Abstract and Introduction
Abstract
Genitourinary syndrome of menopause (GSM) refers to a collection of symptoms resulting from diminished hormonal, primarily estrogenic stimulation to the vulvovaginal or lower urinary tract and may affect up to 50% of postmenopausal women. Symptoms, which are typically progressive and unlikely to resolve spontaneously, may include, but are not limited to, vulvovaginal dryness, burning or irritation, dyspareunia, or urinary symptoms of urgency, dysuria or recurrent urinary tract infection. These symptoms are typically progressive and unlikely to resolve spontaneously. Diagnosis is clinical. Telemedicine may play a role in diagnosis, initiation of treatment, and follow-up of women with GSM. Effective treatments include moisturizers and lubricants, local hormonal therapy with estrogen or dehydroepiandrosterone, and oral selective estrogen receptor agonists. Laser or radiofrequency procedures, although currently utilized, are being studied to comprehensively understand their overall effectiveness and safety. Additionally, the influence and effect of the vaginal microbiome, as well as potential of treatment via its manipulation, is being studied. We performed a literature search of PubMed, Google Scholar, and Ovid with search terms of vulvovaginal atrophy and GSM and reviewed major US Society Guidelines to create this narrative review of this topic. The literature suggests that healthcare providers can make a significant impact of the health and quality of life of women by being proactive about discussing and providing interventions for GSM. A systematic approach with consideration of current guidelines and attention to developing protocols for interventions should be employed.
Video Summary: http://links.lww.com/MENO/A702.
Introduction
Genitourinary syndrome of menopause (GSM) refers to a collection of symptoms women may experience resulting from diminished hormonal (primarily estrogenic) stimulation to the vulvovaginal or lower urinary tract. This terminology, felt more medically objective in depicting these symptoms than prior terms that would describe these women as having vulvovaginal atrophy or atrophic vaginitis, was adopted in 2014 by a consensus panel and approved by The North American Menopause Society (NAMS) and the International Society for the Study of Women's Sexual Health.[1] Up to 50% of postmenopausal women may report symptoms of GSM, and despite GSM being associated with menopause, up to 15% of women may report symptoms during premenopause.[2,3] When reported in premenopausal women, GSM is usually due to a temporary hypoestrogenic state. These include those with hypothalamic amenorrhea, hyperprolactinemia or those on estrogen-blocking medications such as GnRh agonists or aromatase inhibitors. GSM may include one or any combination of genital symptoms such as vulvovaginal dryness, burning or irritation, dyspareunia, or urinary symptoms of urgency, dysuria or recurrent urinary tract infection (UTI).[4] These symptoms are typically progressive and unlikely to resolve spontaneously. Effective treatments include moisturizers and lubricants, local hormonal therapy with estrogen or dehydroepiandrosterone (DHEA), and oral selective estrogen receptor agonists. Laser or radiofrequency procedures, although currently utilized, are being studied to comprehensively understand their overall effectiveness and safety.
Pathophysiology
The underlying pathophysiology of GSM is a state of relative estrogen deficiency. Low circulating levels of estrogens affect the embryologically connected lower urinary tract, vaginal and vestibule, at first from decreased activation of estrogen receptors, but then, over time, from decreased numbers of estrogen receptors overall.[5]
When present, estrogen maintains urogenital health via both vascular, cellular, and structural mechanisms. As a vasoactive hormone, estrogen increases local blood flow, with increased transudative lubrication via blood vessels, Bartholin and endocervical glands.[1] Histologically, the estrogen-exposed vagina is lined by a trilayer of stratified squamous epithelium; a glycogen-rich superficial layer, with intermediate and parabasal layers below. The parabasal cells contain little glycogen and resultantly contain an increased nuclear-to-cytoplasmic ratio. In the presence of estrogen, the superficial and intermediate layers predominate, supplying glycogen to act as a substrate for lactobacilli with a resultant acidic pH of 2.8 to 4.0, via production of organic acids, primarily lactate, but also hydrogen peroxide. This acidity protects the vagina from pathogenic microbiome shifts, and increased risk of vulvo-vaginal infection.[6]
Structurally, estrogen supports the collagen content of the vagina, as well as the production of mucopolysaccharides and hyaluronic acid. These effects combined maintain vaginal wall thickness, elasticity, moisture, vaginal secretions, and lubrication.[4]
In addition to the benefits of estrogen on the vulvo-vagina tissue, these benefits of estrogen are also seen in the bladder, urethra, pelvic floor musculature, and endopelvic fascia where estrogen receptors are found throughout the epithelium, connective tissue, and smooth muscles. The relative contribution of aging versus estrogen deficiency is less well studied in these areas, but estrogen receptors are found throughout, and improvements in urethral closure pressure, blood flow, and increase in the presence of antimicrobial peptides with increased resistance to pathologic bacteria in the bladder have been observed after estrogen replacement.[7]
Estrogen loss results in the reversal of the vascular, cellular, and structural supports of the urogenital tissues that is noted in the well-estrogenized premenopausal woman. With low serum estrogen levels as seen in menopause, collagen and adipose are decreased, leading to diminished elasticity and vaginal mucosal thinning evidenced during pelvic examination by loss of rugae, observable pallor, and friability to swabbing or speculum insertion. Vascular flow decreases with subsequent reduced lubrication that is functionally compounded by attenuation of apocrine and endocrine glands. The epithelium becomes predominantly composed of parabasal cells as glycogen is lost, leading to increased pH levels, loss of lactobacilli, and increased susceptibility to pathogenic bacteria, including those found in the intestines and rectum, as well as on the skin. Further, the decreased vaginal secretions may lead to absent or diminished lubrication with sexual activity, vaginal friability with potential postcoital bleeding, or secondary loss of desire.[5]
Gonadal hormone deficiency, in addition to its impact on the vagina, can adversely affect the epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone. Pubic hair is reduced, the fat pads of the labia majora resorb and the labia minora may thin and regress. The vaginal introitus may retract and lose elasticity and narrowing and stricture of the vaginal canal may occur over time in the sexually inactive woman if not addressed. Urethral prominence with resultant vulnerability to physical irritation and trauma and infection also may occur.[7] These changes are clinically responsible for GSM symptoms in the vulvovaginal area of vaginal dryness, burning, irritation, or itching as well as superficial or deep dyspareunia. In the genito-urinary tract, urinary frequency, urgency, incontinence, or recurrent urinary tract infections may develop (Table 1).
The Vaginal Microbiome and its Role in Vulvovaginal Atrophy
The impact of estrogen on the vaginal microbiome has been the subject of recent interest. In the premenopausal vagina, the microbiome is represented by five Community State Types (CST), four of which are lactobacilli-dominant (CST I, II, III, V) and categorized by the primary lactobacilli type (L crispatus, L gasseri, L iners, and L jensenii, respectively).[8] L crispatus, found in CST I, is the most favorable and associated with the lowest bacterial diversity, lowest pH, and best resistance to pathogens. CST IV (subdivided into A and B based on the bacterial composition) was a non-lactobacillus dominated group, had the most bacterial diversity with a heterogeneous/higher proportion of obligate anaerobes and the highest pH, making it the least desirable and most susceptible microbiome.
Studies of the microbiome of symptomatic postmenopausal women find, as expected, that Lactobacillus species are diminished, with a shift toward CST IV, with increased bacterial diversity, including Prevotella, E coli, Streptococcus, and Bacillus.[9] It follows that the 20% to 50% of postmenopausal women with a lactobacillus-dominated vaginal microbiome tend to be least symptomatic. Vaginal and bladder microbiomes have been shown to correlate with symptoms, although implications for urologic symptoms after menopause are less defined.[10]
Substantiated therapies for the treatment of GSM utilizing microbiome altering or repleting compounds are not available, although many are marketed as over the counter preparations. An estriol and L acidophilus (KS400) combination vaginal cream (Gynoflor) has been shown in a 14-week trial to be superior to placebo to both improve symptoms of GSM and restore a desired vaginal microbiome.[11] Gynoflor is not available in the US.
Epidemiology
The prevalence of GSM has been estimated in many studies and surveys over several years, with each suggesting that the actual prevalence may be higher than noted due to underreporting. Factors such as 1) women's perceptions that the symptoms are normal, 2) they do not think of these symptoms as a medical problem or that they are related to menopause, 3) their discomfort in discussing GSM with a healthcare provider, and 4) women are not being asked by their clinician, are cited as reasons for this underreporting. A 2010 international survey of 4,000 women found 39% suffered from GSM symptoms, while 45% reported symptoms in the 2012 Vaginal Health: Insights, Views and Attitudes Survey, an international online survey of postmenopausal women age 55 to 65.[12] Moral's 2018 study of 430 postmenopausal women living in Spain found a prevalence of 70% of GSM, reflected by either any symptom, regardless of degree of severity, or observed genitourinary changes on physical examination,[13] whereby Geng et al[14] found a prevalence of 31% in his single-center study of women living in China.
The 2016 AGATE Study, which included physical examination findings of pH > 5 and observed signs of vulvovaginal atrophy to diagnose GSM in women who noted that they did have vaginal dryness, found a prevalence rate of 79.1% (64.7%-84.2% starting for 1–6 y after menopause).[15]
Vaginal dryness is generally the most reported and bothersome symptom, reported by 93% of symptomatic women in Moral's study, and 85% of respondents in the EMPOWER Survey, a 2017 Internet-based (with possible inherent bias) survey of 1,858 US women who reported that they had vulvovaginal symptoms.[16] Negative sexual consequences, including dyspareunia and loss of desire, have been reported in up to 85% of symptomatic women.[17] Of the 722 women in the AGATE Study, a study in which entry criteria required the report of vaginal dryness, 77.6% reported dyspareunia, 56.9% burning, 56.6% itching, and 36.1% dysuria.[15] The 2013 Clarifying Vaginal Atrophy's Impact On Sex and Relationships Study noted that in a heterosexual population, the majority (52%-78%) of the male partners of symptomatic women also were aware of the negative sexual consequences of GSM.[18]
Dysuria and urgency or urge incontinence are the most reported urinary symptoms, reported in 29% and 28% of women with GSM, respectively. Other urinary symptoms are less common but may include recurrent urinary tract infections or stress incontinence.[19]
Diagnosis
GSM is a clinical diagnosis, based on history and physical examination. Healthcare providers should be proactive in asking peri- and postmenopausal women about symptoms of GSM (Table 1), as well as taking a sexual history. A response of not being sexually active should prompt further inquiry, as up to 58% of women report they avoid intimacy based on symptoms.[20] Dryness with intercourse and dyspareunia are the most frequently reported symptoms of GSM,[6,15] but postcoital bleeding, soreness, or tearing may also be reported. Many women remain hesitant to report these symptoms, believing they are normal and an inevitable part of the aging cycle. Others may erroneously believe GSM is not a medical condition and therefore, there are no available treatment options.
Further, lack of sexual activity does not preclude GSM as women may have symptoms with daily activities such as exercise, wearing tight clothing, or even at rest. Vaginal symptoms such as discharge, itching, burning, irritation, or discomfort also may be present. Common genito-urinary complaints include urinary urgency, frequency, or incontinence. In some women, urethral tenderness, burning, or recurrent UTI also may be an outcome of estrogen decline.
Physical examination findings (Table 2) do not always correlate with presence or severity of symptoms. External genital characteristics may include thin and pale vulvar skin. Sparse pubic hair, and slight (from loss of adipose) or fused labia may be present. The clitoral hood may retract exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. A urethral caruncle, which appears as a proliferative beefy red tissue at the entrance of the urethra, may be present. Posterior fissuring at the introitus may be present or occur as a result of the examination. Prolonged atrophy may result in introital narrowing, and friability, which may result in pain and/or tearing with sexual activity or insertion of a speculum during pelvic examination. There may be shortening of the vaginal vault. The vagina will have decreased or absent rugae, minimal secretions or possibly yellow, sticky, occasionally malodorous discharge. Inflammation and petechiae, observed as pinpoint, nonraised, round purple-red spots, may be present. The cervix may be fused with the vaginal fornices. Prolapse may be noted, or if present previously, become more prominent (Table 2).
Differential diagnosis of GSM includes infectious, dermatologic, and irritative urogenital disorders. A review of current medical problems, medications, and dermatologic disorders such as eczema or psoriasis should be part of a complete genito-urinary history. All urogenital contacts including detergents, soaps, wipes, and over the counter locally-applied products should be asked about, and those that may be causing allergic or irritative symptoms should be discussed further and the recommendation given to eliminate them on a trial basis to see if there is amelioration or elimination of symptoms. Bladder stimulants like caffeine and alcohol should also be considered, and fluid intake volume and timing discussed. GSM generally does not present with localized or isolated ulcerated or lesions. Any suspicious or nonhealing lesion should be further evaluated and biopsied.
Diagnostic Tools and Laboratory Evaluations
No single diagnostic tool is available for the diagnosis of GSM. The "Vaginal Symptom Questionnaire" developed in 2013 is a validated 21-item questionnaire developed to measure the quality of life impact of genital, but not urinary, symptoms of menopause,[21] and the "Day to day Impact of Vaginal Atrophy " questionnaire has been validated in women of diverse backgrounds to assess impact of vulvovaginal atrophy on the domains of activities of daily living, emotional well-being, sexual functioning, and self-concept and body image.[22] Both of these questionnaires, as well as others, are helpful in a research setting, but do not have wide clinical application. In 2006, the FDA recommended recording the "most bothersome symptom " as part of an effort to better define study outcomes.[23]
The "Vulvovaginal Atrophy Questionnaire (VAQ)" is a new patient-reported outcome measure under development in collaboration with NAMS and the Massachusetts General Hospital Midlife Women's Health Center.[24] The VAQ is intended to be used as both a clinical and epidemiologic tool. Its development is based on existing knowledge, expert input, and the perspectives and experiences of menopausal women interviewed in focus groups. Once developed this tool will be available for clinical use. However, its impact is yet to be determined.
Laboratory tests are not typically necessary for the diagnosis of GSM. Physical examination diagnosis, however, can be supported by office-based testing, including vaginal pH and vaginal maturation index. A vaginal pH of >5, measured from the vaginal sidewall, in the absence of infection or blood, is suggestive of vulvovaginal atrophy. A vaginal maturation index can be performed like a wet mount, with Ratkoff staining used to identify superficial, intermediate, and parabasal cells.[25] The percentage of each cell type, out of 100, is calculated. Parabasal cell counts of 65% or more generally signify changes consistent with vulvovaginal atrophy.
Novel markers of vulvovaginal atrophy, which require further evaluation, include zinc levels found in cervicovaginal lavage[26] or sonographic measurement of the total vaginal wall thickness or total vaginal mucosal thickness at the bladder trigone.[27]
A clinical strategy of combining most bothersome symptom and vaginal pH as a means of following patient response to treatment for GSM has been suggested.[28] Additionally, degree of response can be ascertained by the clinician (eg, no response, minimal response, or adverse response).
In general, whichever method of assessing response is utilized, a follow-up clinical appointment at 8 to 12 weeks should be considered for most patients. If the management has not resulted in adequate relief of symptoms for the woman, reassessment, change of intervention, or further testing should be considered.
Telemedicine and GSM
Covid-19 presented the medical community with an unprecedented situation in terms of providing safe, effective in-office medical care to patients. Telemedicine/telehealth (TMTH) was rapidly approved by the US Office of Health and Human Services for "all Health Insurance Portability and Accountability Act-covered health care providers, with no limitation on the patients they serve with telehealth…" and "all services that a covered health care provider, in their professional judgement, believes can be provided through TMTH in the given circumstances of the current emergency are covered by this Notification."[29] American College of Obstetrics and Gynecology (ACOG) endorsed TMTH and provided recommendations for its use in a February 2020 Practice Bulletin.[30] An expert consensus published in July 2020 reviewed the currently available literature and offers clinical guidance.[31] Although GSM was not included in the review, other vulvovaginal conditions, including vaginitis, were considered appropriate for TMTH.
In considering TMTH for the diagnosis of GSM, a detailed history, even without a complete physical examination, can be sufficient in many cases to make empiric treatment a reasonable medical alternative to office evaluation. Patients may self-report vulvovaginal appearance, or, if allowed by local regulations and with consent from the patient, over an approved secure platform, visual inspection can be done by the healthcare provider. Women with isolated vulvar lesions or symptoms suggesting pathology other than GSM should be asked to come into the office for full assessment, including biopsy and cultures as indicated. Follow-up evaluation of women who are provided treatment for GSM would ideally involve in-person evaluation with examination, especially if adequate response is not achieved.
Treatment
Treatment of GSM involves shared decision making. Initiation of treatment should be based on the impact of symptoms on the woman's personal and sexual needs, not on physical examination findings. Women should be educated that GSM may progress over time or that changes in lifestyle, such as resumption of sexual activity, may exacerbate previously mild symptoms. Ongoing discussion should be encouraged.
In the ongoing development of the VAQ, investigators are using an approach of "Symptoms- Impact -Outcome."[24] This methodology, combined with shared decision making, can provide a framework for providers caring for women with vulvovaginal atrophy.
Treatment options for GSM include over-the counter lubricants and moisturizers, locally applied hormonal therapies including estrogens or DHEA, or oral treatment with the selective estrogen receptor modulator, ospemifene. Adjuvant lifestyle modifications or use of vaginal dilators or pelvic floor PT may be helpful in some women. Oral estrogen or combined estrogen/progestogen therapy is not indicated for vulvovaginal symptoms alone.[32] Laser and radiofrequency-based vaginal devises for GSM are a rapidly evolving field; however, ACOG and other societies recommend randomized studies before considering a standard management option. As well, these modalities are not currently FDA approved for this indication.[33–35] Compounded hormonal therapies, including those with testosterone also, are not FDA approved, nor is a combination of L acidophilus with estriol, which has shown in small studies to provide some relief of symptoms.[36]
Lubricants and Moisturizers
Vaginal lubricants and moisturizers can be offered as first-line therapy, especially for women with mild symptoms of vaginal dryness or dyspareunia.[37] Moisturizers are used regularly while lubricants are intended for use with sexual or other vaginal activity.
Moisturizers act by rehydrating vaginal mucosal tissue. Their bioadhesive nature results in a coating over the vaginal mucosa, aimed to recreate vaginal secretions and lower vaginal pH.[36] Moisturizers need to be used long-term and GSM may progress despite their use, requiring re-evaluation as to their effectiveness on a regular basis. In a 2019 systematic review, moisturizers were shown within the study period to have similar clinical outcomes as locally applied estrogens but did not show similar objective improvements in vaginal pH or maturation index.[37] Large studies on moisturizers and urinary symptoms are lacking, but a recent study of a polycarbophil-based cream demonstrated improvement in urinary symptoms as measured by the International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms after 4 weeks of treatment, sustained at 12 weeks. This study did not have a placebo control.[38]
Lubricants, which are available in water-, mineral-, silicone-, or plant oil-based forms, provide short-term relief of symptoms and are used prior to sexual or vaginal penetrative activity. Lubricants work by relieving friction. Oils or silicone-based products may cause staining. For those women still menstruating, counseling should include effects of various lubricants on condom integrity and spermicides. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially by the patient in a small amount.
Lubricants and moisturizers containing cannabidiol are marketed to not only provide lubrication, but also increased arousal and heightened sexual experience. There are currently no studies that substantiate these claims or provide safety information for these products.
When recommending moisturizers and lubricants to women, specific examples and explanations of the different products available should be used. Women should be advised that trial and error in choosing products may be necessary, and that a "wash out" period between different products will offer the most clarity in result. Handouts can be helpful.
Topical Lidocaine
Lidocaine applied prior to vaginal activity can reduce pain with penetration.[39] Over the counter as well as prescription preparations are available, at varying strengths. Direct application may result in discomfort, so lower strengths and dilution in a water-based lubricant may be recommended initially. Lidocaine may affect the partner's sensation. Attention to the partner's reaction as well as potential allergies is recommended.
Hormonal Therapies
Estrogen. Estrogen is the most effective treatment for GSM (Table 3).[40] Estrogen restores an acidic vaginal pH, improves microflora with an increase in lactobacillus and a decrease in bacterial diversity,[9] and promotes epithelial thickening with an improved maturation index and increased vaginal secretions. Local estrogen also decreases the frequency of recurrent UTI.[5]
Locally applied estrogens are available in estradiol or conjugated equine estrogens creams, an estradiol 10 mcg tablet, 4 or 10 mcg soft gel capsule, or a 7.5 mcg/d ring. A 2016 Cochrane review of 30 randomized controlled trials (over 6,000 women) found all preparations to be equally effective in the relief of vaginal atrophy.[41] This international review may have included preparations not available in the US and may not have included the 4-mcg capsule, which was FDA approved in the US in 2018. One randomized-controlled trail (RCT) of 764 women showed the 4 ug capsule to be equally effective as the 10 mcg tablet in the treatment of dyspareunia and vaginal dryness by 6 weeks, but not vaginal irritation or itching after 12 weeks of use.[42]
Vaginal estrogen seems effective in some women in improving urinary urge incontinence and symptoms of overactive bladder and may be helpful in prevention of recurrent UTI.[40] There is lower quality evidence to support estrogen for improvement of dysuria, nocturia, and stress incontinence.[43]
Locally applied estrogens, at the recommended dosage, have few side effects and fewer adverse events and risks than systemic estrogens.[37] The package labeling for locally applied estrogen products contains the same contraindications and risks as systemic estrogen, including an increased risk of cardiovascular disease, breast, and endometrial cancer and dementia. Most experts believe this labeling is not evidence-based and, risks are believed to be minimal.[44] Estradiol levels generally do not exceed levels which are found in the untreated menopausal population, although an increase within the range of postmenopausal levels is possible, especially in the first month of use when the epithelium is most atrophic. Vaginal creams may be more readily absorbed, are user dependent for dosing, and have the potential to raise serum estradiol levels if the woman inserts an amount above the recommended dosing. For vaginal creams, over time dosing may be tapered to the lowest most effective dose for relief of symptoms.
With the exception of the estradiol ring, which is inserted for a duration of 3 months before replacement, all estrogen products have a manufacturer-recommended tapering approach to treatment with an initial more frequent or higher dose application followed by twice to three times weekly maintenance. In women with significant vulvar symptoms, including cracking and fissuring, initial treatment with externally applied creams in addition to internal application should be considered. The patient should be counseled that response to therapy usually takes from 4 to 6 weeks. Once symptom relief is obtained, treatment should continue indefinitely.
The choice of estrogen product should be the result of shared decision-making, with consideration of patient preference, ease of use, convenience, and cost. Reassuringly, a prospective cohort study using data from the Women's Health Initiative Observational Study showed no increased risk of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, or pulmonary embolism/deep vein thrombosis in users versus nonusers of vaginal estrogens. The risk of coronary heart disease, fracture, and all-cause mortality was lower in users than in nonusers.[44] In this study, average time of follow-up was 6.2 years and women on systemic hormonal therapy were excluded.
Endometrial surveillance with either transvaginal ultrasound or endometrial sampling is not required, even with long-term use, but can be considered in women at high risk of endometrial cancer or with use of higher than usual amount or frequency of application. Progestogen replacement is also not recommended but can be considered as above. Most RCT are limited to 1 year of data regarding endometrial risk, but both ACOG and NAMS advise low-dose vaginal estrogen can be used indefinitely and do not advise discontinuation at a specific age.[36,40] Any bleeding should be considered abnormal and investigated.
Women with a history of breast cancer should be offered nonhormone methods as first-line treatment of GSM. Women with severe or refractory cases can be offered locally applied estrogen treatment after an informed discussion of the risks and benefits, ideally in consultation with the patient's oncologist. This approach was recommended by ACOG as noted in the 2016 ACOG issued Committee Opinion which stated that "data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms."[45] Women on adjuvant therapy for breast cancer with tamoxifen (which competitively binds estrogen receptors) those who have completed adjuvant endocrine therapies, and those with hormone receptor negative cancers may theoretically be at lower risk for locally applied estrogen therapies than those on aromatase inhibitors where absolute circulating estradiol levels are lower, thus possibly causing a relatively greater increase in serum estrogen level, although absolute risks are unknown.[36,45,46]
In all women with a history of or high risk for breast cancer, but especially those on AI, estrogen preparations with the lowest absorption such as the 4-mcg capsule or the 10-mcg tablet or capsule are a reasonable choice. Faubian noted that clinicians should consider a switch to tamoxifen from AI prior to estrogen treatment.[47] The American Society of Clinical Oncology, which also recommends nonhormonal therapies as first line, recommends as second-line low-dose vaginal estrogens, except in women on AI's, in which case they recommend DHEA.[48] Safety studies of DHEA in women on AI's are, however, currently lacking.
Prior to initiation of any hormone treatment in this high risk population, shared decision making is imperative, and should include a careful consideration of risks and benefits, attention to patient preferences and lifestyle needs, and input from clinical oncologists.
DHEA/Prasterone
A daily intravaginal insert of DHEA/prasterone was approved in 2016 for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy. DHEA is an endogenous steroid, converted by aromatase activity at the intracellular level into androgens and estrogens. In safety and efficacy studies up to 52-week serum levels of DHEA, dehydroepiandrosterone sulfate, estradiol, and testosterone remained within the postmenopausal range, with negligible effect on the endometrium.[49] Locally applied DHEA reverses the histologic changes of atrophy, with a decrease in parabasal cells, decrease in pH, and improved vaginal secretions. Additionally, a retrospective cohort analysis showed that when compared with women with untreated GSM, women treated with prasterone had a significantly lower UTI prevalence within 12 months of the first prescription fill.[50] According to a recent expert opinion intravaginal DHEA may be effective in the treatment of other types of sexual dysfunctions that are secondary to menopause, such as decreased lubrication, decreased sexual desire, decreased sexual satisfaction, decreased ability to achieve orgasm, and pain, although further studies, which consider alternative dosing and indications, are pending.[51]
Breast cancer risk has not been fully evaluated for vaginal DHEA, although the FDA-approved labeling for this intervention lists breast cancer as a warning, and not a contraindication.
Ospemifene
Ospemifene is a selective estrogen receptor modulator approved for the treatment of dyspareunia caused by GSM. Taken daily as a 60 mg oral dose, ospemifene is an estrogen agonist in the vagina, with evidence that suggested no estrogenic effects on the endometrium or breast when followed for a 52-week trial period. Its oral formulation makes it a good option for women who cannot or prefer not to use vaginal products, such as those with severe arthritis, mobility issues, or vulvodynia. Vaginal effects include an improved vaginal maturation index, decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) compared with placebo. In one 12-week Phase 3 RCT of 919 women, the Female Sexual Functioning Index domains of Sexual Pain, Arousal, and Desire were significantly improved with ospemifene versus placebo. Again, like vaginal DHEA, further studies are desired before ospemifene can be recommended for these indications.[52] Studies with small cohorts of women suggest efficacy of ospemifene in the treatment of mixed urinary incontinence as well as recurrent UTI.[53,54] The safety of ospemifene for women with a history of breast cancer is not yet established, and although early studies suggest no or even a protective effect on breast, its use in this population is not FDA recommended. In a recent retrospective matched cohort study (1,728 ospemifene users and 3,456 untreated patients), no differences were observed in either breast cancer incidence or recurrence rates in ospemifene users compared with matched controls.[55] However, due to a lack of controlled discussion regarding hot flushes, which may occur in up to 7% of patients, and a slight increased risk of blood clots should be part of the patient counseling. Ospemifene decrease bone turnover, however, long-term effects on bone are unknown.
Laser and Radiofrequency Procedures
Laser and radiofrequency devices have been globally used for the treatment of GSM. They are written about as interventions that improve symptoms through a process of controlled injury to the epithelium, followed by tissue repair and remodeling which has been shown in wound repair in keratinized skin.[56] These therapies, usually performed in a series of two to three treatments over several months, have not been FDA approved for use in the nonkeratinized skin of the vagina or for the indication of vulvovaginal atrophy or GSM. In 2018 the FDA issued a safety communication about the use of these devices for these indications, followed by statements from the ACOG, the International Society for the Study of Vulvovaginal Disease, the International Urogynecological Association, and NAMS, among others, all of whom cautioned against the use of these therapies based on lack of sufficient data from RCTs to support long-term safety or efficacy.[33,34,40,56,57]
Reviews in support of laser and radiofrequency procedures cite the many observational studies that demonstrate a significant improvement in GSM signs and symptoms, including one that reviewed 10 observational studies in women with breast cancer.[58] Other authors cite the lack of reported adverse events or lawsuits for complications as reported in a 10-year review of the FDA Manufacturer and User Facility Device Experience and Bloomberg Law Databases, respectively.[59]
Nonetheless, until well-powered, well-conducted, and well-designed RCTs versus placebo or other interventions are available, these procedures should be cautiously used for the treatment of GSM.
Sexual Activity, Vaginal Dilators, and Pelvic Floor Physical Therapy
Sexual activity, either by self-stimulation or with a partner, helps in maintaining vaginal health by contribution to both increased vascularity and elasticity of tissue. Open conversations about sexual health with women throughout the peri- and postmenopause while conveying a positive attitude toward sexuality and offering availability for further discussion should be incorporated into the health care of this population.
For women who resume sexual activity after a period of inactivity, initiation of GSM treatment before intimacy may be of benefit. For these women, as well as those with long-standing dyspareunia who may have developed secondary vaginismus, the addition of vaginal dilators which aid both in mechanical distention and progressive relaxation of the vaginal musculature may be suggested. Dilators can be in sets with increasing diameters or expanding dilators may be used. Mindfulness exercises combined with dilators may further aid in relaxation and return to painless vaginal penetration.[60] Pelvic floor physical therapy that may utilize biofeedback to teach relaxation, identify and manage areas of trigger point tenderness, and instruct women on home exercises such as vaginal massage may be warranted and should be considered. Pelvic floor physical therapy is well established in the treatment of urinary incontinence and may be used as an adjuvant treatment for urinary symptoms of menopause.
Women with severe vaginal strictures or shortening, labial agglutination, or postoperative or radiation changes who do not respond to conservative measures (including local hormonal therapy) should be referred to specialists for further management, including surgical options.
Testosterone Therapy
Locally applied, compounded testosterone has been used for GSM with limited efficacy and safety data. Topical testosterone cream has been explored as an alternative to estrogen treatment for vaginal dryness and dyspareunia in women with a history of breast cancer, including those on AI's. Two trials, one with 20 breast cancer survivors and one with 76 who were on AI's showed improvement in GSM symptoms with the latter also reporting improvement in sexual desire.[61,62] However, due to a lack of controlled trials for efficacy and safety data, as restated by the International Society for the Study of Women's Sexual Health (ISSWSH, 2018) and NAMS (2020), the use of testosterone is not currently recommended.[40,63]
Bioidentical Hormones
Bioidentical hormones are, by definition, hormones that are chemically similar or identical to those produced by the body. FDA-approved vaginal estradiol and DHEA are therefore bioidentical. Often, however, bioidentical (also called "natural") hormones refer to non-FDA approved, commercially available hormones produced and compounded by specialty pharmacies. Concerns regarding quality, purity, and potency of these products, as well as lack of RCTs, limit their use. For healthcare providers who prescribe these medications, use of established compounding pharmacies, with a known source of medications and good communication with the compounding pharmacist, should be considered.
Nonresponders
Women who begin clinician-directed management for GSM should be followed at regular intervals until symptoms are controlled. This allows for a tiered approach to intervention, strengthens the healthcare provider-patient relationship, and may improve compliance with treatment. For women who do not respond to initial treatment with a pharmacologic intervention, changes can be instituted in a timely manner if the woman has a follow-up appointment. Adherence to adequate dosing frequency and amount should be reviewed at each visit. Increased frequency or dosage may be considered if compliance has been confirmed. For example, the current FDA-approved doses of estradiol vaginal cream (2–4 g/d for 1–2 wks, followed by 1 g/1–3 times per week) and conjugated equine estrogen vaginal cream (0.5–2 g/d for 21 d, then off for 7 d) are higher than the doses currently used in clinical practice proven to be effective (0.5 g twice a week), and increases, with informed review of possible risks, may be warranted. A review of other products such as soaps, wipes, and over-the-counter products should be reviewed and eliminated as a possible source for allergic or irritative vaginitis. In women who have had an initial physical examination, telehealth follow-up may be considered. In women who have not been examined, or in women who do not respond despite treatment adjustments, an in-office evaluation to rule out other pathology is warranted. Differential diagnosis includes vulvar dystrophies or skin disorders like eczema, vaginitis (yeast, bacterial vaginosis trichomonas), vulvodynia, vulvar intraepithelial neoplasia, or cancer. Referral to a vulvar specialist should be considered as needed.
Menopause. 2021;28(5):579-588. © 2021 The North American Menopause Society
