Approximately 64 million women in the United States are postmenopausal. An estimated 50% of them, or more than 32 million women, have symptoms of vulvovaginal atrophy (VVA) and/or dyspareunia.1 Each of these two conditions is a component of the Genitourinary Syndrome of Menopause (GSM), a term introduced in 2014 by the North American Menopause Society (NAMS) and International Society for the Study of Women’s Sexual Health (ISSWSH) to describe the constellation of signs and symptoms associated with the decreased levels of estrogen and other sex steroids associated with menopause.2 GSM manifests with physical and physiologic changes to the labia majora and minora, vestibule/vaginal introitus, vagina, clitoris, urethra, and bladder. Symptoms of GSM include, but are not limited to, vaginal dryness, burning, itching, and irritation; pain with sex (dyspareunia) that may lead to subsequent sexual dysfunction; and bladder and urethral symptoms, including frequent urinary tract infections (UTIs), that are bothersome or distressing.
While most women readily associate vasomotor symptoms (VMS) with menopause, many are less likely to recognize that VVA symptoms such as vaginal dryness and painful intercourse are treatable conditions also stemming from menopausal changes.1,3 They also may not be aware that, unlike the symptoms of VMS that spontaneously resolve, VVA is a chronic condition that worsens over time in the absence of treatment (FIGURE 1).4,5 Consequently, VVA can interfere with a woman’s sexual functioning, create partnership issues, and negatively impact her overall quality of life.6-8
Figure 1: Onset of Vasomotor Symptoms vs. Vulvovaginal Symptoms
Pathophysiology and Diagnosis
The diminishing level of endogenous estrogen (particularly estradiol) during the menopausal transition has a substantial (and rapid) impact on the entire lower urogenital tract. Most notable are distinct atrophic changes in the vulvovaginal tissues and their associated consequences. The vaginal epithelium thins, becoming friable and more vulnerable to injury; even minimal trauma can lead to petechiae and occasional bleeding. Declining estrogen levels lead to pruritus, loss of rugae, loss of vaginal elasticity, and ultimately shortening of the vaginal vault;9 consequently patients may experience VVA symptoms of dryness, irritation, burning, dysuria, and dyspareunia.5.10,11 Atrophic changes are initially most pronounced in the vaginal introitus and distal urethra, which ultimately leads to introital stenosis and consequent dyspareunia.12 Hormonal changes also alter the vaginal microbiome from premenopausal acidic pH (range of 3.5 to 4.5) to postmenopausal alkaline pH (>5), which can predispose to irritation and infection in the vagina and bladder.5,12-14
The diagnosis of dyspareunia associated with postmenopausal VVA is based on patient reported symptoms of pain with penetrative sex and general, internal and external physical findings of vulvovaginal atrophy.5,15 There are a variety of indices clinicians can use to diagnose VVA. The Vaginal Maturation Index (VMI) indirectly assesses the level of estrogen based upon the number of mature and parabasal epithelial cells on a vaginal smear.16 Loss of estrogen associated with menopause leads to a decrease in the percentage of superficial cells and an increase in the percentage of parabasal cells compared to levels in a premenopausal woman. The Vaginal Health Index (VHI) was developed to evaluate vaginal elasticity, fluid secretion, epithelial integrity, pH, and vaginal moisture.17
Survey Data on Postmenopausal Sexual Health
Three major factors have been shown to influence sexuality in older women - age, hormonal insufficiency, and partnership status.2 Of these, age appears to be least important.18 Postmenopausal women cite the consequences of hormonal insufficiency (VVA, dyspareunia) and lack of a partner as the most important determinants of their postmenopausal sexual functioning.1,3,10-21
Table 1 below highlights pertinent findings from the key studies on postmenopausal sexual health. These studies clearly demonstrate a high prevalence of bothersome symptoms of VVA and menopause-related dyspareunia. However, the majority of women (~93%) fail to seek treatment for their symptoms.1 Many reasons have been suggested, including patient embarrassment,12,22 lack of knowledge about VVA/dyspareunia symptoms and treatments,1 and negative attitudes/misperceptions regarding hormone therapy.19 Women also cite a lack of meaningful communication with their healthcare providers (HCPs) regarding VVA and dyspareunia. Women want accurate medical information about these conditions and they want their HCPs to proactively raise these issues. However, the studies note that HCPs rarely initiate these discussions.23
TABLE 1: Key Studies and Findings on Postmenopausal Sexual Health
The effective management of VVA facilitates reduced pain with sex, better overall sexual well-being, and better sexual/personal relationships.1,3,19-21,23 Treatment selection should assess symptom severity, level of distress, risk of medical complications (for hormonal therapies), as well as patient preference and likely compliance with the methods.11,24-26
For women with mild symptoms, nonhormonal therapies – lubricants and moisturizers --are available over-the-counter (OTC). Lubricants are appropriate for acute relief of vaginal symptoms during sexual activity; moisturizers, used several times a week, may be considered for long-term relief of vaginal dryness.27,28 However, OTC products do not treat the underlying pathophysiology and tissue changes causing dyspareunia,29 and thus have limited effectiveness.
Women with moderate-to-severe symptoms generally require prescription systemic or topical hormonal therapies, possibly in conjunction with OTC products.30 Historically, estrogen therapy, administered systemically (oral or patch) or topically (vaginal cream, tablet, ring), has been the standard treatment for VVA. Exogenous estrogen has been shown to rapidly restore vaginal epithelium, improve vaginal secretions, and lower vaginal pH, leading to increased vaginal lubrication and elasticity, and reduced vaginal symptoms of dryness, irritation, dysuria and dyspareunia.28,31-33 Potential side effects include breast pain/tenderness, headache, hair loss, mild nausea or vomiting, spotting or breakthrough bleeding, stomach cramps or bloating, increased vaginal discharge, and/or vaginal yeast infection.34 Estrogen must be administered with progestin in women with a uterus to minimize the risk of uterine cancer. The ‘black box’ warning notes that, because of the stimulatory effect of high estrogen levels on the endometrium, which can lead to proliferation, hyperplasia, or carcinoma, the lowest effective dosage of systemic estrogen therapy should be prescribed. These findings, stemming from the results of the Women’s Health Initiative (WHI), have led to persisting unfavorable opinions among both patients and providers regarding the use of systemic estrogen therapy.35Consequently, the preferred route of estrogen administration is localized -- through topical vaginal cream, vaginal tablets, or an intravaginal ring. Each of these options affords specific benefits and disadvantages, which clinicians must discuss with patients during treatment selection.26,36-39
Two innovative non-estrogen prescription therapies have been approved for the treatment of dyspareunia associated with VVA. Ospemifene (Osphena®, Shionogi Pharmaceuticals), a selective estrogen receptor modulator (SERM), is a non-steroidal estrogen receptor agonist/antagonist; prasterone (dehydroepiandrosterone [DHEA]; IntrarosaTM, Endoceutics Inc.), is an intravaginal steroid transformed into androgens and/or estrogens locally in peripheral tissues.
Ospemifine is unlike other SERMs (including tamoxifen and toremifene), in that it exerts a strong, nearly full estrogen agonist effect (thus mimicking estrogen effects) in the vaginal epithelium.40-42 As such, it is well suited to treat dyspareunia in postmenopausal women. Ospemifene also acts as an antagonist—inhibiting estrogen effects—in other tissues.41,42
Results of 5 Phase III clinical trials (n= 2171 postmenopausal women) demonstrated ospemifene 60 mg significantly improved the VMI, decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) versus placebo (Table 2).43-45 Hot flushes were the most prevalent adverse events (~7.5%), followed by vaginal discharge (3.5%).46 As with estrogen therapy, ospemifene increases the incidence of thromboembolism. Contraindications include estrogen-dependent neoplasia,40 active or prior venous thromboembolism (VTE), previous stroke, active or prior myocardial infarction, or severe hepatic impairment. Long-term safety studies revealed that 60 mg of ospemifene given daily for 52 weeks was well tolerated and was not associated with any endometrium or breast-related safety concerns.47,48 There were no cases of endometrial cancer and <1% of patients experienced endometrial hyperplasia with treatment.49
Table 2: Ospemifene Efficacy Summary43,45,47,48
a calculated from baseline to 12 weeks; b P < 0.001 to placebo; c P < 0.0001 to placebo; d P=0.023 compared to placebo; eP=0.0004 compared to placebo. fP=0.014 compared to placebo; ITT, intent to treat; PP, per protocol
Prasterone, an endogenous steroid hormone, is the most abundant circulating steroid hormone in humans. It functions predominantly as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids. Active hormones made in peripheral tissues are inactivated at their site of synthesis before being released outside the cells as inactive metabolites.50 DHEA is transformed into androgens and/or estrogens locally in peripheral tissues. DHEA has no stimulatory effect on the endometrium as the human endometrium lacks enzymes, especially aromatase, that are able to transform DHEA into estrogens.50 Published literature suggests the absence of aromatase in the normal human endometrium as rationale for lack of endometrial stimulation.50-52 Prasterone also exerts no significant changes in systemic estrogen and androgen levels.53
Prasterone received FDA approval in 2016 for treatment of moderate-to-severe dyspareunia. One vaginal insert (0.50%; 6.5 mg of prasterone) is inserted once daily at bedtime, using a provided applicator.54 Efficacy and safety of prasterone (0.50%) was established in two 12-week placebo-controlled clinical trials in more than 600 postmenopausal women, who identified moderate-to-severe pain during sexual intercourse as their most bothersome symptom of VVA.50,55 Prasterone demonstrated statistically significant superiority over placebo on all 4 coprimary objectives (Table 3): reduced the percentage of parabasal cells, increased the percentage of superficial cells, decreased vaginal pH, and reduced pain associated with sexual activity (dyspareunia). After use for 1 year, the most common adverse reactions were vaginal discharge (14.2%) and abnormal Pap smear (2.1%).50
Table 3: Prasterone (Intrarosa™): Efficacy Summary31, 50
2 pivotal phase III trials (12 weeks) with postmenopausal women with symptomatic VVA randomized to placebo or prasterone 0.50% Trial 1: n= 158; Trial 2: n= 482
The Prescribing Information for prasterone does not include the “Black Box warning” required of conventional estrogen-containing formulations. However, because the use of prasterone in women with breast cancer or a history of breast cancer has not yet been evaluated, no statements can be made about potential safety concerns regarding prasterone in that patient population. Prasterone is contraindicated in women with undiagnosed abnormal genital bleeding, with warnings/precautions for its use in women with current or past history of breast cancer.54
Although VVA and dyspareunia are common conditions in post-menopausal women, they remain under-diagnosed and under-treated. Women expect their HCPs to initiate dialogue about these conditions, and to provide current, objective information regarding risks and benefits of all available OTC and prescription treatments. The introduction of non-estrogen hormonal options affords safer yet equally effective alternatives to systemic or topical estrogen.
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- Brotman RM, Shardell MD, Gajer P, et al. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014;21(5):450-458.
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