Atrophic Vaginitis and Estrogen Treatment (Slides with Transcript)

Peggy Keen, PhD: Hello, I'm Dr. Peggy Keen, Editorial Director of Women's Health at Medscape. I'd like to welcome you to our web conference on Atrophic Vaginitis and Estrogen Treatment. This is a Continuing Educational Activity made possible by an independent educational grant from Novo Nordisk.

We will begin with a presentation from Dr. Raquel Arias, who will provide a review of hormonally induced physiologic changes, common physical findings, and symptoms associated with atrophic vaginitis. This will be followed by a presentation from Dr. George Gorodeski who will discuss treatment.

The first presenter, Dr. Raquel Arias is the Associate Dean of Women and Associate Professor Department of Obstetrics & Gynecology and Clinical Associate Professor Department of Gerontology at the University of Southern California, Los Angeles. She calls atrophic vaginitis the new epidemic. Welcome, Dr. Arias.

Raquel D. Arias, MD: I'm pleased to be here. Atrophic vaginitis -- my title is "The New Epidemic." There may be those out there that say, well how can anything be new? As long as there have been women, there must have been atrophic vaginitis.

The reality is however, that along with an increase in life expectancy, we've had an increase in expectations. There are more women alive today in menopause -- that have cumulatively made it to be menopausal -- than in the history of humankind. In other words, there are more women right now potentially suffering from atrophic vaginitis than all the women who were [previously] able to make it to menopause in the history of human existence.

So, in addition to that, although we've had therapies that might have treated or prevented atrophic vaginitis, there's been a dramatic decline in the use, even the appropriate use, of these hormonal medications in the past 5 years. This has been primarily due to misinterpretation of large studies, notably the Women's Health Initiative.

In Lorraine Dennerstein's rather lovely evaluation of a large cohort in Australia, she was able to show a correlation between vaginal dryness and advancing age. But even more importantly, and separate from aging, is the effect that menopause has on vaginal health. You'll notice that women who were premenopausal rarely or infrequently suffered from vaginal dryness or symptoms associated with vaginal dryness. Whereas, as you approach the menopause, and especially as you become postmenopausal, the risk of complaining of vaginal dryness dramatically increased. Such that, in as little as 3 years after their last period, half of the women evaluated may have vaginal dryness. It's also likely that in the presence of this dryness and with loss of host defenses, other symptoms such as painful intercourse and urinary urgency will become prominent.

Vaginal cell maturation is a healthy thing, in contrast to other types of maturation. We want vaginal cells to be mature. The superficial cells -- large, crisp cells with small pyknotic nuclei and abundant cytoplasm -- are a rich source of glycogen for the lactobacilli, the best inhabitant of the vagina.

In a woman who has a loss of estrogen, you're likely to see more of the intermediate cells -- especially parabasal and metaplastic cells, which are uncommon in the premenopausal woman. In fact, it is a desirable thing to have as many superficial cells as possible. In the absence of estrogen, the percentage of these superficial cells decreases dramatically.

A woman who actually is suffering from atrophic vaginitis is likely to see an increase in the number of parabasal cells -- those the cells you see with the high nuclear-cytoplasmic ratio -- associated inflammatory exudate, and round, basophilic 'blue blobs,' which are characteristic of atrophic vaginitis. A woman with a normal vaginal smear, on the other hand, will have those lovely, fluffy, large, crisp, mature superficial cells, [with] the low nuclear-cytoplasmic ratio, and the tiny pyknotic nuclei.

The woman with the normal smear is much less likely to complain of any problems whatsoever. Whereas the women suffering from atrophic vaginitis is perhaps going to have itching, discharge, unpleasant smell, as well as the other associated effects of vaginal atrophy such as painful intercourse.

Lila Nachtigall was able to [obtain a vaginal] biopsy specimen from a patient presenting with atrophic changes. You'll see that the biopsy [of tissue] with atrophic changes has a tiny, thin, little layer of superficial cells. In fact, very few of those cells are mature and are more likely to be parabasal cells. When they slough into the vaginal space, there's very little to protect the underlying tissues. That little rim you see is all that's protecting this woman from a potentially hostile environment associated with a high pH, lack of lactobacilli, and an overgrowth of other organisms.

On the right side [of this slide] is the same patient after a relatively short period of local vaginal administration of estrogen. She now has a lush, thick, superficial layer of cells. This is actually one of the most dramatic things about vaginal atrophy and one of the most rewarding things about treating and preventing it. The vagina is uniquely responsive to an enriched hormonal milieu. In the presence of estrogen, even some of the most atrophic and symptomatic vaginas can be returned to a relatively healthy normal state.

The postmenopausal changes of the vaginal epithelium are many. A premenopausal woman has plump, pink vaginal tissues, lots of erectile tissue, deep folds of rugae, and an elastic muscular coat underneath the epithelium. It is from these layers that the transudation of fluid in a well-perfused vagina permits moisture and lack of dryness. It is this effluvium that provides glycogen, the substrate for lactobacilli; the lactobacilli become the predominant organism in the premenopausal woman.

In the postmenopausal woman, in contrast, there's a dramatic loss of rugae, a loss of lining as you saw in the previous slides, and a dramatically diminished transudate. The pH in the postmenopausal woman -- due to lack of acid, lack of glycogen, and overgrowth of pathogenic bacteria -- becomes elevated. This is not likely to be associated with a good, asymptomatic outcome. In reality, a healthy vagina is a brilliant microecosystem, a place where millions of organisms -- even some that are potentially pathogenic -- can live together in a healthy, asymptomatic environment.

Atrophy can occur in a very short time. Even in as little as 2 years since natural menopause, a woman who has not had estrogen therapy may suffer dramatic loss of labial and vulvar fullness. The previously pink and well-perfused tissues become pale and thin. The loss of urethral meatal turgor is associated with an increase in urinary tract infections, and associated changes in the bladder can increase the sense of urge even when there's [very] little urine in the bladder.

The difference between vaginal atrophy and the short-term symptoms associated with menopause are dramatic. The reason for that is because short-term symptoms -- all of the ones for which women come in to see a clinician (eg, menstrual irregularities, vasomotor symptoms, hot flashes, fatigue) -- treated or not, eventually get better for most women. However, atrophic vaginitis -- the pain associated with it and concurrent urinary tract infections -- do not get better with time. In fact, problems only become worse.

It may come as a surprise that even among women who have chosen to treat their systemic symptoms with hormone therapy a significant proportion will nonetheless have local urogenital symptoms. In this evaluation by Notelovitz, he found that up to 27% of women -- even women taking systemic hormone therapy -- had complaints associated with estrogen deprivation locally in the vagina. Naturally, women who are not taking systemic therapy are much more likely to suffer from local atrophy and the symptoms associated with atrophy.

There aren't many [local] treatment options for atrophic vaginitis in addition to, or instead of, systemic therapies. The local therapies that are available in the United States include 2 preparations in a cream form, a vaginal ring, and vaginal tablets. It's important to note that all of these therapies are effective in the treatment and prevention of atrophic vaginitis.

The distinctions to be drawn are that the vaginal ring -- this particular vaginal ring -- releases a small dose of estrogen over the course of 3 months. The vaginal tablets are placed twice weekly -- after a priming of 2 weeks, they're used daily, and offer a metered, low-dose therapy with systemic levels that do not exceed the systemic estradiol levels of postmenopausal women not using therapy. In other words, these 2 therapies have been studied and serum levels of estradiol have been shown to remain low and in the postmenopausal range, even in women who have effective treatment of their local symptoms. Women using creams also have effective treatment of their symptoms. But correlation with systemic levels are somewhat more difficult due to the variation in dosing that's inherent with the applicator used with the creams.

Phil Sarrel has published many papers that correlated the lower serum estrogen levels with an increase in the prevalence of sexual problems. Sexual dryness, pain, intensity of pain with intercourse, and burning are all increased in postmenopausal women -- even in premenopausal women who have a serum level of estradiol less than 50 pg/mL.

Lorraine Dennerstein, in addition to publishing the effects of age and menopause on vaginal atrophy and dryness, has also studied the effect of menopause per se and sexual dysfunction. Responsivity is one of the first and most dramatic things to decline in the premenopause and perimenopause, as well as a decrease in frequency of sexual activity, a decrease in libido, an increase in both vaginal dyspareunia, and problems with partners. These things, generally speaking, do not improve with time, although relationships [with a partner] appear to be moderated at the end of the menopausal period. Everything else continues to get dramatically worse, especially vaginal dyspareunia.

We can see from this information that vaginal atrophy is common. In fact, there are more women today alive suffering from vaginal dryness, dyspareunia, and vaginal atrophy than have currently ever made it to be menopausal in the history of humankind. Atrophic vaginitis is easily identifiable not only by symptoms, but also by objective evidence, by looking at tissues, and if necessary, by measuring the pH of the vaginal discharge or effluvium. And it is associated with significant, preventable dysfunction. Vaginal atrophy, I think you would conclude as well as I do, is both treatable and preventable. Thank you.

Dr. Keen: Thank you, Dr. Arias, for that excellent review.

Our next expert is going to address the treatment of atopic vaginitis. Dr. George Gorodeski is Professor of Reproductive Biology, Oncology, and Physiology and Biophysics, Case Western Reserve University and University Hospital, Case Medical Center, Cleveland, Ohio. Welcome, Dr. Gorodeski.

George Gorodeski, MD: Thank you. I'm glad I can be here. I would like to talk about the treatment of atrophic vaginitis.

Based on what we heard before, who is a typical patient seeking symptom relief? About 80% of postmenopausal women are symptomatic. About 20% present with atrophic vaginitis symptoms. Of those, about 1% to 5% will seek specific treatment for atrophic vaginitis symptoms. Many will seek treatment at a relatively advanced age, about 5 to 10 years after menopause. The reason, as we have heard, is an age-related increase in the severity of symptoms -- less than 5% among premenopausal women, going up to about 25% of women by 1 year after menopause, and to 50% by years 3 to 5.

Estrogenic treatment is considered the most effective treatment for symptomatic relief of atrophic vaginitis problems. It is the most accepted treatment among patients and clinicians, despite the turmoil that the field has undergone within the past 10 years. However, it should be patient-driven and patient-tailored.

What can patients expect in terms of estrogenic treatment? A reversal, to a degree, of the vaginal atrophy, promotion of growth and maturation of vaginal cells, enhanced blood flow to vaginal tissue, and a decrease in pH, due to a direct effect on the vaginal epithelial cells.

When we consider estrogenic treatment, we should remember that we use the lowest effective dose of estrogen administered for the shortest possible duration. However, because of the progressive chronic nature of atrophic vaginitis, treatment may be required for a relatively long duration. Therefore, extended use of low-dose estrogenic treatment for atrophic vaginitis, although acceptable, should be individualized in each case, weighing the benefits vs risks.

In the following presentation I will use the common abbreviation for hormone treatment -- HT -- indicating hormone replacement treatment of estrogen and progesterone prescribed for postmenopausal women, and the term estrogen treatment -- ET -- referring to estrogen treatment only.

In general, there are 2 modalities of HT intended for relief of vaginal symptoms: relief of systemic plus, secondarily, vaginal symptoms, and relief of primarily vaginal symptoms. When we consider the hormone treatment relief of systemic symptoms, oral therapy is the most utilized [treatment] method worldwide. The effective systemic hormone treatment therapy requires attainment of plasma levels of 17-beta estradiol of 30-60 pg/mL, or equivalent estrogen activity in the case of conjugated estrogen. Systemic HT administered via oral, vaginal, or transdermal routes (including the patch, gel, and lotions/emulsions) can improve vaginal symptoms of atrophic vaginitis. However, vaginal preparations are usually more potent for alleviating symptoms of atrophic vaginitis than oral or transdermal preparations.

The US Food and Drug Administration (FDA)-approved vaginal preparation for relief of systemic symptoms is currently the vaginal ring, containing 17-beta estradiol -- which can be obtained at 2 doses: 50 or 100 mcg. It is recommended to be used every 3 months.

Preparations for relief of systemic symptoms, including vaginal preparations, are intended primarily to alleviate vasomotor symptoms and prevent bone loss. They usually have a favorable effect on vaginal tissue, but improvement in vaginal symptoms is less consistent. These preparations can also increase plasma activity of estrogen above the postmenopausal level.

Three forms of caution should be mentioned regarding the long-term use of HT for systemic symptoms, including the use of vaginal preparations: (1) long-term use has been associated with an increased risk of breast cancer, (2) long-term use begun after age 60 has been associated with an increased risk of cardiovascular disease, and (3) long-term use unopposed by progesterone may induce endometrial proliferation and bleeding, and may lead to endometrial hyperplasia and cancer in patients with a uterus.

Vaginal ET is a modality that is more specific for treating patients with atrophic vaginitis. As we know, the efficacy of treatment depends on levels/activity in vaginal cells of the estrogen receptor-alpha (ER-alpha) and of ligands such as 17-beta estradiol that bind with high affinity to ER-alpha. This ER-alpha activity in vaginal cells decreases with age. Vaginal estrogen therapy may require long-term treatment with increasing dosage of the hormone. However, the effective dose of vaginal ET is usually smaller than that of ET used for systemic symptom relief.

One of the advances made in recent years has been the generation of new forms of vaginal ET, particularly low-dose vaginal therapies for relief of atrophic vaginitis symptoms. It is now realized that systemic estrogen therapy may not alleviate vaginal symptoms. Five percent to 10% of women treated with oral or transdermal estrogen for relief of vaginal symptoms may require ET applied directly to the vagina. Vaginal ET, intended for alleviation for vaginal symptoms, requires lower doses of hormone than systemic therapy. Therefore, the low-dose vaginal ET is the preferred therapy for women whose primary complaints are related to atrophic vaginitis.

Currently FDA-approved vaginal preparations for relief of vaginal symptoms include 2 types of vaginal creams: 1 containing conjugated equine estrogens (Premarin cream) and 1 (Estrace) vaginal cream containing 17-beta estradiol. The recommended doses and mode of treatment are shown in the table here.

However, there are now relatively new FDA-approved low-dose vaginal preparations for relief of vaginal symptoms. The 2 of those are a vaginal tablet (Vagifem) and the vaginal ring (Estring), both containing 17-beta estradiol. The vaginal tablet is obtained as a 25-mcg tablet preparation; it should be used once a day every day for the first 2 weeks and then continued twice a week. The vaginal ring, containing 7.5-mcg 17-beta estradiol, is recommended to be used every 3 months.

When considering the efficacy of the low-dose vaginal estrogen preparations, we should remember that the vaginal effects are comparable or better than those following systemic HT. The long-term effects are better than those with placebo or nonestrogen treatment, and the preparations improved symptoms and signs of atrophic vaginitis within 3 weeks in more than 80%. Less than 10% of patients experience discharge and/or loss of medication following application.

With regard to safety of the low-dose vaginal estrogen preparations, these preparations induce a small transient increase in plasma 17-beta estradiol. However, levels remain low -- in the postmenopausal range. Patients may complain of vaginal discharge in the form of leukorrhea, which is a common, expected side effect. Caregivers and physicians should explain to patients that they may anticipate this effect.

Interestingly, there are some studies showing that long-term treatment may improve density and reduce serum cholesterol, low-density lipoprotein, and apolipoprotein; the mechanism of this effect is not clear in view of the very mild increase in plasma 17-beta estradiol. Low-dose vaginal therapies are unlikely to experience adverse systemic events, but long-term risk analysis for use longer than 1 year has not been reported.

When considering the risk assessment in patients using long-term, low-dose vaginal ET, one of the important factors is the endometrium, which is the most sensitive tissue to estrogen. Approximately 5% of women may develop endometrial proliferative changes, or exhibit some endometrial response to progesterone. However, no cases of atypical hyperplasia or endometrial cancer have been reported.

It should also be remembered that the estrogen effect on uterine blood flow varies by the vaginal application site. It may increase when estrogen is applied near the cervix and posterior fornix, but it does not change when applied to the distal vagina.

One of the questions that caregivers face with regard to long-term use of low-dose vaginal ET is endometrial protection. In contrast to systemic treatment with estrogen, the addition of a progestin to protect the uterus is not necessary when vaginal ET is administered for less than 3 to 6 months.

At present, there is no evidence-based recommendation to add progestin for women with an intact uterus that are being treated for more than 6 months with low-dose vaginal estrogen preparations.

However, it is my opinion that women with an intact uterus on schedules of low-dose vaginal therapy for longer than 6 to 12 months should be considered for evaluation of endometrial changes. Meticulous endometrial evaluation should be undertaken in women with repeated and marked uterine bleeding, chronic alcohol users, or those with altered liver metabolism.

Endometrial evaluation usually includes office endometrial biopsy but it may require pelvic ultrasound examination, hysteroscopy, and/or dilatation and curettage (D&C).

In addition to estrogen treatment for the relief of atrophic vaginitis symptoms, a number of papers and studies have dealt with nonhormonal remedies for the relief of atrophic vaginitis. Nonhormonal vaginal moisturizers and lubricants are typically used to dyspareunia-related symptoms, but can also be used to alleviate symptoms of atrophic vaginitis in breast cancer survivors (I will talk more about this in a minute). The vaginal moisturizer Replens was found to be effective for the short-term alleviation of vaginal symptoms. Other vaginal moisturizers may also be effective, but have not been tested in randomized trials.

It should be remembered with regard to the nonhormonal remedies that compounds contained in hand cream such as alcohol and perfume can cause or exacerbate vaginal burning and itching. Oil-based products such as petroleum jelly and baby oil can cause vaginal irritation and increase the risk of vaginal infection. Vinegar douches or cultures of lactobacilli are not as effective as moisturizers.

The last topic that I would like to address is the dilemma of hormone treatment, particularly estrogen treatment for breast cancer survivors. Breast cancer survivors, including younger women following chemotherapy with early induced menopause, may present with severe vaginal symptoms. Although a number of prospective cohort studies have dealt with the possible advantages of HT/ET, estrogen treatment in those women, 3 prospective randomized controlled studies of hormone treatment in symptomatic early stage breast cancer survivors were stopped prematurely because interim analysis suggested an increase in disease recurrence.

Safety of HT use in estrogen receptor-negative or in estrogen receptor-positive cases -- in the presence of a selective estrogen-receptor modulator -- isn't clear. It should be realized there are conflicting data about the use of low-dose vaginal estrogenic preparations to alleviate symptoms of atrophic vaginitis in breast cancer survivors.

To summarize, symptoms related to atrophic vaginitis are common in postmenopausal women. The severity of symptoms increases with age and time after the onset on menopause. At present, more women request treatment. Hormone treatment, in particular estrogen treatment, is the most effective and most commonly prescribed by caregivers. The development of low-dose vaginal estrogen preparations provides an important, effective, and relatively safe modality of treatment to those patients.

Dr. Keen: Thanks to both of our experts today for providing this up-to-date overview of atrophic vaginitis. Thanks also to the Medscape audience.

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Supported by an independent educational grant from NovoNordisk