# Genitourinary Syndrome of Menopause

## Introduction

Genitourinary syndrome of menopause (GSM), formerly termed vulvovaginal atrophy or atrophic vaginitis, encompasses the chronic, progressive changes in the vulvar, vaginal, and lower urinary tract tissues attributable to estrogen deficiency. GSM affects up to 50 to 70% of postmenopausal women, yet remains significantly underdiagnosed and undertreated. Unlike vasomotor symptoms, GSM does not resolve spontaneously and typically worsens without treatment.

## Pathophysiology

Estrogen receptors (ER-alpha and ER-beta) are densely distributed throughout the vulvar, vaginal, urethral, and bladder trigone epithelia. Estrogen withdrawal leads to reduced collagen content, diminished elastin fibers, thinning of the vaginal epithelium from 20 to 30 cell layers to 3 to 4 layers, and loss of rugae. The vaginal pH rises from the premenopausal range of 3.5 to 4.5 to a postmenopausal range of 5.0 to 7.0 due to decreased glycogen production and loss of Lactobacillus-dominant flora. Reduced submucosal blood flow leads to decreased transudate-based lubrication. In the lower urinary tract, urethral mucosal thinning, loss of urethral coaptation, and reduced periurethral vascularity contribute to urinary symptoms. GSM is progressive and irreversible without treatment -- unlike vasomotor symptoms, which may self-resolve, GSM worsens over time.

## Clinical Presentation

### Vulvovaginal Symptoms

Vaginal dryness is the most common symptom, reported by 55 to 75% of postmenopausal women. Dyspareunia manifests as superficial pain with intercourse due to reduced lubrication and tissue fragility and may lead to avoidance of sexual activity. Vulvar irritation, burning, and pruritus are common and are often exacerbated by contact irritants. Vaginal discharge may be thin, watery, and occasionally blood-tinged due to epithelial fragility. Reduced vaginal caliber and elasticity result in introital narrowing and foreshortening of the vaginal canal.

### Urinary Symptoms

Urgency, frequency, and nocturia are related to urethral and trigonal atrophy. Recurrent urinary tract infections increase in frequency because loss of Lactobacillus colonization and elevated pH facilitate uropathogen colonization, with incidence increasing 2 to 4 fold after menopause. Stress urinary incontinence results from urethral mucosal thinning, which reduces the coaptive seal. Dysuria from urethral mucosal atrophy causes burning with urination in the absence of infection.

<image>Cross-sectional histologic comparison of premenopausal and postmenopausal vaginal epithelium showing the reduction from thick stratified squamous epithelium with glycogen-rich superficial cells to thin atrophic epithelium with predominantly parabasal cells, along with decreased submucosal vascularity and collagen changes</image>

## Diagnosis

### Clinical Assessment

The history should include directed questions about vaginal dryness, dyspareunia, and urinary symptoms, as many women do not volunteer these symptoms without direct inquiry. Physical examination findings include pale, thin, dry vaginal mucosa, loss of rugae, petechiae, introital narrowing, labial fusion, loss of labia minora volume, and urethral caruncle or prolapse. Vaginal pH above 5.0 supports the diagnosis in the absence of infection or recent intercourse. The vaginal maturation index, which is a microscopic assessment of vaginal epithelial cells showing predominance of parabasal cells indicating atrophy, is not routinely performed but is useful in research settings.

### Differential Diagnosis

The differential diagnosis includes vulvar dermatoses (lichen sclerosus, lichen planus, contact dermatitis), vulvovaginal infections (candidiasis, bacterial vaginosis, trichomoniasis), vulvar malignancy (any suspicious lesion should be biopsied), and desquamative inflammatory vaginitis (purulent discharge, elevated pH, parabasal cells on wet mount, which may respond to intravaginal clindamycin or hydrocortisone).

## Treatment

### Non-Hormonal First-Line Options

Vaginal moisturizers, either polycarbophil-based (Replens) or hyaluronic acid-based products, are applied 2 to 3 times weekly to maintain tissue hydration and do not require a prescription. Lubricants, whether water-based, silicone-based, or oil-based, are used during sexual activity. Silicone-based products last longer, and glycerin-containing products should be avoided as they may promote yeast. Regular sexual activity maintains vaginal blood flow and elasticity and correlates with reduced symptom severity. Pelvic floor physical therapy can address coexisting pelvic floor dysfunction and dyspareunia.

### Low-Dose Vaginal Estrogen

Low-dose vaginal estrogen is the first-line pharmacologic therapy for moderate-to-severe GSM symptoms. Available formulations include vaginal estradiol tablets (Vagifem/Yuvafem) at 10 mcg inserted nightly for 2 weeks then twice weekly, vaginal estradiol cream (Estrace) at 0.5 to 1 g inserted nightly for 2 weeks then 1 to 3 times weekly, the vaginal estradiol ring (Estring) which delivers 7.5 mcg per day and is replaced every 90 days, conjugated estrogen cream (Premarin) at 0.5 to 1 g nightly for 2 weeks then 1 to 3 times weekly, and the vaginal estradiol softgel insert (Imvexxy) at 4 mcg or 10 mcg inserted nightly for 2 weeks then twice weekly.

| Formulation | Brand | Dose | Induction | Maintenance |
|---|---|---|---|---|
| Vaginal estradiol tablet | Vagifem/Yuvafem | 10 mcg | Nightly x 2 weeks | Twice weekly |
| Vaginal estradiol cream | Estrace | 0.5-1 g | Nightly x 2 weeks | 1-3 times weekly |
| Vaginal estradiol ring | Estring | 7.5 mcg/day | Continuous | Replace every 90 days |
| Conjugated estrogen cream | Premarin | 0.5-1 g | Nightly x 2 weeks | 1-3 times weekly |
| Vaginal estradiol insert | Imvexxy | 4 or 10 mcg | Nightly x 2 weeks | Twice weekly |
| Vaginal DHEA | Intrarosa | 6.5 mg | Nightly | Nightly (continuous) |
| Oral SERM (ospemifene) | Osphena | 60 mg PO daily | Daily | Daily (continuous)  |  Systemic absorption with low-dose formulations is minimal, and serum estradiol remains within the postmenopausal range. Progestogen is not routinely required with low-dose vaginal estrogen per NAMS, ACOG, and the Endocrine Society, though data beyond 1 year are limited, and endometrial monitoring should be considered with higher doses or prolonged use. Efficacy is excellent: vaginal estrogen improves all GSM symptoms, restores vaginal pH to premenopausal levels, and increases epithelial thickness within 3 to 6 weeks. |

### Vaginal DHEA (Prasterone)

Intravaginal DHEA 6.5 mg (Intrarosa) is inserted nightly. It works through local conversion to estrogen and testosterone by vaginal tissue intracrinology. It improves vaginal dryness, dyspareunia, and vaginal pH and is FDA-approved for moderate-to-severe dyspareunia due to GSM. Serum estrogen and testosterone levels remain within the postmenopausal range.

### Ospemifene

Ospemifene 60 mg (Osphena) is an oral selective estrogen receptor modulator (SERM) taken daily. It has an estrogen agonist effect on vaginal tissue, improving the vaginal maturation index and reducing dyspareunia. It is indicated for moderate-to-severe dyspareunia due to GSM in women who prefer an oral therapy. Contraindications include history of VTE, endometrial cancer, or undiagnosed vaginal bleeding, and caution is advised in women at high VTE risk. The stimulatory effect on the endometrium is minimal, but monitoring may be indicated with prolonged use.

<image>Comparison infographic of GSM treatment options arranged by invasiveness showing non-hormonal options (moisturizers, lubricants), low-dose local estrogen formulations (cream, tablet, ring, insert), vaginal DHEA, oral SERM, and vaginal laser therapy, with efficacy ratings and key considerations for each</image>

## GSM and Recurrent UTIs

Vaginal estrogen reduces recurrent UTI frequency by approximately 50% in postmenopausal women. The mechanism involves restoration of Lactobacillus colonization, lowering of vaginal pH, and reduced E. coli adherence to the vaginal epithelium. ACOG and AUA guidelines recommend vaginal estrogen as prophylaxis for recurrent UTIs in postmenopausal women. It can be combined with other preventive strategies such as cranberry supplements, D-mannose, and methenamine hippurate.

## Special Populations

### Breast Cancer Survivors

Vaginal estrogen in breast cancer survivors remains controversial. Non-hormonal options should be tried first. Low-dose vaginal estradiol at 4 to 10 mcg may be considered in consultation with oncology for women with persistent symptoms refractory to non-hormonal treatment, particularly those not on aromatase inhibitors. DHEA and ospemifene are generally avoided in hormone receptor-positive breast cancer due to insufficient safety data. Vaginal laser therapy using CO2 fractional laser or erbium:YAG laser has shown short-term improvement in GSM symptoms, but long-term safety and efficacy data are limited, and the FDA has issued warnings about unproven claims.

### Women on Aromatase Inhibitors

GSM associated with aromatase inhibitors is particularly severe and rapid in onset. Non-hormonal options should be tried first, including moisturizers, lubricants, and pelvic floor therapy. Ultra-low-dose vaginal estrogen (4 mcg estradiol) may be discussed with the oncology team, and serum estradiol levels should be monitored.

## Clinical Pearls

GSM is progressive and does not resolve spontaneously, unlike vasomotor symptoms. Treatment must be continued long-term to maintain benefit.

Patients should be asked directly about vulvovaginal and urinary symptoms. The majority will not volunteer these complaints without prompting.

Low-dose vaginal estrogen does not require concomitant progestogen for endometrial protection when standard low doses are used.

Vaginal estrogen reduces recurrent UTIs by approximately 50% and should be considered as part of UTI prevention in postmenopausal women.

The 4 mcg estradiol softgel insert (Imvexxy) provides the lowest available dose with minimal systemic absorption, making it an option for discussion in breast cancer survivors.

## References

1. The NAMS 2020 GSM Position Statement Advisory Panel. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976-992.
2. Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and The North American Menopause Society. Menopause. 2014;21(10):1063-1068.
3. Rahn DD, Carberry C, Sanses TV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol. 2014;124(6):1147-1156.
4. ACOG Committee Opinion No. 659. *The Use of Vaginal Estrogen in Women with a History of Estrogen-Dependent Breast Cancer*. Obstet Gynecol. 2016;127(3):e93-e96.