Systemic Estrogen Therapy
Systemic estrogen therapy is indicated for vulvovaginal atrophy only in the context of menopausal vasomotor symptoms. In this case, a progestin is used to reduce the risk of endometrial cancer associated with unopposed systemic estrogen in women with an intact uterus. While systemic hormone replacement therapy is effective in abating vasomotor-related discomfort, 40% of women using systemic treatment still experience persistent vaginal dryness. Consequently, local estrogen therapy may frequently be required in conjunction with systemic treatment.[3,4]
Local Estrogen Treatment
Local estrogen therapy is the treatment of choice for women with vulvovaginal atrophy who lack other postmenopausal symptoms. Exogenous estrogen promotes the revascularization and thickening of the vaginal epithelium and lower urinary tract, resulting in increased lubrication, improved elasticity, decreased vaginal pH and positive effects on VMI.[6,12,18] Moreover, local estrogen preparations have been shown to decrease symptoms of atrophy, including vaginal dryness, irritation, pruritus, dyspareunia and urinary urgency.[1,19,20] These treatments also increase blood flow and lubrication, which may positively affect sexual function.
While treatments for vulvovaginal atrophy have often focused on the vagina, it is critical to address care for the vulvar vestibule as well. The structures of the external vulva, vulvar vestibule and vagina are derived from different embryologic origins and have separate blood supplies. As such, these anatomic structures respond differently to physical, inflammatory and hormonal insults. Dyspareunia resulting from vulvovaginal atrophy often occurs primarily at the vulvar vestibule, in large part due to the very hormonally sensitive nature of the tissue. Furthermore, the vestibule houses the ostia of the Bartholin's, Skene's and minor vestibular glands, which play an important role in lubrication and arousal. Direct application of local estrogen to the vulvar vestibule, with the consideration of adding a local androgen as well, is important to adequately treat symptoms of vulvovaginal atrophy.
Currently, two vaginal estrogens, estradiol and conjugated estrogens (CE), are approved in the United States for treatment of vaginal atrophy, vaginal dryness and dyspareunia.[201–204] Various formulations for vaginal use include creams, tablets and hormone-releasing rings ( Table 1 ). A Cochrane meta-analysis, which analyzed 19 trials with 4162 women, found that creams, pessaries, tablets and the estradiol vaginal ring appeared to be equally effective in relieving symptoms associated with vaginal atrophy, when compared to placebo and nonhormonal gel. A recent survey of 423 women over age 50 experiencing menopausal symptoms indicated preference using disposable applicators with small tablets to deliver local estrogen.
Estriol, a lower-potency estrogen, has recently been investigated in Europe for the treatment of vulvovaginal atrophy. One study has evaluated the efficacy and safety of a low-concentration estriol formulation, a 0.005% estriol vaginal gel that provides 50 micrograms of estriol per direct application to the vagina. This prospective, double-blind, placebo-controlled study randomized 167 women to receive either 1 g of ultra-low-dose vaginal estriol gel or placebo daily for 3 weeks, then twice weekly for up to 12 weeks. The estriol treatment group showed positive changes in VMI, vaginal pH, vaginal dryness and global symptom score. Treatment-related adverse events were similar among groups.
Present consensus is that the smallest effective dose should be utilized for long-term therapy, with eventual tapering of estrogen to maintenance dosing once urogenital function has improved. Although it is believed to be acceptable to continue treatment indefinitely, safety data beyond one year are not yet available.[1,16] The principal concern with the use of unopposed estrogen in a woman with an intact uterus is endometrial hyperplasia; however, low-dose estrogen formulations have not been shown to increase the incidence of proliferative endometrium when compared with placebo. Furthermore, the North American Menopause Society states that endometrial surveillance and progestin therapy are not indicated in asymptomatic, low-risk women receiving low-dose vaginal estrogen. Nevertheless, it is important to note that although local estrogen therapies may not significantly stimulate the endometrium, all cases of postmenopausal bleeding warrant evaluation with ultrasound examination of endometrial thickness and endometrial sampling.
Selective ER Modulator Treatment
Certain selective estrogen receptor modulators (SERMs), which act as estrogen agonists/antagonists, show promise for the future of vulvovaginal atrophy treatment. Although raloxifene and tamoxifen, commonly used to treat breast cancer and osteoporosis, are of the most well-known SERMs, they are not at the focus of vulvovaginal atrophy therapy. Instead, trials have demonstrated that SERMs ospemifine (Osphena) and lasofoxifene (Fablyn), also utilized for osteoporosis treatment, show greater potential. More specifically, these medications have demonstrated positive effects on vaginal epithelium thereby reducing the symptoms and progression of atrophy.[25,26]
Ospemifene, a triphenylethylene SERM, was initially developed as a treatment for postmenopausal osteoporosis, but was found to have favorable estrogenic effects on the vaginal epithelium in Phase I and II clinical trials. This therapy completed Phase III clinical trials focused on treatment of postmenopausal vulvovaginal atrophy in late 2009 and was approved by the US Food and Drug Administration (FDA) in early 2013 for treatment of moderate to severe dyspareunia.[25,101] In a 12-week Phase III trial, 826 postmenopausal women between the ages of 40 and 80 with vulvovaginal atrophy were randomized to receive ospemifene 30 mg/day, 60 mg/day or placebo orally. Participants of 30 and 60 mg of ospemifene showed statistically significant improvement in VMI, vaginal pH and vaginal dryness, while benefits for dyspareunia were seen only in the 60 mg/day group. The most frequently reported adverse event was hot flushes, found in 8–9% of women taking ospemifene. Furthermore, there was no proliferative effect on endometrial tissue noted. Although more research is necessary, ospemifene's antiestrogenic activity in several preclinical models of breast cancer makes this SERM a possible treatment option for women with breast cancer suffering from vulvovaginal atrophy.
Like ospemifene, lasofoxifene shows promising results for treatment of vulvovaginal atrophy as it has demonstrated positive effects on vaginal epithelium. A series of large multicenter studies referred to as the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) evaluated the efficacy and safety of lasofoxifene for osteoporosis and vulvovaginal atrophy symptoms in postmenopausal women.[28,29] In a Phase III trial, lasofoxifene 0.25 and 0.5 mg significantly reduced symptoms of moderate to severe vulvovaginal atrophy over the course of 12 weeks, while also improving VMI and vaginal pH. Additional studies have supported these findings and have also shown decreased dyspareunia in postmenopausal women treated with lasofoxifene. In the five-year data from the PEARL study, an elevated risk of endometrial cancer was not observed; however, five women were found to develop endometrial hyperplasia. In addition, lasofoxifene increased the risk of both venous thromboembolism and pulmonary embolism.[26,29] Lasofoxine is approved in Europe as a treatment for osteoporosis. Despite the positive PEARL trial results, Pfizer withdrew its FDA application in 2010.
Tissue-selective Estrogen Complexes Therapy
Tissue-selective estrogen complexes (TSECs) pair a SERM with estrogen(s) with the goal of relieving hot flushes, treating vulvovaginal atrophy and preventing bone loss, while also protecting the endometrium and breast. Success with TSECs may potentially be achieved through targeting different molecular and cellular activities of certain estrogen and SERM components. Bazedoxifene (BZA) paired with CE was the first TSEC to undergo review. BZA was initially investigated as an 'ideal' SERM for osteoporosis, as it acts as an ER agonist, providing a protective effect on bone and lipid profile, while serving as an ER antagonist for breast and endometrial protection. Although the FDA declined approval as a stand-alone drug, this compound has shown promise when combined with a CE as a TSEC.[30,32] The Selective Estrogens Menopause and Response to Therapy 1 (SMART-1), a two-year, multicenter, randomized double-blind, placebo- and active-controlled Phase III study, evaluated 3397 postmenopausal women, aged 40–75 years, with intact uteruses. The primary focus of the study was the incidence of endometrial hyperplasia, with secondary attention to bone mineral density, menopausal vasomotor symptoms, VMI, menopause-related quality-of-life measures, overall safety and tolerability. This Phase III trial found that BZA/CE 20 mg/0.625 mg and 20 mg/0.45 mg significantly reduced the frequency and severity of hot flushes at 12 weeks and improved vaginal atrophy with reduced incidence of dyspareunia at 24 months compared to placebo. The incidence of adverse events was similar across treatment groups. Another study from the SMART-1 trial evaluated endometrial safety of BZA/CE in postmenopausal women, finding that treatment was associated with less than a 1% rate of endometrial hyperplasia over two years with no difference in endometrial thickness between the BZA/CE and placebo groups.
The primary objective of the SMART-3 trial was to compare the safety and efficacy of multiple doses of BZA/CE and placebo for treatment of moderate to severe vulvovaginal atrophy associated with menopause. In this Phase III trial, 625 postmenopausal women aged 40–65 with vulvovaginal atrophy were randomized to receive BZA/CE 20 mg/0.625 mg, BZA/CE 20 mg/0.45 mg, BZA 20mg alone or placebo. After 12 weeks of treatment, both BZA 20 mg/CE 0.625 mg and CE 0.45 mg significantly increased vaginal maturation and improved vaginal dryness compared to placebo. Only the higher dose (BZA 20 mg/CE 0.625 mg) estradiol group showed significant improvement in vaginal pH and vulvovaginal atrophy symptoms. Although the BZA/CE treatment groups did not report increased adverse events, there was a significantly higher incidence of vaginitis in all three groups compared with placebo.
Local Androgen Treatment
Although the vagina has previously not been considered an androgen-dependent organ, innovative animal studies suggest that androgens may have a direct effect on vaginal structure and function, independent of estradiol.[36,37] In recent years, the role of testosterone in female sexual function has been explored, with exogenous testosterone administration improving desire, libido and arousal. Androgen receptors (ARs) and aromatase have been identified with immunohistochemistry in vaginal epithelium, suggesting both direct and indirect effects of testosterone on vaginal tissue.[39,40]
A recent study demonstrated AR expression in the vaginal epithelium of premenopausal women, revealed by immunostaining in both the mucosa and stroma. Detection of AR protein in the vagina showed no differences between anterior and posterior walls, or proximal and distal parts. In addition, there appears to be a negative correlation between age and AR score in the vaginal epithelium, with increasing age and postmenopausal status showing less AR protein expression. In support of this theory, in 2003 Baldassarre et al. demonstrated that expression of AR messenger RNA was found to be significantly higher in premenopausal women than postmenopausal women. Furthermore, testosterone administration was shown to increase AR protein expression in both the vaginal mucosa and stroma.
A Phase I/II pilot study examined the impact of vaginal testosterone alone on vaginal atrophy in women with breast cancer on long-term aromatase inhibitor therapy, where estrogen is contraindicated. Twenty-one postmenopausal women with breast cancer on aromatase inhibitors suffering from vaginal atrophy were treated with vaginal testosterone cream (300 or 150 mcg) daily for 28 days. Vaginal atrophy symptoms, including dryness and dyspareunia, improved significantly and this improvement continued to persist after cessation of treatment. In the 300 mcg vaginal testosterone group, vaginal pH decreased from 5.5 to 5.0 and showed a statistically significant 20% increase of VMI. There was no significant difference in estradiol levels before and after treatment, with most levels undetectable (<5 pg/mL) and two levels around 7 pg/mL. Testosterone levels increased from <21 to <42 ng/dL in all patients expect one, where the level was 113 ng/dL. Because estradiol levels remained suppressed after treatment at less than 8 pg/mL, the authors concluded that a four-week course of vaginal testosterone improved signs and symptoms of vaginal atrophy without the potential risks associated with elevated systemic estradiol levels.
DHEA, a sex steroid precursor, has shown to have positive effects on sexual function. However, like estrogen, levels of DHEA decline with age. Despite the fact that a recent randomized controlled trial did not show a benefit of oral DHEA therapy for women, advantages of intravaginal DHEA on sexual function are still emerging. In postmenopausal women, vaginal DHEA has been shown to improve VMI scores and to decrease vaginal pH in seven days, without significantly elevating circulating levels of estrogen. Intravaginal DHEA has been found to act on all three layers of the vagina, inducing mucification of the epithelium, increasing density of collagen fibers in the vaginal wall and stimulating the muscle layer. Consequently, it has been suggested that intravaginal DHEA may be superior to intravaginal estradiol, which acts mainly on the superficial epithelial layer.
In a prospective, double-blind, placebo-controlled Phase III clinical trial, 126 postmenopausal women with moderate to severe vaginal atrophy were randomized to 0.0%, 0.25% (3.25 mg), 0.5% (6.5 mg) or 1.0% (13 mg) intravaginal DHEA for a 12-week study period in order to evaluate effects on sexual dysfunction. Intravaginal DHEA applied daily led to improvements in sexual desire/interest, arousal, orgasm and pain with sexual activity. In a follow-up study, 114 postmenopausal women with dyspareunia as the most bothersome symptom of vaginal atrophy underwent 12 weeks of treatment of varied doses of intravaginal DHEA. Researchers found that both VMI and score of pain severity during sexual activity improved while DHEA levels remained within normal postmenopausal ranges. These results revealed that beneficial local effects may be achieved without significant systemic absorption.
In response to concerns over estrogen therapy, alternative methods, including oxytocin treatments, are being explored to address vulvovaginal atrophy. Oxytocin, a peptide hormone released by the posterior pituitary, best known for its role in female reproduction, has been shown to increase rates of wound healing, mucosal blood flood and secretion of several growth factors. In a small double-blind, randomized pilot study designed to determine the value of intravaginal oxytocin in restoring atrophic vaginal mucosa in postmenopausal women, 20 postmenopausal women with vaginal atrophy symptoms received either intravaginal oxytocin (1 mL of 1 mg oxytocin in a carboxymethylcellulose base) or placebo gel for 7 days. The treatment group showed a significant improvement upon colposcopic examination, with 70% of the treatment group demonstrating no signs of vaginal atrophy. Although 70% of the treatment group reported relief of symptoms, this result was not significantly different from the placebo group. Notably, five of the abnormal biopsies obtained at baseline from participants with vulvovaginal atrophy showed normal results after treatment. Larger studies are currently in progress to further evaluate oxytocin as a clinical treatment for vaginal atrophy.
Phytoestrogens, plant-derived xenoestrogens or dietary estrogens, are being explored as a possible safe alternative to hormonal therapy. Isoflavones, such as genistein and daidzein, which are found in soybeans, are the most studied of the phytoestrogens. When administered orally, phytoestrogens do not seem to have an effect on vaginal epithelium; however, intravaginal application has shown some promise. A small prospective, randomized, controlled study of 62 postmenopausal women demonstrated a significant improvement in genital symptoms, colposcopy scores and VMI after 90 days of daily intravaginal administration of genistein (97 mcg), compared to baseline. However, this improvement was also seen in the control group who applied hyaluronic acid (HA).
In a recent double-blind, randomized placebo-controlled study, the efficacy of new isoflavone vaginal gel was compared with the effectiveness of conjugated equine estrogen (CEE) and placebo in treating vulvovaginal atrophy (Glycine Max L. Merr). In this study, 90 postmenopausal women were treated for 12 weeks with either isoflavone vaginal gel 4% (1 g/day), CEE cream (0.3 mg/day) or placebo gel. Women treated with isoflavone gel showed a similar improvement to the estrogen group for vaginal dryness and dyspareunia, both of which differed significantly from the placebo group. Additionally, there was also a significant increase in VMI with isoflavone gel treatment. No changes in endometrial thickness or estradiol levels were observed in any of the study groups. Accordingly, the authors concluded that isoflavone vaginal gel is effective in the treatment and management of vaginal atrophy and may be a viable option for women who have contraindications or decline hormone therapy.
Expert Rev of Obstet Gynecol. 2013;8(5):457-465. © 2013 Expert Reviews Ltd.