Vulvar and vaginal atrophy (VVA), a chronic and progressive condition common among postmenopausal women, is characterized by symptoms such as dyspareunia and vaginal dryness, irritation and itching.1,2 Physiologic changes that occur with VVA include reduced vaginal superficial epithelial cells and increased parabasal (immature) cells, leading to reduced moisture and elasticity.
VVA symptoms are chronic and progressive and do not resolve without effective treatment.3 In addition, decreased vaginal pH can lead to an increased susceptibility to genitourinary infection.4 Dyspareunia is one of the most bothersome symptoms of VVA and it can be associated with sexual dysfunction, emotional distress and diminished quality of life.1 Given that half of women ages 50 to 79 are sexually active and that women are living longer, healthier lives,5 preserving lifelong vaginal health is an important goal.
Despite its negative impact on a woman's quality of life, VVA is often unrecognized, undiagnosed or undertreated.1,6 In contrast to symptoms such as hot flushes, which women readily associate with menopause, only about 25% of women associate VVA with menopause.7 The poor understanding of VVA is a cause for concern because, unlike hot flushes that usually diminish or resolve within a few years, VVA typically worsens over time.7 In fact, surveys of postmenopausal women show that nearly half of affected women do not mention their symptoms to a healthcare provider.8,9
Several possible reasons for this reticence exist. First, VVA and dyspareunia may be sensitive or embarrassing topics for women.10 Furthermore, women may be resigned to living with symptoms of VVA or may be unaware of available treatment options.6 Among women who have not discussed symptoms of VVA with a healthcare provider, 50% have the misperception that VVA is a natural and unavoidable part of aging.8 This belief is a common reason women do not discuss VVA symptoms with a healthcare provider.
Additionally, many providers do not discuss VVA and related symptoms with their patients. In a recent survey, women reported that at their annual gynecologic visit, only 19% of providers asked them about their sexual lives and only 13% raised the issue of VVA symptoms specifically.8 Forty percent of these women said they expected that their provider would initiate this discussion.8
Patient perceptions are important considerations in the management of VVA. Although vaginal estrogen-based therapies - including creams, tablets, and rings - are commonly used, their acceptance can be limited by inconvenience and concerns about safety. These issues can lead to poor adherence to treatment.8 Convenience-related issues include the vaginal route of administration, the need for privacy during application, and the messiness of creams.8
The dosing of vaginal creams can be confusing because the specified dose is given in milligrams for the active estrogen cream, in grams for the base cream, and in proportions for the applicator volume.4 Dosing errors may result in undertreatment or overtreatment. Inappropriate dosing may also occur when women act on the misconception that a vaginal estrogen cream should be used on an as-needed basis or as a lubricant.11 Over-the-counter lubricants and moisturizers are inadequate in that they provide only temporary relief and do not treat the underlying physical changes associated with VVA.12-14
Safety-related concerns such as worry about an increased risk for breast cancer represent another barrier to the acceptance of vaginal and systemic estrogen-based therapy.8 For example, between 2009 and 2010, the prevalence of systemic hormone use by postmenopausal women in the United States was only 4.7%.15 This is in sharp contrast to a decade earlier, when the overall prevalence of oral hormone use was 22.4% among postmenopausal women 40 and older.15 A challenge to effective treatment of VVA may be the mistaken belief that vaginal symptoms will be permanently cured with short-term treatment. This belief may exist, in part, because most women do not understand the physiologic changes underlying VVA or that it is a chronic and progressive condition.8 In contrast, women are familiar with the short-term management of other, more commonly known genitourinary conditions such as yeast and urinary tract infections. This familiarity may foster the misconception that VVA can also be successfully treated in the short term, which in turn may contribute to poor adherence to long-term treatment regimens.
A New Treatment Option
The US Food and Drug Administration recently approved an oral estrogen agonist/antagonist with tissue-selective effects, also referred to as a selective estrogen receptor modulator. This new treatment, ospemifene (Osphena), is the first oral prescription alternative to vaginal estrogen therapies for the treatment of dyspareunia, a common symptom of VVA.16 Phase 3 clinical studies demonstrated the efficacy and safety of this oral treatment in postmenopausal women with VVA.17-19
The safety and efficacy of ospemifene 60 mg/day for the treatment of VVA were investigated in two cohorts from a randomized, double-blind, placebo-controlled, 12-week, Phase 3 multicenter clinical trial conducted in the United States.19 The differentiating factor between the cohorts was their most bothersome symptom (MBS). One cohort self-identified dyspareunia (vaginal pain with sexual intercourse) as the MBS; the other cohort self-identified vaginal dryness as the MBS. The cohorts were randomized separately, and data were collected and analyzed in two separate databases. Data for the dyspareunia cohort (n = 605) were published earlier this year.19 This group represents the largest study population to date of women with VVA experiencing moderate to severe dyspareunia.19
This study included postmenopausal women between 40 and 80 years of age who had a diagnosis of VVA, defined as 5% or fewer superficial cells in the maturation index (MI) of the vaginal smear and a vaginal pH >5.19 Study participants were also required to have the MBS of moderate to severe vaginal pain with sexual activity (based on a 4-point scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe). Of the 605 women in the intent-to-treat population (all randomized participants who took at least one dose of study medication), 303 were randomized to receive ospemifene 60 mg/day, and 302 were randomized to receive placebo.
Ospemifene 60 mg/day demonstrated statistically significant efficacy compared with placebo in the mean change from baseline for all four co-primary endpoints (percentage of superficial cells and percentage of parabasal cells in the MI of the vaginal smear, vaginal pH, and severity of the MBS).19 By Week 12, treatment with ospemifene was associated with greater improvements in physiologic changes associated with VVA. The ospemifene group had a 12.3% increase in superficial cells compared with 1.7% in the placebo group (P <.0001). The ospemifene group had a 40.2% reduction in parabasal cells compared with no reduction in the placebo group (P <.0001). Improvement in vaginal pH was also observed: The ospemifene group had a -0.94 mean reduction compared with -0.07 in the placebo group (P <.0001).
Consistent with improvement in the physiologic changes of VVA, ospemifene also produced symptom relief: The mean reduction in MBS severity score was significantly greater in the ospemifene group (-1.5) than in the placebo group (-1.2; P = .0001). A two- to three-level improvement from baseline in the MBS of dyspareunia (from severe to mild or none, or from moderate to none) occurred in 52.8% of ospemifene recipients compared with 38.8% of placebo recipients. Therefore, ospemifene improves the underlying physiologic changes that trigger VVA symptoms. It increases superficial cells, decreases parabasal cells and decreases vaginal pH, effects that improve VVA symptoms.
A secondary analysis assessed the same four co-primary endpoints at Week 4, and significant improvement was observed for ospemifene 60 mg/day versus placebo in the mean change from baseline in superficial cells, parabasal cells and vaginal pH.19 Ospemifene demonstrated a greater increase in the percentage of superficial cells (13.0%) compared with placebo (1.8%), and a greater reduction in the percentage of parabasal cells (-38.0%) compared with placebo (0.3%) (P <.0001 for both comparisons; data on file) at Week 4. The reduction in vaginal pH at Week 4 also differed significantly between the study groups (-0.82% vs -0.15%; P <.0001; data on file). Thus, by Week 4 of treatment, ospemifene demonstrated improvement in physiologic changes associated with VVA.
The study also evaluated clinical signs of VVA. Investigators performed a visual examination of the vagina to assess five parameters (vaginal dryness, petechiae, pallor, friability and redness of the mucosa) on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). At 12 weeks, analysis of each of the parameters showed that the ospemifene group had more participants with improvement from baseline from "severe" to "none," from "severe" to "mild," and from "moderate" to "none."19 This improvement in the clinical signs of VVA is consistent with the improvement reported in physiologic changes, and may reflect the benefit of ospemifene on vulvar and vaginal tissues in addition to cellular and pH parameters.
The safety analysis in the dyspareunia cohort showed that the incidence of treatment-emergent adverse events (TEAEs) was 26% and 15% in the ospemifene and placebo groups, respectively. The incidence of hot flush, the most commonly reported TEAE, was 7% and 4%, respectively. However, hot flushes led to treatment discontinuation for only one woman in the treatment group and one in the placebo group. Other TEAEs that occurred in 3% or less of patients treated with ospemifene included urinary tract infection, vaginal candidiasis, vaginal discharge, vulvar and vaginal mycotic infection, nasopharyngitis, and headache. Most TEAEs were mild or moderate in severity. The incidence of serious adverse events (SAEs) was 1.3% (n = 4) in each group, and no SAEs were considered related to the study drug.
The researchers documented no clinically meaningful estrogenic effects (such as atypical endometrial hyperplasia or significant proliferation on the endometrium). From baseline to Week 12, slight clinically insignificant increases in endometrial thickness, as assessed by transvaginal ultrasonography, were observed in women who received ospemifene (0.4 mm) and in those who received placebo (0.1 mm). Based on endometrial biopsy samples, no cases of endometrial hyperplasia, polyps or cancer occurred in either study group during the study period. Ospemifene was effective and generally well tolerated.19
Available clinical and preclinical data support that ospemifene has a unique activity profile, with beneficial effects in the vagina,17-19 neutral effects in the breast,18,20,21 and minimal stimulatory effects on the endometrium.17,18 For additional information, refer to the full prescribing information, including the black box warning, available at http://www.shionogi.com/pdf/PI/Osphena-PI.pdf.22
Multiple clinical trials, including a long-term (52-week) study, have demonstrated that ospemifene can provide an effective treatment alternative for postmenopausal women with moderate to severe VVA.17-19,23 Ospemifene 60 mg has consistently achieved significant improvement in the common and distressing symptom of dyspareunia.17,19 Ospemifene may help fill a void in therapy. For example, a potential benefit of ospemifene (in addition to clinical efficacy) is oral dosing. Some women may find oral administration to be more discreet and convenient than vaginal administration. The once-daily regimen may also simplify treatment. Additionally, ospemifene may offer an alternative for women who should avoid estrogen therapy or who do not wish to use it.
Making a Difference
NPs and PAs can make a significant difference in the lives of women with VVA. By approaching their patients holistically and using effective, empathetic communication skills, NPs and PAs can break down barriers to an open discussion of VVA and dyspareunia. In addition to proactively identifying women in need of treatment, they can raise awareness of VVA as a condition of menopause and guide patients to appropriate treatments. The availability of a new treatment option for VVA provides additional opportunity to have a meaningful discussion with patients about important quality-of-life issues.
Susan Wysocki is a women's health nurse practitioner who is president of iWoman's Health in Washington, D.C. David Portman is a physician who is director of the Columbus Center for Women's Health Research in Columbus, Ohio. The authors have completed disclosure statement and report that editorial assistance for this manuscript was provided by The Medicine Group and funded by Shionogi, Inc. Wysocki is a member of the speaker bureau and clinical advisory board for Shionogi, Novo Nordisk and Pfizer.
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