Abstract
Ospemifene is a novel, oral selective estrogen receptor modulator that has been approved in the USA for treatment of dyspareunia. The decline in estrogen during menopause creates vulvovaginal changes that can cause symptoms that adversely impact women psychosexually. Many women are reluctant to discuss painful sex and providers must proactively inquire about sexuality issues. Ospemifene has been shown to reverse changes associated with vulvovaginal atrophy and relieve symptoms of dyspareunia. Safety studies of treatment up to 52 weeks have shown ospemifene to be safe with no impact on endometrial hyperplasia/carcinoma, venous thrombotic events or pelvic organ prolapse. Further studies are needed to evaluate its role in bone and breast health.
Keywords
The rapid decline in serum estrogen associated with the late menopause transition (STRAW Stage −1) results in major transformations in vulvovaginal anatomy and physiology. The vagina becomes thin, pale and dry. Elasticity diminishes and vaginal rugae disappear. Changes in microflora result in a decrease in acid-producing bacteria causing a rise in pH and an alteration in resident flora.
Approximately 60% of postmenopausal women experience symptoms of vulvovaginal atrophy (VVA), such as vaginal dryness, itching, burning and dyspareunia [1]. Unlike other menopausal symptoms (e.g., hot flashes), which often disappear, complaints associated with atrophy persist or worsen. Women's psychosexual wellbeing is adversely impacted.
Several studies have shown that VVA negatively affects sexual health. In a population-based study, Levine et al. noted that postmenopausal women with female sexual dysfunction were nearly four times more likely to have vaginal atrophy than those without [2]. The REVIVE study, an online survey of 3,046 postmenopausal American women, revealed that 59% of participants reported that VVA symptoms adversely impacted their enjoyment of sex [3]. This same survey reported that a large proportion of these women were unaware that their symptoms were menopause-related and that healthcare providers often failed to initiate a dialogue concerning age-related sexual concerns.
Overview of treatment of VVA
Numerous remedies have been used to treat VVA symptoms and it is recommended that treatment begins early before irreversible anatomical changes occur [4]. Vaginal lubricants and moisturizers are available as over-the-counter preparations. These nonhormonal products are water-, silicon- or oil-based. While these are helpful in relieving symptoms, they have little impact on underlying vaginal physiology. Additionally, some women consider them messy and inconvenient [5].
Hormonal replacement therapy has been the mainstay of treatment. Systemic estrogen and progesterone in various combinations and delivery modes have been used to treat menopausal symptoms and vaginal changes. The Women's Health Initiative emphasized the potential for adverse side effects. The North American Menopause Society Hormone Therapy Position Statement recommends individualizing treatment using the lowest effective dose of estrogen consistent with treatment goals, benefits and risks for the individual woman [6]. Exogenous estrogen use has been linked to endometrial hyperplasia, cancer and venous thromboembolism. When vaginal symptoms are the primary complaint vaginal estrogens are preferred [7]. Localized treatment is not only more effective, it bypasses first-pass metabolism by the liver and limits systemic exposure resulting in fewer side effects [8,9]. Topical vaginal estrogens can be delivered via creams, tablets and slow-releasing rings.
Perceptions about the dangers of hormones can be a barrier to compliance and long-term use. In a US-based online survey of 1,038 postmenopausal women safety concerns were commonly cited by women with symptoms of VVA [1].
Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs), also known as estrogen agonists/antagonists, are nonestrogenic pharmacologic agents that induce agonistic effects on some targeted tissues with neutral or antagonistic effects on other tissues. Characterized by their structure, they induce 3D changes in the confguration of estrogen receptors, which lead to different biologic activities that are unique for each SERM and target cell type [10]. Examples of SERMs include two breast cancer therapeutic agents, tamoxifen and toremifene, as well as ospemifene, which all share the triphenylethylene backbone structure (Figure 1).
SERMs are tissue-specific. Almost all have agonistic effects on bone, but effects on vaginal tissue are quite diverse. Tamoxifen has both estrogen agonistic and antagonistic effects on the vaginal epithelium. Users of tamoxifen experience vaginal dryness and dyspareunia yet studies report an estrogen-like change in the cellular maturation index [10]. Ospemifene was observed to be a weak/inactive hormonal metabolite of toremifene. It was hypothesized that developing ospemifene, a less potent agent, could lead to a therapeutic benefit on vaginal atrophy while carrying fewer adverse effects [11]. Ospemifene has had positive effects on the vaginal epithelium and bone, neutral effects on the endometrium and minimal effects on the breast [12].
Chemistry & pharmacodynamics
Peak median serum concentrations of ospemifene were reached at approximately 2 hours in fasting postmenopausal women [13]. Food increases bioavailability two-to threefold. Steady state concentrations are reached by day 7 [14]. Ospemifene is highly (>99) bound to serum proteins and is metabolized in the liver. It has a half life of 26 hours and is metabolized by CYP450 enzymes to 4-hyrdroxyospemifene, its major metabolite [15]. Approximately 75% and 7% of the dose was excreted in feces and urine, respectively [16].
Clinical efficacy
Twelve- and 52-week studies of postmenopausal women have shown the efficacy and safety of ospemifene [15,17–20].
In a 12-week study, 826 postmenopausal women (mean ages 58–59 years) were randomized 1:1:1 to receive ospemifene 30 or 60 mg/day or placebo orally for 12 weeks. Subjects were permitted use of vaginal lubricants. Primary inclusion criteria included a maturation index of 5% or less superficial cells, vaginal pH greater than 5.0 and at least one moderate or severe symptom of VVA, including dyspareunia. Significant improvements in the vaginal maturation index were observed within 4 weeks of treatment. At 12 weeks, compared with placebo, ospemifene 60 mg significantly increased the percentage of superficial cells and decreased the percentage of parabasal cells, decreased vaginal pH and improved symptoms of vaginal dryness and dyspareunia. Ospemifene was well tolerated. The most frequent reported adverse events were hot flushes, generally mild or moderate, which had little impact on discontinuation [17].
Upon completion of the 12 week trial, subjects were eligible to enroll in one of two extension studies based on the presence or absence of an intact uterus. A total of 180 women (ages 46–79 years, mean 57.7–58.2 years) with an intact uterus enrolled in the 40-week, double-blind, safety extension study [18]. They received either placebo, ospemifene 30mg/day or ospemifene 60mg/day. After 52 weeks of treatment no clinically significant adverse changes in safety assessments were observed. No cases of endometrial hyperplasia, carcinoma or venous thromboembolism occurred. Because of an increased incidence of pelvic organ prolapse and incontinence associated with SERMs, emphasis was placed on detecting these treatment-emergent adverse events. No increased incidence in prolapse was noted. The most common side effect of treatment was hot flushes described as mild to moderate.
A total of 301 hysterectomized postmenopausal women (ages 40–80 years, mean 59.4 years) from the pivotal trial enrolled in the 52-week safety extension. There were no instances of pelvic organ prolapse, incontinence, venous thromboembolism, fractures, breast cancers or death [19]. The most common treatment-emergent adverse event was hot flushes.
In a study designed to assess the role of ospemifene in the treatment of VVA in postmenopausal women who self-report their most bothersome symptom as dyspareunia, 605 subjects (median age 58 year) were randomized to either ospemifene 6 0mg or placebo [20].
After 12 weeks the percentage of superficial cells significantly increased, while the percentage of parabasal cells and vaginal pH decreased and dyspareunia was reduced in those women receiving ospemifene. No clinically significant estrogenic effects on the endometrium were observed. Hot flushes, the most frequently reported treatment-related adverse event, were seen in 6.6% of the ospemifene group and 3.6% of the placebo group.
The safety of ospemifene 60 mg was evaluated in 426 postmenopausal women aged 40–80 years (median 61.7–62.9 years) over a 52-week period, at which time assessments included endometrial histology and thickness, breast and gynecological evaluations [15]. Statistically significant and sustained improvement for all efficacy measurements including increases in superficial cells and decreases in parabasal cells and vaginal pH were reported. No significant estrogen-related or clinically important adverse effects on endometrial or breast tissue were observed. Most treatment-emergent adverse events were categorized as mild to moderate. Hot flashes resulted in limited discontinuation (2.2%, n = 8).
Safety & tolerability
Each SERM has a unique action on the endometrium, with some, such as tamoxifen, having strong stimulatory actions that could result in hyperplasia or cancer. As such ospemifene has been closely examined in all clinical trials performed to date. Endometrial thickness assessed via transvaginal ultrasound remained relatively unchanged in two 12-week Phase II studies and there were no reports of vaginal bleeding or endometrial hyperplasia [21,22].
The effects of ospemifene on breast tissue have not been adequately investigated in clinical studies. Preclinical studies suggest that ospemifene serves as an antiestrogen in the breast. The effect of ospemifene has been studied in in vitro and in vivo preclinical models. Ospemifene appears to act as an antiestrogen in animal models of estrogen receptor-positive breast cancer and ductal carcinoma in situ with similar activity to tamoxifen [11,23]. Longer term data with clinical use will need to occur before conclusions about the impact of ospemifene on the breast can be made. As ospemifene has not been studied in women with breast cancer it should not be used in women with known or suspected breast cancer or with a history of breast cancer.
Preclinical and clinical data suggest that ospemifene may have an estrogen-like effect upon bone. In vivo, ospemifene was shown to prevent ovariectomy-induced bone loss and maintain bone strength in ovariectomized rats at doses of 1 mg/kg and 10 mg/g daily for 4 weeks [24]. The effects of ospemifene on bone turnover serum markers were evaluated in two Phase II studies. In both studies there were decreases in biochemical markers of bone resorption and increases in bone formation, but no fracture data is available [25,26].
In clinical trials the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per 1000 women, respectively, in ospemifene 60 mg treatment groups and 1.04 and 0 per 1000 in placebo [13]. The incidence of deep vein thrombosis in clinical trials was 1.45 per 1000 women in the ospemifene 60 mg treatment group and 1.04 per 1000 women in placebo. Ospemifene is contraindicated in women with active arterial thromboembolic disease or a history of these conditions. If feasible ospemifene should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Rates for hot flashes amongst postmenopausal women range from 8 to 80%, with a median of 41.5% [27]. It is not surprising that women using ospemifene experience hot flashes. While in the studies [15,17–20] the incidence of hot flashes in those on ospemifene was higher than placebo, the reported hot flashes did not lead to increased discontinuation rates and were generally mild in nature.
Regulatory affairs
Ospemifene has been approved in the USA under the name Osphena® (Shionogi Inc., NJ, USA) for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause. It is available in 60 mg tablet form to be taken orally once daily with food. The US FDA has classified Osphena as an estrogen agonist/antagonist with tissue-selective effects and, as such, has required a black box warning concerning endometrial cancer and cardiovascular disorder risks. Osphena should be prescribed for the shortest duration consistent with treatment goals and risk for the individual women.
Conclusion
VVA is an inevitable consequence of aging. A significant number of postmenopausal women complain of bothersome symptoms that impact psychosexual function. Many women are reluctant to inform their healthcare provider of sexual discomfort. Treatments have traditionally been estrogen-based. Due to adverse perceptions or medical contraindications to estrogen use many potential patients are not receiving therapy. Ospemifene serves as a safe, effective alternative in those women who prefer a nonhormonal regimen. Long-term studies on breast and bone health are needed.
Future perspective
Other nonestrogen therapies to treat symptoms of VVA are currently under investigation. Dehydroepiandrosterone has shown promise in improving symptoms and signs of VVA as well as all domains of sexual dysfunction [28]. Very early reports suggest there may be a potential role for topical oxytocin in reversing vaginal atrophy [29].
Disclosure
In addition to the peer-review process, with the author's consent, the manufacturer of the product discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made at the discretion of the author and based on scientific or editorial merit only.
Financial & competing interests disclosure
SE Eder participated in the investigation of osepemifene as part of The Ospemifene Study Group and received financial compensation from QuatRx Pharmaceuticals. Additionally SE Eder is a paid speaker for Osphena by Shionogi Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Executive summary
Ospemifene (Osphena, Shionogi Inc., NJ, USA) is a selective estrogen receptor modulator that binds to estrogen receptors in the vagina reversing menopausal alterations.
Peak serum concentrations at approximately 2 h.
Steady state after 7 days.
Excreted in feces and urine.
Clinical efficacy
Decreases vaginal pH, increases superficial cells, decreases parabasal cells.
Decreases painful intercourse.
No adverse effects on endometrium, venous thromboembolic events.
Do not use estrogens or estrogen agonists/antagonists, fluconazole or rifampin concomitantly.
Coadministration of ospemifene with drugs that inhibit CYP3A4 and CYP2C9 may increase risk of adverse reactions.
Available as a 60 mg tablet taken once daily with food.