Effects of preoperative local estrogen in postmenopausal women with prolapse: a randomized trial.

CONTEXT: Pelvic organ prolapse (POP) increases in prevalence with age; recurrence after surgical repair is common. OBJECTIVE: The objective of the study was to determine the effects of local estrogen treatment on connective tissue synthesis and breakdown in the vaginal wall of postmenopausal women planning surgical repair of POP. DESIGN: This was a randomized trial. SETTING: The study was conducted at an academic tertiary medical center. PATIENTS OR OTHER PARTICIPANTS: Postmenopausal women with a uterus and symptomatic anterior and/or apical prolapse at stage 2 or greater participated in the study. INTERVENTION: Estrogen (Premarin) or placebo cream for 6 weeks preoperatively was the intervention. MAIN OUTCOME MEASURES: Full-thickness anterior apical vaginal wall biopsies were obtained at the time of hysterectomy and analyzed for mucosa and muscularis thickness, connective tissue synthesis, and degradation. Serum levels of estrone and 17ß-estradiol were analyzed at baseline and the day of surgery using highly sensitive liquid chromatography-tandem mass spectrometry. RESULTS: Fifteen women per group (n = 30 total) were randomized; 13 per group underwent surgery. Among drug-adherent participants (n = 8 estrogen, n = 13 placebo), epithelial and muscularis thickness was increased 1.8- and 2.7-fold (P = .002 and P =.088, respectively) by estrogen. Collagen types 1α1 and 1α2 mRNA increased 6.0- and 1.8-fold in the vaginal muscularis (P < .05 for both); collagen type Ia protein increased 9-fold in the muscularis (P = .012), whereas collagen III was not changed significantly. MMP-12 (human macrophage elastase) mRNA was suppressed in the vaginal mucosa from estrogen-treated participants (P = .011), and matrix metalloprotease-9 activity was decreased 6-fold in the mucosa and 4-fold in the muscularis (P = .02). Consistent with menopausal norms, serum estrone and 17ß-estradiol were low and did not differ among the two groups. CONCLUSIONS: Vaginal estrogen application for 6 weeks preoperatively increased synthesis of mature collagen, decreased degradative enzyme activity, and increased thickness of the vaginal wall, suggesting this intervention improves both the substrate for suture placement at the time of surgical repair and maintenance of connective tissue integrity of the pelvic floor.

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans.

Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the ß1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5RGE/RGE) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5-/-), Fbln5RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with ß-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5-/- mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre- and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women.

Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery.

OBJECTIVE: We sought to describe relationships of clinically relevant nerves and vessels of the anterior abdominal wall. STUDY DESIGN: The ilioinguinal and iliohypogastric nerves and inferior epigastric vessels were dissected in 11 unembalmed female cadavers. Distances from surface landmarks and common incision sites were recorded. Additional surface measurements were taken in 7 other specimens with and without insufflation. RESULTS: The ilioinguinal nerve emerged through the internal oblique: mean (range), 2.5 (1.1-5.1) cm medial and 2.4 (0-5.3) cm inferior to the anterior superior iliac spine (ASIS). The iliohypogastric emerged 2.5 (0-4.6) cm medial and 2.0 (0-4.6) cm inferior. Inferior epigastric vessels were 3.7 (2.6-5.5) cm from midline at the level of the ASIS and always lateral to the rectus muscles at a level 2 cm superior to the pubic symphysis. CONCLUSION: Risk of anterior abdominal wall nerve and vessel injury is minimized when lateral trocars are placed superior to the ASISs and >6 cm from midline and low transverse fascial incisions are not extended beyond the lateral borders of the rectus muscles.

Pathophysiology of urinary incontinence, voiding dysfunction, and overactive bladder.

Urinary incontinence and voiding dysfunction are common forms of pelvic floor dysfunction affecting women. The complex interactions between the nervous system and lower urinary tract anatomy allow for the coordinated functions of urine storage and evacuation. A thorough understanding of these components and their interactions is the foundation for the diagnosis and treatment of pathologic conditions affecting urine storage or evacuation. These components include changes in neurologic or muscular function, alterations in anatomy, and the deleterious effects of many common comorbid conditions on the lower urinary tract.

Failure of pelvic organ support in mice deficient in fibulin-3.

Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3(-[supi]/-)), and overt vaginal, perineal, and rectal prolapse occurred in 26.9% of animals. Prolapse severity increased with age but not parity. Fibulin-5 was up-regulated in vaginal tissues from Fbln3(-[supi]/-) mice regardless of prolapse. Despite increased expression of fibulin-5 in the vaginal wall, pelvic organ support failure occurred in Fbln3(-[supi]/-) animals, suggesting that factors related to aging led to prolapse. Elastic fiber abnormalities in vaginal tissues from young Fbln3(-[supi]/-) mice progressed to severe elastic fiber disruption with age, and vaginal matrix metalloprotease activity was increased significantly in Fbln3(-[supi]/-) animals with prolapse compared with Fbln3(-[supi]/-) mice without prolapse. Overall, these results indicate that both fibulin-3 and -5 are important in maintaining pelvic organ support in mice. We suggest that increased vaginal protease activity and abnormal elastic fibers in the vaginal wall are important components in the pathogenesis of pelvic organ prolapse.

Does supracervical hysterectomy provide more support to the vaginal apex than total abdominal hysterectomy?

OBJECTIVE: The objective of the study was to assess whether cervical preservation at the time of hysterectomy may help prevent subsequent apical vaginal vault prolapse. STUDY DESIGN: Supracervical hysterectomies were performed in 12 unembalmed cadavers. Successive hanging weights of 1, 2, 3, and 4 kg were loaded against the cervical stump and distances moved were recorded. The same process was repeated after completion of a total hysterectomy. RESULTS: Average distances pulled with 1, 2, 3, and 4 kg of traction against the cervical stump were 17.8 +/- 1.9, 24.1 +/- 2.5, 29.0 +/- 2.8, and 34.3 +/- 3.5 mm, respectively. After total hysterectomy, these distances were 17.5 +/- 2.5, 23.5 +/- 2.6, 29.3 +/- 3.1, and 34.5 +/- 3.6 mm, respectively. CONCLUSION: In unembalmed cadavers, it appears that total abdominal hysterectomy and supracervical hysterectomy provide equal resistance to forces applied to the vaginal apex.

Posterior division of the internal iliac artery: Anatomic variations and clinical applications.

OBJECTIVE: The objective of the study was to characterize the anatomy of the internal iliac artery (IIA) and its posterior division branches and to correlate these findings to IIA ligation. STUDY DESIGN: Dissections were performed in 54 female cadavers. RESULTS: Average length of IIA was 27.0 (range, 0-52) mm. Posterior division arteries arose from a common trunk in 62.3% (66 of 106) of pelvic halves. In the remaining specimens, branches arose independently from the IIA, with the iliolumbar noted as the first branch in 28.3%, lateral sacral in 5.7%, and superior gluteal in 3.8%. The average width of the first branch was 5.0 (range, 2-12) mm. In all dissections, posterior division branches arose from the dorsal and lateral aspect of IIA. The internal iliac vein was lateral to the artery in 70.6% (12 of 17) of specimens on the left and 93.3% (14 of 15) on the right. CONCLUSION: Ligation of the IIA 5 cm distal from the common iliac bifurcation would spare posterior division branches in the vast majority of cases. Understanding IIA anatomy is essential to minimize intra-operative blood loss and other complications.

Neurovascular anatomy of the sacrospinous ligament region in female cadavers: Implications in sacrospinous ligament fixation.

OBJECTIVE: The objective of the study was to further characterize the anatomy of the coccygeus muscle-sacrospinous ligament (C-SSL) complex and to correlate the findings with sacrospinous ligament fixations (SSLF). STUDY DESIGN: Dissections were performed in 21 female cadavers. RESULTS: In all dissections, nerves originating from S3, S4, S5, or a combination passed over the anterior surface of the C-SSL at its midsegment, and either the pudendal or third sacral nerve coursed on the superior border of C-SSL at its midpoint. In 100% of specimens, the internal pudendal artery (IPA) passed behind or just medial to the ischial spine. The average distance of the inferior gluteal artery (IGA) from the ischial spine and the superior border of the C-SSL was 24.2 (range, 15-35) mm and 3.4 (range, 1-5) mm, respectively. CONCLUSION: Nerves to the coccygeus and levator ani coursed over the midportion of the C-SSL where SSLF sutures are placed. The pudendal nerve and IGA were in proximity to the superior border of the C-SSL at its midportion, whereas the IPA passed behind the ischial spine, lateral to the recommended site for suture placement.

Anatomic relationships of the distal third of the pelvic ureter, trigone, and urethra in unembalmed female cadavers.

OBJECTIVE: The objective of the study was to examine the relationship of the ureter to paravaginal defect repair (PVDR) sutures and to evaluate the anatomy of distal ureter, trigone, and urethra relative to the anterior vaginal wall. STUDY DESIGN: Dissections of the retropubic space were performed in 24 unembalmed female cadavers following placement of PVDR sutures. Lengths of the vagina, urethra, and trigone were recorded. RESULTS: The mean distance between apical PVDR sutures and the ureter was 22.8 (range, 5-36) mm. The average lengths of the urethra, trigone, and vagina were 3 cm, 2.8 cm, and 8.4 cm, respectively. The trigone was positioned over the middle third of the anterior vaginal wall in all specimens and the distal ureters traversed the anterolateral vaginal fornices. CONCLUSION: The ureters may be injured during paravaginal defect repairs, anterior colporrhaphies, and other procedures involving dissection in the upper third of the vagina. Cystotomy during vaginal hysterectomies is most likely to occur 2-3 cm above the trigone.

Uterosacral ligament suspension sutures: Anatomic relationships in unembalmed female cadavers.

OBJECTIVE: The objective of the study was to characterize anatomic relationships of uterosacral ligament suspension (USLS) sutures. STUDY DESIGN: The relationship of USLS sutures to the ureters, rectal lumen, and sidewall neurovascular structures was examined in 15 unembalmed female cadavers. RESULTS: The mean distance of the proximal sutures to the ureters and rectal lumen was 14 mm (range, 0-33) and 10 mm (range, 0-33), respectively. The mean distance of the distal sutures to the ureters was 14 mm (range, 4-33) and to the rectal lumen 13 mm (range, 3-23). Right sutures were noted at the level of S1 in 37.5%, S2 in 37.5%, and S3 in 25% of specimens. Left sutures were noted at the level of S1 in 50%, S2 in 29.2%, and S3 in 20.8% of cadavers. Of 48 sutures passed, 1 entrapped the S3 nerve. Sutures perforated the pelvic sidewall vessels in 4.1% of specimens. CONCLUSION: USLS sutures can directly injure the ureters, rectum, and neurovascular structures in the pelvic walls.