Marsha K. Guess

HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse.

Pelvic organ prolapse (POP) is a common, debilitating disorder affecting millions of women. Uterosacral ligaments (USLs) are the main supportive structures of the uterus and vagina and are often attenuated in women with POP. Although the mechanical strength of USLs is known to be dependent on collagen synthesis and catabolism and the degradation protein MMP2 has been implicated in POP, the molecular mechanisms involved in the development of POP are currently unknown. Homeobox (HOX) genes are transcriptional regulators that orchestrate embryonic development of the urogenital tract. We demonstrated here that HOXA11 was essential for organogenesis of the USL by showing that USLs were absent in Hoxa11-null mice. We compared expression of HOXA11, collagen type I, collagen type III, MMP2, and MMP9 in USLs of women with and without POP. Expression of HOXA11 and both collagens was dramatically decreased while MMP2 was increased in women with POP. Constitutive expression of Hoxa11 in murine fibroblasts resulted in significantly increased expression of collagen type III and decreased expression of MMP2. These results identified HOXA11 as an essential gene for the development of the USL and suggested that women with POP might have weakened connective tissue due to changes in a signaling pathway involving HOXA11, collagen type III, and MMP2.

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

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.

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity

ABSTRACT Homeobox (HOX) genes are evolutionarily conserved genes encoding transcription factors that regulate mammalian embryonic growth and development of the urogenital tract. In both humans and mice, HOXA11 persists in the adult reproductive tract and is thought to play an important role in maintaining tissue developmental plasticity by regulating the expression of genes involved in extracellular matrix metabolism in the reproductive organs. Previously, we have shown that HOXA11 is necessary for development of the uterosacral ligaments in mice and is deficient in women with pelvic organ prolapse. Therefore, we hypothesized that Hoxa11 regulates the synthesis and/or metabolism of collagens in the uterosacral ligaments and uterus, and tested this by establishing an in utero and peritoneal Hoxa11 gene knockdown system in C57/BL6 mice using vectors bearing Hoxa11 short hairpin RNA. Specific knockdown of Hoxa11 transcripts and protein levels were confirmed versus control vectors. Protein and mRNA expression of collagen types I and III exhibited significant decreases following Hoxa11 knockdown according to Western blot analysis and real-time PCR. Tissue inhibitor of matrix metalloproteinase 1 (MMP1) expression also exhibited a significant decrease. Gelatinase zymography confirmed increases in pro-MMP2 and MMP9, as well as activated MMP2, following Hoxa11 knockdown. These results reveal that Hoxa11 knockdown in the uterosacral ligaments and uterus increases extracellular matrix degradation. More importantly, it suggests a mechanism in the weakening of the pelvic floor support in women, because decreased HOXA11 gene expression has been reported to be associated with decreased collagen and increased MMP2 expression in the uterosacral ligaments of women with pelvic organ prolapse.

Women's Bike Seats: A Pressing Matter for Competitive Female Cyclists

INTRODUCTION There are numerous genital complaints in women cyclists, including pain, numbness, and edema of pelvic floor structures. Debate ensues about the best saddle design for protection of the pelvic floor. AIM To investigate the relationships between saddle design, seat pressures, and genital nerve function in female, competitive cyclists. METHODS We previously compared genital sensation in healthy, premenopausal, competitive women bicyclists and runners. The 48 cyclists from our original study comprise the study group in this subanalysis. MAIN OUTCOME MEASURES Main outcome measures were: (i) genital vibratory thresholds (VTs) determined using the Medoc Vibratory Sensation Analyzer 3000 and (ii) saddle pressures as determined using a specially designed map sensor. RESULTS More than half of the participants (54.8%) used traditional saddles, and the remainder (45.2%) rode with cut-out saddles. On bivariate analysis, use of traditional saddles was associated with lower mean perineal saddle pressures (MPSP) than riding on cut-out saddles. Peak perineal saddle pressures (PPSP) were also lower; however, the difference did not reach statistical significance. Saddle design did not affect mean or peak total saddle pressures (MTSP, PTSP). Saddle width was significantly associated with PPSP, MTSP, and PTSP but not with MPSP. Women riding cut-out saddles had, on average, a 4 and 11 kPa increase in MPSP and PPSP, respectively, compared with women using traditional saddles (P = 0.008 and P = 0.010), after adjustment for other variables. Use of wider saddles was associated with lower PPSP and MTSP after adjustment. Although an inverse correlation was seen between saddle pressures and VTs on bivariate analysis, these differences were not significant after adjusting for age. CONCLUSION Cut-out and narrower saddles negatively affect saddle pressures in female cyclists. Effects of saddle design on pudendal nerve sensory function were not apparent in this cross-sectional analysis. Longitudinal studies evaluating the long-term effects of saddle pressure on the integrity of the pudendal nerve, pelvic floor, and sexual function are warranted.

HOXA11 Promotes Fibroblast Proliferation and Regulates p53 in Uterosacral Ligaments

The uterosacral ligaments (USLs) are key support structures of the uterus and upper vagina. Previously, we have shown that HOXA11 is necessary for the development of the USLs, is deficient in women with pelvic organ prolapse (POP) and regulates expression of extracellular matrix (ECM) proteins. Here we sought to determine if HOXA11 regulates cell proliferation in the USLs in women. Like others, we have found that, there is decreased cellularity in prolapsed USLs compared to USLs in women with normal pelvic support. We have also demonstrated that HOXA11 promotes cell proliferation in murine fibroblasts and primary human USL cells in vitro. These findings support a relationship between HOXA11 expression, rates of proliferation and phenotypic abnormalities in the USL. Based on these findings, we sought to determine if HOXA11 regulates p53, a tumor suppressor gene which controls progression through the cell cycle and regulates ECM genes. We have demonstrated that expression of HOXA11 represses expression of p53, suggesting a mechanism by which HOXA11 regulates of the morphology and integrity of the USLs. A better understanding of the influence of these genes on the homeostasis of the ECM and interactions with each other may prove beneficial in defining the underlying etiologies of the development of POP and aid in the development of new treatment options for women with this disorder.

Racial Disparities in Knowledge of Pelvic Floor Disorders Among Community-Dwelling Women.

Objective To evaluate racial and ethnic differences in knowledge about preventative and curative treatments for pelvic floor disorders (PFD). Methods The is a secondary analysis of responses from 416 community-dwelling women, aged 19 to 98 years, living in New Haven County, CT, who completed the Prolapse and Incontinence Knowledge Questionnaire. Associations between race/ethnicity (categorized as white, African American, and other women of color [combined group of Hispanic, Asian or “other” women] and knowledge proficiency about modifiable risk factors and treatments for PFD were evaluated. Associations were adjusted for age, marital status, socioeconomic status, education, working in a medical field, and PFD history. Results Compared to white women, African American women were significantly less likely to recognize childbirth as a risk factor for urinary incontinence (UI) and pelvic organ prolapse (POP), to know that exercises can help control leakage, and to recognize pessaries as a treatment option for POP. Other women of color were also significantly less likely to know about risk factors, preventative strategies, and curative treatment options for POP and UI; however, these findings may not be generalizable given the heterogeneity and small size of this group. Conclusions Significant racial disparities exist in womens baseline knowledge regarding risk factors and treatment options for POP and UI. Targeted, culturally sensitive educational interventions are essential to enhancing success in reducing the personal and economic burden of PFD, which have proven negative effects on womens quality of life.

Sexual function in older women after oophorectomy

OBJECTIVE: To compare the sexual function of older women who had bilateral oophorectomy with that of older women who had retained their ovaries. METHODS: This cross-sectional study involved analysis of 1,352 women aged 57 to 85 years from the National Social Life, Health, and Aging Project. Women with previous bilateral oophorectomy were compared with women who retained their ovaries. The primary outcome of interest was self-report of sexual ideation, chosen because having thoughts about sexual experiences is not prohibited by either a partner or a womans own physical limitations. RESULTS: Three hundred fifty-six (25.8%) women reported previous bilateral oophorectomy. Our analysis achieved 90% power to detect a difference of 10% in sexual ideation. No significant difference in the report of sexual ideation was found between women with previous bilateral oophorectomy and women who retained their ovaries (54.5% and 95% confidence interval [CI] 48.1–61.0 compared with 49.9% and 95% CI 45.3–54.5, P=.230), even after adjusting for current hormone therapy, age, education, and race (adjusted odds ratio 1.32, 95% CI 0.96–1.80). CONCLUSION: Bilateral oophorectomy may not play a pivotal role in sexual ideation and function among older women. LEVEL OF EVIDENCE: II

Les lanternes rouges: the race for information about cycling-related female sexual dysfunction.

INTRODUCTION Cycling is growing in popularity among women. As in men, it is associated with genital neuropathies and decreased sensation in female riders. However, there is a gap in research and information addressing the relationship between cycling and female sexual dysfunction (FSD) in women. AIMS To review the literature investigating pelvic floor injuries and sexual dysfunction in female cyclists. METHODS Searches in several electronic databases were conducted, and relevant articles that met the inclusion criteria were identified for critical review. MAIN OUTCOME MEASURES The main outcome measure to be determined was the strength of the current body of evidence in published literature of a correlation between cycling-related pelvic floor injuries and FSD. RESULTS Data on FSD from cycling-related injuries in women are limited. Research indicates that bicycle setup and riding equipment may be contributing factors. Womens ergonomics and physiology interact differently with the bicycle than mens. Current evidence offers insufficient foundation to recommend various effect-mitigating equipment and products. CONCLUSIONS While gender-specific cycling products offer a promising direction for protecting women riders, studies addressing FSD and pelvic floor injuries in women cyclists are inadequate to indicate clear etiology or provide treatment recommendations. Current evidence is also insufficient to recommend effect-mitigating equipment and products.

Diminished vaginal HOXA13 expression in women with pelvic organ prolapse.

Objective: Homeobox genes are transcriptional regulators that orchestrate embryonic development. The HOXA13 gene is responsible for the development of the vagina and regulates extracellular matrix constituents. We hypothesized that vaginal expression of HOXA13 may be decreased in women with pelvic organ prolapse (POP) and sought to determine if hypoestrogenism affects its expression. Methods: Biopsy specimens were obtained from the anterior apex of the vagina from women with and without POP. Immunohistochemistry and real-time polymerase chain reaction were used to determine HOXA13 expression in premenopausal controls, in premenopausal women receiving leuprolide acetate, and in premenopausal and postmenopausal women with POP. Results: HOXA13 was expressed in all specimens. HOXA13 expression was 14-fold lower in premenopausal women with prolapse than in premenopausal controls (P < 0.001). In both POP groups, HOXA13 expression was lower than in the leuprolide group (P ≤ 0.001). There were no differences in HOXA13 expression between premenopausal controls and women treated with leuprolide acetate (P = 1.0) or between the premenopausal and postmenopausal POP group (P = 1.0). Conclusions: Vaginal HOXA13 expression is diminished in women with POP compared with women with normal support. In women with POP, expression of HOXA13 was not affected by menopause. Expression of HOXA13 was also not affected by exposure to leuprolide acetate, suggesting that estrogen and HOXA13 work through separate pathways in the extracellular matrix metabolism of the vagina. Understanding genetic predispositions to developing POP may identify younger patients at risk who may benefit from preventive strategies such as weight loss or smoking cessation and not necessarily from estrogen therapy.

The Effect of Body Mass Index on Pelvic Floor Support 1 Year Postpartum

Elevated body mass index (BMI) is associated with the incidence, prevalence, and progression of pelvic organ prolapse (POP). This study investigated the effect of peripartum BMI on pelvic floor support 1 year postpartum (PP1y). One hundred eight nulliparous women had their BMI recorded and underwent POP assessments using the Pelvic Organ Prolapse Quantification System at baseline, third trimester (36th to 38th week of pregnancy [G36-38w]), and PP1y. Pelvic organ prolapse was defined as ≥stage II. Women gained on average 1.9 kg between baseline and PP1y. After adjustment, increasing BMI PP1y was associated with increasing anterior wall descent (P < .0001) and higher odds of having POP PP1y (odds ratio: 1.41, 95% confidence interval: 1.01-1.97, P = .045). Trial of labor compared to unlabored cesarean delivery, POP G36-38w, and decreased fetal weight were independently associated with anterior vaginal wall laxity PP1y. Our finding suggests that postpartum BMI influences pelvic floor laxity 1 year after delivery. Postpartum weight reduction may serve as a strategy for POP prevention in some women.