Vulvar and Vaginal Atrophy: Physiology, Clinical Presentation, and Treatment Considerations

Transcription

1 CLINICAL OBSTETRICS AND GYNECOLOGY Volume 58, Number 3, Vulvar and Vaginal Atrophy: Physiology, Clinical Presentation, and Treatment Considerations AHINOAM LEV-SAGIE, MD Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Abstract: Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching, soreness, burning, dyspareunia, discharge, urinary frequency, and urgency. It can occur at any time in a woman s life cycle, although more commonly in the postmenopausal phase, during which the prevalence is approximately 50%. Despite the high prevalence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreported and undertreated. This article aims to review the physiology, clinical presentation, assessment, and current recommendations for treatment, including aspects of effectiveness and safety of local vaginal estrogen therapies. Key words: atrophy, vulva, vagina, low estrogen Introduction Genitourinary syndrome of menopause (GSM), also known as vulvovaginal atrophy Correspondence: Ahinoam Lev-Sagie, MD, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. levsagie@netvision.net.il The author declares that there is nothing to disclose. (VVA), urogenital atrophy, or atrophic vaginitis, is a condition that results from decreased estrogen in the urogenital tissues. It can occur at any time in a woman s life cycle, although it is most common in postmenopausal women, when it is reported in up to 50% of women. 1 Other conditions associated with hypoestrogenism and with development of similar characteristics include surgical menopause (bilateral oophorectomy), lactation, hypothalamic amenorrhea caused by excessive exercise or disordered eating, hyperprolactinemia, various cancer treatments that render the ovaries inactive (pelvic radiation therapy, chemotherapy, endocrine therapy), and usage of certain medications, such as gonadotropin-releasing hormone (GnRH) agonists (to manage endometriosis and uterine fibroids), GnRH antagonists, tamoxifen, and aromatase inhibitors (AIs). Recently, the Boards of North American Menopause Society (NAMS) and the International Society for the Study of Women s Sexual Health (ISSWSH) reviewed CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 58 / NUMBER 3 / SEPTEMBER

2 Vulvovaginal Atrophy Diagnosis and Treatment 477 current terminology associated with genitourinary tract symptoms related to menopause, and endorsed a new term, Genitourinary Syndrome of Menopause (GSM). The new term, attended to replace the terms VVA and atrophic vaginitis was chosen because it is a medically more accurate, all-encompassing, and publicly acceptable term than VVA. 1 GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the vulva, vagina, urethra, and bladder. The syndrome may include, but is not limited to, genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections (UTIs). Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. Physiology Estrogen is a dominant regulator of vaginal physiology. During the reproductive years, estrogen plays a major role in maintaining the normal vaginal environment. This includes a thickened rugated vaginal surface, increased blood flow and lubrication, lactobacillus-dominant flora, and a low (<4.5) ph. 2 With estrogen withdrawal during menopause, significant anatomic and physiological changes occur in the urogenitaltissues. The epithelium becomes pale, thin, less elastic, and progressively smoother as rugal folds decrease. Other changes include reduced collagen content and hyalinization, decreased elastin, altered appearance and function of smooth muscle cells, increased density of connective tissue, and fewer blood vessels. The vagina can narrow and shorten, the labia minora thin and regress, and the introitus may constrict. 1,2 Blood flow and secretions diminish; flexibility and elasticity of the vaginal vault decrease; and the tissues become more friable. Epithelial thinning with decreased glycogenated superficial cells leads to changes in vaginal flora, shifting from a lactobacillus-dominant flora to anaerobic Gram-negative rods and Gram-positive cocci flora, and ph increases. Vulvar and vaginal atrophic changes increase the likelihood of trauma, infection, and pain. Severe VVA/GSM can result in a vaginal surface that is friable, with petechiae, ulcerations, and tears, accompanied in some cases by vaginal stenosis if left untreated. Urinary tract structures are derived from thesameembryologicoriginasthegenital tract and also contain estrogen receptors (ERs). Thus, the urinary system, including the bladder and urethra is also affected by decreased estrogen levels, as are the pelvic floor musculature and endopelvic fascia. 3 Thinning of the urinary epithelium and weakening of the surrounding tissue may promote reduced urethral closure pressure, reduced sensory threshold in the bladder, and in some cases, recurrent UTIs. These changes result from a decline in the serum estrogen concentration; in the premenopausal state, estradiol is the predominant form of circulating estrogen. Its levels fluctuate from 10 to 800 pg/ml during the cycle. 4 In the postmenopausal state, circulating estradiol is derived from estrone, which is peripherally converted in adipose tissue from adrenal androstenedione, and its levels are typically <30 pg/ml. 4 The effects of endogenous estrogens on urogenital tissues are mediated through ERs a and b, which are found throughout the urogenital tissues, including the vagina, vulva, labia, urethra, and the bladder trigone. 2 In a study evaluating the effect of estradiol on the vagina at the molecular level, differentially expressed mrna transcripts in vaginal biopsies were determined by microarray analysis in women with VVA/GSM before and after estradiol treatment. 5 Transcriptional profiling of vaginal biopsies identified over 3000 estradiol-regulated genes, involved in several signaling pathways that promote tissue repair and remodeling in the vagina.

3 478 Lev-Sagie Therefore, it is possible that the variation in urogenital symptoms between menopausal women may result from individual features of estrogen metabolism, different expression of ERs in the vaginal tissue, and different genetic regulation. Vaginal microbiome research studies in menopausal women, exploring how bacterial species interact with each other and with the host vaginal epithelium may allow for a more complete understanding of VVA/GSM. 1,2 In addition, factors other than low estrogen levels can modulate the degree of atrophy: cigarette smoking, cessation of coital activity, vaginal nulliparity, and vaginal surgery may intensify vaginal atrophy symptoms. 3 Assessment and Diagnosis The diagnosis of VVA/GSM is clinical, based upon characteristic symptoms, typical signs on physical examination, and laboratory tests. HISTORY Up to 70% of women with symptoms of VVA/GSM do not discuss their condition with a health care provider. This may be attributed to the common belief that symptoms are an essential part of the aging process, inconvenience to discuss intimate symptoms, or unawareness to treatment options. 6 Therefore, care providers should ask about symptoms of urogenital atrophy during routine clinical visits. The goal of the history is to determine whether symptoms of VVA/GSM are present, whether they are bothersome, and how they affect the woman s sexual health and quality of life (QOL). In the absence of symptoms, VVA/GSM does not necessarily require treatment, although women should be informed that it may worsen over time without proactive management. 1 Patients should be asked about menstrual history, symptoms, and their severity and response to previous medications or interventions. A complete review should be performed, as urogenital symptoms may be due to etiologies other than loss of estrogen, such as infection, inflammatory conditions, dermatoses, usage of vulvar irritants and allergens, pelvic radiation, previous surgeries, and systemic medications. Sexual history should be taken to evaluate whether sexual activity is associated with symptoms. QOL issues should also be assessed; these include degree of discomfort, behavioral responses to symptoms, as well as the impact of symptoms on daily activities, sexual activity, and relationships. 2,3 SYMPTOMS Although all menopausal women undergo the same hormonal changes, only B50% of them will become symptomatic (Table 1). It is not known which women will develop symptoms and at what point after the onset of menopause. In a longitudinal, population-based study, the prevalence of vaginal dryness increased over time. In early perimenopause, the prevalence was 4%, rising to 25% one year after menopause and to 47% three years after menopause. 7 These changes usually develop gradually, over a period of years, and generally persist unless they are treated. 1,3 In addition, it was reported that while many women exhibited signs of VVA/GSM, not all were symptomatic. The initial symptom is often lack of lubrication during intercourse. 4 As the hypoestrogenic state becomes chronic, patients will generally complain of vaginal dryness during sexual activity, dryness during daily activities, irritation, dyspareunia, pruritus, soreness, and stinging pain. 2 Although normal secretions are decreased, patients may note an abnormal yellow or watery discharge. Vaginal spotting may occur from minimal trauma or sexual intercourse if atrophy is severe. 2 Other symptoms include irritative urinary complaints (urgency, frequency, nocturia), vestibular dysuria resulting from irritation of the thin vestibule by urine, and recurrent UTIs, that can affect 5% to 17% of postmenopausal women. 2,4

4 Vulvovaginal Atrophy Diagnosis and Treatment 479 TABLE 1. Symptoms and Signs of Vulvovaginal Atrophy Symptoms Vaginal dryness (during sexual activity and\or daily activities) Irritation Dyspareunia Pruritus Soreness and stinging pain Discharge abnormal yellow or watery Spotting Urinary urgency, frequency Dysuria Recurrent urinary tract infections Signs Pale, dry, smooth, shiny vaginal epithelium Vaginal discharge: thin watery or purulent Patchy erythema Petechiae Scant pubic hair Diminished elasticity Introital narrowing Short, less distensible, narrow vagina Fusion or resorption of the labia minora Pseudoclitromegaly Urethral caruncle Obliterated fornices Vaginal phz5 Awareness of the association between VVA/ GSM and recurrent UTIs may guide care givers to treat patients with topical vaginal estrogen and prevent unneeded treatment with antibiotics. A number of surveys of postmenopausal women have shown that VVA/GSM negatively affects sexual health and QOL. Most menopausal women (28% to 61% in different age groups) remain sexually active after menopause. Unfortunately, it appears that many women tolerate painful sex, whereas others may reduce the frequency of sexual activity or discontinue it entirely. It was reported that one quarter of women experience dyspareunia at least sometimes, of whom 72% is engaged in sexual intercourse at least once a month and 34% at least once a week, despite the pain they were experiencing. 6 Remarkably, 80% of them reported that they had learned to live with vulvovaginal symptoms of menopause as a normal part of getting older; 30% of them reported that the pain required pause or discontinuance of sexual activity; 56% said they were sexually less active as a result of the pain, whereas 6% said that the pain prevented any attempt at sexual activity. 6 Other studies found that 64% of postmenopausal women reported painful sex, 64% experienced loss of libido, and 58% noted that they avoided intimacy. 6 Although the relationship between VVA/GSM and sexuality is complex, and sexual dysfunction cannot be attributed solely to VVA/GSM, it was reported in multiple studies that postmenopausal women attributed loss of libido and lower arousal to vaginal dryness and dyspareunia secondary to vaginal dryness. 6 SIGNS Signs observed during evaluation of the vulva and vagina vary with the degree of atrophy (Table 1). The external genitalia may show scarce pubic hair, diminished elasticity and turgor of the vulvar skin, introital narrowing or decreased moisture, and fusion or resorption of the labia minora. 8 Loss of the labial fat pad makes the labia minora less distinct and/or makes the clitoris appear more protuberant. An urethral caruncle may be present and appear as a proliferative red tissue at the opening of the urethra. Classic vaginal findings of atrophy include a pale, dry vaginal epithelium that is smooth and shiny with loss of most rugation. Blood vessels may be visible through the thinned epithelium. A thin watery yellow vaginal discharge may be observed. If inflammation is present, there may be patchy erythema, petechiae, friability, bleeding, and purulent discharge. The vagina loses elasticity, shortens, narrows, becomes less distensible, and the fornices may become obliterated, making the cervix flush with the vault. 2,8 LABORATORY STUDIES Laboratory studies can confirm the diagnosis and are also used to exclude other diagnoses. The vaginal ph is generally elevated >5 (as opposed to the ph of an

5 480 Lev-Sagie estrogenized vagina, which ranges from 3.5 to 5.0), but a whiff test is usually negative. On saline microscopy, the squames, large superficial cells, are replaced by parabasal or intermediate cells, which are smaller, rounder, and have a relatively large nucleus (Fig. 1). In addition, vaginal flora are scant and of a mixed pattern with a relative absence of lactobacilli. A maturation index (MI), measuring the proportion of parabasal, intermediate, and superficial squamous mature cells can aid in the diagnosis if a provider is unable to recognize intermediate and parabasal cells by microscopy. In general, measuring serum estrogen levels does not aid in the diagnosis of VVA/ GSM. Serum estradiol levels of <20 pg/ ml support a clinical diagnosis of a hypoestrogenic state; however, estradiol values are laboratory dependent and most assays for estradiol have beendevelopedtomeasure premenopausal levels and are neither sufficiently sensitive nor reliable for diagnosis of hypoestrogenic states. 3 Treatment Although the vasomotor symptoms of menopause generally improve over time, vaginal symptoms usually worsen and do not improve without treatment. 2 Symptomatic VVA/GSM can range in severity from bothersome to debilitating, and the extent of adverse consequences of VVA/GSM makes treatment essential in many women. The primary indication for treatment of VVA/GSM is the relief of bothersome symptoms. 9 First-line treatments recommended by the NAMS 2 are nonhormonal vaginal lubricants and moisturizers, as well as continued sexual activity. When symptoms persist, vaginal local estrogen therapy (ET) is considered effective and well tolerated for the treatment of moderate to severe symptoms. VAGINAL LUBRICANTS Lubricants are used immediately before and during sexual activity to decrease tissue irritation due to friction, and their action is temporary. Lubricants are available as water-soluble products, silicone-based, or oil-based. The choice of lubricant is based on individual preference, and it is recommended that women should try various products until they find one that suits them. Vaginal lubricants can occasionally cause irritation related to the product s osmolarity (greater osmolarity causes greater irritation) or the presence of chemically irritating or allergenic agents. Lubricants do not address the underlying tissue atrophy, and may be perceived as messy and inconvenient by many women. 10 MOISTURIZERS Vaginal moisturizers are intended for regular use (not just during sexual activity), are applied into the vagina at regular intervals (one or more times per week), are long acting, and can decrease vaginal dryness and lower vaginal ph as they are meant to replace normal vaginal secretions. 10,11 Various moisturizer products are available over the counter; examples include Replens, Summer s Eve, Emerita, RepHresh, Me Again, Feminease, K-Y SILK-E, and more. Some moisturizers contain bioadhesives that bind to vaginal epithelial cells and maintain hydration, leading to an improvement in vaginal fluid volume, moisture, and elasticity. Replens (Anglian Pharma, Hampshire, UK), for example, contains polycarbophil, a polymer that forms a thin film over the cells and remains adherent to the epithelial surface for 24 to 72 hours. Other products avoid the use of bioadhesives with similar relief of vaginal dryness, suggesting that bioadhesion is not essential in achieving vaginal moisture. 10 Additional ingredients used in vaginal moisturizers include hyaluronic acid, naturally present in the vaginal epithelium and other body tissues, where it is responsible for maintaining correct levels of hydration in moisture-sensitive environments and genistein, an isoflavone, which have been shown to interact with ERs, producing similareffectstoestrogen. 10

6 Vulvovaginal Atrophy Diagnosis and Treatment 481 FIGURE 1. Microscopic findings in normal, estrogenized vaginal epithelium compared with atrophic vaginal epithelium. A, Normal wet mount (estrogenized): mature squamous epithelial cells (1), appear as large, polygonal cells. There is one or no white blood cell (2) per epithelial cell, and Gram-positive rods (lactobacillus morphotypes) (3) are present. This wet mount represents normal, estrogenized discharge, and is accompanied with a normal ph of r4.5. B, Vaginal atrophy characteristic findings are the presence of parabasal cells (arrow), which are smaller, rounder, and have a large nucleus compared with mature squamous epithelial cells, with scanty vaginal flora as well as an elevated ph (>4.5). There are scarce data regarding the efficacy of vaginal moisturizers. 10 Small randomized trials and small observational studies evaluated Replens, hyaluronic acid preparations, and genistein. All reported relief of vaginal symptoms, although mild irritation was reported by some women. In clinical experience, however, estrogen is more effective than vaginal moisturizers. 9 In addition, the products were tested for a maximal duration of 3 months, and there are no data relating to long-term safety and efficacy. 10 INTERCOURSE AND MECHANICAL MEASURES Continued vaginal sexual activity provides protection from VVA/GSM. Postmenopausal women with higher frequency of intercourse reported significantly less severe

7 482 Lev-Sagie VVA/GSM symptoms and had less evidence of shrinkage and stenosis on vaginal examination. 9 It is presumed that sexual activity increases blood flow to the pelvic organs, provide mechanical stretching of the tissue, and therefore maintain vaginal elasticity. 9 The type and frequency of sexual activity required to preserve vaginal elasticity and to prevent VVA/GSM are not known. 9 Women may also improve vaginal function with the use of vaginal dilators. Dilators may be particularly practical for women who avoid intercourse due to pain, as they are available in sets of graduated sizes and the smallest dilator can be used initially. Nevertheless, maintaining sexual activity may be impossible for women with VVA/ GSM and dyspareunia. In addition, lubricants and moisturizers may improve coital discomfort and increase vaginal moisture, but they do not restore the normal vaginal environment and in some patients may be insufficient or inadequate to resolve symptoms. Thus, they are useful mostly for women with mild symptoms and those with symptoms associated with vaginal penetration. With symptom persistence, or with initial moderate to severe symptoms, vaginal local ET is recommended. VAGINAL ET Estrogen is considered the most effective treatment for moderate to severe symptoms of VVA/GSM. It leads to reestablishment of the premenopausal vaginal environment, as well as relieves urogenital symptoms. Before initiating treatment for VVA, other conditions should be ruled out, and women with postmenopausal bleeding should be evaluated. Caution is required in women with, or who are at increased risk for, estrogen-dependent tumors. In addition, testosterone is aromatized to estrogen, and thus, similar precautions are warranted if testosterone therapy is to be used. Vaginal administration of a low-dose estrogen preparation is superior to systemic therapy regarding efficacy and safety for treatment of urogenital symptoms. A meta-analysis of 58 comparative studies of postmenopausal women with VVA/GSM found that vaginal ET provides significantly higher symptoms relief compared with systemic ET. 12 As the reported efficacy rate is approximately 80% to 90% for vaginal therapy and 75% for systemic therapy, 9 it is not uncommon for women receiving systemic ET for other menopausal symptoms to require additional vaginal ET if relief of urogenital symptoms is insufficient. Lowdose vaginal therapy also avoids or minimizes systemic estrogen effects. Vaginal estrogen preparations have been used for many years. Available products differ in the type of estrogen [estradiol, estriol, conjugated estrogen (CEE)], its dosage, and the device used (cream, tablet, ovules, and ring). Low-dose vaginal estrogen is defined as r50 mg estradiol or r0.3 mg CEE/r0.5 g cream. 9 Commercial products in the USA and Europe include estradiol-containing tablets and rings; estriol pessaries, creams and ovules; promestriene and CEE creams. Many trials demonstrating the effectiveness of vaginal ET have been reported in the literature. In 2006, a Cochrane systematic review 13 identified 19 good-quality trials with over 4000 women from a total of 37 trials. When comparing the efficacy of different estrogenic preparations in relieving the symptoms of VVA/GSM, results indicated significant findings favoring estrogencontaining preparations when compared with placebo and nonhormonal gel, and that estrogen-containing creams, tablets, and rings were all similarly effective in relieving symptoms of VVA/GSM. Consequently, systemic absorption, patient preference, convenience, and cost should guide the choice of preparation. Since 2006, new preparations with lower doses have been evaluated and become accessible.

8 Vulvovaginal Atrophy Diagnosis and Treatment 483 VAGINAL TABLET The Vagifem vaginal tablet (Novo Nordisk A/S, Bagsvaerd, Denmark) contains 10 mg estradiol. This ultra low-dose product is the lowest approved dose available. It was introduced in 2010, and replaced the 25 mg vaginal tablet that was previously available. According to the manufacturer, the tablet is placed in the vagina daily for the first 2 weeks of use, and then twice weekly thereafter ( dosing-and-administration). Randomized trials have demonstrated that the 10-mg tablet is effective for relief of vaginal symptoms. 9 Symptom relief was apparent and approached statistical significance after 4 weeks of treatment and the beneficial effects of treatment maintained through week 52 of the trial. Although the 10-mg estrogen dose is significantly more effective than placebo therapy, it appears to be slightly less effective than the 25 mg dose for initially inducing maturation, providing relief of vaginal symptoms, decreasing ph, and improving urogenital atrophy. 9 VAGINAL CREAM Two creams for vaginal ET are available in the United States: Premarin (Wyeth Pharmaceuticals Inc., part of Pfizer Inc., New York, NY) and Estrace (Warner Chilcott, Rockaway, NJ). In Europe, estriol cream is available as Ovestin (Organon, Ireland). The cream preparations contain different types of estrogens, and the estrogen dose varies with the amount of cream used (Table 2); the creams are supplied in a tube with an applicator marked with various doses, so that the patient can measure the prescribed amount. In a randomized, placebo-controlled study, postmenopausal women with moderate to severe VVA/GSM who received low-dose CEE cream (0.3 mg, equivalent to 0.5 g Premarin vaginal cream) exhibited improved MI, improved vaginal ph, and improved most troublesome symptom scores, including those for dyspareunia, at week 12 of treatment. 9 After the initial 12 weeks, open-label treatment was continued for 40 weeks, consistent with the patient s prior regimen. No serious adverse events were considered related to the study drug. Estriol cream (Ovestin) is available for the treatment of VVA/GSM in European countries. Estriol is a short-working estrogen with low potency. Low doses (0.2 and 0.03 mg) of estriol were found effective in treating VVA/GSM,compared with placebo. ESTROGEN RING Estring (Pfizer Inc.) is a silastic ring with a core containing a drug reservoir of 2 mg estradiol which delivers estrogen locally to the vagina. The ring is designed to release 7.5 mg of estradiol to the vagina daily for a period of 90 days, at which time it should be replaced with a new ring ( aspx?id = 568). Effective relief of VVA/ GSM symptoms, including dyspareunia, dysuria, and urge incontinence, has been consistently documented in randomized, controlled trials.the ring was well tolerated and did not interfere with intercourse; however,womenwithvaginalwallprolapseor those who had previously undergone a hysterectomy sometimes had problems with ring retention. 9 Femring (Warner Chilcott) is a vaginal ring aimed at systemic ET. It releases higher doses of estradiol (50 to 100 mg/d) and is available for the treatment of both vasomotor and VVA/GSM symptoms. Given the systemic effect, a progestin is advised for endometrial safety. PROMESTRIENE Promestriene (Colpotrophine) is a diethyl-ether of estradiol available as a vaginal cream or ovule in a number of European and Asian countries. Athough there is a long-term market experience, there are little data available in the literature, mostly consisting of small, open-label,

9 484 Lev-Sagie TABLE 2. Vaginal Estrogen Products Product Type of Estrogen Dose Premarin vaginal cream Estrace vaginal cream Conjugated estrogens 17b-estradiol ng/1 g cream 100 mg/1 g cream Recommended Dosage 0.5 to 2.0 g, equals 0.3 to 1.25 mg conjugated estrogens 1to4gof cream, equals 100 to 400 mg of estradiol Ovestin* Estriol 1 mg/1 g cream One application contains 0.5 g cream, equals 0.5 mg estriol Regimen Recommended by the Manufacturer Either 2/wk, or in a cyclic regimen: 1/d for 21 d then off for 7 d, repeated in a 28-d cycle 2 to 4 g/d for 1-2 wk, then gradually reduce to half the initial dosage for a similar period. A maintenance dose: 1 g/1 to 3/wk 1 application/d 2 wk, followed by a gradual reduction, based on Systemic Estrogen Levels w The plasma estradiol after use of conjugated estrogens bears no relationship to actual activity, as it contains >200 compounds, some of which are estrogenic and some antiestrogenic mg of estradiol cream results in a serum estradiol level of approximately 40 pg/ml The maximal doses of Estrace indicated on the package insert (2.0 g) produce premenopausal plasma levels of estradiol, and should not be used long-term without an opposing progestin and/or endometrial assessment 9

10 Vulvovaginal Atrophy Diagnosis and Treatment 485 TABLE 2. (Continued) Product Type of Estrogen Dose Vagifem Estradiol (as hemihydrate) Recommended Dosage Regimen Recommended by the Manufacturer relief of symptoms, until a maintenance dosage of 2 applications/ wk 10 mg 1 tablet 1 tablet/d for 2wk Maintenance: 1 tablet twice/ wk Estring 17b-estradiol 2 mg 7.5 mg/d Replace every 90 d Systemic Estrogen Levels w 3 to 11 pg/ml 5 to 10 pg/ml Data from Bachmann and colleagues 2,9 and manufacturer s official Web sites. *Available in Europe. w Estradiol levels for the available vaginal estrogen preparations, used as recommended by the manufacturer. short duration studies, and few randomized-controlled studies. It was shown to significantly improve VVA/GSM and related symptoms in menopausal women with minimal systemic absorption. ESTROGEN TREATMENT CONSIDERATIONS Because of similar efficacy of the various vaginal products, patient preference, convenience, and cost should guide the choice of preparation. In clinical practice, it is common to start with daily dosing, and when a therapeutic response is attained, typically after 2 weeks of daily use, the frequency of use can often be reduced. A maintenance schedule of 2 to 3 doses per week is common, but dosing should be titrated to the lowest dose and frequency of vaginal estrogen that provides the desired effect. 2 Inwomenwithmoreseveresymptoms, the clinician may start with a larger amount of vaginal estrogen cream (Z0.5 g of cream), and then taper to one of the lower estrogen dose options. 9 Patients should be informed that improvement is expected in 2 to 4 weeks, and that bothersome symptoms will recur on cessation of treatment; therefore, local ET should be continued for as long as necessary for symptom control. Occasionally, a woman with severe VVA/ GSM may require additionial treatment beyond the standard doses. Thus, it is not uncommon that recommendations for some women beyond regular doses may not be consistent with product label and should rely on the physician s judgment and expertise. The dose and duration of treatment needed to improve symptoms vary across patients, and should be individualized according to the woman s degree of VVA/GSM symptoms. Low-dose vaginal ET may be used indefinitely, based upon the low risk of adverse effects, although clinical trials to date have not followed women beyond 1 year. 2 The duration of higher dose vaginal ET or systemic ET should be guided by the risks and benefits of therapy.

11 486 Lev-Sagie Systemic Absorption Potential risks of low-dose vaginal ET have not been evaluated in well-designed studies. 9 It is commonly believed that estrogen administered vaginally is not absorbed systemically. Apparently, this is not the case. Women using low-dose vaginal ET have small increments of estradiol when ultrasensitive estradiol assays were used, but not with commercially available assays. In general, serum estrogen levels reported with use of low-dose vaginal estrogen are below the average level for postmenopausal women.- Therefore, systemic risks are possible, although unlikely. The absorption is determined by the formulation, the dose, and method of administration. The effect of the severity of vaginal atrophy on systemic estrogen absorption is controversial. Some studies have reported that systemic absorption is highest in the first days or weeks of therapy, whereas the vagina is atrophic with thin, friable epithelium. The systemic absorption may cause up to 5-fold increase in serum estradiol in postmenopausal women, thus indicating that systemic effects are expected. Absorption decreases with ongoing treatment, subsequent to thickening and cornification of the epithelium. The decline in systemic absorption takes approximately 3 to 4 months, after which lesser but still significant absorption takes place. The vaginal estrogen preparations with the lowest systemic absorption are the standard regimens of the 10-mg estradiol tablet and the 7.5 mg/d estradiol ring. 9 For vaginal estrogen creams, only the lowest dose of CEE (0.3 mg in 0.5 g of cream) is a low-dose preparation (Table 2). The role of low-dose vaginal ET in women at increased risk of thrombosis has not been studied. 2 Endometrial Safety Endometrial safety is a major concern whenever unopposed estrogen is given, as estrogen normally promotes mitotic growth of the endometrium. The risk of hyperplasia and/or carcinoma seems to increase with higher doses and increased duration of unopposed ET, but there are no studies of endometrial effects in women who have been treated with low-dose vaginal ET for longer than 1 year. 9 Several studies evaluated the effect of vaginal preparations on the endometrium, using ultrasonography (to measure endometrial thickness) or biopsies. The 2006 Cochrane review concluded that available data cannot answer the question of whether women need progestogen to counter possible adverse effects on the endometrium from vaginal absorption of estrogen. 13 According to NAMS recommendations, a progestogen is generally not indicated when low-dose vaginal estrogen is used for r1 year, and data are insufficient to recommend annual endometrial surveillance in asymptomatic women using vaginal ET. If a woman is at high risk for endometrial cancer (eg, obese) or is using a higher dose of vaginal ET than typically recommended, surveillance using annual transvaginal ultrasound or progestogen withdrawal may be considered. However, any spotting or uterine bleeding requires a thorough evaluation, which may include a transvaginal ultrasound and/or endometrial biopsy. 2 Adverse Effects Adverse effects of vaginal ET are infrequent. Women may complain of vaginal irritation, vaginal bleeding, or breast tenderness. Recurrent Vulvovaginal Candidiasis Postmenopausal women taking ET are significantly more prone to develop recurrent vulvovaginal candidiasis than women who are not taking hormonal therapy. In a study that evaluated 149 healthy postmenopausal women, 14 positive cultures for Candida were found in 48.5% of patients taking hormones, compared with 3% subjects not taking hormones; and clinical vulvovaginal candidasis

12 Vulvovaginal Atrophy Diagnosis and Treatment 487 was identified in 49% of women using hormonal therapy as opposed to 1% of women not using it (P<0.001). Sixtyseven perecnt of the patients with vulvovaginal candidasis reported a history of recurrent or chronic candidiasis before menopause. All had been unresponsive to antifungal treatment or had relapse after treatment if hormonal therapy was continued. All patients responded to the antifungal treatment provided hormonal therapy was suspended or prophylactic antifungal treatment was used. 14 Absorption of Estrogen by a Male Partner An often ignored concern is the possible transfer of estrogen to the male partner during intercourse. Estradiol was found to be transferred to male partners by means of vigorous skin-to-skin contact and vaginal intercourse. Although the increase in postexposure levels of estradiol was statistically significant, all levels were still below the upper limit of the normal range for men. Vestibular Application In clinical practice, it is common that patients whose symptoms are mainly vulvar or vestibular (painful penetration, vestibular dysuria, etc.) fail to improve when being treated with intravaginal preparations such as the vaginal tablet. It is possible that local effects of estrogen may vary, based on the location of absorption. Doppler flow studies showed preferential delivery toward the uterus when a vaginal tablet was placed in the inner third of the vagina, and preferential delivery toward periurethral areas when placed in the outer one third of the vagina. In cases with vulvar or vestibular complaints, it is recommended to advise the patient to apply estrogen cream directly to the vestibule. NONESTROGEN THERAPIES Selective Estrogen Receptor Modulators (SERMs) Ospemifene is a SERM that acts as an estrogen agonist in the vagina and appears to have no clinically significant estrogenic effect on the endometrium or breast. Ospemifene was approved by the US Food and Drug Administration in February, 2013 for the treatment of moderate to severe dyspareunia caused by VVA/GSM. 9 It was found effective in treating dyspareunia and vaginal dryness in menopausal women with VVA/ GSM compared with placebo, although the benefit beyond that of placebo was modest; no studies to date have compared ospemifene with vaginal ET. Ospemifene appears to have a favorable endometrial safety profile. Its safety has not been established in women with a prior history or an increased risk of breast cancer (BC) or in women with an increased risk of thromboembolism. 9 Bachmann and Santen 9 suggest ospemifene rather than vaginal ET for women with symptomatic VVA/GSM that is not relieved with nonpharmacologic therapy, and who cannot use (severe arthritis, obesity, vulvodynia) or prefer not to use a vaginal product. 9 The disadvantages of ospemifene compared with vaginal estrogen are the need for daily use and hot flashes. DEHYDROEPIANDROSTERONE (DHEA) Another approach to alleviate vaginal atrophy in postmenopausal women is the intravaginal administration of DHEA and its sulfate (DHEAS). This sex hormone is mainly produced in the adrenal cortex, and constitutes a precursor for estrogen and androgen production. To date, the majority of the evidence for the beneficial effects of vaginally administered DHEA is from a single randomized study conducted by Labrie and colleagues, which has resulted in 5 publications. 15,16 The use of vaginal DHEA was evaluated over 12 weeks in 218 postmenopausal women primarily presenting

13 488 Lev-Sagie with dyspareunia and subjective vaginal dryness and irritation. Women were randomized to placebo, 0.25% (3.25 mg), 0.5% (6.5 mg), or 1.0% (13 mg) vaginal cream daily. Vaginal atrophy was reversed with minimal changes in serum steroid hormone levels, which remained within the normal postmenopausal range. Beneficial effects on sexual dysfunction were also reported. These data suggest that local combined androgenic/ estrogenic stimulation in the vagina may exert favorable effects on VVA/GSM and hence improved sexual function. Although there is some evidence to support the use of intravaginal DHEA for postmenopausal women with symptoms of VVA/GSM, independent, larger studies of longer duration arerequiredtoconfirmthatdheacanbe considered a therapeutic option for the management of VVA/GSM. 16 ALTERNATIVE AND COMPLEMENTARY THERAPIES Alternative and complementary therapies, including oral vitamin D and vaginal vitamin E, have been proposed, but efficacy data are limited and/or discordant. 9 Women who use an alternative or complementary treatment should check whether the product contains estrogen, phytoestrogens, and other hormones. Treatment of Women With Breast Cancer The advances in the diagnosis and therapy for BC have led to a declining mortality of BC patients. However, an emerging topic is the long-term side effects that may be caused by operations, radiotherapy, chemotherapy, or endocrine therapy. The most commonly reported menopausal symptoms in BC survivors are vasomotor symptoms (hot flushes, night sweats, and sleep disturbances) and impaired sexual functioning, including vaginal dryness, painful intercourse, and loss of sexual interest reported by up to 35% of patients. The average age of onset of BC is about 62 years, 17 thus most patients are postmenopausal at the first diagnosis of BC. Chemotherapy itself can result in VVA/GSM, due to chemotherapy-induced ovarian failure and possible direct effect on vulvovaginal epithelium. 4 Premenopausal women with hormone receptor positive (ER+) BC may be offered GnRH agonists to induce a temporary menopause through suppression of ovarian function, also causing VVA/GSM. The prevalence of VVA/GSM in BC survivors is higher compared with that reported in the general population. Vaginal dryness was present in 23.4% of the premenopausal patients and in 61.5% of the postmenopausal patients who had had BC. 16 In addition, the majority of these patients suffer from ER+ BC and therefore receive an adjuvant therapy with tamoxifen or AIs. Tamoxifen, a SERM, blocks the effects of endogenous estrogen in the normal breast and in BC. In addition to being a treatment option for ER+ BC, it is approved in the United States for use as prevention in women considered at high risk for BC. In premenopausal women, tamoxifen exerts antiestrogenic effects on the vagina, hence causing symptoms of VVA/GSM, whereas in postmenopausal women it exerts weak estrogenic effects. 9 The AIs suppress plasma estrogen levels by inhibition of the enzyme aromatase, which is responsible for the peripheral conversion of androgens to estrogens. AIs act by blocking 95% of estrogen synthesis, typically resulting in circulating estradiol levels of <1 pg/ml 2. Very often, both endocrine therapies increase estrogen deficiency symptoms. A population-based, cross-sectional study on postmenopausal BC patients and agematched control subjects found that 58% of AI-treated and 32% of tamoxifentreated BC patients reported moderate or severe symptoms of VVA/GSM which was significantly more common than in control subjects. 18 The symptoms of VVA/GSM

14 Vulvovaginal Atrophy Diagnosis and Treatment 489 have a severe effect on the QOL of BC patients and it is estimated that up to 20% of all patients do actually terminate or consider terminating adjuvant endocrine therapy for this reason. 17 ET IN BC PATIENTS First-line treatment of VVA/GSM in women with BC includes nonhormonal options (lubricants and moisturizers). Because of the possible systemic absorption and an eventually increased probability of recurrences, the use of vaginal estrogen in BC patients has been a subject of controversy. There are few data regarding the safety of vaginal ET in women with BC and there are also a lack of data about whether the efficacy of endocrine therapy is effected by concurrent low-dose vaginal ET. In a subgroup analysis of the HABITS trial, no increase in the recurrence rate could be detected. 17 A prospective cohort study of 1472 women with BC which included 69 women treated with vaginal estrogen (estriol cream 0.5 mg or estradiol vaginal tablets, 25 mg) for an average of 1 year (range, 0.1 to 5 y), found no increase in recurrence of BC. 19 In contrast, 2 small, prospective, randomized studies of 6 and 24 BC patients under endocrine therapy showed a significant increase in the serum estradiol level upon use of estradiol vaginal tablets (25 mg) or estradiol vaginal ring, and clearly illustrated that a systemic absorption is possible. 17 Same controversy also exists regarding estriol-containing vaginal preparations. In a prospective, randomized study of 10 postmenopausal BC patients under AIs therapy it was found that the daily use of 0.5-mg estriol for 2 weeks did not result in elevated serum levels of estriol or estradiol. In some earlier studies on postmenopausal patients, however, increases of the serum estriol concentrations to values between 100 and 150 pg/ml were observed within 2 hours after use of 0.5 mg of estriol. 17 OTHER TREATMENTS IN BC PATIENTS Few data are available on vaginal testosterone treatment after BC. A small study evaluated the use of topical testosterone in women on AIs. A significant improvement of VVA/GSM symptoms was reported, in the absence of elevated estradiol or estrone serum levels. Nonhormonal treatments (lubricants and moisturizers) are recommended, although only few studies have evaluated these treatments in women with BC. 9 Improvement of symptoms achieved by these methods is generally only of short duration, and they are not suitable to eliminate VVA/GSM and treat severe symptoms. A recent randomized-controlled, double-blind trial explored the effect of 4% aqueous lidocaine applied to the vulvar vestibule in BC patients with VVA and severe penetrative dyspareunia. 20 Users of lidocaine had significantly less intercourse pain and 90% of the patients reported comfortable penetration. Because of the contradicting data and small number of patients in the studies evaluating estrogen treatment in BC patients, large, prospective randomized studies for a final concluding assessment of the safety of vaginal ET in BC patients are required. Meanwhile, some clinical suggestions were made by experts: As it is accepted that any amount of estrogen absorption may be clinically relevant in a BC patient, nonhormonal options are the first line of treatment of VVA/GSM in women with BC. 9 With AIs, the aim of therapy is to maximally reduce the systemic estrogen level. Therefore, it is suggested not to use vaginal ET in this group. 9 It is reasonable to treat women on tamoxifen who have symptomatic VVA/GSM with low-dose vaginal estrogen. Under these circumstances, the small amounts of absorbed estrogen are likely blocked by the systemic antiestrogen actions of tamoxifen. 9 On the basis of the above-mentioned results it can be assumed that ultra low-

15 490 Lev-Sagie dosed estriol is safe despite the lack of studies with the endpoint recurrence-free or total survival. Estriol is probably safer compared with other estrogen preparation in BC patients. 17 Vaginal estriol preparations (Ortho-gynest pessary, Ortho-gynest cream, and Ovestin cream) are available in Europe, but not in the United States. Use of low-dose vaginal estrogen in women with BC is reasonable in women with impairments of QOL due to VVA/GSM, who failed nonhormonal treatments, with low risk of recurrence, who are not on an AI. Such treatment can be initiated only after appropriate informed consent discussions with the individual patient and after consultation with the patient s oncologist. 9,17 Patients with hormone receptor negative BC should be treated analogously to those with hormone receptor positive BC. 17 Vaginal Atrophy During Lactation Similar to postmenopausal patients, breastfeeding women immediately after delivery experience decline of estrogen levels, and this decline may persist as long as lactation is continued. Therefore, many women after delivery may experience VVA due to transitional lack of estrogen. Dyspareunia is extremely common in the first 3 to 6 months postpartum; it was reported that 55% of women experienced painful penetration at 2 months postpartum, and that breastfeeding confers an increased odds ratio of 4.4 (95% confidence interval, ) for dyspareunia at 6 months. 21 However, only scarce data are available regarding vaginal atrophy in puerperium, as well as the association between breastfeeding and VVA in these patients. Wisniewski and Wilkinson 22 studied 215 puerperal patients attending a 4-week postpartum visit. They found clinical vaginal atrophy in 17%, supported by MI and ph measurements. Symptoms included dyspareunia (80%), stinging (16%), vaginal tightness (11%), and dysuria (3%). They found significant correlation between breastfeeding and VVA, however, only 68% of nursing mothers had VVA. All the patients were treated with CEE (2 g twice a week), with resolution of atrophy within 40 days. No systemic side effects were reported. This single avialable clinical study is supported by an older cytologic study that found that atrophic smears predominated 3 to 6 weeks after delivery in women who were lactating. Unfortunately, VVA in the puerperium is an underrecognized and understudied phenomenon, and trials regarding possible treatment modalities are lacking. Summary VVA/GSM is a common, underdiagnosed, and undertreated condition. Symptoms can adversely affect QOL, sexuality, and intimacy. The impact of VVA can extend beyond sexual and urinary functions and affect daily activities, including sitting and exercise. Clinicians can improve the sexual health and QOL of postmenopausal women by educating women about, diagnosing, and appropriately managing symptomatic VVA/ GSM. In most cases it is a chronic condition and long-term therapy is required to provide relief from symptoms. Without appropriate treatment, symptoms can increase in severity, and it is therefore recommended that in symptomatic patients, treatment should be started early, upon onset of menopause. Choice of therapy depends on the severity of symptoms, the effectiveness and safety of therapy for the individual patient, and patient preference. Treatment goals include symptom relief while reducing the systemic exposure to estrogen and minimizing the potential for adverse effects. Care givers should keep in mind that only a minority of affected women seek help, and it is therefore important that clinicians engage

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