Sage Journals: Discover world-class research

Abstract

Vaginal or vulvovaginal atrophy is a widespread but poorly recognized condition of peri- and post-menopausal women. It causes urogenital symptoms of dryness, reduced lubrication, itching, burning, irritable bladder symptoms and painful intercourse. This impacts quality of life and sexual health, but increases with time rather than reduces, as with most other menopausal symptoms. With early identification, treatments can improve these symptoms and reverse the physical changes. However, when embedded, bladder and sexual changes have occurred and these may be more difficult to remedy. Therefore, it is important to educate both healthcare professionals and women about these symptoms and advise on the range of interventions available.

Keywords

female sexual dysfunction overactive bladder testosterone topical estrogens vaginal atrophy vulvovaginal atrophy

Vaginal atrophy develops with estrogen-deficiency states most commonly during and after the menopause, but also postpartum during lactation. Rather than the diminution of other symptoms associated with the menopause, such as hot flushes and sweats, vulvovaginal atrophy (VVA) increases and worsens with time. It causes local symptoms of vaginal dryness, itch, discomfort, symptomatic prolapse, change in vaginal discharge, dyspareunia and changes in the genital tract. Dyspareunia then impacts on sexual functioning and, therefore, sexual relationships and overall quality of relationship in some cases. The urogenital tract can be affected by urinary frequency, urgency and nocturia. The greatest issue with vaginal atrophy is that it is frequently unrecognized by both women and healthcare professionals. The symptoms, therefore, remain untreated until significant behavioral changes have developed, which are more difficult to resolve.

Diagnosis

In practice, a diagnosis is made by clinical suspicion and the classical symptoms described are increasing vaginal dryness, itch, soreness, irritable bladder symptoms and dyspareunia. Up to 45% of postmenopausal women will develop these symptoms [1]; however, recognition of their etiology is poorly understood by women and their partners [2]. In addition, the symptoms are infrequently discussed by healthcare professionals; therefore, the sequelae to these long-term issues become predominant. This causes sexual difficulties, which become sexual dysfunction, starting as a reduction in lubrication and arousal, increasing pain, reduced orgasm, and subsequently lower interest and libido. Bladder symptoms can be more prevalent at the perimenopause and worsen with increasing vaginal atrophy. This includes increasing overactive bladder symptoms, recurrent urinary tract infections (UTIs) and noninfective cystitis. Overall, quality of life is reduced in women with VVA [1].

The visual changes of VVA include dryness, redness, loss of rugae, pallor, petechiae, phimosis of the clitoral hood, friability and stenosis. The tissues of endodermal origin are affected by stenosis or contracture of the distal vagina, and can involve urethra caruncle formation or urethral mucosal prolapse, and reduction in size and fatty tissues of the vulva. The trigone of the bladder is also of endodermal origin, and the physical changes correspond with the epidemiological increase in bladder symptoms and cystitis. The urogenital sinus of endodermal origin is very sensitive to estrogens as opposed to the upper vagina and uterus, which are mesodermal in origin and less estrogen-sensitive, with fewer estrogen receptors. The physical changes may take 2–3 years to develop; however, the symptoms with or without minor perceivable visual changes predate them.

In most intervention studies, as the visual judgment of VVA is relatively subjective, the vaginal cell maturation index is used from a vaginal smear with the addition of a pH test. The vaginal health index, proposed by Bachmann, includes assessment of elasticity, fluid secretion, epithelial mucosa and moisture; however, in practice and for clinical trials, the vaginal cell maturation index and pH are more reproducible [3]. With increasing atrophy, there is an increase in the percentage of parabasal cells, and a reduction in the intermediate and superficial cells, which cushion the tissue owing to their higher glycogen content. The vagina is also dependent on transudate from the more superficial epithelial cells, which reduce in number and glycogen content. The pH increases to a less acidic environment of over 4.5 compared with a pH of 3.5–4.5 during the reproductive years. This may occur within 12 months in 95% of estrogen-deficient women [4], and is also demonstrated in lactating women. Lactobacilli reduce in proportional numbers in the vagina, increasing the pH and preventing the natural defenses of the vagina from gastrointestinal organisms. This in turn increases bacterial vaginosis and thrush infections.

Prevalence

Approximately 50% of postmenopausal women will experience some symptoms of vaginal atrophy; however, the rate of reporting varies according to different methodologies and study samples [5,6]. The changes will increase with time, and as women in the developed world may spend up to 40% of their lives in a postmenopausal state, this is of great significance for quality-of-life healthcare. Dryness is the most commonly reported symptom in 55–83% of women with VVA, pain during intercourse 42%, involuntary urination a third, soreness and itching 25–30%, and burning 14% [1,2]. However, the severity of symptoms varies: studies targeting women with vaginal symptoms report more significant distress and bother than those reviewing general samples of postmenopausal women, although, the visual changes of VVA are highly prevalent in all postmenopausal women. Two-thirds of women participating in the Women's Health Initiative (WHI) trial had physical evidence of VVA, but only 10% were symptomatic [7]. There is evidence that dryness increases with age and other symptoms may become more bothersome [8]. However, the etiology of urogenital disorders related to estrogen deficiency may be forgotten given the time scale that they can take to develop. With prolonged deterioration, the changes in sexual functioning and relationships may be more resistant to intervention.

Prevalence studies

There have been several very large prevalence studies of VVA, mostly supported by the pharmaceutical industry, surveying thousands of women (VIVA, REVEAL, HealthyWomen, CLOSER and REVIVE) [6]. Most are online surveys and, therefore, prone to bias; however, they still reveal the widespread nature of the problem and its management. There are interesting variations in diagnosis, awareness and treatment between countries that raise questions regarding women's healthcare provision. Although the prevalence of symptomatic VVA is consistently up to 50%, there is variation in presentation of self-reported symptoms to healthcare professionals. Overall, 63% of sufferers from an international study had never been treated for their symptoms [9]. In Finland, only 37% had never been treated compared with 70–74% in the UK and North America. The VIVA study indicated that 25% of women were concerned about their vaginal health and 20% about their sexual health [1]. However, 45% did not know of a specific condition in postmenopausal women causing these problems. They were also not keen on the phrase ‘vaginal atrophy’, therefore, nomenclature is divergent between women and their healthcare professionals. Most refer to vaginal dryness despite its limitations in describing all symptoms associated with VVA. Of those with symptoms, 50% will describe them as moderate and approximately 10% as severe in surveys. Half of the individuals will have had the problems for at least 3 years. The prevalence of overactive bladder increases significantly in women postmenopausally [10] and, in part, is related to hormonal change in women. An overactive bladder has a significant impact on quality of life, and is a huge economic burden for both the patient and healthcare systems.

Impact

These symptoms have an impact on aspects of women's lives beyond the physical changes. In one of Nappi's surveys, Women's Voices in the Menopause, half of the study participants reported a negative impact of their symptoms with 40% suggesting it caused sexual problems, 17% reported an impact on self-esteem and 13% on their relationship [11]. However, 38% of this group did not feel that they had a significant impact. Women also report that the symptoms make them feel old – they are often perceived as a natural part of aging rather than specific to estrogen deficiency. Postmenopausal women with sexual dysfunction were found to be four-times more likely to have symptoms of VVA when compared with women with normal sexual functioning [12]. In the MenopauseMatters UK website surveys, 62% of menopausal women felt that these specific vaginal symptoms had affected their confidence [13,14]. In the VIVA study, 80% considered that these symptoms had a negative effect on their lives and in the REVIVE study, 85% of partnered women had ‘some loss of intimacy’ [1,2]. However, only 7% of healthcare professionals had initiated a discussion regarding these symptoms in the REVIVE study from the USA [2].

Vaginal & bladder symptoms

Vaginal discomfort and sexual pain are the two most reported symptoms relating to VVA. The presumed diagnosis of fungal infection is a frequent mistake, and although thrush infection may be more common in the less acidified vagina, the symptoms are more likely to be noninfective. Mucosa with inflammatory changes can be termed atrophic vaginitis. Overgrowth of gut organisms leading to bacterial vaginosis or a change in vaginal discharge to thin and abundant, but with concurrent dryness symptoms, are secondary to the vaginal changes described earlier. Irritable bladder symptoms become more prevalent and the frequent misdiagnosis of UTI, despite no culture of organisms, is common. The thinning of urethral mucosa and change in vaginal flora also increases the likelihood of lower UTIs, sometimes increased by the friction of penetrative intercourse. Prolapse, which may have been present since childbirth, can become symptomatic as the mucosa becomes less elastic and the pelvic floor loses tone. The relationship between urogenital atrophic change and stress urinary incontinence is more controversial, with the finding that systemic estrogen replacement in the WHI and Nurses Health studies increased the risk of stress incontinence; however, this was self-reported rather than objectively measured [15,16].

Effect on sexual function & relationships

Sexual functioning may change during and after the menopause. To what degree this is influenced by hormones and/or aging is debatable. The PRESIDE study reported that the prevalence of sexual problems causing distress was highest in women aged 45–64 years (14.8%) compared with younger (10.8%) and older women (8.9%) [17]. Sexual activity may decline with age [18]; however, often this may be due to partner-related issues rather than female factors. Those who continue with sexual activity are likely to be satisfied, although, those who were not wished for more activity [7]; those with clinically demonstrable VVA were more likely to be sexually inactive from this analysis of the WHI study.

Sexual activity and desire is perceived to reduce with age, but the decline in distress associated with this, preclude diagnosis of a dysfunction. As there is a perception that vaginal changes are equivalent to the aging effects on tissue elsewhere in the body, the impact on sexual function is often accepted as normal. The dryness and discomfort with or without intercourse may then lead to reduced desire, arousal difficulties and orgasmic problems [12]. Loss of lubrication is cited as a factor in 90% of women with loss of sexual desire in these age groups in one study [13].

The changes in desire that occur due to fear and anxiety related to dyspareunia and loss of lubrication have been demonstrated to impact on couple relationships. The CLOSER surveys have demonstrated avoidance of intimacy that is compounded by inadequate knowledge of the reason for the symptoms and poor communication between women, their partners and healthcare professionals [19 –22]. There were important differences between countries in women's perception of availability of information, but all showed improvement in intimacy with the use of local estrogen therapy.

Alternative diagnoses to vaginal atrophy

It is important that other diagnoses are excluded given the ubiquity of vaginal changes with estrogen deficiency, particularly if they do not respond to interventions. All vulval skin conditions can produce symptoms of VVA. The classical signs of pale external genital skin with fusion and loss of architecture of lichen sclerosis, or the easily traumatized tissue of lichen planus, should be distinguished. Infection can be superimposed and increase with VVA. There is some evidence that transmission of sexually transmitted infections is higher in friable, delicate, atrophic mucosa [23]. Atrophy causing postmenopausal bleeding should be a diagnosis of exclusion and warrants full investigation. Hematuria is also another potentially sinister sign that should be heeded.

Treatments

Women with minimal symptoms may suffice by using over-the-counter measures of lubricants, pH-restoring gels and vaginal remoisturizers. However, those with moderate-to-severe bothersome symptoms should be encouraged to use topical estrogens as these are of proven benefit and very safe, easy and acceptable to use for the majority of women. Newer treatments are currently being investigated, which will be described in the text (see ‘Newer agents’ section).

Topical estrogens

Vaginal estrogens have been used most frequently for the treatment of vaginal atrophy. Pessaries, tablets, creams, ovules and rings containing estradiol, estriol, promestriene and conjugated equine estrogens (CEEs) are available in various countries worldwide. They have all been shown to improve the visual maturation index, decrease vaginal pH, thicken epithelium and increase vaginal secretions. The most recent Cochrane systematic review, regarding treatment of vaginal atrophy with estrogen, summarizes 19 good-quality trials out of a total of 37 (total 4162 women) [24]. Both subjective and objective measures are used to judge the effectiveness of therapy. The benefit of estrogen-containing preparations was confirmed in comparison to placebo and other nonhormonal gels. Safety data indicate few adverse effects, although, vaginitis and burning have been more frequently reported in active groups. Endometrial hyperplasia has only been significantly increased compared with placebo groups with CEE products, which also have more reports of bleeding and breast pain compared with other estrogens, owing to increased systemic absorption. Estradiol tablets have an indefinite license in the UK, although, safety data have only been evaluated over 12 months.

Of the synthetic and natural estriol or CEE creams available, those with the lowest potency are the estriol creams. These may be used internally, but are also useful to apply to atrophic external genitalia. Absorption is greatest when the tissue is most atrophic, with a reduction in systemic absorption as the tissue becomes more resistant and mature. Estriol is also not converted to other more potent estrogens, therefore, even though absorption is initially measurable, this has limited systemic effects.

Ovules and pessaries have been shown to be efficacious in relieving VVA [24]. The vaginal estradiol ring is similarly effective and may be more favored by women for its convenience. It is changed on a 90-day basis. This is not to be confused with the vaginal ring, which delivers systemic estrogen levels and, therefore, requires progestogenic opposition in women with a uterus. Uterine bleeding, breast and perineal pain have particularly been reported with CEE products, but have been noted with all hormonal agents.

The estradiol tablet is now available at a dose of 10 μg with data indicating efficacy for treatment of VVA. Previously, studies were performed and regulatory approval was gained from the 25-μg dose. The 25-μg dose achieved steady-state levels of 5–10 pg/ml compared with <5 pg/ml with 10 μg on the twice-weekly dosing [25]. Although both doses reduce symptoms, the improvement was greater with the 25-μg dose [26].

Endometrial hyperplasia is reported at rates of a postmenopausal population not taking hormones except for CEE products. Therefore, treatment with progestogens is not warranted and may increase the risk profile with respect to thrombosis and breast cancer. Unscheduled bleeding should be investigated as indicated for any postmenopausal bleed. No increased risk of thrombosis has been proven with these low-dose products.

Systemic HRT

Systemic HRT can be used for urogenital symptoms; however, up to 10–25% of women using systemic HRT will continue to experience symptoms of vaginal atrophy. They may be used in addition on initiation of therapy and then potentially removed after re-establishment of comfortable intercourse. Although, a meta-analysis of 58 studies concluded that HRT preparations were effective, systemic HRT was less effective than local estrogen for treatment of VVA (75 vs 80–90%) [27]. However, the studies have not evaluated treatment efficacy beyond 6 months. The WHI study reported that, of the 10% of women complaining of VVA in the combined estrogen and progestogen treatment group, 74% had relief by the end of year 1 in comparison to 54% in the placebo arm [7]. Owing to safety concerns regarding HRT, and consequent women and healthcare professional reticence to use this long term, topical estrogens or alternatives may be more appropriate.

Nonhormonal treatment for vaginal atrophy

pH-balanced gels

One pH-balanced vaginal gel was tested in 19 women with a history of breast cancer and VVA symptoms compared with placebo. Although there was an improvement in the placebo group, the pH-balanced gel showed greater reduction in dyspareunia and an increase in the vaginal maturation index, in addition to a decrease in vaginal pH [28]. There are several products on the market available for correction of vaginal pH to a more acidic environment, which may also decrease fungal infections and bacterial vaginosis.

Water-based remoisturizers

Replens™ (Anglia Pharma, Hampshire, UK) is a water-based polycarbophil that binds to the vaginal epithelium and releases water over 24–72 h to hydrate the underlying cells. Studies have indicated Replens may be as effective as topical estrogen [29], another confirmed an improvement in cytology [30], but a fourth reported no change in the vaginal cell maturation index [31]. It appears to reduce pH sufficiently to have a positive effect on vaginal flora.

Hyaluronic acid

Hyaluronic acid is present in the vaginal epithelium as a proposed reservoir for moisture and appears to relieve irritation associated with dryness. A small study of a hyaluronic acid product was compared with a 25-μg estradiol tablet [32]. This indicated improvement in symptoms, atrophy, pH and vaginal epithelial cell proportions, but the estradiol group were significantly better. A small, placebo-controlled study also indicated a benefit of hyaluronic acid for itching, burning and erythema, although, dryness was improved in both groups [33].

Lubricants

Lubricants are frequently promoted for treatment of vaginal symptoms and sought by women. However, they do not generally treat the underlying cause, and can result in irritation or an increase in thrush secondary to constituents such as glycerine. Some may have a pH-balancing effect and be retained for longer than others, but they should generally be advocated for use during penetration to reduce discomfort, although, there may also be reduction in vulval rubbing sensations. Lubricants can be water-, oil- or silicone-based. Trying different sorts may be helpful for those struggling with side effects or persistent discomfort. It may be appropriate for specific women to be prescribed topical anesthetic gels or ointments, although, they can also cause burning on application.

Newer agents

New drug applications for the treatment of vaginal atrophy in the USA recommend three primary efficacy end points when compared with placebo over a minimum of 12-week studies. These include improvement in most bothersome moderate-to-severe symptoms identified by the patient, lowering vaginal pH and change in the vaginal maturation index – that is, decrease in parabasal cells and increase in superficial cells.

Ospemifene is an oral selective estrogen receptor modulator (SERM), newly approved for the treatment of moderate-to-severe dyspareunia secondary to VVA. It appears to target the vaginal epithelium with minimal endometrial stimulation [34]. Studies in women aged 40–80 years using an additional nonhormonal lubricant, at doses of 30 and 60 mg, reported a significant decline in dryness and pH; however, only 60 mg resulted in a reduction in dyspareunia [35]. A 52-week extension study confirmed sustained symptom relief and no cases of endometrial, breast or thromboembolic adverse events [36]. However, it may increase vasomotor symptoms and, similar to other SERMs, could increase thrombotic risk [35,37]. Otherwise, it was well tolerated in reported studies [36 –38].

Lasofoxifene, although not currently available or seeking further formulary approval, has been demonstrated to have a positive effect at doses of 0.25 and 0.5 mg in studies conducted over 12 weeks [39,40]. A reduction in parabasal cells by 40% and an increase in superficial cells by 7% compared with placebo, in addition to a reduction in vaginal pH and dyspareunia, has been reported. However, as with other SERMs, an increase in the risk of venous thromboembolism and pulmonary embolism was also found, with an increase in all-cause mortality found with the 0.25- but not 0.5-mg doses. Interestingly, a reduction in breast cancer has been reported, but there may be a possible increase in endometrial thickening.

Newer compounds of tissue selective estrogen complexes (TSEC) combine a SERM with an estrogen. The first of these compounds is CEE with bazedoxifene (BZA), studied at doses of BZA/conjugated estrogen 20 mg/0.625 mg and 20 mg/0.45 mg when compared with placebo and BZA 20 mg alone. The primary end points as specified by the US regulatory body, indicated significantly improved vaginal symptoms and vaginal maturity index with both TSEC products. The most bothersome vaginal atrophy symptom and vaginal pH did not reduce in the lower dose CEE TSEC, placebo or BZA groups [41,42]. There are no differences in adverse effects, except for the estrogen-containing groups having a significantly higher incidence of vaginitis.

Topical testosterone

In pursuit of topical agents that can relieve symptoms in those not suitable for estrogen, a testosterone preparation was tested on a small number of women after treatment for breast cancer with aromatase inhibitors (which can cause profound VVA symptoms), reporting significant relief of dyspareunia and dryness [43]. Estradiol levels were maintained in low levels (>8pg/ml); however, in women not using aromatase inhibitors there may be concerns of aromatization to estrogen, so may still be contraindicated in those not suitable for topical estrogens.

Dihydroepiandrostenedione

Dihydroepiandrostenedione (DHEA) is the precursor of sex steroids in postmenopausal women and the developing understanding of intracrinology, by which local tissues convert precursors into estrogens and androgens, will lead to therapeutic interventions for pathological processes. Therefore, the potential for local DHEA is of great interest. It has been tested at a variety of doses compared with placebo. In one study lasting 12 weeks, a reduction in vaginal pH was shown, in addition to an increase in vaginal superficial cells and a decrease in parabasal cells, at three doses [44]. The placebo group did not show a difference in vaginal cell structure, but did reveal a reduction in vaginal pH. All groups had a reduction in dyspareunia, but more significantly in the three doses of DHEA. Unfortunately, DHEA is not widely available internationally and further work needs to be undertaken to expand the applications of intracrinology.

Oxytocin

A total of 20 women were enrolled in a 1-mg oxytocin study used for 7 days compared with the carrier base [45]. They were assessed with a vaginal punch biopsy, and visual and colposcopic examination. Based on visual and colposcopic examination, 70% of the active treatment group demonstrated no signs of atrophy, with no improvement seen in the placebo group. However, there was no difference between the active and placebo groups on punch biopsy, although, histological examination reported four normal biopsies in the active treatment group and five in the placebo group before treatment. Three of the eight biopsies from the placebo group showed atrophy, but all nine of the biopsies from the active group were normal after treatment (although this was not statistically significant). This study did not have high enough numbers to evaluate the effectiveness of oxytocin on vaginal atrophy in postmenopause.

Genistein & hyaluronic acid

A study compared genistein with hyaluronic acid taken daily for 15 days per month for 3 months and was investigated by vaginal and cervical smear, in addition to colposcopy and microbiopsy [46]. Both groups showed a statistically significant improvement in genital scores. Another compared hyaluronic acid to topical estrogen and was shown to be less effective in relieving symptoms [32]. Other combination products have also indicated possible benefit.

Therapy duration

Although data exist for only 12 months with respect to endometrial and breast safety, the vaginal estradiol tablet preparation has an indefinite license. The annual exposure to estradiol of the 10-μg dose used as recommended is 1.14 mg – that is, an average daily systemic HRT dose. Symptoms may resolve rapidly, but it can take at least 4–6 weeks before relief is achieved. However, for those with significant stenosis it may take a longer period of application of appropriate products to achieve resolution. Unfortunately symptoms of VVA may recur on cessation of any therapy and would need the initiation doses to be repeated before the maintenance dose is resumed.

Use in women with a history of breast & pelvic cancer

Urogenital symptoms are common in women after diagnosis of breast cancer, with induction of early menopause by chemotherapy and tamoxifen, or reduction in estrogen levels with aromatase inhibitors. This can have a significant impact on quality of life and relationships [47]. Use of aromatase inhibitors, which reduce the circulating estrogen levels to less than 5 pmol/l, causes significant vaginal symptoms. Starting vaginal estradiol 25 μg on a daily dose for 14 days causes an increase in estradiol levels to within that of a postmenopausal women (mean: 72 pmol/l) at 2 weeks with a reduction on the maintenance dose of twice-weekly to 35 pmol/l. However, doses of 10 μg, now available worldwide, increase the estradiol level to much lower levels and are only detectable systemically during the first 2 weeks of daily-dosing; however, they are not maintained on the twice-weekly dose. A short course may be enough to allow sexual relations to resume. A study of breast cancer sufferers who had used a vaginal estrogen followed-up for a mean of 5.5 years showed no increase in recurrence; however, the design methodology does not confirm the safety of their use [48].

Women treated for pelvic cancers with surgery ± radiotherapy can have significant vaginal symptoms from hormonal and physical factors that severely impact on sexual functioning and quality of life [49]. Greater distress is reported in younger women [50]. Use of vaginal treatments can help with their recovery and facilitate bleed-free intercourse and vaginal dilator use.

Role of vaginal atrophy in urinary incontinence & prolapse

The role of estrogens in the management of urinary incontinence is controversial and unknown. Although there is evidence of benefit for overactive bladder symptoms with topical estrogens, systemic HRT does not improve (and may worsen) stress incontinence. Perimenopausal women may develop more symptomatic prolapse due to exposed atrophic tissue; however, a Cochrane review did not confirm a preoperative benefit using end points of bleeding, transfusion and tissue healing [51], although, accompanied by pelvic floor muscle training, there may be a reduction in postoperative cystitis [52].

Role for cervical cytology assessment

Data for the use of topical estrogen prior to cervical cytology sampling are also limited, although, one study of estradiol tablet 25 μg used for 5 nights before a smear test indicated a significantly lower chance of an atrophic smear, but one tablet alone had no effect [53]. Use of estrogens by women who have had previous discomfort at smear-taking can be advised to use vaginal estrogen for at least a fortnight beforehand and this also decreases the chance of a false-positive diagnosis of abnormality.

Role of vaginal atrophy in recurrent UTI

One episode of UTI occurs in 8–10% of postmenopausal women per year and 5% will have a recurrence within the year. Recurrent UTI is defined as three episodes of UTI in 12 months or two episodes in 6 months. Postmenopausal risk factors for UTI include prolapse, a significant postvoid residual urine, vaginal flora changes and urinary incontinence [53 –55], although, there is less association in postmenopausal women with sexual intercourse compared with premenopausal women. The change in vaginal flora allows an increase in Gram-negative bacteria and their potential to act as uropathogens. A Cochrane review indicated a reduction in UTI with vaginal estrogens, but not with systemic estrogen. Low-dose antibiotics are more efficacious than other interventions for prevention of UTI [56].

How to discuss vaginal atrophy with women

A total of 10–40% of postmenopausal women report symptoms of vaginal atrophy; however, only one in four seeks medical help [57]. Women are aware of vasomotor symptoms associated with the menopause, but are less likely to link the more delayed appearance of urogenital symptoms or the impact on their relationships. Direct questioning during history taking is important in peri- and post-menopausal women. If genital symptoms are not admitted to prior to examination but they are then noted, this should be reviewed. It is also important that healthcare professionals are aware that women are not familiar with the phrase ‘vaginal atrophy’ and report not liking it [1], therefore, discussing the range of possible symptoms may be more helpful.

Women should be reassured that vaginal atrophy is reversible and that topical estrogen is not equivalent to systemic hormone therapy, despite the patient information in the packaging. Initiating discussions regarding appropriate lubricant use may also be beneficial, and confirming the benefits of regular sexual activity for preventing vaginal stenosis is relevant and important. This should occur at an early stage of the perimenopausal transition before sexual behaviors have adapted and will be more difficult to address. Psychosexual issues will then need more formal input.

Executive summary

Impact & diagnosis of vulvovaginal atrophy

Increased recognition of vulvovaginal atrophy through the education of women, their partners and healthcare professionals is required to prevent the current unnecessary morbidity.

Symptoms include vaginal itch, burning, discomfort, dyspareunia, which lead to sexual and bladder symptoms reducing quality of life in up to 50% of peri- and post-menopausal women.

Enhanced awareness of the long-term consequences of vulvovaginal atrophy will reduce sexual dysfunction, poor self-esteem, reduced quality of life and bladder symptoms.

Treatments

First-line treatment for minimal symptoms can be over-the-counter treatments including lubricants, pH-balancing gels and vaginal remoisturizers.

For persistent and bothersome symptoms, vaginal estrogen therapy is highly effective and safe, and can be used long term in the form of a tablet, pessary, cream or ring.

Systemic HRT is beneficial for vulvovaginal atrophy symptoms, but may persist in 10–25% of patients.

Nonhormonal treatments are also available and in development.

Endometrial and breast safety data confirms no stimulation by topical estrogen products currently available for up to 12 months.

Other hormonal treatments need confirmation of safety.

Alternative diagnoses should be considered in those resistant to topical treatment interventions.

In women with a history of hormone-sensitive tumors, topical estrogens can be considered in conjunction with their oncologist.

There is a potential benefit of topical estrogens for the management of overactive bladder, symptomatic prolapse and recurrent urinary tract infection.

Conclusion

VVA is prevalent among women from the menopause onwards with an increase in symptoms over time leading to a separation of the etiological factors from the consequent problems for urogenital health. This can affect quality of life significantly and, therefore, it is beholden on healthcare professionals to seek out these symptoms from their patients early in the menopausal transition, and offer education and interventions to prevent long-standing morbidity and sexual dysfunction.

Future perspective

In the future, the aim is to increase awareness among women in the peri- and post-menopause of the effects of estrogen deficiency on the genital tract. Women would then understand the consequences of vaginal dryness, bladder symptoms and altered lubrication for their long-standing urogenital and sexual health. Education of healthcare professionals is equally important in recognition of the consequences of VVA on the urogenital tract to prevent the embedded behaviors with these changes in the vagina, the bladder and sexual relationships. This then avoids the impact on quality of life, self-esteem and self-confidence. Development of new vaginal remoisturizers and lubricants that suit women who do not want to or cannot use hormonal management, including topical estrogens, will be helpful. The failure of topical estrogen regimens to relieve the symptoms of vaginal atrophy in some, require consideration of other products, such as topical testosterone and DHEA, although, more work is required to ascertain their role. Newer agents, such as the tissue SERMs, ospemifene and lasofoxifene, and the TSECs, also need further work to establish their place in the management of the vaginal atrophy.

Financial & competing interests disclosure

C Domoney has membership for the Institute of Psychosexual Medicine. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

Nappi

Kokot-Kierepa

. Vaginal health: insights, views and attitudes (VIVA) – results from an international survey. Climacteric 15(1), 36–44 (2012).

Kingsberg

Wysocki

Magnus

Krychman

. Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (Real Womens Views of Treatment Options for Menopausal Vaginal ChangEs) survey. J. Sex. Med. 10(7), 1790–1799 (2013).

Bachmann

Notelowitz

Gonzalez

Vaginal dryness in menopausal women: clinical characteristics. Clin. Pract. Sexual 7, 25–32 (1991).

Freeman

Sammel

Lin

Gracia

Kapoor

. Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet. Gynecol. 111(1), 127–136 (2008).

Nappi

Lachowski

. Menopause and sexuality: prevalence of symptoms and impact on quality of life. Maturitas 63, 138–141 (2009).

Parish

Nappi

Krychman

Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. Int. J. Womens Health 5, 437–447 (2013).

Overview of the international surveys detailing the impact of vulvovaginal atrophy in varying populations.

10.

Gass

Cochrane

Larson

Patterns and predictors of sexual activity among women in the hormone therapy trials of the Women's Health Initiative. Menopause 18(11), 1160–1171 (2011).

11.

Dennerstein

Dudley

Hopper

Guthrie

Burger

. A prospective population based study of menopausal symptoms. Obstet. Gynecol. 96, 351–358 (2000).

12.

Santoro

Komi

. Prevalence and impact of vaginal symptoms among postmenopausal women. J. Sex. Med. 6(8), 2133–2142 (2009).

13.

Milsom

Coyne

Nicholson

Kvasz

Chen

Wein

. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur. Urol. 65(1), 79–95 (2014).

14.

Nappi

Kokot-Kierepa

. Women's Voices in the Menopause: results from an international survey on vaginal atrophy. Maturitas 67(3), 233–238 (2010).

15.

Levine

Williams

Hartmann

. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active post menopausal women. Menopause 15(4 Pt 1), 661–666 (2008).

16.

Cumming

Currie

Moncur

Lee

. Web-based survey on the effect of menopause on women's libido in a computer-literate population. Menopause Int. 15(1), 8–12 (2009).

17.

Cumming

Herald

Moncur

Currie

Lee

. Women's attitudes to hormone replacement therapy, alternative therapy and sexual health: a web-based survey. Menopause Int. 13(2), 79–83 (2007).

18.

Hendrix

Cochrane

Nygaard

Effects of estrogen with and without progestin on urinary incontinence. JAMA 293(8), 935–948 (2005).

19.

Grodstein

Lifford

Resnick

Curhan

. Postmenopausal hormone therapy and risk of developing urinary incontinence. Obstet. Gynecol. 103(2), 254–260 (2004).

20.

Shifren

Monz

Russo

Segreti

Johannes

. Sexual problems and distress in United States women: prevalence and correlates. Obstet. Gynecol. 112(5), 970–978 (2008).

21.

Schneidewind-Skibbe

Hayes

Koochaki

Meyer

Dennerstein

. The frequency of sexual intercourse reported by women: a review of community-based studies and factors limiting their conclusions. J. Sex. Med. 5(2), 301–335 (2008).

22.

Domoney

Currie

Panay

Maamari

Nappi

. The CLOSER survey: impact of postmenopausal vaginal discomfort on women and male partners in the UK. Menopause Int. 19(2), 69–76 (2013).

23.

Nappi

Mattsson

LÅ

Lachowsky

Maamari

Giraldi

. The CLOSER survey: impact of postmenopausal vaginal discomfort on relationships between women and their partners in northern and southern Europe. Maturitas 75(4), 373–379 (2013).

24.

Simon

Nappi

Kingsberg

Maamari

Brown

. Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on north American postmenopausal women and their partners. Menopause 21(2), 137–142 (2014).

25.

Nappi

Kingsberg

Maamari

Simon

. The CLOSER (CLarifying Vaginal Atrophy's Impact On SEx and Relationships) survey: implications of vaginal discomfort in postmenopausal women and in male partners. J. Sex. Med. 10(9), 2232–2241 (2013).

26.

Study on the impact on partners and relationships with postmenopausal changes.

27.

Martin

. The microbiota of the vagina and its influence on women's health and disease. Am. J. Med. Sci. 343, 2–9 (2012).

28.

Suckling

Lethaby

Kennedy

. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst. Rev. 4, CD001500 (2006).

29.

Eugster-Hausmann

Waitzinger

Lehnick

. Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets. Climacteric 13, 219–227 (2010).

30.

Bachmann

Lobo

Gut

Nachtigall

Notelovitz

. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet. Gynecol. 111(1), 67–76 (2008).

31.

Cardozo

Bachmann

McClish

Fonda

Birgerson

. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet. Gynecol. 92(4 Pt 2), 722–727 (1998).

32.

Lee

Chung

Kim

Park

Song

Kang

. Vaginal pH-balanced gel for the control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet. Gynecol. 117, 922–927 (2011).

33.

Bygdeman

Swahn

. Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 23, 259–263 (1996).

34.

Nachtigall

. Comparative study: Replens versus local estrogen in menopausal women. Fertil. Steril. 61, 178–180 (1994).

35.

van der Laak

de Bie

de Leeuw

de Wilde

Hanselaar

. The effect of Replens on vaginal cytology in the treatment of postmenopausal atrophy: cytomorphology versus computerised cytometry. J. Clin. Pathol. 55(6), 446–451 (2002).

36.

Ekin

Yaşar

Savan

The comparison of hyaluronic acid vaginal tablets with estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Arch. Gynecol. Obstet. 283(3), 539–543 (2011).

37.

Grimaldi

Restaino

Inglese

Role of high molecular weight hyaluronic acid in postmenopausal vaginal discomfort. Minerva Ginecol. 64(4), 321–329 (2012).

38.

Goldstein

Bachmann

Koninckx

Lin

Portman

Ylikorkala

; the Ospemifene Study Group. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric doi: 10.3109/136 97137.2013.834493 (2013) (Epub ahead of print).

39.

New oral nonhormonal agent for the treatment of vulvovaginal atrophy and consequent dyspareunia caused by menopausal changes.

40.

Portman

Bachmann

Simon

; Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 20, 623–630 (2013).

41.

Simon

Lin

Radovich

Bachmann

; Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause 20, 418–427 (2013).

42.

Bachmann

Komi

; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal Phase 3 study. Menopause 17, 480–486 (2010).

43.

Rutanen

Heikkinen

Halonen

Komi

Lammintausta

Ylikorkala

. Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause 10, 433–439 (2003).

44.

Portman

Moffett

Kerber

Drosman

Somayaji

Lee

. Vaginal effects of lasofoxifene and raloxifene: preliminary evidence suggests lasofoxifene, but not raloxifene, improves indices of vaginal health. Menopause 11, 675 (2004).

45.

Bachmann

Gass

Kagan

Moffett

Barcomb

Symons

. Lasofoxifene (LASO), a next generation selective estrogen response modulator (SERM) improves dyspareunia in postmenopausal women with vaginal atrophy (VA). Menopause 12, 238 (2005).

46.

Lobo

Pinkerton

Gass

Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil. Steril. 92, 1025–1038 (2009).

47.

Kagan

Williams

Pan

Mirkin

Pickar

. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause 17, 281–289 (2010).

48.

Witherby

Johnson

Demers

Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: a Phase I/II study. Oncologist 16, 424–431 (2011).

49.

Labrie

Archer

Bouchard

High internal consistency and efficacy of intravaginal DHEA for vaginal atrophy. Gynecol. Endocrinol. 26, 524–532 (2010).

50.

Jonasson

Edwall

Uvnäs-Moberg

. Topical oxytocin reverses vaginal atrophy in postmenopausal women: a double-blind randomized pilot study. Menopause Int. 17(4), 120–125 (2011).

51.

Le Donne

Caruso

Mancuso

The effect of vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in postmenopause. Arch. Gynecol. Obstet. 283(6), 1319–1323 (2011).

52.

Baumgart

Nilsson

Evers

Kallak

Poromaa

. Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer. Menopause 20, 162–168 (2013).

53.

Dew

Wren

Eden

. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric 6, 45–52 (2003).

54.

Incrocci

Jensen

. Pelvic radiotherapy and sexual function in men and women. J. Sex. Med. 10(Suppl. 1), 53–64 (2013).

55.

Ganz

Desmond

Belin

Meyerowitz

Rowland

. Predictors of sexual health in women after a breast cancer diagnosis. J. Clin. Oncol. 17, 2371–2380 (1999).

56.

Maher

Feiner

Baessler

Schmid

. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst. Rev. 4, CD004014 (2013).

57.

Ismail

Bain

Hagen

. Oestrogens for treatment or prevention of pelvic organ prolapse in postmenopausal women. Cochrane Database Syst. Rev. 9, CD007063 (2010).

58.

Bateson

Weisberg

. An open-label randomized trial to determine the most effective regimen of vaginal estrogen to reduce the prevalence of atrophic changes reported in postmenopausal cervical smears. Menopause 16(4), 765–769 (2009).

59.

Brown

Vittinghoff

Kanaya

Agarwal

Hulley

Foxman

; Heart and Estrogen/Progestin Replacement Study Research Group. Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstet. Gynecol. 98(6), 1045–1052 (2001).

60.

Raz

Gennesin

Wasser

Recurrent urinary tract infections in postmenopausal women. Clin. Infect. Dis. 30(1), 152–156 (2000).

61.

Perrotta

Aznar

Mejia

Albert

. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst. Rev. 2, CD005131 (2008).

62.

The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of the North American Menopause Society. Menopause 14, 168–182 (2007).

Treatment of Vaginal Atrophy

Abstract

Keywords

Diagnosis

Prevalence

Prevalence studies

Impact

Vaginal & bladder symptoms

Effect on sexual function & relationships

Alternative diagnoses to vaginal atrophy

Treatments

Topical estrogens

Systemic HRT

Nonhormonal treatment for vaginal atrophy

pH-balanced gels

Water-based remoisturizers

Hyaluronic acid

Lubricants

Newer agents

Topical testosterone

Dihydroepiandrostenedione

Oxytocin

Genistein & hyaluronic acid

Therapy duration

Use in women with a history of breast & pelvic cancer

Role of vaginal atrophy in urinary incontinence & prolapse

Role for cervical cytology assessment

Role of vaginal atrophy in recurrent UTI

How to discuss vaginal atrophy with women

Conclusion

Future perspective

Financial & competing interests disclosure

References