Efficacy of Intravaginal Dehydroepiandrosterone (DHEA) on Moderate to Severe Dyspareunia and Vaginal Dryness, Symptoms of Vulvovaginal Atrophy, and of the Genitourinary Syndrome of Menopause

Fernand Labrie, MD, PhD; David F. Archer, MD; William Koltun, MD; Andrée Vachon, MD; Douglas Young, MD; Louise Frenette, MD; David Portman, MD; Marlene Montesino, MD; Isabelle Côté, BSc; Julie Parent, PhD; Lyne Lavoie, MSc; Adam Beauregard, BSc, MBA; Céline Martel, PhD; Mario Vaillancourt, BSc, MBA; John Balser, PhD; Érick Moyneur, BSc, MA; the members of the VVA Prasterone Research Group

Disclosures

Menopause. 2016;23(3):243-256. 

In This Article

Discussion

The present data confirm the beneficial effects of intravaginal DHEA on the coprimary parameters recommended by the US FDA[28] for evaluation of therapeutic efficacy on the symptoms and signs of VVA. The present study is in close agreement with the data obtained in our previous clinical trials,[5,24,26,34] and completes the requirements of the ICH guideline for 1,500 participants exposed to a new chemical entity.

The arrest of estrogen secretion by the ovaries at menopause,[18] combined with the decreased secretion of the sex steroid precursor DHEA by the adrenals starting at the age of 30 years and continuing after menopause,[23,35] is accompanied by a long series of symptoms/signs associated with the aging process in the vagina, genitourinary system, vasomotor system, skin, skeleton, brain, cardiovascular system, and probably at various degrees in all other body systems.[36,37] VVA has been reported in more than 60% of women after the fourth year of menopause.[38,39,40]

The intracellular transformation of DHEA into estrogens is apparently responsible for the maturation of the parabasal cells which are transformed into intermediate and then into superficial cells.[5] DHEA has also been shown in preclinical studies to induce mucification of the epithelium or superficial layer of the vaginal mucosa while increasing the density of the collagen fibers in the second layer (lamina propria) and stimulating the muscular third layer.[41]

Systemic HT does not permit control of the urogenital atrophy in up to 45% of the women.[38] It is estimated that only about 7% of postmenopausal women suffering from VVA receive treatment (Kingsberg S, personal communication). The REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs)[42] has indicated that women have a lack of symptom relief with the over-thecounter products and have concerns about the safety of estrogen-based therapies. As far as nonhormonal moisturizers/lubricants are concerned, there is no evidence that they have an effect other than placebo[38] and certainly do not correct the problems responsible for the VVA symptoms.

The VVA symptomatology can affect daily activities, including walking, sitting, and exercising.[43] The urogenital symptoms not only represent a much more common problem than is recognized not only by the medical community but also by women themselves, who are often unwilling or too embarrassed to complain about these symptoms while believing that it is an unavoidable part of getting older. The effects on the individual can be serious when they markedly impact their sexuality, redefining their feminine role and ultimately negatively impacting their physical and mental well being.[40]

So far, VVA treatment with estrogens has essentially been limited to the most superficial or epithelial layer, which is largely responsible for pain at sexual activity or dyspareunia. Contraction of the introitus, and shortening and narrowing of the vaginal canal are not related to the superficial layer, but rather depend upon loss of collagen and muscular components in the lamina propria and muscularis layers, respectively.[41] In animal models, androgens have been shown to maintain structural integrity of vaginal tissues and to enhance vaginal hemodynamics independently from estrogens.[44]

The loss of rugosity and elasticity of the vagina related to menopause is due to the breakdown of collagen supporting the vaginal epithelium.[45,46] Our preclinical studies[41] have clearly demonstrated a stimulatory effect of the androgens derived from DHEA on collagen formation in the second layer of the vagina, namely the lamina propria. This effect is in agreement with the recently described stimulatory effect of DHEA on collagen formation in the human skin dermis, the equivalent of the lamina propria in the vagina.[47]

The decrease of glycogen in VVA is accompanied by increased pH, which modifies the vaginal microflora with the loss of protective microorganisms and the increased risk of overgrowth of pathogenic species.[40,48] Recurrent urinary tract infections are thus more common in postmenopausal women, with a higher incidence of infection complications including pyelonephritis.[49]

The International Menopause Society Writing Group, due to the progressive severity of VVA, has recommended to start treatment early upon onset of menopause before irreversible atrophic changes occurred.[1,50] If VVA is left untreated, these is increased probability of the epithelium becoming friable, thus causing ulcerations, petechiae, and tears, with bleeding at minimal trauma (intercourse, insertion of a speculum, etc).[51,52] Since vaginal atrophy is a chronic condition, which, unlike hot flushes, does not tend to diminish over time, long-term treatment is frequently required as symptoms may recur upon cessation of therapy.[53] In fact, VVA symptoms persist and increase in severity with time in the absence of treatment.[8]

Safety is thus particularly important for VVA therapy since treatment needs to be continued to maintain the benefits.[1] Nonestrogenic treatments for VVA are required to avoid the serious concerns regarding the potential stimulatory effects of estrogens on the endometrium and breast.[54,55,56,57] A sign of systemic estrogenic effect of ospemifene—a mixed estrogenic/antiestrogenic compound—is the 49% increase in serum sex hormone binding globulin (SHBG), an estrogen-sensitive parameter, from 54.48±25.19 at baseline to 81.31±3.90 nmol/L at 52 weeks.[58] No change was observed in the placebo group (59.33±25.43 nmol/L at baseline vs 54.37±26.44 nmol/L at 52 wks). At the same 60-mg daily dose of ospemifene, there was a 52% increase in endometrial thickness. Stimulatory effects with ospemifene have also been observed on the endometrium.

Major progress in the field of intracrinology has been made by the elucidation of the structure of most of the tissue-specific genes that encode the steroidogenic enzymes responsible for the transformation of DHEA into androgens and/or estrogens locally in peripheral tissues.[17,59,60,61,62,63,64] This cellspecific transformation of DHEA is, however, exerted at different levels, and ratios of estrogens and androgens in different cell types. Most importantly, to protect the uterus and other tissues after menopause, the active hormones made in peripheral tissues are inactivated at their site of synthesis before being released outside the cells as inactive metabolites, thus explaining why there is no or no biologically significant leakage of the active sex steroids into the circulation after their formation from DHEA.[17,35]

A most important characteristic of DHEA is the absence of possible stimulatory effect on the endometrium.[65] In fact, even if women continue to be exposed to relatively high circulating levels of DHEA after menopause, it is well recognized that endometrial atrophy is observed in all normal women as a characteristic of menopause.[20,21] This finding is in agreement with the absence of enzymes, especially aromatase, able to transform DHEA into estrogens in the human endometrium, despite its exposure to DHEA from the circulation.[66,67,68] Protection of the endometrium is the most obvious reason why evolution over 500 million years has succeeded in engineering an endocrine system unique to the human species and able to protect women from systemic exposure to estrogens after menopause.

Most importantly, no biologically significant leakage into the circulation of the active sex steroids made intracellularly takes place with intravaginal DHEA, thus explaining the highly beneficial effects observed in the vagina in the absence of significant changes in circulating estrogens or androgens.[5,25,26,69,70,71,72,73] In fact, as mentioned above, the active steroids are inactivated locally in the vagina before being released as inactive metabolites into the general circulation from which they are eliminated by the kidneys and the liver.

In agreement with this well recognized observation of nature of an absence of effect of DHEA on the endometrium, the endometrial atrophy observed in all women at the start of treatment remained unaffected at 12 months of percutaneous DHEA administration, even if serum DHEA was increased by 5.5-fold.[74] Moreover, no change in endometrial thickness was found after 6 months of daily oral dosing with 50 mg DHEA in postmenopausal women.[75]

In addition to the observation that serum DHEA remains within normal postmenopausal values after intravaginal administration of 0.50% DHEA,[18,69,70,72]the absence of aromatase in the human endometrium[67] explains the absence of estrogen formation from DHEA in the endometrium of normal women and the endometrial atrophy observed in all normal postmenopausal women. To further support the above explanation, we have obtained endometrial histology in 422 women who had endometrial biopsy at baseline and at exit of study after intravaginal administration of 0.50% DHEA for 52 weeks.[65] Other studies with intravaginal DHEA doses of 3.25 mg (n=126), 6.5 mg (n=129), and 13 mg (n=30) were performed for 12 weeks in women who similarly had baseline and end-ofstudy biopsies.[65] Endometrial tissue for histology was available in a total of 668 women at both baseline and end-of-study exposure. Endometrial atrophy or inactive endometrium was found in all women treated with intravaginal DHEA.[65]

All estrogen-based vaginal formulations, on the contrary, increase serum estrogens, even at low dose.[76] In fact, the vagina seems to be able to transport E2 towards the circulation with little or no metabolism,[77,78] thus resulting in higher serum E2 concentrations.[79]

It seems of interest to mention that despite the complete arrest of estrogen secretion by the ovaries at the time of menopause, while serum E2 levels are kept at biologically inactive concentrations in all women, not all postmenopausal women suffer from menopausal symptoms despite a common absence of biologically active circulating estrogens. Consequently, the hormonal difference between postmenopausal women suffering from vaginal atrophy symptoms (approximately 75% of women) and those without symptoms (approximately 25%) is not related to the estrogens, which remain at biologically inactive serum levels in all women. In fact, the possible hormonal difference between the two groups of women may be the difference in the availability of DHEA—the exclusive source of sex steroids in women after menopause.[18]

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