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Intravaginal DHEA for the Treatment of Vulvovaginal Atrophy, Intracrinology at Work

Part of the ISGE Series book series (ISGE)

Abstract

The normal blood estrogen concentrations in women treated with physiological amounts of DHEA are not different from the situation observed in about 25% of normal postmenopausal women who have sufficiently high endogenous DHEA activity to avoid the symptoms of menopause: these women are not symptomatic and, consequently, do not need DHEA replacement. The administration of intravaginal DHEA permits to increase DHEA availability locally in the vagina where the symptoms of sex steroid deficiency are present, especially pain at sexual activity and vaginal dryness. The local addition of exogenous DHEA permits to compensate for the absence of a specific stimulator of DHEA secretion when serum DHEA decreases and becomes symptomatic.Starting at menopause, DHEA becomes the exclusive source of all estrogens and androgens in women. It remains, however, that both sex steroids are essential for the normal functioning of most tissues during the remaining life of women. In fact, the marked and continuing decrease in DHEA availability with age is responsible for the menopausal symptoms which should best be corrected by replacing the missing amount of DHEA. It should also be taken into account that women are not only missing estrogens after menopause but are exposed to declining levels of androgens in parallel with the decreasing serum DHEA concentrations starting at the age of 30 years with an average 60% loss already observed at time of menopause.

An efficacious and safe treatment of menopause must obey the rules of physiology and maintain blood concentrations of estradiol (E2) within the normal postmenopausal range or below the 95th centile of 9.3 pg E2/ml as measured by validated, accurate, and reliable mass spectrometry assays. Based upon this new understanding of sex steroid physiology in women, our objective was to develop a novel tissue-specific prohormone replacement therapy using DHEA. This strategy should provide the appropriate physiological amounts and ratios of androgens and estrogens in the various cell components of the vagina in need of these two sex steroids, while avoiding exposure of the extravaginal tissues.

The clinical efficacy and metabolism of intravaginal DHEA have been evaluated in six clinical studies, including three 12-week efficacy studies (ERC-210, ERC-231, and ERC-238). In the three independent prospective, randomized, double-blind, and placebo-controlled clinical trials, the effect of daily intravaginal 0.50% (6.5 mg) prasterone administered for 12 weeks was examined on the four co-primary objectives suggested by the FDA and EMA guidance in women having moderate to severe pain at sexual activity (dyspareunia) identified at baseline as their most bothersome symptom. In 436 women treated with 0.50% prasterone and 250 women who received placebo, an average 35.1% decrease in the percentage of parabasal cells (p < 0.0001 over placebo), an average 7.7% increase in the percentage of superficial cells (p < 0.0001 over placebo), and a mean 0.72 unit decrease in vaginal pH (p < 0.0001 over placebo) were observed. The severity score of dyspareunia was decreased by a 0.46 unit (49% over placebo) (p < 0.0001). The severity score of moderate to severe vaginal dryness, on the other hand, decreased by 0.31 unit over placebo (p < 0.0001). A very positive evaluation was recorded on the acceptability of the technique of application of the prasterone insert while the male partners gave a positive evaluation of the changes observed in their sexual relationship.

The efficacy data demonstrate highly beneficial effects on all the VVA symptoms and signs evaluated in the absence of significant systemic exposure to the sex steroids in agreement with the physiology of menopause and intracrinology. The sophisticated pathways of local and intracellular estrogen and androgen biosynthesis from DHEA and the intracellular inactivation of the sex steroids at their site of formation in the vagina eliminate a meaningful change of estrogens and androgens in the circulation which all remain within the normal biologically inactive postmenopausal range, thus avoiding exposure of the other tissues and side effects.

The administration of intravaginal DHEA increases DHEA availability exclusively locally in the vagina where symptoms of sex steroid deficiency, especially pain at sexual activity and vaginal dryness, have become most bothersome. Accordingly, the intravaginal addition of a small amount of DHEA simply compensates for the decreased availability of serum DHEA with age. Most importantly, the VVA steroid deprivation symptoms which are reported in at least 50% of postmenopausal women can be avoided without safety concerns.

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Labrie, F. (2018). Intravaginal DHEA for the Treatment of Vulvovaginal Atrophy, Intracrinology at Work. In: Birkhaeuser, M., Genazzani, A. (eds) Pre-Menopause, Menopause and Beyond. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-319-63540-8_24

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