The symptoms of vulvovaginal atrophy are caused by loss of estrogen production with menopause [1]. After menopause, serum estrogen levels fall from about 120 to about 20 pg ml⁻¹. Decreased estrogen levels lead to transformation of the vulvovaginal epithelium from a thick appearance to one that is pale, thin, prone to inflammation, and increased friability [4, 5]. A large number of estrogen receptors are found in the vulvovaginal area, which indicates the important role of estrogen to maintain the structure and function of this area [6]. The decreased levels of estrogen that accompany menopause cause atrophy of the vulva and vagina. Concurrently, the vagina shortens, narrows, and becomes less elastic. Blood flow to the vagina decreases which causes it to become pale and thin, which results in decreased vaginal secretions and increased susceptibility to vaginal pain and trauma [4, 7]. The degree of vaginal dryness increases in severity as time after menopause progresses [7].

For women with vulvovaginal atrophy who lack other postmenopausal symptoms, local estrogen therapy is the treatment of choice [3]. Exogenous estrogen promotes the revascularization and thickening of the vaginal epithelium, resulting in increased lubrication and elasticity [5, 8, 9]. Moreover, local estrogen preparations have been shown to decrease symptoms of atrophy, including vaginal dryness, irritation, pruritus, and dyspareunia [1, 10, 11]. These treatments may also improve sexual desire, arousal, and orgasmic function through increased blood flow and lubrication [7]. Since the vulva is also affected, treatment of vulvovaginal atrophy should ideally involve both the vagina and the vulva [12]. Nevertheless, most treatments thus far have focused on the vagina.

Two estrogens, estradiol and conjugated estrogens, are currently approved in the United States for treatment of vaginal atrophy, vaginal dryness, and dyspareunia. The various formulations for vaginal use include creams, tablets, and hormone-releasing rings. Although all of these formulations are equally effective, some women prefer the 3-month vaginal ring due to increased comfort, satisfaction, and ease of use [13]. In addition, estriol, a lower potency estrogen, has recently been investigated for the treatment of vulvovaginal atrophy. A double-blind and placebo-controlled study in 167 women evaluated the efficacy and safety of 0.005 % estriol vaginal gel when used daily for 3 weeks and then twice weekly for up to 12 weeks. The estriol treatment group showed positive changes in vaginal maturation index (VMI), vaginal pH, vaginal dryness, and a global symptom score, whereas treatment-related adverse events were similar among groups [14]. For long-term local estrogen therapy, it is recommended that the smallest effective dose is utilized, with the goal of eventually tapering local estrogen to maintenance dosing once urogenital function has improved. Although it may be acceptable to continue treatment indefinitely, safety data for local estrogen beyond 1 year is currently not available [1, 15].

Endometrial hyperplasia is the main concern with the use of unopposed estrogen by woman with an intact uterus. Local low-dose estrogen formulations, however, have not been shown to increase the incidence of proliferative endometrium when compared with placebo [15]. Furthermore, in the opinion of the North American Menopause Society, endometrial surveillance and progestin therapy are not indicated in asymptomatic, low-risk women receiving low-dose vaginal estrogen [1]. Nevertheless, although local estrogen therapies may not significantly stimulate the endometrium, all cases of postmenopausal bleeding should be evaluated by ultrasound of endometrial thickness and endometrial sampling [16].

Systemic estrogen therapy is indicated for vulvovaginal atrophy if menopausal vasomotor symptoms are also experienced. In this case, a progestin is used to reduce the risk of endometrial cancer associated with unopposed systemic estrogen for patients with an intact uterus [15]. Despite reduced vasomotor-related discomfort, 40 % of women who use systemic hormone therapy still experience persistent vulvovaginal dryness [17]. Consequently, local estrogen may frequently be needed in conjunction with systemic treatment [3, 4].

Certain selective estrogen receptor modulators (SERMs), which act as estrogen agonists/antagonists, are promising future treatments for vulvovaginal atrophy. Raloxifene and tamoxifen, commonly used in the setting of breast cancer and osteoporosis, are of the most well-known SERMs; however, they are not optimal for the treatment of vulvovaginal atrophy [18]. Instead, SERMs ospemifene (Osphena) and lasofoxifene (Oporia) are preferred due to their positive effects on vaginal epithelium and the progression of atrophy and symptoms, as demonstrated in placebo-controlled clinical trials [19, 20].

Ospemifene, which was initially developed as a treatment for postmenopausal osteoporosis, was found to have favorable estrogenic effects on the vaginal epithelium in phase I and II clinical trials. This SERM was approved by the US Food and Drug Administration (FDA) in early 2013 for the treatment of moderate to severe dyspareunia after completing a 12-week phase III trial in 826 postmenopausal women between the ages of 40 and 80 with vulvovaginal atrophy randomized to receive ospemifene 30 mg/day, 60 mg/day, or placebo orally [19]. Participants receiving 30 and 60 mg of ospemifene showed statistically significant improvement in VMI, vaginal pH, and vaginal dryness, while benefits for dyspareunia were only seen in the 60 mg/day group. The most frequently reported adverse event was hot flushes; no proliferative effects on endometrial tissue were observed [21]. In addition, ospemifene’s antiestrogenic activity in several preclinical models of breast cancer makes this SERM a potential candidate for the treatment of women with breast cancer suffering from vulvovaginal atrophy [19]. Another SERM, lasofoxifene, shows promising results for treatment of vulvovaginal atrophy. A series of large multicenter studies with lasofoxifene (PEARL) evaluated the efficacy and safety of this medication for osteoporosis and vulvovaginal atrophy symptoms in postmenopausal women [22, 23]. Lasofoxifene significantly reduced the symptoms of moderate to severe vulvovaginal atrophy while improving VMI and vaginal pH over a 12-week treatment period [24]. Additional studies have supported these findings and have also revealed decrease in dyspareunia in postmenopausal women treated with lasofoxifene [25]. Whereas in those studies that did not reveal an elevated risk of endometrial cancer, five women developed endometrial hyperplasia, and an increased risk of both venous thromboembolism and pulmonary embolism was observed [23]. Lasofoxifene is currently not approved for use in the United States.

Tissue-selective estrogen complexes (TSECs) pair a SERM with estrogen(s) aiming to relieve hot flushes, treat vulvovaginal atrophy, and prevent bone loss, while protecting the endometrium and breasts [25, 26].

The SERM bazedoxifene paired with conjugated estrogens was evaluated in a multicenter, randomized double-blind, placebo- and active-controlled phase III study in 3,397 postmenopausal women with intact uteruses aged 40–75 years [27]. This study revealed that bazedoxifene combined with conjugated estrogens significantly reduced the frequency and severity of hot flushes at 3 months and improved vaginal atrophy with reduced incidence of dyspareunia at 24 months as compared to placebo, while the incidences of adverse events were similar. Another study in postmenopausal women demonstrated that the combination of bazedoxifene with conjugated estrogens was associated with less than 1 % rate of endometrial hyperplasia over 2 years with no difference in endometrial thickness between the bazedoxifene/conjugated estrogens and placebo groups [28].

The primary objective of a further trial was to compare the safety and efficacy of multiple doses of bazedoxifene/conjugated estrogens for the treatment of moderate to severe vulvovaginal atrophy associated with menopause [29]. In this trial with 625 postmenopausal women aged 40–65, vaginal pH and vulvovaginal atrophy symptoms significantly improved as compared with placebo in the group treated with the higher dose of bazedoxifene/conjugated estrogens for 12 weeks. Although the treatment groups did not report increased adverse events, there was a significantly higher incidence of vaginitis in the groups receiving bazedoxifene/conjugated estrogens as compared with placebo.

Although the vagina has previously not been considered an androgen-dependent organ, studies suggest that androgens may have a direct effect on vaginal structure and function, independent from estradiol. Androgen receptors and aromatase have been identified in the vaginal epithelium, suggesting both direct and indirect effects of testosterone on vaginal tissue [30, 31]. In addition, less androgen receptor mRNA and proteins are expressed in the vaginal epithelium with increasing age and postmenopausal status. Furthermore, testosterone administration was shown to increase androgen receptor protein expression in both the vaginal mucosa and stroma [32].

An exploratory study examined the impact of vaginal testosterone alone on vaginal atrophy in 21 postmenopausal women with breast cancer on long-term aromatase inhibitor therapy [33]. After treatment with a vaginal testosterone cream daily for 28 days, the vaginal atrophy symptoms, including dryness and dyspareunia, improved significantly, and this improvement persisted after cessation of treatment. Since estradiol levels remained suppressed after the treatment, the authors concluded that a 4-week regimen with vaginal testosterone improved vaginal atrophy without the potential risks associated with elevated systemic estradiol levels.