What's new for the treatment of dyspareunia associated with GSM?
Intrarosa, a once-daily vaginal insert containing prasterone as the active ingredient, was recently approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause
FDA approves Intrarosa for postmenopausal women experiencing pain during sex [news release]. Silver Spring, MD: US Food and Drug Administration; November 17, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm529641.htm. Accessed December 19, 2017.
Intrarosa [package insert]. Quebec City, Canada: Endoceutics Inc; 2016.
On November 17, 2016, the US Food and Drug Administration (FDA) approved Intrarosa, vaginal dehydroepiandrosterone (DHEA)--also known as prasterone--for women experiencing moderate to severe pain during sexual intercourse due to menopause-related genital atrophy, or GSM. In clinical trials, daily treatment with a 6.5-mg vaginal ovule of DHEA was found effective in reducing symptoms of atrophy. Vaginal discharge was the most common adverse effect.
After menopause, DHEA, which is produced largely by the adrenal glands, represents the dominant source of all sex steroids. DHEA is enzymatically transformed at the intracellular level into estrogens. Because estradiol is inactivated at the site of its synthesis, use of vaginal DHEA causes little if any rise in serum estradiol levels.1,2
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Details of 2 studies
A pivotal randomized, double-blind, placebo-controlled phase 3 trial of intravaginal DHEA (6.5 mg daily) for treating postmenopausal dyspareunia in women with vulvovaginal atrophy was conducted over 12 weeks.1 The trial included 325 women treated with DHEA and 157 who received placebo.
All 4 coprimary objectives measured improved with treatment compared with mean baseline levels: percentage of parabasal cells in treated participants decreased by 27.7% over placebo (P<.0001); percentage of superficial cells increased by 8.44% over placebo (P<.0001); vaginal pH decreased by 0.66 pH unit over placebo (P<.0001); and pain with sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = .0002). In addition, participant-reported moderate to severe vaginal dryness (present in 84% of women at baseline) improved considerably at 12 weeks, and gynecologic evaluation revealed improvements in vaginal secretions, epithelial integrity and surface thickness, and color.1
About 6% of participants reported vaginal discharge as an adverse effect. Levels of serum steroids remained within the normal range for postmenopausal women.1
Another study, in which authors integrated data from four phase 3 clinical trials of postmenopausal women with vulvovaginal atrophy treated with vaginal DHEA (n = 723) or placebo (n = 266) for 12 weeks, analyzed serum steroid levels measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry.2
At 12 weeks' treatment, mean levels of the most relevant sex steroid, serum estradiol, was noted to be 3.36 pg/mL, 19% below the normal postmenopausal value of 4.17 pg/mL.The mean level of estrone sulfate was noted to be 209 pg/mL, lower than the normal 220 pg/mL level in postmenopausal women. Further, androsterone glucuronide, the primary metabolite of androgens, also remained well within normal postmenopausal values.2
The authors concluded that the study data demonstrate that a daily 6.5-mg dose of intravaginal DHEA in postmenopausal women achieves the desired local efficacy (ie, amelioration of vulvovaginal atrophy symptoms) without systemic sex steroid exposure.2
WHAT THIS EVIDENCE MEANS FOR PRACTICEIn postmenopausal breast cancer survivors with hormone receptor-positive tumors, adjuvant therapy with AIs profoundly reduces endogenous estrogen levels and reduces recurrence risk. Unfortunately, AI use also increases symptomatic genital atrophy. Since the efficacy of AIs in preventing recurrence appears to relate to suppression of systemic estradiol, oncologists understandably are often reluctant for such patients to use even low-dose vaginal estrogen.
The new information detailed in this article indicates that the recently FDA-approved vaginal DHEA (prasterone) ovules, as well as the 3-month low-dose estradiol vaginal ring, improve symptoms of genital atrophy without causing appreciable elevations in serum estradiol levels. This will be welcome news for all women with symptomatic genital atrophy, including those who have been treated for estrogen-sensitive cancers. Clinicians should be aware that, although package labeling for vaginal prasterone does not list a history of breast cancer as a contraindication, a history of breast cancer is listed in the Warning and Precautions section of package labeling, noting that this medication has not been studied in women with a history of breast cancer.
-- Andrew M. Kaunitz, MD
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