Genitourinary Syndrome of Menopause: Pathophysiology, Clinical Presentation, and Differential Diagnosis.

Scientific information is incomplete regarding the genitourinary syndrome of menopause. Both the lower genital and urinary tracts are rich in receptors for reproductive hormones and are highly susceptible to waning ovarian hormones at menopause. Symptoms of dryness and pain emerge in late perimenopause, but they can also result earlier from cancer therapies or bilateral oophorectomy. Lower urinary tract symptoms rise in prevalence at midlife and increase further with advancing age. Because ovarian senescence is typically followed by years of aging, some postmenopausal complaints may be attributable to increasing longevity.

Improving management of the genitourinary syndrome of menopause: evaluation of a health system-based, cluster-randomized intervention.

BACKGROUND: Genitourinary symptoms are common in postmenopausal women and adversely affect the quality of life. National surveys and data collected from our healthcare system indicate that postmenopausal women with the genitourinary syndrome of menopause often fail to receive appropriate diagnosis or treatment. OBJECTIVE: To promote greater detection and treatment of the genitourinary syndrome of menopause, we created and tested a clinician-focused health system intervention that included clinician education sessions and a suite of evidence-based electronic health record tools. STUDY DESIGN: Using a cluster-randomized design, we allocated primary care (16) and gynecology (6) clinics to the intervention or control group. From September to November 2014, we provided training about the diagnosis and treatment of genitourinary syndrome of menopause in face-to-face presentations at each intervention clinic and in an online video. We developed clinical decision support tools in the electronic health record that contained an evidence-based, point-of-care knowledge resource, a standardized order set, and a checklist of patient education materials for the patient's after visit summary. The tools aimed to facilitate accurate diagnostic coding and prescribing (SmartSet, SmartRx) along with relevant patient information (SmartText). Clinicians who only performed visits at control clinics received no training or notification about the tools. Our primary outcome was vulvovaginal diagnoses made at well visits for women at the age of 55 years and older from November 15, 2014 to November 15, 2015. We also assessed urinary diagnoses, vaginal estrogen prescriptions, and use of the electronic tools. There was departmental support for the intervention but no prioritization within the healthcare system to incentivize change. RESULTS: In the 1-year period, 386 clinicians performed 14,921 well visits for women at the age of 55 years and older. Among the 190 clinicians who performed well visits in the intervention clinics, 109 (57.4%) completed either in-person or online educational training. The proportion of visits that included a vulvovaginal (7.2% vs 5.8%; odds ratio, 1.27; 95% confidence interval, 0.65-2.51) or urinary diagnosis (2.5% vs 3.1%; odds ratio, 0.79; 95% confidence interval, 0.55-1.13) or vaginal estrogen prescription (4.5% vs 3.7%; odds ratio, 1.24; 95% confidence interval, 0.63-2.46) did not differ between study arms. There was a significant interaction for primary care and gynecology, which revealed more vulvovaginal diagnoses by gynecology but not primary care intervention clinics (odds ratio, 1.63; 95% confidence interval, 1.15-2.31), but there was no significant interaction for prescriptions. Clinicians in the intervention clinics were more likely to use decision support tools than those in control clinics-SmartSet (22.2% vs 1.5%; odds ratio, 18.8; 95% confidence interval, 5.5-63.8) and SmartText for patient information (38.0% vs 24.4%; odds ratio, 1.91; 95% confidence interval, 1.10-3.34). A per-protocol analysis revealed similar findings. CONCLUSION: Overall, the intervention did not lead to more diagnoses or prescription therapy for postmenopausal genitourinary symptoms but did result in greater distribution of patient information. Gynecology clinicians were more likely to address genitourinary symptoms generally and were more likely to make a vulvovaginal diagnosis after the intervention. Further efforts for improving care should consider ongoing clinician education beginning with enhanced menopause curricula in residency training. Additional interventions to consider include greater access for postmenopausal women to gynecologic care, addressing treatment barriers, and development of national performance metrics.

MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2.

Understanding cell cycle regulation in postmitotic cardiomyocytes may lead to new therapeutic approaches to regenerate damaged cardiac tissue. We have demonstrated previously that microRNAs encoded by the Gtl2-Dio3 noncoding RNA locus function downstream of the MEF2A transcription factor in skeletal muscle regeneration. We have also reported expression of these miRNAs in the heart. Here we investigated the role of two Gtl2-Dio3 miRNAs, miR-410 and miR-495, in cardiac muscle. Overexpression of miR-410 and miR-495 robustly stimulated cardiomyocyte DNA synthesis and proliferation. Interestingly, unlike our findings in skeletal muscle, these miRNAs did not modulate the activity of the WNT signaling pathway. Instead, these miRNAs targeted Cited2, a coactivator required for proper cardiac development. Consistent with miR-410 and miR-495 overexpression, siRNA knockdown of Cited2 in neonatal cardiomyocytes resulted in robust proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of VEGFA, a growth factor with proliferation-promoting effects. Therefore, miR-410 and miR-495 are among a growing number of miRNAs that have the ability to potently stimulate neonatal cardiomyocyte proliferation.

MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation.

Skeletal muscle differentiation requires precisely coordinated transcriptional regulation of diverse gene programs that ultimately give rise to the specialized properties of this cell type. In Drosophila, this process is controlled, in part, by MEF2, the sole member of an evolutionarily conserved transcription factor family. By contrast, vertebrate MEF2 is encoded by four distinct genes, Mef2a, -b, -c, and -d, making it far more challenging to link this transcription factor to the regulation of specific muscle gene programs. Here, we have taken the first step in molecularly dissecting vertebrate MEF2 transcriptional function in skeletal muscle differentiation by depleting individual MEF2 proteins in myoblasts. Whereas MEF2A is absolutely required for proper myoblast differentiation, MEF2B, -C, and -D were found to be dispensable for this process. Furthermore, despite the extensive redundancy, we show that mammalian MEF2 proteins regulate a significant subset of nonoverlapping gene programs. These results suggest that individual MEF2 family members are able to recognize specific targets among the entire cohort of MEF2-regulated genes in the muscle genome. These findings provide opportunities to modulate the activity of MEF2 isoforms and their respective gene programs in skeletal muscle homeostasis and disease.

MEF2D deficiency in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death in vitro.

The cardiomyocyte cell cycle is a poorly understood process. Mammalian cardiomyocytes permanently withdraw from the cell cycle shortly after birth but can re-enter the cell cycle and proliferate when subjected to injury within a brief temporal window in the neonatal period. Thus, investigating the mechanisms of cell cycle regulation in neonatal cardiomyocytes may provide critical insight into the molecular events that prevent adult myocytes from proliferating in response to injury or stress. MEF2D is a key transcriptional mediator of pathological remodeling in the adult heart downstream of various stress-promoting insults. However, the specific gene programs regulated by MEF2D in cardiomyocytes are unknown. By performing genome-wide transcriptome analysis using MEF2D-depleted neonatal cardiomyocytes, we found a significant impairment in the cell cycle, characterized by the up-regulation of numerous positive cell cycle regulators. Expression of Pten, the primary negative regulator of PI3K/Akt, was significantly reduced in MEF2D-deficient cardiomyocytes and found to be a direct target gene of MEF2D. Consistent with these findings mutant cardiomyocytes showed activation of the PI3K/Akt survival pathway. Paradoxically, prolonged deficiency of MEF2D in neonatal cardiomyocytes did not trigger proliferation but instead resulted in programmed cell death, which is likely mediated by the E2F transcription factor. These results demonstrate a critical role for MEF2D in cell cycle regulation of post-mitotic, neonatal cardiomyocytes in vitro.

Resident training to optimize patient-focused menopause management: a multispecialty menopause curriculum to enhance knowledge and preparedness.

OBJECTIVE: Surveys of residents in obstetrics and gynecology, internal medicine, and family medicine have demonstrated low levels of knowledge and comfort in treating patients with menopausal symptoms, suggesting a need for improved training during residency. To address this problem, we used a flipped classroom design to deliver a novel menopause curriculum for medical residents. The curriculum included six podcast episodes followed by an interactive case-based classroom session. We then assessed effects of the curriculum on the residents' knowledge and preparedness to manage menopause symptoms. METHODS: We targeted 200 residents (43 obstetrics and gynecology, 86 internal medicine, and 71 family medicine) from six residency programs from 2019 to 2020. Of these, 115 (58%) completed both pre- and postcurriculum assessments, including a 15-item knowledge test and self-ratings of their knowledge, comfort, and preparedness to manage menopause. RESULTS: Following the curriculum, the proportion of correctly answered knowledge questions rose from 60.8% to 79.1% (+18.3%; 95% confidence interval, 15.4-21.2; Cohen's d = 1.2). Improvement did not significantly differ by specialty or year of residency. There were higher gains for residents who listened to the entirety of all six podcast episodes ( b = 11.4, P < 0.001) and who attended the classroom session ( b = 11.6, P = 0.003). Residents' self-ratings of knowledge, comfort, and preparedness also improved following the curriculum across all medical specialties (Cohen's d = 0.47-1.2). Residents rated the podcast format as convenient (73%) and effective (65%) compared with an equivalent amount of reading. CONCLUSIONS: Pairing a podcast with a classroom discussion was found to be an effective combination for improving menopause knowledge.

Treating where it hurts-a randomized comparative trial of vestibule estradiol for postmenopausal dyspareunia.

OBJECTIVE: To compare efficacies of two strengths of estradiol cream applied to the vulvar vestibule and use of silicone lubricant to reduce intercourse pain scores in postmenopausal women with moderate/severe dyspareunia. METHODS: This pilot randomized comparative trial assigned 50 women to nightly applications of estradiol cream, 50 or 100 µg, for 12 weeks. We asked women to have lubricated penetration twice weekly, with intercourse or performing a tampon test. Pain, recorded in dairies, was rated using the 0-10 Numerical Rating Scale. We assessed biopsychosocial outcomes, urinary symptoms, and measured serum estradiol levels and endometrial stripe thicknesses. We performed physical examinations to determine tenderness levels of the vestibule, vagina, pelvic floor muscles, bladder, uterus, and adnexa. Comparisons were made using two-sample t test, Wilcoxon rank-sum test, or χ2 /Fisher's exact test. RESULTS: Forty-seven women (94%), with a mean age of 59.7 years, completed the trial. The baseline median intercourse pain score was 8/10 (interquartile range, 6, 8). After 12 weeks, we measured no statistically significant difference between groups in the primary outcome, intercourse pain score, or any secondary outcome measure. For both groups together, the median intercourse pain score diminished by 50% after 4 weeks and 75% after 12 weeks ( P < 0.001). The most tender anatomic area, the vulvar vestibule, improved by 82% to 100% ( P < 0.001) with therapy. We did not measure a statistically significant difference in serum estradiol levels or endometrial stripe thickness between groups. CONCLUSION: Estradiol cream applied to the vulvar vestibule, paired with precoital silicone lubricant, is a promising alternative to vaginal therapy for dyspareunia.

Where does postmenopausal dyspareunia hurt? A cross-sectional report.

OBJECTIVE: A common symptom of genitourinary syndrome of menopause (GSM) is dyspareunia, attributed to vulvovaginal atrophy. Our objective was to systematically describe the pain characteristics and anatomic locations of tenderness in a cohort with moderate/severe dyspareunia likely due to GSM. METHODS: This cross-sectional study reports the baseline data of postmenopausal women with dyspareunia screened for an intervention trial of topical estrogen. Postmenopausal women not using hormone therapy who had moderate or severe dyspareunia were eligible if estrogen was not contraindicated. Biopsychosocial assessments were performed using the Vulvar Pain Assessment Questionnaire, and participants underwent a systematic vulvovaginal examination that included a visual assessment and cotton swab testing for tenderness rated using the Numerical Rating Scale (0-10). Vaginal pH and mucosal sensitivity were assessed; pelvic floor muscles and pelvic viscera were palpated for tenderness. RESULTS: Fifty-five eligible women were examined between July 2017 and August 2019. Mean age was 59.5 ±â€Š6.8 years, and duration of dyspareunia was 6.2 ±â€Š4.3 years. The mean intercourse pain score was 7.3 ±â€Š1.8, most often described as "burning" and "raw." Ninety-eight percent had physical findings of vulvovaginal atrophy. Median pain scores from swab touch at the vulvar vestibule (just outside the hymen) were 4 to 5/10, and topical lidocaine extinguished pain. Median vaginal mucosal pain was zero. CONCLUSIONS: Participants described their pain as "burning" and "dry." Tenderness was most severe and most consistently located at the vulvar vestibule. Correlating the symptom of dyspareunia with genital examination findings may further our understanding of treatment outcomes for GSM.

Video Summary:http://links.lww.com/MENO/A916 .

Using the Brink score to predict postpartum anal incontinence.

OBJECTIVE: To evaluate whether antepartum pelvic floor muscle strength, as measured by the Brink scale, predicts postpartum anal incontinence. STUDY DESIGN: This prospective cohort study of primigravid women used validated questionnaires and standardized pelvic examinations to evaluate subjects during the third trimester and at 2 postpartum time points. RESULTS: Of the initial 129 subjects, 102 and 81 completed 2 week and 6 month postpartum visits. 35% had cesarean deliveries. The antepartum prevalence of fecal incontinence (14%) did not differ significantly from the postpartum (17% at 2 weeks, 11% at 6 months). However, the prevalence of flatal incontinence fell from antepartum (65%) to postpartum (47% at 2 weeks, P = .001; 49% at 6 months, P = .012). Mean Brink score decreased postpartum; no correlations were found between Brink score and questionnaire scores. CONCLUSION: Anal incontinence symptoms are common in the third trimester of a first pregnancy and may regress or resolve after delivery. Brink score did not predict postpartum anal incontinence.

Effect of unsaturation in fatty acids on the binding and oxidation by myeloperoxidase: ramifications for the initiation of atherosclerosis.

Oxidation of low density lipoproteins (LDL) in the presence of myeloperoxidase and subsequent uptake of the oxidized LDL by specialized receptors on macrophages has been suggested as an initiating event of atherosclerosis. Oxidized fatty acid chains within the glycerophospholipids of LDL have been implicated as the recognition feature by the receptors. The ability of three fatty acids (oleic, linoleic, and arachidonic acids) typically contained in the lipid portion of the glycerophospholipids to bind and be oxidized by myeloperoxidase was measured by spectroscopically observing interactions of the lipids with the heme prosthetic group of the enzyme. As unsaturation increases in the lipid chain, myeloperoxidase binds and oxidizes the fatty acid more readily, as measured by K(D), K(M), and k(cat). A possible mechanism of the free radical oxidation by myeloperoxidase is discussed.

Clinician knowledge, attitudes, and barriers to management of vulvovaginal atrophy: variations in primary care and gynecology.

OBJECTIVE: Vulvovaginal atrophy is a common, but under-recognized condition affecting postmenopausal women. To guide development of an intervention to boost its detection and treatment, we surveyed primary care and gynecology clinicians practicing in an integrated healthcare system. METHODS: We constructed a three-part survey that contained (1) eight multiple-choice knowledge questions; (2) three Likert-scale questions regarding clinicians' likelihood of assessing for vulvovaginal atrophy symptoms at a routine (well) visit, confidence in advising patients about symptoms and counseling about therapy; and (3) a 12-item check list of potential barriers to diagnosis and treatment. Analyses were performed using multiple regression. RESULTS: Of the 360 clinicians who were sent an e-mail request, 119 (90 primary care, 29 gynecology) completed the survey (33%). Responders and nonresponders did not differ by age, specialty, or clinician type. The proportion with correct responses to knowledge questions differed between primary care (63%) and gynecology (77%) (adjusted mean difference [AMD] =16, 95% CI [10-22]). Primary care clinicians were less likely than gynecology clinicians to assess for symptoms (AMD = 1.04, 95% CI [0.55-1.52]), and were less confident about their ability to advise on symptoms (AMD = 0.66, 95% CI [0.33-0.99]) and to counsel patients about treatment (AMD = 0.76, 95% CI [0.42-1.10]). Lack of time (71%) and educational materials (44%) were the most common barriers to diagnosis and treatment. CONCLUSIONS: Primary care and gynecology clinicians differ in their knowledge and confidence in managing vulvovaginal atrophy but report similar practice barriers. Addressing identified knowledge deficits and practice barriers may lead to improved management of vulvovaginal atrophy.

Complex Female Pelvic Pain: A Case Series From a Multidisciplinary Clinic in Urogynecology and Physiatry.

OBJECTIVE: The internal pelvic floor muscles that support the pelvic viscera lie within the external pelvic structures, which support posture and locomotion. The presence of pain in the hip, groin, leg, abdomen, and/or back in patients with pelvic pain suggests that external pelvic sites may act as pain generators that contribute to chronic pelvic pain (CPP). The aim of this study was to report musculoskeletal diagnoses resulting from including a physiatry evaluation as part of a Multidisciplinary Pelvic Pain Clinic for women with complex chronic pain. METHODS: This retrospective case series was conducted by chart review of all women attending the clinic from February 2016 through March 2018. Variable definitions were created for each demographic and clinical characteristic and used to guide a structured review of the chart. Descriptive statistical analysis was performed. RESULTS: Ninety-six percent of the 68 women (mean age, 51 years) had CPP of 6 months' duration or longer. Levator ani tenderness was present in 81% and obturator internus tenderness in 81%. Seventy-one percent of women had failed pelvic physical therapy. Musculoskeletal diagnoses included osteoarthritis, tendinopathies, enthesopathies, osteitis pubis, ischiofemoral impingement, Paget disease, and other systemic conditions. CONCLUSIONS: Musculoskeletal abnormalities were common in this highly selected cohort of complex CPP cases with external pelvic symptoms. The imaging findings and specific diagnoses allowed targeted therapy beyond generalized physical therapy for CPP. The expertise of urogynecologists and physical therapists who evaluate the internal pelvic muscles and viscera combined with the physiatrist's expertise in musculoskeletal assessment and imaging provides an expanded, collaborative approach for managing these patients.

Quantitative anal sphincter electromyography in primiparous women with anal incontinence.

OBJECTIVE: The purpose of this study was to determine whether evidence of denervation/reinnervation of the external anal sphincter is associated with anal incontinence symptoms immediately after delivery. STUDY DESIGN: After a first vaginal delivery, 42 women completed an anal incontinence questionnaire. They also underwent concentric needle electromyography of the external anal sphincter. For each subject, motor unit action potential and interference pattern parameters were determined. RESULTS: For the motor unit action potential, no difference was observed between patients with and without anal incontinence symptoms (t-test). For the interference pattern, the amplitude/turn was greater in subjects with fecal urgency (318 +/- 48 [SD] microV) and fecal incontinence (332 +/- 48 microV), compared with those without fecal urgency (282 +/- 38 microV) and fecal incontinence (286 +/- 41 microV; P = .02, t-test). CONCLUSION: In this group of postpartum women with mild anal incontinence symptoms, interference pattern analysis shows evidence of denervation and subsequent reinnervation.

Reoperation 10 years after surgically managed pelvic organ prolapse and urinary incontinence.

OBJECTIVE: This study measured the 10-year risk of reoperation for surgically treated pelvic organ prolapse and urinary incontinence (POPUI) in a community population. STUDY DESIGN: We conducted a prospective cohort analysis of 374 women who were > 20 years old and who underwent surgery for POPUI in 1995. RESULTS: The 10-year reoperation rate was 17% by Kaplan Meier analysis. Previous POPUI surgery at the time of index surgery conferred a hazard ratio of 1.9 (95% CI, 1.1-3.2; P = .018). The abdominal approach was protective against reoperation compared with the vaginal approach (hazard ratio, 0.37; 95% CI, 0.17-0.83; P = .02) With the use of Cox regression, no association was observed for age, vaginal parity, previous hysterectomy, body mass index, prolapse severity, ethnicity, chronic lung disease, smoking, estrogen status, surgical indication, or anatomic compartment. CONCLUSION: A reoperation rate of 17% is unacceptably high and likely represents an underestimate of the true rate. Most of the factors that influence reoperation have not yet been identified.

Validating a clinical measure of levator hiatus size.

OBJECTIVE: We evaluate the interrater reliability of levator hiatus (LH) size and correlate size to other measures of muscle function. STUDY DESIGN: Participants were examined independently by 2 examiners. During maximal contraction of the levator ani, the muscle was assessed by using Brink's scale. The LH was measured in the transverse and sagittal dimensions by digital palpation. The paired t test was used to compare continuous variables and Spearman's coefficient was used for correlations. RESULTS: The mean LH transverse was 4.5 cm and the mean LH sagittal was 3 cm. The inter-rater correlation for the LH transverse measurement was 0.6 (P < .01) and 0.8 (P < .01) for the LH sagittal measurement. The correlations between the LH size and Brink's scale were moderate (correlation coefficient -0.4 to -0.5, P < .01). Eighty-three percent of measurements were within 1 cm. CONCLUSION: This technique for clinical measurement of levator hiatus size shows good interrater reliability.

Neutrophil Gelatinase-Associated Lipocalin Biomarker and Urinary Tract Infections: A Diagnostic Case-Control Study (NUTI Study).

OBJECTIVES: Acute uncomplicated urinary tract infection (UTI) in women is often treated based on symptoms alone. Urinary tract infection symptoms are highly sensitive but lack specificity and result in overuse of antibiotics. We sought to determine if urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in urine can accurately discriminate between UTI and healthy women. METHODS: We recruited adult women aged 18 to 85 years presenting in the ambulatory setting from November 2014 to January 2016. Cases were defined as women with Centers for Disease Control and Prevention-defined UTI symptoms and a positive urine culture of more than 10 organisms/mL on a midstream clean-catch specimen. Women without UTI symptoms were matched by age and menopausal status as control subjects. Exclusion criteria were no UTIs within 8 weeks, urinary tract anomalies, renal disease, pregnancy, or diabetes. Clean-catch urine samples were obtained for measuring uNGAL, prior to antibiotic treatment of cases. We used Mann-Whitney U test to compare the 2 groups. Receiver operating characteristic curves were plotted to compare the performance of uNGAL to established urinary markers. RESULTS: We enrolled 50 UTI cases and 50 control subjects. Urine NGAL levels were higher in the UTI group than in the control subjects (P < 0.0001). Using a cutoff of 23.9 ng/mL, NGAL achieved 98% sensitivity and 100% specificity. The receiver operating characteristic curve had an area under the curve of 0.97 (95% confidence interval, 0.93-1.00), which was significantly high and showed that uNGAL can identify UTI. CONCLUSIONS: Urine NGAL has the potential as a biomarker for diagnosing UTIs in adult women.

External anal sphincter volume measurements using 3-dimensional endoanal ultrasound.

OBJECTIVE: Significant nerve injury to a muscle can be associated with muscle atrophy and volume loss. Three-dimensional (3D) ultrasound can measure muscle volume, but the reproducibility of the technique has not been established for the anal sphincter. STUDY DESIGN: Using a 10 MHz 360-degree rotating endoanal probe, we performed 3D endoanal ultrasounds on 9 nulliparous and 23 asymptomatic primiparous subjects at 12 weeks' postpartum. Two blinded examiners measured the length of the external anal sphincter (EAS) from a midsagittal image, and the width of the EAS and internal anal sphincter (IAS) from axial images at mid anal canal. The EAS volume was calculated by repetitively outlining only the EAS in each sequential axial view. Both examiners measured the EAS volumes twice, blinded to previous calculations. RESULTS: The intrarater reliability for EAS volume was 0.79 to 0.89 (intraclass coefficient). The mean difference of the EAS volume between the 2 examiners was 0.5 mL (P = .3, t test). Correlation between the 2 examiners for measuring EAS volume was r = 0.77 (P < .001, Pearson's). The "limits of agreement" (between 2 examiners) varied by as much as 40% of the mean volume. CONCLUSION: Quantitative 3D ultrasound of the anal sphincter is moderately reproducible.