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Abstract

Urogenital atrophy, although a frequently occurring symptom of aging for all women, is a condition often not thought of as a symptom of distress for older women or a sign of pelvic pathology requiring treatment by clinicians. Rather, many clinicians feel it is an expected consequence of aging, and older women themselves assimilate their lifestyle to the uncomfortable symptoms of dryness, irritation, itching and malodorous discharge. At times, when symptoms become intolerable with coitus, women will abandon sexual intercourse with their partners due to dyspareunia and not seek intervention to reverse the condition owing to embarrassment in raising this sensitive topic. When urogenital atrophy is diagnosed and the patient requests treatment, the gold standard intervention is estrogen, which can either be delivered systemically or vaginally. Since the Women's Health Initiative data, low-dose, vaginally delivered estrogen is recommended.

Keywords

atrophic vaginitis dyspareunia hypoestrogenic tissue nonhormonal lubricants urogenital atrophy vaginal estrogen

Healthcare providers who perform the menopausal and postmenopausal woman's routine gynecologic examination and Pap smear are usually the first clinicians to make the diagnosis of urogenital atrophy. Despite the fact that many women may not present with complaints stemming from vaginal atrophy due to loss of estrogenic stimulation because of embarrassment, the signs of hypoestrogenic vulva and vagina are markedly obvious during the pelvic exam. In fact, vulvo–vaginal atrophy may be so severe that at times it can interfere with performing an adequate examination and obtaining enough cells for an interpretable Pap smear. That is, the vaginal tissue is thin and friable such that bleeding from speculum insertion initially occurs and then is exacerbated by the scraping of the cervix by the spatula for Pap smear sampling, which increases bleeding and decreases the number of cervical cells obtained for cancer screening. In addition, stenosis of the cervix is often present, which then eliminates a substantial amount of the endocervical component of the Pap smear, resulting in a sample that has insufficient cells for proper evaluation.

Clearly, urogenital atrophy is a morbid condition that not only affects the lifestyle of the patient, but also the ability of the clinician to perform an adequate pelvic examination, Pap smear and other procedures, such as an endometrial biopsy or coloscopy in high-risk women. Hypoestrogenism also contributes to pelvic floor dysfunction and uterine and vault prolapse since estrogen is necessary to maintain vascularity, collagen and tone of the pelvic floor and supporting uterine ligaments.

However, even if it is obvious during pelvic examination that the patient has evidence of severe atrophy of the external genitalia, the clinician frequently does not suggest treatment as he or she would with a vulvar lesion noted during evaluation because atrophy is considered an expected part of the aging process. Women themselves may not relate to clinicians the extent of their vulvo–vaginal discomfort, as many are wearing constant perineal protection at this stage in their life and attribute all symptoms to this. Many women, in the hope of obtaining some relief, use several nonhormonal systemic and vaginal pharmacologic interventions they purchase as over the counter products or as dietary, herbal and complementary supplements. Details of self-selected remedies for this condition are not offered by the patient during the medical history taking and the healthcare provider frequently does not ask about their use. Unfortunately, most of the nonestrogen-containing interventions are mainly useful for sexual intercourse and do not provide an effective treatment for the reversal of atrophic changes on a long-term basis. This article will review the epidemiology of urogenital atrophy, the signs and symptoms of this condition, how the diagnosis can be made in a cost-effective manner and the treatment options for this condition.

Epidemiology

The cause and effect between lack of adequate estrogenic stimulation to the urogenital tract and atrophy of these genital tissues has been objectively demonstrated not only by observation of the natural progression of chronic hypoestrogenism during the postmenopausal years, but also in medical conditions characterized by decreased estrogen levels such as lactation, gonadotropin-releasing hormone therapy and premature ovarian failure or ovarian excision [1]. It follows that estrogen therapy with adequate dosing, regardless of the delivery system, reverses atrophic changes and maintains the health of these tissues as long as estrogenic intervention is continued. Atrophic conditions will return with discontinuation of exogenous estrogen treatment in postmenopausal women, whereas situations that lead to temporary hypoestrogenism will not require chronic intervention during the reproductive years [2,3]. A total of 20–25% of the menopausal population will report symptoms of urogenital atrophy to their clinicians. In addition, 10–25% of postmenopausal women taking standard-dose systemic estrogen therapy, described as 0.625 mg or its equivalent, may also report symptoms of vaginal atrophy and require local estrogen delivered vaginally to relieve symptoms [4]. Apparently, the blood levels achieved with systemic estrogen may not be sufficient to reverse atrophic urogenital changes.

Since menopause is a universal event occurring in all women who reach their sixth decade of life, every woman will eventually develop atrophic changes to the urogenital tissue. Although genetic factors play a role in the severity, other factors include intrinsic levels of estrogen produced by the ovarian stroma, and the conversion of testosterone and androstendione in the adrenal gland after the menopause. In addition, clinical trial data suggest that maintaining sexual activity, either with a partner or through self-stimulation, is beneficial to maintaining vaginal health [5]. When vaginal health was evaluated in a group of women not on estrogen therapy, women who were sexually active had overall better urogenital health scores than sexually abstinent women [5]. Other women who report the more severe symptoms of urogenital atrophy are those who have had a hysterectomy, either with an oophorectomy or without ovarian removal. In a study examining the efficacy and safety of a nonhormonal vaginal moisturizer, one surprising finding was the relatively large percentage of hysterectomized women who complained of vaginal atrophy symptoms as compared with women who had not had a hysterectomy [6].

Clinical presentation

Until the last decade, the study of atrophic changes of the urogenital tissue focused on the changes that occur in the vulvo–vaginal areas with scant attention to the accompanying changes in the urinary tract. However, the urethral orifice, openings of Skene's ducts, openings of Bartholin's ducts and openings of the minor vestibular glands have the same surface of stratified nonkeratinized squamous epithelium as does the vaginal introitus and vault. This epithelial layer in the estrogenized state is approximately 1 mm thick. With loss of estrogenic stimulation, resulting from decreases in systemic levels of estrogen caused by ovarian atrophy, the epithelium surface becomes thinner and basal/parabasal cells no longer mature to superficial cells.

The visibility of changes on pelvic examination to the vulva and the vaginal vault and the inability to directly observe the lumen of the urethra or bladder cavity, contributed to the focus being solely on vaginal changes. In fact, over the last century, it was common for physicians to refer to the condition of atrophy that resulted from chronic hypoestrogenism as atrophic vaginitis, with the term ‘vaginitis’ referring to the more severe inflammatory-like changes that occur in the vagina from chronic lack of adequate estrogenic stimulation to a tissue that is naturally rich in estrogen receptors. Usually, women with malodorous discharge and with bleeding occurring with minimal contact, such as during intercourse or pressure during perineal cleansing after bowel movements, were diagnosed with this condition. Pelvic exam was confirmatory with obvious extremely friable tissue, scant, cloudy secretions with a marked elevation in pH and visible loss of vascularity and elasticity to the region. Today, urogenital atrophy refers to the visible changes that occur in the genitourinary tract with loss of estrogen, regardless of whether the woman is symptomatic or asymptomatic. Atrophic vaginitis is a subset of urogenital atrophy in which there is inflammation of the vaginal vault and malodorous vaginal secretions.

Symptoms of urogenital atrophy may be insidious at first, and perimenopausal women may initially notice a lack of adequate vaginal lubrication with coitus. These early symptoms of inadequate lubrication with sexual arousal may be misinterpreted by the woman and her partner as stemming from interpersonal problems rather than from loss of estrogen. Nonhormonal lubricants and moisturizers are the interventions usually tried first by couples for loss of adequate vaginal secretions with sexual intercourse. Over time, as atrophy in the genitalia progresses, estrogen delivered vaginally by cream, ring or tablet becomes necessary for comfortable sexual intercourse.

Diagnosis

Since only 20–25% of women spontaneously report symptoms of vaginal atrophy to their clinicians, the first step in diagnosing this condition is asking women about their medical history and if they have symptoms indicative of this condition [7]. Common vaginal symptoms are dryness – especially with coitus – itching unrelated to a yeast infection, burning and soreness to the vaginal vault and, in severe cases in which the friable epithelium of the vaginal vault becomes inflamed, an inflammatory discharge. Urethral and bladder symptoms are also commonly reported with atrophy and include urinary frequency and urgency, nocturia, dysuria and a history of recurrent urinary tract infections. Urinary stress incontinence is not directly linked to atrophy and some data suggest that estrogen therapy may exacerbate this condition [8,9]. Many older women present to the clinician's office alarmed because of ‘vaginal bleeding’, which they assume is originating from a uterine cancer. In many instances, the bleeding is of vaginal origin stemming from a friable, one or two cell layer thick vaginal epithelium that has bled after minimal introital or vaginal contact. In the past, before sonographic evaluation and in-office endometrial sampling, many older women were admitted to the hospital for a dilation and curettage (D&C) to rule out endometrial malignancy. In addition to the increased incidence of urinary tract infection, hematuria from a friable urethral epithelium contributes to many women being evaluated for bladder tumors with cystoscopic evaluation.

Objective signs of urogenital atrophy that should be observed during the pelvic exam are:

Loss of adipose tissue to the mons pubis and labia majora

Sparseness of pubic hair

Diminished rugation and elasticity of the vaginal vault

Absence of vaginal secretions with tissue-thin epithelium lining the vagina

Lack of color due to the loss of vascularity of the region

If secretions are present in the vagina they are of the inflammatory type with an elevated pH: a pH greater than five is an objective sign of atrophy [6]. For this reason it is recommended that pH testing is performed when there is a question of diagnosis, as this is easy and cost-effective in most ambulatory settings [6]. With microscopic capabilities, a cervical and vaginal smear may also be helpful. If cervical secretions are air-dried and evaluated microscopically, the presence of ferning confirms that estrogen is present, either from intrinsic or extrinsic sources, which would not support the diagnosis of atrophy. When vaginal secretions are evaluated under a microscope, the presence of superficial cells is also indicative of adequate estrogen. A large percentage of parabasal cells, as compared with superficial or intermediate cells infers a hypoestrogenic environment and vaginal atrophy.

Currently there is no grading system to objectively quantify the degree of atrophy. At the University Medical and Dental School of New Jersey – Robert Wood Johnson Medical School, NJ, USA, an attempt was made by Bachmann and colleagues to develop a Vaginal Health Index, where the clinician routinely completed and ranked the degree of atrophy (after visual inspection) of the external genitalia and vaginal region [6]. However, this tool has not been validated. Others, such as Sarrel, have used Doppler flow studies of vascularity [10]. The most widely accepted data quantifying vaginal atrophy and the effects of exogenous administration of estrogen result from the studies conducted by Semmens and colleagues [2]. These seminal studies not only confirmed the effect of estrogen in reversing atrophy but also showed that the response was not immediate and that it could take weeks of continued therapy to become effective.

Over time, atrophic changes in the urogenital area, which must be differentiated from pathologic changes such as those seen with Lichen sclerosis atrophicus, may progress to vaginal vault stenosis and fusion of the labia minora resulting in labial adhesions. Both of these conditions make speculum evaluation of the vaginal vault and cervix extremely difficult, if not impossible. For women with these conditions, topical estrogen may be necessary for 4–6 weeks to separate the labia and reverse some of the stenosis in the vault. Dilators in conjunction with cream may also be necessary for older women with vaginal vault stenosis.

Urogenital atrophy often accompanies pelvic floor dysfunction, such as cystocoele, rectocoele and uterine prolapse. When nonsurgical interventions are attempted, such as pessary placement, symptoms of atrophy often worsen if an estrogen (either systemic or local) is not used simultaneously with the vaginal device, since the vaginal tissue will tear and erosion will develop due to the thin outer layer [4]. The vaginal device, in the presence of an atrophic vagina, may produce erosion, bleeding, frequent urinary tract infections and purulent or malodorous discharge.

Treatment

The management of urogenital atrophy depends upon the type and severity of symptoms. When a woman is symptomatic, options for management include:

Lifestyle modification

Nonhormonal treatment (vaginal lubricants or moisturizers)

Hormonal treatments (usually local but in some instances systemic, especially if vasomotor symptoms are also present)

Lifestyle modification

Since a decline in estrogen levels is the primary etiology behind vulvo–vaginal atrophy, modifying lifestyle factors that accelerate this decline may be beneficial in slowing this process. Smoking results in an increased metabolism of estrogen and is associated with higher rates of osteoporosis as well as vaginal atrophy [11]. While evidence concerning the association between smoking and vaginal atrophy is conflicting, smoking cessation should be encouraged for optimal health, not just urogenital. Continued regular vaginal coital activity provides protection from urogenital atrophy, probably by increasing blood flow to the pelvic organs as well as maintaining elasticity in the vaginal vault [5]. To accomplish this, sexual intercouse with a partner is not necessary; masturbation has also been shown to increase genital blood flow in menopausal women and may help to maintain urogenital health [12].

Lubricants

Lubricants are considered temporary measures to relieve vaginal dryness during intercourse. Most formulations bought over-the-counter are a combination of protectants and thickening agents in a water-soluble base. Short durations of action limit their usefulness as a long-term solution. In fact, women may complain that the effect does not always continue throughout the entire period of the sexual encounter. Therefore, lubricants must be applied at intercourse and for more continuous relief, reapplication during sexual activity may be necessary. Examples include Astroglide®, K-Y Jelly®, Lubrin®, H-R Jelly™, Surgilube®, Touch™, glycerin, petroleum jelly, olive oil and vegetable oils.

Moisturizers

Replens™ and Moist Again® vaginal moisturizing gels with aloe vera moisturize the vagina and their labels note that these products provide more than transient lubrication during intercourse. Therefore, they are promoted as providing long-term relief of vaginal dryness rather than just being sexual aids.

Replens is a bioadhesive polycarbophil-based polymer. The polymer attaches to mucin and epithelial cells on the vaginal wall and carries up to 60-times its weight in water, holding water in place against the vaginal epithelial surface [6]. Due to this prolonged contact with the vaginal surface, the suggested dosing of Replens is two to three applications weekly. Reapplication is not recommended before sexual intercourse. Replens lowers vaginal pH through its acidity and buffering capacity [6]. It has been shown to decrease pH from 5.8 to 4.8 [13] and from 5.2 to 4.7 [14] after 12 weeks of therapy in two separate studies.

In a double-blind, crossover randomized trial in 45 subjects with a history of breast cancer, Replens performed similarly to an active placebo preparation, decreasing vaginal dryness by 64% and improving dyspareunia scores by 60% [15].

In a 12-week comparative study, conjugated equine estrogen (CEE) vaginal cream 1.25 mg and Replens three times weekly, were similar in providing symptom relief and in reducing vaginal atrophy and pH, but Replens had no effect on cell morphology [13] in 30 postmenopausal women. Dienestrol cream 0.01%, 0.5 g/day for 2 weeks, then three times weekly, was superior to Replens used three times weekly in improving a vaginal dryness index in a 12-week comparative study of 39 postmenopausal women; however, the treatments had a similar effect on vaginal pH, itching, irritation and dyspareunia [14].

Oral estrogens

Systemic hormone therapy is indicated for women seeking treatment for a variety of vasomotor symptoms associated with the estrogen deprivation of menopause. A woman who is experiencing general symptoms of menopause such as hot flushes and sleep disturbance may choose either oral or nonoral routes of systemic administration. However, systemic hormone therapy may be unacceptable in certain populations, such as older women with established atherosclerotic vascular changes. Of note, women on low-dose systemic therapy for the treatment of vasomotor symptoms may find that their vaginal complaints are not adequately addressed in this manner. In these patients, nonhormonal lubricants or low-dose estrogen delivered vaginally should also be offered [16,17]. Currently, there are no indications to increase the dosage of systemic estrogen solely for the purpose of relieving vaginal atrophy symptoms.

Vaginal atrophy

In a meta-analysis, the efficacy of both oral and topical estrogen was evaluated in postmenopausal women with urogenital atrophy [3]. Studies conducted between 1969 and 1995 containing control groups or uncontrolled studies measuring change from baseline were included. Of the 77 studies reviewed, nine contained randomized, controlled trials. Outcomes included patient symptoms, physician reports, pH or cytologic change. Meta-analysis revealed a statistically significant benefit of estrogen therapy for all outcomes studied. In 54 uncontrolled case series, the patients' symptoms were treated by 24 different treatment modalities. All routes of administration appeared to be effective and maximum benefit was obtained between 1 and 3 months after the start of treatment. The lowest levels of systemic absorption of estrogen were seen with estriol (administered orally or vaginally) then vaginal estradiol, as measured by pre- and post-therapy serum estradiol and estrone. The authors concluded that estrogen is efficacious in the treatment of urogenital atrophy and that low-dose vaginal estradiol preparations are as effective as systemic estrogen therapy in the treatment of urogenital atrophy in postmenopausal women.

More recent studies confirmed these findings. The women's Health, Osteoporosis, Progestin, Estrogen (HOPE) study, a 2-year, double-blind, placebo-controlled trial, compared conventional doses of CEE to lower-dose regimens (0.625, 0.45 or 0.3 mg) and medroxyprogesterone acetate (1.5 or 2.5 mg) in 2673 postmenopausal women [18].

Lower does of CEE plus medroxyprogesterone acetate relieved vasomotor symptoms and vaginal atrophy (measured by the vaginal-maturation index) as effectively as commonly prescribed doses. In this study, data on relief of vaginal complaints were not collected. Vaginal bleeding, breast enlargement and vaginal moniliasis were more prevalent at the higher doses. These results suggest that lower doses of estrogens should be considered for initial treatment of vasomotor symptoms. If vaginal atrophy symptoms are still present, a nonhormonal or hormonal vaginal preparation should be considered.

In a more recent 16-week multicenter trial, 71 postmenopausal women with vaginal atrophy were randomly assigned to either 0.3 mg CEE or placebo [19]. Low-dose CEE produced significantly greater changes from baseline than placebo in vaginal-maturation index improvement, parabasal cell reduction and vaginal pH reduction. There were no significant differences in adverse events. These results confirmed the findings of the HOPE study; that low-dose estrogen is safe and effective in reversing vaginal atrophy in postmenopausal women. However, studies that assess the relief of symptoms when estrogen is systemically delivered at ultra-low doses are still necessary.

Urinary symptoms

Clinicians believed that estrogen would improve urinary symptoms, such as incontinence, as well as vaginal symptoms, since the lower urinary tract shares a common embryologic origin with the genital tract and the urogenital sinus, and because estrogen and progesterone receptors are present in the vaginal epithelium, urethra and bladder trigone [20].

The effect of oral hormone therapy on urinary incontinence has been evaluated in three studies. In the Heart and Estrogen/progestin Replacement Study (HERS), 1525 naturally menopausal women less than 80 years of age, with at least one episode of incontinence, were followed for 4 years [21]. Participants received either 0.625 mg CEE plus 2.5 mg medroxyprogesterone acetate daily or placebo. Both stress and urge incontinence improved in 26% of the women in the placebo group and 21% of the active treatment group. Exacerbation of incontinence occurred in 39% of the hormone group and 27% of the placebo group, and the number of incontinent episodes increased by an average of 0.7 per week in the treatment group and 0.1 in the placebo group.

As part of the Women's Health Initiative clinical trial (WHI), hormone therapy was evaluated in 27,347 postmenopausal women aged 50–79 years [22]. Women were randomized to either active treatment (CEE 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day [hysterectomized], or CEE 0.625 mg/day alone [nonhysterectomized groups]) or placebo. CEE alone and CEE plus medroxyprogesterone acetate increased the risk of urinary incontinence among continent women and worsened the characteristics of urinary incontinence among symptomatic women after 1 year.

In a recent study, the efficacy of CEE (0.625 mg/day) and two doses of raloxifene (60 and 150 mg/day) on urinary incontinence were investigated in 619 surgically menopausal women aged between 40 and 60 years [23]. At the 3-year follow-up, the percentage of estrogen subjects reporting urinary incontinence was significantly greater than that for placebo and both doses of raloxifene.

Based on the evidence from these trials, oral estrogen regimens cannot be recommended as treatment for any type of urinary incontinence and may exacerbate symptoms. Currently, the recommended treatment for urge incontinence is pelvic floor muscle exercises and, if indicated, medications such as oxybutynin (Ditropan XL®), tolerodine (Detrol®), darifenacin (Enablex®), trospium chloride (Sanctura™) and solifenacin succinate (Vesicare™™) as adjunct therapy [24]. For stress incontinence, pelvic floor muscle exercises, surgery, pessaries and intraurethral inserts are recommended [24].

The efficacy of oral estriol in treating urinary tract infections in postmenopausal women has also been evaluated. In the HERS trial [21], the frequency of urinary tract infections was higher in the group randomized to receive oral hormone therapy (CEE 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day), although the differences were not statistically significant (odds ratio [OR]: 1.1695%; confidence interval [CI]: 0.99–1.37).

The effect of estriol in treating urinary tract infections was evaluated in two trials. In the first 6-month trial, there was no improvement in the frequency of urinary tract infections in 72 postmenopausal women with a 3 mg daily dose of estriol [25]. Similar results were found in a study of 40 postmenopausal women receiving 3 mg estriol daily compared with placebo [26].

A meta-analysis of 334 subjects that included five randomized control trials, two case-controlled studies and three self-control series concluded that oral hormone therapy did not offer a significant benefit over placebo in preventing recurrent urinary tract infections (OR: 2.5195%; CI: 1.48–4.25) [27].

These findings strongly suggest that oral estrogen therapy should not be recommended for treatment of recurrent urinary tract infections.

Risks of hormone therapy

One major concern with using oral hormone therapy is the increased risk of breast cancer. The Million Women Study [28], which followed 1,084,110 women aged 50–64 years, confirmed previous findings from the estrogen/progestin arm of the Women's Health Initiative trial [29] showing that current or recent users of hormone therapy have an increased risk of invasive breast cancer, and that the relative risk of breast cancer in current users increases with increasing duration of use of hormone therapy. There were no large variations in breast cancer levels between the groups taking specific estrogens (CEE and estradiol) or between specific progestagens (medroxyprogesterone acetate, norgestrel and norethisterone), nor between progestagen given sequentially or continuously.

Topical estrogens

Local delivery of estrogen by vaginal cream, ring or tablet is the preferred method of estrogen therapy for women with complaints stemming from urogenital atrophy. The goal of local hormone therapy is to provide sufficient estrogen to reverse atrophic changes in the local tissues and relieve associated symptoms, while at the same time avoiding systemic effects.

Vaginal atrophy

Suckling and colleagues conducted a meta-analysis of local estrogen products to treat vaginal atrophy in postmenopausal women (Table 1) [30]. Studies were conducted between 1966 and 2003 and contained randomized comparisons of estrogen preparations administered intravaginally in postmenopausal women. A total of 29 trials were identifie and 16 were included, containing 2129 women.

Table 1.

Meta-analysis of local estrogen for vaginal atrophy in postmenopausal women.

Design	Estrogen	Efficacy	Adverse events	Acceptability	Ref.
12-week, randomized, comparative, parallel-group study in 30 postmenopausal women	Nonhormonal vaginal gel three-times weekly vs 1.25 mg CEE vaginal cream daily	CEE vaginal cream > vaginal gel in cell morphology; CEE vaginal cream = vaginal gel in vaginal atrophy, pH	None in either group	Not measured	[30]
12-week, randomized, comparative, parallel group study in 39 postmenopausal women	Nonhormonal vaginal gel three-times weekly vs 5 mg dienestrol vaginal cream three-times weekly	Dienestrol vaginal cream > vaginal gel in vaginal dryness index Dienestrol vaginal cream = vaginal gel in vaginal itching, irritation, dyspareunia, pH	None found in either group	Not measured	[30]
12-week, randomized, double-blind, placebo-controlled, parallel-group study in 84 postmenopausal women	2 mg estradiol vaginal ring vs placebo vaginal pessary	Estradiol vaginal ring > placebo vaginal ring in maturation value, pH, symptom improvement	Estradiol vaginal ring = placebo vaginal ring in endometrial thickness	Not measured	[39]
12-week, randomized, comparative, parallel group study in 190 postmenopausal women	2 mg estradiol vaginal ring vs estriol vaginal pessary 0.5 mg	Estriol vaginal pessary > estradiol vaginal ring in pH, patient response	Estradiol vaginal ring = estriol vaginal pessary in adverse events	Estradiol vaginal ring > estriol vaginal pessary	[39]
12-week, randomized, comparative parallel group study in 146 postmenopausal women	2 mg estradiol vaginal ring vs 0.5 mg estriol vaginal pessary twice weekly	Estradiol vaginal ring = pessary in physician assessment, patient ratings, pH estradiol vaginal ring > estriol vaginal pessary in vaginal dryness, irritation, atrophy, maturation value	Estradiol vaginal ring > estriol vaginal pessary in comfort Estradiol = estriol in adverse events	Estradiol vaginal ring > estriol vaginal pessary	[38]
24-week, randomized, comparative, parallel group study in 254 postmenopausal women	2 mg estradiol vaginal ring vs estriol 0.5 mg vaginal pessaries four-times weekly	Pessary > vaginal ring in patient ratings, vaginal dryness, dyspareunia Pessary = vaginal ring in pH	Vaginal ring = pessary in adverse events	Vaginal ring > pessary	[37]
Comparative, parallel group study in 185 postmenopausal women*	2 mg estradiol vaginal ring vs 25 μg estradiol vaginal tablet twice weekly	Estradiol vaginal tablet > estradiol vaginal ring in subject assessment	Estradiol vaginal tablet > estradiol vaginal ring in estradiol levels	Not measured	*
12-week, randomized, comparative parallel group study of 194 postmenopausal women	2 mg estradiol vaginal ring vs 0.625 mg CEE vaginal cream 21 of 28 days	Estradiol vaginal ring = CEE vaginal cream in vaginal atrophy, physician assessment, maturation value, pH	Estradiol vaginal ring = CEE vaginal cream in endometrial thickness, bleeding	Estradiol vaginal ring > CEE vaginal cream	[42]
24-week, randomized, comparative, crossover study in 168 postmenopausal women	2 mg estradiol vaginal ring vs 1 mg estriol vaginal cream three-times weekly	Estradiol vaginal ring = estriol vaginal cream in patient ratings, vaginal atrophy, dryness, pH, maturation value	Estradiol vaginal ring = CEE vaginal cream in endometrial thickening, bleeding	Estradiol vaginal ring > CEE vaginal cream	[40]
15-week, randomized, comparative, parallel group in 192 postmenopausal women	2 mg estradiol vaginal ring vs 1.25 mg CEE vaginal cream three-times weekly	Estradiol vaginal ring = CEE vaginal cream in physician assessment, vaginal atrophy, pH	CEE vaginal cream > estradiol vaginal ring in endometrial thickness, bleeding	Estradiol vaginal ring > CEE vaginal cream	[41]
24-week, randomized, double-blind, placebo-controlled parallel group study in 109 postmenopausal women	3.5 mg estriol vaginal supp 1–2/week vs placebo vaginal supp 1–2/week	Estriol vaginal supp > placebo vaginal supp in patient ratings, vasomotor symptoms, pH	Estriol vaginal supp = placebo vaginal supp in endometrial thickening	Not measured	[36]
16-week, randomized, double-blind, parallel group study in 30 postmenopausal women	3.5 mg estradiol vaginal ovules once weekly vs placebo vaginal ovules once weekly	Estradiol vaginal ovule > placebo vaginal ovule in symptom improvement	Not measured	Not measured	[31]
12-week, randomized, double-blind, placebo-controlled, parallel group study in 164 postmenopausal women	25 μg estradiol vaginal tablet twice weekly vs placebo vaginal tablet twice weekly	Estradiol vaginal tablet > placebo vaginal tablet in vaginal atrophy, dryness, itching, dyspareunia	Not measured	Not measured	[32]
24-week, randomized, comparative, parallel group study in 96 postmenopausal women	25 μg estradiol vaginal tablet twice weekly vs 0.5 mg estriol vaginal tablet twice weekly	Estradiol vaginal tablet = estriol vaginal tablet in vaginal dryness, irritation, atrophy, itching, dyspareunia	Estradiol vaginal tablet = estriol vaginal tablet in endometrial thickness	Estriol vaginal tablet > estradiol vaginal tablet in tolerability	[34]
12-week, randomized, comparative, parallel group in 53 postmenopausal women	25 μg estradiol vaginal tablet once weekly vs 0.625 mg CEE vaginal cream twice weekly	CEE vaginal cream > estradiol vaginal tablet in dryness, dyspareunia Estradiol vaginal tablet = CEE vaginal cream in vaginal health index, maturation value, pH	CEE vaginal cream = estradiol vaginal tablet in endometrial thickness	Estradiol vaginal tablet > CEE vaginal cream	[33]
24-week, randomized, comparative, parallel group study in 159 postmenopausal women	25 μg estradiol vaginal tablet once weekly vs 1.25 mg CEE vaginal cream three times weekly for 4 weeks	Estradiol vaginal tablet = CEE vaginal cream in vaginal dryness and irritation	CEE vaginal cream > estradiol vaginal tablet in endometrial proliferation, bleeding, estradiol levels	Estradiol vaginal tablet > CEE vaginal cream in acceptability	[17]
			Estradiol vaginal tablet = CEE vaginal cream in adverse events

CEE: Conjugated equine estrogen; Supp: Suppository

Fraser I, Ayton R, Farrell L, O'Neil S, Weisberg E: Endometrial and vaginal effects of low-does oestradiol delivered by vaginal ring or vaginal tablet. Edith Weisberg Pers. Comm. (2000).

In addition to placebo-controlled studies, comparative studies evaluating the efficacy of various types of topical estrogens and dosage forms have been conducted. Estradiol vaginal tablets (Vagifem®) were shown to be more effective than placebo in improving patient ratings in a 16-week controlled study in 30 postmenopausal women [31], and in improving vaginal atrophy, dryness, and dyspareunia in a 12-week controlled study in 164 postmenopausal women [32]. Estradiol vaginal tablets were as effective as CEE cream (Premarin®) in alleviating vaginal dryness and irritation in a 24-week comparative study of 159 postmenopausal women [17]. Estradiol vaginal tablets were less effective than CEE vaginal cream in a 12-week comparative study of 53 postmenopausal women in relieving vaginal dryness and dyspareunia, but comparable in the vaginal health index, maturation value and pH [33]. Estradiol vaginal tablets were more effective than the estradiol vaginal ring (Estring®) in patients' ratings in a comparative study of 185 postmenopausal women [Fraser I, Ayton R, Farrell L, O'Neil S, Weisberg E: Endometrial and vaginal effects of low-dose oestradiol delivered by vaginal ring or vaginal tablet. Edith Weisberg Pers. Comm. (2000).], as effective as estriol vaginal tablets in a 24-week comparative study of 96 postmenopausal women in reducing vaginal dryness, atrophy and dyspareunia [34], and as effective as the estradiol vaginal ring in patient ratings, vaginal atrophy and maturation value in a 12-month comparative study of 185 postmenopausal women [35].

Patient ratings and vasomotor symptoms were significantly improved and pH decreased with estriol vaginal tablets compared with placebo in a 24-week study of 109 postmenopausal women [36]. In a 24-week study of 254 postmenopausal women, estriol vaginal tablets were more effective than the estradiol vaginal ring in improving patient ratings, vaginal dryness and dyspareunia, but had a similar efficacy in reducing pH [37]. Estriol vaginal tablets and the estradiol vaginal ring were similar in efficacy in a 12-week study of 146 postmenopausal women in improving patient ratings and pH, but the vaginal ring was more effective in relieving vaginal dryness, atrophy and maturation value [38]. Estriol vaginal tablets were more effective than the estradiol vaginal ring in a 12-week study of 190 postmenopausal women in improving patient response and decreasing pH [39]. Estriol vaginal cream was as effective as the estradiol vaginal ring in a 24-week study of 168 postmenopausal women in improving patient ratings, vaginal atrophy, pH and maturation value [40].

One placebo-controlled study found that the estradiol vaginal ring was superior to placebo in a 12-week study of 84 postmenopausal women in decreasing patient symptoms, maturation value and pH [39]. The vaginal ring was as effective as CEE vaginal cream in a 15-week comparative study of 192 postmenopausal women [41] and in a 12-week study of 194 postmenopausal women in relieving vaginal atrophy, maturation value and pH [42].

It can be concluded that all vaginal delivery systems of estrogen (creams, tablets and ring) will be efficacious. The type (estradiol, estriol CEE) depends on patient preference in most instances.

Urinary symptoms

The effect of topically administered estrogen in relieving postmenopausal urinary symptoms has been inadequately studied. One study showed that intravaginal estriol (1 mg twice weekly) was more effective than placebo in reducing stress incontinence at 6 months in 88 postmenopausal women [43].

There is limited evidence of efficacy for topical but not oral hormone therapy. An estradiol-releasing vaginal ring was tested in a 9-month, open, randomized, controlled trial of women with recurrent urinary tract infections [44]. The group treated with the estradiol-releasing vaginal ring had a prolonged interval to the next episode of recurrent urinary tract infection and a decreased number of recurrences per year. Similarly, the incidence and risk of recurrent urinary tract infections in 93 postmenopausal women receiving intravaginal estriol was significantly lower than in a control group in a randomized, controlled study of women experiencing recurrent urinary tract infections (0.5 vs 5.9 episodes/patient/year) [45].

Risks of topical hormone therapy

The risks of breast cancer with topical hormone therapy have been investigated in only one study. As part of the Million Women Study, the incidence of breast cancer in 69 subjects (4% of database) with histologically confirmed breast cancer who used topical estrogen alone for menopausal symptoms, was compared with 1403 nonusers [46]. Those using topical estrogen did not have an increased probability of breast cancer reccurrence compared with the rest of the database (corrected hazard ratio [HR]: 0.57; 95% CI: 0.20–1.58; p = −0.280). However, the small numbers of this study precluded a definitive result.

Limited data exist regarding the risk of endometrial hyperplasia and adenocarcinoma. One case-control study reported odds ratios for endometrial cancer of 0.90 (95% CI: 0.29–4.28) and 0.82 (95% CI: 0.46–3.20) using two different sampling methods [47]. A second case-control study reported an OR of 1.1 (95% CI: 0.8–1.6) for the risk of developing endometrial cancer in patients receiving vaginal estriol and similar results for the risk of endometrial hyperplasia [48].

Endometrial stimulation was comparable between the vaginal ring and CEE cream in two studies [40,42]. The ring showed less hyperplasia than the cream in two others [36,41]; however, the dosage was higher in the estrogen cream. Similarly, the estradiol vaginal tablet produced similar endometrial proliferation to estriol [34] and CEE cream [33] in two studies, but produced less stimulation than cream in another [17].

Selective estrogen-receptor modulators

Selective estrogen-receptor modulators (SERMs) act as estrogen agonists in some target tissues while acting as estrogen antagonists in others. In general, currently available SERMs mimic the effects of estrogen on bone and the cardiovascular system, while functioning as anti-estrogens in the breast [49 –51]. Tamoxifen and toremifene, used primarily in adjuvant chemotherapy for breast cancer [52 –54], have stimulatory effects on the endometrium [50,51]. Raloxifene has an estrogenic impact on bone-mineral density [49] and does not stimulate breast and endometrial cell growth [16,55 –57].

The ideal SERM should have estrogenic effects on bone density and vaginal epithelium, and anti-estrogenic effects on breast and endometrial tissue. Although no such compound is currently available, lasofoxifene and ospemifene appear promising. Ospemifene, developed for osteoporosis prevention [58], has beneficial effects on bone metabolism and vascular surrogate markers [59]. In a 3-month randomized, double-blind, placebo-controlled study, ospemifene (30–90 mg/day) did not stimulate the endometrium, and slightly increased uterine volume and intermediate and superficial cells in 160 postmenopausal women, suggesting a mild estrogenic effect on the vaginal epithelium [60]. Similarly, ospemifene (25–200 mg/day) induced estrogenic effects in vaginal epithelium and produced no clinically significant change in endometrial thickness compared with placebo in a 12-week, randomized, double-blind, placebo-controlled study of 40 postmenopausal women [58]. Lasofoxifene, which was initially studied for osteoporosis indications, was later evaluated for efficacy in the treatment of vaginal atrophy. Older women in these initial bone trials noted improvement in urogenital symptoms as a side effect of therapy. In a subsequent 12-week double-blind, placebo-controlled study, lasofoxifene (0.075–1.5 mg/day) improved vaginal dryness and soreness and dyspareunia compared with placebo in 400 postmenopausal women [61]. Bazedoxifene and arzofoxifene are tissue-selective estrogens currently under investigation for osteoporosis and may also provide future treatment options for urogenital atrophy.

Thus, older agents such as tamoxifen and toremifene appear to have anti-estrogenic effects on the vaginal epithelium, raloxifene appears to have neutral effects, ospemifene appears to have mild stimulatory effects and lasofoxifene appears to have moderate stimulatory effects. Thus, the newer, more selective SERMs show promise in relieving vaginal atrophy while limiting breast and endometrial stimulation.

Synthetic hormone products

Tibolone, although widely used in other parts of the world, is not available for clinical use in the USA; however, clinical-trials of this compound have been carried out in the USA recently. This pharmacologic intervention is a synthetic hormone product with weak estrogenic, progestogenic and androgenic activity. Data have shown that tibolone increases the maturation value and karyopknotic index and improves symptoms of vaginal atrophy [62]. In one small study, tibolone 2.5 mg/day for 6 months in 36 postmenopausal women with vaginal atrophy significantly improved vaginal dryness, dyspareunia and signs of atrophic vaginitis [63]. Although no endometrial proliferation was found in this small study, a large cohort study showed that women receiving tibolone experienced an increased risk of endometrial cancer, increasing with duration of use [64].

Herbal products

Data suggest that 10% of women use herbal remedies to treat postmenopausal symptoms [65]. Agrimony, black cohosh, chaste tree (Vitex agnus castus), dong quai, witch hazel, phytoestrogens and topical progesterone and wild yam creams are specifically promoted to treat vaginal dryness and/or dyspareunia [66]. Scant evidence exists to support their efficacy and some products such as agrimony, topical progesterone and wild yam creams lack published clinical-trial data.

Black cohosh is approved by the German Commission E for ‘premenstrual discomfort, dysmenorrhea or climacteric (menopausal) symptoms of depression, low energy and insomnia’. Controlled trials suggest that black cohosh improves menopause symptoms on the Kupperman menopausal index (e.g., hot flushes, paresthesia, insomnia, nervousness, melancholia, vertigo and weakness), but the index does not assess vaginal dryness [67]. Studies reported no change [67] or stimulation of vaginal epithelium [65].

Chaste tree extracts contain progesterone, hydroxyprogesterone and androstenedione-like compounds. It is widely used in Germany to treat breast pain, ovarian insufficiency and uterine bleeding [68], but has not been specifically studied for vaginal dryness.

Dong quai treatment for a period of 24 weeks was not effective in relieving menopause symptoms and did not change endometrial thickness or vaginal maturation index [69]. This study was criticized since herbalists do not use this traditional Chinese remedy as monotherapy. Phytoestrogen supplementation with soy protein 60 g daily did not change vaginal maturation indexes [70] but 20 g daily improved vasomotor symptoms [71].

Research has failed to demonstrate any beneficial effect of ‘dietary estrogen’ [72] or supplements such as dong quai [69] on vaginal atrophy.

Conclusions

Until the availability of a SERM that has positive effects on the external genitalia rather than a negative or at best neutral effect, low-dose vaginal estrogen remains the mainstay of treatment for this distressing condition that affects both sexual and nonsexual health. Short treatment courses of estrogen are often useful to reverse significant atrophy, especially for women who want to continue or resume coital activity. After adequate estrogenization of the urogenital tissue and reversal of the atrophy, nonestrogen-containing products may supplement estrogen for long-term management. Encouraging sexual activity for women both with and without a partner also helps to maintain urogenital health.

It is clear that questioning older women about urogenital symptoms, especially those with marked atrophic changes on pelvic examination, is a critical part of the medical history. Treatment should be offered to women who are distressed from this condition, especially since a wide variety of vaginally delivered low-dose estrogen options that have minimal systemic absorption of estrogen are available. Atrophic vaginitis may be a natural part of aging, but for many women this condition is not a welcome part and for them, morbidity accompanying loss of estrogen to the vaginal tissues will be lessened with effective counseling and intervention.

Future perspectives

Over the next 5–10 years, as the human genome is explored and the implications of pharmacologic interventions based on these data are utilized, this information will help identify women who will benefit from vaginal estrogen use into and throughout their menopausal and geriatric years. New SERMs will also be available to treat urogenital atrophy. These compounds will be estrogen receptor-positive in tissues in which stimulation is desirable, such as the bone and urogenital tract, and estrogen receptor-negative in tissues where estrogenic stimulation is not wanted, such as the endometrium and breast.

Executive summary

Diagnosis

Since menopause is a universal event occurring in all women reaching the sixth decade of life, every woman will eventually develop atrophic changes to the urogenital tissue.

Atrophic changes occur in the vaginal area as well as in the urinary tract.

The first step in diagnosing vaginal atrophy is by medical history, followed by physical examination for objective signs of urogenital atrophy.

Treatment

Treatment options for urogenital atrophy include lifestyle modifications, vaginal lubricants, moisturizers and local estrogen therapy.

Estrogen therapy continues to be the gold standard for the treatment of urogenital atrophy.

Regular sexual activity should be encouraged to maintain vaginal health.

Nonhormonal vaginal preparations typically provide temporary relief of vaginal dryness during intercourse.

Oral estrogen therapy is indicated for menopausal women with vasomotor symptoms, and women on low-dose systemic estrogen may still require additional low-dose vaginal estrogen.

There is insufficient data to recommend endometrial monitoring when unopposed vaginal estrogen is given.

Estrogen therapy is not recommended for treatment of any type of urinary incontinence.

The newer, more selective, selective estrogen receptor modulators and tibolone show promise in relieving vaginal atrophy without producing adverse cardiovascular, bone density and endometrial effects.

Research has failed to demonstrate any beneficial effects of phytoestrogens, black cohosh, chaste tree or dong quai on vaginal atrophy.

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Treating Urogenital Atrophy

Abstract

Keywords

Epidemiology

Clinical presentation

Diagnosis

Treatment

Lifestyle modification

Lubricants

Moisturizers

Oral estrogens

Vaginal atrophy

Urinary symptoms

Risks of hormone therapy

Topical estrogens

Vaginal atrophy

Urinary symptoms

Risks of topical hormone therapy

Selective estrogen-receptor modulators

Synthetic hormone products

Herbal products

Conclusions

Future perspectives

References