Vaginal Atrophy and Common Skin Disorders of the Vulva and Vagina
Anita H. Chen
VAGINAL ATROPHY
Introduction
Menopause is characterized by loss of ovarian function and as life expectancy has risen, women can spend 30 or more years living with changes that affect them physically, emotionally, functionally, and histologically.1 Menopause symptoms include vasomotor symptoms, sleep disturbances, changes to sexual function, urinary tract symptoms, and vulvovaginal symptoms. Hypoestrogenic changes can occur to the labia majora, labia minora, clitoris, introitus, vagina, urethra, and bladder; these physical changes have been referred to as vulvovaginal atrophy (VVA), vaginal atrophy, and atrophic vaginitis. Resulting symptoms include vaginal dryness, burning, and irritation; sexual symptoms of dyspareunia and impaired function; urinary symptoms of urgency, dysuria, and recurrent urinary tract infection.2 In 2014, the North American Menopause Society and the International Society for the Study of Women’s Sexual Health proposed the term genitourinary syndrome of menopause (GSM). GSM acknowledges the changes that occur to the lower urinary tract as well as the vulvar and vaginal tissues from postmenopausal estrogen deficiency and specifically avoids the negative connotations associated with the term atrophy.2,3 As many as 84% of postmenopausal women will experience GSM symptoms from decreased estrogen levels.4 GSM is a clinical diagnosis and is made with a combination of characteristic examination findings and bothersome symptoms which are known to be chronic and progressive.3,4 VVA is a subset of GSM. Vaginal physiology and resulting symptomatology is an indicator of the levels of circulating estrogen.5 The prevalence of GSM is not well established; however, a longitudinal study evaluating presence of vaginal dryness symptoms by age group found that 3% of women of reproductive age, 4% of women in early menopause transition, 21% of women in later years of menopause transition, 40% of women 3 years after menopause, and 83% of women 6 years after menopause reported symptoms.6 The incidence of GSM symptoms in women visiting a gynecology or menopause clinic is over 90%.7
Anatomy and Physiology
The female genital and lower urinary tract both arise from the primitive urogenital sinus and share common estrogen receptor function.8 The vaginal wall consists of nonkeratinized stratified squamous vaginal epithelium; lamina propria with dense connective tissue rich in blood and lymphatic vessels; muscular layer of smooth muscle; and tunica adventitia with loose connective tissue, collagen, and elastic fiber.9 Although sometimes referred to as mucosa, glands are not present. Vaginal epithelium is composed of deep immature parabasal cells, intermediate cells, and mature superficial cells which store glycogen in the presence of estrogen.8 The ratio of these cell types change over a woman’s lifetime and is based on estrogen stimulation. Before menarche, the vaginal cytology is composed primarily of parabasal cells, whereas superficial cells are most prominent during the reproductive years. Declining estrogen levels in menopause result in a return of parabasal cell predominance with fewer intermediate and superficial cells.10
Estrogen, progesterone, and androgen have important effects on the genitourinary system.11 Androgen receptors have been detected in the genitourinary system and contribute to the maintenance of tissue structure and function.11 Androgen receptors are most dense in the external genitalia, whereas progesterone receptors are found in the vagina and vulvovaginal transitional epithelium.4 Vaginal physiology is dominated by estrogen. Estrogen receptors are most dense in the vagina and are also located in the vulva, urethra, and trigone of the bladder.4 Two estrogen receptors have been identified, designated as estrogen receptor alpha (ER-a) and estrogen receptor beta (ER-β) with relative expression and actions of the two receptors varying among tissues.12 In premenopause, the vagina, vulva, pelvic floor skeletal muscles, urethra, and bladder trigone display a
significant number of both α and β estrogen receptors. In the vagina, estrogen receptors are expressed in the epithelium, stroma, and muscle cells13 and expression of ER-a decreases after menopause. Estrogen therapy increases ER-a receptor content, although not to premenopausal levels; ER-β, however, exhibits a dramatic decline after menopause, regardless of exogenous estrogen supplementation.12 These findings indicate that the beneficial response to exogenous estrogen after menopause is modulated by ER-a receptors.12 Estrogen affects thickness and elasticity of the vagina by maintaining collagen content of the epithelium, keeps the epithelial surface moist by maintaining intercellular acid mucopolysaccharides and hyaluronic acid, and maintains optimal genital blood flow.13,14
significant number of both α and β estrogen receptors. In the vagina, estrogen receptors are expressed in the epithelium, stroma, and muscle cells13 and expression of ER-a decreases after menopause. Estrogen therapy increases ER-a receptor content, although not to premenopausal levels; ER-β, however, exhibits a dramatic decline after menopause, regardless of exogenous estrogen supplementation.12 These findings indicate that the beneficial response to exogenous estrogen after menopause is modulated by ER-a receptors.12 Estrogen affects thickness and elasticity of the vagina by maintaining collagen content of the epithelium, keeps the epithelial surface moist by maintaining intercellular acid mucopolysaccharides and hyaluronic acid, and maintains optimal genital blood flow.13,14
Estradiol levels from premenopausal to postmenopausal state can decrease approximately 95%. This marked decrease in serum estrogen along with the normal aging process results in many of the changes that comprise vaginal atrophy. With decreasing estrogen, the vaginal epithelium and lamina propria thins, smooth muscle atrophies, blood flow decreases, and tissue elasticity decreases from fusion and hyalinization of collagen fibers and fragmentation of elastin; loss of vaginal rugal folds results in a shortened and narrow vagina with loss of distensibility and thinning of the epithelium become apparent.5,8,13 Reduction of blood supply leads to a decrease in volume of transudate and other glandular secretions.5,13 Thinning of the vaginal epithelium leads to susceptibility for inflammation and infection. As the epithelium thins, glycogen which is stored in mature cells decreases; this results in a reduction of lactic acid production by lactobacilli, causing an increase in vaginal pH.10,15 This change in vaginal microbiota can result in colonization by pathogenic organisms resulting in vaginal and urinary tract infections.16,17 Hypoestrogenic changes to the urethral epithelium and suburethral plexus along with loss of protective urogenital lactobacilli increase risk of recurrent urinary tract infections after menopause.18
Impact on Quality of Life
Vasomotor symptoms of hot flashes or night sweats can affect up to 80% of women across the menopause transition and is a motivator for seeking medical care.19 Of the women who suffer from menopausal symptoms, approximately 50% will have GSM symptoms.20 Studies indicate that vasomotor symptoms can improve over time; however, symptoms of GSM can be progressive and may not resolve without treatment.3,4,21 GSM has significant negative impact on a woman’s quality of life and sexual health. Quality of life surveys conducted in multiple countries including the United States have reported negative effects on women’s lives (75% to 80%), adverse effects on intimacy (75% to 85%), and impact on personal relationships (33% to 47%).22,23,24,25 Despite these findings, large-scale surveys of menopausal women and their physicians demonstrate that GSM is often ignored by women and overlooked by clinicians and up to one-third of the women surveyed wanted their physician to start the conversation.26,27 Vaginal dryness is the most prevalent and also the most bothersome symptom of GSM.7,28
Investigators have analyzed the relationship of vaginal atrophy with subjective symptoms of vaginal dryness and the Female Sexual Function Index (FSFI) score, a questionnaire of 19 questions around the domains of desire, arousal, orgasm, dyspareunia, lubrication, and sexual satisfaction.29 They found that vaginal dryness was the one symptom which most closely related to all domains of female sexuality, thereby identifying a treatable factor that could improve female sexual function during the menopause transition.30 Women whose symptoms of GSM are confirmed by physical examination have even lower quality of life and sexual function scores.7,31,32
Surveys evaluating menopausal women’s understanding of VVA found that almost 75% have not discussed concerns with their clinician.20,25,27,33,34 In addition, a survey querying physicians who self-identified as providing care to menopausal women with GSM found that up to 15% of women with symptomatic VVA were not offered any form of treatment.21 Likely, this percentage would be even higher for providers who infrequently treated women with GSM concerns.21,35 Potential explanations for these findings include the assumption that women and health care providers may feel symptoms are a natural part of aging, may be embarrassed to discuss symptoms, may not have sufficient knowledge about disease progression or long-term treatment strategies, or may not have adequate time during the visit.6,22,32,33,34
Clinical Manifestations
As mentioned earlier, common presenting symptoms of GSM include vaginal dryness (75%), dyspareunia (38%), vaginal itching, discharge, and pain (15%).5,8 Urinary symptoms include urinary frequency, dysuria, and increased risk for urinary tract infection.6,17 Symptoms may progress to the point of precluding penetrative sexual activity.4 Some women report discomfort even with activity such as sitting or wiping.4 Of the different symptoms, vaginal dryness is the only symptom to increase with years since menopause.28 Dyspareunia symptoms decreased after the first 6 years since menopause, likely a reflection of less frequency of sexual activity over time from sexual discomfort or aging.28
Evaluation
Evaluation of GSM includes a medical history and pelvic examination. Women who are peri- or postmenopausal should be asked about symptoms of urogenital
atrophy during their visit as many women are hesitant to bring up symptoms.26 It is important to detail the obstetric and gynecologic history including menstrual history. Other contributors to low estrogen status such as use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) should be assessed.5 Responses to previous intervention should be reviewed and a pertinent sexual history should be taken to ascertain whether symptoms impact sexual activity and cause distress. A thorough review of systems focusing on history of pelvic radiation, exposures to irritants or allergens, and infectious or inflammatory conditions can aid in differential diagnosis. Quality-of-life issues should be assessed, and impact of symptoms on daily activities, sexual activity, and partner relationships should be reviewed. The clinician should have a discussion about the woman’s therapeutic goals.
atrophy during their visit as many women are hesitant to bring up symptoms.26 It is important to detail the obstetric and gynecologic history including menstrual history. Other contributors to low estrogen status such as use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) should be assessed.5 Responses to previous intervention should be reviewed and a pertinent sexual history should be taken to ascertain whether symptoms impact sexual activity and cause distress. A thorough review of systems focusing on history of pelvic radiation, exposures to irritants or allergens, and infectious or inflammatory conditions can aid in differential diagnosis. Quality-of-life issues should be assessed, and impact of symptoms on daily activities, sexual activity, and partner relationships should be reviewed. The clinician should have a discussion about the woman’s therapeutic goals.
Office pelvic exam begins after a review of the exam process and informed consent is obtained. Providing the patient with a mirror during the pelvic exam may be helpful to mutually evaluate areas of concern. The appropriate size speculum with adequate lubrication should be used as even gentle contact with atrophic changes can result in pain and bleeding. Common changes on physical examination include a decrease in pubic hair, loss of labial adipose, thinning and resorption of the labia minora, narrowing of the introitus, and increased vaginal pH.2 The urethral meatus may appear more prominent and erythematous as the mons pubis, labia majora, and minora lose bulk (Fig. 61.1). Speculum examination findings include reduced vaginal caliber, smooth, shiny, pale mucosa with loss of folds, loss of cervical length with cervix flush with the vaginal apex, and obliteration of the vaginal fornices.4 The vagina may appear erythematous, develop petechiae, and become more friable with inflammation.4 The prevalence of objective signs increase with time since menopause, reaching 90% with findings of mucosal pallor and rugae thinning, 80% mucosal fragility, and 51% presence of petechiae.17 Pelvic examination also evaluates for other vulvar and vaginal conditions including contact dermatitis, inflammatory vaginitis, vulvar dermatoses, and neoplasm.4 Visual assessments of the vagina appear to be a useful measurement to diagnose VVA; however, there is no consensus on best visual assessment tool.36
Laboratory tests are not usually necessary for diagnosis and evaluation of GSM; however, these exclude other etiology such as infectious vaginitis or urinary tract infection. pH testing, performed by placing a piece of litmus paper on the lateral vaginal wall at the time of speculum exam, will typically show a pH >5.0.37 Vaginal maturation index (VMI) is a quantification of the estrogenic effect on vaginal cytology and describes the relative proportions of parabasal, intermediate, and superficial cells.14 A vaginal smear is collected from the lateral wall of the upper third of the vagina. VMI is reported as the percentage of superficial, intermediate, and parabasal cells and indicates the degree of tissue maturation.38 With menopause, superficial cells are either diminished or disappear, and intermediate and parabasal cells increase.37 Measurement of pH and VMI have limited utility in the clinical setting as these measures are not typically obtained.36
 FIGURE 61.1 VVA. Urethral caruncle presenting as a bright, red, fleshy protuberance from the distal urethral as a result of shrinkage of the surrounding vaginal epithelium from decreased estrogen. (Courtesy of Dr. Anita Chen.) |
Management of Genitourinary Syndrome of Menopause
Despite the prevalence of symptoms, treatment for GSM remains low. More than half of women who are symptomatic have never used therapy.4 In addition, lifestyle modifications which have been shown to reduce symptoms of GSM such smoking cessation, increased coital activity, and pelvic floor physiotherapy are not routinely discussed.8,38 Management strategies will vary according to symptom severity, and life-long management is essential.
Lubricants and moisturizers
Lubricant and moisturizers are useful for women with mild to moderate vaginal dryness and are recommended as first-line therapy (Table 61.1).4 Vaginal moisturizers are commercially available insoluble hydrophilic crosslinked polymer bioadhesives that adhere to the vaginal
wall by retaining water.38 These products trap moisture, improve vaginal pH balance, and reduce itching and are meant to be used on a regular basis as they tend to have a longer lasting effect.38,39,40 Some vaginal moisturizers contain hyaluronic acid, a polymer that has a high capacity to bind water.38 Data, however, have not shown that products containing hyaluronic acid have a greater benefit than those that do not.4
wall by retaining water.38 These products trap moisture, improve vaginal pH balance, and reduce itching and are meant to be used on a regular basis as they tend to have a longer lasting effect.38,39,40 Some vaginal moisturizers contain hyaluronic acid, a polymer that has a high capacity to bind water.38 Data, however, have not shown that products containing hyaluronic acid have a greater benefit than those that do not.4
TABLE 61.1 Topical Nonhormonal Treatments for Genitourinary Syndrome of Menopause | ||||||||||||||||||||||
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Lubricants are used for short-term relief of vaginal dryness during intercourse to reduce dyspareunia.38 Lubricants are also commercially available and may be water, silicone, or oil based. These products decrease friction during intercourse to relieve discomfort related to vaginal dryness.39 Water-based lubricants are nonstaining and are associated with fewer genital symptoms than silicone-based lubricants.40 Oil-based lubricants can cause breakdown of latex condoms, but most water- and silicone-based lubricants are latex safe. Even though clinicians commonly recommend use of over-the-counter lubricants and moisturizers, there is limited data on safety and effectiveness. A study evaluating the safety of lubricants found that iso-osmolar (pH 4.0) water-based gels and silicone-based gels were the safest in regard to cellular toxicity and epithelial damage.41 Mild to moderate symptoms of vaginal dryness can be managed by routine, two to three times per week use of vaginal moisturizing agents with vaginal lubricants added during sexual intercourse.42 Although these products may improve discomfort during intercourse and also increase vaginal moisture, they do not reverse atrophic vaginal changes.
Low-dose vaginal estrogen
Vaginal estrogen therapy is a common second-line treatment for GSM not responding to first-line therapy; it is administered via cream, ring, insert, or tablet (Table 61.2). There are two vaginal creams commercially available: a 17β-estradiol vaginal cream and a conjugated estrogen cream. Vaginal creams can be applied digitally or with the supplied plastic applicator. The only vaginal tablet product currently available in the United States contains 10 µg of estradiol hemihydrate. The tablet is placed vaginal with a single-use plastic applicator. There are two estrogen vaginal rings available, only the 17β-estradiol silastic vaginal ring delivers low-dose hormone to the vaginal tissues without systemic levels of hormone. The estradiol acetate ring provides systemic levels of hormone.43 Vaginal rings are placed in the vagina and switched out every 3 months. For women who prefer not to use an applicator, vaginal estrogen inserts are available in 4- and 10-µg doses; these are digitally placed in the vagina. Different vaginal estrogen therapy have variable rates of systemic absorption; however, overall vaginal preparations have minimal systemic absorption, are generally safe, do not require concomitant progesterone therapy for endometrial protection, and have similar efficacy.4,44,45,46 These local preparations may be more effective than the systemic estrogen therapy for treatment of GSM as some woman receiving systemic estrogen therapy for menopausal symptoms often have persistent GSM symptoms.3 Endometrial evaluation should be performed if a woman reports abnormal uterine bleeding; otherwise, routine endometrial surveillance is not recommended.4,42
For postmenopausal women, topical vaginal estrogen use can decrease recurrent urinary tract infections and improve overactive bladder symptoms with reduction in urinary urgency and frequency.18,47,48 Trials have shown an increased incidence of stress incontinence in users of systemic estrogen; however, users of vaginal estrogen have demonstrated a decreased incidence of incontinence in addition to reduced urinary urgency.47
The American College of Obstetricians and Gynecologists and the North American Menopause Society advise that low-dose vaginal estrogen therapy may be used as long as needed.4,42,49 In fact, if hormone
therapy is discontinued, GSM will recur.4 Data from the Women’s Health Initiative and the Nurses’ Health Study have shown no increase in risk of invasive breast cancer, stroke, colorectal cancer, endometrial cancer, pulmonary embolism or deep vein thrombosis, coronary heart disease, or death with vaginal estrogen.50 Despite this data, the current U.S. Food and Drug Administration (FDA) package labeling for low-dose vaginal estrogen has not changed and remains the same as that for systemic formulations with a black-box warning of risk of endometrial cancer, myocardial infarction, stroke, invasive breast cancer, pulmonary embolism, and dementia.51 GSM symptoms can be successfully managed with local estrogen therapy; however, surveys aimed at evaluating the attitudes of menopausal women regarding use of vaginal hormone therapy have shown that women avoid or discontinue vaginal estrogen therapy because of concerns of risk, side effects, and cost.25,27
therapy is discontinued, GSM will recur.4 Data from the Women’s Health Initiative and the Nurses’ Health Study have shown no increase in risk of invasive breast cancer, stroke, colorectal cancer, endometrial cancer, pulmonary embolism or deep vein thrombosis, coronary heart disease, or death with vaginal estrogen.50 Despite this data, the current U.S. Food and Drug Administration (FDA) package labeling for low-dose vaginal estrogen has not changed and remains the same as that for systemic formulations with a black-box warning of risk of endometrial cancer, myocardial infarction, stroke, invasive breast cancer, pulmonary embolism, and dementia.51 GSM symptoms can be successfully managed with local estrogen therapy; however, surveys aimed at evaluating the attitudes of menopausal women regarding use of vaginal hormone therapy have shown that women avoid or discontinue vaginal estrogen therapy because of concerns of risk, side effects, and cost.25,27
TABLE 61.2 Topical Vaginal Therapies | |||||||||||||||||||||||||||||||||
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Selective estrogen receptor modulators
SERMs are synthetic nonsteroidal agents that exert estrogen agonist or antagonist effects based on target tissue. Ospemifene and lasofoxifene show the most targeted beneficial effects for treatment of GSM.52 Ospemifene is the only SERM currently FDA approved for the treatment of moderate to severe dyspareunia caused by VVA in menopausal women with or without a uterus.4,38,53 Histologically, ospemifene has been found to increases cell maturation and ER-a expression of the vaginal epithelium.54 Additional effects to the vagina and vulva vestibule include increased epithelial thickness, glycogen content, collagen content, and proliferation index.55 An oral dose of 60 mg per day exerts estrogenic defects on the vulva vaginal tissue resulting reduction of severity of vaginal dryness and dyspareunia with improvements of VMI, vaginal pH, and FSFI scores.56,57 Safety data for ospemifene show no detrimental impact on breast, bone, and cardiovascular health and no endometrial hyperplasia or carcinoma were observed.58,59,60 There is not enough data, however, to demonstrate safety in patients with personal history or high risk of breast cancer or for women with increased risk of thromboembolic events.4 Treatment adverse events include hot flushes (6.3%) and vaginal bleeding (1.3%).58
Other SERMs under investigation for improvement of GSM symptoms include lasofoxifene and bazedoxifene used in combination with conjugated equine estrogen. It should be noted that bazedoxifene alone and raloxifene do not exert a positive effect on the vagina. Tamoxifen exerts a mixed effect on the vagina and has been reported to cause dyspareunia, increased vaginal discharge, and vaginal dryness.52
Vaginal dehydroepiandrosterone
Clinical trials with daily use of vaginal dehydroepiandrosterone (DHEA) (prasterone) have found improvement in GSM symptoms, specifically dyspareunia, vaginal pH, and VMI.3,61 Prasterone is a precursor of intracellular sex steroid androgens and estrogens. The intracellular transformation of DHEA into estrogen results in maturation of the parabasal cells into intermediate and then superficial cells with increase in density of collagen.61 Prasterone tablets are administered intravaginally with a single-use plastic applicator on a nightly basis. Research has shown that serum estrogens and androgens and their metabolites remain in the normal postmenopausal range; however, safety in women with breast cancer or taking AIs is unknown as this group was excluded from the study.61,62,63
Therapy under investigation
Energy-based devices have been used to treat GSM. The most commonly used are the fractional microablative carbon dioxide (CO2) laser, nonablative photothermal erbium-doped:yttrium aluminum garnet (Er:YAG) laser, and radio frequency (RF) laser. The CO2 fractional microablative laser burns a grid of tiny holes on the surface tissue; this microtrauma induces a healing response to increase production of collagen, elastin, and glycogenated cells.8,38,64 The nonablative Er:YAG laser produces a photothermal effect by heating underlying tissue resulting in an increase in heat shock proteins and collagen production without harming the surface.64 GSM treatment of the vaginal wall with CO2 or Er:YAG laser has been reported in small studies with short-term follow-up and the number of publications continue to grow.65,66,67,68 Nonablative RF devices which emit focused electromagnetic waves that heat the superficial layers of tissue are used to remodel the vaginal and vulvar tissue. Small case series have found benefit on vaginal, sexual, and urinary symptoms.69 Randomized controlled trials comparing microablative laser therapy to vaginal estrogen have demonstrated similar effects, and investigation of laser therapy as a treatment option for breast cancer survivors have been conducted.70,71,72,73 Typically, laser treatment is performed as a series of three sessions, 4 to 6 weeks apart with one session per year as maintenance therapy. A recent review of published literature found that these short-term, small longitudinal studies appear to demonstrate reductions in GSM symptoms. In the absence of clinical practice guidelines supported by highlevel evidence, clinical consensus statements are created based on rigorous criteria and expert opinion after review of the available literature. A clinical consensus statement from a global group of experts summarized that energy-based therapy to the vagina results in thickening of glycogen-enriched epithelium, neovascularization, collagen growth in the lamina propria, increased lactobacilli, reduced pH, vaginal wall tightening, and improved urinary control with favorable safety profile.74 The American Urogynecologic Society published a consensus statement on vaginal energy-based devices in 2020 to provide guidance.75 Consensus in efficacy outcomes were reached for the statements that energy-based therapy demonstrated up to 1 year efficacy in conditions of VVA, vaginal dryness, and dyspareunia with positive short-term effect on sexual function.75 The preferred energy device, optimal number of treatments, timing of maintenance therapy, and add-on treatments such as estrogen need to be further studied.74,75 As of this writing, the FDA has not approved laser therapy and both the FDA and several professional organizations have recommended against widespread use without long-term and well-controlled studies to evaluate safety and efficacy of the various lasers.76,77,78,79
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