Bertha Chen

Menopausal symptoms and treatment-related effects of estrogen and progestin in the women's health initiative

OBJECTIVE: To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women. METHODS: Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50–79 (mean ± standard deviation 63.3 ± 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out. RESULTS: Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40–5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04–3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90–3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24–1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08–1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59–5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44–5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27–1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08–1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001). CONCLUSION: Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery. LEVEL OF EVIDENCE: I

Collagen Metabolism and Turnover in Women with Stress Urinary Incontience and Pelvic Prolapse

The aim of this study was to investigate quantitative mRNA expression of matrix metalloproteinases MMP-1, MMP-2, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, in vaginal wall tissue from women with stress urinary incontinence compared to continent controls. Vaginal wall tissues were obtained from 7 women with stress urinary incontinence/severe pelvic prolapse and 15 continent controls. RNA was then extracted and quantified. Quantitative competitive reverse transcription (QC-RT-PCR) was carried out with oligonucleotide primers to quantify MMP-1, MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-3 mRNA expression. Stress continent women demonstrated a significant decrease in TIMP-1 and mRNA expression (P= 0.03). There was no difference in TIMP-2, TIMP-3, MMP-2 or MMP-9 mRNA expression between stress incontinent women and controls. However, MMP-1 mRNA expression was significantly increased (P= 0.05) in the incontinent group and the MMP-1/TIMP-1 ratio (P= 0.04) was consistent with increased collagen degradation in the stress incontinence. Stress incontinent women demonstrated an increase in MMP-1 mRNA expression and a decrease in the inhibitor TIMP-1 mRNA expression. Both these findings are consistent with increased collagen breakdown as a pathologic etiology of incontinence.

DISTINCTIVE PROLIFERATIVE PHASE DIFFERENCES IN GENE EXPRESSION IN HUMAN MYOMETRIUM AND LEIOMYOMATA

OBJECTIVE To gain a comprehensive view of the gene expression and regulation involved in uterine leiomyomata and matched normal myometrium using oligonucleotide microarray-based hybridization analysis. DESIGN Retrospective analyses of tissue obtained in a prospective randomized clinical study. SETTING Academic institution. PATIENT(S) Seven patients with leiomyomata scheduled for surgery during the proliferative phase. INTERVENTIONS(S) Seven paired samples of leiomyomata and adjacent myometrium were obtained from patients undergoing hysterectomy. MAIN OUTCOME MEASURE(S) The total RNA extracted from leiomyomata and myometrium was used for gene expression profiling of 6800 human genes using high-density oligonucleotide microarrays. In addition, reverse transcriptase-semiquantitative polymerase chain reaction and immunohistochemistry were used to validate tumor-specific gene expression. RESULT(S) A comparison of expression patterns in each paired sample revealed 68 genes significantly up- or down-regulated in each paired tissue sample, of which 23 genes showed increased expression and 45 showed decreased expression in leiomyomata compared with normal myometrium. Cluster analysis supported the relevance of these candidate genes for distinguishing between normal myometrium and leiomyomata biologic activity. CONCLUSION(S) Expression profiling of uterine leiomyomata using high-density oligonucleotide microarrays yields signature patterns that reflect the distinctive differences between normal human myometrium and leiomyomata during the proliferative phase. These observations suggest that a number of genes are involved in the tumorigenesis of leiomyomata.

Alterations in connective tissue metabolism in stress incontinence and prolapse.

PURPOSE We describe current knowledge about collagen/elastin and extracellular matrix metabolism in the genitourinary tract with special emphasis on stress urinary incontinence. We also explored the influence of genetics and reproductive hormones on extracellular matrix metabolism. MATERIALS AND METHODS We performed a MEDLINE® search from 1995 to February 2011 using the key words stress urinary incontinence, pelvic organ prolapse, extracellular matrix, collagen, elastin, matrix metalloproteinase, collagenase, tissue inhibitors of matrix metalloproteinase, elastin metabolism, elastase, connective tissue, supportive tissue, mechanical stress, biomechanical properties, selective estrogen receptor modulators, transforming growth factor-β and wound healing. RESULTS The literature searched produced data on 4 areas of significance for extracellular matrix metabolism in patients with stress urinary incontinence and prolapse, including collagen, elastin and transforming growth factor-β. Data on collagen metabolism continue to support the hypothesis of increased turnover involving matrix metalloproteinases and serine proteases in pelvic tissues of affected individuals. Elastin metabolism studies suggest increased degradation but also abnormal elastin fiber synthesis. Epidemiological data indicate a genetic predisposition to abnormal extracellular matrix in affected individuals while human tissue and animal models reveal differential expression of candidate genes involved in structural proteins. Transforming growth factor-β pathways have been documented to be involved in stress urinary incontinence in human tissues and animal models. Finally, these extracellular matrix metabolisms are modulated by reproductive hormones and selective estrogen receptor modulators. CONCLUSIONS Pelvic tissue from women with stress urinary incontinence and pelvic organ prolapse show a genetic predisposition to abnormal extracellular matrix remodeling, which is modulated by reproductive hormones, trauma, mechanical stress load and aging. This progressive remodeling contributes to stress urinary incontinence/pelvic organ prolapse by altering normal tissue architecture and mechanical properties.

Retained Products of Conception Spectrum of Color Doppler Findings

Objective. The purpose of this study was to characterize color Doppler imaging features of retained products of conception (RPOC) with gray scale correlation. Methods. Clinically suspected cases of RPOC between January 2005 and February 2008 were reviewed. Patient data and relevant color Doppler and gray scale features were recorded. Results. A total of 269 patients referred for sonographic evaluation for RPOC were identified. Thirty‐five patients had confirmed pathologic diagnoses, 28 of whom had RPOC. In those with RPOC, 5 (18%) were avascular (type 0); 6 (21%) had minimal vascularity (type 1); 12 (43%) had moderate vascularity (type 2); and 5 (18%) had marked vascularity (type 3). Peak systolic velocities ranged from 10 to 108 cm/s (average, 36.1 cm/s). Resistive indices in arterial waveforms ranged from 0.33 to 0.7 (average, 0.5). Five (45%) of the patients with type 0 vascularity had RPOC; 6 (86%) of those with type 1 had RPOC; and 17 (100%) of those with types 2 and 3 had RPOC. An echogenic mass had a moderate positive predictive value (80%) but low sensitivity (29%) for RPOC. Conclusions. Color Doppler evaluation of the endometrium is helpful in determining the presence of RPOC. Endometrial vascularity is highly correlated with RPOC, whereas the lack of vascularity can be seen in both intrauterine clots and avascular RPOC.

Robot-Assisted Versus Open Sacrocolpopexy: A Cost-Minimization Analysis

PURPOSE Abdominal sacrocolpopexy is considered a standard of care operation for apical vaginal vault prolapse repair. Using outcomes at our center we evaluated whether the robotic approach to sacrocolpopexy is as cost-effective as the open approach. MATERIALS AND METHODS After obtaining institutional review board approval we performed cost-minimization analysis in a retrospective cohort of patients who underwent sacrocolpopexy at our institution between 2006 and 2010. Threshold values, that is model variable values at which the most cost effective approach crosses over to an alternative approach, were determined by testing model variables over realistic ranges using sensitivity analysis. Hospital billing data were also evaluated to confirm our findings. RESULTS Operative time was similar for robotic and open surgery (226 vs 221 minutes) but postoperative length of stay differed significantly (1.0 vs 3.3 days, p <0.001). Base case analysis revealed an overall 10% cost savings for robot-assisted vs open sacrocolpopexy (

Impact of the 2011 FDA transvaginal mesh safety update on AUGS members' use of synthetic mesh and biologic grafts in pelvic reconstructive surgery.

10,178 vs

Radiofrequency Treatment of Vaginal Laxity after Vaginal Delivery: Nonsurgical Vaginal Tightening

11,307). Tornado analysis suggested that the number of institutional robotic cases done annually, length of stay and cost per hospitalization day in the postoperative period were the largest drivers of cost. Analysis of our hospital billing data showed a similar trend with robotic surgery costing 4.2% less than open surgery. CONCLUSIONS A robot-assisted approach to sacrocolpopexy can be equally or less costly than an open approach. This depends on a sufficient institutional robotic case volume and a shorter postoperative stay for patients who undergo the robot-assisted procedure.

Concurrent Generation of Functional Smooth Muscle and Endothelial Cells via a Vascular Progenitor

Objective To describe the frequency of use and recent change in use of synthetic mesh and biologic grafts in pelvic organ prolapse (POP) and stress urinary incontinence surgery by American Urogynecology Society (AUGS) members. Methods An electronic survey of AUGS members was conducted between December 2011 and January 2012. Frequency of graft use in POP (overall and by transvaginal and transabdominal approaches) and stress urinary incontinence surgery was queried relative to the timing of the 2011 Food and Drug Administration (FDA) safety update. Rates of materials’ use before and after the statement were compared using Wilcoxon signed rank test. Results Fifty-three percent (507/962) of AUGS members responded and were included in analysis; 79% were urogynecologists. Before the FDA warning, in POP surgery, most (90%) used synthetic mesh and fewer (34%) used biologic grafts; 99% used synthetic mesh slings. After the FDA statement, respondents reported an overall decrease in the percent of POP cases in which they used synthetic mesh (P < 0.001) but no change in biologic graft use for POP (P = 0.37) or synthetic mesh sling use (P = 0.10). Specifically, transvaginal mesh use decreased: 40% reported decreased use and 12% stopped use. However, transvaginal mesh was still used by 61% of respondents in at least some cases. No change (62%) or increased use (12%) of mesh was reported for transabdominal POP procedures. Conclusions Synthetic mesh use in transvaginal POP surgery decreased after the 2011 FDA safety update, but synthetic mesh use for transabdominal POP repair and sling procedures and overall biologic graft use in POP surgery did not decrease.

Biomechanical Properties and Associated Collagen Composition in Vaginal Tissue of Women with Pelvic Organ Prolapse

INTRODUCTION All women who have given birth vaginally experience stretching of their vaginal tissue. Long-term physical and psychological consequences may occur, including loss of sensation and sexual dissatisfaction. One significant issue is the laxity of the vaginal introitus. AIM To evaluate safety and tolerability of nonsurgical radiofrequency (RF) thermal therapy for treatment of laxity of the vaginal introitus after vaginal delivery. We also explored the utility of self-report questionnaires in assessing subjective effectiveness of this device. METHODS Pilot study to treat 24 women (25-44 years) once using reverse gradient RF energy (75-90 joules/cm(2) ), delivered through the vaginal mucosa. Post-treatment assessments were at 10 days, 1, 3, and 6 months. MAIN OUTCOME MEASURES Pelvic examinations and adverse event reports to assess safety. The author modified Female Sexual Function Index (mv-FSFI) and Female Sexual Distress Scale-Revised (FSDS-R), Vaginal Laxity and Sexual Satisfaction Questionnaires (designed for this study) to evaluate both safety and effectiveness, and the Global Response Assessment to assess treatment responses. RESULTS No adverse events were reported; no topical anesthetics were required. Self-reported vaginal tightness improved in 67% of subjects at one month post-treatment; in 87% at 6 months (P<0.001). Mean sexual function scores improved: mv-FSFI total score before treatment was 27.6 ± 3.6, increasing to 32.0 ± 3.0 at 6 months (P < 0.001); FSDS-R score before treatment was 13.6 ± 8.7, declining to 4.3 ± 5.0 at month 6 post-treatment (P < 0.001). Twelve of 24 women who expressed diminished sexual satisfaction following their delivery; all reported sustained improvements on SSQ at 6 months after treatment (P = 0.002). CONCLUSION The RF treatment was well tolerated and showed an excellent 6-month safety profile in this pilot study. Responses to the questionnaires suggest subjective improvement in self-reported vaginal tightness, sexual function and decreased sexual distress. These findings warrant further study.