Yutaka Osuga

Preimplantation exposure to bisphenol A advances postnatal development

Prenatal exposure to bisphenol A (BPA), an estrogenic compound, has been shown to alter postnatal development at an environmentally relevant exposure level. To elucidate these low dose effects of preimplatation exposure to BPA, two-cell mouse embryos were cultured with 1 nM BPA. More embryos exposed to 1 nM BPA than controls reached the blastocyst stage. When the blastocysts with or without BPA exposure were transferred to uterine horns of pseudopregnant recipient mice not treated with BPA, the number of pups per litter and body weight at birth did not differ. At weaning on postnatal day 21, however, pups treated with 1 nM BPA during the preimplantation period were significantly heavier than controls. These findings suggest that BPA may not only affect early embryonic development even at low, environmentally relevant doses, but also may exert late effects on postnatal development.

Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis.

Problem:  Endometriosis accompanies local inflammatory reactions in the peritoneal cavity. We examined the phosphorylation of mitogen‐activated protein kinases (MAPKs), i.e. extracellular signal‐regulated kinase (ERK), p38 MAPK (p38) and c‐Jun N‐terminal kinase (JNK) in endometriotic stromal cells, and their possible pathophysiological roles in endometriosis in relation to proinflammatory substances.

Lymphocytes in Endometriosis

Citation Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. Lymphocytes in Endometriosis. Am J Reprod Immunol 2011; 65: 1–10

Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements : A consensus opinion from the International Deep Endometriosis Analysis (IDEA) group

The IDEA (International Deep Endometriosis Analysis group) statement is a consensus opinion on terms, definitions and measurements that may be used to describe the sonographic features of the different phenotypes of endometriosis. Currently, it is difficult to compare results between published studies because authors use different terms when describing the same structures and anatomical locations. We hope that the terms and definitions suggested herein will be adopted in centers around the world. This would result in consistent use of nomenclature when describing the ultrasound location and extent of endometriosis. We believe that the standardization of terminology will allow meaningful comparisons between future studies in women with an ultrasound diagnosis of endometriosis and should facilitate multicenter research. Copyright

Role of Laparoscopy in the Treatment of Endometriosis-Associated Infertility

Endometriosis is assumed to be one of the causative factors of infertility, although the mechanism remains to be elucidated. Mechanical factors distorting the pelvic anatomy and/or changes in the biochemical and cellular environment in the peritoneal cavity are possible contributing factors impairing fertility. Laparoscopy is a widely used diagnostic and therapeutic means of treating endometriosis-associated infertility. However, pregnancy outcome after laparoscopy varies depending on preexisting tubal adhesions and endometriosis. Without tubal adhesions, the pregnancy rate is essentially the same irrespective of the presence or stages of endoemetriosis. Minimal/mild endometriosis benefited the most from laparoscopic manipulation when tubal adhesions were present. On the other hand, IVF-ET outcome of patients who previously underwent laparoscopy was not influenced by preexisiting tubal adhesions and endometriosis.

Recruitment of CCR6-Expressing Th17 Cells by CCL 20 Secreted from IL-1β-, TNF-α-, and IL-17A-Stimulated Endometriotic Stromal Cells

In a novel paradigm of T cell differentiation, type 17 T helper (Th17) cells may play a significant role in endometriosis, a chronic inflammatory disease. However, the mechanism regulating the accumulation of Th17 cells in endometriotic tissues remains unknown. We hypothesized that Th17 cells migrate to endometriotic tissues through an interaction of the chemokine CC chemokine ligand (CCL)20 and its receptor CCR6. Using endometriotic tissues from women with endometriosis, we demonstrated, by flow cytometry, that Th17 cells in endometriotic tissues express CC chemokine receptor (CCR)6. Immunohistochemistry also revealed that CCL20 was expressed in the epithelial cells and stromal cells beneath the epithelium of endometriotic tissues. CCR6+ cells were small and round and scattered in the stroma in which abundant CCL20+ cells were detected. CCL20 caused selective migration of Th17 cells in the peripheral blood in a migration assay. IL-1β, TNF-α, and IL-17A increased the secretion of CCL20 in cultured endometriotic stromal cells. Inhibitors of p38- and p42/44-MAPKs, and stress-activated protein kinase/c-Jun kinase suppressed the secretion of CCL20 increased by IL-1β, TNF-α, and IL-17A. This suggests that the CCL20/CCR6 system is involved in the migration of Th17 cells to endometriotic tissues and that proinflammatory cytokines contribute to the development of endometriosis via up-regulation of CCL20 secretion from endometriotic stromal cells.

Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids

BACKGROUND The relationship between fibroids and infertility remains an unsolved question, and management of intramural fibroids is controversial. During the implantation phase, uterine peristalsis is dramatically reduced, which is thought to facilitate embryo implantation. Our aims were to evaluate (i) the occurrence and frequency of uterine peristalsis in infertile women with intramural fibroids and (ii) whether the presence of uterine peristalsis decreases the pregnancy rate. METHODS Ninety-five infertile patients with uterine fibroids were examined using magnetic resonance imaging (MRI). Inclusion criteria were as follows: (i) presence of intramural fibroids, excluding submucosal type; (ii) no other significant infertility factors (excluding endometriosis); and (iii) regular menstrual cycles, and MRI performed at the time of implantation (luteal phase day 5-9). The frequency of junctional zone movement was evaluated using cine-mode-display MRI. After MRI, patients underwent infertility treatment for up to 4 months, and the pregnancy rate was evaluated prospectively. RESULTS Fifty-one patients fulfilled the inclusion criteria, and 29 (57%) and 22 (43%) patients were assigned to the low (0 or 1 time/3 min) or high frequency (≥ 2 times/3 min) uterine peristalsis group, respectively. Endometriosis incidence was the same in both groups. Ten out of the 29 patients (34%) in the low-frequency group achieved pregnancy, compared with none of the 22 patients (0%) in the high-frequency group (P< 0.005). Comparing pregnant and non-pregnant cases, 4 of 10 patients (40%) and 9 of 41 patients (22%), respectively, had endometriosis (not significant). CONCLUSIONS A higher frequency of uterine peristalsis during the mid-luteal phase might be one of the causes of infertility associated with intramural-type fibroids.

Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormone receptor, inhibin/activin β subunits, and anti-Müllerian hormone in human granulosa cells

Immunohistochemical staining using human normal ovaries showed that bone morphogenetic protein-6 (BMP-6) was abundantly present in the granulosa cells (GC) of healthy tertiary follicles but not in atretic follicles. An in vitro study showed that BMP-6 induced gene expression of FSH receptor, inhibin/activin beta subunits, and anti-Müllerian hormone (AMH) in human GCs, suggesting that BMP-6 is an important mediator to support healthy follicle growth in the human ovary.

Toll-like Receptors at the Maternal-Fetal Interface in Normal Pregnancy and Pregnancy Complications

Toll‐like receptors (TLRs) form the major family of pattern recognition receptors (PRRs) that are involved in innate immunity. Innate immune responses against microorganisms at the maternal‐fetal interface may have a significant impact on the success of pregnancy, as intrauterine infections have been shown to be strongly associated with certain complications of pregnancy. At the maternal‐fetal interface, TLRs are expressed not only in the immune cells but also in non‐immune cells such as trophoblasts and decidual cells; moreover, their expression patterns vary according to the stage of pregnancy. Here, we will update potential functions of TLRs in these cells, their recognition and response to microorganisms, and their involvement in the innate immunity. The impact of TLR‐mediated innate immune response will be discussed via animal model studies, as well as clinical observations.

Interleukin-4 stimulates proliferation of endometriotic stromal cells.

Several lines of evidence indicate that the Th2 immune response is associated with endometriosis. Although an increased concentration of interleukin (IL)-4, a typical Th2 cytokine, has been reported in endometriotic tissues, the implication of this for endometriosis has not been determined. To investigate a possible role of IL-4 in the development of endometriosis, we examined the presence of IL-4-producing cells in endometriotic tissues and the effect of IL-4 on proliferation of endometriotic stromal cells. Endometriotic stromal cells were isolated from endometriotic tissues obtained from women undergoing surgery for endometrioma. Immunohistochemistry of endometriotic tissues revealed that IL-4-positive cells were abundant in the stroma. The effect of IL-4 on proliferation of endometriotic stromal cells was studied using cell counting and BrdU incorporation assays. IL-4 (0.1 to 10 ng/ml) significantly increased cell number and BrdU incorporation in a dose-dependent manner, and the proliferative effect of IL-4 was inhibited by anti-IL-4 receptor antibody. IL-4-induced activation of mitogen-activated protein kinases in endometriotic stromal cells was examined by Western blotting. IL-4 induced phosphorylation of p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun kinase, and p42/44 mitogen-activated protein kinase and inhibitors of these kinases suppressed IL-4-induced proliferation of endometriotic stromal cells. These findings suggest that proliferation of endometriotic stromal cells induced by locally produced IL-4 is involved in the development of endometriosis.