Inhibition of TP signaling promotes endometriosis growth and neovascularization.

Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A2 (TXA2) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA2 receptor)­deficient (TP­/­) mice into TP­/­ mice (TP­/­â†’TP­/­), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro­angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP­/­â†’TP­/­ mice had a higher number of F4/80+ cells than that of WT→WT mice, with increased expression of genes related to the anti­inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)­derived macrophages, the levels of VEGF­A, VEGF­C, and VEGF­D decreased in a TP­dependent manner. Furthermore, TP signaling affected the polarization of cultured BM­derived macrophages to the anti­inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.

Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Has the Same Effect as Gonadotropin-Releasing Hormone Agonist Injections in Terms of Preparation for Transcervical Resection Myomectomy.

For preparing the optimal condition in transcervical resection (TCR) surgery, gonadotropin-releasing hormone (GnRH) agonist has been utilized. Recently, an oral GnRH antagonist (relugolix) is available and acts directly on GnRH receptor, avoiding flare up and reducing blood E2 levels rapidly. We retrospectively compared the oral GnRH antagonist (n = 14) effect to that of subcutaneous GnRH agonist (n = 19) for the pretreatment of endometrium in TCR myomectomy. Endometrial thickening was determined by intraoperative videos. The color tone of the endometrium in the normal part was assessed by digital image processing. The median duration of the first GnRH agonist injection and the surgery was 67 days (21-136 days), which is significantly longer than that of the oral GnRH antagonist group, 18.5 days (7-157 days P < 0.01). Both the GnRH agonist and antagonist groups did not exhibit prominence in the endometrium. The GnRH antagonist group showed the same degree of whiteness in the normal endometrium as the GnRH agonist group. The oral GnRH antagonist administration could rapidly atrophy the endometrium and create an optimal surgical field for TCR in a short period.

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis.

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis.

CD206+ macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model.

In endometriosis, M2 MΦs are dominant in endometriotic lesions, but the actual role of M2 MΦ is unclear. CD206 positive (+) MΦ is classified in one of M2 type MΦs and are known to produce cytokines and chemokines. In the present study, we used CD206 diphtheria toxin receptor mice, which enable to deplete CD206+ cells with diphtheria toxin (DT) in an endometriosis mouse model. The depletion of CD206+ MΦ decreased the total weight of endometriotic-like lesions significantly (p < 0.05). In the endometriotic-like lesions in the DT group, a lower proliferation of endometriotic cells and the decrease of angiogenesis were observed. In the lesions, the mRNA levels of VEGFA and TGFß1, angiogenic factors, in the DT group significantly decreased to approximately 50% and 30% of control, respectively. Immunohistochemical study revealed the expressions of VEGFA and an endothelial cell marker CD31 in lesions of the DT group, were dim compared to those in control. Also, the number of TGFß1 expressing MΦ was significantly reduced compared to control. These data suggest that CD206+ MΦ promotes the formation of endometriotic-like lesions by inducing angiogenesis around the lesions.

Ultrasonic findings of fetal axillary lymphangioma with intralesional hemorrhage.

We report a case of an axillary lymphangioma in a fetus delivered at 30 weeks' gestation with suspected intralesional hemorrhage based on the ultrasonic findings. In the ultrasonic examination at 15 weeks' gestation, the fetus was found to have a multilocular mass spreading from the axilla to the chest wall, which was diagnosed as an axillary lymphangioma. Chromosome analysis by amniocentesis showed a normal karyotype, and no other malformations were observed. At 29 weeks, the mass had increased in size, and color Doppler ultrasound examination revealed that the middle cerebral artery peak systolic velocity (MCA-PSV) reached 80.2 cm/s [1.86 MoM (multiples of the median)]. Intralesional bleeding was suspected because of the multiple images of hemorrhage in which sites of blood spouting in a pulsatile fashion were detected within the mass. Cordocentesis at 30 weeks revealed that fetal hemoglobin concentration was 5.1 g/dL. An emergency Cesarean section was performed. A female weighing 2810 g, including the mass, was delivered, and the blood hemoglobin level was 5.9 g/dL at birth. Blood transfusion, fine-needle aspiration of the fluid in the mass, intralesional injection of OK-432, and partial excision of the lymphangioma were performed after birth. Ultrasonic examination proved useful in the diagnosis of intralesional bleeding in this lymphangioma.