Course Authors
Nancy A. Phillips, M.D., and Gloria A. Bachmann, M.D.
Dr. Phillips is Clinical Assistant Professor and Dr. Bachmann is Professor, Department of Obstetrics and Gynecology, and Professor of Medicine, Interim Chair of Obstetrics/Gynecolgy, Associate Dean for Women's Health and Chief of the OB/GYN Service at Robert Wood Johnson University Hospital, and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
Within the past 12 months, Dr. Phillips reports no commercial conflicts of interest and Dr. Bachmann has received grant/research support and been a consultant to Shionogi, Inc.
Albert Einstein College of Medicine, CCME staff, and interMDnet staff have nothing to disclose.
This activity is certified for women’s health, primary care (internal medicine, family practice and gynecology), endocrinology and for all HCPs interested in the treatment of patients with VVA. This CME activity has been peer-reviewed by Judi Chervenak, M.D., Associate Professor of Obtetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
This activity is made possible by an unrestricted educational grant from Novo Nordisk
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Discuss the physiology of menopausal symptoms including risk factors and associated comorbidities
Discuss the data emerging from recent clinical trials of prospective VVA therapies/strategies including safety, efficacy and side effects
Discuss the management of VVA, particularly with respect to overcoming medical professional and patient barriers to diagnosis and treatment.
This presentation may include discussion of commercial products and services.
Vulvo-vaginal atrophy (VVA) in peri- and post-menopausal women is caused by declining, then deficient estrogen levels. It frequently results in distressing symptoms that include burning, irritation, discharge and dyspareunia. A Cochrane review (2006) estimates that in healthy women over age 60, 50% experience one or more of these symptoms.(1) Other studies report a similar estimated prevalence of 39-47%, with up to 52% of those affected reporting these symptoms have a negative impact on their quality of life.(2)(3) An international survey (2010) of 4,246 women aged 55-65 found 39% (range 34-43%) experienced symptoms of vaginal atrophy. Two-thirds of the women described these symptoms as moderate to severe and 60% found these symptoms to impair their quality of life.(4)
As our aging population expands and women live one-third of their life in a menopausal state, physicians can expect to see an increasing number of older women. Currently, over two million American women reach menopause annually, which translates to approximately 6,000 women per day.(5) Caring for these women will require not only treating medical conditions, but also providing preventive care and implementing strategies for improved quality of life, including addressing vulvo-vaginal complaints.
A pro-active approach to the symptoms of vulvo-vaginal atrophy should be included in the system review of this population. Studies have shown that only 25% of symptomatic women will seek help for VVA and that a large majority of women (77%) are uncomfortable discussing these symptoms with their health care providers.(6)
Additionally, women of any age who have low estrogen levels may present with symptoms related to VVA. Disorders such as premature ovarian failure, hypothalamic amenorrhea, prolonged lactation or medication side effects from, for example, a GnRh agonist, aromatase inhibitor or chemotherapy may lead to women developing symptoms of vulvo-vaginal atrophy.
Health care providers have an opportunity to positively influence the quality of life and sexual well being of these populations by including VVA in the medical history, evaluating atrophic changes on pelvic examination and discussing treatment options for those distressed by their symptoms.
Pathophysiology
In pre-menopausal women the vagina and vestibule are lined by glycogen-rich, keratinized squamous epithelium. The glycogen acts as a substrate for lactobacilli producing a low vaginal pH (2.8 to 4) which maintains normal vaginal flora with resultant protection from infection. The squamous epithelium of the labia and vulva are non-keratinized. Estrogen is responsible for the maintenance of the vaginal epithelium via estrogen receptors in the vagina, vulva, urethra and trigone of the bladder.(7)
With menopause, estrogen levels decline, as much as 90% compared to the reproductive years.(8) This plunge in estrogen levels adversely affects vulvo-vaginal tissues. Cellular glycogen levels decrease with a resultant increase in vaginal pH. This changed pH subsequently inhibits lactobacilli colonization and allows increased populations of more diverse flora, including pathogenic organisms.
Additionally, without the vasoactive property of estrogen, blood flow in the lower genital tract diminishes, leading to decreased secretions as well as delayed and reduced lubrication with sexual stimulation. The collagen content of the connective tissue decreases, resulting in decreased elasticity.
The ratio of the three vaginal cells types (parabasal, intermediate and superficial) shifts from the glycogen-rich, estrogen-stimulated superficial and intermediate cells to less mature parabasal cells with subsequent epithelial thinning. In some women, especially those who are not sexually active, narrowing and stricture of the vaginal canal and introitus may result.(9)
Vaginal health may progressively worsen with prolonged hypoestrogenism. Therefore, with increased age, a previously asymptomatic menopausal woman may develop troublesome symptoms. With this possibility in mind, health care providers should routinely continue to inquire about vulvo-vaginal symptoms, and not only in the immediate menopausal period.
Diagnosis of VVA
Diagnosis of vulvo-vaginal atrophy is based on history and physical exam. Although some correlates with systemic levels estrogen levels have been suggested (e.g., more symptoms with serum estradiol less than 50 pg/mL), obtaining a serum estrogen level is not necessary for diagnosis.(10)
Peri- and post-menopausal women should be routinely screened for VVA. The health care provider should initiate the conversation, as women are often reluctant to do so. Common complaints include vaginal dryness, burning or itching, abnormal vaginal discharge, vulvo-vaginal discomfort with exercise, sitting or tight clothing and dyspareunia. Complaints of diminished arousal or decreased desire may be secondary to vulvo-vaginal atrophy when pain accompanies sexual activity. Urinary frequency, urgency or dysuria may also be symptoms of vulvo-vaginal atrophy.
Physicians must remember that VVA is not only a sexual complaint. As dramatized by actors in our first video "patient-physician" office visit below, activities ranging from vigorous exercise to simply wearing fitted clothing may elicit discomfort in the patient with VVA.
The medical history should include current medications, medical conditions, use of soaps, detergents, over-the-counter remedies or other irritants which may contribute to vulvo-vaginal symptoms (see Table 1). A comprehensive review of sexual functioning should be obtained.
Table 1. Possible Causes of Vulvo-Vaginal Complaints
- Allergic reaction to soaps, bubble baths, over the counter feminine hygiene products
- Bacterial vaginosis
- Certain diseases (e.g., Crohn's, diabetes, SLE)
- Vaginal infections, including yeast and trichomoniasis
- Douching
- Foreign body
- Hypoestrogenic states (e.g., menopause, premature ovarian failure)
- Medications (e.g., antibiotics which contribute to candida, GnRH leading to hypoestrogen)
- Skin conditions such as eczema or lichen sclerosis
- Vulvar epithelial neoplasia
- Vulvodynia
- Psychological causes
Source: adapted from The American College of Obstetrics & Gynecology, Diagnosis and management of vulvar skin disorder. ACOG Practice Bulletin No 93, May 2008.
The history must assess the impact of symptoms on quality of life. For many women, the symptoms are not distressing and treatment is not necessary. Instead, information concerning the availability of treatment when and if necessary is sufficient. Counseling about over-the-counter options is often helpful.
Physical examination findings that indicate VVA are numerous. With external genital inspection, you will often find loss of pubic hair or labial fat. The vulvar skin will be thin and pale, with attenuation of the labia majora and minora. Fissures may develop in the posterior forchette and clitoral hood fusion may occur. The vaginal mucosa will be pale and dry, with loss of rugae. Inflammation and petechiae may be present within the vaginal walls, which may be friable and bleed easily.(11) Vaginal shortening or stricture may be present. In some women, introital narrowing may be present.
Objective measurements of vulvo-vaginal atrophy include vaginal pH and Maturation Index. A vaginal pH 5.0 or greater, in the absence of blood, semen or infection, is an indicator of vaginal atrophy. Similarly, a shift to increased parabasal cells and loss of superficial cells on a wet preparation microscopic evaluation of a vaginal smear, called the Maturation Index, is another indicator of vaginal atrophy.(12)
Treatment of Vulvovaginal Atrophy
Vulvo-vaginal atrophy should be treated in symptomatic women who are distressed by the symptoms and desire intervention. Over-the-counter, non-hormonal products are the first line of therapy. If these are not effective, local vaginal estrogen is an FDA-approved therapy that has proven efficacy: systemic estrogen should not be used for symptoms that involve vulvo-vaginal atrophy only. For those with moderate to severe dyspareunia from menopausal VVA, ospemifene, a new, FDA-approved oral option, soon can be prescribed.
Non-hormonal
Vaginal lubricants and moisturizers are non-hormonal alternatives for treatment of vulvo-vaginal atrophy, available over-the-counter. Vaginal lubricants are primarily used to relieve symptoms for a short period of time, most often during sexual intercourse. They are applied locally and act immediately.
Vaginal lubricants can be water- , silicone- or oil based. The oil-based, or petroleum-containing lubricants, interfere with condom integrity, and although pregnancy may not be a concern in this age-group, protection from sexually transmitted infection may be. Women who experience irritation from lubricants should be encouraged to find preservative–free solutions, even vegetable or mineral oil (see Table 2).(13)
In contrast to vaginal lubricants, vaginal moisturizers are applied regularly, not just with or in anticipation of coital or other vaginal irritative activity. Moisturizers provide longer lasting relief of vaginal dryness. They are bio-adhesive and attach to vaginal epithelium, retaining water and decreasing vaginal pH. Studies have shown increased transient lubrication with moisturizers and decreased discomfort during intercourse, but studies comparing vaginal moisturizers to local estrogen have almost uniformly found better long-term symptom relief with estrogens (Table 2).(11)(14)
Table 2. Vaginal Lubricants.
- Astroglide*, K-Y Gel*, Summer's Eve*, Pre-seed*
- ID Lube Millennium, Pink*, Pjur
- Elegance Woman's Lubricant, mineral oil, vegetable oil
Vaginal Moisturizers
- Replens, Moist Again*, K-Y Silk-E
*safe to use with a condom
Source: adapted from Mischell DM, Iglesia CI. A guide to lotions and potions for treating vaginal atrophy. J Fam Practice 2009;21(12).
Products which add heating sensations, other arousal enhancers or topical herbal preparations are successful in some women, but have not been well studied in clinical trials. They may cause irritation and should be tried initially in very small quantities. Neogyn, a hormone-free, vulvar-soothing cream containing cutaneous lysate has been used to relieve pain associated with vulvar atrophy. This product is currently available online but will be for sale in retail stores shortly.(15) Placebo-controlled clinical trials are needed to assess its efficacy.
Hormonal
Estrogen, delivered locally, has been the mainstay of treatment for vaginal atrophy. Estrogen restores the Maturation Index to the premenopausal state -- increased superficial and intermediate cells with increased glycogen storage, ultimately an environment characterized by an acidic pH and normal lactobacilli-predominant flora. With these changes, the epithelium thickens and elasticity increases, as does blood flow.
If systemic estrogen is not needed for the relief of vasomotor symptoms, local estrogen is recommended. Local therapy's benefits include avoidance of first pass metabolism in the liver, lower systemic hormone levels, avoidance of most adverse events and probable better efficacy for vaginal symptoms.(16)
Indeed the International Menopause Society Group has stated that preventive low-dose local estrogen should be considered to forestall the development of VVA. As this professional society has noted: "In view of the virtual absence of risks and side effects of most low-dose vaginal preparations (although long-term data are lacking), a case could be made for not only intervention when symptoms are established, but also for the prevention of atrophy before symptoms become troublesome."(17) Even in women on systemic estrogen therapy, there may be a need for local estrogen treatment if relief of vaginal symptoms is not sufficient.
Women often believe that taking systemic hormones will restore their pre-menopausal state. As such, they may not attribute local symptoms to estrogen deficiency. In our third patient, who is young, healthy and pelvic pain-free after hysterectomy for endometriosis, attention to local vaginal health is essential to restore pain-free sexual function, despite systemic hormonal treatment.
In the US, locally applied estrogen is available in cream, tablet and ring form (see Table 3). The Estring vaginal ring delivers the lowest dose of estrogen (7.5 micrograms estradiol daily), remains in place for 90 days and may need to be removed for sexual activity. Vagifem tablets contain 10 micrograms of estradiol daily. They are used two or three times a week. Premarin vaginal cream is recommended at .5 mg dosage two to three times a week. Estrace cream is recommended at 1 g twice a week.
Table 3. Local Estrogen Preparations.
| COMPOSITION | PRODUCT NAME | DOSING |
|---|---|---|
| Vaginal Creams | ||
| 17?2-estradiol | Estrace Vaginal Cream | Initial: 2–4 g/d for 1–2 weeks Maintenance: .5-1 g 1-2/week |
| Conjugated estrogens | Premarin Vaginal Cream | .5–2 g/daily |
| Vaginal Rings | ||
| 17?2-estradiol | Estring | 7.5 mcg/d for 90 days |
| Estradiol acetate | Femring | .05-.1mg/d estradiol for 90 days |
| Vaginal Tablet | ||
| Estradiol hemihydrates | Vagifem | Initial: 1 tablet (10 mcg)/d for 2 weeks Maintenance: 1 tablet (10 mcg) twice a week |
Source: adapted from The North American Menopause Society, 2010 Position Statement.
As with any regimen, increased frequency of dosing at the start of therapy may be necessary for initial relief, followed by gradual weaning to the recommended FDA dosing or, at times, less frequent dosing. With severe vulvar symptoms, including fissures, estrogen creams may be applied topically as well as intra-vaginally until resolution of symptoms and healing of fissures occur, at which point the patient can then be weaned to the lowest effective dose.
Systemic absorption of vaginally delivered estrogen is dose dependent. Endometrial and breast stimulation may become a concern as the longevity of use and dose increase. However, studies looking at systemic estrogen levels when local estrogen is prescribed at FDA-approved dosages have shown that estradiol levels usually do not exceed levels which occur naturally in a post-menopausal population.(18)
Similarly, studies investigating endometrial thickness do not find significant change with use of vaginal estrogen preparations, regardless of method of delivery. The 2006 Cochrane review of estrogen use in post-menopausal women reported no significant differences among the delivery methods (ring, tablet, cream) in terms of endometrial hyperplasia, endometrial thickness or the proportion of women with adverse events.(1) Long-term data are not available.
There is no current recommendation for progesterone supplementation in women with an intact uterus or for endometrial screening. Any vaginal bleeding should be promptly evaluated.(19)(20)
There is some evidence that estradiol levels are higher at the initiation of local treatment, perhaps due to increased absorption through thin or broken epithelium. Additionally, higher levels of estradiol may be absorbed in the days immediately after placement of the vaginal ring, resulting in a spike of blood levels.(17)
For most women, this spike is acceptable, as it is low and of short duration. However, in some women, even the potential for a change in serum estrogen levels is unacceptable, for example, for our 43-year-old video patient who has been treated for estrogen receptor positive breast cancer.
For women with a history of breast cancer, especially ER (+) tumors, an increase in serum estradiol levels may not be acceptable. In this population, often prematurely menopausal as the result of chemotherapy or adjuvant treatment for the cancer, the presence of severe vulvo-vaginal atrophy symptoms may have a significant negative psychosocial impact. The practitioner should discuss with this patient the risks and benefits of local estrogen therapy. In this population, monitoring serum estradiol levels and using non-cream preparations, which are less user-dependent for exact dosage, should be considered. The patient's medical oncologist should be included in the decision-making process.
Another group of women who may seek therapies other than locally applied treatments, hormonal or otherwise, are those who are unable or unwilling to apply them. Our next video patient, for example, is trying to improve her physical condition and mobility, but is hampered by VVA during exercise attempts.
In February 2013, the FDA approved ospemifene, for the treatment of dyspareunia caused by vulvo-vaginal atrophy. Ospemifene is an oral selective estrogen receptor modulator (SERM) that acts as an estrogen agonist in the vagina without clinical or animal model effects on breast or endometrium.(22)(23)
Ospemifene is appropriate for the treatment of VVA in women who have not had the desired results with vaginal estrogen use or who are unable or unwilling to use vaginal preparations for treatment of symptoms. This group may include women with disabling arthritis or older women with limited mobility where insertion of any vaginal product is difficult or impossible. Side effects of ospemifene include hot flushes and potential risk of thromboembolism.
Other SERMs, such as tamoxifen and raloxifen, have beneficial safety profiles for breast cancer and osteoporosis but not for VVA symptoms. Preliminary human and animal data suggest that ospemifene has no effect on the breast tissue, and in fact may even be inhibitory. There is limited information on bone effects. Currently, there are not enough data to recommend its use in women with a personal history of breast cancer, or to support its use for breast or bone health.
DHEA is a pro-hormone produced primarily in the adrenal gland, which may decrease by as much as 70% in the postmenopausal years. DHEA is metabolized by aromatase into estradiol and testosterone. Vaginal, but not oral DHEA, has been shown in clinical studies to reverse vaginal atrophy, clinically and histologically.(23) Vaginal ovules (12.5 mg) studied over 12 weeks produced no increase in serum levels of estrogen, testosterone or their metabolites.(24) Endometrium stimulation did not occur with 52 weeks of oral treatment.(25) However, the safety of DHEA in breast cancer survivors has not been established and, as of this publication date (June 2013), DHEA is not FDA-approved for the treatment of VVA.
Most recently, Lima et al. have investigated the use of vaginal isoflavone gel for the treatment of vaginal atrophy in post-menopausal women. Isoflavones are phytoestrogens commonly found in soy. In a double-blind, randomized, placebo-controlled study evaluating the treatment of vaginal dryness and dyspareunia, 4% isoflavone vaginal gel was as effective as conjugated equine estrogens and superior to placebo. No changes in endometrial thickness or serum estradiol levels were noted over the 12-week course.(26) Isoflavone gel is not available in the US but, as data accumulate, this treatment may someday provide another topical, non-hormonal option for those suffering from vulvo-vaginal atrophy.
Conclusion
Vulvo-vaginal atrophy is the underlying cause of many vaginal and sexual problems in the postmenopausal population. Health care providers should discuss, diagnose and treat vulvo-vaginal atrophy symptoms in their older population, which will improve their patients' sexual and overall health.