Genitourinary Syndrome of Menopause

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 treatment^r7r6
    • 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

• 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

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

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 markings^r9
  • 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

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)

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.

  Treatment	Brand name	Initial dosage	Maintenance dosage	Comments
  Vaginal cream
  Estradiol-17β	Estrace	0.5-1 g daily for 2 weeks	0.5-1 g, 1-3 times weekly	Initial dose approved by FDA is higher (2-4 g daily)
  Conjugated estrogens	Premarin	0.5-1 g daily for 2 weeks	0.5-1 g, 1-3 times weekly	FDA 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 hemihydrate	Vagifem, Yuvafem	10 mcg tablet insert daily for 2 weeks	1 twice weekly
  Estradiol tear-shaped vaginal inserts	Imvexxy	4 mcg insert daily for 2 weeks	4-10 mcg insert twice weekly	FDA approved May 2018 Initial dose is 4 mcg, may titrate dose based on clinical response; Max dose: 10 mcg/dose vaginally
  Dehydroepiandrosterone	Intrarosa	6.5 mg once daily	6.5 mg once daily	Steroid 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-17β	Estring	Insert for 90 days	Change every 90 days	2 mg releases approximately 7.5 mcg daily
  Estradiol acetate	Femring	Insert for 90 days	Change every 90 days	Vaginal 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

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

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