Efficacy and safety of follitropin delta versus follitropin alpha/beta in infertility treatment: A systematic review and meta-analysis.

Background: Follitropin δ may be an alternative to conventional follitropin α/ß for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/ß. Methods: We searched randomized controlled trials comparing follitropin δ and follitropin α/ß using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework. Results: Three studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/ß. Conclusion: Follitropin δ may result in little to no difference in COS compared with follitropin α/ß, especially in terms of live births and safety.

Differences between Japanese new criteria and pregnancy-specific modified ISTH DIC scores for obstetrical DIC diagnosis.

The new Japanese diagnostic criteria for obstetrical disseminated intravascular coagulation (DIC) (tentative version) were released in June 2022. We aimed to demonstrate the differences in characteristics between women with DIC diagnosed using the new Japanese criteria and those diagnosed using the pregnancy-specific modified International Society on Thrombosis and Hemostasis DIC score, also known as the pregnancy-specific modified ISTH DIC score, which was released in 2014. In this retrospective cohort study, all participants were retrospectively diagnosed based on both criteria. Six women were diagnosed with obstetrical DIC based on both criteria (Group A). Of the 43 women diagnosed with obstetrical DIC based on the worldwide criteria, 36 were diagnosed with non-obstetrical DIC based on the new Japanese criteria (Group B). Group A had significantly lower fibrinogen levels and significantly higher prothrombin time differences and scores of underlying diseases (particularly postpartum hemorrhage with coagulopathy) and laboratory findings than Group B. Additionally, Group A had significantly higher rates of platelet concentrate (PC) transfusion therapy for obstetrical DIC and more transfusions of fresh frozen plasma and/or cryoprecipitate, red blood cells and PC than Group B. Thus, the new Japanese criteria detected more severe cases of obstetrical DIC compared with the worldwide criteria.

Changes in the conflicting nongenomic effects of progesterone in rat myometrium during pregnancy.

AIMS: Although the functions of progesterone in the myometrium are well-established, the nongenomic effects of progesterone in pregnant myometrial contractions are still unclear. Therefore, this study aimed to investigate changes in the nongenomic effects of progesterone during pregnancy. MAIN METHODS: Myometrial strips were obtained from non-pregnant, pregnant, and postpartum rats, and the nongenomic effects of progesterone in the myometrium during pregnancy were examined. Additionally, the influence of actinomycin D and cycloheximide and the effects of Org OD-02-0 (a specific membrane progesterone receptor (mPR) agonist) in the myometrium were investigated. Moreover, DNA microarray and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to identify genes involved in progesterone-induced effects in the myometrium. KEY FINDINGS: Progesterone did not cause rhythmic contractions in non-pregnant myometrium but induced rhythmic contractions in pregnant myometrium, with the effects peaking at 20 d + 8 h of pregnancy. However, myometrial contractions decreased after delivery and were restored to non-pregnant levels at 7 d postpartum. Additionally, progesterone stably inhibited high KCl-induced myometrial contractions during pregnancy. Moreover, the nongenomic effects of progesterone were unaffected by actinomycin D or cycloheximide, and Org OD-02-0 effectively mimicked these effects. DNA microarray analysis and qRT-PCR revealed a significant increase in mPRß gene expression during pregnancy. However, mPRα, mPRγ, mPRδ, and mPRε expression levels remained unchanged. SIGNIFICANCE: The stimulatory nongenomic effect of progesterone, which was inducible and mPRß-dependent during pregnancy, may be involved in parturition. The inhibitory effect, which was constitutive and depended on other mPRs, may be involved in pregnancy maintenance.

Successful pneumovaginoscopic surgery for recurrent abscess of OHVIRA syndrome, preventing further recurrence and subsequent pregnancy.

INTRODUCTION: OHVIRA syndrome is a rare congenital anomaly of Müllerian duct development characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. The primary treatment is surgical excision of the obstructed hemivaginal septum and hematometrial drainage. In recent years, minimally invasive approaches such as hysteroscopic or vaginoscopic septum resection have been reported. Furthermore, we originally developed some novel pneumovaginoscopic gynecologic surgeries for years using a device that consists of a cylinder that fits into the vagina and a lid that mounts multiple ports, allowing the vagina to be dilated with carbon dioxide gas, similar to a single-port laparoscope. MATERIALS AND SURGICAL TECHNIQUE: We report a successful pneumovaginoscopic surgery for a complicated recurrent abscess in a patient with OHVIRA syndrome. Conventional surgery was performed with a single forceps in a liquid, as in cystoscopy or hysteroscopy. However, this new surgery allowed multiple forceps in a gas, as in laparoscopy. So pus and blood were aspirated and washed away without leaking into the abdominal cavity via fallopian tubes. The surgical smoke generated by thermal coagulation also aspirated to clean the field of vision immediately. And thick, complicated abscesses were drained successfully. The patient conceived through IVF with ICSI and delivered safely at full term. DISCUSSION: Pneumovaginoscopy could benefit complex vaginal surgery cases, such as abscess formation in patients with OHVIRA syndrome.

Pneumovaginoscopy-assisted radical hysterectomy for early-stage cervical cancer: a novel bidirectional approach for tumor spillage prevention and R0 resection.

OBJECTIVE: This study evaluated the feasibility and outcomes of pneumovaginoscopy-assisted radical hysterectomy (PVRH) for cervical cancer up to stage IIA using a bidirectional fascia-oriented and nerve-sparing surgical approach. METHODS: This retrospective observational cohort study examined the operative outcomes and prognoses of patients who underwent PVRH (n=59) for up to stage IIA cervical cancer. The basic procedure was Kyoto B2 (Viper Type II nerve-sparing) radical hysterectomy and pelvic lymphadenectomy through simultaneous vaginal and abdominal (open or laparoscopic) approaches. In all cases, pneumovaginoscopy (PV) was used to create a vaginal cuff and dissect the paracolpium and paracervical endopelvic fascia to minimize nerve damage. RESULTS: Thirty-eight (64.4%) patients had stage IB1 cancer. Seven (11.9%) had vaginal invasion (stage IIA1, n=4; IIA2, n=3). The abdominal approach was open in 38 cases and laparoscopic in 21. Adjuvant therapy was administered to 24 patients (41%); one patient received concurrent chemoradiotherapy for gastric-type adenocarcinoma. There were three (6.1%) intraoperative complications (CO2 gas embolism [n=1], sigmoid colon musculosa injury [n=1], and ureteral injury [n=1]) and 8 (14%) postoperative complications (lymphedema with cellulitis [n=4], vaginal cuff dehiscence [n=1], sub-ileus [n=1], symptomatic lymphocyst [n=l], and ureterovaginal fistula [n=1]). The median urination recovery period was 3 days. Microscopic R0 was achieved in all cases. The median follow-up was 44.5 (2-122) months, and no recurrence occurred. CONCLUSION: PVRH is a new fascia-oriented and nerve-sparing surgery for early-stage cervical cancer. Further, it has favorable operative outcomes and good prognoses, similar to those of adjacent pelvic surgery such as trans-anal total mesorectal excision and radical prostatectomy.

A pilot study of repeated 5-aminolevulinic acid photodynamic therapy for cervical intraepithelial neoplasia by a newly developed intravaginal irradiation system.

The pilot study was performed to assess the usefulness of a newly developed patientand physician-friendly intravaginal irradiation system for photodynamic therapy with 5-aminolevulinic acid (5-ALA PDT) for cervical intraepithelial neoplasia (CIN). We used an intravaginal balloon applicator to make the cervix upright and to adjust the position and direction of the laser source in the vagina, resulting in minimal patient discomfort and minimal effort required by the physician during irradiation. Ten outpatients of CIN2 or 3 with high-risk human papillomavirus (HPV) infection without a history of HPV vaccination were treated by 5-ALA PDT. Each patient underwent PDT four times every two weeks. Nine patients showed pathological improvement, and the HPV clearance rate was 80%, and no recurrence was observed at two-years follow-up. Serum anti-HPV16 antibodies were detected in seven patients, and the antibody levels of three patients were high, equivalent to those acquired after HPV vaccination. Our newly developed irradiation system enabled easy repeat 5-ALA PDT in the outpatient clinic resulting in the improvement of CIN lesions and HPV clearance. Our results also suggested that repeated 5-ALA PDT might enhance HPV antibody production in CIN patients.

Inflammatory Cytokine-Induced HIF-1 Activation Promotes Epithelial-Mesenchymal Transition in Endometrial Epithelial Cells.

The endometrium undergoes repeated proliferation and shedding during the menstrual cycle. Significant changes to this environment include fluctuations in the partial pressure of oxygen, exposure to a high-cytokine environment associated with intrauterine infection, and inflammation. Chronic endometritis is a condition wherein mild inflammation persists in the endometrium and is one of the causes of implantation failure and miscarriage in early pregnancy. It is thought that the invasion of embryos into the endometrium requires epithelial-mesenchymal transition (EMT)-associated changes in the endometrial epithelium. However, the effects of inflammation on the endometrium remain poorly understood. In this study, we investigated the effects of the intrauterine oxygen environment, hypoxia-inducible factor (HIF), and inflammation on the differentiation and function of endometrial epithelial cells. We elucidated the ways in which inflammatory cytokines affect HIF activity and EMT in an immortalized cell line (EM-E6/E7/TERT) derived from endometrial epithelium. Pro-inflammatory cytokines caused significant accumulation of HIF-1α protein, increased HIF-1α mRNA levels, and enhanced hypoxia-induced accumulation of HIF-1α protein. The combined effect of inflammatory cytokines and hypoxia increased the expression of EMT-inducing factors and upregulated cell migration. Our findings indicate that pro-inflammatory factors, including cytokines and LPS, work synergistically with hypoxia to activate HIF-1 and promote EMT in endometrial epithelial cells.

Fertility-sparing radical resection of juvenile clear cell adenocarcinoma of the cervix by pneumovaginal endoscopic surgery.

Vaginoscopy has been mainly used diagnostically due to the lack of adequate equipment for performing complicated surgeries (Johary et al., 2015). However, herein, we report therapeutic vaginal endoscopic surgery (pneumovaginoscopy) for secondary malignant vaginal tumors using the vNOTES technique and devices (Kita et al., 2021, Yokoe et al., 2022). To our knowledge, this report and surgical video demonstrate the first case of successful fertility-sparing R0 tumor resection of a rare primary cervical clear cell adenocarcinoma using pneumovaginoscopy. A 12-year-old girl was referred to our outpatient clinic with a chief complaint of a genital tumor and possible clear cell carcinoma on biopsy. There was no history of diethylstilbestrol exposure. MRI and CT images suggested a polypoid cervical tumor without metastatic lesions. Therefore, we performed therapeutic pneumovaginoscopic surgery with diagnostic laparoscopy and hysteroscopy. The cervical tumor was resected completely, and hysteroscopy and laparoscopy revealed no abnormalities. The total surgical time was 123 min, and the blood loss volume was minimal. R0 resection was achieved microscopically. Postoperatively, we performed a partial cervical resection around the first surgical scar to confirm no residual tumor. There were no postoperative complications, and a 2-year follow-up revealed no recurrence. The standard treatment for early-stage cervical cancer (IA2-IB1) remains radical hysterectomy with pelvic lymphadenectomy. However, fertility-sparing minimally invasive surgery has recently been introduced for clear cell adenocarcinoma of the cervix (Su et al., 2020). Our report supports the possibility of this minimally invasive surgery under exceptional conditions. This study was approved by the ethics committee of Kansai Medical University. Written and signed informed consent was obtained from the patient's legal guardian.

R0 resection of vaginal stump recurrence of gynecologic malignancy by bi-directional endoscopic approach: A case series of four patients.

Vaginal stump recurrence post-hysterectomy for gynecologic malignancies occurs in 2%-3% of cases. Local excision has been recognized as the primary treatment of localized recurrence, in which precise surgical margin is critical. However, R0 resection is not always easy, given the deep and narrow operation field, as well as severe postoperative fibrosis or adhesion of the vaginal stump at times. Here, we report four cases of vaginal stump recurrence of gynecologic malignancies resected by bi-directional (laparoscopic and pneumovaginoscopic) endoscopy to overcome these difficulties. The primary tumors were uterine cancer in two cases and uterine cervical and ovarian cancer in one case each. The mean operating time was 199 (162-235) minutes, blood loss was minimal, and no perioperative complications were observed. Postoperative follow-up (7.0-19.4 months) revealed no recurrence. This combined procedure could be a therapeutic option for localized vaginal stump recurrence.

Significance of placental CD200 expression in patients with preeclampsia: Comparison between early­ and late­onset patients.

Preeclampsia, characterized by high blood pressure and proteinuria during pregnancy, causes serious complications in both the mother and the fetus. Although there have been several studies on the causes of preeclampsia, the detailed mechanism of this disease remains unclear. Moreover, a few reports have focused on the causes of preeclampsia in number of weeks at onset. The present study aimed to elucidate the differences between early­ and late­onset preeclampsia. This study enrolled patients with preeclampsia from January 2014 to December 2020. They were classified into early­ (<34 weeks) and late­onset (≥34 weeks) preeclampsia groups. The expression profiles of 770 immune­related genes were studied in the placental tissue from five patients each in the early­ and late­onset groups. The expression of CD200 in the trophoblasts of the placenta of 26 and 27 patients in early­ and late­onset groups, respectively, was also analyzed using immunostaining. Analysis of extracted RNA indicated that CD200 was significantly upregulated in the early­onset group compared with late­onset group and normal control. Immunostaining for CD200 demonstrated a significantly increased expression in the early­onset group compared with the late­onset group. The present study demonstrated that upregulation of CD200, which belongs to the immunoglobulin superfamily and is recognized as a molecule that acts in immune tolerance via inhibition of classical macrophage activation, may be associated with early­onset preeclampsia, although it remains unknown whether upregulation of CD200 expression is a cause or effect of the development of early­onset preeclampsia. Early­onset preeclampsia might have a different mechanism from that of late­onset; thus, further studies are needed to clarify the mechanism of these conditions for adequate treatment.

The Regulators of Human Endometrial Stromal Cell Decidualization.

Several factors are important for implantation and subsequent placentation in the endometrium, including immunity, angiogenesis, extracellular matrix, glucose metabolism, reactive oxidative stress, and hormones. The involvement or abnormality of these factors can impair canonical decidualization. Unusual decidualization can lead to perinatal complications, such as disruption of trophoblast invasion. Drastic changes in the morphology and function of human endometrial stromal cells (hESCs) are important for decidualization of the human endometrium; hESCs are used to induce optimal morphological and functional decidualization in vitro because they contain estrogen and progesterone receptors. In this review, we will focus on the studies that have been conducted on hESC decidualization, including the results from our laboratory.

Lysophosphatidic acid production from lysophosphatidylcholine by lysophospholipase D activity of autotaxin in plasma of women with normal and adverse pregnancies.

To identify biomarker lipids causing preterm delivery, we focused on lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA). The results of liquid chromatography-tandem mass spectrometry revealed that plasma levels of LPCs and LPAs were higher in the first and third (T3) trimesters of human normal and adverse pregnancies than in the second trimester, suggesting the direct metabolic conversion of LPC to LPA by lysophospholipase D (lysoPLD) activity of autotaxin. The elevated LPC and LPA levels in women with preterm deliveries in T3 were higher than in women with term deliveries under normal pregnancy in T3. We measured lysoPLD activity of diluted sera of pregnant women by quantification of choline released from exogenous LPC, and found progressive increases of lysoPLD activities in women with normal and adverse pregnancies. Ratios of lysoPLD activities for linoleoyl LPC to that for palmitoyl LPC were found to be decreased in pregnant women compared to that in non-pregnant women. These results may be due to the altered patterns of endogenous modulators for autotaxin and the profiles of the bound metal ion.

Small-cell neuroendocrine carcinoma of the cervix accompanied by adenocarcinoma and high-grade squamous intraepithelial lesion.

Few cytological reports have described small-cell neuroendocrine carcinoma (SCNEC) in the female genital tract. In the present study, we describe a cytological case of SCNEC accompanied by adenocarcinoma, as well as high-grade squamous intraepithelial lesion (HSIL). A Japanese woman (42 years old) presented with abnormal genital bleeding. A conventional Papanicolaou smear revealed an inflammatory condition with three neoplastic components: SCNEC as irregular aggregates of neoplastic small round cells with nuclear molding and granular chromatin; adenocarcinoma as columnar cell clusters with peripherally located large nuclei, and HSIL as sheets or clusters of dysplastic basal-type squamous cells with irregular hyperchromatic nuclei. Accordingly, a cytodiagnosis of SCNEC with adenocarcinoma and HSIL was made. Owing to the rarity of cervical SCNEC, cytological diagnosis may be difficult. Due to its aggressive clinical behavior, the presence of an SCNEC component should be verified in any cytodiagnosis of adenocarcinoma or HSIL.

Laparoscopic hemostasis and drainage for postpartum retroperitoneal hematoma complicated with an infection: A case report and surgical video.

Introduction: and importance: Postpartum retroperitoneal hematomas are a potential complication of childbirth. The management of secondary infections of such hematomas has not been fully elucidated. We present a typical case of such management via laparoscopic surgery, and include a surgical video. Case presentation: A woman in her 20s experienced fever and right lower quadrant pain and distension on postpartum day 2. Pelvic examination revealed a hump on the vaginal wall on the right side of the uterine cervix, and ultrasonography revealed a hematoma. Contrast-enhanced computed tomography revealed no active extravasation into the hematoma. Conservative antibiotic treatment was started; however, on postpartum day 6, her pain increased and her C-reactive protein concentration and white blood cell count were high. Magnetic resonance imaging revealed a paravaginal/upper vaginal wall hematoma (80 × 70 × 63 mm) located to the right of the uterus and bladder. Hence, laparoscopic drainage was performed on postpartum day 7. The retroperitoneal hematoma was incised and drained. The source of bleeding was the right vaginal vein, and bleeding was halted via electrocoagulation. The patient's symptoms improved immediately, and the postoperative course was uneventful. Clinical discussion: The laparoscopic approach enabled immediate hemostasis and identification of the source of bleeding. The drainage route was cleaner than would be possible via a vaginal approach, possibly preventing postoperative retrograde re-infection. Conclusion: Laparoscopic surgery for postpartum retroperitoneal hematoma with infection was useful for both drainage and hemostasis.

The novel oral gonadotropin-releasing hormone receptor antagonist relugolix is a new option for controlled ovarian stimulation cycles.

Purpose: Relugolix is an oral gonadotropin-releasing hormone antagonist (GnRHant), which was first introduced in 2019. This study investigated the effects of the conventional injectable GnRHant formulation and this new oral GnRHant formulation on controlled ovarian stimulation (COS) cycles. Methods: Relugolix was administered in 126 cycles and conventional GnRHant injection was administered in 658 cycles (controls). The follicle stimulation was performed by an antagonist method, and for final oocyte maturation, recombinant human chorionic gonadotropin (rHCG), or gonadotropin-releasing hormone agonist (GnRHa), or both (dual trigger) were selected. The number of retrieved oocytes was counted and then they were evaluated for subsequent development up to cleavage stage. Results: The number of retrieved oocytes which was the primary outcome of this research was affected by the combination of GnRHant type and the final oocyte maturation agent. The combination of relugolix and a GnRHa trigger showed a significantly lower number of retrieved oocytes (p < 0.001) than the other combinations. Conclusions: Relugolix is a new option for COS cycles, but should be carefully combined with the final maturation agent. Clinical trial approval: This study was conducted after approval by the Medical Corporation Sankeikai Institutional Ethics Committee (approval number: 2019-34).

NDRG1 is expressed in human granulosa cells: An implicative role of NDRG1 in the ovary.

Purpose: N-myc downstream-regulated gene 1 (NDRG1) is expressed in various human tissues and plays a role in regulating cellular proliferation, angiogenesis, and hypoxia sensing. However, the role of NDRG1 in the ovary remains poorly understood. Therefore, we investigated NDRG1 expression and the role of NDRG1 in the human ovary. Methods: Follicular fluid (FF) and luteinized granulosa cells were collected from follicles during oocyte retrieval. KGN cells were cultured with cobalt chloride (CoCl2, a hypoxia-mimicking agent) and/or echinomycin. mRNA, protein levels and secretion, and localization were assessed by real-time PCR, Western blotting, ELISA, and immunohistochemical analysis, respectively. KGN cells were also transfected with NDRG1 siRNA for 72 h. Results: NDRG1 protein was expressed in luteinized granulosa cells. NDRG1 concentration was positively correlated with vascular endothelial growth factor (VEGF) and progesterone concentrations in FF. CoCl2-induced hypoxic stress significantly increased NDRG1 and VEGF mRNA and protein and hypoxia-inducible factor-1α expression compared with those in the controls. The CoCl2-induced overexpression of NDRG1 and VEGF was suppressed by echinomycin. Transfection with NDRG1 siRNA significantly suppressed the release of progesterone in the culture medium. Conclusions: These results indicate that ovarian NDRG1 may play important roles in follicular development, especially in the early luteinization of pre-ovulatory follicles.

MinION, a portable long-read sequencer, enables rapid vaginal microbiota analysis in a clinical setting.

BACKGROUND: It has been suggested that the local microbiota in the reproductive organs is relevant to women's health and may also affect pregnancy outcomes. Analysis of partial 16S ribosomal RNA (rRNA) gene sequences generated by short-read sequencers has been used to identify vaginal and endometrial microbiota, but it requires a long time to obtain the results, making it unsuitable for rapid bacterial identification from a small specimen amount in a clinical context. METHODS: We developed a simple workflow using the nanopore sequencer MinION that allows high-resolution and rapid differentiation of vaginal microbiota. Vaginal samples collected from 18 participants were subjected to DNA extraction and full-length 16S rRNA gene sequencing with MinION. RESULTS: The principal coordinate analysis showed no differences in the bacterial compositions regardless of the sample collection method. The analysis of vaginal microbiota could be completed with a total analysis time of approximately four hours, allowing same-day results. Taxonomic profiling by MinION sequencing revealed relatively low diversity of the vaginal bacterial community, identifying the prevailing Lactobacillus species and several causative agents of bacterial vaginosis. CONCLUSIONS: Full-length 16S rRNA gene sequencing analysis with MinION provides a rapid means for identifying vaginal bacteria with higher resolution. Species-level profiling of human vaginal microbiota by MinION sequencing can allow the analysis of associations with conditions such as genital infections, endometritis, and threatened miscarriage.

Hypoxia: Role of SIRT1 and the protective effect of resveratrol in ovarian function.

BACKGROUND: Ovarian function is closely related to the degree of vascular network development surrounding the ovary. Maternal aging-related construction defects in this vascular network can cause ovarian hypoxia, which impedes oocyte nutrient supply, leading to physiological changes in the ovaries and oocytes. The anti-aging gene Sirtuin 1 (SIRT1) senses and adapts to ambient stress and is associated with hypoxic environments and mitochondrial biogenesis. METHODS: The present study is a literature review focusing on investigations involving the changes in SIRT1 and mitochondrial expression during hypoxia and the cytoprotective effects of the SIRT1 activator, resveratrol. MAIN FINDINGS: Hypoxia suppresses SIRT1 and mitochondrial expression. Resveratrol can reverse the hypoxia-induced decrease in mitochondrial and SIRT1 activity. Resveratrol suppresses the production of hypoxia-inducible factor-1α and vascular endothelial growth factor proteins. CONCLUSION: Resveratrol exhibits protective activity against hypoxic stress and may prevent hypoxia- or aging-related mitochondrial dysfunction. Resveratrol treatment may be a potential option for infertility therapy.

The efficacy of human papillomavirus vaccination in young Japanese girls: the interim results of the OCEAN study.

Human papillomavirus (HPV) vaccine has been used to prevent chronic HPV infection, which accounts for cervical cancer. Japanese Ministry of Health, Labor and Welfare (MHLW) conducted an HPV vaccination campaign in 2010 and the Obstetrical Gynecological Society of Osaka initiated a multicenter, prospective cohort study in Osaka, Japan - OCEAN (Osaka Clinical resEArch of HPV vacciNe) study - to investigate the oncogenic HPV prevalence and the long-term protection rate of HPV vaccine. A total of 2814 participants were enrolled on their visit for HPV vaccination between 12 and 18 years old. Among them, 102 participants received HPV/Pap co-test as primary cancer screening at the age of 20-21. We compared the prevalence in two groups (the vaccinated and the unvaccinated group). HPV infection ratio was significantly lower in the vaccinated group compared to the unvaccinated (12.9% vs. 19.7%; p = .04). In particular, HPV 16 and 18 were not detected in the vaccinated group, while 4.9% of participants in the unvaccinated group were infected (p = .001), suggesting that vaccination provided effective protection against high-risk types of HPV. The cross-protection effect of HPV vaccines was also observed against HPV 31, 45, and 52. Although HPV vaccines were not contributed to the reduction of cervical intraepithelial neoplasia 1 (CIN) (p = .28), CIN2 or worse was not observed in vaccinated group. Our research showed that at the age of 20-21, HPV vaccine inhibited the infection of high-risk HPV and had impacted on the development to CIN2 or worse in Japan.