DHEA for Urogenital Atrophy and Sexual Function

Susan R. Davis, MBBS, FRACP, PhD

Disclosures

January 15, 2015

Question

What is the current evidence on the use of intravaginal dehydroepiandrosterone (DHEA) in urogenital atrophy and sexual function?

Commentary from Susan R. Davis, MBBS, FRACP, PhD

Sex steroids are vital for the integrity of the urogenital tract (vagina, vulva, lower urinary tract, and supporting pelvic structures). These tissues are rich in estrogen and androgen receptors.[1] In addition, estrogen and testosterone enhance blood flow to the genital tract,[2] which is fundamental for genital sexual arousal and lubrication.[3]

The fall in estrogen at menopause and the gradual decline in androgen levels with age[4] result in what is now described as genitourinary syndrome of menopause (GSM). This includes vulvovaginal atrophy (VVA) and an increase in vaginal pH.[3] At a cellular level, there is a reduction in healthy vaginal epithelial superficial cells and an increase in parabasal cells. The increase in vaginal pH changes the vaginal microflora. Lactobacilli disappear, and as a consequence there is increased vulnerability to vaginal infection. Symptoms of VVA include vaginal dryness, irritation, itching, infection, and dyspareunia.[5] This in turn leads to diminished sexual desire, arousal difficulties, diminished physical and emotional sexual satisfaction, and relationship issues.[6]

Most postmenopausal women will experience some GSM symptoms.[7] Symptoms of VVA can be effectively treated with either vaginal or systemic estrogen therapy.[8] Estrogenization will thicken and revascularize the vaginal epithelium, lower vaginal pH, and normalize vaginal flora. The number of vaginal epithelial superficial cells will increase.[8,9] Although data show that vaginal estrogen acts locally, thus minimizing systemic exposure to estrogen, some studies have shown blood estradiol levels increase with vaginal application.[10,11,12] A two- to fivefold increase in serum estradiol has been reported after one week of vaginal administration of a 25 µg estradiol vaginal tablet or 1g of 0.625 mg conjugated estrogen cream.[10] After 24 weeks of treatment, only 2% of women have estradiol levels outside the postmenopausal range.[13]

Researchers have looked for alternative approaches for GSM management. In postmenopausal women, adrenal dehydro-epiandrosterone (DHEA) is an important precursor for extra-gonadal biosynthesis of estrone (by aromatization) and testosterone (by 5-alpha reduction). Casson and colleagues first studied the effects of a vaginal DHEA 150 mg pessary versus placebo in five premenopausal women as a mode of hormone delivery and reported an increase in blood levels of DHEA with this approach.[14] The daily vaginal application of three different doses of DHEA cream (6.5 mg, 13 mg, and 23.5 mg) was studied for one week in postmenopausal women.[15] Labrie and colleagues reported a decrease in vaginal pH, an improvement in the vaginal cell maturation index, and restoration of DHEA levels to the range for premenopausal women at the highest dose.[15] The circulating levels of other sex steroids remained within the normal range for postmenopausal women.

A randomized controlled trial of the daily application of three different doses of vaginal DHEA ovules (3.25 mg, 6.5 mg, or 13 mg) was studied over 12 weeks in 218 postmenopausal women who met the entry criterion of dyspareunia. This single study has resulted in a number of publications to support the efficacy of this treatment for VVA.[16,17,18,19,20,21] In these various publications, the investigators have reported an improvement in vaginal cytology and a reduction in pH. An analysis restricted to the women who fulfilled investigational criteria for a low percentage of vaginal epithelial cells and vaginal pH greater than 5 reported an increase in superficial cells and a reduction in pH with an associated improvement in dyspareunia compared with placebo.[21] Sexual function was assessed by three questions in the Menopause Quality of Life Questionnaire (sexual desire, vaginal dryness during intercourse, or avoiding intimacy) and by the Abbreviated Sexual Function Questionnaire. At 12 weeks the total Menopause Quality of Life Questionnaire sexual domain score showed a significantly greater response for each treatment group versus placebo, with more mixed findings in the Abbreviated Sexual Function Question-naire.[17]

The main limitation in interpreting the data on DHEA as a treatment for VVA and associated sexual function is that the clinical findings to date are all from a single 12-week study. This study was analyzed as intention to treat with the last observation carried forward for women who dropped out of the trial. Unfortunately, the publications have reported neither how many women actually completed the 12-week trial in each group nor the extent of missing data for each time point. The effects in terms of improvement in the study overall are interesting, as is the reported complete lack of absorption of the administered DHEA or change in blood levels of the metabolites. Considering how well drugs are absorbed through the vaginal mucosa, this is reassuring but also surprising.

It is biologically plausible that DHEA may alleviate VVA, and hence reduce dyspareunia, because the DHEA effects are likely to be mediated by local metabolism to estrone and testosterone. Thus vaginal DHEA can be considered a promising treatment alternative, but further large studies are needed to confirm efficacy and safety. Ideally these studies should evaluate less frequent self-administration of the DHEA ovule because most women would find the need to self-treat on a daily basis unacceptable.

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