INTRODUCTION — Vulvovaginal atrophy (VVA; also referred to as vaginal atrophy, urogenital atrophy, or atrophic vaginitis) results from estrogen loss and is often associated with vulvovaginal complaints (eg, dryness, burning, dyspareunia) in menopausal patients [1]. Urinary frequency and recurrent bladder infections may also occur.
In 2014, the new term genitourinary syndrome of menopause (GSM) was introduced by the International Society for the Study of Women's Sexual Health and the North American Menopause Society [2]. This term encompasses all of the atrophic symptoms patients may have in the vulvovaginal and bladder-urethral areas from loss of estrogen that occurs with menopause. The spectrum of adverse consequences makes long-term treatment essential in many patients, not only for relief of symptoms, but also for the more troublesome problems that may occur, such as sexual dysfunction, postcoital bleeding, and recurrent urinary tract infections. Treatment options include both hormonal and nonhormonal interventions.
Treatment of GSM is reviewed here. Clinical manifestations and diagnosis of vaginal atrophy, as well as use of estrogen therapy for other menopausal symptoms, are discussed in detail separately. Recent guidelines from the Endocrine Society cover each of these issues [3]. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis" and "Treatment of menopausal symptoms with hormone therapy" and "Preparations for menopausal hormone therapy" and "Menopausal hormone therapy: Benefits and risks".)
CLINICAL APPROACH — The primary indication for treatment of GSM is to relieve symptoms that cause distress in a patient who has diminished ovarian estrogen production due to menopause or other etiologies. Vulvovaginal symptoms include vaginal dryness, burning, pruritus, dyspareunia, vaginal discharge, bleeding, or spotting. Urinary tract symptoms include dysuria, urinary frequency, urethral discomfort, or, infrequently, hematuria. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis", section on 'Clinical presentation'.)
Many patients with GSM do not seek medical care for these issues (due to embarrassment, cultural, religious, or societal beliefs, or lack of awareness about safe and effective treatments) and many clinicians fail to ask their menopausal patients about GSM symptoms [4]. This is discussed in detail separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis", section on 'Clinical presentation'.)
Management is guided by the patient's symptoms, overall medical health, and goals. Barriers to effective management include product cost and labelling. High cost of a specific therapy may lead a clinician to recommend a less expensive (and less effective) over-the-counter alternative which may improve mild GSM symptoms, but does not treat the underlying pathology (ie, decline in serum estrogen levels). In addition, product labeling including a black box warning for safety (as required for low-dose vaginal estrogen-containing therapies to treat GSM) may overstate potential risks and discourage use [5].
For symptoms of vaginal dryness, discomfort, or dyspareunia associated with vaginal atrophy, first-line treatments are often nonhormonal vaginal moisturizers and lubricants. These are particularly helpful for those with mild symptoms or may be the only alternative for those with estrogen-sensitive neoplasias (see 'Patients with breast cancer' below). If first-line therapies do not provide adequate symptom relief, vaginal estrogen therapy or other hormonal medications may be prescribed for patients without contraindications to their use [6]. Estrogen therapy may also help to ameliorate some urinary tract symptoms of GSM, including frequent urinary tract infections or stress or urgency incontinence in the absence of infection [7]. This is discussed in more detail separately. (See "Female urinary incontinence: Treatment", section on 'Topical vaginal estrogen'.)
Most patients with GSM achieve adequate symptom relief with vaginal estrogen therapy, but other modes of treatment, such as physical therapy or vaginal dilators, may be used for refractory symptoms or if hormone therapy is contraindicated.
Prior to initiating treatment for vaginal atrophy, other conditions should be excluded, in particular:
●Patients with postmenopausal bleeding should be evaluated for endometrial hyperplasia or cancer. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease".)
●Patients with postcoital bleeding should be evaluated for infectious, noninfectious (eg, cervical ectropion, cervical polyp), and premalignant or malignant conditions. (See "Postcoital bleeding in females".)
●Patients with urinary tract symptoms should be evaluated for urinary tract infection or other conditions (interstitial cystitis, urinary tract malignancy), as appropriate. (See "Acute simple cystitis in females" and "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis".)
●Patients with symptoms of vaginitis should be evaluated for infectious and noninfectious etiologies. (See "Vaginal discharge (vaginitis): Initial evaluation".)
A detailed discussion regarding the differential diagnosis of symptomatic urogenital atrophy is found elsewhere. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)
INITIAL THERAPY WITH MOISTURIZERS AND LUBRICANTS — First-line therapy for GSM includes nonhormonal vaginal moisturizers and lubricants. Symptoms of vaginal dryness can be managed by the regular use of vaginal moisturizing agents with supplemental use of vaginal lubricants for sexual intercourse [8]. These agents may improve coital comfort and increase vaginal moisture, but they do not reverse most atrophic vaginal changes [9]. Thus, while vaginal moisturizers and lubricants are useful for patients with mild symptoms, many patients will have persistent systems and require hormonal medications or other treatments [10].
Product types and use — Patients should be counseled about the difference between vaginal moisturizers and lubricants and how to use them. Patients should try various products until they find one that meets their needs and to find the one they like best and within their price range. The only contraindication is allergy to a particular product.
●Vaginal moisturizers are intended for use routinely, typically two or three days per week, not just during sexual activity. These products are typically bioadhesives. Hyaluronic acid is often used as a key ingredient in vaginal moisturizers. Many moisturizer products are available in pharmacies and online (eg, Replens, Vagisil Moisturizer, Feminease, Moist Again, K-Y Liquibeads, Hyalo GYN, Revaree suppositories).
●Lubricants are used only at the time of sexual activity. Lubricants may be water-based (eg, Astroglide, Slippery Stuff, K-Y Jelly), silicone-based (eg, Pjur, ID Millennium), or oil-based (Elegance Women's Lubricant); oil-based lubricants cause breakdown of latex condoms. Some clinicians counsel that lubricants with glycerin (also referred to as glycerol) may result in an increased risk of vulvovaginal candidiasis, but there is no evidence to support this and some data suggest that glycerin inhibits candidal growth [11,12].
Both moisturizers and lubricants are also available in preservative-free preparations.
Efficacy — Vaginal moisturizer and lubricant therapy appear to be effective in many patients, and some data suggest that they are as effective as vaginal estrogen. However, data are limited by sample size and duration of follow-up; more study is needed of this issue.
The largest randomized trial regarding treatment options for GSM found few differences in efficacy between vaginal estrogen and two nonhormonal lubricants/moisturizers but had significant methodological limitations [6]. The trial assigned 302 postmenopausal patients with vulvovaginal symptoms to one of three vaginal therapy regimens: estradiol tablet (10 mcg) and placebo gel, vaginal moisturizer (Replens) and placebo tablet, or placebo tablet and placebo gel (dual placebo). The vaginal moisturizer and placebo gel had similar ingredients, but the placebo did not contain the bioadhesive polymer polycarbophil, which is intended to improve efficacy.
●The primary outcome measure was decrease in severity of most bothersome symptom (eg, vulvovaginal pain, itching, dryness). At 12 weeks, all groups had similar reductions in severity from a baseline score of approximately 2.5 (moderate to severe) to 1.3 (mild to moderate); no significant differences in severity of most bothersome symptom were found between groups. The only significant differences found were in scores on the Vaginal Symptom Index, with dual placebo compared with moisturizer found to be slightly superior in improvement in pain with vaginal penetration. Improvement in mean Female Sexual Function Index scores was also similar across groups.
●A separate report using data from the trial found greater improvement in menopause-specific quality of life scores in the estradiol tablet group compared with the other two groups [13].
●In a subsequent post hoc analysis that assessed the impact of 12 weeks of treatment, the patient-reported number of days with sexual activity in the past month, sexual activity in the past week, and penetrative sex in the past week, as well as average pain with sexual activity, were similar for both interventions compared with placebo [14]. Major limitations of this post hoc analysis include that it only had the power to detect large differences in outcomes and had insufficient power to allow direct comparison of the active treatments (vaginal estrogen versus moisturizer).
A major limitation of this study design overall was that it is uncertain whether it is generalizable to clinical care since the standard of care is to use nonhormonal interventions first and to limit vaginal estrogen therapy to patients who fail nonhormonal management. Also, the study regimens were not consistent with usual therapy (all patients had five days per week of treatment, while the majority of patients likely use vaginal estrogen or a moisturizer two to three days per week). Limitations in study design were that all groups were treated with two interventions concurrently, so it did not provide a direct comparison between the three interventions. Also, the placebo gel was similar to commonly used products and thus was not a nonactive comparator, although this would be difficult to avoid.
Other data regarding the efficacy of vaginal moisturizers include a small randomized trial and a small observational study that compared Replens and a vaginal estrogen preparation and reported that relief of vaginal dryness and restoration of normal vaginal pH were similar for both agents [15,16]. In contrast with estrogen, Replens does not affect the vaginal maturation index [17]. In our experience, however, estrogen is more effective than vaginal moisturizers.
There are inconsistent data regarding whether moisturizers or lubricants that result in an acidic pH (in premenopausal patients, normal vaginal secretions have a pH of 4.0 to 4.5) are more effective. As an example, a randomized trial of postmenopausal breast cancer survivors with vaginal atrophy found that a gel with added lactic acid (pH 4.0) decreased vaginal irritation, dryness, and dyspareunia compared with a gel without lactic acid (pH 7.2) [18]. However, a subsequent trial found no improvement in dyspareunia with a pH-balanced gel compared with placebo [19]. Further study is needed to validate these results. (See "Vaginal discharge (vaginitis): Initial evaluation", section on 'Normal discharge'.)
PERSISTENT SYMPTOMS — Vaginal estrogen therapy is a common second-line treatment for GSM that does not adequately respond to moisturizers and lubricants.
Vaginal estrogen is effective treatment for symptoms of vulvovaginal dryness or discomfort (burning, itching, irritation), tissue fragility (this may result in postcoital bleeding or fissures), or dyspareunia.
Vaginal estrogen therapy is also likely to effectively treat vaginal discharge if the sole etiology is hypoestrogenism. If vaginal discharge continues despite vaginal estrogen therapy, the patient should be evaluated for other etiologies of vaginitis. Of note, vaginal estrogen creams will leak out of the vagina for a few days after application and may be appear to be discharge; however, the creamy consistency of this leakage typically makes it easy to differentiate from pathologic vaginal discharge. (See "Vaginal discharge (vaginitis): Initial evaluation".)
Some urinary tract symptoms of GSM are ameliorated by vaginal estrogen therapy, including frequent urinary tract infections and urinary frequency and urgency without infection, but urinary incontinence typically requires other modes of treatment [7]. (See "Female urinary incontinence: Treatment".)
Hormonal medications other than estrogen are also available for GSM treatment: vaginal dehydroepiandrosterone (DHEA) or testosterone and oral ospemifene. These are less commonly used, but patients should be counseled about all treatment options, and some may prefer another medication. There are also other types of treatment available, including complementary medications or laser surgery, but the safety and efficacy of these are uncertain.
Vaginal estrogen therapy — Low-dose vaginal estrogen is the most effective treatment for moderate to severe symptoms of vaginal atrophy not responsive to nonhormonal intervention. Use of estrogen therapy is appropriate for patients with symptoms of vaginal atrophy in the setting of low estrogen levels, provided that there are no contraindications to this therapy (eg, some patients with estrogen-dependent tumors, particularly those on antiestrogen therapy).
Adequate estrogen therapy leads to restoration of the normal vaginal acidic pH and microflora, thickening of the epithelium, increased vaginal secretions, and decreased vaginal dryness and resultant dyspareunia. In addition, estrogen therapy is associated with urinary tract benefits. These include a reduction in the incidence of urinary tract infections and overactive bladder symptoms. Urgency and stress urinary incontinence, however, do not improve with estrogen therapy alone [20,21]. (See "Menopausal hormone therapy: Benefits and risks", section on 'Recurrent urinary tract infection'.)
Adverse effects of vaginal estrogen therapy are uncommon. Patients may complain of vaginal irritation or itching, vaginal bleeding, or breast tenderness; headaches or hot flashes are rare.
Serum absorption — Vaginal estrogen therapy at recommended doses results in estrogen absorption into the circulation, although to a lesser degree than oral or transdermal estrogen therapy. The serum estradiol levels attained with the low-dose preparations are slightly higher than the average level for postmenopausal patients, which is approximately 5 pg/mL [22,23]. For the same dose of estrogen, a vaginal dose results in lower serum estradiol and estrone levels than oral estrogen (30 percent lower in a study of conjugated estrogens) [24].
In general, the plasma estradiol assays used in studies of vaginal estrogen absorption have not been sufficiently sensitive to measure the low serum levels of estradiol in menopausal patients and to measure compounds other than estradiol [22]. Measurements of estradiol by mass spectrometry assays or ultrasensitive bioassays find much lower levels in postmenopausal patients than do radioimmunoassays [25]. When highly sensitive assays were used, increments in estradiol can be detected at very low levels (ie, 5 pg/mL) but not to premenopausal levels (ie, 40 to 600 pg/mL) [26].
The effect of the severity of vaginal atrophy on systemic estrogen absorption is controversial. Some studies have reported that systemic absorption is highest in the first days or weeks of therapy and then decreases with ongoing treatment [27,28]; however, a study using highly sensitive estradiol measurements did not support this finding [26]. When present, a higher level of absorption with initial therapy may be due to increased estrogen absorption through the thin atrophic vaginal epithelium, which then cornifies with treatment [27]. In patients who use the low-dose vaginal ring, another possibility is that the device may release a higher dose of estradiol during the first 24 hours of use. This was illustrated in an in vitro study in which the ring released up to 55 mcg during day 1 of testing, versus 7 to 8 mcg during days 2 to 90 [29].
There are no long-term randomized trials evaluating the safety of low-dose vaginal estrogen use. However, long-term observational data has not shown any increased risk of breast or endometrial cancer, coronary heart disease, stroke, or venous thromboembolism [30,31]. Despite this lack of adverse safety data, vaginal estrogen carries the same box warning as systemic hormone therapy.
Low-dose vaginal hormone therapies may also be an option for some patients with estrogen-sensitive cancers (eg, endometrial, breast) who fail nonpharmacologic and nonhormone treatments [32], but requires a discussion of risks and benefits with the patient and involvement of the patient's oncologist. (See "Overview of approach to endometrial cancer survivors", section on 'Sexual dysfunction' and 'Patients with breast cancer' below.)
Absorption by sexual partners — Clinical implications of the absorption of vaginal estrogen by a sexual partner is generally unknown, and there are no data to support refraining from coital activity for a specific period of time after use of a vaginal estrogen [10]. Exposure of a male partner to vaginal estrogen cream during sexual intercourse is rarely clinically significant [33-35].
Preparations: Cream, tablet, capsule, ring — The preparations of vaginal estrogen that are commercially available in the United States are conjugated estrogens (cream) and estradiol (cream, tablet, capsule, and ring) (table 1). In Europe and some other countries, estriol cream or suppositories also are available.
A systematic review of 19 randomized trials including over 4000 patients investigated local estrogen treatment and found that creams, inserts, and rings were all similarly effective in relieving symptoms of vaginal atrophy [20].
The vaginal estrogen preparations with the lowest systemic absorption are the standard regimens of the 4 mcg or 10 mcg estradiol tablet or capsule and the 7.5 mcg/day estradiol ring [36-39].
We define low-dose vaginal estrogen as ≤50 mcg estradiol or ≤0.3 mg conjugated estrogens (in ≤0.5 g cream). Other doses of conjugated estrogens cream (≥0.625 mg in 1 g of cream) and the estradiol vaginal cream (>1 g) are considered higher dose preparations. Higher serum estrogen concentrations potentially result in endometrial proliferation [39,40]. (See 'Use of an opposing progestin' below.)
Systemic absorption, patient preference, convenience, and cost should guide the choice of preparation. In our practice, we use cream for patients who have symptomatic vulvar atrophy (eg, fissures) so that cream may also be applied to areas of the vulva affected by atrophy. When the vulvar atrophy improves, we switch to a vaginal insert or ring, depending on patient preference. For other patients, we start the vaginal insert and switch to the ring if long-term therapy is desired and if the patient is comfortable with use of the ring.
●Tablet or capsule – There are two strengths of vaginal estradiol inserts in the United States: 10 mcg (Vagifem, Yuvafem, Imvexxy, generics) or 4 mcg (Imvexxy) [26,41,42]. A 25 mcg tablet was discontinued in 2010. The insert is placed in the vagina daily for the first two weeks of use and then twice weekly thereafter [43,44]. In our experience, thrice-weekly use may be used for patients in whom twice-weekly therapy does not provide sufficient symptom relief.
Randomized trials have demonstrated that the 10 mcg estradiol insert is effective for relief of vaginal symptoms [26,41,42]. Although the 10 mcg estrogen dose is significantly more effective than placebo therapy, one randomized trial found it to be slightly less effective than a 25 mcg dose for initially inducing maturation, providing relief of vaginal symptoms, decreasing pH, and improving urogenital atrophy [41]. Another randomized trial (n = 764) comparing 4, 10, or 25 mcg doses with placebo found that all three doses were more effective than placebo at treating GSM symptoms [45]. Efficacy was fairly similar across doses. Dyspareunia was improved at two weeks with all three doses. Vaginal dryness was improved at two weeks with the 10 and 25 mcg doses and at six weeks with the 4 mcg dose. Vaginal irritation and/or itching was improved at 12 weeks with the 10 and 25 mcg doses but not the 4 mcg dose.
In terms of serum estrogen absorption, in one 12-week study of postmenopausal patients with baseline serum estradiol concentrations of approximately 7 to 8 pg/mL, mean serum estradiol concentrations over a 24-hour period for 10 and 25 mcg estradiol inserts were 11 and 23 pg/mL [40.4 and 84.4 pmol/L], respectively [38]. Another randomized trial (n = 72) evaluated serum estradiol levels in postmenopausal patients using a 4, 10, or 25 mcg dose (daily for two weeks followed by twice weekly for 10 weeks) versus placebo [46]. Compared with placebo, 4 mcg showed no significant difference in any serum estradiol measures; 10 mcg showed an increase in the maximum estradiol concentration on day 1 (10.9 versus 6.6 pg/mL in patients in the placebo group) but not on day 14; and 25 mcg showed both higher maximum and average levels on both day 1 and day 14.
●Ring – A silastic ring impregnated with estradiol (Estring) delivers estrogen locally to the vagina [47-49]. The ring is designed to release 7.5 mcg of estradiol to the vagina daily for a period of 90 days, at which time the patient or clinician replaces it with a new ring [50].
In prospective studies of the low-dose estradiol ring, symptomatic improvement was comparable to that of orally administered estrogen, and vaginal cytology resembled that of premenopausal patients [48,49,51-55]. The ring was well tolerated and did not interfere with intercourse; however, patients who had previously undergone a hysterectomy sometimes had problems with ring retention.
The serum estradiol levels with use of the low-dose ring, 7.5 mcg/day, are 5 to 10 pg/mL serum estradiol [29,36,37,56].
Of note, another vaginal ring (Femring), releases much higher doses of estradiol (50 to 100 mcg per day) and is considered systemic rather than local vaginal estrogen therapy. It is used for the treatment of both vasomotor and GSM symptoms. (See 'Patients also on systemic hormone therapy' below.)
●Cream – The effectiveness of vaginal estrogen cream for treating vaginal atrophy is well established. Studies have consistently found that in postmenopausal patients initially given 0.5 g conjugated estrogen daily intravaginally vaginal cytology changed to that of normal premenopausal patients [40,47,57].
Two creams for vaginal estrogen therapy are available in the United States. The estrogen dose varies with the amount of cream used; the creams are supplied in a tube with an applicator marked with various doses so that the patient can measure the prescribed amount [58,59]. For patients who are not sexually active, cannot, or choose not to use the cream applicators, an alternative method of delivery is the 'fingertip' method; a 1 g dose (eg, a dime-sized amount or amount equal to the length of the index fingertip) is applied to the introitus.
In our practice, we start vaginal estrogen creams with daily dosing for two weeks and then change to twice weekly. Patients often achieve relief of symptoms with doses lower than the manufacturer-recommended doses. For patients with more severe symptoms, the clinician may start with a dose on the higher end of recommended doses and then decrease the dose when symptoms improve or switch to the lower dose options, the tablet, capsule, or ring. Since the goal is symptomatic relief, after this goal is achieved, the patient is often able to determine the lowest effective dose.
The two cream preparations available in the United States contain different types of estrogens:
•Conjugated estrogens (0.625 mg conjugated estrogens/1 g cream [40]; Premarin) – Doses range from 0.5 to 2 g of cream. This equals 0.3 to 1.25 mg conjugated estrogens.
The regimens recommended by the manufacturer for vulvovaginal atrophy (VVA) are: 0.5 to 2 g of cream intravaginally administered in either a continuous regimen (twice weekly) or cyclic regimen (daily for 21 days then off for 7 days) [60]. We do not use a cyclic regimen in our practice.
Serum absorption is difficult to measure since conjugated estrogens contain more than 200 compounds, some of which are estrogenic, with 50 to 58 percent consisting of sodium oestrone sulfate and 25 to 35 percent consisting of sodium equilin sulfate. The plasma estradiol after use of conjugated estrogens bears no relationship to actual activity since activation of some components can take place in the tissue itself [61].
•Estradiol (100 mcg estradiol/1 g cream; Estrace, generics) – Doses range from 0.5 to 4 g of cream. This equals 50 to 400 mcg of estradiol. 200 mcg of estradiol cream results in a serum estradiol level of approximately 40 pg/mL [62]. We use 0.5 g of estradiol cream, lower than recommended by the manufacturer.
The regimen recommended by the manufacturer is 2 to 4 g of cream intravaginally administered daily for one or two weeks, then gradually reduced to half the initial dose for a similar period [63]. A maintenance dose of 1 g of cream, one to three times per week, may be used.
It should be noted that the maximal doses of various forms of vaginal creams indicated on the package insert produce premenopausal plasma levels of estradiol (premenopausal estradiol ranges from 40 to 600 pg/mL, depending upon the phase of the menstrual cycle) [64] and should not be used long term without an opposing progestin and/or endometrial assessment. (See 'Use of an opposing progestin' below.)
For patients who develop sensitivity to the preservatives in the creams, preservative-free estradiol cream can be compounded.
•Estriol – Estriol vaginal cream and suppositories are available in many countries outside the United States [65]. Estriol is the 16-hydroxylated metabolite of estradiol. In vulvar and vaginal tissues, estriol is a weak estrogen agonist. Estriol is not approved by the US Food and Drug Administration (FDA) for the treatment of GSM.
Use of an opposing progestin — For patients with GSM treated with low doses of vaginal estrogen (table 1), a progestogen (progestin or progesterone) is generally not indicated to protect against endometrial hyperplasia or carcinoma [64,66]. However, clinical trial data supporting endometrial safety beyond one year are lacking [67,68].
Estrogen creams that are used for systemic therapy and not local therapy for GSM may result in higher serum estrogen levels, but in our practice, we do not use an opposing progestin with estradiol cream and conjugated estrogen cream doses as prescribed for GSM. The total impact on endometrial neoplasia is likely to be impacted by dose, frequency, and duration of therapy.
As noted above, the systemic estrogen absorption of the vaginal creams is difficult to quantify precisely due to limitations of assays and the difficulty in measuring the total serum estrogen level of the multiple estrogens in conjugated estrogen cream. There are few data regarding the risk of endometrial neoplasia with these preparations, and there are no studies of the impact of low-dose estrogen on endometrial activity after more than one year of treatment.
Studies that have evaluated the endometrial effect of the vaginal estrogen preparations by ultrasonography or by biopsy include the following:
●For the 10 mcg estradiol insert (Vagifem), a prospective study evaluated daily use for two weeks then twice weekly for 52 weeks [69]. Among the 386 patients who had an evaluable biopsy 52 weeks after beginning therapy, there was one case of complex hyperplasia without atypia in a patient exposed to the drug for only nine days (suggesting a preexisting abnormality) and one case of endometrioid adenocarcinoma (in whom preexisting disease could not be excluded because the pretreatment biopsy sample was inadequate for analysis). A previous study had supported the endometrial safety of the 25 mcg estradiol vaginal insert, which has been discontinued [37].
●For the low-dose estradiol ring (Estring), 60 postmenopausal patients were randomly assigned to receive Estring or no treatment for 12 months [36]. Sonographic evaluation found no significant increases in endometrial thickness in either group.
●For low-dose conjugated estrogens cream (Premarin), a study of 20 participants (treated with 0.3 mg of conjugated estrogens, administered vaginally three nights per week for six months) found evidence of endometrial hyperplasia on biopsy in one, even though the sonographic endometrial thickness was normal [70]. This observation suggests caution, but further study is needed.
Regardless of the estrogen dose, patients with postmenopausal bleeding, including those who report this while using vaginal estrogen, should be evaluated, as appropriate. (See "Approach to the patient with postmenopausal uterine bleeding".)
Response and duration of therapy — In our experience, patients usually have improvement in symptoms after two to four weeks of vaginal estrogen therapy. In a trial comparing the 4 and 10 mcg dose of estradiol vaginal tablets, a positive response by two weeks of treatment was indicative of continued response at 12 weeks [71]. The duration of treatment needed to improve symptoms and maintain this improvement may vary across patients and should be individualized according to each patient's degree of vaginal atrophy symptoms. Low-dose vaginal estrogen therapy may be used indefinitely, based upon the low risk of adverse effects, although clinical trials to date have not followed patients beyond one year. The duration of higher dose vaginal therapy or systemic estrogen therapy should be guided by the risks and benefits of therapy.
Patients also on systemic hormone therapy — We suggest low-dose vaginal estrogen therapy (vaginal administration of a low dose) rather than prescribing systemic estrogen therapy (oral, transdermal, or vaginal administration of a higher dose) for patients who only report vaginal atrophy symptoms [8]. This is consistent with North American Menopause Society guidelines that state that for urogenital atrophy alone, local vaginal estrogen therapy is generally recommended and patients treated with systemic therapy should be asked whether they have persistent atrophy symptoms [66].
For patients receiving systemic estrogen therapy for other menopausal effects (eg, vasomotor symptoms), low-dose vaginal therapy may be added if relief of atrophic symptoms is insufficient. Prevention/treatment of osteoporosis is another benefit of systemic hormone therapy, although estrogen is not considered first-line therapy for this. Low-dose vaginal estrogen is unlikely to be effective in osteoporosis, although one study reported a reduction in bone resorption in postmenopausal patients receiving low-dose vaginal estradiol (7.5 mcg/24 hours), which suggests that a systemic effect is possible [72].
The preference for vaginal estrogen is based on its superior efficacy for GSM symptoms and the risks of systemic menopausal hormone therapy. A meta-analysis of 58 comparative studies of patients with urogenital atrophy found that patients' report of symptom relief was significantly higher for vaginal versus oral estrogen therapy [73]. The reported efficacy rate is approximately 80 to 90 percent for vaginal therapy and 75 percent for systemic therapy, based upon observational data [49,74-77]. In addition, the increased risks of breast cancer and thrombosis with systemic estrogen and progestin compared with placebo were best demonstrated by the Women's Health Initiative randomized trial; some of these risks vary depending upon whether a progestin is used in combination with estrogen [78]. (See "Menopausal hormone therapy and the risk of breast cancer" and "Menopausal hormone therapy: Benefits and risks", section on 'Cardiovascular effects'.)
Other medications — There are alternative hormonal medications other than estrogen that are used to treat GSM. Vaginal DHEA may result in decreased exposure to estrogen, but there appears to be some increase in serum estrogen levels even with this formulation. Some data suggest an improvement in libido with vaginal DHEA, but there are few data and the effect, if present, is modest. Oral ospemifene, a selective estrogen receptor modulator (SERM), is another option for patients who prefer oral medications or who are not able to insert a vaginal medication. Some clinicians prescribe vaginal testosterone off-label for GSM. This is usually with the concurrent goal of treating low libido.
Dehydroepiandrosterone (prasterone) — Vaginal DHEA, also referred to as prasterone, is a treatment option for dyspareunia associated with GSM. Prasterone is effective but is associated with a slight increase in circulating DHEA, testosterone, and estrone levels, and its efficacy has not been compared directly with vaginal estrogen [79,80]. In 2016, the FDA approved the use of prasterone 6.5 mg (0.5% formulation) as a daily vaginal suppository for the treatment of dyspareunia in the setting of vulvar or vaginal atrophy due to menopause [81].
For most patients with symptomatic VVA who do not improve with vaginal lubricants and moisturizers and who are candidates for hormonal therapy, we suggest low-dose vaginal estrogen therapy rather than vaginal DHEA. There are more data and clinical experience regarding vaginal estrogen, and the twice weekly dosing is likely to be easier for most patients than the daily dosing required with DHEA. For patients with no strong contraindications to estrogen therapy, but who value avoiding estrogen more than dosing convenience, vaginal DHEA is a reasonable option.
The mechanism of action of prasterone on the vagina is likely due to the aromatization of androstenedione and testosterone locally to estrone and estradiol through a process referred to by some investigators as intracrinology [82]. In one study, weeks of vaginal DHEA (6.5 mg) caused estrone to rise from 15 to 18 pg/mL and estradiol from 2 to 3 pg/mL [79]. It has also been proposed that testosterone acting through the androgen receptor is a possible mechanism of action, but this is only based on rodent data and may not apply to people.
Prasterone was found to be an effective treatment for dyspareunia in a randomized trial that assigned postmenopausal patients (n = 482) with dyspareunia to prasterone or placebo for 12 weeks and found improved Female Sexual Function Index (FSFI) overall scores and in the pain and satisfaction domains [83]. At 12 weeks, treatment with vaginal DHEA resulted in a significant increase from baseline in serum DHEA, testosterone, and estrone but not estradiol levels, although DHEA, estradiol, estrone, and testosterone remained within the range of an average postmenopausal patient [84].
The small elevations of estrone in patients treated with prasterone raise concern for use of this treatment in patients with or at risk for estrogen-sensitive malignancies, particularly for those with breast cancer who are treated with an aromatase inhibitor (AI). (See 'Patients with breast cancer' below.)
DHEA has been studied as a potential medication to increase libido in postmenopausal patients, but its efficacy is uncertain, and the serum DHEA levels with this dose of vaginal prasterone are unlikely to have an impact. Also, libido often improves with any adequate treatment of dyspareunia and is likely due to a reduction in pain or discomfort and increased blood flow and lubrication.
Ospemifene — Ospemifene is a SERM that acts as an estrogen agonist in the vagina and appears to have no clinically significant estrogenic effect on the endometrium or breast. Ospemifene was approved by the FDA in 2013 for the treatment of moderate to severe dyspareunia and/or vaginal dryness caused by VVA in menopausal patients [85].
For patients with symptomatic VVA that is not relieved with nonpharmacologic therapy, we suggest ospemifene rather than vaginal estrogen therapy for those who cannot (severe arthritis, obesity, vulvodynia) or prefer not to use a vaginal product. The disadvantages of ospemifene compared with vaginal estrogen are need for daily use and systemic side effects (hot flashes, potential risk of thromboembolism). The safety of ospemifene has not been demonstrated in patients with a prior history or an increased risk of breast cancer or in patients with an increased risk of thromboembolism.
Ospemifene is effective in treating dyspareunia and vaginal dryness in menopausal patients with VVA compared with placebo; no studies to date have directly compared ospemifene with vaginal estrogen therapy. Two randomized trials found that ospemifene (60 mg/day, oral, 12 weeks of therapy) was significantly more effective than placebo in improving dyspareunia, although the benefit beyond that of placebo was modest [86,87]. Severity of dyspareunia was rated with a four-point scale; in one trial, dyspareunia decreased by two to three points in 53 percent of participants in the treatment group compared with 39 percent of those who received placebo [87]. The proportion of those for whom dyspareunia was absent or mild was 38 and 25 percent, respectively, compared with 28 and 19 percent in the placebo group. In addition, either 30 or 60 mg of ospemifene was found to significantly decrease vaginal dryness in one trial [86]. Another randomized trial (n = 919) found that ospemifene (60 mg/day, 12 weeks) resulted in improvements in the sexual pain, arousal, and desire domains of the FSFI, a validated measure of female sexual function [88]. Lastly, a trial comparing 12 weeks of oral ospemifene 60 mg with placebo reported improved vulvar-vestibular health indices and FSFI scores in the ospemifene group [89].
Hot flushes are the most common adverse effect of ospemifene [87,90]. In one trial, the rate of hot flushes was 6.6 percent in the treatment group compared with 4.3 in the placebo group; however, symptoms typically resolved by six months and led to discontinuation in only two patients [87]. Ospemifene appears to have a favorable endometrial safety profile. Ospemifene results in an increase in endometrial thickness (0.4 to 0.7 mm in 12 weeks [86,87,91]), but studies of one year of use have found no cases of atypical endometrial hyperplasia or endometrial carcinoma [92,93].
Thrombotic adverse effects are a potential risk with SERMs. There have been no reports of such complications with ospemifene, but more data are needed to detect this relatively rare complication.
Animal and preclinical data suggest that ospemifene has a neutral or inhibitory effect on carcinogenesis in the breast [94,95]. As an example, one tissue culture study found that ospemifene had an antiproliferative effect on human breast tissue but was less potent an inhibitor than tamoxifen or raloxifene [96]. Further study is needed to evaluate the safety of ospemifene in patients with breast cancer or whether it may have a protective effect for patients at high risk for breast malignancy.
A potential benefit of ospemifene is a reduction in bone turnover [97,98]. Use of SERMs for the prevention and treatment of osteoporosis is discussed in detail separately. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis".)
Testosterone — Existing data provide some support for the concept that vaginal testosterone may stimulate vaginal mucosa and improve symptoms of vaginal atrophy [99]. However, none are FDA approved for use in females [100]. A common reason to use vaginal testosterone for GSM appears to be for patients who also desire treatment with testosterone for low libido. There has also been interest in using vaginal testosterone for GSM in patients on AI therapy, but the safety of this approach remains uncertain. (See "Overview of sexual dysfunction in females: Management", section on 'Androgens' and 'Patients with breast cancer' below.)
Several studies have reported therapeutic effects of testosterone on the vaginal epithelium, including:
●Studies have reported the presence of androgen receptors in vaginal tissue and an inverse correlation with age [101,102].
●Two studies examined the effect of vaginally administered androgen on vaginal maturation parameters in patients receiving AIs. In these studies, blockade of conversion of androgen to estrogen allowed one to conclude that the effects were androgen-mediated. In one study of 21 patients, the vaginal maturation index increased, and dyspareunia and vaginal dryness improved [103]. In another study, for 33 patients in the vaginal testosterone arm, the score for rugae, petechiae, elasticity, and dryness improved, but serum testosterone increased from a mean of 33 ng/100 mL to 171 ng/100 mL at 12 weeks [104].
Therapies needing further evaluation
Laser or radiofrequency devices — Laser and other energy-based devices (eg, fractional microablative CO2 laser, erbium:YAG [Er:YAG] laser, temperature-controlled radiofrequency [RF] laser) have been marketed for treatment of VVA, but the safety and efficacy of these devices remain uncertain. Thus, in our practice, we do not perform laser treatment for VVA. We understand that others are performing laser treatment for GSM, but data suggest that positive results may result from a placebo effect. In a properly counseled patient who has no other options, this may be considered for treatment of GSM but should not be considered for other indications, including sexual enhancement, lichen sclerosis, and vulvar vestibulitis syndrome without more data.
Laser technologies deliver fractional CO2 laser energy, and some systems use nonablative photothermal Er:YAG laser to the vaginal wall tissue. Laser therapy typically consists of three laser treatment sessions over a specified time period (usually one session every four to six weeks). Beneficial effects appear to result from remodeling of vaginal tissue [105]. However, optimal patient inclusion or exclusion criteria, treatment number, and maintenance therapy are not yet known [106].
Laser or energy-based devices have not been cleared or approved by the FDA for the treatment of VVA. In July 2018, the FDA issued a safety communication warning patients about the risks associated with use of these devices, which include vaginal burns, scarring, pain during sexual intercourse, and recurring/chronic pain [107]. In August 2018, the American College of Obstetricians and Gynecologists advised that additional data from randomized trials are needed to further assess the efficacy and safety of this procedure [108]. A 2020 clinical consensus statement by the American Urogynecologic Society also noted that, while energy-based therapies had shown treatment promise, long-term outcomes were not yet understood [106].
Randomized trials on laser treatment for GSM are limited [109-111]:
●In a multicenter randomized trial of 69 menopausal patients comparing treatment of vaginal dryness with either vaginal laser or estrogen cream, patient-reported symptoms of vaginal dryness, sexual function, and urinary distress improved, but results were similar between groups [110]. Vaginal maturation index scores, an objective measure of vaginal health, were higher after treatment in the estrogen group. Overall patient satisfaction scores were between 70 and 85 percent in both groups, and no serious adverse effects were noted. One major limitation was the early closure of this trial due to the FDA imposing an investigational device exemption, which was not obtained.
●In a subsequent randomized trial including 85 postmenopausal patients with vaginal symptoms, patients treated with CO2 laser or sham therapy experienced improvement in symptom severity (as assessed on visual analogue scale) at 12 months, but the magnitude of improvement was similar between groups; both participants and outcome assessors were masked to group assignment [109]. Quality of life scores and histologic changes on vaginal biopsy were also similar. Adverse events occurred in both groups and included vaginal pain, lower urinary tract symptoms, and vaginal discharge; no severe adverse events were reported. These results were supported in an animal study including 24 ewes with surgically induced menopause and vaginal atrophy [112]. In this randomized trial, more animals treated with an estradiol implant demonstrated a reversal of vaginal atrophy (ie, increase of epithelial thickness, glycogen-positive cell layers, and lubrication) compared with those treated with Er:YAG or sham laser. The response in ewes treated with YAG and sham laser were similar.
Systematic reviews including randomized trials and/or observational studies have reported that, overall, laser intervention appears to be a safe and potentially effective nonpharmacologic intervention for GSM [113-115]. However, the evidence was low or very low quality and did not include the randomized trial comparing CO2 laser with sham therapy discussed above. Additional large randomized clinical trials are needed to determine the benefits, risks, and cost-effectiveness of laser therapy for VVA.
Alternative and complementary therapies — Oral vitamin D and vaginal vitamin E have been proposed, but efficacy data are limited and/or discordant [116-118]. Oral and vaginal probiotics to alter the vaginal microbiota could possibly be beneficial for treatment of symptoms of GSM, but comprehensive trials are needed for validation [119]. Patients who use an alternative or complementary treatment should check with the manufacturer regarding whether the product contains estrogen or other hormones.
SYMPTOMS REFRACTORY TO HORMONE THERAPY — Given the proven success of estrogen therapy, treatment failure warrants evaluation for other etiologies of the patient's symptoms. Prior to proceeding with further evaluation, compliance with therapy should be confirmed. In addition to reviewing the treatment plan with the patient, an additional option is to check a vaginal maturation index and pH to assess for adequate response to hormonal treatment. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis", section on 'Laboratory evaluation'.)
Evaluate for other etiologies — Vulvovaginal pain, dyspareunia, urinary incontinence, dysuria, or urinary frequency are associated with GSM and may also be associated with vulvodynia, pelvic floor dysfunction, or bladder pain syndrome. Patients should be evaluated for these conditions and receive appropriate therapy. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)
A common clinical scenario is continued vulvovaginal discomfort and/or dyspareunia due to co-occurrence of GSM and vulvodynia. The vulvodynia may not have been suspected during the initial evaluation, but once the atrophy is managed, pain may continue from the vulvodynia.
These conditions are discussed in detail separately. (See "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis" and "Myofascial pelvic pain syndrome in females: Clinical manifestations and diagnosis" and "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis".)
Pelvic physical therapy — Pelvic physical therapy is a component of therapy in many pelvic pain syndromes and also for urinary incontinence and pelvic organ prolapse. Patients with GSM who do not respond to other therapies or who have contraindications to hormone therapy should be referred for evaluation and treatment by a pelvic physical therapist. Levator spasm often occurs after dyspareunia and can be improved with pelvic floor therapy and/or vaginal dilators after atrophy has been treated.
Vaginal dilators — Vaginal dilators are a component of pelvic physical therapy. This may be particularly effective for patients who avoid intercourse due to pain since vaginal dilators are available in sets of graduated sizes and a narrow dilator can be used initially. Vaginal dilator use can be taught to patients by their clinician, or they can be referred to a pelvic physical therapist.
In our practice, we use vaginal dilators for patients with introital stenosis or vaginal shortening/stenosis. Dilators may also be helpful for patients with GSM who have contraindications to estrogen therapy and have failed moisturizers and lubricants. Some data suggest that dilators improve vaginal function [120]. However, in patients with vaginal atrophy, dilators are likely to be more effective after hormonal treatment as elasticity within the vaginal and introitus improve.
SPECIAL CONSIDERATIONS
Asymptomatic patients — Treatment of asymptomatic patients for vaginal atrophy is indicated in some clinical contexts, including:
●Prior to vulvovaginal surgery – Systemic or vaginal estrogen therapy is given with the goal of optimizing the identification of tissue planes and promoting wound healing. There are few data regarding this use, and it is employed depending upon surgeon preference [121,122].
●Pelvic organ prolapse or urinary incontinence – Some clinicians treat patients with symptomatic pelvic organ prolapse or urinary incontinence with estrogen therapy, although the benefit of this approach is uncertain. However, when pessary use is employed in the management of these conditions, estrogen therapy is beneficial to prevent vaginal abrasions caused by the pessary. (See "Pelvic organ prolapse in females: Epidemiology, risk factors, clinical manifestations, and management", section on 'Estrogen therapy'.)
●The menopausal patient who is currently sexually inactive and is planning to become sexually active – Patients who have never had vaginal intercourse or have not been sexually active for some time may ask what they can do to be sure it is pleasurable for them, as they are planning to commence/resume sexual relations with vaginal penetration. If there is significant vaginal atrophy on pelvic examination such that speculum insertion or digital insertion is painful, treatment should be offered before the patient engages in vaginal intercourse.
●Worsening examination findings – Asymptomatic patients with evidence of worsening vulvovaginal atrophy (VVA) on examination should be informed of these findings and preventive measures should be offered to prevent future issues (eg, recurrent vaginitis, urinary tract infection, painful intercourse).
Patients with severe anatomic changes — Hypoestrogenism may cause moderate to severe anatomic changes in the vulva and vagina. These may include labia majora agglutination, introital narrowing, vaginal shortening or stenosis, and changes in the vaginal vault (cervix becomes flush with the vagina, fornices are obliterated).
Patients with abnormal findings on examination should be carefully examined for lesions that raise suspicion of a vulvovaginal dermatosis or malignancy, which can also cause anatomic distortion. The patient should be asked about postmenopausal bleeding and evaluated, as appropriate. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers" and "Approach to the patient with postmenopausal uterine bleeding".)
For patients with severe atrophic changes on examination, the first aspect of care is to ask the patient about symptoms and goals. If the patient is asymptomatic and reports no need for correction, treatment is not necessary unless urinary flow is impeded.
Labial agglutination — For patients with labial agglutination who are symptomatic or who want to resume sexual activity with vaginal penetration, first-line therapy is to treat with vaginal estrogen cream for four to six weeks (using a typical regimen of daily for two weeks followed by twice weekly). The patient should be instructed to apply the vaginal estrogen to the area of agglutination and also to apply gentle digital pressure. However, in cases in which a plane cannot be easily created by gentle digital pressure, surgical management with lysis of adhesions is an option and should be performed by a gynecologic surgeon experienced with this procedure.
Vaginal narrowing or shortening — For patients with symptomatic introital narrowing and/or vaginal shortening or stenosis, first-line therapy is vaginal estrogen therapy and use of graduated vaginal dilators; an expanding dilator may also be used (eg, Milli). Estrogen cream may be applied to the dilator. If there is no improvement in four to six weeks, surgical options should be discussed with the patient, and surgery should be performed only be a gynecologic surgeon experienced with surgical treatment of this issue [123]. (See 'Vaginal dilators' above.)
Patients with breast cancer — Symptoms of GSM are highly prevalent in breast cancer survivors because of the use of antiestrogen cancer therapies and the onset of treatment-related menopause. As an example, a study of 97 patients with breast cancer reported moderate or severe symptoms of vaginal atrophy in 58 percent of patients on aromatase inhibitors and 32 percent of those on tamoxifen [124].
●Irrespective of breast cancer treatment, for patients with breast cancer with GSM symptoms, nonhormonal options (eg, lubricants, moisturizers) are first-line therapy [18,125,126] (see 'Initial therapy with moisturizers and lubricants' above). In one single-arm prospective study including 101 postmenopausal patients with hormone receptor-positive cancer, treatment with a vaginal moisturizer (Hyalo GYN) for 12 weeks improved vulvar and vaginal symptoms in 88 and 92 percent of patients, respectively; more frequent dosing (three to five versus one to two times per week) may be required compared with postmenopausal patients without cancer [126].
When subsequent-line therapy is needed, decisions regarding treatment are guided by the type of breast cancer treatment the patient is receiving. In general, there are insufficient data regarding the safety of hormonal therapy for the treatment of GSM in females with breast cancer [10].
●For patients with breast cancer treated with selective estrogen receptor modulators, patients who have completed a full course of adjuvant endocrine therapy, or for those with hormone receptor negative disease:
•Low-dose vaginal estrogen or vaginal dehydroepiandrosterone (DHEA; prasterone) are likely reasonable subsequent-line choices if symptoms do not improve with nonhormonal treatments. In a retrospective study based on a Danish national cohort enrolled between 1997 and 2004, postmenopausal patients with early stage (nonmetastatic) invasive estrogen receptor-positive (ER+) breast cancer were followed until a first event (eg, breast cancer recurrence, diagnosis of a secondary malignancy, death) or a maximum of 10 years [127]. Data from a national prescription registry were used to identify those taking vaginal and/or systemic hormone therapy; those using such medications within two years of enrollment were excluded from the analysis. Of the 2007 patients with breast cancer treated with tamoxifen therapy, those receiving vaginal estrogen (17 percent) compared with no vaginal estrogen had similar rates of breast cancer recurrence during the 9.8 years (median) of follow-up; vaginal estrogen was not associated with an increase in mortality. (See 'Vaginal estrogen therapy' above and 'Dehydroepiandrosterone (prasterone)' above.)
•However, these medications should be initiated only after consultation with the patient's oncologist and after comprehensive counseling of the patient about potential risks. Limited data suggest that breast cancer survivors derive the same type of benefits as other patients when treated with intravaginal estrogen products. Furthermore, use of low-dose vaginal estrogen therapy has not been found to be associated with an increased risk of breast cancer recurrence [128,129]. However, studies have shown that there can be low levels of systemic absorption of estrogens in breast cancer survivors using intravaginal estrogens, which may decline as the GSM resolves [128,129].
Effects of systemic hormone replacement in breast cancer survivors is discussed elsewhere. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Personal history of breast cancer'.)
●For patients with breast cancer treated with aromatase inhibitors (AIs):
•For most patients, we suggest not using vaginal estrogen, DHEA (prasterone), or testosterone. However, for patients with marked symptoms of GSM, and who are willing to accept that vaginal hormonal therapy may limit the effectiveness of their cancer treatment, short-term exposures are unlikely to affect long-term cancer outcomes. For such patients, low-dose vaginal estrogen or prasterone is reasonable. Alternatively, some oncologists may switch treatment from AI therapy to tamoxifen, depending upon the risk features of the cancer and patient preferences, because of the lower risk of developing GSM.
The rationale for caution with vaginal hormones is that the aim of AI therapy is to maximally reduce serum estrogen levels, which may be slightly increased with topical hormones. However, we recognize that data are limited and that survival outcomes and recurrence rates among patients on AIs and topical hormone preparations are not available [130].
-There are limited data regarding the use of vaginal estrogen therapy in patients with early hormone receptor-positive breast cancer receiving AI therapy [104,131]. In one randomized trial of 76 patients with early-stage breast cancer taking AIs, vaginal estrogen (in the form of the estradiol ring) resulted in transient elevations of serum estradiol levels (>10 pg/mL) in 11 percent of patients [104]. No patients had persistent elevation of serum estradiol levels. Vaginal atrophy and sexual interest and dysfunction improved in all patients.
In the same Danish retrospective study discussed above, of the 403 patients with breast cancer treated with AI therapy, those receiving vaginal estrogen (23 percent) compared with no vaginal estrogen had higher rates of breast cancer recurrence (adjusted hazard ratio [HR] 1.39, 95% CI 1.04-1.85) during the 9.8 years (median) of follow-up [127]. Vaginal estrogen was not associated with an increase in mortality, which was similar between groups. There are several limitations to this study, including that only a minority (4.8 percent) of patients were treated with AI therapy and these patients may have been at higher risk for recurrence compared with those chosen for tamoxifen (or no) therapy [132]. In addition, no data were available regarding the type or dose of vaginal estrogen used, which has decreased significantly over time (see 'Preparations: Cream, tablet, capsule, ring' above). Further studies are needed to assess the safety of low-dose vaginal estrogen in patients with breast cancer taking AIs.
-Vaginal testosterone therapy has also been evaluated based on the hypothesis that testosterone therapy should not increase serum estrogen levels [103,104,133,134]. However, in the randomized trial detailed above, vaginal testosterone resulted in both transient and persistent elevations of serum estradiol levels (12 percent of patients in both groups); vaginal atrophy and sexual interest and dysfunction improved in all patients [104].
-Vaginal DHEA therapy (prasterone) in patients with breast (97 percent) or gynecologic cancer was evaluated in a randomized trial of 464 postmenopausal patients, approximately 60 percent of whom were on AI therapy [135]. Participants received 12 weeks of treatment with either 3.25 mg DHEA, 6.5 mg DHEA, or nonhormonal vaginal moisturizer. Patient-rated severity of dryness or dyspareunia was similar across all three groups, although those on the higher dose of DHEA reported better sexual function as measured by the Female Sexual Function Index. Circulating DHEA-sulfate and testosterone levels were increased in the vaginal DHEA groups [136]. Estradiol was slightly increased with DHEA 6.5 mg/day (from an average of 3.6 pg/mL to 4 pg/mL) but not with 3.25 mg/day.
Other therapies have been proposed to treat GSM in breast cancer survivors. Use of estriol rather than estradiol has been suggested for patients with breast cancer since its metabolic clearance is more rapid [130]. Vaginal estriol preparations are available in many countries but not in the United States. However, while clearance is more rapid, if used in a manner in which serum levels are consistently elevated, estriol can act as a systemic estrogen; therefore, the same cautions as vaginal estradiol use are applied here.
Pilocarpine, a cholinergic agonist used to treat Sjögren syndrome, was investigated for this indication but was not found to improve vaginal dryness compared with placebo in a randomized trial of 201 patients [137].
Fractional CO2 laser therapy has also been studied in breast cancer survivors and may improve GSM symptoms [138]; however, the safety and efficacy of these devices remain uncertain, as discussed in detail above. (See 'Laser or radiofrequency devices' above.)
Patients with hereditary cancer syndromes — The management of GSM in patients with hereditary cancer syndromes (eg, breast cancer type 1 or 2 susceptibility genes [BRCA1 and BRCA2]) without a cancer diagnosis is discussed in detail separately. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Vaginal estrogen therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Menopause".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Vaginal dryness (The Basics)")
●Beyond the Basics topics (see "Patient education: Vaginal dryness (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical approach – Genitourinary syndrome of menopause (GSM) is defined as a collection of symptoms and signs (eg, dryness, burning, dyspareunia) related to a decrease in estrogen and other sex steroids. GSM affects the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. Clinicians should ask hypoestrogenic patients about these symptoms as many do not discuss them on their own. Management is guided by the patient's symptoms and goals. (See 'Clinical approach' above.)
●Initial therapy – For most patients with GSM, nonhormonal vaginal moisturizers and lubricants are the preferred approach to initial therapy. (See 'Initial therapy with moisturizers and lubricants' above.)
●Subsequent therapy for most patients – For most patients with GSM who are not adequately treated with vaginal moisturizers and lubricants, we suggest low-dose vaginal estrogen rather than dehydroepiandrosterone (DHEA; prasterone) or ospemifene (Grade 2C). (See 'Patients also on systemic hormone therapy' above.)
•Available vaginal estrogen preparations include conjugated estrogens (cream) and estradiol (cream, tablet, capsule, and ring) (table 1). In Europe and some other countries, estriol cream or suppositories are also available. All preparations are effective in relieving symptoms of vaginal atrophy. Systemic absorption, patient preference, convenience, and cost should guide the choice of preparation. (See 'Preparations: Cream, tablet, capsule, ring' above.)
•In our practice, we use cream for patients who have symptomatic external atrophy (eg, vulvar fissures) so that the cream may also be applied directly to these areas. When the vulvar atrophy improves, we switch to a vaginal insert or ring, depending on patient preference. For patients without external atrophy, we start with a vaginal insert and switch to the ring if long-term therapy is desired and if the patient is comfortable with use of the ring. (See 'Preparations: Cream, tablet, capsule, ring' above.)
●Alternative therapies for most patients
•For most patients with GSM who want to avoid using vaginal estrogen but have no contraindications to estrogen itself and no objections to vaginal therapy, vaginal DHEA (prasterone) is an option. One disadvantage is the frequent dosing schedule (daily as compared with twice weekly for vaginal estrogen). (See 'Dehydroepiandrosterone (prasterone)' above.)
•For most patients with GSM who cannot or prefer not to use a vaginal product, oral ospemifene is an option. Disadvantages of ospemifene include daily use and systemic side effects (eg, hot flashes, potential risk of thromboembolism). (See 'Ospemifene' above.)
•Some clinicians prescribe vaginal testosterone off-label for GSM. This is usually with the concurrent goal of treating low libido. (See 'Testosterone' above.)
●Subsequent therapy for patients with breast cancer – For patients with breast cancer in whom symptoms of GSM are not adequately managed with nonhormonal vaginal moisturizers and lubricants, management is guided by the type of breast cancer treatment the patient is receiving:
•For patients treated with selective estrogen receptor modulators, we suggest treatment with low-dose vaginal estrogen or vaginal DHEA (prasterone) (Grade 2C). These medications are not associated with an increased risk of breast cancer recurrence. (See 'Patients with breast cancer' above.)
•For most patients treated with aromatase inhibitors (AIs), we suggest not using vaginal estrogen, DHEA (prasterone), or testosterone (Grade 2C). However, for those patients with marked symptoms of GSM who are willing to accept that vaginal hormonal therapy may limit the effectiveness of their cancer treatment, low-dose vaginal estrogen or prasterone is reasonable. Alternatively, some oncologists may switch treatment from AI therapy to tamoxifen, depending on the risk features of the cancer and patient preferences, because of the lower risk of developing GSM. (See 'Patients with breast cancer' above.)
●Patients with refractory symptoms or severe anatomic changes – Patients with refractory symptoms of GSM or severe anatomic changes (eg, introital narrowing, vaginal shortening) may benefit from pelvic physical therapy and vaginal dilators. Some patients with severe anatomic changes require surgery. Laser and other energy-based devices have been marketed for treatment of vulvovaginal atrophy (VVA), but the safety and efficacy of these devices remain uncertain. (See 'Symptoms refractory to hormone therapy' above and 'Patients with severe anatomic changes' above and 'Laser or radiofrequency devices' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Santen, MD, who contributed to earlier versions of this topic review.
