Impact of the difference in diagnostic criteria for adolescent polycystic ovary syndrome excluding polycystic ovarian morphology.

AIM: Exclusion of polycystic ovarian morphology (PCOM) from the diagnostic criteria for adolescent polycystic ovary syndrome (PCOS) has been proposed. We analyzed the profiles of adolescent women with suspected PCOS based on the Japan Society of Obstetrics and Gynecology (JSOG) diagnostic and Rotterdam criteria, excluding those with PCOM. METHODS: Thirteen- to twenty-one-year-old women with suspected or confirmed diagnosis of PCOS according to the JSOG and Rotterdam criteria were included in this study. Patient characteristics such as hormone levels and body mass index (BMI) were compared between the groups. Correlations between BMI and testosterone, and BMI and time to diagnosis were also analyzed. RESULTS: Twenty-nine patients were diagnosed with adolescent PCOS according to the JSOG criteria, and 11 patients according to the Rotterdam criteria after excluding the patients fulfilling the PCOM criteria. Serum testosterone levels were significantly higher in adolescents diagnosed with PCOS using the Rotterdam criteria than in those diagnosed using the JSOG criteria (p < 0.001). The obese group had significantly higher testosterone levels and a longer time from menarche to PCOS diagnosis. A positive correlation was observed between BMI and testosterone levels (r = 0.318, p = 0.014). CONCLUSION: Although adolescents with PCOS diagnosed using the Rotterdam criteria exhibited higher testosterone levels, which is a typical characteristic of this condition, the JSOG criteria may be useful for the early diagnosis of adolescent PCOS, including suspected cases. The differences between the two criteria may reflect the natural history of PCOS and its different reproductive and metabolic phenotypes.

Factors related to clearance of the small pelvic cavity during gynecologic laparoscopic surgery.

AIM: To identify factors influencing the Trendelenburg angle required during laparoscopic gynecological surgery. METHODS: Patients who underwent laparoscopic surgery at a single university hospital between May 1, 2019, and March 31, 2021 were enrolled. Data were extracted from the medical records, while magnetic resonance imaging scans and all laparoscopic surgery videos were retrospectively reviewed to assess the presence of the small intestine in the pelvic cavity as well as the adhesions at each site. Groups with and without the small intestine in the pelvic cavity, and those requiring a Trendelenburg angle above or below 13° were compared. RESULTS: In total, 219 patients were examined. The Trendelenburg angle was significantly higher (p = 0.004), while a significant increase in ovarian adhesions was observed (p = 0.033; odds ratio [OR], 2.30; 95% confidence interval [CI], 1.05-5.01) in the group without the presence of the small intestine in the pelvic cavity. Furthermore, the group requiring a Trendelenburg angle of ≥13° had significantly thicker subcutaneous fat (p = 0.044) and more ileal adhesions (p = 0.040, OR, 1.82; 95% CI, 1.03-3.23) than the group with an angle of <13°. CONCLUSION: Cases of ileal adhesions or thick subcutaneous fat are more likely to require a Trendelenburg angle of ≥13°. Therefore, Trendelenburg complications should be considered in this group. In addition, ovarian adhesions make it more difficult to exclude the small intestine from the small pelvic cavity, and may be associated with endometriosis.

Cervical angle as a possible predictor of abnormal placental position in women with endometriosis.

BACKGROUND: We aimed to examine the effects of endometriosis on the rate of abnormal placentation by comparing the data of pregnant women with and without endometriosis. METHODS: A case-control study was conducted to compare the perinatal outcomes between women with and without endometriosis. In the subgroup analysis, magnetic resonance imaging (MRI) scans of pregnant women with placenta previa were used to measure the cervical angle and its relationship with endometriosis. The cervical angle was measured as the angle between the cervical glands and the line perpendicular to the spinal column in each sagittal MRI section. RESULTS: We retrospectively analyzed data from 3453 cases of singleton deliveries between 2015 and 2019 at two study facilities. Among them, 159 had clinically or surgically confirmed endometriosis. The odds ratio (OR) for abnormal placental position was significantly higher in pregnant women with endometriosis (OR. 2.82; 95% confidence interval [CI], 1.58-5.04). The OR was 3.21 (95% CI, 1.57-6.55) in the endometriosis-surgery group (91 patients) and 2.32 (95% CI, 0.91-5.88) in the non-surgery group (68 patients). Furthermore, 44 women who underwent pelvic MRI after 30 weeks of gestation were included to examine the cervical angle. Then, we compared the date of pregnant women with (n = 6) and without endometriosis (n = 38). Regardless of placental attachment position, the cervical angle was significantly lower in the group with than in the group without a history of endometriosis. CONCLUSION: Pregnant women with a history of endometriosis may have stronger uterine retroversion, which could potentially contribute to abnormal placental positioning.

Anti-Müllerian hormone beyond an ovarian reserve marker: the relationship with the physiology and pathology in the life-long follicle development.

Anti-Müllerian hormone (AMH), an indirect indicator of the number of remaining follicles, is clinically used as a test for ovarian reserve. Typically, a decline suggests a decrease in the number of remaining follicles in relation to ovarian toxicity caused by interventions, which may implicate fertility. In contrast, serum AMH levels are elevated in patients with polycystic ovary syndrome. AMH is produced primarily in the granulosa cells of the preantral and small antral follicles. Thus it varies in association with folliculogenesis and the establishment and shrinking of the follicle cohort. Ovarian activity during the female half-life, from the embryonic period to menopause, is based on folliculogenesis and maintenance of the follicle cohort, which is influenced by developmental processes, life events, and interventions. AMH trends over a woman's lifetime are associated with in vivo follicular cohort transitions that cannot be observed directly.

Serum leucine-rich α2-glycoprotein as a possible marker for inflammatory status in endometriosis.

Purpose: This study aimed to investigate whether serum leucine-rich α2-glycoprotein (LRG) is a useful diagnostic biomarker for endometriosis, including the evaluation of treatment efficacy and exploration of LRG production in endometriotic lesions. Methods: Forty-three women with endometriomas were compared to 22 women with benign ovarian cysts and 30 women who underwent assisted reproduction as controls. Changes in serum LRG levels were assessed before and after surgery, and during dienogest treatment. LRG expression in endometriotic tissue samples was evaluated using immunoblotting. Results: Serum LRG levels in the endometrioma group (80.0 ± 36.3 µg/mL) were significantly higher than those in the benign ovarian cyst (65.1 ± 27.0 µg/mL, p = 0.0265) and control (57.8 ± 22.3 µg/mL, p = 0.0028) groups. Serum LRG levels after endometrioma surgery were significantly lower than preoperative levels (p = 0.0484). Serum LRG levels consistently decreased during dienogest treatment. LRG expression levels were significantly higher in endometriotic tissues than in the normal endometrium. Conclusion: Serum LRG, possibly derived from local and systemic origins, could be used as a potential biomarker for the diagnosis and treatment of endometriosis.

Text mining in a literature review of abnormal uterine bleeding according to the FIGO classification.

AIM: Abnormal uterine bleeding, as proposed in 2007, is defined as unexpected uterine bleeding in women of reproductive age; the cause of the bleeding is categorized using the PALM-COEIN system. Identifying the diagnostic and treatment modalities for each cause might be intriguing. To summarize the options for abnormal uterine bleeding assessment, we employed text-mining analysis for each of its causes. METHODS: We analyzed abstracts based on PALM-COEIN from PubMed and Web of Science in March 2022. The literature was divided into categories; topics about the disorders were retrieved, and covalent network analysis was conducted to find information for evaluating abnormal uterine bleeding. RESULTS: Diagnostic approaches for PALM included histological and image analysis, including computerized tomography, magnetic resonance imaging, sonography, and hysteroscopy. The therapeutic approaches varied according to the cause. Diagnostic approaches for COEIN were mostly medical history interviews and blood sampling, and the therapeutic approaches for COEIN were ablation, hysteroscopy, and hormonal treatment. The PALM-COEIN classification co-occurrence search revealed each cause's diagnostic procedures, symptoms, and treatment procedures. CONCLUSION: Our text-mining methodology revealed comprehensive insights, important study themes, and clinical trends for abnormal uterine bleeding. A tailored approach to medical realities is required for treating abnormal uterine bleeding properly.

National survey of abnormal uterine bleeding according to the FIGO classification in Japan.

AIM: To investigate the status of abnormal uterine bleeding (AUB) in Japan using the International Federation of Gynecology and Obstetrics (FIGO) classification (AUB system 1 and 2; PALM-COEIN) and to clarify the relationship between AUB symptoms and the diseases causing AUB. METHODS: In a nationwide study, we enrolled first-time patients who visited target facilities during two consecutive weeks from December 1, 2019 to January 31, 2020. The FIGO classification was used to investigate patients with symptoms and causative diseases of AUB. Based on the proportion of patients in the nationwide study, 373 cases were included in the detailed survey. Survey items included symptoms of AUB according to AUB system 1, examination details, and causative diseases according to the PALM-COEIN classification. RESULTS: Within the study period, we encountered 61 740 first-time patients, of which 8081 (13.1%) were diagnosed with AUB. Among them, 39.9% had abnormal menstrual cycles and 56.9% had abnormal menstrual bleeding. In the survey, PALM had the highest percentage of AUB-L and COEIN had the highest percentage of AUB-O. Correspondence analysis showed that COEIN was strongly associated with abnormal menstrual cycles and PALM with abnormal menstrual bleeding. CONCLUSION: We conducted the first nationwide survey of AUB in Japan. The FIGO classification was a useful tool for the diagnosis of AUB, with a strong correlation between symptoms of AUB by AUB system 1 and the causative disease of AUB by PALM-COEIN. Conversely, a high percentage of AUB-N and AUB-E suggests that AUB system 1 and PALM-COEIN are ambiguous as diagnostic tools.

Reassessment of intensive surveillance practices adopted for endometrial cancer survivors.

BACKGROUND: In Japan, 17,000 women are newly diagnosed with endometrial cancer in 2018. The healthcare insurance policy in Japan provides more intensive patient surveillance compared with the United States and European countries. The aim of this study was to retrospectively analyze data, including surveillance methods, recurrence sites, salvage therapy, and survival period after recurrence, to consider the benefits of surveillance for patients with endometrial cancer. METHODS: Between January 2009 and December 2015, the medical records of patients who were initially diagnosed with the International Federation of Gynecology and Obstetrics stage I-IV endometrial cancer and treated were enrolled in this retrospective study. Only patients with stage IV cancer with peritoneal dissemination were included. Within the first 2 years, the included patients underwent tumor marker tests, Papanicolaou smear test every 1-3-months, and imaging analysis at 6-12- month intervals. Until 4 years, the patients underwent regular surveys every 4 months and imaging analysis annually. Subsequently, the patients received regular surveys every 6 -to 12-months. RESULTS: Among 847 patients, 88 experienced recurrence, and their clinicopathological data were statistically analyzed. The recurrence site was not associated with the initial treatment method or histology. Among the patients with recurrence, 75% were asymptomatic. Univariate analysis demonstrated that time to recurrence and local recurrence were significant factors for survival outcomes, whereas multivariate analysis indicated that only local recurrence was a significant factor. In patients with distant metastasis, neither symptomatic nor asymptomatic recurrence showed a significant difference in survival. CONCLUSIONS: In this retrospective study, an intensive surveillance protocol did not benefit patients with endometrial cancer. Thus, we hypothesize that the characterization of tumors by emerging technologies that can precisely predict the nature of the tumor will help tailor individualized and efficient surveillance programs. In addition, the ideal salvage therapy needs to be developed to benefit patients after recurrence.

Anti-Müllerian hormone levels in the diagnosis of adolescent polycystic ovarian syndrome: a systematic review and meta-analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that causes menstrual cycle irregularities and infertility. PCOS is diagnosed based on hyperandrogenism, polycystic ovarian morphology (PCOM), and an-/oligo-ovulation. Upregulation of anti-Müllerian hormone (AMH) in the serum of women with PCOS may be another suitable alternative diagnostic criterion for PCOM. However, previous meta-analyses have reported conflicting results due to the age-dependent decline in serum AMH levels. Therefore, we performed a meta-analysis to evaluate the threshold of AMH for the diagnosis of PCOS in adolescents and women in their early twenties. Fifteen trials were included in this meta-analysis. PCOS is diagnosed with either Rotterdam criteria, NIH, or AE-PCOS. AMH levels were significantly higher in adolescents with PCOS (weighted mean difference, 3.05; 95% confidence interval: 2.09-4.01) than in the control group. The cutoff values of AMH for the diagnosis of adolescent PCOS were 6.1, 6.26, 7.03, 7.11, 7.2, and 7.25 ng/mL in the studies that reported the usefulness of AMH levels. The summary receiver operating characteristic analysis of the diagnostic accuracy demonstrated that the specificity and sensitivity were 81% and 66.3%, respectively. Our meta-analysis demonstrates that AMH may be a useful diagnostic test for adolescent PCOS and, based on the previous studies included in the meta-analysis, its cutoff value was estimated to be 6-7 ng/mL.

Effect of salpingectomy on ovarian reserve: A systematic review and meta-analysis.

AIM: To determine the effect of salpingectomy on ovarian reserve. METHODS: PubMed, EMBASE, Web of Science, Dynamed plus, and Cochrane Controlled Trials Register databases were searched from their inception to December 2020 to identify relevant studies, including cross-sectional studies, retrospective studies, and randomized controlled trials. Studies that compared anti-Müllerian hormone (AMH) levels and/or antral follicle count (AFC) between the control and salpingectomy groups or before and after surgery were included. RESULTS: Twenty-one articles were included in the systematic review. Meta-analyses were performed on 16 studies in which data were presented as mean ± SD values. A meta-analysis comparing AMH levels before and after surgery in the same patients showed no significant decrease in all cases, irrespective of whether it was unilateral or bilateral salpingectomy. There was no significant decrease in the AFC in the meta-analysis comparing levels before and after bilateral salpingectomy, either. In contrast, in the case-controlled study the salpingectomy group had significantly lower levels of AMH in all meta-analyses of unilateral and bilateral surgery (mean difference: -0.31, 95% confidence interval [CI]: -0.55, -0.07), only unilateral cases (mean difference: -0.28, 95% CI: -0.50, -0.06), and only bilateral cases (mean difference: -0.71, 95% CI: -1.19, -0.23). The salpingectomy group that included unilateral and bilateral cases had significantly lower AFC compared with no-surgery controls (mean difference: -1.31, 95% CI: -2.13, -0.48). CONCLUSION: Although not conclusive, it does appear that patients who underwent salpingectomy (either unilateral or bilateral) have a decreased ovarian reserve.

Optimal timing of elective repeat cesarean deliveries of term singleton pregnancies: A multicenter cross-sectional study.

OBJECTIVE: Cesarean deliveries must be optimally timed to minimize their effects on mothers and neonates. This study aimed to determine the optimal timing of elective repeat cesarean deliveries to reduce the incidence of neonatal respiratory disorders and of emergent cesarean deliveries. MATERIALS AND METHODS: This multi-center, cross-sectional, retrospective analysis evaluated data on the maternal and neonatal outcomes of 856 singleton pregnancies scheduled for elective repeat cesarean deliveries at 37-39 weeks' gestation. The emergent cesarean delivery and neonatal respiratory disorder risks were analyzed according to the scheduled cesarean delivery times. RESULTS: The elective cesarean delivery rates were 91.0% during the first and 92.6% during the second half of the 37th week of gestation, 88.7% during the first and 82.9% during the second half of the 38th week of gestation, and 62.5% during the first and 33.3% during the second half of the 39th week of gestation. The neonatal respiratory disorder rates were 21.8% for elective cesarean deliveries during the first half of the 37th week of gestation and approximately 8% for elective cesarean deliveries during the second half of the 37th week until the first half of the 38th week of gestation. No neonatal respiratory disorders occurred among the babies delivered by elective cesarean deliveries during the 39th week of gestation. CONCLUSION: For improved maternal and neonatal outcomes in the Asian population, it may be better to perform scheduled elective repeat cesarean deliveries from the second half of the 37th week of gestation until the 38th week of gestation following confirmation of gestational age by early first trimester ultrasonography.

Prevalence of the Use of Oral Contraceptives and Hormone Replacement Therapy in Japan: The Japan Nurses' Health Study.

BACKGROUND: There have been few community-based epidemiological studies in which the prevalence of exogenous hormone use, including the use of oral contraceptives (OCs) and hormone replacement therapy (HRT), has been accurately assessed in Japan. METHODS: We have been conducting repeated surveys of participants in the Japan Nurses' Health Study (JNHS), as a nationwide prospective cohort study, since 2001. We determined the prevalence of exogenous hormone use at baseline and during a 10-year follow-up period. A total of 15,019 female nurses participated in the JNHS follow-up cohort. We determined the prevalence of OC use in 14,839 women <60 years of age at baseline and the prevalence of HRT use in 7,915 women, excluding premenopausal women, at the last time they answered a questionnaire. The duration of HRT use was estimated using the Kaplan-Meier method. RESULTS: Six percent of the participants used OCs. The proportion of HRT users who stopped HRT before the baseline survey, the proportion of women using HRT during the follow-up period, and the proportion of all of the participants who had used HRT were 3.2%, 10.6%, and 13.8%, respectively. The median duration of HRT use was 2 years. CONCLUSIONS: The lifetime prevalences of exogenous hormone use during this prospective study conducted in Japanese nurses were 6.0% for OCs and 13.8% for HRT. The information obtained in this study will be useful for clarification of the association between exogenous estrogen exposure and estrogen-related diseases as future research.

Effect of hypothyroidism and thyroid autoimmunity on the ovarian reserve: A systematic review and meta-analysis.

BACKGROUND: Evidence suggests that hypothyroidism and thyroid autoimmunity (TAI) are possibly associated with ovarian dysfunction. This meta-analysis aimed to investigate whether hypothyroidism and/or TAI affect the ovarian reserve and evaluated using the anti-Mullerian hormone (AMH). METHODS: PubMed, EMBASE, Web of Science, and Cochrane Controlled Trials Register databases from inception to October 2020 were searched to identify relevant studies. Studies comparing the AMH levels between the control and the affected groups were included in the data synthesis. The primary endpoint in the meta-analysis was AMH levels compared with the controls. MAIN FINDINGS: Nine trials were included in the analysis. The AMH levels were significantly lower in the adults with euthyroid TAI (mean difference -0.12, [95% CI: -0.18 to -0.06]). The AMH levels tended to be lower in subclinical hypothyroidism and overt hypothyroidism than in the control group, although the differences were not significant. The AMH levels were significantly higher in the euthyroid TAI group in the adolescents (mean difference 2.51, [95% CI 1.82 to 3.21]). CONCLUSION: TAI and hypothyroidism may affect the ovarian reserve. The opposite effects on AMH levels depending on age suggest that TAI may be implicated in the depletion of follicles in adults following extensive activation of primordial follicles in adolescence.

Nadir CA-125 serum levels during neoadjuvant chemotherapy and no residual tumor at interval debulking surgery predict prognosis in advanced stage ovarian cancer.

BACKGROUND: Recent phase III randomized trials have suggested that neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) is a treatment option for patients with advanced epithelial ovarian cancer. This study aimed to use CA-125 and computed tomography (CT) scanning to generate a simple and clinically applicable model of predicting complete cytoreduction by interval debulking surgery (IDS) and the overall survival in patients who receive taxane/platinum-based chemotherapy as neoadjuvant chemotherapy (NACT). METHODS: Patients with stage IIIc or IV epithelial ovarian cancer who underwent taxane/platinum-based NACT followed by IDS in Gunma Prefectural Cancer Center, Takasaki General Medical Center, and Gunma University from April 2009 to March 2015 were included. Patients underwent a CT scan to confirm confirm tumors unresectable by standard surgery before NACT. CA-125 levels were measured pre-NACT, after each cycle of NACT, and before IDS. CT was also performed before IDS to evaluate tumor metastasis. Data were collected retrospectively and analyzed to determine the predictive factors of complete resection and overall survival. RESULTS: Among 63 patients who received NACT-IDS, 43 and 20 patients had stages IIIc and IV epithelial ovarian cancer at diagnosis, respectively. CT predictors of residual tumors after IDS such as extra-ovarian implants (P = 0.009) and omental cakes (P = 0.038) were not present. Univariate analysis revealed that the independent factors for overall survival were no residual tumor by IDS (P = 0.0016) and CA125 ≤ 20 U/ml before IDS (P = 0.0011). CONCLUSIONS: Although this study had a small sample size, NACT-IDS used to completely remove macroscopic disease which significantly improved the prognosis of patients with preoperative CA-125 ≤ 20 U/ml. Results from this study provide useful information for future studies on the management of patients with advanced epithelial ovarian cancer.

Association between FSH, E1, and E2 levels in urine and serum in premenopausal and postmenopausal women.

OBJECTIVE: We aimed to establish correlations for the levels of follicle-stimulating hormone (FSH), estrone (E1) and estradiol (E2) between urine and serum in premenopausal and postmenopausal women using immunoassays. METHODS: In this study of 92 women (61 postmenopausal, 31 premenopausal), both urine and blood specimens were collected on the same day and stored at 4 °C for analysis by chemiluminescent immunoassay, radioimmunoassay and/or electrochemiluminescent immunoassay. RESULTS: There were correlations in the levels of FSH, E1 and E2 between urine and serum in both postmenopausal (r = 0.96 for FSH, r = 0.91 for E1, r = 0.80 for E2) and premenopausal (r = 0.98 for FSH, r = 0.92 for E1, r = 0.90 for E2) women. It is indicated that the correlations were stronger in the premenopausal group compared with the postmenopausal group, especially for FSH. CONCLUSION: The levels of FSH, E1 and E2 in urine correlated with those in the serum in premenopausal and postmenopausal women. Urine samples could be used instead of serum samples to measure hormone levels, which would reduce the difficulty of conducting large survey studies.

An electrical scalpel conization versus Shimodaira-Taniguchi conization procedure for cervical intraepithelial neoplasia.

The incidence of cervical intraepithelial neoplasia(CIN) among reproductive-aged women has increased in Japan. Cervical conization is commonly applied for local cervical treatment to preserve fertility. The Shimodaira-Taniguchi (S-T) conization procedure is widely used in Japan. S-T conization uses a high-frequency current and a triangular probe with a linear excision electrode to remove cervical tissue as a single informative specimen. However, alternative of an electrosurgical scalpel (ES) has the advantage of adjusting the surgical margin to the transformation zone in order to preserve the maximum amount of healthy cervical tissue with good hemostasis. The aim of this study is to retrospectively analyze data regarding surgical margin status, perioperative adverse events, cervical stenosis, and preterm birth between S-T and ES.Between January 2009 and December 2014, the medical records of 1166 patients who were diagnosed as CIN II, III, or stage 1a1 cervical cancer and who were treated with conization in 7 hospitals in Gunma Prefecture, Japan were enrolled for this retrospective study. The clinicopathological data was analyzed to statistically compare outcome between S-T and ES conization.There was no difference for age or post-operative follow-up period between ES and S-T treatments. However, positive surgical margins were significantly less frequent in patients who were treated with S-T than in those treated with ES, resulting in a reduced incidence of re-treatment for S-T in comparison with ES patients. In perioperative adverse events, S-T had more patients who were administered antibiotics. The incidence of preterm delivery and cervical stenosis did not differ significantly between the groups.We demonstrate here that S-T is an alternative procedure for cervical conization with a low risk of recurrence and acceptably low rate of adverse events such as cervical stenosis and preterm delivery. The results of this study can provide useful information for future management of patient with cervical intraepithelial neoplasia.

Expression of the gonadotropin receptors during follicular development.

Background: Gonadotropins induce follicular development that leads to ovulation and luteinization. In women, the level of gonadotropins, along with the expression of their receptors, changes dynamically throughout the menstrual cycle. This study aimed to clarify the mechanisms underlying these phenomena. Methods: The literature was reviewed, including that published by the authors. Main findings Results: Follicle-stimulating hormone receptor expression in the granulosa cells was induced by androgens that were derived from growth differentiation factor-9-stimulated theca cells. In the theca cells, luteinizing hormone receptor (LHR) expression was noted from their appearance. In the granulosa cells, follicle-stimulating hormone (FSH) stimulation was essential for LHR expression. However, FSH alone was not sufficient to respond to the luteinizing hormone (LH) surge for oocyte maturation, ovulation, and subsequent luteinization. To achieve these stages, various local factors that were derived from the granulosa and theca cells in response to FSH and LH stimulation had to work synergistically in an autocrine/paracrine manner to strongly induce LHR expression. Following the LH surge, the LHR expression decreased markedly; miRNAs were involved in this transient LHR downregulation. Following ovulation, LHR expression drastically increased again toward luteinization. Conclusion: The expression of gonadotropin receptors is controlled by sophisticated and complicated systems; a breakdown of this system could lead to ovulation disorders.

Analysis of the effect of adjuvant radiotherapy on outcomes and complications after radical hysterectomy in FIGO stage IB1 cervical cancer patients with intermediate risk factors (GOTIC Study).

BACKGROUND: There are no definitive criteria for identifying which patients with The International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical cancer will benefit from adjuvant therapy after radical hysterectomy. The aims of this study were to clarify the efficacy of adjuvant therapy and assess complications after radical hysterectomy in patients with FIGO stage IB1 cervical cancer with intermediate risk factors. METHODS: Between January 2005 and December 2009, the medical records of 75 stage IB1 patients' intermediate risk factors (i.e., tumor size 2-4 cm, lymphovascular involvement, and/or deep stromal invasion >1/2) who underwent radical hysterectomy at six institutions were collected, and these patients were enrolled in this nonrandomized retrospective study. We simplified the criteria of intermediate risk factors as much as possible, as the criteria adopted in some clinical studies are complicated in practice. RESULTS: The patients were grouped according to the receipt of adjuvant therapy as follows: 46 patients, no further treatment; 19 patients, external beam radiation treatment, including 9 patients who received brachytherapy; 5 patients, concurrent chemoradiotherapy (CCRT); and 5 patients, chemotherapy (CT). The clinical outcomes and complications in each group were analyzed. After an average follow-up of 82.6 months (range, 24-135 months), only one patient with all three risk factors who received radiotherapy (RT) experienced recurrence. Excluding this patient, the remaining patients who received RT, CCRT, or CT had two or three risk factors. Lymphedema was significantly more common among patients who received RT or CCRT, whereas the incidence of ileus and ureteral obstruction was not different among the treatment groups. However, an unsutured peritoneum increased the risk of ileus. CONCLUSIONS: The findings of this study suggest that RT and CCRT after radical hysterectomy are not beneficial in patients with intermediate risk factors. In particular, RT and CCRT appeared to increase the incidence of lymphedema. A prospective randomized study is needed to verify the findings of this study.

MicroRNA-376a regulates 78-kilodalton glucose-regulated protein expression in rat granulosa cells.

The 78-kilodalton glucose-regulated protein (GRP78) is a molecular chaperone that assists in protein assembly, folding, and translocation. Recently, our laboratory reported that GRP78 regulates the expression of luteinizing hormone-human chorionic gonadotropin receptor (LHR) in the early stage of corpus luteum formation. In this study, we investigated whether microRNAs (miRNAs), which post-transcriptionally regulate mRNA, are involved in the regulation mechanism of GRP78 in the ovary. A miRNA microarray was performed to analyze the overall miRNA expression profile, and the results indicated that 44 miRNAs were expressed highly after ovulation was induced. The results from a bio-informative database analysis and in vitro granulosa cell culture studies led us to focus on rno-miR-376a for further analysis. In both in vivo and in vitro studies, rno-miR-376a levels increased 12 h after human chorionic gonadotropin (hCG) administration. To elucidate whether rno-miR-376a induced mRNA destabilization or translational repression of GRP78, rno-miR-376a was transfected into cultured granulosa cells, resulting in decreased GPR78 protein levels without an alteration in GRP78 mRNA levels. To confirm that rno-miR-376a binds to GRP78 mRNA, we cloned the 3'-end of GRP78 mRNA (nucleotides 2439-2459) into a reporter vector that contained a Renilla luciferase coding region upstream of the cloning site. The luciferase assays revealed that rno-miR-376a bound to the 3'-end of GRP78 mRNA. From these data, we conclude that rno-miR-376a potentially negatively regulates GRP78 protein expression through translational repression at an early stage transition from the follicular phase to luteinization.

Role of microRNA-136-3p on the expression of luteinizing hormone-human chorionic gonadotropin receptor mRNA in rat ovaries.

MicroRNAs (miRNAs) are small noncoding RNAs that interact with mRNAs and trigger either translation repression or RNA cleavage of target genes. In this study, we investigated whether miRNA was involved in down-regulation of the luteinizing hormone receptor (LHR) in rat ovaries. An miRNA microarray was used to analyze the overall miRNA expression profile of rat ovaries in association with the down-regulation of LHR mRNA. We found that 23 miRNAs were highly expressed during this period. Combining these results with data from a bioinformatics database, clustering analysis led us to focus on miR-136-3p for further analysis. In both in vivo and in vitro studies, miR-136-3p expression levels were increased at 6 h after human chorionic gonadotropin (hCG) administration, concurrent with down-regulation of LHR mRNA. Moreover, transfection of cultured granulosa cells with miR-136-3p resulted in a significant decrease in LHR mRNA levels in comparison with those of cells transfected with negative control. In contrast, transfection with a miR-136-3p inhibitor increased LHR mRNA levels. Finally, cotransfection of granulosa cells with a miR-136-3p inhibitor and a reporter vector containing the 3'-untranslated region (UTR) of LHR mRNA and Renilla luciferase coding sequence revealed that miR-136-3p bound directly to the 3'-UTR of LHR mRNA. These data demonstrated that miR-136-3p participated in the down-regulation of LHR mRNA by binding directly to LHR mRNA.