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Background: The use of total laparoscopic hysterectomy is increasing. However, as with conventional abdominal hysterectomy, vaginal bacteria-related postoperative complications need to be managed in total laparoscopic hysterectomy. Therefore, we started to combine metronidazole vaginal tablets with intravenous administration of cephem antibiotics immediately before starting surgery to reduce complications. To evaluate the effect of this combination, and to determine the risk factors for these complications, we retrospectively collected medical records from our hospital and performed a multivariate analysis. Methods: We reviewed the medical records of 520 patients who underwent total laparoscopic hysterectomy from 1 January 2015 to 31 December 2021. Among these cases, we identified 16 cases as having vaginal bacteria-related postoperative complications, defined as needing more than one additional day for treatment of postoperative complications, namely postoperative infection (10 cases) and vaginal dehiscence (6 cases). First, we evaluate the effect of metronidazole vaginal tablets by dividing the patients into two groups according to whether metronidazole vaginal tablets were used, and comparing the vaginal bacteria-related postoperative complication rates and other indices. Second, we performed a multivariate logistic regression analysis to assess the influence of each of 17 representative factors, including patient characteristics and symptoms, uterus and leiomyoma sizes, concomitant procedures such as laparoscopic cystectomy and pelvic lymphadenectomy, and others. Results: In the multivariate analysis of the 520 cases, we confirmed that the use of metronidazole vaginal tablets could reduce the vaginal bacteria-related postoperative complications rate by more than half (odds ratio, 0.36). In addition to metronidazole vaginal tablets use, concomitant laparoscopic cystectomy and blood transfusion were associated with significant increases in the vaginal bacteria-related postoperative complication rate. Conclusions: The effect of the addition of metronidazole vaginal tablets to pre- and postsurgical treatment on the reduction of vaginal bacteria-related postoperative complications was confirmed. This easy, safe, and low-cost method may improve the management of total laparoscopic hysterectomy. [ABSTRACT FROM AUTHOR]

Background: Acute puerperal uterine inversion is rare but may cause massive postpartum blood loss due to uterine atony. Therefore, these patients must be diagnosed, and uterine replacement must be performed as soon as possible. However, in some cases, active bleeding due to uterine atony becomes uncontrollable, even though the uterine inversion itself is treated. In these cases, additional treatments, including surgical procedures, are needed.Case Presentation: A 41-year-old Japanese woman, gravida 1, para 0, was hospitalized for labor induction at 40 weeks and 3 days of gestational age. She had a vacuum-assisted delivery after 3 days of oxytocin administration, but acute uterine inversion occurred. Although replacement of the inverted uterus was successful by manual repositioning and Bakri balloon tamponade insertion, massive postpartum hemorrhage caused by uterine atony became uncontrollable. In this situation, since disseminated intravascular coagulation had developed, we used uterine artery embolization to stop the bleeding. After detecting the pseudo-aneurysmal sac and tortuous vessels of the right uterine artery, transcatheter right-sided uterine artery embolization was performed. Thirteen days after uterine artery embolization, she was discharged with no complications.Conclusions: In cases of disseminated intravascular coagulation caused by massive postpartum bleeding, uterine artery embolization may often be selected. In our case, since we performed angiography to detect the main bleeding site, the hemorrhage could be stopped with unilateral uterine artery embolization alone, without hysterectomy. [ABSTRACT FROM AUTHOR]

Background: We present a minimal skin wound abdominal hysterectomy for patients with leiomyomas and describe the characteristics of this technique. The skin wound was made as small as possible, with a maximum length of 6 cm.Methods: In addition to introducing minimal skin wound abdominal hysterectomy, we retrospectively analyzed the medical records of 82 patients treated with minimal skin wound abdominal hysterectomy exclusively by two experts at Maruyama Memorial General Hospital between January 2013 and December 2016. Relationships between the leiomyoma characteristics and the difficulty of this operation, as estimated by operation time and blood loss, were statistically investigated.Results: First, we introduce a case in which we performed minimal skin wound abdominal hysterectomy on a 46-year-old Japanese patient with multiple leiomyomas (maximum 8 cm in diameter). Then, we assessed the impacts of the leiomyoma characteristics on the difficulty of this operation. On multivariate analysis, the number of leiomyomas significantly affected operation difficulty. Other characteristics of the target leiomyoma showed no effect. Additionally, higher body mass index also made the operation more difficult.Conclusions: Although multiple leiomyomas can make this procedure difficult, minimal skin wound abdominal hysterectomy is safe and effective for use in many cases. [ABSTRACT FROM AUTHOR]

Background: The application of laparoscopic surgeries has been increasing, and various uterine diseases in addition to leiomyoma/adenomyoma have become indications for total laparoscopic hysterectomy (TLH). Therefore, data acquisition and analysis of TLH procedures, including TLH for rare uterine diseases, have become important for improving surgical procedures and patient selection. To determine the prevalence of and risk factors for the occurrence of intraoperative and postoperative complications of TLH, we performed a multivariate analysis of the records in our hospital.Methods: We retrospectively reviewed the medical records of 323 patients who underwent TLH for the treatment of leiomyoma/adenomyoma (278 cases), low-grade (pre)malignant uterine tumours (40 cases) and other rare uterine diseases (5 cases) from January 1, 2015, to December 31, 2019. Of the rare uterine diseases, one case of caesarean scar pregnancy for which TLH was performed is introduced as a case report. To assess the effects of 11 representative factors, including patient characteristics, uterus and leiomyoma sizes, indications for TLH and others, we performed a multivariate logistic regression analysis.Results: Among the 323 cases, 20 intraoperative complications and 15 postoperative complications were reported. In the multivariate analysis, "ovarian tumour" and "heavy uterus" were positively associated and "nulliparity" was negatively associated with intraoperative complications. There were no significant risk factors for postoperative complications. The only risk factor for operative complications directly related to the resected uterus was "heavy uterus". Therefore, we could perform TLH relatively safely for patients with other indications besides leiomyoma/adenomyoma.Conclusions: Considering the factors detected in this analysis, the indications for TLH may be expanded. Owing to the increase in TLH for indications other than leiomyoma/adenomyoma, a more accurate determination of the treatment approach can be achieved. [ABSTRACT FROM AUTHOR]

Aim: To determine the efficacious treatment for infertile couples, we assessed the impact of infertility factors including endometriosis on assisted reproductive technology (ART) and non‐ART treatment, and the effect of age in infertility treatment outcomes was also investigated. Methods: The medical records of 1864 females, infertile patients from January 2000 to December 2015 at our hospital, were retrospectively reviewed under the approval of the Institutional Review Board. We extracted 10 representative factors and calculated the cumulative live birth rate (CLBR) in these patients. Multivariate analysis of ART and non‐ART treatment was performed to assess the impact of infertility factors, and the age‐related decline in cumulative live birth rate was calculated by creating eight age‐stratified subgroups. Results: In total, 21.9% and 49.4% of the patients conceived after being treated with non‐ART and ART, respectively. Multivariate analysis revealed that age > 35, advanced endometriosis defined by the revised American Society for Reproductive Medicine classification system stages III to IV, and the past history or current presence of uterine fibroid had significantly negative impact on the outcome of non‐ART. Age stratification revealed that advanced endometriosis adversely affected the outcome of non‐ART, especially for patients in their 30s. Assisted reproductive technology treatment for patients with advanced endometriosis was shown to be efficacious because the negative impact had been diminished. Conclusion: Considering that non‐ART treatment had limited role in patients with advanced endometriosis, prompt initiation of ART in these patients aged as young as 30 years can be recommended to achieve conception. [ABSTRACT FROM AUTHOR]

Purpose: To preoperatively predict the operative time (OT) for hysteroscopic myomectomy for G1 or G2 leiomyoma based on leiomyoma weight. Methods: The data from 544 patients who underwent one‐step hysteroscopic myomectomy were analyzed retrospectively. A total of 340 patients with leiomyoma penetrating the intramural cavity were identified as suitable candidates for calculation of the OT based on leiomyoma weight; we considered leiomyoma weight to be the most objective parameter for evaluating leiomyoma tissues. Additionally, 460 patients with a single leiomyoma were analyzed to estimate the weight of the resected leiomyoma based on its diameter. Results: Considering total leiomyoma weight (TLW) and two additional coefficients (1.5: G2 leiomyoma, 0.75: vaginal parity of the patient), we demonstrated that our formula correlated well with OT (R2 = 0.72). TLW also correlated well with the cube of the average diameter (AD) of leiomyomas (R2 = 0.89). Predicting TLW significantly improved the application of specific coefficients depending on its value (1.0: AD 0.1‐2.0 cm, 0.8: AD 2.1‐3.0 cm, 0.7: AD 3.1‐5.7 cm). Conclusion: The OT for hysteroscopic myomectomy of intracavital leiomyoma can be predicted prior to surgery using simple clinical information of the target leiomyoma and the patient. After predicting the leiomyoma weight by multiplying the cube of average diameter of leiomyoma and considering two coefficients, we could estimate difficulty of hysteroscopic myomectomy. [ABSTRACT FROM AUTHOR]

Age-related fertility decline is hypothesized to occur mainly by the spontaneous exhaustion and deterioration of the ovarian follicle, and the accumulation of ovarian tissue damage resulting from the ovulation cycle may play roles in the process. In this study, we hypothesized that suppressing ovulation would exert protective effects against age-related fertility decline. To test this hypothesis, we established a mouse model in which oral contraceptives (OCs) were administered daily. Female C57BL/6N mice were administered OCs daily from the age of 2 months to 12 months as an ovulation suppression mouse model. Mouse fecundity was investigated by counting oocyte number after ovarian stimulation and by examining live fetuses after mating. We found that compared with control mice administered vehicle alone, 12-month-old mice administered 2-fold dose OCs used for treating humans exhibited a significantly greater average oocyte number after ovarian stimulation (8.5 ± 0.6 vs 5.9 ± 0.6, P < .01). In addition, spontaneous conception with living fetuses after mating was strikingly increased in 12-month-old mice administered OCs relative to controls (6.0 ± 1.2 vs 0.4 ± 0.3, P < .01). In the histological examination of mouse ovarian tissues, we did not detect a significant difference in ovarian follicle number, but reduced amount of brownish foamy fibrous tissues, which might reflect ovarian tissue damage, was detected in aged mice administered OCs. These results suggest the possibility that long-term OC administration might alleviate age-related fertility decline, and the improvement mechanism could be attributed to the prevention of ovarian tissue damage by suppressing ovulation. [ABSTRACT FROM AUTHOR]

It has been widely accepted that the age of women plays a fundamental role in fecundity, and age-related fertility decline has one of the most significant and detrimental effects on the success rate of infertility treatment. Therefore, treatment cycles of non-in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment for infertile women of advanced aged have been limited due to their lack of efficacy, and they are often optimized, compared to IVF/ICSI treatment. Recent trends in infertility treatment apparently indicate that IVF/ICSI treatment, including egg donation, is frequently offered to aged women for first-line management, despite its heavy burden, but hasty IVF/ICSI treatment should be avoided, considering its socioeconomic problems. It is important to distinguish women who could conceive by non-IVF/ICSI treatment, although the optimization of non-IVF/ICSI treatment protocols remains poorly understood. This review focuses on extracting aged patients who have higher chance of conceiving with non-IVF/ICSI treatment and providing necessary and sufficient infertility treatment. After initial evaluation for fertility, including tubal factor, male factor, the presence of endometriosis and/or adenomyosis, and ovarian reserve, the outcomes of fertility treatment can be predicted to some extent in aged infertile women. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To identify the frequency and assess risk factors for unexpected discovery of peritoneal endometriotic implants in patients who underwent myomectomy or hysterectomy for symptomatic uterine leiomyomas. Study design: We retrospectively collected medical records of 829 patients with symptomatic leiomyomas in The University of Tokyo Hospital. All the patients underwent abdominal or laparoscopic surgeries between January 2001 and December 2010 and the presence or absence of endometriosis during surgery was analyzed. Possible determinant to predict coexistent endometriosis was statistically investigated. Results: In total, 105 leiomyoma cases (12.7% in 829 patients) were diagnosed with endometriosis. Patients with small dominant leiomyomas were significantly complicated by peritoneal endometriotic implants (small leiomyomas were classified as <8cm). The patients with both diagnoses were more likely to be infertile and at age 39 years or younger than those with leiomyoma alone. Conclusions: Women undergoing myomectomy or hysterectomy with both endometriosis and leiomyomas have several different clinical features compared with women with only leiomyomas. The size of largest leiomyoma may provide an important clue for coexistent endometriosis. Women with substantial infertility despite a smaller leiomyomas burden may be more likely to have a surgical indication for concomitant endometriosis. [Copyright &y& Elsevier]

Purpose: This study aimed to maximize the chance of pregnancy and provide an optimal protocol for infertile female patients of advanced reproductive age as an alternative to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Methods: We retrospectively analyzed medical records of 432 infertile women aged ≥38 at the beginning of the treatment. Stepwise non-IVF/ICSI treatments using timed intercourse or intrauterine insemination, with or without controlled ovarian stimulation, were adopted for all patients. In this population, we extracted 8 representative infertility factors and examined these effects on fertility rate by calculating clinical pregnancy rate. Results: The prognosis for infertile women possessing at least one of the three factors, 'advanced female age (≥42 years)', 'endometriosis/adenomyosis', and 'tubal infertility' was apparently poor because only 5 out of 155 women were able to conceive (1.02% per cycle). In contrast, 95 patients without the four factors, 'advanced female age', 'endometriosis/adenomyosis', 'tubal infertility', and 'male infertility', were more likely to conceive (9.14% per cycle). Conclusions: Fertility centers can offer appropriate protocols for non-IVF/ICSI treatment and establish guidelines for aged infertile patients by examining infertility factors and considering their combinations. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS). Material and Methods: By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed. Results: The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) ∗ 100, odds = eX and X = 8.18 + 1.23 ∗ BW (kg) − 7.74 ∗ MH (m) − 0.253 ∗ BS. Conclusion: This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome. [ABSTRACT FROM AUTHOR]

Background: To determine the prevalence of and risk factors for malignant transformation of ovarian endometrioma during dienogest therapy, which is very rare, we examined multiple cases of malignant transformation of ovarian endometrioma during dienogest therapy and performed a multivariate analysis of the records in our hospital.Methods: The medical records of 174 patients who underwent DNGT for the treatment of OMA from June 1, 2011, to May 31, 2018, were reviewed retrospectively with the approval of the Human Ethical Committee of the University of Teikyo Hospital. And we provided one representative case of MT with obtaining written informed consent. To assess the effects of six representative factors, including advanced age, parity, surgical history, and endometrial cyst characteristics (including 3 factors), on the possibility of malignant transformation, we performed a multivariate logistic regression analysis.Results: Of the 174 cases, 4 were diagnosed with malignant transformation, and these cases are reported. In the multivariate analysis, advanced age (P = 0.0064), nullipara (P = 0.0322), and enlargement (P = 0.0079) showed significant differences for malignant transformation occurrence. All 4 malignant transformation cases were among the 19 patients who had all of these 3 factors.Conclusions: For a more accurate determination of the treatment approach, a larger sample size will be needed to determine the risk factors for malignant transformation during dienogest therapy. [ABSTRACT FROM AUTHOR]

Background: The presence of uterine endometrial polyps is associated with not only abnormal uterine bleeding but also infertility, so the use of hysteroscopic polypectomy has been increasing. This operation is considered to increase cost-effectiveness when performed prior to infertility treatments. However, there are typical problems to consider, including the possibility of spontaneous regression of the polyp and the duration of complete endometrial wound healing after surgery. Meaningless interventions must be avoided, when possible. Therefore, data acquisition and analysis of various findings obtained from surgery have become important for improving treatment procedures and patient selection. To estimate the spontaneous regression rates and contributions of multiple factors to uterine endometrial polyps during the waiting period (approximately 2-3 months) before hysteroscopic polypectomy, we performed a multivariate analysis of data from the records in our hospital.Methods: The medical records of 450 cases from September 2014 to April 2021 in our hospital were retrospectively reviewed under the approval of our Institutional Review Board. We included all cases of hysteroscopic polypectomy with postoperative pathological diagnosis. We defined cases as having a "spontaneously regressed polyp" when the target polyp was not detected by postoperative pathological examination. We extracted data on the following ten factors: "Advanced age" (≥ 42 years), "Small polyp" (< 10 mm), "High body mass index" (≥ 25 kg/m2), "Nulliparity," "Single polyp," "Infertility," "Hypermenorrhea," "Abnormal bleeding," "No symptom," and "Hormonal drug use." We also classified cases into five groups according to the size of the polyp (≤ 4.9 mm, 5.0-9.9 mm, 10.0-14.9 mm, 15.0-19.9 mm, and ≥ 20.0 mm) and determined the frequency of spontaneously regressed polyp in each group.Results: After exclusion of cases with insufficient data or other diseases, such as submucosal leiomyoma, 424 cases were analyzed. Among them, 28 spontaneously regressed polyps were identified, and the highest frequency of spontaneously regressed polyp was detected among the cases with polyps measuring 5.0-9.9 mm (16.4%). On multivariate analysis of the ten factors, "Small polyp" and "Hormonal drug use" were found to significantly impact the frequency of spontaneously regressed polyp.Conclusions: On the basis of the factors identified in this analysis, the indications for observation or medical therapy adapted to small polyps might be expanded. [ABSTRACT FROM AUTHOR]

Background: We present a minimal skin wound abdominal myomectomy performed in our hospital and attempt to identify the optimal range of this technique by considering the characteristics of target leiomyomas. In this procedure, we attempted to make the skin wound as small as possible, with a maximum length of approximately 5 cm.Methods: In addition to introducing the minimal skin wound abdominal myomectomy, we retrospectively collected and analyzed the medical records of 76 patients treated with minimal skin wound abdominal myomectomy exclusively by the same physician at Maruyama Memorial General Hospital between January 2007 and December 2016. We statistically investigated relationships between ten factors, including body mass index; patient's age; patient's parity; administration of gonadotropin-releasing hormone analogue; presence of anemia; the uterine leiomyomas' number, size, weight, and location; operation time; and blood loss.Results: First, we introduce a case in which we performed minimal skin wound abdominal myomectomy for a 36-year-old Japanese patient with a large leiomyoma (10 cm in diameter). Then, we assessed the impacts of patient characteristics and leiomyoma characteristics on operation time and blood loss for this surgical method. In a multivariate analysis, only the number of resected leiomyomas significantly affected massive bleeding. Other factors showed no difference on operation time and the amount of blood loss.Conclusions: Minimal skin wound abdominal myomectomy is safe and effective for use in many patients, because only the number of leiomyomas affects the amount of blood loss. No other factor affected operation time. We suggest the possibility that the expanded use of minimal skin wound abdominal myomectomy may reduce the number of patients waiting for long periods to undergo laparoscopic surgery and may optimize the use of medical resources in rural areas. [ABSTRACT FROM AUTHOR]

Background: Age-associated infertility is a problem worldwide, and management of oxidative stress is known to be essential. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway works as an essential defense mechanism against oxidative stress, and an oral drug Dimethylfumarate (DMF) is known to activate the pathway. Methods: We tested the hypothesis that oral DMF could alleviate oxidative stress in the ovary, resulting in salvation of age-associated infertility in a mouse model of reproductive age, and we examined the effects of DMF administration. 20 mg/kg DMF was administrated to female mice from 32 to 48 weeks, and Nrf2 levels, antioxidant levels, ovarian reserve, DNA damage, and oxidative stress were examined. Results: DMF administration resulted in elevated mRNA and protein levels of Nrf2, antioxidants, and telomere, and serum levels of Nrf2 and anti-mullerian hormone were also elevated. Results of TUNEL assay and Immunohistochemistry of mice ovarian tissues showed that DNA damage and oxidative stress were decreased by DMF administration, and significantly more oocytes were collected along with preservation of 60% more primordial follicles. Conclusions: Our data suggest that DMF administration activates the Nrf2/Keap1 pathway, elevate levels of antioxidants, and decrease DNA damage and oxidative stress, resulting in improved ovarian reserve in the mouse ovary. [ABSTRACT FROM AUTHOR]

Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs. Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs. Human luteinized GCs were isolated and cultured, and hydrogen peroxide (H 2 O 2 ) or Dimethylfumarates (DMF), an activator of Nrf2, were added to GCs to analyze the relationship between Nrf2 and antioxidants by quantitative RT-PCR. The mRNA levels of Nrf2, catalase, superoxide dismutase 1 (SOD1), and 8-Oxoguanine DNA glycosylase (OGG1) were elevated by H 2 O 2 , and DMF treatment showed similar but pronounced effects through activation of Nrf2. To determine the relationship of Nrf2 and the generation of antioxidants, siRNAs were used and quantitative RT-PCR were conducted. Decreased expression of Nrf2 resulted in a decreased level of these antioxidant mRNA. Intracellular levels of ROS were investigated by fluorescence of 8-hydroxy-2′-deoxyguanosine and fluorescent dye, 2′,7′-dichlorodihydrofluorescein diacetate after H 2 O 2 and/or DMF treatment, and DMF treatment quenched intracellular ROS generation by H 2 O 2 . These results show that activation of Nrf2 might lead to alleviate OS in human GCs, and this could provide novel insight to conquer the age-related fertility decline that is mainly attributed to the accumulation of aberrant OS. [ABSTRACT FROM AUTHOR]

Germline mutations of the fork-head transcriptional factor forkhead box L2 (FOXL2) predispose embryos to autosomal-dominant blepharophimosis–ptosis–epicanthus inversus syndrome with primary ovarian insufficiency in female patients, but the mechanisms of FOXL2 in ovarian follicular development remain elusive. Estrogens produced by ovarian granulosa cells and estrogen receptor (ER) α and ERβ play fundamental roles in ovarian pathophysiology, and a previous study revealed that ERα and ERβ physically interact with FOXL2. However, the underlying functions of these interactions have not been investigated. Herein, we report an ERβ-specific repressive function of FOXL2. Histological examination demonstrated that FOXL2 expression tends to be intense during early follicular development. Immunoprecipitation revealed that ERβ and FOXL2 interact in a ligand-independent manner. In vitro pull-down assays revealed a direct interaction between FOXL2 and the activation function (AF)-1/2 domain of ERβ. The expression of FOXL2 represses the ligand-dependent transcriptional activation of ERβ, but FOXL2 does not influence the ligand-dependent transcriptional activation of ERα. Consistent with these results, RNA interference-mediated depletion of FOXL2 stimulates the expression of the ERβ-downstream gene p450 aromatase. The convergence between FOXL2 functions and ERβ-mediated transcription in the ovary suggests the putative mechanism of FOXL2 in early-phase follicular development, which may be partially attributed to the regulation of ERβ-dependent gene expression. [ABSTRACT FROM AUTHOR]

Liver X receptors (LXRs) monitor endogenous sterol levels to maintain whole-body cholesterol levels and regulate inflammatory responses. Recent studies have demonstrated that LXRs may inhibit cellular proliferation, but the underlying mechanism remains unclear. Cell cycle and apoptosis regulator 2 (CCAR2), previously known as DBC1/KIAA1967, is a transcriptional regulator that regulates cellular proliferation and energy metabolism by inhibiting sirtuin 1 (SIRT1) deacetylase. Based on the findings that CCAR2 regulates several nuclear receptors, including the estrogen receptors and androgen receptor, we aimed to identify the underlying mechanism of CCAR2 regulation of LXRα. We found that CCAR2 formed a complex with LXRα in a ligand-independent manner in HepG2 cells, and in vitro pull-down assays, it revealed a direct interaction between the amino terminus of CCAR2 and the AF-2 domain of LXRα. Thereby, CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRα. RNA interference-mediated depletion of endogenous CCAR2 potentiated the expression of the LXRα target genes ATP-binding cassette transporter A1 and G1, and the abrogation of CCAR2 resulted in decreased cellular proliferation. Moreover, competitive immunoprecipitation studies revealed that the LXRα downregulation involves the inhibition of SIRT1–LXRα complex formation. Therefore, these results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRα due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation. [ABSTRACT FROM AUTHOR]