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.

Prasterone for Vulvovaginal Atrophy – What is it and How to Prescribe

CLINICAL ACTIONS:

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:

• Confirm diagnosis of postmenopausal atrophy through vaginal exam
• Discuss use of vaginal estrogen as an option
• If patient is not an appropriate candidate for local estrogen or if patient would prefer not to use a direct estrogen product, prasterone may be an effective alternative
  • One vaginal insert (6.5 mg of prasterone) each evening at bedtime

SYNOPSIS:

Prasterone is an approved, steroid-based FDA treatment for postmenopausal vaginal atrophy. Use is appropriate for women who complain of dyspareunia, or general discomfort due to dryness and thinning of the vaginal mucosa.

KEY POINTS:

• During perimenopause and menopause, estrogen levels decline in vaginal tissues and is referred to as vulvovaginal atrophy (VVA), which may result in discomfort or pain during intercourse
  • Local estrogen can be considered a first line treatment of VVA but may not be appropriate or desired by all patients
• The FDA approved prasterone to treat women experiencing moderate to severe dyspareunia, a symptom of VVA, due to menopause
  • Prasterone is the first FDA approved product containing the synthetic active ingredient dehydroepiandrosterone (DHEA)
• DHEA can convert to androgens and/or estrogens and, while the likelihood is low and the quantities minimal, a physician should disclose the following
  • Based on the fact that there is minimal data on safety in the setting of hormonally sensitive malignancy, the FDA warns against using prasterone if there is a history of or known or suspected breast cancer
  • Unexplained uterine bleeding is a contraindication to use
  • It is indicated for use only in postmenopausal women

Learn More – Primary Sources:

FDA approves Intrarosa for postmenopausal women experiencing pain during sex

FDA: Prescribing information for Intrarosa (prasterone)

ACOG Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen Dependent Breast Cancer

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

Treating Postmenopausal Vaginal Atrophy When Estrogen is Not an Option

CLINICAL ACTIONS:

If a patient complains of dyspareunia, and clinical examination is consistent with postmenopausal vaginal atrophy / atrophic vaginitis, local estrogen is the first line of treatment, but there are alternatives that can be considered if the following two criteria are met:

• Ascertain if the patient can, indeed, use estrogen and ensure that option was offered and an informed decision to decline was met
• Screen for a history of breast or uterine cancer, history of blood clots or liver conditions

SYNOPSIS:

Some postmenopausal patients will not or cannot use local estrogen replacement therapy to treat vaginal atrophy/atrophic vaginitis. Common situations in which this is the case may include personal history of estrogen-sensitive breast cancer or endometrial cancer, although NAMS guidelines do recommend that low-dose local HT may be an option, in consultation with a patient’s oncologist in certain situations. Fortunately, a number of effective options are available for these women.

When a clinician cannot prescribe local estrogen, alternatives for postmenopausal vaginal atrophy include

•  Ospemifene – 60 mg daily
  • Should not be used concomitantly with estrogens
  • Should be used for 12 continuous weeks in order to gauge effectiveness
  • Ospemifene is a SERM
    • According to the FDA, there is insufficient data to use ospemifene in women with breast cancer
    • While there do not appear to be any cases of ospemifene causing endometrial cancer, a potential risk for this particular malignancy is mentioned in a boxed warning
• Prasterone – One vaginal insert (6.5 mg) each evening at bedtime
  • FDA approved, steroid-based treatment for postmenopausal vaginal atrophy
  • Use is appropriate for women who complain of dyspareunia due to dryness and thinning of the vaginal mucosa
  • Based on the fact that there is minimal data on safety in the setting of hormonally sensitive malignancy, the FDA warns against using prasterone if there is a history of or known or suspected breast cancer
• Lubricants
  • Have been found to be efficacious and may help alleviate symptoms

Laser Treatment – FDA Statement

• The FDA has released a statement (August 2018) warning that “…safety and effectiveness of these devices hasn’t been evaluated or confirmed by the FDA for “vaginal rejuvenation.” In addition to the deceptive health claims being made with respect to these uses, the “vaginal rejuvenation” procedures have serious risks.”
• NAMS has also responded and while welcoming the FDA’s mandate requiring companies to provide adequate data, the NAMS statement includes the following to assist with counseling

NAMS recommends that healthcare providers discuss the benefits and risks of all available treatment options for vaginal symptoms, including over-the-counter lubricants, vaginal moisturizers, and FDA-approved vaginal therapies such as vaginal estrogen and
intravaginal dehydroepiandrosterone and oral therapies such as hormone therapy and ospemifene to determine the best treatment for women with GSM. When discussing vaginal energy-based therapies, informed discussion should include that these are FDA-approved devices for gynecology but have not received FDA approval for vaginal rejuvenation or procedures for GSM, sexual function, incontinence, or pelvic laxity and that even though short-term data are promising, more robust, sham-controlled, and longer-term data are needed.

KEY POINTS:

• While alternative treatments will address vaginal dryness and atrophy, patients should be informed of the limitations of these treatments
• Treatments that are effective for managing vaginal atrophy, may not help with other menopausal symptoms such as hot flashes, night sweats or mood

Learn More – Primary Sources:

Effect of Ospemifene on Moderate or Severe Symptoms of Vulvar and Vaginal Atrophy

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

FDA Statement: Statement from FDA Commissioner Scott Gottlieb, M.D., on efforts to safeguard women’s health from deceptive health claims and significant risks related to devices marketed for use in medical procedures for “vaginal rejuvenation”

NAMS Response: FDA Mandating Vaginal Laser Manufacturers Present Valid Data Before Marketing