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    Aug.19.2022

    Genitourinary Syndrome of Menopause

    Synopsis

    Key Points

    • Genitourinary syndrome of menopause is a collection of signs and symptoms associated with postmenopausal-reduced estrogen and other sex steroids that lead to changes in the labia, clitoris, vestibule/introitus, vagina, urethra, and bladder
    • Primary symptoms include, but are not limited to:
      • Urinary: urgency, dysuria, frequency, and recurrent urinary tract infections
      • Genital: dryness, burning, and irritation
      • Sexual: lack of lubrication, impaired function, and dyspareunia
    • In most females, diagnosis is established by clinical presentation; both history and examination are needed
    • Treatment options include nonhormonal methods (moisturizers, lubricants, vaginal dilation) and hormones
      • Mild to moderate symptoms: preferred initial treatment is nonprescription vaginal lubricants and moisturizers
      • Moderate to severe symptoms and symptoms unresponsive to nonprescription therapy: first line treatment is low-dose vaginal estrogen when patient has no contraindications. Vaginal estrogen preparations may be used alone or in combination with vaginal lubricants and moisturizers
      • Alternative approved treatment options include selective estrogen receptor modulators and vaginal dehydroepiandrosterone
    • Ask females nearing menopause if they are experiencing any symptoms; most will not initiate discussion about symptoms with health care providers
    • Prognosis is excellent for females with symptoms that are responsive to standard care; symptoms are unlikely to resolve without treatment

    Urgent Action

    • Assess females who do not respond to standard treatment of other urogenital conditions and coexisting urogenital diagnoses
    • Promptly evaluate any postmenopausal vaginal bleeding to exclude endometrial hyperplasia and/or adenocarcinoma. Full evaluation with imaging and possibly biopsy is indicated even if bleeding is suspected to be the result of genitourinary syndrome of menopause or secondary to hormonal treatment of genitourinary syndrome of menopause

    Pitfalls

    • Many females do not initiate discussion with health care providers despite significant symptoms (eg, urinary tract infection, genital irritation, sexual dysfunction); therefore, syndrome is underdiagnosed and undertreated
      • Maintain awareness to ask about symptoms; effective treatment is available. Untreated symptoms can lead to worsening sexual dysfunction and vaginal stenosis
    • Genitourinary syndrome of menopause poses some diagnostic challenges r1
      • Many females with mild to moderate signs of syndrome on examination remain asymptomatic
      • Symptoms often correlate poorly with physical examination findings
    • Infectious or inflammatory vaginitis may coexist with syndrome
      • Concern for presence of concomitant diagnosis requires separate evaluation and treatment when indicated
    • Weigh risks and benefits of treatment options (eg, vaginal hormonal treatments) in females with history of hormone-sensitive cancers (eg, breast cancer) r2r3

    Terminology

    Clinical Clarification

    • Genitourinary syndrome of menopause is a collection of signs and symptoms associated with postmenopausal reduced estrogen and other sex steroids that lead to changes in the labia, clitoris, vestibule/introitus, vagina, urethra, and bladder r4
    • Primary symptoms include but are not limited to: r4
      • Urinary: urgency, dysuria, frequency, and recurrent urinary tract infections
      • Genital: dryness, burning, and irritation
      • Sexual: lack of lubrication, impaired function, and dyspareunia
    • Terms previously used to describe this condition include vulvovaginal atrophy, vaginal atrophy, and atrophic vaginitisr3

    Classification

    • By cause r5
      • Hypoestrogenism due to natural menopause
      • Hypoestrogenic states occurring for reasons other than natural menopause
        • Surgical menopause (bilateral oophorectomy with or without hysterectomy)
        • Primary ovarian insufficiency
        • Hypothalamic amenorrhea
        • Postpartum state and breastfeeding
        • Medications (eg, gonadotropin-releasing hormone agonists, aromatase inhibitors)
        • Cancer treatments such as surgery, pelvic radiation therapy, or chemotherapy that render ovaries inactive

    Diagnosis

    Clinical Presentation

    History

    • Many females do not self-report symptoms and must be asked about them specifically
      • Minority of postmenopausal females initiate conversation about vaginal symptoms with their health care provider; about 25% of females with genitourinary syndrome of menopause actually seek treatmentr7r6
        • Females may consider symptoms to be part of aging and be unaware of possible treatments
      • Up to 50% of females with signs lack symptoms r8
      • Symptom severity may be reported as minor, bothersome, or significant, affecting sexual health and/or quality of life
      • Most common symptoms are vaginal dryness (up to 75%) and dyspareunia (up to 44%) r9
      • Severe symptoms may cause discomfort with sitting and bathroom hygiene (wiping) and provoke avoidance of sexual activity r3
      • Symptoms may develop or persist despite receiving systemic estrogen replacement therapy prescribed for other menopausal symptoms r3
    • Urologic symptoms c1
      • Frequency, urgency, dysuria, and hematuria c2c3c4c5
      • Postvoid dribbling c6
      • Nocturia c7
      • Stress and/or urge incontinence c8c9
      • Recurrent urinary tract infections c10
    • Genital symptoms c11
      • Vulvar irritation, itching, and burning c12c13c14
      • Vulvodynia (pain involving vulva); vaginal, pelvic, and suprapubic pain or pressure c15c16c17c18c19c20
      • Vaginal dryness, irritation, pruritus, and burning c21c22c23c24
      • Vaginal discharge, which varies (eg, watery, yellow, brownish, blood-tinged, bloody) c25
    • Sexual symptoms
      • Loss of libido and arousal c26
      • Lack of lubrication c27
      • Dyspareunia c28
      • Dysorgasmia c29
      • Pelvic pain c30
      • Coital or postcoital bleeding or spotting c31

    Physical examination

    • General issues regarding examination
      • More than half of females will show signs of the condition on vaginal examination 4 years postmenopause r10
      • Assess for presence and degree of vaginal introital stenosis with digital examination before inserting speculum to avoid trauma; may need smaller (eg, pediatric) speculum r1c32
        • May need to defer direct vaginal examination for patients with severe stenosis of vaginal introitus; instead, may need to use vaginoscopy to allow visualization
      • Use adequate lubricant during examination, which may be performed with topical anesthesia, if necessary
    • External genitalia findings r3r5
      • Thinning or graying pubic hair c33c34
      • Thinning and resorption of the labia minora; labia minora may fuse c35c36
      • Loss of labial fat pad c37
        • Renders appearance of labia majora as more pendulous and clitoris more prominent c38
      • Decreased width of introitus; introital stenosis (defined as width of fewer than 2 fingers) may develop c39
      • Loss of hymenal remnants c40
      • Prominent urethral meatus and/or urethral caruncula (erythematous polypoid tissue proliferation involving urethral meatus) c41
    • Internal examination findings r1r3
      • Diminished vaginal caliber and depth c42c43
      • Shiny and pale vaginal mucosa c44
      • Decreased vaginal rugae and elasticity c45c46
      • Cervical flush (cervix becomes flush with vaginal vault and identifiable only as small opening in apex of vagina) and obliteration of vaginal fornices c47c48
      • Decreased vaginal secretions is typical; vaginal discharge may be present with concomitant inflammation c49c50
      • Signs of inflammation with vaginal erythema, friability, and easy bleeding c51
      • Signs of trauma (secondary to intercourse with lack of lubrication and thinning of mucosa) with mucosal petechiae, ecchymoses, abrasions, and lacerations c52c53c54c55c56

    Causes and Risk Factors

    Causes

    • Decline in estrogen is responsible for most symptoms; decrease in other sex steroids also may contribute (eg, low androgen levels) c57c58
      • Physiologic effects of hypoestrogenemia r1r6c59c60
        • Loss of dermal collagen in vagina, bladder, and urethra; overall decrease in compliance of urogenital tissue c61c62
        • Decreased vaginal rugae and diminished vaginal elasticity c63c64
        • Decreased vaginal blood flow (estrogen is a vasoactive hormone) c65c66
        • Thinning and pallor of vaginal wall, bladder, and urethral epithelium c67c68c69
        • Vaginal pH increased to 5 or higher r1c70
        • Decreased lactobacilli and diminished diversity of species in bacterial microbiome
          • Lactobacilli may help prevent urogenital conditions (eg, bacterial vaginosis, yeast infection, urinary tract infection) r11
          • Higher proportion of vaginal lactobacilli in postmenopausal females correlates inversely with vaginal dryness r12c71
        • Decreased vaginal lubrication, related to decreased blood flow, decreased rugae, and change in the microbiome c72c73c74
        • Decreased sensory threshold when bladder is distended and impaired urethral closure pressure or urethral sphincter dysfunction, leading to urinary urgency, frequency, and incontinence r13c75c76c77
    • Underlying causes:
      • Menopausal hypoestrogenism r5c78
        • Natural menopause c79
      • Other causes of hypoestrogenism r1r5r10
        • Surgical menopause (bilateral oophorectomy) c80c81
        • Ovarian failure c82c83c84c85
          • Premature ovarian failure
          • Pelvic radiation
          • Autoimmune disease affecting ovaries
        • Hypothalamic causes
          • Inadequate energy intake (eg, eating disorders, starvation) c86c87c88
          • Excessive energy expenditure (eg, extreme exercise) c89
        • Pituitary causes
          • Tumor or autoimmune pituitary destruction c90c91
        • Postpartum state r14
          • Transient; duration depends on length of breastfeeding and may last 3 to 12 months c92
        • Hyperprolactinemia c93
          • Secondary to lactation or pituitary tumor c94c95
        • Pharmacotherapy
          • Gonadotropin-releasing hormone agonist (eg, leuprolide, nafarelin) and some gonadotropin-releasing hormone antagonists (eg, ganirelix, cetrorelix) c96c97c98c99c100c101
          • Specific selective estrogen receptor modulators (eg, tamoxifen) c102c103
          • Aromatase inhibitors c104
          • Danazol c105
          • Depot medroxyprogesterone acetate c106
          • Chemotherapeutic agents c107

    Risk factors and/or associations

    Age
    • Condition is most commonly associated with natural menopause r10
      • Average age for menopause in Western countries is 51 to 52 years r10c108
      • Affects more than 50% of postmenopausal females r3c109
    • Less commonly may occur in premenopausal females
      • May be noted in prepubertal girls secondary to poorly estrogenized vaginal and vulvar tissue c110
      • May be noted in up to 15% of premenopausal females r7c111
    Ethnicity/race
    • Black and Hispanic females in the United States reach menopause approximately 2 years earlier than White females r10c112c113c114
    Other risk factors/associations r1r15
    • Cigarette smoking c115
    • Alcohol use disorder c116
    • Decreased frequency of intercourse and sexual abstinence c117
    • Lack of physical activity c118
    • Absence of vaginal childbirth c119

    Diagnostic Procedures

    Primary diagnostic tools

    • In most patients, diagnosis is established by clinical presentation r3c120
      • Symptoms do not necessarily correlate with physical findings; therefore, both history and examination are needed to establish diagnosis r5c121
    • Ancillary studies are unnecessary for establishing diagnosis in most patients r3c122
      • Testing may be performed in some patients to exclude alternate diagnosis and in patients with atypical presentation to strengthen suspicion of diagnosis
      • Cell cytology analysis (eg, Papanicolaou test, vaginal cytology, endometrial cytology) is required to exclude suspected malignancy c123c124c125
      • Imaging (eg, transvaginal ultrasonography) is indicated to evaluate patients with postmenopausal vaginal bleeding c126

    Laboratory

    • Vaginal ancillary tests that may strengthen suspicion for diagnosis:
      • Saline wet mount c127
        • Findings consistent with diagnosis include: r5r16
          • More than 1 WBC per epithelial cell
          • Presence of parabasal cells (immature vaginal epithelial cells with relatively large nuclei)
          • Reduced or absent lactobacilli
      • Vaginal pH c128
        • Measure by placing litmus paper against lateral vaginal wall until moist r17
        • Healthy estrogenized vagina (without infection or vaginitis) of an adult ranges from pH of 3.8 to 4.5 r18
        • pH of 5 or above is consistent with low estrogen state r19
        • In the absence of bacterial pathogens, a vaginal pH of 6.0 to 7.5 strongly suggests a hypoestrogenemic state r20
        • Certain infections (eg, bacterial vaginosis, trichomoniasis) may result in elevated vaginal pH
          • Elevated pH is common in premenopausal patients with pathologic bacterial pathogens r20
        • Vaginal pH may be increased by presence of semen in the vagina, which also may confound pH testing results
      • Vaginal maturation index c129
        • Rarely used outside of research settings; performed on Papanicolaou test specimen
        • Quantifies estrogen status of vaginal epithelium as indicated by proportion of 3 types of epithelial cells collected from upper portion of vagina: r21
          • Parabasal: least mature
          • Intermediate: moderately mature
          • Superficial: most mature
        • Predominance of parabasal cells and low proportion or absence of superficial epithelial cells is indicative of low circulating estrogen levels r21
          • Less than 5% superficial cells is typical proportion in postmenopausal atrophic state r17
        • Predominance of superficial and intermediate epithelial cells and absence of parabasal cells is indicative of higher circulating estrogen levels r21
          • More than 15% superficial cells is considered within reference range for premenopausal state r17
    • Urinalysis c130
      • Useful to exclude alternative diagnosis when urinary symptoms predominate and to evaluate for urinary tract infection
      • Microscopic hematuria may be noted in patients with genitourinary syndrome of menopause
      • Pyuria and test results positive for leukocyte esterase and/or nitrates may indicate urinary tract infection; confirm with culture d1
    • Vaginal swabs for nucleic acid amplification testing c131c132
      • Useful to exclude alternate diagnosis when symptoms of vaginal itching, burning, or discharge predominate
      • Vaginal swab can test for bacterial vaginosis, vaginal yeast infection, trichomoniasis, gonorrhea, and chlamydia. Commercial laboratories have swabs that are capable of testing for all in 1 test; alternatively, clinician may specify testing for individual pathogens based on clinical concern

    Imaging

    • Transvaginal ultrasonography c133
      • Useful for evaluating postmenopausal bleeding
        • Endometrium shows up as a dark line—sometimes called the endometrial stripe—and is examined to determine thickness of endometrial tissue
        • Average postmenopausal endometrial stripe is 5 mm or thinner (consistent with decreased estrogen stimulation) r1
        • Thickened endometrial stripe raises suspicion for endometrial hyperplasia or endometrial cancer; endometrial biopsy is indicated
        • May need to perform hysteroscopy or dilation and curettage to further evaluate abnormal findings on transvaginal ultrasonography or endometrial biopsy
      • Useful for surveillance of females at high risk of endometrial cancer who are receiving long-term topical estrogen therapy or systemic estrogen therapy without opposing progestin

    Procedures

    c134

    Differential Diagnosis

    Most common

    • Bacterial vaginosis c135d2
      • Common cause of vaginal discharge
      • Females with genitourinary syndrome of menopause are at increased risk for bacterial vaginosis
      • Presents similarly with various symptoms, including vaginal discharge associated with elevated pH, vaginal pruritus, and vaginal burning
      • Diagnose bacterial vaginosis with wet mount revealing clue cells and positive whiff test result (add potassium hydroxide to sample of discharge; if there is fishy odor, then whiff test result is positive)
      • Postmenopausal females often harbor more bacterial vaginosis–like organisms, and nucleic acid amplification may give a false-positive result for bacterial vaginosis
      • Resolution of symptoms after usual treatment of bacterial vaginosis may help to further differentiate diagnoses
      • Recurrence is not uncommon if concomitant genitourinary syndrome of menopause is not treated
    • Candida vaginitis c136d3
      • Common cause of vaginal discharge
      • Females with genitourinary syndrome of menopause are at increased risk for Candida vaginitis
      • May present similarly with several symptoms, including vulvodynia, vulvar and vaginal pruritus, dysuria, and dyspareunia
      • Thick, clumpy, white discharge, intensely erythematous mucosa, discharge that is adherent to vaginal mucosa, and healthy vaginal pH is classic for Candida and may help to differentiate from genitourinary syndrome of menopause
      • Diagnose Candida vaginitis using potassium hydroxide preparation of discharge; may need to use culture or various molecular diagnostic methods (nucleic acid amplification) to confirm when diagnosis remains in question
      • Response to usual treatment of Candida vaginitis with topical or systemic antifungals may help to further differentiate diagnoses
    • Vaginal trichomoniasis c137d4
      • Common cause of vaginitis; infection may be asymptomatic
      • Females with genitourinary syndrome of menopause are at increased risk for vaginal trichomoniasis
      • May present similarly with vaginal discharge, elevated vaginal pH, vulvar irritation, vulvar and vaginal pruritus, dysuria, postcoital bleeding or spotting, and dyspareunia
      • Purulent, green-yellow, frothy, malodorous discharge is more typical of symptomatic trichomoniasis than genitourinary syndrome of menopause; intensely inflamed cervix (colpitis macularis, also called strawberry cervix) is uncommon but highly suggestive of trichomoniasis
      • Confirm using wet mount, rapid antigen testing, or nucleic acid amplification testing
      • Response to usual treatment of trichomoniasis with metronidazole or tinidazole may help to further differentiate diagnoses
    • Vulvar contact dermatitis c138
      • Common cause of perineal irritation. May be caused by contact with various products (eg, lubricants, moisturizers, powders, soaps, detergents, irritants in sanitary or bladder leakage pads, spermicides, condoms)
      • Females with genitourinary syndrome of menopause are at increased risk for perineal contact dermatitis and may be particularly vulnerable to contact dermatitis from lubricants or moisturizers
      • May present similarly with vulvar pruritus and burning, vulvodynia, dyspareunia, and perineal dryness. Findings range from erythema and scaling to fissuring with thickened, lichenified tissue primarily involving the labia majora
      • Diagnosis is established by clinical presentation with history of product use and examination findings in most patients
      • Response to usual treatment of contact dermatitis with discontinuation of offending agent and mild topical steroid, when necessary, may help to further differentiate diagnoses
    • Lichen sclerosis r22c139
      • Common problem affecting 1 in 300 to 1 in 1000 postmenopausal females; cause is uncertain r23
      • Associated with vulvar epithelial inflammation and thinning that does not extend to the vagina
      • Presents similarly with vulvar pruritus, burning, dryness, and vulvodynia
      • Dyspareunia may occur; rectal symptoms may develop (eg, pruritus ani, rectal bleeding)
      • May coexist with genitourinary syndrome of menopause
      • Classic appearance is hypopigmented, atrophic-appearing papules that may coalesce into plaques resulting in thin, wrinkled, parchment-looking skin in a figure-of-eight (keyhole) distribution around vulva and anus r9
        • Purpura, fissures, and eventually lichenification may develop as a result of excoriation from scratching
        • Distinction between labia majora and minora may be lost
      • Lichen sclerosis is an important diagnostic consideration; a minority of older females with this diagnosis will have evidence of malignant epithelial changes or squamous cell neoplasia r23
      • Diagnosis is based on clinical presentation; response to usual treatment of lichen sclerosis with potent topical steroid may help to further differentiate diagnoses. Treatment with topical estrogen is ineffective
      • Confirm diagnosis with vulvar biopsy showing characteristic histologic changes when diagnosis remains in question
    • Lichen planus r24c140
      • Idiopathic mucocutaneous inflammatory disease involving skin, hair, nails, and mucous membranes; skin and oral mucosa are the most commonly involved sites
      • Most commonly affects middle-aged adults; cause is unclear r25
      • May coexist with genitourinary syndrome of menopause
      • Typical skin lesions are described as polygonal, hyperpigmented, erythematous, violaceous, flat-topped, pruritic papules with overlying reticular white striae without extension into vagina; severe disease may result in vaginal stenosis at the vaginal introitus r25
      • Oral lesions vary in appearance (eg, reticular, papular, plaque, atrophic, erosive) and often involve buccal mucosa, tongue, and gingiva
      • Vulvar lesions present similarly to genitourinary syndrome of menopause with irritation, pruritus, burning, pain, dryness, dysuria, and dyspareunia
      • Lesions may be difficult to differentiate from other dermatoses when vulva is involved; differentiate by clinical presentation and involvement of other areas of skin and mucous membranes
      • Response to usual treatment of lichen planus with topical steroids may help to further differentiate diagnoses; treatment with topical estrogen is ineffective r25
      • Confirm diagnosis with vulvar biopsy showing characteristic histologic changes when diagnosis remains in question
    • Lichen simplex chronicus r26c141
      • Inflammatory condition involving the vulva that results secondary to vulvar pruritus and itching; underlying cause is often multifactorial and often includes elements of chronic irritation and allergic contact dermatitis
      • Presents similarly with vulvar pruritus, irritation, dryness, and dysuria secondary to excoriation
      • Characteristically, itching is somewhat relieved by rubbing or scratching, thus perpetuating a vicious itch-scratch cycle; examination findings usually reveal thickened, lichenified plaques with excoriations and accentuated skin markingsr9
      • Diagnosis is usually established by clinical presentation and response to usual treatment with topical corticosteroids
    • Vulvar intraepithelial neoplasia c142
      • Worldwide, there are an estimated 5 cases per 100,000 females r27
        • Becoming more common in young females
        • Oncogenic HPV is implicated in most cases
        • Cigarette smoking and HIV infection increase risk
      • Presents similarly either asymptomatically or with itching or burning of vulva
      • May coexist with genitourinary syndrome of menopause
      • Appearance on physical examination varies but is distinct from genitourinary syndrome of menopause, ranging from erythematous well-demarcated plaques to verrucalike white plaques, erosions, or hyperpigmented patches r27
      • Confirm diagnosis with punch biopsy or excisional tissue biopsy revealing characteristic histology
    • Vulvar cancer c143
      • Rare, affects 1 or 2 females in 10,000 annually r28
        • Usually squamous cell, rarely adenocarcinoma or melanoma
        • Oncogenic HPV is implicated in most cases
      • Symptoms include itching, pain, and burning of the vulva not relieved by antifungals or steroid creams
      • Examination findings usually differentiate conditions; progressive thickening of skin with white or erythematous patches—and sometimes scaling—is characteristic of malignancy r28
      • Over time, mass develops with ulceration, bleeding, and associated lymphadenopathy
      • Confirm diagnosis with punch biopsy or excisional tissue biopsy revealing characteristic histology r28
    • Vulvar Paget disease r22c144
      • Usually presents clinically with eczemalike inflammatory skin changes overlying carcinoma of the breast; extramammary disease can manifest as vulvar intraepithelial adenocarcinoma
      • Condition is rare, with a peak incidence around age 65 years r23
      • Presents similarly with vulvar irritation with pruritus, burning, and dyspareunia
      • Lesions are often multifocal involving other areas of perineum; appearance is eczematoid with well-demarcated and slightly raised edges
      • Differentiate by clinical presentation and confirm diagnosis with biopsy. Paget cells are pathognomonic
    • Desquamative inflammatory vaginitis r29c145
      • Chronic severe purulent vaginitis with nonspecific features and unknown cause
      • Occurs most commonly in perimenopausal females
      • May coexist with genitourinary syndrome of menopause
      • Presents similarly with vaginal discharge, dyspareunia, vaginal pain and burning, elevated vaginal pH, increased number of parabasal cells, and loss of Lactobacillus species dominance
      • Appearance includes diffuse erythema and inflammation of vulva and vagina
      • Unlike in genitourinary syndrome of menopause, 30% to 70% of patients have a spotted petechial or ecchymotic vaginal rash, and annular erythematous papules with a pale center may be noted r29
      • Response to usual treatment of desquamative inflammatory vaginitis with topical clindamycin or topical steroids may help to further differentiate diagnoses; topical estrogen is ineffective treatment
    • Trauma c146
      • Trauma to the vagina or vulva may present similarly with pain, dyspareunia, and even pruritus c147
      • Differentiate by history and physical examination
    • Foreign body c148
      • Vaginal foreign body may present similarly with pain, pruritus, discharge, and dyspareunia c149
      • Differentiate by history and physical examination findings with presence of foreign body
    • Vulvodynia r30c150
      • Chronic pain in the vulva for more than 3 months r23
      • Most females with condition experience localized vulvar pain provoked by vaginal penetration (eg, tampon use, intercourse)
        • Other comorbidities (eg, chronic pain syndrome, interstitial cystitis, fibromyalgia) may be present
        • This condition can occur at times other than at the menopausal transition
      • A neuropathic quality is characteristic of pain and itching is rare; physical examination is normal; pain may be elicited by light touch of vestibule with a cotton swab
      • Diagnosis is clinical, based on characteristic history, a positive cotton swab test eliciting pain in the vestibule, and exclusion of other diagnoses
    • Vaginismus c151
      • Involuntary vaginal muscle spasm creates pain on vaginal penetration (eg, tampons, intercourse)
      • Cause may include undiagnosed vulvovaginal disorders or other factors (eg, prior sexual trauma, anxiety, cultural or religious beliefs)
      • May be a complication of or coexist with genitourinary syndrome of menopause
      • Presents similarly with vaginal pain and dyspareunia
      • Differentiating features include absence of pruritus and discharge; physical examination does not demonstrate cutaneous or mucosal abnormalities
      • Diagnose by clinical presentation; can confirm diagnosis by lack of spasm during examination under anesthesia r31
    • Urinary tract infection d1
      • Presents similarly with frequency, urgency, dysuria, and hematuria c152
      • Difficult to distinguish clinically without urinalysis
      • Findings consistent with urinary tract infection include presence of leukocytes and positive leukocyte esterase and/or nitrates
      • Confirm with urine culture

    Treatment

    Goals

    • Reduce urinary, genital, and sexual symptoms
    • Improve functional limitations affecting sexual health and/or quality of life
    • Prevent chronic urinary tract infections and other potential complications (eg, vaginal stenosis)

    Disposition

    Recommendations for specialist referral

    • Refer to gynecologist for further diagnostic and treatment recommendations
      • Patients with recalcitrant disease not responding to first line measures
      • Patients with significant disease complications (eg, vaginal introital stenosis, pelvic organ prolapse)

    Treatment Options

    Mild to moderate symptoms

    • First line treatment for most patients includes OTC lubricants and moisturizers
      • Nonprescription lubricants and moisturizers alone may be provide sufficient mild to moderate symptom relief r5
      • Lubricants are recommended for short-term relief of vaginal dryness and discomfort associated with sexual activity r32
        • Designed to reduce friction-related irritation to atrophic tissues during intercourse r33
        • Products may be water-, silicone-, and oil-based
          • Oil-based products may degrade latex condoms
          • Water-based, hyperosmolar products may result in mucosal irritation
      • Recommend regularly using vaginal moisturizers in females with ongoing discomfort due to vaginal dryness r32r33
        • Moisturizers mimic vaginal secretions (eg, increase vaginal mucosal moisture, reduce pH)
        • Used independently of sexual activity r33
        • Recommended frequency of use is daily or every other day, depending on symptom severity r3
        • Long-acting products may decrease vaginal pH to premenopausal levels r5
      • Many options are available; products most closely resembling healthy vaginal pH, osmolality, and composition of secretions are preferred r32
        • Ideal osmolality for water-based products is below 380 mOsm/kg; avoid hyperosmolar preparations. Very high osmolality (greater than 1200 mOsm/kg) may result in irritation, contact dermatitis, and cytotoxicity r15
        • Choose products with pH within reference range for healthy adult females (3.8-4.5 pH); pH levels of 3.0 or less are poorly tolerated r18
        • Hyaluronic acid products are described as an effective alternative to estrogen-based treatments, eg, in females with contraindications to estrogen-based therapy; however, there is no evidence that these produce greater benefits than nonhyaluronic acid lubricants or moisturizers r5r34r35r36
        • Avoid products with parabens, glycerin, warming properties, flavors, and spermicides owing to potential for tissue irritation r18

    Moderate to severe and persistent mild to moderate symptoms

    • First line treatment is low-dose vaginal estrogen when patient has no contraindications r3r37
      • Useful to treat symptoms unresponsive to nonprescription therapy (eg, nonprescription lubricants, moisturizers);r38 may be used in addition to nonprescription treatments r3
        • Vaginal estrogen is contraindicated in patients with undiagnosed vaginal bleeding, and its use is considered controversial in those with a history of a hormone-sensitive malignancy r39
          • Involve oncologists in decisions regarding use of vaginal estrogen for females with estrogen-sensitive cancers r40
        • Vaginal estrogen carries the same black box warnings as systemic estrogen with progestin, despite minimal systemic absorption and reassuring long-term observational studies r1r3
          • Listed contraindications include:
            • Undiagnosed vaginal bleeding
            • Known or suspected breast cancer
            • Estrogen-dependent cancer
            • Endometrial hyperplasia or cancer
            • History of thromboembolism or known thrombophilia
            • Hypertension
            • Hyperlipidemia
            • Liver disease
            • History of stroke or venothrombotic events
            • Coronary artery disease
            • Pregnancy
            • Smoking in patients aged 35 years and older
            • Migraines with neurologic symptoms
            • Cholecystitis/cholangitis
        • Patients with contraindication to low-dose vaginal estrogen may require management with multiple nonhormonal modalities
      • Replenishes local estrogen receptors and reverses physiologic vaginal mucosal changes, improves vaginal secretions, lowers vaginal pH to restore healthy vaginal flora, prevents frequent urinary tract infections, and alleviates overall vulvovaginal symptoms r1r7r10
      • More effective than systemic estrogen to treat vulvovaginal, urinary, and intercourse symptoms associated with genitourinary syndrome of menopause r3r41r42
        • Many females who require estrogen replacement therapy for other menopausal symptoms also require supplemental topical estrogen for persistent symptoms of genitourinary syndrome of menopause r3
        • Use of vaginal estrogen diminishes urinary urgency, urinary incontinence, and reduces risk of urinary tract infections r40r43
      • Use lowest dose and frequency of vaginal estrogen therapy to effectively manage symptoms
        • Vaginal estrogen may be used intermittently for 1 to 3 months or may be used long-term r16
        • Improvement may be noted within a few weeks of starting treatment; 8 to 12 weeks is required for most patients to experience maximum benefit of therapy r16
        • Up to 90% of females report symptom improvement with low-dose vaginal estrogen therapy r1
      • Various low-dose vaginal estrogen formulations (eg, cream, tablets, capsule, sustained-release estradiol-17β vaginal ring) with comparable efficacy and safety profiles are available r44r45
        • Determine choice of formulation based on patient and physician preference r3
        • Vaginally inserted tablets or capsules instead of cream may be preferred in situations requiring controlled dosing r3
      • Systemic estrogen absorption is thought to be minimal; serum estradiol remains in the healthy menopausal range for creams, tablets, capsules, and estradiol-17β vaginal ring r3
        • Despite minimal systemic absorption, the same warnings exist for vaginal estrogen preparations as systemic estrogen preparations for cardiovascular disease, thrombosis, endometrial cancer, breast cancer, and other hormone-sensitive cancers r46
        • Minimal absorption may be a concern for females receiving aromatase inhibitors because even minimal absorption may affect efficacy of aromatase inhibitor therapy r40r42
        • Estradiol acetate vaginal ring is an exception resulting in systemic hormone levels effective at treating vasomotor symptoms in addition to genitourinary syndrome of menopause symptoms r3
      • Vaginal estrogen therapy is unlikely to pose risks for survivors of hormone-dependent cancers (eg, breast cancer, endometrial cancer) owing to minimal systemic absorption. Findings from clinical trials and observational studies are reassuring though not definitive; consider the following recommendations: r5
        • Strongly preferred first line treatments are nonhormonal r2r3
        • Individualized management must take into account both patient needs and oncologist recommendations r38
        • Ultra-low-dose vaginal estrogen (preferably estriol) therapy may be used in select females with refractory symptoms that significantly affect quality of life for short duration after thorough consideration of risk-benefit ratio r2r47
      • Data do not suggest increased risk for endometrial hyperplasia or cancer with unopposed low-dose vaginal estrogen r48
        • Progestins are not indicated in most situations for endometrial protection in those using low-dose vaginal estrogen r3r38
        • Consider yearly transvaginal ultrasonography for endometrial surveillance or prescribe yearly progesterone withdrawal for females at high risk for endometrial cancer (eg, obesity, use of higher doses than recommended) r3
    • Alternate management strategies
      • Ospemifene
        • Only selective estrogen receptor modulator approved to treat genitourinary syndrome of menopause r3
          • Other available selective estrogen receptor modulators (eg, tamoxifen, raloxifene, bazedoxifene) are not approved to treat this syndrome; tamoxifen may cause vaginal dryness and dyspareunia
        • Synthetic nonsteroidal agent that exerts mixed estrogen agonist and antagonist effects on vulvovaginal tissue at doses of 60 mg daily; does not appear to target or affect breast or endometrial tissue r3
        • Improves vaginal pH, vaginal dryness, vaginal maturation index, and dyspareunia; findings consistent with improved mucosal estrogen effects are noted on examination. Additionally, reduces bone turnover markers r3r49r50
        • Approved to treat moderate to severe dyspareunia associated with genitourinary syndrome of menopause; option for some patients who cannot (eg, severe arthritis, obesity) or prefer not to use intravaginal treatment r3
        • Although package insert stresses monitoring females taking ospemifene to treat endometrial cancer, risk of endometrial hyperplasia appears to be very low (0%-1%). Most data suggest ospemifene has favorable endometrial safety profile; addition of progestin not recommended r16
        • Current recommendations suggest avoiding use in patients both with and at high risk for breast cancer; data are limited but suggest drug may exert antiestrogenic effect in breast tissue r3r38r51
        • As with estrogen therapy, ospemifene increases risk of thromboembolism; avoid in patients at high risk of venous thromboembolism r52
      • Vaginal dehydroepiandrosterone
        • Steroid prohormone that converts locally to testosterone and estrogen when applied to mucosal tissue
        • Improves vaginal pH and vaginal maturation index, and diminishes vaginal dryness and dyspareunia r3r53r54
        • FDA-approved for dyspareunia associated with genitourinary syndrome of menopause r3
        • Not associated with proliferative endometrial effects, and minimal increases in systemic hormone levels are noted r3r55r56
        • However, vaginal dehydroepiandrosterone is not uniformly recommended for cancer survivors because studies assessing its safety in this population are limited r56
      • Systemic estrogen therapy with or without progesterone
        • Appropriate when needed for other symptoms of menopause (eg, vasomotor symptoms, sleep and mood dysregulation) and protection from osteoporosis r1
        • Progestogen is recommended for females without history of hysterectomy (presence of intact uterus)
        • Systemic hormone therapy relieves vaginal symptoms for most patients; however, 10% to 15% may require addition of low-dose vaginal estrogen r16
        • Systemic therapy is not expected to improve urinary incontinence and may increase risk for stress urinary incontinence r42r43r47
        • Contraindicated in patients with estrogen-sensitive cancers and in those with high risk of thromboembolic disease r47
      • Bazedoxifene and conjugated estrogen combination
        • Bazedoxifene plus conjugated estrogens is designated as a tissue-selective estrogen complex
          • Bazedoxifene (a selective estrogen receptor modulator) alone does not improve vaginal symptoms of genitourinary syndrome of menopause
          • No progestin is needed to allow for endometrial shedding in females with intact uterus given selectivity profile of bazedoxifene (bazedoxifene has limited, if any, stimulation of uterine endometrium)
        • Significant data support improvement in symptoms; rate of endometrial hyperplasia is similar to placebo r57r58r59
      • Tibolone
        • Synthetic steroid that has mild estrogenic, progestogenic, and androgenic properties
        • Improves vaginal maturation index, increases sexual desire, and decreases nocturia and urinary urgency r60
        • Data are limited regarding cardiovascular effects; initial data indicate effects similar to estrogen plus progesterone r61r62
        • Available in many countries to treat menopausal symptoms, but not available in the United States r61
      • Topical lidocaine r63
        • Apply to introitus a few minutes before sexual activity to diminish pain with intercourse
        • May be used as an adjunct to lubricants and physical therapy in breast cancer survivors with dyspareunia
      • Energy-based therapies
        • Lasers therapy and radio-frequency devices are being studied as treatment but none have FDA approval specifically to treat genitourinary syndrome of menopause
        • Based on preliminary limited data, laser therapy is promising; however, these are not recommended until longer, larger studies confirm safety and efficacy r5r64
          • In a 2018 Safety Communication, FDA issued a warning about the use of these devices for vaginal cosmetic purposes, stating that the effectiveness and safety of the devices have not yet been established r65
        • Used to stimulate remodeling of vaginal connective tissue and improve vaginal epithelium (eg, promote increased thickening, improve glycogen storage) r1
        • Fractional CO2 and Erbium:YAG lasers have demonstrated improvements in vaginal dryness, discomfort, pruritus, and dyspareunia r52r66
      • Testosterone r5
        • Topical testosterone cream has been used for the treatment of vulvovaginal conditions such as lichen sclerosus and vestibulodynia
        • Systemic testosterone may be indicated for the treatment of hypoactive sexual desire disorder/dysfunction use in postmenopausal females r47r67
        • A small 4-week pilot study found that vaginal testosterone improved dyspareunia, vaginal dryness in postmenopausal females with breast cancer
        • Systemic or local testosterone are not recommended for treatment of genitourinary syndrome of menopause until further studies establish safety and efficacy r5r67
      • Vaginal oxytocin gel
        • Small studies have yielded conflicting results regarding effect on menopausal symptoms; one study showed no more effective than an equivalent non–hormone-containing gel r68

    Drug therapy

    • Vaginal estrogen c153
      • Estradiol cream c154
        • Guideline-recommended dosing
          • Estradiol Vaginal cream; Adult menopausal and postmenopausal females: Initially, 0.5 to 1 g (50-100 mcg of estradiol) vaginally once daily for 2 weeks; then maintenance dosing of 0.5 to 1 g (50-100 mcg of estradiol) vaginally 1 to 3 times per week. r3
        • FDA label dosing
          • Estradiol Vaginal cream; Adult menopausal and postmenopausal females: Initially, 2 grams to 4 grams (200 mcg to 400 mcg of estradiol) vaginally once daily for 1 to 2 weeks; then gradually reduce over 1 to 2 weeks. Usual maintenance: 1 gram (estradiol 100 mcg) vaginally 1 to 3 times per week. Treatment is cyclic (3 weeks on, then 1 week off).
      • Estradiol vaginal inserts c155
        • Vagifem, Yuvafem vaginal tablets only c156c157
          • Estradiol Vaginal insert; Adult menopausal and postmenopausal females: Insert 1 tablet (10 mcg) vaginally once daily for 2 weeks into the upper third of the vaginal vault using the supplied applicator. After 2 weeks, insert 1 tablet vaginally twice weekly (e.g., every Tuesday and Friday).
        • Imvexxy vaginal insert only c158
          • Estradiol Vaginal insert; Adult menopausal and postmenopausal females: Place 1 insert vaginally once daily at approximately the same time of day for 2 weeks, followed by 1 insert twice weekly (e.g., Monday and Thursday). Generally, initiate with the 4 mcg insert. Max: 10 mcg/dose vaginally. Use the lowest effective dose.
      • Estradiol ring c159
        • Estradiol Vaginal insert; Adult menopausal and postmenopausal females: Insert 1 vaginal system ring (delivering estradiol 7.5 mcg/24 hours) deep into the upper third of the vaginal vault. Keep in place continuously for 3 months, then remove. If appropriate, insert a new system. Estring vaginal system ring is not effective at treating vasomotor symptoms.
      • Conjugated estrogen cream c160
        • Guideline-recommended dosing
          • Conjugated Estrogens Vaginal cream; Adult menopausal and postmenopausal females: Initially, 0.5 to 1 g vaginally once daily for 2 weeks; then maintenance dosing of 0.5 to 1 g vaginally 1 to 3 times per week. r3
        • FDA label dosing
          • Conjugated Estrogens Vaginal cream; Adult menopausal and postmenopausal females: Initially, 0.5 grams PV once daily for 21 days; then, no treatment for 7 days. May titrate up to 2 grams/day PV depending on response. Repeat cyclically. Use lowest effective dose. For moderate to severe dyspareunia, 0.5 grams PV twice weekly (e.g., every Monday and Thursday) may be sufficient; otherwise, consider the usual vaginal dose. Reassess hormone therapy periodically.
      • Estriol cream c161
        • Not FDA approved for usage in the United States; however, has been studied and used in Europe.
        • Not commercially available in the United States.
        • Estriol Vaginal cream; Adult menopausal and postmenopausal females: Initially 0.5 mg vaginally once daily for 2 weeks; then maintenance dosing of 0.5 mg vaginally 2 to 3 times weekly. Use lowest effective dose. r2r47r69
    • Ospemifene c162
      • Ospemifene Oral tablet; Adult menopausal and postmenopausal females: 60 mg PO once daily with food. Consider the addition of a progestin in postmenopausal women with an intact uterus to reduce risk for endometrial hyperplasia. Assess the need for continued treatment periodically.
    • Vaginal dehydroepiandrosterone (prasterone) r53c163
      • Prasterone Vaginal insert; Adult menopausal and post-menopausal females: 1 insert (6.5 mg) administered vaginally once daily at bedtime, using the provided applicator.
    • Systemic hormone therapy c164
      • Oral
        • Estradiol Oral tablet; Adult menopausal and postmenopausal females: 0.5 mg to 2 mg PO once daily. Usual initial dose: 1 or 2 mg PO once daily. Less than 1 mg/day PO may suffice for vaginal/vulvar symptoms only. Administration should be cyclic (e.g., 3 weeks on and 1 week off). In women with an intact uterus, estrogen may be given cyclically or combined with a progestin for at least 10 to 14 days per month.
        • Conjugated Estrogens Oral tablet; Adult menopausal and postmenopausal females: Initially, 0.3 mg PO once daily. May titrate if needed. Use lowest effective dose. Few patients need up to 1.25 mg/day PO. Doses of less than 0.45 mg/day may be adequate for vaginal/vulvar symptoms only. Continuous, unopposed estrogen is acceptable in women without a uterus. In women with an intact uterus, estrogen may be given cyclically (e.g., 25 days of month then 5 days off) or combined with a progestin for at least 10 to 14 days per month to reduce risk of endometrial hyperplasia. Reassess hormone therapy every 3 to 6-months.
        • Conjugated Estrogens, Medroxyprogesterone Acetate Oral tablet; Adult menopausal and postmenopausal females: 1 tablet PO once daily. Dosage titration options include: A) 0.3 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, B) 0.45 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, C) 0.625 mg conjugated estrogen/2.5 mg medroxyprogesterone acetate tablet, or D) 0.625 mg conjugated estrogen/5 mg medroxyprogesterone acetate tablet. Titrate as needed, using the lowest effective dose. Cycles are repeated continuously, using a new blister card every 28 days. Reevaluate at 3 to 6 month intervals to determine appropriate dose and need for continued treatment.
      • Transdermal patch c165
        • Estradiol Transdermal patch - weekly; Adult menopausal and postmenopausal females: 1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, or 0.1 mg per day) applied and replaced every 7 days. Usual initial dose is 0.0375 mg/day or 0.05 mg/day. Use lowest effective dose.
        • Estradiol Transdermal patch - biweekly; Adult menopausal and postmenopausal females: 1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day); replace twice weekly (every 3 to 4 days). Usual initial dose is 0.0375 mg/day or 0.05 mg/day; see individual patch recommendations.
    • Bazedoxifene and conjugated estrogen combination c166
      • Conjugated Estrogens, Bazedoxifene Oral tablet; Adult menopausal and postmenopausal females: 1 tablet PO once daily (conjugated estrogens 0.45 mg and bazedoxifene 20 mg per tablet). Reevaluate every 3 to 6 months to determine if the dose and continued hormone replacement are appropriate.
    • Tibolone c167
      • In June 2006, tibolone did not receive FDA approval in the United States for treatment of symptoms related to menopause. Tibolone is available in Europe and many other countries globally under the trade name Livial and is approved in European countries for relief of vasomotor symptoms related to menopause and for the prevention of osteoporosis in postmenopausal females.
      • Tibolone Oral tablet; Adult menopausal and postmenopausal females: 2.5 mg PO once daily.
    • Lidocaine r70c168
      • Lidocaine Hydrochloride 5% Topical gel or ointment; Adults: Apply to the vestibule with a cotton ball 30 minutes before intercourse as needed for adequate control of symptoms.
    • Topical estradiol therapies for genitourinary syndrome of menopause.Systemic estrogen absorption is minimal with low-dose vaginal estrogen treatments. Serum estradiol remains in menopausal reference range for creams, tablets, capsules, and estradiol-17β vaginal ring; estradiol acetate vaginal ring is an exception and does result in systemic hormone levels effective at treating vasomotor symptoms.Data from Faubion SS et al: Genitourinary syndrome of menopause: management strategies for the clinician. Mayo Clin Proc. 92(12):1842-9, 2017; and TherapeuticsMD: Imvexxy--estradiol insert. Prescribing information. National Library of Medicine DailyMed website. Updated December 6, 2019. Accessed February 4, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=104be9f2-a8f6-430e-9e01-2ee7cc1861f1.
      TreatmentBrand nameInitial dosageMaintenance dosageComments
      Vaginal cream
      Estradiol-17βEstrace0.5-1 g daily for 2 weeks0.5-1 g, 1-3 times weeklyInitial dose approved by FDA is higher (2-4 g daily)
      Conjugated estrogensPremarin0.5-1 g daily for 2 weeks0.5-1 g, 1-3 times weeklyFDA approval calls for cyclical administration and higher dose (for genitourinary syndrome of menopause: 0.5-2 g daily for 21 days then off for 7 days; for dyspareunia: 0.5 g daily for 21 days then off for 7 days or 0.5 g twice weekly)
      Vaginal insert
      Estradiol hemihydrateVagifem, Yuvafem10 mcg tablet insert daily for 2 weeks1 twice weekly
      Estradiol tear-shaped vaginal insertsImvexxy4 mcg insert daily for 2 weeks4-10 mcg insert twice weeklyFDA approved May 2018

      Initial dose is 4 mcg, may titrate dose based on clinical response; Max dose: 10 mcg/dose vaginally
      Dehydroepiandrosterone Intrarosa6.5 mg once daily6.5 mg once dailySteroid prohormone with effects from local conversion to testosterone and estrogen; associated with minimal increase in systemic hormone levels and may be safer option than vaginal estrogen in patients with contraindications to use of estrogen (eg, hormone-sensitive breast and endometrial cancer survivors)
      Vaginal ring
      Estradiol-17βEstringInsert for 90 daysChange every 90 days2 mg releases approximately 7.5 mcg daily
      Estradiol acetateFemringInsert for 90 daysChange every 90 daysVaginal delivery provides systemic hormone levels to treat vasomotor symptoms and genitourinary syndrome of menopause; 12.4 mg releases 0.05 mg and 24.8 mg releases 0.1 mg daily

    Nondrug and supportive care

    Other supportive measures

    • Educate patient about cause of symptoms and options for treatment c169
      • Advise that symptoms are not likely to improve without treatment, and untreated pain may lead to worsening sexual dysfunction r3
    • Suggest importance of healthy sexual choices in effort to maintain vaginal health r10
      • Regular penetrative sexual activity with or without a partner can help maintain vaginal health; patients can use vibrators therapeutically to stimulate blood flow and maintain vaginal function r1r3c170c171
      • The lubricative response to sexual arousal is believed to aid maintenance of vaginal elasticity r33
    • Risk factor modification (eg, smoking cessation, wearing loose undergarments and pants) may help diminish symptoms r1c172c173c174c175d5
    • Specific symptomatic care measures include:
      • May use lubricated dilators for vaginal stretching to treat patients with vaginal constriction and vaginismus r16c176
      • May use pelvic floor physical therapy to treat patients with pelvic floor muscle dysfunction, urinary incontinence,r71r43 vaginal constriction, or vaginismus r3c177c178
      • Consider sex therapy for patients with refractory sexual dysfunction or dyspareunia c179
    Procedures
    • Laser therapies c180
      • Not yet FDA approved to treat genitourinary syndrome of menopause. Although large-scale and rigorous safety and efficacy data are lacking, laser therapy is being used off-label in clinical settings r72
      • Considered a possible alternate approach for patients with absolute contraindications to available hormonal treatments or inability or unwillingness to use moisturizers, lubricants, or vaginal estrogen r66r72
      • Data are not available regarding prevention of recurrent urinary tract infection associated with genitourinary syndrome of menopause
      • Optimal number of treatments is unclear; typical course of treatment includes 3 treatments, each 1 month apart r66r72
      • Available laser types include:
        • Fractional microablative carbon dioxide laser
          • Limited data support short-term efficacy r73r74r75r76
          • May improve symptoms of vaginal dryness, pruritus, dysuria, and dyspareunia r73r74r75r76
          • Serious adverse effects have not been reported r73r74r75r76
          • Study of 50 females reported sustained effects at 12 weeks with no adverse effects r73
          • Improvement in genitourinary syndrome of menopause symptoms and urinary and sexual function at 6-month follow-up similar to that seen with vaginal estrogen r77
        • Erbium:YAG laser c181c182
          • Limited data support short-term efficacy up to 18 to 24 months r78r79r80
          • May improve symptoms of vaginal dryness, dyspareunia, and stress urinary incontinence r78r79r80
          • Serious adverse effects have not been reported r78r79r80

    Special populations

    • Patients with breast cancer or at high risk for breast cancer r18
      • Treatment is individualized:
        • First line treatments are nonhormonal (eg, lubricants, and moisturizers,r2 dilators, pelvic floor therapy, topical lidocaine)
        • If symptoms are severe or recalcitrant, laser therapy may be offered
      • Considerations include cancer recurrence risk, symptom severity, response to previous therapy, and personal preference
      • Vaginal hormone therapies may be an option for some females for whom nonpharmacologic and nonhormone treatments do not work after discussing risks and benefits with patient and reviewing strategy with treating oncologist
        • Use the less potent form of estrogen, estriol, in lowest available doses r2r47
      • Varying consensus recommendations exist for females with estrogen-receptor positive breast cancers, females with triple-negative breast cancers, females with metastatic disease, and females at high risk for breast cancer
      • Use extreme caution in females taking aromatase inhibitors for breast cancer r3
        • Aromatase inhibitors, used in the treatment of postmenopausal breast cancer, are used to decrease serum estradiol levels r3
        • Patients being treated with aromatase inhibitors who are also using the estradiol ring or 25-mcg vaginal tablets (currently off-market in the United States) have small but significant increases in serum estradiol levels r3r81
    • Females after treatment of endometrial cancer
      • There is a theoretical risk of promoting recurrence of endometrial cancer with use of hormone therapy in survivors of endometrial cancer, as this carcinoma is usually estrogen receptor–positive
      • Local and systemic menopausal hormone therapy is not recommended for females with advanced endometrial cancer r82
      • There is a lack of high-level evidence demonstrating safety of either systemic or local menopausal hormone therapy in females with history of early-stage endometrial cancer; thus, most experts consider there to be insufficient evidence to inform decisions about hormone therapy for this population r83
        • Retrospective series show incidence of recurrence of endometrial cancer in females who are prescribed vaginal estrogen is approximately 7% r84

    Monitoring

    • Clinically monitor for efficacy of treatment and potential adverse treatment effects
      • Assess annually for treatment efficacy, additional clinical needs, and any necessary additional treatment options r52c183
      • Laboratory testing (eg, vaginal maturation index, vaginal pH) is not routine unless manifestations are recalcitrant to typical measures or a concomitant diagnosis is suspected c184
      • Assess for adherence issues in patients with minimal or no response to typical measures r3c185
        • Some females discontinue low-dose vaginal estrogen cream within several months of starting for various reasons, including messiness, inconvenience, cost, and safety concerns
        • Continued education and change of formulation may effectively address barriers to continued treatment
      • Monitor for vaginal bleeding during treatment with vaginal estrogen r3r38
        • Evaluate any reported spotting or bleeding with pelvic imaging (eg, ultrasonography) and endometrial biopsy when indicated
    • Consider yearly transvaginal ultrasonography to assess for endometrial proliferation in the following patients: r3c186
      • Those at high risk for endometrial cancer who use vaginal estrogen therapy c187
      • Those who use a higher-than-recommended dose of vaginal estrogen therapy c188

    Complications and Prognosis

    Complications

    • Vaginal trauma (eg, laceration, hemorrhage) c189
    • Vaginal stenosis and shortening c190c191
    • Introital stenosis c192
    • Vaginismus (involuntary contraction of muscles surrounding vagina) c193
    • Increased risk for developing both vaginal and urinary tract (including chronic) infections c194c195c196c197
    • Prolapse of urethra, uterus, pelvic organ, or vaginal vault c198c199c200c201
    • Urethral meatal stenosis, urethral atrophy, and retraction of urethral meatus inside vagina (associated with vaginal voiding) c202c203c204
    • Urethral polyp or caruncle c205c206
    • Cystocele and rectocele c207c208
    • Chronic pelvic pain c209
    • Sexual dysfunction c210
      • May develop secondary to dyspareunia and vaginismus c211c212
      • May manifest as loss of interest in sex and cessation of sexual activity c213c214
      • Reported up to 4 times more frequently in females with symptoms of syndrome than in females without symptoms of syndrome r52

    Prognosis

    • Syndrome is chronic and progressive; manifestations are unlikely to improve or resolve without treatment and often worsen with increasing duration of hypoestrogenism r3
    • Prognosis is excellent in females who have mild symptoms controllable by lubricants and/or moisturizers
    • Prognosis and symptom control is excellent in the vast majority of females with use of topical estrogen therapy
      • Up to 90% of females report symptom improvement with low-dose vaginal estrogen therapy r1
      • Expect most genital, urinary, and sexual symptoms to improve with low-dose vaginal estrogen; however, low-dose vaginal estrogen alone does not effectively treat urinary incontinence r44

    Screening and Prevention

    Screening

    At-risk populations

    • Perimenopausal, menopausal, and postmenopausal females c215
    • Patients with medication-induced hypoestrogenemia, eating disorders, hypogonadism, primary ovarian insufficiency, premature ovarian failure, or hyperprolactinemia c216
    • Patients who are lactating c217

    Screening tests

    • Ask all females who are at-risk if they have symptoms of genitourinary syndrome of menopause; encourage regular gynecologic visits c218
      • Ask about sexual concerns or painful intercourse; recognize that both urinary and genital symptoms may develop from genitourinary syndrome of menopause c219
      • US Preventive Services Task Force recommendations include:
        • Gynecologic examination with Papanicolaou test every 5 years if HPV cotesting is done or every 3 years if HPV cotesting is not done, for females aged 21 to 65 years r85c220c221
        • Sufficient evidence is not available to recommend screening pelvic examinations in any age group r85
      • American College of Obstetrics and Gynecology recommendations include:
        • No recommendations for or against pelvic examinations in asymptomatic patients r86c222
        • Shared decision-making between asymptomatic females and their physicians r86c223
        • Pelvic examinations, when indicated by medical history or symptoms r86c224
        • Screening females who have current or history of gynecologic malignancy, cervical dysplasia, or diethylstilbestrol exposure, according to guidelines specific to those conditions r86c225
        • At least yearly visits with gynecologist for well-female care, even if a pelvic examination is not required. Provides an opportunity to inquire about symptoms of genitourinary syndrome of menopause r86c226c227
          • Pelvic examinations allow for diagnosis of vulvar lesions and dermatologic conditions, vulvar neoplasia, anogenital cancers, and vaginal atrophy that could be missed if not performed c228

    Prevention

    • Genitourinary syndrome of menopause may be prevented by systemic hormone therapy in females who require it for other symptoms or conditions r87c229
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