Histologic Analysis of 'Distraction Vaginogenesis' in a Rat Model.

Vaginal agenesis (VA) is frequently associated with mullerian agenesis. VA treatments include mechanical dilation and surgical vaginoplasty. We created a vaginal expansion sleeve (VES) as a novel device to progressively lengthen the vaginal canal. This study evaluated the histologic effects of the VES on rat vaginal tissue. The VES is a spring-like device made of proprietary woven cylindrical material and flat resin caps. The VESs were constructed as 25-30 mm, pre-contracted springs, which were secured into the vaginas of six Sprague Dawley rats and allowed to re-expand post-surgically. After one week, the VESs were removed, and the vaginas were harvested and measured in length. Test (n = 6) and control (n = 4) formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E), Masson's trichrome, and anti-Desmin antibodies. The VESs achieved significant vaginal lengthening. The mean vaginal canal length increased from 20.0 ± 2.4 mm to 23.8 ± 1.2 mm after removal of the VESs (n = 6, p < 0.001), a 19% increase. There was a positive correlation between the expander/tension generated in the vagina and the amount of acute and chronic inflammation. H&E staining revealed increased submucosal eosinophilia in five of the six test tissues. One VES sample that was lengthened to 30 mm long showed evidence of lymphocytic and neutrophilic inflammation. Desmin immunostaining and Masson's trichrome stain revealed a thinner muscularis with more infiltrative fibrous tissue between muscle fibers in the test tissue compared to the control tissue. Although effective, the VES may provoke at least a transient increase in eosinophils consistent with a localized immune reaction during muscularis remodeling.

'Distraction Vaginogenesis': Preliminary Results Using a Novel Method for Vaginal Canal Expansion in Rats.

Vaginal atresia is seen in genetic disorders such as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which can cause significant sexual dysfunction. Current treatments include surgical reconstruction or mechanical dilation of the vaginal canal. Mechanical dilation requires patients to be highly motivated and compliant while surgical reconstruction has high rates of complications. This study evaluated a novel vaginal expansion sleeve (VES) method as an alternative treatment for vaginal atresia. The proprietary cylindrical VES is a spring-like device consisting of polyethylene terephthalate helicoid trusses capped at each end with a fixed diameter resin cap for fixation within tissues. Following the development of the VES and mechanical characterization of the force-length relationships within the device, we deployed the VES in Sprague Dawley rat vaginas anchored with nonabsorbable sutures. We measured the VES length-tension relationships and post-implant vaginal canal expansion ex vivo. Vaginal histology was examined before and after implantation of the VES devices. Testing of 30 mm sleeves without caps resulted in an expansion force of 11.7 ± 3.4 N and 2.0 ± 0.1 N at 50% and 40%, respectively. The implanted 20 mm VES resulted in 5.36 mm ± 1.18 expansion of the vaginal canal, a 32.5 ± 23.6% increase (p = 0.004, Student t test). Histological evaluation of the VES implanted tissue showed a significant thinning of the vaginal wall when the VES was implanted. The novel VES device resulted in a significant expansion of the vaginal canal ex vivo. The VES device represents a unique alternative to traditional mechanical dilation therapy in the treatment of vaginal atresia and represents a useful platform for the mechanical distension of hollow compartments, which avoids reconstructive surgeries and progressive dilator approaches.

Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2.

FGF21 contributes to the metabolic response to dietary protein restriction, and prior data implicate GCN2 as the amino acid sensor linking protein restriction to FGF21 induction. Here, we demonstrate the persistent and essential role of FGF21 in the metabolic response to protein restriction. We show that Fgf21 KO mice are fully resistant to low protein (LP)-induced changes in food intake, energy expenditure (EE), body weight gain, and metabolic gene expression for 6 months. Gcn2 KO mice recapitulate this phenotype, but LP-induced effects on food intake, EE, and body weight subsequently begin to appear after 14 days on diet. We show that this delayed emergence of LP-induced metabolic effects in Gcn2 KO mice coincides with a delayed but progressive increase of hepatic Fgf21 expression and blood FGF21 concentrations over time. These data indicate that FGF21 is essential for the metabolic response to protein restriction but that GCN2 is only transiently required for LP-induced FGF21.