with breast cancer due to potential systemic absorption.
Melisko and colleagues evaluated the safety of intravaginal testosterone cream (IVT) or estradiol-releasing vaginal ring in postmenopausal patients with early-stage hormone-receptor positive breast cancer receiving aromatase inhibitors who self-reported vaginal dryness, dyspareunia or decreased libido. Secondary endpoints included adverse events, changes in sexual quality of life, changes in vaginal atrophy and estradiol levels.
Overall, 76 women (mean age, 56 years; range, 37-78) were enrolled and 69 completed 12 weeks of treatment with the vaginal ring (n = 35) or IVT (n = 34).
Researchers measured patients’ estradiol at baseline and weeks 4 and 12, and they measured follicle-stimulating hormone levels at baseline and week 4. The intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (> 10 pg/mL).
At baseline, estradiol was above the postmenopausal range (> 10pg/mL) in 28 women (37%). However, persistent estradiol elevation was observed in none of those who used a vaginal ring and in four of 34 women (12%) using IVT, suggesting the study reached its safety endpoint. Transient estradiol elevation occurred in four women (11%) with a vaginal ring and in four women (12%) using IVT.
“The reason for the significant difference in elevated baseline estradiol between treatment arms is unclear because the arms were evenly paired for age, cause of menopause, BMI, race, and time on aromatase inhibitor,” Melisko and colleagues wrote.
Vaginal dryness — measured using a validated 4-point scale — and sexual interest and dysfunction, reported by women using the Cancer Rehabilitation Evaluation System sexuality subscales, improved for all patients who used IVT or estradiol-releasing vaginal rings.
In women who used the vaginal ring for 12 weeks, dryness improved from 1.5 to 0.5; sexual interest improved from 1.2 to 0.9; and sexual dysfunction improved from 2.9 to 2. Women using IVT reported vaginal dryness improvement from 1.5 to 0.8; sexual interest improvement from 1.4 to 1; and sexual dysfunction improvement from 2.9 to 1.9.
All treatment-related adverse events were grade 1 or grade 2. Eight percent of women experienced vaginal discharge (vaginal ring, n = 4; IVT, n = 2) or facial hair growth (vaginal ring, n = 1; IVT, n = 5); 5% reported vaginal or vulvar irritation (vaginal ring, n = 4) or urinary tract or yeast infection (vaginal ring, n = 1; IVT, n = 3); and 4% reported vaginal odor (IVT, n = 3). One patient in each group discontinued therapy for vaginal odor or irritation, or vulvar irritation.
Melisko and colleagues noted the small study size and high percentage of patients with elevated baseline estradiol as limitations.
“This study provides further evidence that both an estradiol-releasing vaginal ring and IVT are effective in treating urogenital symptoms in patients with breast cancer taking aromatase inhibitors,” Melisko and colleagues wrote. “The American Menopausal Society and the American College of Obstetricians and Gynecologists recommend that in patients with a history of estrogen-sensitive cancer, nonhormonal options including vaginal moisturizers, pH–balanced gels, topical oils and lubricants be tried first for urogenital atrophy, and vaginal estrogens be reserved for patients who are nonresponsive and only after consultation with the medical oncologist.”
Because study data support the use of aromatase inhibitors as a chronic medication for up to 10 years in addition to avoiding systemic hormone therapy for relief of menopausal symptoms among otherwise healthy breast cancer survivors, it is warranted to research better ways to address vaginal symptoms and sexual dysfunction, Katherine Reeder-Hayes, MD, MBA, MSCR, and Hyman B. Muss, MD, both of University of North Carolina at Chapel Hill School of Medicine and Lineberger Comprehensive Cancer Center, wrote in an accompanying editorial.
“Evidence on the risks for vaginal hormonal interventions remains extremely limited, although we may hope for additional research to advance this area of supportive care,” Reeder-Hayes and Muss wrote. “In the meantime, if nonhormonal approaches are initially considered and found to be unhelpful and after a frank discussion and shared decision-making the interventions such as those proposed by Drs. Melisko and colleagues that may have a meaningful effect on quality of life, relationship satisfaction and ability to move on beyond breast cancer, appears the best strategy.” – by Chuck Gormley
Disclosure: The trial was funded in full by AstraZeneca. Melisko reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Hayes and Muss report no relevant financial disclosures.
Perspective
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Don S. Dizon
Despite the well-established efficacy of adjuvant endocrine therapy, up to 20% of women with a hormone receptor–positive breast cancer consider stopping or actually cease treatment due to genitourinary symptoms of menopause, including vulvovaginal atrophy. In these women, the reported incidence of vaginal dryness ranges from 19% to 23% in premenopausal patients and 42% to 70% in postmenopausal patients. Dyspareunia is reported in 10% to 16% of premenopausal patients and 27% to 39% of postmenopausal patients. That aromatase inhibitors worsen or induce vaginal atrophy, dryness and dyspareunia in most women has been documented, and because these symptoms have an impact on overall sexual response — low sex drive, poor arousal and sexual satisfaction — they likely also impact quality of life. While oral estrogen therapy remains contraindicated, vaginal hormonal preparations are becoming acceptable. Indeed, the American College of Obstetrics and Gynecology has determined that the benefits of local estrogen therapy appear to outweigh the risks of treatment in this population. Thus, it is considered a reasonable option to explore with patients, particularly if nonhormonal treatments have been ineffective.
There are few prospective studies on vaginal hormonal preparations for women treated for breast cancer. In this study by Melisko and colleagues, researchers sought to evaluate a vaginal testosterone preparation and an estradiol vaginal ring in this patient population. The endpoint was not superiority — rather, they sought to evaluate both in a noncomparative trial, where the safety — characterized by levels of estradiol — and efficacy of both could be evaluated simultaneously.
As reported, both preparations met their safety endpoints though baseline estradiol levels were reported to be elevated even before any intervention. In addition, although both were seen to be effective for sexual health endpoints, it remains unclear if the statistically significant changes reported in sexual interest, sexual dysfunction and sexual satisfaction for either preparation was of clinical significance.
The use of CARES and the researchers’ choice of the vaginal atrophy scale in this study is interesting. In general, vaginal health is typically evaluated using the Vaginal Health Score — a system that considers not only the subjective impression but includes objective data, including vaginal pH. The score is considered internationally valid and hence, is the one most typically used in menopausal studies. CARES is typically not used in sexual health studies, because it does not represent the various domains of sexual function in women; in such case, typically the Female Sexual Function Index is used, although the recall period for use (4 weeks) can be problematic.
Disclosure: Dizon and Preti report no relevant financial disclosures.
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