Dyspareunia: Enhancing Diagnosis and Management via Enhanced Patient/Clinician Discussion
Approximately 64 million women in the United States are postmenopausal, and more than 32 million of them 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, 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) such as hot flushes and night sweats with menopause, many are less likely to recognize that VVA symptoms are treatable conditions also stemming from menopausal changes.1,3 With VMS, these symptoms generally persist for 4 years before spontaneously resolving.4 On the other hand, VVA is a chronic condition that worsens over time in the absence of treatment (Figure 1).5 Consequently, VVA can interfere with a woman’s sexual functioning, partnership, and her overall quality of life.6-8
An Unmet Clinical Need
GSM is underdiagnosed and undertreated, leaving many women with symptoms that will continue to worsen over time.2 This is partly due to the fact that many women perceive their symptoms as normal consequences of aging. In addition, a recent survey showed that 93 percent of women do not seek treatment due to lack of knowledge about GSM, embarrassment to talk about it with their healthcare professional (HCP), concerns about adverse effects of management strategies, dissatisfaction with estrogen-based treatment, or lack of awareness of new treatment options.1,9,10 Conversely, while many women expect that their HCP will initiate a discussion related to menopausal symptoms, HCPs only bring up the issue about 10 percent of the time.1,3
There is an important unmet need to identify women with GSM symptoms to initiate effective treatment. Clinicians should take advantage of the annual well woman exam to ask about menopausal symptoms of both VSM and VVA (Table 1). The goals are to identify the presence of symptoms, determine if their timing correlates with menopause, and identify their impact on sexuality and quality of life.
Pathophysiology and Diagnosis of VVA
GSM results from decreased levels of estrogens and androgens, which induce physiologic changes in vulvovaginal tissue.11-13 Low levels of estrogen and androgens cause the epithelium of these tissues to become fragile and dry, and damage and bleeding can occur with very little contact. If untreated, these tissues eventually become less elastic due to loss of collagen and they lose the ability to stretch to accommodate penetration (thus, painful intercourse). They can eventually become so stenotic that intercourse is impossible.14
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. [Nilsson 1995] 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 (Figure 2).14
On clinical exam, patients with VVA oftentimes present with very clear internal and external physical findings. As shown in Figure 3 these may include the urethra becoming prominent and appearing to be replacing the introitus, the labia regressing, and the tissue losing elasticity. Having a clear picture of the presentation of VVA is essential to making an accurate diagnosis and ruling out other vulvovaginal conditions.2,11,15
Figure 3: Appearance of VVA on physical exam
The photo shows a loss of labial and vulvar fullness, pallor of urethral and vaginal epithelium, and decreased vaginal moisture in a 67-year-old woman, naturally menopausal for 2 years, not taking estrogen replacement therapy.16
Simple tests can be performed to confirm a diagnosis of GSM at the time of the well woman exam. If a simple pH test is alkaline and the patient’s symptoms started during menopause, then the diagnosis of VVA or GSM can be made with a high degree of certainty. The Pap smear can also provide important information.17
Management of GSM
There are several treatment options that can improve the symptoms of GSM. The dosage form, route of administration, and disadvantages and advantages of the available treatment options approved for GSM are summarized in Table 2.
Lubricants for on-demand use can help with pain on penetration and intercourse. There are also several vaginal moisturizers including new formulations with hyaluronic acid that are used twice a week on a maintenance basis. Lubricants and moisturizers do not reverse the physiologic changes, but they can provide relief of mild symptoms and discomfort.23,24
The traditional treatment for GSM is vaginal estrogen. It thickens the epithelium, increases lubrication and elasticity, alleviates dryness, soreness, irritation, pruritus, and urinary urgency, and improves sexual function.15,25 However, there continues to be several important challenges to estrogen therapy. Vaginal formulations can cause systemic symptoms (i.e., breast pain, headache, hair loss, mild nausea or vomiting, breakthrough bleeding, cramps or bloating, increased vaginal discharge and yeast infection).26 But the most important limitations to the use of estrogen are concerns raised in the Women’s Health Initiative study, which showed a slight but significantly increased risk of breast cancer, stroke, and dementia with standard hormone replacement therapy compared to placebo.27 Despite current evidence and greater understanding of the WHI study data, all estrogen products, including vaginally applied formulations, continue to have boxed warnings, which lead to reluctance on the part of both HCPs and postmenopausal women to use estrogen.28
Two new treatment options are available: ospemifene and intravaginal DHEA.29,30 Ospemifene is an oral triphenylethylene selective estrogen receptor modulator (SERM) originally developed for the treatment of osteoporosis.31 It optimizes the effects of estrogen to stimulate the endometrium and urogenital tissue. It is given as a 60 mg tablet, once daily, with food. 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 3).
Regarding adverse events, the incidence of hot flushes in clinical trials was 7.5 percent.29 Other common side effects included vaginal discharge, leg cramps, and sweating. As with estrogen therapy, ospemifene increases the incidence of thromboembolism. A 12-month trial specifically evaluated endometrial safety and found that hyperplasia occurred in less than 1 percent of women treated with ospemifene, and no endometrial cancer was reported, so there is no significant endometrial proliferative effect.34 Nevertheless, the ospemifene label includes boxed warnings similar to that for estrogen, addressing the risk for endometrial cancer and cardiovascular disorders. The label also includes a warning regarding the use in women with current or a history of venous thromboembolism, known, suspected, or history of breast cancer, and severe hepatic impairment. Ospemifene is contraindicated in women with undiagnosed abnormal genital bleeding, known or suspected estrogen-dependent neoplasia, active or history of venous (deep vein thrombosis, pulmonary embolism) or arterial (stroke, myocardial infarction) thromboembolic events, and hypersensitivity to the product or any ingredients.29
The other innovative, non-estrogenic agent is intravaginal prasterone, a synthetic compound identical to endogenous dehydroepiandrosterone (DHEA), a precursor to both estrogens and androgens. It is converted into estrogens and androgens intracellularly in the vulvovaginal and other peripheral regions, where it has local physiologic effects. Prasterone was approved by the FDA in 2016 for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. One vaginal insert (0.50 percent; 6.5 mg of prasterone) is inserted once daily at bedtime, using a provided applicator.35 Efficacy and safety of prasterone (0.50 percent) 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.17,25 Prasterone demonstrated statistically significant superiority over placebo on all 4 coprimary endpoints: decreased the percentage of parabasal cells, increased the percentage of superficial cells, decreased vaginal pH, and reduced pain associated with sexual activity (dyspareunia) (Table 4).17
TABLE 4: Prasterone: Efficacy Summary17,25
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
Women using prasterone for 12 weeks also had statistically significant improvements in all domains of the Female Sexual Function Index (FSFI), with a 41.3 percent greater total score change compared to placebo (P = 0.0006). The increases in the specific domains in the prasterone group compared to placebo (all statistically significant) were: desire by 0.24 unit, arousal by 0.42 unit, lubrication by 0.57 unit, orgasm by 0.32 unit, satisfaction by 0.44 unit, and pain at sexual activity by 0.62 unit (Figure 4).36
The most common adverse reaction was increased vaginal discharge, which was reported by 14.2 percent of patients in a 52-week study.17,25 There were no endometrial effects seen in 422 women who had endometrial biopsy.17 While the prasterone prescribing information label has no boxed warnings, it is contraindicated in women with a history of undiagnosed abnormal genital bleeding and has a warning against the use in women with current or history of breast cancer.30
In summary, GSM is the most common cause of dyspareunia in postmenopausal women. It adversely impacts urogenital and sexual health, as well as overall quality of life of those who are affected. Despite its prevalence, however, GSM and dyspareunia are both underdiagnosed and undertreated. Luckily, there are two new, non-estrogen treatment options: ospemifene, an oral selective estrogen receptor modulator, and prasterone, a DHEA-containing topical agent. Finally, it should be noted that these agents are now covered through Medicare Part D, thereby enhancing women’s access to these important new options.
- Kingsberg SA, Wysocki S, Magnus L, Krychman ML.Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey. J Sex Med. 2013;10:1790-1799.
- Portman DJ, Gass ML; Vulvovaginal Atrophy Terminology Consensus Conference Panel.. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society.Menopause. 2014;21:1063-1068.
- Krychman M, Graham S, Bernick B, Mirkin S, Kingsberg SA. The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate. J Sex Med. 2017;14:425-433.
- Umland EM, Falconieri L. Treatment options for vasomotor symptoms in menopause: focus on desvenlafaxine. Int J Women’s Health. 2012;4:305-319.
- Minkin MJ. Postmenopausal vulvovaginal atrophy: communication and care. Clinical Advisor. 2013.
- DiBionaventura M, Luo X, Moffatt M, Bushmakin AG, Kumar M, Bobula J. The association between vulvovaginal atrophy symptoms and quality of life among postmenopausal women in the United States and Western Europe. J Womens Health (Larchmt). 2015;24(9):713-722.
- Freedman MA. Quality of life and menopause: the role of estrogen. J Womens Health (Larchmt).2002;11(8):703-718.
- Freedman M. Perceptions of dyspareunia in postmenopausal women with vulvar and vaginal atrophy: findings from the REVIVE survey. Womens Health (Lond). 2014;10(4):445-454.
- Nappi RE, Kokot-Kierepa M. Women's voices in the menopause: results from an international survey on vaginal atrophy. Maturitas. 2010;67:233-238.
- Simon JA, Kokot-Kierepa M, Goldstein J, Nappi RE. Vaginal health in the United States: results from the Vaginal Health: Insights, Views & Attitudes survey. Menopause. 2013;20:1043-1048.
- Freedman M. Vaginal pH, estrogen and genital atrophy. Menopause Manage. 2008;17(4):9-13.
- Rosenzweig BA Bolina PS Birch L et al. Location and concentration of estrogen, progesterone, and androgen receptors in the bladder and urethra of the rabbit. Neurourol Urodyn. 1995;14:87-96.
- Kalloo NB, Gearhart JP, Barrack ER. Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia. J Clin Endocrinol Metab. 1993;77:692-698.
- Reiter S. Barriers to effective treatment of vaginal atrophy with local estrogen therapy. Int J Gen Med. 2013;6:153-158.
- North American Menopause Society (NAMS). Vaginal and Vulvar Comfort: Lubricants, Moisturizers, and Low Dose Vaginal Estrogen. NAMS 2013. Available at:http://www.menopause.org/for-women/sexual-health-menopause-online/effective-treatments-forsexual-problems/vaginal-and-vulvar-comfort-lubricants-moisturizers-and-low-dose-vaginal-estrogen. Accessed Oct. 24, 2018.
- Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486.
- Labrie F, Archer DF, Koltun W, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016;23:243-256.
- Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85:87-94.
- Suckling JA, et al. Local oestrogen for vaginal atrophy in postmenopausal women (review). Cochrane Database Syst Rev. 2006;4(CD001500):1-91.
- Weisberg E, Ayton R, Darling G, et al. Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Climacteric. 2005;8:83-93.
- Buckler H, al Azzawi F. The effect of a novel vaginal ring delivering oestradiol acetate on climacteric symptoms in postmenopausal women. BJOG. 2003;110:753-759.
- Jane FM, Davis SR. A practitioner's toolkit for managing the menopause. Climacteric. 2014;17:1-16.
- Edwards D, Panay N. Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition? Climacteric.2016;19:151-161.
- Palma F, Xholli A, Cagnacci A; as the writing group of the AGATA study. Management of vaginal atrophy: a real mess. Results from the AGATA study.Gynecol Endocrinol. 2017;33:702-707.
- Archer DF, Labrie F, Bouchard C, et al; VVA Prasterone Group. Treatment of pain at sexual activity (dyspareunia) with intravaginal dehydroepiandrosterone (prasterone). Menopause. 2015;22:950-963.
- National Institutes of Health. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a606005.html Accessed October 18, 2018.
- Writing Group for the Women's Health Initiative Investigators. Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321-333.
- New York Times Jan. 9, 2003. F.D.A. Orders Warning on All Estrogen Labels. Available at: https://www.nytimes.com/2003/01/09/us/fda-orders-warning-on-all-estrogen-labels.html. Accessed Oct. 23, 2018.
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- Portman D, Palacios S, Nappi RE, Mueck AO. Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: a randomised, placebo-controlled, phase III trial. Maturitas. 2014;78:91-98.
- Goldstein SR, Bachmann GA, Koninckx PR, Lin VH, Portman DJ, Ylikorkala O. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric. 2014;17(2):173–182.
- Constantine G, Graham S, Portman DJ, Rosen RC and Kingsberg SA. Female sexual function improved with ospemifene in postmenopausal women with vulvar and vaginal atrophy: results of a randomized, placebo-controlled trial. Climacteric. 2015;226-232.
- Constantine GD, Goldstein SR, Archer DF. Endometrial safety of ospemifene: results of the phase 2/3 clinical development program. Menopause. 2015 Jan;22(1):36-43.
- Center Watch. Intrarosa (prasterone vaginal insert). Available at: https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100174/intrarosa-prasterone-vaginal-insert. Accessed Oct. 24, 2018.
- Labrie F, Derogatis L, Archer DF, et al; Members of the VVA Prasterone Research Group. Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy.J Sex Med. 2015;12:2401-412.