Urinary manifestations of genitourinary syndrome of menopause: a review of the pathophysiology, clinical presentation, and management

Introduction

Genitourinary syndrome of menopause (GSM) encompasses a compilation of vulvovaginal, sexual, and lower urinary tract symptoms (LUTS) resulting from hypoestrogenism after menopause. In 2014, the North American Menopause Society (NAMS) opted to replace previous terms such as vulvovaginal atrophy, atrophic vaginitis, or urogenital atrophy with a more inclusive term that minimizes stigma and reflects the broader lower urinary tract involvement (1). Urinary symptoms include urgency, frequency, nocturia, dysuria, stress, and urgency urinary incontinence (UUI), as well as recurrent urinary tract infections (rUTIs) (2). Cross-sectional population-wide studies found 45–80% of post-menopausal women suffer from GSM, with up to 62% reporting moderate to severe symptoms and a significant impact on their quality of life (3-7). However, most studies focus on vaginal symptoms, including dryness, burning, and dyspareunia, and do not address the LUTS of GSM.

Despite the aging population and increasing prevalence, there is a lack of awareness of GSM. Among respondents of the VIVA survey, while nearly half of the women experienced vaginal symptoms, only 4% attributed these symptoms to GSM (6). In the REVEAL survey, while 56% of women discussed their vaginal symptoms with their health care provider, only 13% of conversations were initiated by the provider (8). Half of the survey responders assume their vaginal symptoms were a natural consequence of aging. Furthermore, only 9% of women recall receiving an official diagnosis of GSM. Among women who opted for treatment, over-the-counter moisturizers/lubricants were preferred due to safety concerns despite NAMS recommending vaginal estrogen (VE) for moderate to severe or refractory vaginal symptoms of GSM (5,9). In one study evaluating barriers to VE therapy, fear of side effects (38.4%), cost (13%), and inability to access medicine (5%) were cited (10). As of 2025, the United States Food and Drug Administration (FDA) announced the removal of all black box warnings related to estrogen products, which may diminish some of the unwarranted anxiety associated with VE.

The majority of studies evaluating GSM focus on vaginal symptoms and overlook the bother associated with LUTS of GSM. Our aim is to review contemporary data pertaining to the pathophysiology, clinical presentation, and treatment strategies of lower urinary tract manifestations of GSM.

Pathophysiology

The underlying cause of GSM is hypoestrogenism by physiological or iatrogenic menopause (Table 1). Given the common embryologic origins of the vagina, the urethra, the urinary bladder and the trigone, hypoestrogenism affects the lower urinary tract as well. In the vagina, estrogen receptors have been shown to decrease with menopause, but can return to premenopausal levels with exogenous estrogen replacement (11,12). Estrogen receptors have also been identified in the urethra, the bladder trigone, and the connective tissue surrounding the urethra (12).

Estrogens are vasoactive hormones that help increase blood flow through the release of endothelial mediators. In studies of oophorectomized rabbits, the urothelium demonstrates atrophy with significantly decreased blood flow to the mucosa and smooth muscle, with resulting hypoxia (13). Replacement of estrogen increased blood flow, angiogenesis, and vascular density, with recovery from tissue hypoxia.

Estrogen has also been shown to directly mediate epithelial cell turnover, with deficiency resulting in thinned urothelium, decreased glycogen concentrations, and decreased defenses against uropathogen colonization and invasion (14). Estrogen has also been shown to strengthen intercellular junctions of the urothelium, which is important in maintaining a superficial epithelial layer to reduce invasion of bacteria, notably Escherichia coli (15).

Atrophic urethral mucosa lacks collagen content and demonstrates reduction in vascular flow, decreased urethral pressure, decreased sensory threshold of the bladder, with decreased response to adrenergic stimulation, all of which are reversed with estrogen replacement (2,12). Changes in collagen and systemic collagenase activity in response to estrogen deficiency have been implicated in the pathogenesis of stress urinary incontinence (SUI) and urogenital prolapse (2). Mean maximal urethral pressures and maximal urethral closing pressures (MUCP) are significantly higher in pre-menopausal women compared with post-menopausal women, and correlated with circulating estrogen levels (16).

In a population-based cross-sectional analysis, low serum estrogen levels were associated with increased likelihood of UUI (17). Evidence suggests that estrogen directly affects detrusor muscle activity through the modification of muscarinic receptors, which are known therapeutic targets for the treatment of overactive bladder (OAB) symptoms (18). Increased estrogen leads to inhibition of extracellular calcium ion movement into muscle cells, resulting in reduced detrusor contractions (19). Several studies indicate that OAB symptoms improved when anti-muscarinic medication was combined with estrogen compared with antimuscarinic treatment alone (20,21).

Estrogen withdrawal triggers progressive changes in epithelial thickness, vascularity, and connective-tissue composition; the result is a decline in urethral closure pressure, increased epithelial permeability and heightened infection risk. In the vaginal wall, glycogen is converted to glucose, which is subsequently metabolized by Lactobacillus into lactic and acetic acid, thereby maintaining an acidic vaginal fluid (22). The loss of estrogen results in a decrease in Lactobacillus, an alkalinization of vaginal fluid to pH >5, favoring the growth of bacteria typically responsible for urinary tract infections (UTIs) and vaginal infections. It has been shown that various Lactobacillus species can inhibit Escherichia coli growth, which is the most common bacterial cause of UTIs in women of all ages (23). Furthermore, urinary microbiome diversity has also been associated with OAB symptoms, which overlaps with GSM. Studies of the urinary microbiome have identified differences between pre- and postmenopausal samples, with greater diversity of Lactobacillus species in premenopausal samples, and decreased Lactobacillus diversity accompanied by an increased contribution of uropathogens in postmenopausal urine samples (24). Another study comparing women with UUI compared to women without UUI demonstrated differences in the diversity and make-up of the urobiome (25). Women with UUI were older, heavier, and less likely to use estrogen therapy. Lactobacillus species were the most common in the urinary microbiome.

Progesterone receptors have also been identified in the human lower urogenital tract, although with variable concentration depending on location and hormonal status (26). Androgen receptors have also been isolated in the lower urinary tract. While conversion of testosterone to estrogen via aromatase may explain some effects of androgens on the genitourinary system, direct effects of testosterone have been noted, including regulation of mucin levels and nerve density in the vagina, volume of urethrovaginal tissue, and collagen turnover (27). Dehydroepiandrosterone (DHEA) is a sex steroid precursor produced by the adrenal gland that is converted to both androgens and estrogens, thus exerting effects on receptive urogenital structures (28).

In summary, hypoestrogenism as well as accompanying hormonal changes lead to both comprehensive structural and functional degradation, in conjunction with disruption of the local environment, leading to the urogenital symptoms and signs of GSM.

Diagnosis: clinical manifestations and physical exam

The diagnosis of GSM is mainly clinical. Typically, bothersome symptoms are present and accompany characteristic examination findings consistent with a hypoestrogenic state (9). The most common initial symptoms expressed are symptoms that render intimacy more difficult, such as vaginal dryness, pruritus, or burning, and a superficial dyspareunia that may even be accompanied by post-coital bleeding. On further questioning, patients often elicit urinary symptoms such as urinary frequency, urgency, nocturia, urinary incontinence (UI), dysuria, or increased frequency of UTIs. Systematic screening questions can increase the likelihood of diagnosis and treatment.

A thorough history of comorbidities, past and current treatments, and surgical interventions is crucial. Description of symptoms, timing of onset, associated symptoms such as discharge, skin lesions, or bleeding, aggravating and alleviating factors, and impact on quality of life should be established. Efforts should be made to distinguish GSM from other differential diagnoses (see Table 2). Symptoms presenting prior to the onset of menopause point toward an alternative diagnosis. Assessing and optimizing modifiable risk factors is important. Patients with diabetes mellitus have a significantly higher risk of UTIs; awareness of their glycemic control is crucial for optimizing management. Furthermore, patients taking sodium-glucose cotransporter-2 (SGLT2) inhibitors have an increased risk of vaginal candidiasis, which can mimic GSM symptoms (29).

In patients with a history of malignancy, knowledge of the type of cancer and hormonal receptor status, age of diagnosis, as well as current and prior treatment, are crucial for safe and optimal management of GSM symptoms. Urinary sequelae following radiation and chemotherapy treatments can mimic LUTS of GSM (30). Knowledge of comorbidities helps to determine whether further investigations are necessary to establish or exclude competing diagnoses.

Typical clinical signs of GSM on physical exam are listed in Table 3. Patients may express discomfort on exam, notably pain with speculum insertion, and may even bleed. This can be minimized by setting patient expectations, using the smallest possible speculum, a generous amount of lubricant, and introducing the speculum at a slow pace set by the patient. At times, just an inspection of the vulva and vaginal introitus is sufficient to assess for atrophic changes and exclude some dermatologic conditions such as lichen sclerosus. Introduction of a single lubricated gloved digit at a patient-set pace can help to exclude pelvic floor hypertonia, myofascial pain, and urethral diverticula. If physical examination is severely limited by pain or anxiety, a second attempt may be performed after the introduction of topical anesthesia or following ingestion of a low-dose oral anxiolytic.

Complementary investigations

No single test is diagnostic of GSM. Several tests, mostly for research purposes, can be used to support the diagnosis. The vaginal maturation index (VMI) is a cytological evaluation of the proportion of superficial and intermediate cells to parabasal epithelial cells (31). In response to estrogen, the superficial and intermediate epithelial cells increase in proportion. The VMI can be used to support the diagnosis of GSM and evaluate the response to treatment.

Vaginal pH is typically >5 in GSM. However, vaginal pH may be basic in the setting of bacterial vaginosis. A wet mount looking for clue cells or a vaginal culture may be useful to exclude a vaginal infection that requires alternative treatment.

With respect to LUTS of GSM, ancillary testing may include a urinalysis to rule out microscopic hematuria and alternative etiology with irritative symptoms, such as malignancy. A cystoscopy can be considered in patients with rUTIs unresponsive to prevention strategies, a history of prior anti-incontinence or prolapse repair, or positive screening for hematuria. Findings on cystoscopy consistent with a hypoestrogenic state include pale mucosa of the trigone and urethra, and shortening of the functional urethra. Bladder mucosal ulcerations, telangiectasia, erythema, papillary or polypoid lesions, foreign bodies, or shrunken fibrotic bladders are not consistent with GSM and an alternative diagnosis must be considered (30). A biopsy should be considered when the diagnosis is unclear. Assessing bladder capacity can be performed in patients with irritative symptoms such as urgency, frequency, and nocturia. An elevated post-void residual may help to identify patients with increased risk of rUTIs as well as OAB symptoms. Urodynamics do not contribute to the diagnosis of GSM, but may help in the management of comorbid urinary conditions, such as severe SUI or refractory OAB symptoms despite initial treatment.

Treatment options for GSM

Non-hormonal topical interventions (lubricants and moisturizers)

Vaginal moisturizers are gel products applied regularly and function by mimicking the natural vaginal secretions independent of sexual intercourse (32). Lubricants are water-, silicone-, or oil-based fluids that are used at the time of sexual activity to provide short-term relief of discomfort by minimizing friction (33). Both have been recommended to help manage mild vulvovaginal symptoms of GSM. Topical non-hormonal products include lactic-acid-based vaginal gel, hyaluronic acid gel, polyacrylic acid vaginal cream, and polycarbophil-based vaginal gel. Often, these products serve as controls/“placebo” to interventions such as estrogen in clinical trials, when in fact there is some medical benefit. In a systematic review published in 2014, 6 studies comparing VE to non-hormonal alternatives were included and concluded no difference between VE and non-hormonal moisturizers/lubricants in improving individual atrophic symptoms, including dysuria and urinary urgency (34). However, patients with two or more symptoms of GSM were significantly more relieved with VE.

One prospective observational study of 42 women with GSM and at least one urinary symptom who completed 12 weeks of polycarbophil-based cream treatment experienced significantly improved LUTS and quality of life at 12 weeks of follow-up (35). Compared to baseline, void volume was significantly increased from 246.93±156.06 to 298.87±148.11 mL (P=0.038).

Currently, vaginal moisturizers and lubricants are low-risk interventions recommended for the management of mild vulvovaginal symptoms and in women where estrogen is contraindicated (Table 4). Understanding of non-hormonal topicals in alleviating LUTS appears limited and necessitates further research.

Local VE therapy

Vaginal estrogen is generally considered the cornerstone of GSM treatment, given its efficacy in improving symptoms with minimal systemic absorption and adverse events. It is available in multiple formulations and delivery systems (see Table 5). According to a systematic review including 18 studies involving 2,236 patients, no differences in efficacy or safety were noted between various formulations of VE in the treatment of GSM (34).

Not only is VE effective in relieving vulvovaginal symptoms, but level I evidence suggests improvement in irritative voiding symptoms, including urgency, frequency, nocturia, and even UI. In a Cochrane review evaluating VE’s effect on the improvement of UI, when compared with placebo or no treatment, meta-analysis favored VE in the improvement of UI [relative risk (RR) 0.74, 95% confidence interval (CI): 0.57–0.95], number of voids per 24 hours [weighted mean difference (WMD) of −1.80, 95% CI: −2.58 to −1.03], and nocturnal voids (WMD −2.03, 95% CI: −2.82 to −1.24) (38). Local estrogen also improved urgency (RR 0.38, 95% CI: 0.15–0.99) and frequency (RR 0.43, 95% CI: 0.19–0.98). In 2 systematic reviews involving women with GSM comparing VE to placebo or no treatment, urinary manifestations were improved with VE (34,39).

In a randomized controlled trial (RCT) comparing low-dose estrogen-secreting vaginal ring (Estring^®) and oxybutynin 5 mg among 51 post-menopausal women with OAB for 12 weeks, there was no significant difference in reduction in number of voids per day (−4.5 voids and −3 voids per day, respectively; P=0.71), quality of life, or discontinuation rates (15%) between groups (40).

In another RCT, 80 postmenopausal women with OAB were randomized to tolterodine or tolterodine plus vaginal conjugated equine estrogen (CEE) for 12 weeks (41). Among women receiving combined treatment, there was a greater reduction in number of voids per 24 hours, increased mean voided volume, with greater subjective improvement in symptoms based on validated questionnaires compared to women receiving tolterodine alone. Both groups showed subjective improvement in nocturia, urgency, and UUI. However, in a similar trial comparing combined antimuscarinics and VE to antimuscarinics alone, both groups showed significant improvement in OAB symptoms and quality of life at 12-week follow-up, but no difference was noted between groups (20,42).

Few studies evaluate VE in the management of SUI in post-menopausal women. An RCT of 88 women with GSM and SUI demonstrated a 68% subjective improvement when treated with estriol 1 mg compared to 16% of women in the placebo arm after 6 months (P<0.01) (43). The MUCP was also significantly improved. When considering urodynamic parameters across two systematic reviews, MUCP, volume at first desire to void, and bladder capacity all increased with VE compared to placebo, while detrusor overactivity decreased (34,38).

The role of VE in UTI prevention is more established. Raz and Stamm’s pivotal RCT (1993) demonstrated a substantial reduction in UTI recurrence with intravaginal estriol compared with placebo (0.5 versus 5.9 UTI per person per year, P<0.001) (44). Subsequently, multiple RCTs have demonstrated reduced UTIs among post-menopausal women using VE compared to placebo or no treatment (45,46). In a large retrospective cohort study involving 5,638 women prescribed VE, there was a 51.9% reduction in UTIs in the first year since the index VE prescription relative to the year prior to the filled VE prescription (3.9 versus 1.8, P<0.001) (47). In a systematic review of 596 patients across 5 trials evaluating VE, all formulations demonstrated a significant reduction in UTIs compared to placebo or no treatment (48). When VE is compared with antibiotic use in UTI prevention, nitrofurantoin 100 mg daily was more effective than an estriol-containing vaginal pessary (0.5 mg) twice weekly in reducing UTIs (48 versus 124 UTIs, P=0.003) over 9 months (49). Women were more likely to remain UTI-free with nitrofurantoin (P=0.0004).

Safety of VE

Vaginal estrogen is systemically absorbed in a dose-dependent manner and depends on formulation and frequency of use (50). In general, systemic absorption of VE, when following the insert package instructions, does not surpass physiologic post-menopausal serum estrogen levels (estradiol <20 pg/mL). Levels tend to peak by 12-week use and then return to baseline, with the highest levels seen with vaginal creams (51). This may result from decreased absorption due to thickening of the vaginal epithelium in response to therapy.

Typical adverse effects of VE that may lead to discontinuation include vaginal bleeding, undesired vaginal discharge, candidiasis, burning on application, nausea, and breast tenderness (9).

Systemic hormone therapy (HT) is associated with increased risk of breast and endometrial cancer, venous thromboembolic (VTE) events, and cardiovascular disease. However, given the significantly lower levels of circulating estrogen with VE formulations, the risk profile appears to be minimal. Two systematic reviews have focused on adverse events from clinical trials and observational data of FDA-approved VE therapies (51,52). Among 20 RCTs involving 2,983 women followed for up to 1 year that reported endometrial histology data, 12 cases of endometrial hyperplasia (0.4%) and 1 case of endometrial cancer (0.03%) were found (52).

Observational studies have provided some long-term safety data. Among participants of the Women’s Health Initiative (WHI) with an intact uterus who took VE for a median 2-year duration, no increased risk of endometrial cancer (hazard ratio 1.47, 95% CI: 0.75–2.90) was noted compared to non-VE users (53). Several studies have confirmed similar results with longer-term VE use (54,55). However, an updated meta-analysis from 2016 found that VE creams were linked to slightly increased endometrial thickness relative to VE rings, but no difference was detected between creams and tablets; histology was not reported (56). Given the current safety profile, routine endometrial surveillance in low-risk asymptomatic patients using VE therapies for GSM is not recommended (9,57).

Given the increased risk of breast cancer in women on systemic therapy, concerns have been expressed over the risk of breast cancer in cancer-naïve patients (58). Among 4,210 VE users within the WHI observational study, with a median use duration of 3 years, no difference in risk of invasive breast cancer relative to non-VE users was found (53). In the same study, the risk of VTE, colorectal cancer, stroke, and death was similar between VE and non-VE users. Furthermore, relative to non-VE users, VE users had a lower risk of coronary heart disease and risk of hip fracture. Similar results were published from the Nurses’ Health Study (59). Overall, VE does not increase the risk of breast or other invasive cancers, VTEs, or cardiac events. To reflect the current safety evidence, the FDA recently changed its label warnings to minimize unnecessary anxiety relating to VE usage (60).

Based on current understanding of the pathophysiology of GSM, local estrogen improves superficial epithelial proliferation, increases vascularity, restores periurethral collagen, and maintains an acidic vaginal milieu that favors a non-pathogenic urogenital microbiome (61). These improvements lead to fewer UTIs, reduced urinary symptoms, and better quality of life, with an acceptable safety profile that does not require continued surveillance.

Systemic hormonal therapy

While local estrogen remains the mainstay of therapy in appropriate patients, the relationship between systemic HT and urinary symptoms remains complex. Despite decades of controversy, HT in the form of oral or transdermal estrogen (E), without or with progesterone (E+P) therapy based on the absence or presence of a uterus, is currently available for the management of moderate to severe vasomotor symptoms in eligible candidates (62). Multiple large prospective epidemiologic studies have evaluated the effect of systemic HT on cardiovascular health. The relationship between HT and urinary symptoms has been evaluated in several post hoc analyses.

A post hoc analysis of the Nurses’ Health Study found that the risk of UI among women taking HT was greater regardless of route, type of hormone, or dose used (63). Interestingly, 10 years following discontinuation, incidence matched those never on hormone use. A sub-analysis of the Heart and Estrogen/Progestin Replacement Study (HERS) found an increased risk of weekly UUI [odds ratio (OR) 1.5, 95% CI: 1.2–1.8; P<0.001] and weekly SUI (OR 1.7, 95% CI: 1.5–2.1; P<0.001) with E+P compared with placebo (64). A sub-analysis of over 25,000 participants of the WHI spanning all three treatment arms (E only, E+P, placebo) and noted that HT, regardless of type, increased the risk of all UI in previously continent women (65). When specific UI types were evaluated, E alone increased risk of SUI [RR 2.15 (95% CI: 1.77–2.62)] and UUI [RR 1.32 (95% CI: 1.10–1.58)], while E+P had no effect on UUI and worsened SUI. Women with baseline UI experienced worsening frequency and severity of incontinence episodes. Similar findings were published in a meta-analysis evaluating the effects of estrogen on UI of over 19,000 women (38).

Nocturia also worsened among women taking systemic HT [mean difference 1.08 (95% CI: 0.48–1.68, 2 series, N=70, P=0.0004)] (66). In a Cochrane review from 2008, oral estrogen was not better than placebo at preventing rUTIs in postmenopausal women (RR 1.08, 95% CI: 0.88–1.33, 4 studies, N=2,798) (67).

Animal studies have noted that systemic administration of estrogen alters muscarinic receptors in the body and midsection of the bladder, but sparing the trigone and urethra (68). Furthermore, it has been shown to increase smooth muscle to collagen ratios, increasing detrusor contractility and also affecting peri-urethral tissue quality, which may potentiate OAB and SUI symptoms (69,70). While it is unclear why systemic action differs from local effects of estrogen therapy, current evidence suggests a deleterious impact of systemic HT on LUTS in GSM. Currently, NAMS supports the use of systemic HT only when moderate to severe vasomotor symptoms are present.

Ospemifene

Ospemifene is a selective estrogen receptor modulator (SERM) with agonist action on the vaginal epithelium and bone, as well as partial agonistic effect on the endometrium; it has an antagonistic effect on breast tissue (71). It is currently the only oral treatment for GSM available in the United States and Europe. At present, level 1 evidence exists that ospemifene 60 mg per day improves vulvovaginal symptoms related to GSM, notably dyspareunia and vaginal dryness (72). However, less is known about its effects on urinary symptoms of GSM.

One study of 39 women with GSM and rUTIs taking ospemifene for 6 months demonstrated a significant reduction in positive culture episodes (3.65±2.12 vs. 0.25±0.17, P<0.0001) and symptomatic UTIs (4.76±2.45 vs. 0.89±1.12, P<0.0001) (73). Several small studies evaluated the impact of ospemifene on OAB symptoms and noted improvements after 12 weeks of treatment as assessed by validated questionnaires and bladder diary episodes (74,75). Urodynamic parameters were also improved (76). In menopausal women with mixed UI who were treated with trans-obturator tape (TOT) mid-urethral slings, ospemifene treatment resulted in significant improvement in cystometric bladder capacity, increased capacity at first desire, peak urinary flow, a decrease in detrusor pressure at peak flow, and a decrease in detrusor overactivity relative to TOT alone (77). Urgency, frequency, and UUI daily episodes decreased significantly, while OAB-related quality of life improved. Currently, no studies address the effects of ospemifene on SUI. Ospemifene may be offered to women with irritative symptoms related to GSM (78).

In 180 women taking ospemifene for >52 weeks, there were no cases of VTE, endometrial hyperplasia, or endometrial cancer, and thus no routine surveillance is recommended in women taking ospemifene (79). Current recommendations discourage use of ospemifene in women with known or suspected breast cancer, but this is based on inadequate evidence (9). Preliminary preclinical data suggest ospemifene has an inhibitory effect on breast tissue.

Intravaginal DHEA

Intravaginal DHEA, known as prasterone, is converted intracellularly into estrogens and androgens. Prior studies have demonstrated the efficacy of prasterone in treating vaginal symptoms of GSM through the improvement of the VMI, vaginal pH levels, vaginal dryness, and epithelial thickness (80,81). In 2016, the FDA approved prasterone 6.5 mg (Intrarosa^®) for the treatment of dyspareunia related to GSM. However, fewer studies evaluate its effect on LUTS related to GSM. In post-menopausal women with GSM and OAB symptoms, prasterone demonstrated improvement in OAB symptoms after 12 weeks (82). When compared with hyaluronic acid, nearly 90% of women treated with prasterone expressed significant improvement in their UUI symptoms (versus 10%) at 12-week follow-up (83). In women without urodynamic detrusor overactivity treated with prasterone for 12 weeks, patients showed significant improvement in symptoms, quality of life, and frequency of daily incontinence and nocturia episodes based on bladder diaries (84). In a prospective observational study of 34 postmenopausal women with GSM and SUI treated with prasterone for 12 weeks, quality of life, SUI episodes, and pelvic muscle tone were significantly improved (85).

Prasterone has also shown promise in preventing UTIs among women with GSM. In a large population-based study of women >45 years of age with a diagnosis of GSM, prasterone treatment was associated with a lower prevalence of UTIs across all age groups (86).

At present, intravaginal prasterone is recommended for the treatment of moderate to severe dyspareunia with GSM, but may improve OAB symptoms, SUI and reduce incidence of UTIs. Patients should be reassured that there is no increased risk of breast cancer or endometrial cancer, nor do they require particular surveillance while taking intravaginal DHEA (33). However, patients should be counseled that they may experience increased facial hair, voice changes, and headaches.

Vaginal energy-based devices (VEBD)

Though numerous VEBD exist, the three main technologies that have been studied within the context of treating GSM include the fractional micro-ablative CO₂ laser, the non-ablative Er:YAG laser, and RF treatment. These devices are thought to cause microtrauma, stimulating collagen production, angiogenesis, and epithelial thickening. In 2018, the FDA issued a warning regarding the use of vaginal lasers for “vaginal rejuvenation”, stating that efficacy and safety have yet to be established (87). Consensus based on currently available data suggests there is short-term (<12 months) promise in the treatment of vulvovaginal symptoms of GSM with VEBDs, but not necessarily more efficacious than VE (33,88-90). However, data regarding the use of VEBDs in the management of LUTS in GSM is limited. Several RCTs have compared VEBDs to sham devices after short-term follow-up, with the majority finding no significant difference between treatment and sham groups when assessing LUTS using visual analog scales (VAS) and validated questionnaires (91-95). Longer-term data regarding VEBDs on urinary symptoms of GSM is scarce.

Several RCTs have evaluated VEBDs compared with other treatments. The VeLVET trial compared CO₂ laser to VE in women with GSM, and found that at 6 months following treatment, there was no difference in LUTS between groups (96). Adverse events were mild and did not differ between groups; VE tended to induce more systemic effects such as breast tenderness, migraine, or abdominal cramping, while laser was associated with local adverse events such as vaginal pain, discharge, and UTI. Rates of vaginal bleeding were similar. Aguiar et al. compared CO₂ laser to vaginal promestriene or vaginal lubricant in post-menopausal women, with primary outcome being SUI and OAB symptoms following treatment (97). Post-treatment total SUI-related scores between groups did not differ at 14-week follow-up (P=0.116). When comparing OAB symptoms, CO₂ laser was superior to lubricant (P=0.02) but did not differ from promestriene. Nocturia was significantly improved among women treated with CO₂ laser compared to other interventions (P=0.004).

Fewer studies have evaluated the effect of vaginal Er:YAG laser on LUTS of GSM. One study compared women treated with laser to vaginal estriol gel and found a significant improvement in SUI symptoms from baseline among women treated with laser (98). However, no comparison was offered between the laser and the estriol group. Long-term follow-up found that Er:YAG treatment provided sustained SUI symptom improvement for at least 12 months, but symptoms were not different from baseline at 18 and 24 months (99). In a randomized sham-controlled study, post-menopausal women who underwent laser treatment had improved total Overactive Bladder Symptom Score, improved nocturia, and improved urgency compared with sham controls at 12 weeks post-therapy (100). One RCT in post-menopausal women with rUTIs randomized to either local VE or Er:YAG laser for 12 weeks showed no difference in UTI rates between groups (101).

Studies evaluating radiofrequency (RF) ablation for the treatment of GSM are underway. In a three-arm RCT comparing CO₂ laser to RF and sham-control, women with mild SUI were treated with three monthly sessions and followed every 6 months for up to 4 years (102). The CO₂ laser and RF treatments resulted in over 50% of women being completely continent with mean durations of 26.7 and 24.6 months, respectively, relative to control (8.2 months). The study population was not exclusive to post-menopausal women, however the mean age was 50.4±9.5 years, so the majority were likely already perimenopausal at the time of treatment. In another sham-controlled RCT, women who underwent behavioral therapy for the management of OAB were randomized to RF or sham, with no differences between groups following treatment (103).

One meta-analysis evaluating the efficacy of laser treatment in women with GSM demonstrated that vaginal laser therapy improved dysuria (mean difference −2.9, 95% CI: −5.1 to −0.7, 4 studies, N=185) and UI (mean difference −4.9, 95% CI: −6.4 to −3.4, 2 studies, N=54) at one month following treatment completion (104). Another reported significant improvement in urinary symptoms with CO₂ laser relative to controls (standard difference in means 0.51, 95% CI: 0.23 to 0.78, N=173, P<0.001) (105). A meta-analysis of RCTs comparing fractionated CO₂ laser to VE found no significant difference in urinary symptoms (106). However, findings were based on two studies, one of which is the VeLVET RCT discussed above. In a meta-analysis including randomized and non-randomized studies, a significant improvement in dysuria at 1-month follow-up after CO₂ laser [mean difference −2.14, 95% CI: −3.41 to −0.87, 7 studies, N=281, P<0.001] was found (107). In a Bayesian network analysis of 29 studies evaluating various therapies targeting GSM, laser was found to be the most effective treatment option for UI, with local estrogen therapy ranking second (108).

Data on the adverse effects of VEBDs is limited to small relatively short-term studies (<12 months) (33,90). While rare severe events such as burns and scarring have been reported, commonly encountered adverse effects include vaginal discharge, vaginal bleeding, local discomfort or pain, dysuria, vaginal infection, UTIs, dyspareunia, local inflammation (edema and erythema), vaginal itching (107). Studies generally show low discontinuation rates due to adverse events in the short and medium term (90).

At present, VEBDs are not approved by the FDA for the treatment of GSM given the lack of proven superiority over sham and standard treatment options, as well as a paucity of long-term safety and efficacy. Currently, VEBDs are considered experimental and most practical guidelines from expert societies recommend that VEBD use be limited to well-monitored research protocols (33,90,109-112).

Patients with high risk or history of gynecologic cancers

Breast cancer

While low-dose VE is contraindicated in breast cancer survivors according to the FDA, both NAMS and American College of Obstetricians and Gynecologists (ACOG) recommend shared decision making that involves the oncologist to determine whether women suffering from GSM may benefit from VE (9,57,113). One large cohort study of 49,237 women with breast cancer found a slight decrease in breast cancer-specific mortality among VE users compared with non-users (HR 0.77, 95% CI: 0.63–0.94), and this remained the case in long-term users (114). Furthermore, no increased risks were observed among estrogen receptor-positive breast cancer, or with aromatase inhibitor and/or tamoxifen and concurrent VE use (114,115). In a meta-analysis of 8 studies evaluating VE use among breast cancer survivors, the risk of recurrence was lower among VE users (OR 0.48, 95% CI: 0.23–0.98, P=0.04) (116). There was no significant difference in breast cancer-specific mortality and all-cause mortality was lower among VE users (OR 0.46, 95% CI: 0.42–0.49, P<0.01). Overall, the current evidence regarding VE use in women with current or prior breast cancer is reassuring; low-dose VE can be considered in a shared-decision-making fashion when GSM symptoms are refractory to non-hormonal options. Currently, ultra-low-dose VE formulations (4 and 10 µg inserts) are available in the United States and Canada, which may be used off-label to optimize the risk-benefit balance in this unique population.

Gynecologic cancers (ovarian, endometrial, cervical, vulvar, vaginal)

In one retrospective study of 185 women with breast and gynecologic cancers receiving either vaginal estriol, vaginal DHEA (prasterone), or ospemifene, there was no cancer recurrence after 6 months of follow-up, and no increased endometrial thickness among any treatment groups compared with baseline (117). Estrogen therapy in endometrial and ovarian cancers is limited, but extrapolating from systemic HT data, there does not seem to be an increased risk of recurrence or mortality, and it appears to be a safe option for the treatment of LUTS of GSM when non-hormonal options fail (118-120). Most cervical, vaginal and vulvar cancers are not considered hormonally active, thus use of VE should pose little to no additional risk.

Cost of treatment and economic implications

Given the prevalence of the GSM, cost of management can be quite expensive. A recent study showed that the cost and insurance coverage of VE formulations in the United States were inconsistent and expensive, despite multiple generic options; the median cost was > $44/month or over $528/year, while the VE ring (Estring^®) cost more than $300/month among some insurance providers (36). Ospemifene, the only oral alternative, costs ~$160/month. Laser treatments vary by state, ranging from $1,950 to $3,000 for three-treatment series (37). Ultimately, there is a huge cost associated with symptom management of GSM, which can be prohibitive for many patients. In a recent cost-savings analysis regarding the use of VE in UTI prevention among post-menopausal women, it was estimated that relative to no prevention, Medicare spending may be reduced by $3,670 to $5,499 per person per year with use of topical estrogen (121). These findings should incentivize governing bodies to reduce the cost and increase the accessibility of VE as a cost-saving intervention for post-menopausal women suffering from rUTI among other GSM-related symptoms.

Strengths and limitations

While most reviews tend to highlight vulvovaginal and sexual symptoms, this article maintains a focus on a less-discussed and complex component of GSM – urinary manifestations. Another strength is the broad nature of the review with a focus on up-to-date evidence. The article strives to be clinically relevant, providing practical information regarding patient evaluation, management options, and economic implications, including cost. Limitations of this review include the lack of rigid methodology seen in systematic reviews, allowing for potential bias, and its relatively American-centric focus.

Conclusions

Urinary manifestations constitute a fundamental dimension of GSM. Estrogen deficiency induces epithelial atrophy, diminished vascular density, collagen disorganization, and microbial imbalance, culminating in LUTS and rUTIs. Despite its prevalence, GSM remains underdiagnosed and undertreated, possibly due to a lack of screening, unfamiliarity with therapeutic options, or treatment cost.

Robust level I evidence supports local VE as an effective and safe therapy across low and high-risk populations and is considered the gold standard for the treatment of GSM-related symptoms, whether urinary or vulvovaginal. Guidelines uniformly endorse VE as first-line treatment. Ospemifene and vaginal DHEA are also evidence-based effective alternatives that may improve LUTS of GSM, while energy-based devices are considered experimental. Not only does treating GSM improve women’s quality of life, but there is an economic incentive to help prevent rUTIs and reduce already astronomical healthcare costs. Ultimately, optimizing urinary health in post-menopausal women demands interdisciplinary collaboration and evidence-based, individualized care.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-79/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-79/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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