Genitourinary Syndrome of Menopause: New Name, Old Problem

Previously known as atrophic vaginitis, vulvovaginal atrophy (VVA), or urogenital atrophy, genitourinary syndrome of menopause (GSM) is a composite of genital, urologic and sexual sequelae of chronic hypoestrogenism.  Sexual dysfunction and quality of life impairment are important to identify, as treatment options are available. Incidence is unknown as the syndrome is often underreported by women due to embarrassment, disregard, or a sense of inevitability.

KEY POINTS:

Risk Factors

• Lactation
• Hyperprolactinemia
• Autoimmune disorders
• Bilateral oophorectomy
• Pelvic radiation
• Chemotherapy
• Medications including
  • GnRH agonists (leuprolide, nafarelin)
  • SERMs (such as tamoxifen)
  • Aromatase inhibitors,
  • Danazol
  • Progestins
• Lifestyle risk factors including
  • Cigarette smoking, Alcohol abuse | Sexual abstinence | Lack of exercise | Lack of vaginal birth

Diagnosis

• Include the following on history
  • Irritants: Lubricants, powders, soaps, spermicides, panty liners
  • Hypoestrogenism: Oophorectomy, antiestrogen medications, radiation, chemotherapy
• Ask about the following symptoms
  • Vulvovaginal: Itching, burning, pain, discharge, dyspareunia
  • Urinary: Frequency, dysuria, urgency, dribbling, incontinence, recurrent urinary tract infections
• On pelvic exam look for the following
  • Pale vaginal epithelium with areas of erythema
  • Lacerations, stenosis, friable epithelium, labial fusion
• Consider the following on differential diagnosis
  • Infection
  • Contact irritants
  • Foreign body
  • Sexual trauma
  • Neoplasm
  • Radiation effect
  • Dermatologic conditions such as lichen sclerosis or lichen planus
• Diagnostic tests should be individualized and risk-based
  • Vaginal pH (5-7 in GSM)
  • Vaginal cytology (primarily basal cells)
  • Wet mount
  • Cervical cytology
  • Depending on history and physical findings, other tests to consider
    • Transvaginal ultrasound
    • Hysteroscopy

Treatment

Estrogen Therapy (Summary of dosage regimens can be found in the ObG NAMS entry below)

• Management of moderate/severe GSM is best treated with estrogen therapy (ET)
  • Up to 90% of women will improve with local ET, whether vaginal ring, cream, gel, or tablet
    • Progestin is not necessary to protect the endometrium
    • Treatment is long term
• Consider systemic ET in patients with GSM and/or vasomotor symptoms, risk factors for osteoporosis
  • Progestin needed in women with an intact uterus
  • Both systemic and local ET may be necessary based on clinical response

Estrogen Therapy Alternatives (More information including medications can be found in ObG entries below)

• Be mindful of contraindications and precautions related to ET use (see “Special Populations” below)
  • Known/suspected breast cancer | Estrogen-dependent cancers | Undiagnosed vaginal bleeding | Endometrial hyperplasia/cancer | Hypertension | Hyperlipidemia | Liver disease | History of CVA/VTE/CAD or thrombophilic disorders (e.g., protein C, protein S, antithrombin deficiency) | Pregnancy | Smoking | Migraine with aura | Acute cholecystitis/cholangitis

• Other options include the following
  • SERMs, such as ospemifene and bazedoxifene
    • Contraindications: Undiagnosed abnormal genital bleeding | Known or suspected estrogen-dependent neoplasia | Active arterial thromboembolic event
  • Vaginal dehydroepiandrosterone (DHEA) – Prasterone
    • Contraindications: Undiagnosed abnormal genital bleeding
  • Tibolone (Not available in US or Canada)
  • Moisturizers and lubricants
• Homeopathic remedies have no proven efficacy on the vaginal epithelium and treatment of GSM
• Smoking cessation may be helpful

Special Populations: History of Estrogen Dependent Breast Cancer

Nonhormonal Methods: First Line Therapy

• Lubricants: Silicone | Polycarbophil | Water based
• Moisturizers: Hyaluronic acid | Polyacrylic acid | Polycarbophil based
• Vaginal suppositories: Vitamin E | Vitamin D
• 4% aqueous lidocaine: Applied to vulvar vestibule
• Laser therapy: Not currently FDA approved | Additional research needed before recommending

Hormonal Methods: Consider if Nonhormonal Treatments Fail 

• Low dose vaginal estrogen 
  • Discuss risks/benefits 
  • Can be used with history of breast cancer 
  • Can be used if taking tamoxifen 

Note: If patient taking aromatase inhibitor, decision should involve oncologist 

• Vaginal Dihydroepiandrosterone (DHEA) or testosterone 
  • Can help with dyspareunia and vaginal atrophy 
  • Second line to vaginal estrogen 

• Ospemifene/SERMs 
  • Long term safety data in patients with ER-dependent breast cancer is limited 
  • Can be considered 

Learn More – Primary Sources:

ACOG Practice Bulletin 141: Management of Menopausal Symptoms

Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: a practical guide

Kaunitz and Manson: Management of Menopausal Symptoms

ACOG Clinical Consensus 2: Treatment of Urogenital Symptoms in Individuals With a History of Estrogen-dependent Breast Cancer

Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation and management

Effect of a pH-balanced vaginal gel on dyspareunia and sexual function in breast cancer survivors who were premenopausal at diagnosis: a randomized controlled trial

JAMA Insights: Treatment of Vulvovaginal Atrophy

Local Estrogen Treatment Options for Vaginal Atrophy

CLINICAL ACTIONS:

A growing number of estrogen treatment options are available for postmenopausal vaginal atrophy. Vulvovaginal atrophy is a common symptom of atrophic vaginitis (also referred to as the genitourinary syndrome of menopause or GSM) and can occur in both perimenopausal and postmenopausal women. If a patient reports vaginal dryness, consider the following

• Establish a diagnosis of postmenopausal atrophy based on thorough history and physical exam
  • Confirm with an appropriate pelvic/ vaginal exam
• Discuss use of estrogen, understanding that for some women based on medical history, systemic estrogen might not be an appropriate option
  • Even with a personal history of cancer, local estrogen may be an appropriate treatment (see ‘Key Points’ and ‘Related ObG Topics’ below) depending on the clinical scenario
• Vaginal estrogens can be prescribed as
  • A cream inserted twice weekly using an applicator
  • A tablet inserted with an applicator
  • A soft gel pellet inserted twice weekly with no applicator (FDA approved May, 2018)
  • Ring made of silicone elastomere containing a drug core of estradiol hemihydrate (replaced every 3 months)

Local Estrogen Routes and Dosing for GSM

• Estradiol-17β ring (releases 7.5 micrograms/d)
  • Replace every 3 months
• Estradiol vaginal tablet (10 micrograms/d)
  • Place nightly for 2 weeks
  • Maintenance is one tablet 2 times/week
  • Note: this is the corrected dose in ACOG PB 141
• Estradiol-17β cream (0.1 mg active ingredient/g)
  • 2-4 g/d for 1 to 2 weeks
  • Gradually reduce to ½ initial dosage for 1 – 2 weeks
  • Maintenance is 1 g, 1 to 3 times/week
• Conjugated estrogen cream (0.625 mg/g)
  • 0.5–2 g/d for 21 days then off for 7 days
  • In practice during maintenance therapy, most women apply 1 – 3 times /week
• Vaginal inserts (4-μg and 10-μg)
  • 1 vaginal insert daily for 2 weeks
  • Maintenance is 1 insert twice weekly

SYNOPSIS:

Patients may experience vaginal atrophy as itching, dryness or pain during sexual activity. Vaginal estrogen has been shown to improve moderate to severe menopausal vaginal atrophy. Options for topical estrogen treatment are increasing. Women’s healthcare professionals need to confirm appropriate use of estrogen and help patients identify which treatment option will work best for their situation and lifestyle.

KEY POINTS:

• During perimenopause and menopause, estrogen levels decline in vaginal tissues
  • Referred to as vulvovaginal atrophy (VVA), this may result in discomfort or pain during intercourse or general dryness and discomfort
• If patient complains of dyspareunia, and clinical examination is consistent with postmenopausal vaginal atrophy / atrophic vaginitis, local estrogen is the first line and most effective treatment
  • Estrogen treatment may not be appropriate or desired by all patients
• Ascertain if estrogen is an appropriate option for the patient
  • Screen for a history of breast or uterine cancer
  • History of blood clots
  • Liver conditions
• If patient is appropriate for treatment with local estrogen, offering the spectrum of choices can help a patient identify the product that will work best for them
• While there is a theoretical concern regarding systemic estrogen absorption and risk for uterine cancer, based on evidence, professional organizations  consider “the addition of progestin for endometrial protection is not needed” (ACOG)

Differentiating factors include

• Creams
  • Can be used on the vulva as well as internally in the vagina
• Tablets or caplets
  • Some can be used during the day
  • Some tablets may need to be used at night because of the way they dissolve
• Applicators
  • May be an issue of patient preference and warrants discussion
• Ring
  • Benefits include ease of use
  • For some women, there may be structural issues related to comfort and/or retention  (e.g., short or narrow vagina / prolapse)
• Make patients aware that there are non-estrogen options available for use by women who are not appropriate candidates for local estrogen including
  • Prasterone | Ospemifene
• Laser Treatments have been advocated as a possible treatment, however VVA not a currently FDA-approved indication

Learn More – Primary Sources:

ACOG Practice Bulletin 141: Management of Menopausal Symptoms

Practice Bulletin 141: Management of Menopausal Symptoms: Correction

A Randomized, Multicenter, Double-Blind, Study to Evaluate the Safety and Efficacy of Estradiol Vaginal Cream 0.003% in Postmenopausal Women with Vaginal Dryness as the Most Bothersome Symptom.

FDA Highlights of Prescribing Information for IMVEXXY

Drugs@FDA: Estring

Drugs@FDA: Estrace Cream

Drugs@FDA: Premarin Vaginal Cream 

Drugs@FDA: Vagifem Tablet 

Estradiol vaginal inserts (4 µg and 10 µg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data

Reviewing the options for local estrogen treatment of vaginal atrophy

More Follow-Up Data from the Estrogen vs Lubricant RCT

BACKGROUND AND PURPOSE:

• RCTs have shown that vaginal estrogen creams and tablets, prasterone and ospemifene will provide relief from postmenopausal vaginal atrophy symptoms, but few studies have looked at sexual health and quality of life issues
• Diem et al. (Menopause 2018) compared the efficacy of vaginal estradiol tablets and vaginal moisturizer to treat menopause-related quality of life and mood in women with vulvovaginal symptoms

METHODS:

• Secondary data analysis of a 12-week, double-blind, placebo-controlled randomized trial (RCT)
• Previous primary results on sexual function and decrease in severity of most bothersome symptoms were recently reported in JAMA Int Med (see summary below in ‘Related ObG Topics’)
• Participants: Patients with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration
  • Age 45 to 70 years, at least 2 years since last menses, report of at least 1 moderate to severe symptom at least weekly within the past 30 days or
  • Pain with penetration at least once monthly
• Women were randomized to
  • 10 µg estradiol tablet plus placebo gel
  • vaginal moisturizer plus placebo tablet
  • dual placebo
• Tablets were daily for 2 weeks then twice weekly for remaining 10 weeks
• Vaginal gel was used every 3 days for 12 weeks
• The Menopause-Specific Quality of Life (MENQOL) questionnaire was used to assess changes in quality of life
• Evaluated specifically
  • Depressive symptoms as measured by Patient Health Questionnaire 8
  • Anxiety symptoms as measure by the Generalized Anxiety Disorder (GAD-7)

RESULTS:

• Vaginal estradiol resulted in a greater improvement in total MENQOL scores, compared to dual placebo
  • Mean difference between arms -0.3 at 12 weeks; 95% CI, -0.5, 0.0; P = 0.01
• A favorable group mean difference was observed for vaginal estradiol for MENQOL sexual function domain
  • -0.4 at 12 weeks; 95% CI -1.0, 0.1; P = 0.005
  • A favorable group mean difference for vaginal estrogen was not observed in any of the other domains
• Treatment with vaginal moisturizer did not provide greater improvement compared to placebo in total MENQOL scores or any MENQOL domains
  • Mean difference 0.2 at 12 weeks; 95% CI -0.1, 0.4; P = 0.38
• Neither treatment group showed improvement compared with placebo in the Patient Health Questionnaire 8 or Generalized Anxiety Disorder Questionnaire

CONCLUSION:

• Treatment with low-dose vaginal estradiol modestly improved menopause-related quality of life and sexual function domain scores in postmenopausal women with moderate-severe vulvovaginal symptoms
• Effect on MENQOL score was similar to low-dose oral 17-beta estradiol 0.5mg/day noted in a previous study
• The previous paper that reported on this study did not find a significant difference in sexual function using Female Sexual Function Index (FSFI) as the primary measuring tool
  • FSFI is much more detailed, while MENQOL asks three questions but focuses on whether a woman is bothered by a decrease in sexual deire, vaginal dryness during intercourse and avoiding intimacy
• The authors conclude that “multiple approaches to measuring sexual QOL are needed”

Learn More – Primary Sources:

Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized clinical trial.