LAS VEGAS – Application of vaginal estrogen cream 6 weeks before undergoing hysterectomy resulted in increased thickness of both the vaginal epithelium and the muscularis, results of a randomized trial showed.
"Surgical repair remains the mainstay treatment for symptomatic prolapse," Dr. David D. Rahn said at the annual meeting of the American Urogynecologic Society. "Despite advances in surgical techniques, reoperation for recurrent prolapse is common. Clearly, there are significant trade-offs to adding graft material to surgical repairs. Given that our population is aging, there will be more women requiring surgical management of prolapse. Therefore, there’s a need to identify adjuncts to native tissue prolapse repairs that may minimize recurrent disease or lessen the likelihood of graft-associated complications."
Dr. David D. Rahn
Both basic science and clinical investigations indicate that estrogen plays an important role in the function of supportive connective tissues at the pelvic floor, said Dr. Rahn of the department of obstetrics and gynecology at the University of Texas Southwestern Medical Center, Dallas. However, clinical research regarding the effects of systemic hormone therapy on prevention or treatment of prolapse "has led to contradictory findings, with some studies suggesting a protective effect while others demonstrating either no difference or perhaps higher rates of prolapse in women using hormone therapy."
To determine the effects of vaginal estrogen on collagen synthesis in connective tissues of the vaginal muscularis and mucosa in postmenopausal women, Dr. Rahn and his associates enrolled 30 women who were 1-10 year postmenopausal with at least stage 2 anterior or apical prolapse planning total hysterectomy as part of a surgical repair. They excluded women with a body mass index of greater than 35 kg/m2, current users of tobacco or steroids, and those with a vaginal infection. Of the 30 patients, 15 were randomized to receive Premarin, a conjugated estrogens cream, while the remaining 15 received placebo cream. "They were instructed to apply 1 g using the plastic applicator nightly for 2 weeks and then twice weekly for 4 more weeks until surgery," Dr. Rahn said. "A computer-generated randomization table was used to allocate patients to one of the treatment groups. Only the pharmacist remained unblinded to treatment allocation."
The researchers performed histomorphology, quantitative polymerase chain reaction, hydroxyproline assays, and immunoblot analyses to evaluate vaginal epithelium and muscularis from standardized full thickness anterior vaginal cuff biopsies obtained at the time of surgery. Zymography was used to assess matrix metalloproteinase (MMP) activity.
Full biopsy data were available from 12 patients in each arm. Dr. Rahn reported that their mean age was 57 years, slightly more than half (57%) were Hispanic, and their mean BMI was 30.5 kg/m2. On histological assessment, the epithelial and the muscularis layer were thicker among samples from women treated with estrogen. Specifically, mean epithelial thickness was increased 1.8-fold in the estrogen group, while the muscularis thickness was increased 2.7-fold.
To determine if these estrogen-induced increases in muscularis thickness were associated with increased collagen synthesis, relative messenger RNA levels of collagen type I, alpha-1, type I, alpha-2, and collagen type III mRNA were quantified in the muscularis samples from both groups. Collagen I, alpha-1 was increased sixfold in the vaginal muscularis in the estrogen group, while collagen type I, alpha-2 and collagen type III mRNA were increased 1.8- and 2.5-fold, respectively.
Immunoblot analysis was completed in four patients in each treatment group who had sufficient tissue for protein analysis. Collagen type 1a monomers, dimers, and trimers were all increased 10-fold in the muscularis from samples of women treated with estrogen. In contrast, differences in collagen 3 protein were not significant. Further, with respect to matrix degradation, in patients adherent with local estrogen, human macrophage elastase mRNA was suppressed in the vaginal mucosa from estrogen-treated participants, and MMP-9 activity was decreased 6-fold in the mucosa and 4-fold in the muscularis. There was no change in expression of several protease inhibitors.
"Our findings from this trial suggest that 6 weeks of preoperative vaginal estrogen in postmenopausal women with prolapse may improve the substrate for suture placement at the time of repair while mitigating surgical induction of several degradative enzymes," Dr. Rahn concluded.
The study was funded by an Astellas Research Award/AUGS Foundation grant. Dr. Rahn said that he had no relevant financial conflicts to disclose.