Advancing fertility preservation in prepubertal mice: Efficacy of ovarian tissue culture and in vitro growth in mature oocyte development.

AIM: This study aimed to evaluate the ovarian tissue culture and in vitro follicle growth as safer alternatives to cryopreservation for generating in vitro fertilization (IVF)-ready mature oocytes from prepubertal mice without the risk of cancer cell contamination. METHODS: Ovaries from prepubertal B6D2F1 mice were cultured in α-minimum essential medium supplemented with an estrogen receptor antagonist, ICI 182780. Culture duration was investigated to identify the optimal timeframe for follicle growth and oocyte maturation. Follicles were isolated mechanically or using 1 mg/mL collagenase and cultured in Matrigel matrix or polyvinylpyrrolidone. Oocyte development at metaphase II was induced by in vitro maturation, followed by IVF. RESULTS: The optimal culture duration was 2-4 days, and tissues cultured beyond this period showed significant follicular degeneration. ICI 182780 supplementation resulted in the recovery of 20.5 follicles per ovary compared with 9.5 follicles in non-supplemented cultures (p < 0.05). Of the 452 isolated follicles, 237 (52.4%) showed growth, 150 (33.2%) underwent germinal vesicle breakdown, and 18 (4.0%) reached metaphase II. However, none of the metaphase II oocytes were successfully fertilized after IVF. Matrigel demonstrated a significantly higher in vitro maturation rate compared with polyvinylpyrrolidone in a comparative analysis of culture matrices (p < 0.001). CONCLUSIONS: This study highlighted ovarian tissue culture and in vitro growth as effective strategies for producing mature oocytes from prepubertal mice. Further studies are required to overcome fertilization hurdles and understand the mechanisms that improve post-IVF embryo viability.

The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Primordial follicles remaining in young cancer survivors who received chemotherapy.

AIM: Ovarian tissue cryopreservation (OTC) is performed for fertility preservation in cancer patients undergoing chemotherapy. Although anti-Müllerian hormone is used as a marker for ovarian reserve, serum levels do not always correlate with the number of follicles. Additionally, the follicle development stage most affected by chemotherapy is unclear. We examined the association between serum anti-Müllerian hormone levels and the number of remaining primordial follicles after chemotherapy, as well as which follicle stage is most affected by chemotherapy before ovarian cryopreservation. METHODS: Thirty-three patients who underwent OTC were divided into the chemotherapy (n = 22) and non-chemotherapy (n = 11) groups; their ovarian tissues underwent histological examination. Pathological ovarian damage induced by chemotherapy was assessed. Ovarian volumes were estimated from weights. We compared the number of follicles at each developmental stage as a percentage of primordial follicles between the groups. The relationship between serum anti-Müllerian hormone level and primordial follicle density was analyzed. RESULTS: The chemotherapy group had a significantly lower serum anti-Müllerian hormone level, ovarian volume, and density of developing follicles than the non-chemotherapy group. Serum anti-Müllerian hormone levels correlated with primordial follicle density only in the non-chemotherapy group. The chemotherapy group had significantly lower numbers of primary and secondary follicles. CONCLUSIONS: Chemotherapy induces ovarian damage and follicle loss. However, serum anti-Müllerian hormone level does not always reflect the number of primordial follicles after chemotherapy, and chemotherapy more significantly affects primary and secondary follicles than primordial follicles. Many primordial follicles remain in the ovary after chemotherapy, supporting OTC for fertility preservation.

Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part).

BACKGROUND: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE). PATIENTS AND METHODS: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period. RESULTS: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks. CONCLUSION: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000024113).

A phase II study of the safety of olanzapine for oxaliplatin based chemotherapy in coloraectal patients.

Olanzapine has exhibited efficacy as an antiemetic agent when used with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists for patients receiving highly emetogenic chemotherapy. In addition, several studies have reported the efficacy or safety of olanzapine in patients receiving moderately emetogenic chemotherapy, including carboplatin, irinotecan, and oxaliplatin. However, no reports of olanzapine use have focused on patients receiving oxaliplatin-based chemotherapy. Therefore, we analyzed the safety of antiemetic therapy using olanzapine, palonosetron, aprepitant, and dexamethasone in colorectal cancer patients undergoing oxaliplatin-based chemotherapy. This study was a prospective phase II single-institution study of 40 patients (median age 60 years, 23 patients were male). The primary endpoint was the incidence of adverse events, and the exploratory endpoints were the rate of chemotherapy-induced nausea and vomiting. Almost all patients (90%) had a performance status of 0. All patients received the scheduled antiemetic therapy. The most common adverse event was somnolence (n = 7 patients, 17.5%). All adverse events were grade 1. Thirty-six patients were included in the exploratory analysis of efficacy. No patients experienced vomiting during the first 120 h after chemotherapy, and complete response and complete control were both 86.1%. The rate of total control was 55.6% during the same time period. Olanzapine use with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists was safe for colorectal cancer patients receiving oxaliplatin-based chemotherapy.

Aldehyde dehydrogenase 2 genotype in tolerability of alcohol contained in paclitaxel in Japanese breast cancer patients.

BACKGROUND: Paclitaxel (PTX) is an essential anticancer drug used to treat breast cancer. Because it contains alcohol as a solvent, it is contraindicated in many Japanese breast cancer patients when they are suspected of alcohol intolerance. Aldehyde dehydrogenase 2 (ALDH2) is one of several enzymes that catalyzes dehydrogenation of aldehydes, and plays an important role in ethanol metabolism. Deficiency of this isozyme is believed to be responsible for facial flushing and other unpleasant symptoms following ethanol intake. In this study, we examined the safety of PTX for patients with the ALDH2 GA genotype. METHODS: We performed ALDH2 genotyping on 25 patients with various cancers who were suspected to be intolerant to alcohol based on an interview using a simple question. Ten patients with the ALDH2 GA genotype, including 5 breast cancer patients, underwent chemotherapy containing PTX up to 100 mg/m2 (range 80-100 mg/m2), and were questioned about 16 alcohol-related symptoms at 11 timepoints to evaluate sensitivity to alcohol. RESULTS: All patients completed the first course of planned chemotherapy with either no or grade 1 alcohol-related symptoms. CONCLUSIONS: Our study suggests that PTX up to 100 mg/m2 can be used safely for patients with the ALDH2 GA genotype. To confirm the necessity of a genotyping test for ALDH2, further studies evaluating alcohol sensitivity in response to PTX among patients with the ALDH2 AA genotype are required.

Fertility preservation and pregnancy outcomes in adolescent and young adult male patients with cancer.

PURPOSE: Sperm cryopreservation is the gold standard for maintaining fertility in male survivors of cancer. In order to help increase the future success of fertility preservation in these patients, the present state of sperm cryopreservation was examined at the current institution and its challenges were discussed. METHODS: Between January, 2004 and February, 2017, 31 male patients with cancer were introduced to the center for fertility preservation. The ages and semen characteristics of these patients were examined and compared between those whose sperm were cryopreserved before (the pretreatment group) and after (the post-treatment group) cancer treatment. RESULTS: The mean sperm concentration of the pretreatment group was significantly higher than that of the post-treatment group. Normozoospermia was found in eight and three patients in the pretreatment and the post-treatment groups, respectively, albeit this difference was not significant. In contrast, the prevalence of azoospermia was higher in the post-treatment group (five patients) than in the pretreatment group (one patient). CONCLUSION: As many patients possibly suffer from infertility following chemotherapy, it is necessary to provide fertility preservation opportunities to young male patients with cancer prior to the commencement of cancer treatment.

Suturing method as a factor for uterine vascularity after laparoscopic myomectomy.

OBJECTIVE: To evaluate the vascularity of the myometrium after laparoscopic myomectomy sutured by two different methods using contrast-enhanced Magnetic Resonance Imaging. STUDY DESIGN: Twenty-eight women who had symptomatic leiomyomas and underwent laparoscopic myomectomy between June 2013 and July 2014 were included in the present study. In the first half period, continuous sutures were used in 12 patients, and in the latter half period, single interrupted sutures were used in 16 patients. Contrast-enhanced Magnetic Resonance Imaging was used 3 or 6 months after surgery to evaluate vascularity after laparoscopic myomectomy. We defined avascularity index as the percentage of avascular area after surgery to cross sectional area of myoma before surgery. The Wilcoxon rank-sum test was applied to compare avascularity indeces in the two study groups. RESULTS: At 3 months after surgery, avascularity index in continuous sutures group was significantly higher than that in single interrupted sutures group (median 5.0 vs.1.2, p<0.001), suggesting a poorer vascular recovery of the myometrium sutured continuously. CONCLUSION: Simple interrupted suturing might be superior to continuous suturing in terms of vascularity evaluated using contrast enhanced Magnetic Resonance Imaging.

Effects of gremlin-2 on the transition of primordial follicles during early folliculogenesis in the human ovary.

OBJECTIVE: To investigate the localization and function of gremlin-2 during human ovarian folliculogenesis. STUDY DESIGN: Ovarian tissue from a gynecologic cancer patient was cultured in the presence or absence of gremlin-2 and then analyzed histologically. Growing follicles were counted by the microscopic observations of ovarian histological sections. Immunocytochemical staining was carried out to detect the expression of bone morphogenetic protein (BMP) 4 and phosphorylated Smad 1/5/8 (p-Smad 1/5/8). RESULTS: Gremlin-2 was detected in human primordial, primary, and early growing follicles before culture. By day 4 of culture, the follicle growth rate in the presence of gremlin-2 (13.7%; 24/175) was significantly lower than that of the control (54.8%; 92/175; p<0.01). BMP4 expression was similar in the presence and absence of gremlin-2, whereas the p-Smad 1/5/8 signal was noticeably stronger in the absence of gremlin-2 in primordial and early-stage growing follicles. CONCLUSIONS: Gremlin-2 maintains the follicle store as primordial follicles by suppressing Smad 1/5/8 signaling in the human ovary. The data presented here provide potential insight into reproductive medicine for cases of intractable infertility, such as premature ovarian insufficiency and cancer survivors.

Intrinsically disordered region of influenza A NP regulates viral genome packaging via interactions with viral RNA and host PI(4,5)P2.

To be incorporated into progeny virions, the viral genome must be transported to the inner leaflet of the plasma membrane (PM) and accumulate there. Some viruses utilize lipid components to assemble at the PM. For example, simian virus 40 (SV40) targets the ganglioside GM1 and human immunodeficiency virus type 1 (HIV-1) utilizes phosphatidylinositol (4,5) bisphosphate [PI(4,5)P2]. Recent studies clearly indicate that Rab11-mediated recycling endosomes are required for influenza A virus (IAV) trafficking of vRNPs to the PM but it remains unclear how IAV vRNP localized or accumulate underneath the PM for viral genome incorporation into progeny virions. In this study, we found that the second intrinsically disordered region (IDR2) of NP regulates two binding steps involved in viral genome packaging. First, IDR2 facilitates NP oligomer binding to viral RNA to form vRNP. Secondly, vRNP assemble by interacting with PI(4,5)P2 at the PM via IDR2. These findings suggest that PI(4,5)P2 functions as the determinant of vRNP accumulation at the PM.

Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells.

OBJECTIVE: To investigate the in vitro effect of drospirenone on human eutopic endometrial (EuSC) and ectopic endometriotic stromal cells (EcSC). DESIGN: Comparative and laboratory study. The experimental procedures were approved by the Institutional Review Board of the University of Tokyo (registration no. 0324-4). SETTING: University research laboratory. PATIENTS(S): Eight patients undergoing hysterectomy for benign gynecologic disease and 19 patients undergoing cystectomy or adnectomy for endometriosis. INTERVENTION(S): EuSC and EcSC were treated with drospirenone. MAIN OUTCOME MEASURE(S): For the analysis of decidualization of EuSC, cells were observed using microscopy, and the production of PRL was measured using enzyme immunoassay. For the analysis of DNA synthesis of EcSC, 5-bromo-2'-deoxyuridine incorporation was measured by ELISA. Cells in apoptosis were detected and measured by flow cytometry. RESULT(S): Drospirenone induced decidualization in EuSC, and the induction was negated by RU486. Drospirenone reduced DNA synthesis on EcSC, and this reduction was negated by RU486 or P receptor silencing, but not by aldosterone or mineralocorticoid receptor silencing. Drospirenone did not cause EcSC to undergo apoptosis. CONCLUSION(S): Our study demonstrates the direct effects of drospirenone: decidualization of EuSC and reduced DNA synthesis of EcSC, but it does not cause EsSC apoptosis.

Laparoscopic ovarian-sparing surgery for a young woman with an exophytic ovarian fibroma.

Ovarian fibroma can occur in young women of reproductive age. Despite its benign feature, most surgical removals are done in open surgery with oophorectomy. However, an ovarian-sparing tumor resection can be an option, especially for an exophytic type of fibroma, which accounts for more than half of ovarian fibromas. Here we report a case of exophytic ovarian fibroma in a young woman treated by laparoscopic ovarian-sparing surgery. A 27-year-old woman presented with a pelvic mass. Magnetic resonance imaging revealed an 11 cm × 8 cm solid mass connected to the normal-appearing left ovary by a pedicle-like structure. A clinical diagnosis of an exophytic ovarian fibroma was made, and laparoscopic ovarian-sparing surgery with an intraoperative pathological examination was planned. The tumor was resected by cutting the pedicle, morcellated in a pouch and removed. All procedures were performed laparoscopically and the affected ovary was completely preserved. Having confirmation of its benign characteristics by the intraoperative examination, no further excision was performed. The patient conceived 3 months after the surgery and no recurrence was reported. We propose that gynecologists should consider laparoscopic ovarian-sparing surgery for exophytic ovarian fibroma in women of reproductive age.

Interleukin-4 and prostaglandin E2 synergistically up-regulate 3ß-hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells.

CONTEXT: Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease. OBJECTIVE: The objective of the investigation was to study the effect of IL-4 on the expression of 3ß-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay. RESULTS: IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA. CONCLUSIONS: IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease.

Interleukin-17A is present in neutrophils in endometrioma and stimulates the secretion of growth-regulated oncogene-α (Gro-α) from endometrioma stromal cells.

OBJECTIVE: To investigate a new role of interleukin (IL)-17A in endometriosis. DESIGN: Laboratory study. SETTING: University hospital. PATIENT(S): Patients with ovarian endometrioma undergoing laparoscopy or laparotomy. INTERVENTION(S): Primary culture of endometrioma stromal cells (EoSCs) was stimulated with IL-17A. Sections of endometrioma tissue were immunostained with antibodies for IL-17A, growth-regulated oncogene-α (Gro-α), and elastase, a marker of neutrophils. They were also examined with immunofluorescent double staining for IL-17A and myeloperoxidase, another marker of neutrophils. MAIN OUTCOME MEASURE(S): Concentration of Gro-α was measured using a specific ELISA. Neutrophil chemotaxis was measured with Boyden chamber method. Immunostained sections were examined under microscope. RESULT(S): Interleukin-17A increased the secretion of Gro-α from EoSCs dose-dependently. The conditioned medium of EoSCs stimulated with IL-17A attracted more neutrophils than that of EoSCs stimulated with vehicle, and the increase was inhibited by the addition of Gro-α-neutralizing antibody. On immunostaining, IL-17A and Gro-α were detected in similar areas of the stroma beneath the epithelium, where Gro-α was detected in cells with a stromal cell appearance whereas IL-17A was detected in neutrophils as determined by detection of elastase. Fluorescent immunostaining corroborated that myeloperoxidase-positive neutrophils were also positive for IL-17A. CONCLUSION(S): It is suggested that IL-17A produced by neutrophils stimulates Gro-α secretion from EoSCs, thereby recruiting more neutrophils and inducing perpetuating inflammation in endometriosis.

The N-linked carbohydrate moiety of male reproductive tract CD52 (mrt-CD52) interferes with the complement system via binding to C1q.

Antisperm antibody detected in infertile female patients' sera has been shown to correlate with reduced fertility. The antibody showed strong complement-dependent cytotoxicity as determined by the sperm immobilization test (SIT). CD52 is a human glycosylphosphatidylinositol (GPI)-anchored antigen present in lymphocytes and male reproductive tracts (mrt), including mature sperm and seminal plasma. Recently, purified mrt-CD52 from human seminal plasma has been reported to interfere with the classical complement pathway, but not lectin binding or alternative pathways of the complement system. The purpose of this study is to determine which stage of the classical pathway mrt-CD52 regulates. mrt-CD52 was purified from human seminal plasma or intact sperm membrane. Immunoprecipitation assay was performed with the reaction of mrt-CD52, human complement and mAb H6-3C4. Immunoprecipitate was formed by the carbohydrate moiety of mrt-CD52, but not by the GPI-anchor peptide. The C1q molecule (29 kDa) was detected in the immunoprecipitates by Western blotting analysis probed with anti C1q antibody, indicating that the carbohydrate moiety of mrt-CD52 binds to C1q. Also, the complement-dependent SIT revealed that purified CD52 inhibited sperm immobilization activity by antisperm antibody. These results suggest that mrt-CD52 protects sperm function from complement attack if antisperm antibody is generated in the female reproductive tracts.

How to reconstruct a natural and deep umbilicus: three methods of umbilicoplasty for five types of umbilical deformities.

UNLABELLED: Conventional methods of umbilicoplasty using V-Y advancement flap often result in unnatural wide or shallow umbilical depressions facing upward or downward. Moreover, although the umbilical deformities have many variations, no report has described the selection of an umbilicoplasty method for types of umbilical deformity. To resolve these problems, we devised 3 methods of umbilicoplasty. In this report, we classified all kinds of umbilical deformities into 5 types, and studied the most suitable method for each type of umbilical deformity. METHOD: The umbilical deformities are classified into Type 0: the defect of umbilicus; Type I, the low-grade protrusion; Type II, the high-grade protrusion with wide base; Type III, the high-grade protrusion with narrow base; and Type IV, the protrusion in depression. The most suitable method among our 3 methods was adapted to each type. Method 1 with a S-shaped skin incision was adapted to Type 0 and I, Method 2 with fan-style flaps was adapted to Type II, and Method 3 with dividing the umbilical protrusion was adapted to Type III and IV. RESULTS: Sixty-three patients (10 cases of Type 0, 31 cases of Type I, 10 cases of Type II, 5 cases of Type III, and 7 cases of Type IV) underwent umbilicoplasty using the suitable method, and all were well corrected. CONCLUSIONS: Using the best choice among our 3 methods, it is easy to create a natural, vertically long and deep umbilical depression without conspicuous scars in all types of umbilical deformities.

Interleukin-17F increases the secretion of interleukin-8 and the expression of cyclooxygenase 2 in endometriosis.

OBJECTIVE: To examine the effects of interleukin (IL)-17F on the secretion of IL-8 and the gene expression of cyclooxygenase 2 (COX2) in endometriotic stromal cells. DESIGN: In vitro experimental study using human samples. SETTING: University hospital. PATIENT(S): Endometriotic tissues were obtained from women with ovarian endometriomas undergoing laparoscopic surgery. INTERVENTION(S): Endometriotic stromal cells (ESCs) were cultured with IL-17F. MAIN OUTCOME MEASURE(S): Concentrations of IL-8 were measured by a specific ELISA, and messenger RNA levels of IL-8 and COX2 were measured by real-time reverse transcription-polymerase chain reaction (PCR). RESULT(S): IL-17F increased the secretion of IL-8 from ESCs, and the effect was inhibited by antibodies for IL-17 receptor A and IL-17 receptor C. Tumor necrosis factor α (TNF-α) synergistically enhanced IL-17F-induced increase in IL-8 secretion from ESCs. The IL-17F increased the gene expression of IL-8 and COX2 in ESCs. CONCLUSION(S): These findings suggest that IL-17F may stimulate the development of endometriosis by up-regulation of IL-8 and COX2.

Hyaluronic acid reagent suppressed endometriotic lesion formation in a mouse model.

In an animal endometriosis model, the administration of hyaluronic acid (HA) reagent significantly suppressed the formation of endometriotic lesions in both number and weight. This effect was found when HA treatment was conducted at the time of endometrial fragment inoculation.

Progesterone decreases bone morphogenetic protein (BMP) 7 expression and BMP7 inhibits decidualization and proliferation in endometrial stromal cells.

BACKGROUND: Regulation of decidualization is decisive for proper implantation and the establishment of pregnancy. Recent studies have suggested that several bone morphogenetic proteins (BMPs) play physiological roles in reproduction. In the present study, we examined the expression of BMP7 in the endometrium and the effect of BMP7 on decidualization and proliferation of endometrial stromal cells (ESC). METHODS: The gene expression of BMP7 in endometrial tissues collected from women with regular menstrual cycles was determined and the effect of ovarian steroid hormones on BMP7 gene expression was investigated in cultured ESC. The effect of BMP7 on the decidualization of ESC was determined by measuring the gene expression and protein secretion of insulin-like growth factor binding protein 1 (IGFBP1), a marker of decidualization. The effect of BMP7 on the proliferation of ESC was examined by the bromodeoxyuridine (BrdU) incorporation assay. RESULTS: The gene expression of BMP7 in endometrial tissues was low at and after the mid-secretory phase of the menstrual cycle. Progesterone suppressed the gene expression of BMP7 in cultured ESC. Treatment with progesterone and estradiol for 12 days achieved decidualization of ESC, increasing the gene expression and protein secretion of IGFBP1. Addition of BMP7 protein to the culture almost completely inhibited these increases. BMP7 suppressed BrdU incorporation in ESC, which indicated an antiproliferative effect of BMP7 on ESC. CONCLUSIONS: Progesterone-induced suppression of BMP7 and BMP7-induced inhibition of decidualization and proliferation of ESC suggest an elaborate regulatory mechanism for decidualization through BMP7 in the endometrium.

Functional aspects of CD52 in reproduction.

CD52 is a GPI-anchored protein present in lymphocytes and male reproductive tissues (mrt) including mature sperm and seminal plasma. It has been shown that mrt-CD52 is synthesized in epithelial cells of the epididymis and vas deferens, but not in the testis. The mrt-CD52 is transported to mature sperm during sperm transition in the male reproductive tract. Lymphocyte CD52 functions to stimulate suppressor T cell induction, while mrt-CD52 is associated with seminogelin and involved in clot formation and liquefaction of semen. In a landmark study, a monoclonal antibody (Mab H6-3C4) from peripheral B lymphocytes of a patient with complement-dependent sperm-immobilizing antibody in the serum has been generated. Using Mab H6-3C4, the carbohydrate moiety of CD52 as an epitope for infertility-related antigen was identified. Mab H6-3C4 also shows strong complement-dependent sperm-immobilizing activity. This suggests CD52 may have a function in protecting sperm from complement activation. Indeed, purified mrt-CD52 from human sperm interferes with the classical pathway, but not lectin-binding or alternative pathways, of the complement systems. Recently, we found CD52 in ovulated cumulus cells from the female reproductive tissues (frt). The frt-CD52 is not recognized by Mab H6-3C4, suggesting that it harbors distinct carbohydrate antigenicity. Further studies are necessary to determine the molecular features and biological functions of CD52 in male and female reproductive tissues.