COCHRANE FOR CLINICIANS: PUTTING EVIDENCE INTO PRACTICE

Vaginal Estrogen Preparations for Relief of Atrophic Vaginitis

MELISSA NOTHNAGLE, M.D., and JULIE SCOTT TAYLOR, M.D., M.SC., Brown Medical School, Providence, Rhode Island

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Melissa Nothnagle, M.D., and Julie Scott Taylor, M.D., M.Sc., present a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB001500.htm.

Clinical Scenario

A 60-year-old woman presents with vaginal dryness and dyspareunia. She has declined systemic hormone therapy because of concerns about potential complications.

Clinical Question

Should we prescribe a vaginal estrogen preparation for relief of atrophic vaginitis?

Evidence-Based Answer

Vaginal estrogen preparations are safe and effective as short-term treatment in patients with vaginal atrophy who are not candidates for systemic hormone therapy. Compared with estradiol products, conjugated equine estrogen creams may be associated with a higher incidence of adverse effects. Women may prefer the estradiol-releasing vaginal ring over other delivery systems.

Cochrane Abstract Background. Vaginal atrophy is a frequent condition in postmenopausal women. Symptoms include vaginal dryness, itching, discomfort, and painful intercourse. Treatment with oral hormone therapy is not always necessary; alternatives include estrogenic preparations administered vaginally (e.g., creams, pessaries, tablets, and the estradiol-releasing ring). Objectives. To compare the effectiveness, safety, and acceptability of estrogenic preparations for women with vaginal atrophy. Search Strategy. The authors1 searched the Cochrane Menstrual Disorders and Subfertility Group register of trials (searched January 2003), the Cochrane Library (Issue 2, 2003), MEDLINE (1966 to January 2003), EMBASE (1980 to January 2003), Current Contents (1993 to January 2003), Biological Abstracts (1969 to 2002), Social Sciences Index (1980 to January 2003), PsycINFO (1972 to February 2003), CINAHL (1982 to January 2003), and reference lists of articles. They also contacted manufacturers and researchers in the field. Selection Criteria. Randomized comparisons of estrogenic preparations administered intravaginally in postmenopausal women for the treatment of symptoms of vaginal atrophy or vaginitis were included. Data Collection and Analysis. Of the 29 trials identified, 13 were excluded. Trials were assessed for quality, and two reviewers extracted data independently. Ratios for dichotomous and means for continuous outcomes were estimated. Outcomes analyzed were included under the headings of efficacy, safety, and acceptability. Primary Results. Sixteen trials with 2,129 women were included in this review. The overall quality of the studies was good, although not all trials measured the same outcomes. All trials measured efficacy with various outcome measures. When comparing efficacy of estrogenic preparations (in the form of creams, pessaries, tablets, and the estradiol-releasing vaginal ring) in relieving the symptoms of vaginal atrophy, results indicated significant differences in favor of the cream, ring, and tablets. Fourteen trials compared safety. Four focused on hyperplasia, four focused on endometrial overstimulation, and six focused on adverse effects. One trial found significant adverse effects (i.e., uterine bleeding, breast pain, perineal pain) associated with conjugated equine estrogen cream compared with estradiol tablets (odds ratio [OR], 0.18; 95 percent confidence interval [CI], 0.07 to 0.50). Two trials found significant endometrial overstimulation (as evaluated by a progestogen challenge test) in women who used the cream compared with women who used the ring (OR, 0.29; 95 percent CI, 0.11 to 0.78). Although not statistically significant, there was a 2 percent incidence of simple hyperplasia in women who used the ring compared with women who used cream, and a 4 percent incidence of hyperplasia in women who used cream compared with women who took estradiol tablets. Nine studies compared acceptability by comparing comfort of the product, ease of use, overall product rating, delivery system, and satisfaction. Results showed a significant preference for the estradiol-releasing vaginal ring. Reviewers' Conclusions. Creams, pessaries, tablets, and the estradiol-releasing vaginal ring appeared to be equally effective in treating the symptoms of vaginal atrophy. One trial found significant side effects (i.e., uterine bleeding, breast pain, perineal pain) in women who used conjugated equine estrogen cream compared with women who took tablets. Another trial found significant endometrial overstimulation in women who used a cream compared with women who used the ring. As a treatment choice, women appeared to favor the estradiol-releasing vaginal ring for its ease of use, comfort, and overall satisfaction. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Practice Pointers

Decreased estrogen levels after menopause are associated with multiple changes in vaginal tissue, including reduced blood flow, decreased collagen content, decreased mucosal thickness, and increased pH. These physiologic changes may manifest as vaginal dryness, pruritus, dyspareunia, and recurrent infection. The estimated prevalence of symptoms related to vaginal atrophy in healthy postmenopausal women varies widely but affects a significant number of women.2,3

Hormone therapy is effective in treating vaginal atrophy in postmenopausal women, but some patients and physicians prefer to avoid systemic hormone therapy because of potential harmful effects. Topical estrogen preparations offer an alternative approach to managing symptoms of vaginal atrophy. Several products are available in the United States, including estradiol vaginal creams, tablets, and rings, and conjugated equine estrogen vaginal creams. Because topical estrogen delivery avoids hepatic first-pass metabolism, lower dosages are needed for symptom relief compared with oral therapy.

In the studies reviewed, adverse effects from vaginal estrogens were rare. In one trial, conjugated equine estrogen cream was associated with more adverse effects, including vaginal bleeding, breast pain, and perineal pain, than estradiol vaginal tablets. Two studies showed increased rates of endometrial hyperstimulation (measured by bleeding after a progesterone challenge) in women using conjugated equine estrogen cream compared with women using the estradiol ring. However, this finding is difficult to interpret because of differences in dosing recommendations among the various estrogen preparations.

For example, conjugated equine estrogen cream was prescribed according to the manufacturers' instructions, at dosages of 0.625 to 1.25 mg per day. This dosage is similar to the usual dosage of oral conjugated equine estrogens in hormone therapy. In contrast, daily dosages of estradiol delivered by the estradiol-releasing ring or vaginal estradiol cream are about one tenth the recommended oral dosage of estradiol in hormone therapy. The higher relative dosage of vaginal conjugated equine estrogens may explain the greater incidence of adverse effects.

Accordingly, two studies that evaluated serum estradiol levels found higher levels in women using conjugated equine estrogen cream than in women taking estradiol tablets; the lowest levels were found in women using the estradiol ring. Even the highest serum estradiol levels were within the normal menopausal range.

Vaginal estrogen therapy is indicated for short-term treatment of symptoms related to vaginal atrophy in postmenopausal women. In women with an intact uterus, progestin treatment is not needed for short-term local estrogen treatment.4 However, data are limited about the use of local estrogen therapy for longer than six months. Patients should not be prescribed vaginal estrogens if they have undiagnosed vaginal bleeding, current breast cancer, history of endometrial cancer, or a thromboembolic disorder, or are pregnant or breastfeeding. Local estrogen therapy should be used with caution in patients with impaired liver function.

Postmenopausal bleeding in women using local estrogen therapy should be evaluated as in any other postmenopausal patient. In women with a history of breast cancer, systemic estrogen or progesterone therapy is contraindicated because of the increased risk of breast cancer recurrence. Vaginal estrogen preparations often are used to treat symptoms of vaginal atrophy in these patients because of the low levels of systemic absorption.5

Manufacturers of all products available in the United States recommend limiting treatment to three to six months. Anecdotally, many physicians prescribe vaginal estrogens for periods much longer than three to six months, but data on long-term safety are lacking. The current review is limited to short-term studies (three to six months of follow-up) with small numbers of participants (ranging from 30 to 251 women). Further trials that provide data on long-term safety of local estrogen therapy are needed.

Melissa Nothnagle, M.D., is clinical assistant professor of family medicine at Brown Medical School in Providence, R.I. She is also assistant residency director in family medicine.

Julie Scott Taylor, M.D., M.Sc., is assistant professor of family medicine at Brown Medical School. She is also director of predoctoral education in family medicine.

Address correspondence to Melissa Nothnagle, M.D., Department of Family Medicine, Memorial Hospital of Rhode Island, 111 Brewster St., Providence, RI 02860 (e-mail: Melissa_nothnagle@mhri.org). Reprints are not available from the authors.

REFERENCES

1. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2003:CD001500.

2. Rekers H, Drogendijk AC, Valkenburg HA, Riphagen F. The menopause, urinary incontinence and other symptoms of the genito-urinary tract. Maturitas 1992;15:101-111.

3. Molander U, Milsom I, Ekelund P, Mellstrom D. An epidemiological study of urinary incontinence and related urogenital symptoms in elderly women. Maturitas 1990;12:51-60.

4. Willhite LA, O'Connell MB. Urogenital atrophy: prevention and treatment. Pharmacotherapy 2001;21:464-80.

5. Pritchard KI. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer and a review of possible alternatives. Ann Oncol 2001;12:301-10.