Sertoli cells are the source of stem cell factor for spermatogenesis.

Several cell types have been proposed to create the required microenvironment for spermatogenesis. However, expression patterns of the key growth factors produced by these somatic cells have not been systematically studied and no such factor has been conditionally deleted from its primary source(s), raising the question of which cell type(s) are the physiological sources of these growth factors. Here, using single-cell RNA sequencing and a series of fluorescent reporter mice, we found that stem cell factor (Scf), one of the essential growth factors for spermatogenesis, was broadly expressed in testicular stromal cells, including Sertoli, endothelial, Leydig, smooth muscle and Tcf21-CreER+ stromal cells. Both undifferentiated and differentiating spermatogonia were associated with Scf-expressing Sertoli cells in the seminiferous tubule. Conditional deletion of Scf from Sertoli cells, but not any other Scf-expressing cells, blocked the differentiation of spermatogonia, leading to complete male infertility. Conditional overexpression of Scf in Sertoli cells, but not endothelial cells, significantly increased spermatogenesis. Our data reveal the importance of anatomical localization for Sertoli cells in regulating spermatogenesis and that SCF produced specifically by Sertoli cells is essential for spermatogenesis.

Prevalence and associated risk factors for anxiety and depression in infertile couples of ART treatment: a cross-sectional study.

BACKGROUND: Infertility now is a public health concern and is associated with increased psychological distress. METHODS: We enrolled 1247 infertile couples and assessed their anxiety and depression status before and during assisted reproductive technology (ART) treatment using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). The Chi-square or fisher's exact test was used to analyze the prevalence of anxiety and depression in infertile couples. Multivariate logistical regression was performed to analyze the risk factors for anxiety and depression. RESULTS: The prevalence of anxiety was 13.5% and 8.7% (p < 0.05), and that of depression was 9.4% and 7.9% (p = 0.2) in female and male partners, respectively. Female SAS and SDS scores were positively associated with male SAS and SDS scores, respectively (r = 0.52 and r = 0.50, respectively, both p < 0.0001), and were positively associated with their own SDS and SAS scores, respectively (r = 0.63 and r = 0.62, respectively, both p < 0.0001). Their own depression or partners' anxiety was associated with the anxiety, and their own anxiety or partners' depression was associated with the depression in infertile couples. No children, unemployment, and low education level were also associated with female anxiety. SAS and SDS scores were significantly decreased during ART treatment. CONCLUSIONS: Females were more vulnerable to having anxiety than males in infertile couples. Anxiety and depression in infertile couples could interact, therefore, anxiety and depression would be simultaneously counseled, and their partners also should be given supportive psychotherapy. TRIAL REGISTRATION: It was an observational study and had no health care interventions on participants. So it was not registrated.

Prevalence and predictors of sexual function in midlife partnered Chinese women assessed by two simple indicators: Sexual frequency and sexual desire.

AIM: To investigate the prevalence and predictors of sexual frequency, sexual desire in midlife partnered Chinese women. METHODS: Sexual frequency, sexual desire over the past 3 months, menopausal symptoms and other socioeconomic information were assessed for women aged 40-65 years in the Shanghai Sixth People's Hospital. RESULTS: Among 3485 eligible partnered participants, the prevalence of low sexual frequency (less than once per week) and low sexual desire (less than 5 scores) were 72.74% (95% confidence interval (CI) = 71.16%-74.23%) and 71.79% (95% CI = 70.30-73.17%), respectively. Multivariable logistic regression analysis revealed that age (odds ratio (OR) = 1.20, 95% CI = 1.17-1.23), more educated (>15 years) (compared with<10 years, OR = 0.62, 95% CI = 0.48-0.82), perimenopause, postmenopause (compared with premenopause, OR = 1.48, 95% CI = 1.02-2.15, OR = 2.76, 95% CI = 1.80-4.23), sleep disorder (OR = 1.24, 95% CI = 1.02-1.50), unemployment (OR = 2.05, 95% CI = 1.45-2.92) were independently associated with low sexual frequency, while multiple linear regression revealed that age ß = -0.126, 95% CI = -0.139--0.114), unemployment (ß = -0.792, 95% CI = -0.954 to -0.629),chronic diseases (compared with no disease, single disease (ß = -0.200, 95% CI = -0.020 to -0.077, multiple diseases (ß = -0.792, 95% CI = -0.859 to -0.372), body mass index (ß = -0.615, 95% CI = -0.859 to -0.372), postmenopause (ß = -0.915, 95% CI = -1.143 to -0.759) were independent indicators for low sexual desire after adjusting for confounders. CONCLUSION: Low sexual frequency and low sexual desire were quite prevalent in midlife Chinese partnered women. Some factors, such as sleep disorder, obesity are modifiable or can be prevented or treated with safe and effective therapies.

Immune inhibitory receptor LILRB2 is critical for the endometrial cancer progression.

Although leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is known as an immune inhibitory receptor to suppress the immune system, its function in cancer development remains largely unknown. Herein, we provide the first body of information showing that LILRB2 is highly expressed in the endometrial cancer. More importantly, the expression levels of LILRB2 are inversely correlated with the overall patients' survival. Knockdown of LILRB2 results in a dramatic decrease in the proliferation, colony formation and migration in several endometrial cancer cell lines in vitro. Furthermore, in vivo xenograft experiments reveal a notable reduction of tumor cell growth. Mechanistically, LILRB2 enhances the SHP2/CaMK1/CREB signaling pathways to support the expansion and migration of the endometrial cancer cells. These findings unravel an unexpected role of LILRB2 in solid cancers except for its canonical role in immune surveillance, which may serve as a potential endometrial stem cell marker and may benefit the development of novel strategies for the treatment of endometrial cancers.

Knowledge and attitude towards menopause and hormone replacement therapy in Chinese women.

OBJECTIVE: To explore the knowledge and prevalence of menopausal symptoms as well as the use and attitude toward hormone replacement therapy (HRT) in Chinese women. METHODS: A cross-sectional study was conducted between May 2011 and April 2012 in Shanghai, China. The structured questionnaire addressing sociodemographic characteristics, knowledge and prevalence of menopausal symptoms, and knowledge and attitude towards HRT and its use were investigated. RESULTS: 3,619 women aged 40-65 years were included in the analysis. The majority of the women had knowledge of menopause. Symptoms were prevalent in 16.1% of premenopausal women and in 49.3% of peri-, post- and surgical-menopausal women. Back and joint pain, sleeplessness, fatigue and sweating/hot flushes were frequently reported. HRT awareness among women was 3.5% and was related to menopausal, working and marital status; 75 (2.1%) women had used or were using HRT, of which 57.3% used HRT with a doctor's prescription and 29.3% experienced side effects from the use of HRT. CONCLUSION: Most Chinese women had knowledge of menopause and thought menopausal symptoms should not be treated. The awareness of HRT was poor and influenced by menopausal, working and marital status. Chinese health care providers have to assume responsibility for educating women about menopause and HRT use.

The efficacy and safety of short-term and low-dose IL-2 combined with tocilizumab to treat rheumatoid arthritis.

Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.

Deciphering the comprehensive knowledgebase landscape featuring infertility with IDDB Xtra.

Infertility affects ∼15% of couples globally and half of cases are related to genetic disorders. Despite growing data and unprecedented improvements in high-throughput sequencing technologies, accumulated fertility-related issues concerning genetic diagnosis and potential treatment are urgent to be solved. However, there is a lack of comprehensive platforms that characterise various infertility-related records to provide research applications for exploring infertility in-depth and genetic counselling of infertility couple. To solve this problem, we provide IDDB Xtra by further integrating phenotypic manifestations, genomic datasets, epigenetics, modulators in collaboration with numerous interactive tools into our previous infertility database, IDDB. IDDB Xtra houses manually-curated 2369 genes of human and nine model organisms, 273 chromosomal abnormalities, 884 phenotypes, 60 genomic datasets, 464 epigenetic records, 1144 modulators relevant to infertility diagnosis and treatment. Additionally, IDDB Xtra incorporated customized graphical applications for researchers and clinicians to decipher in-depth disease mechanisms from the perspectives of developmental atlas, mutation effects, and clinical manifestations. Users can browse genes across developmental stages of human and mouse, filter candidate genes, mine potential variants and retrieve infertility biomedical network in an intuitive web interface. In summary, IDDB Xtra not only captures valuable research and data, but also provides useful applications to facilitate the genetic counselling and drug discovery of infertility. IDDB Xtra is freely available at https://mdl.shsmu.edu.cn/IDDB/and http://www.allostery.net/IDDB.

Trends of menarcheal age in women in the reproductive age and menopause in Shanghai.

AIM: To explore the factors affecting menarcheal age by investigating two groups of women differing in age by 10-15 years in Shanghai. METHODS: Data on 5,207 women were collected from January 2011 to May 2012: 2,151 women of reproductive age from the Obstetrical Department and 3,056 women in menopause from the Medical Center of the Sixth Hospital of Shanghai City. General data and data on menarcheal age and medical history were collected. The two groups were divided into subgroups from <10 to ≥20 years, i.e. 12 subgroups in total, respectively. SPSS 17.0 software was used to examine statistical differences. RESULTS: The onset of menarcheal age of reproductive age women was 0.5 years earlier than that of menopause women (p < 0.05). In the early menarche age group (<13 years old), there were more reproductive age and high-educated women. Correlation analysis found the current body mass index in menopausal women was significantly negatively correlated with their menarcheal age (r = -0.033, p < 0.05). CONCLUSIONS: There was a downward trend in menarcheal age in women of Shanghai and its surrounding areas. Economic environment and education background were the main factors affecting menarcheal age, and menarcheal age may be considered as a predictor of adult obesity.

Vitamin D levels and other factors related to bone mineral density during pregnancy.

BACKGROUND: Multiple factors appear to affect bone mineral density (BMD) during pregnancy. AIMS: The aim of this study was to determine the relationships between BMD of the os calcaneus as measured by quantitative ultrasound (QUS) and levels of vitamin D3, parathyroid hormone (PTH), albumin (Alb), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) in a group of Chinese women. METHODS: Multiple parameters, including density of the os calcaneus, were recorded for a group of 130 women in early (mean gestation, 16.09 ± 2.65 weeks) and late (mean gestation, 32.01 ± 3.45 weeks) stages of pregnancy; 139 nonpregnant women served as controls. RESULTS: Bone mineral density was lower in pregnant women than in controls at both early and late stages of pregnancy. Levels of Ca, P and ALP were significantly negatively correlated with BMD over the course of pregnancy. Levels of D3, PTH and Alb showed a falling trend from early to late pregnancy as with QUS BMD of the os calcaneus, but the correlations were not statistically significant. CONCLUSIONS: Many factors are correlated with BMD. We suggest that levels of Ca and ALP should be included in the routine examination of pregnant women.

Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute lymphoblastic leukemia.

How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3',5'-monophosphate response element-binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C-induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C-induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.

Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models.

How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remains largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferentially localized to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7. P2x7 deletion led to notably impaired homing and self-renewal capacities of LICs and contributed to an approximately 5-fold decrease in the number of functional LICs but had no effect on normal hematopoiesis. ATP/P2X7 signaling enhanced the calcium flux-mediated phosphorylation of CREB, which further transactivated phosphoglycerate dehydrogenase (Phgdh) expression to maintain serine metabolism and LIC fates. P2X7 knockdown resulted in a markedly extended survival of recipients transplanted with either human AML cell lines or primary leukemia cells. Blockade of ATP/P2X7 signaling could efficiently inhibit leukemogenesis. Here, we provide a perspective for understanding how ATP/P2X7 signaling sustains LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells.

Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer.

Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP-insensitive CC cell lines with CDDP-sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

Skeletal myogenesis by human primordial germ cell-derived progenitors.

We have isolated and cultured human primordial germ cells (PGCs) from early embryos. The PGCs expressed embryonic germ (EG) cell-specific surface markers, including Oct4 and Nanos. We derived a cell population from these PGCs that we termed embryoid body-derived (EBD) cells. EBD cells can be extensively expanded in vitro for more than 50 passages and express lineage markers from all three primary germ layers. The myogenic potential of the EBD cells was examined both in vitro and in vivo.In vitro, the EBD cells can be induced to form multinucleated myotubes, which express late skeletal muscle-specific markers, including MHC and dystrophin, when exposed to human galectin-1. In vivo, the EBD cells gave rise to all the myogenic lineages, including the skeletal muscle stem cells known as satellite cells. Strikingly, these cells were able to partially restore degenerated muscles in the SCID/mdx mouse, an animal model of the Duchenne's muscular dystrophy. These results indicate the EBD cells may be a promising source of myogenic stem cells for cell-based therapies for muscle degenerative disorders.

Urothelial carcinoma associated 1 promotes trophoblast invasion by regulating MMP9.

BACKGROUND: The long non-coding RNA UCA1 is reportedly increased in several human tumors and critical for the cell migration, invasion, or proliferation of several cancer cells. However, the potential roles of UCA1 in trophoblasts at early pregnancy still poorly understood. Here, we sought to unravel the roles of UCA1 in the occurrence of the recurrent miscarriage (RM) disorders. RESULTS: The knockdown of UCA1 in human HTR-8 trophoblast cell line reduced their cell proliferative and invasive ability. Conversely, the UCA1 overexpression promoted the cell proliferation and invasion of HTR-8 cells. Quantitative RT-PCR screening revealed that UCA1 overexpression significantly enhanced MMP9, but not MMP2, mRNA expression in trophoblast cells. The overexpression of UCA1 also promoted trophoblast invasion by upregulating MMP9 expression and activity both in vitro and ex vivo. Consistently, UCA1 and MMP9 mRNA expression level was notably reduced in placental villi derived from patients with RM diseases. CONCLUSION: This study revealed that UCA1 is critical for the regulation of invasive ability in trophoblasts. The abnormal UCA1/MMP9 pathway might result in the impaired trophoblast activities and lead to the development of RM. Our data may also provide a novel angle for the treatment in RM patients.

PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21.

In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we could monitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells.

Follicle-Stimulating Hormone, Its Association with Cardiometabolic Risk Factors, and 10-Year Risk of Cardiovascular Disease in Postmenopausal Women.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in postmenopausal women. Follicle-stimulating hormone (FSH) shows negative associations with obesity and diabetes mellitus in postmenopausal women. We aimed to study the associations between FSH and 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women. METHODS AND RESULTS: SPECT-China (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors) is a 22-site, population-based study conducted during 2014-2015. This study included 2658 postmenopausal women. A newly developed effective tool for 10-year ASCVD risk prediction among Chinese was adopted. Regression analyses were performed to assess the relationship among FSH, 10-year ASCVD risk, and multiple cardiometabolic risk factors. With the increase in FSH quartiles, the mean 10-year ASCVD risk in postmenopausal women decreased from 4.9% to 3.3%, and most metabolic parameters were significantly ameliorated (all P for trend <0.05). In regression analyses, a 1-SD increment in ln-FSH was negatively associated with continuous (B -0.12, 95% confidence interval, -0.16, -0.09, P<0.05) and categorical (odds ratio 0.65, 95% confidence interval, 0.49, 0.85, P<0.05) 10-year ASCVD risk. These significant associations existed in subgroups with or without medication use, obesity, diabetes mellitus, hypertension, and dyslipidemia. Body mass index and waist circumference (both B -0.35, 95% confidence interval, -0.40, -0.30, P<0.05) had the largest associations of all metabolic measures, and blood pressure had the smallest association. CONCLUSIONS: Serum FSH levels were negatively associated with 10-year ASCVD risk in postmenopausal women. Among cardiometabolic factors, obesity indices had the largest associations with FSH. These results indicated that a low FSH might be a risk factor or a biomarker for cardiovascular disease risk in postmenopausal women.

Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis.

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B). Deletion of VPS33B in either mouse or human HSCs resulted in impaired exosome maturation and secretion as well as loss of stemness. Additionally, VPS33B deficiency led to a dramatic delay in leukemogenesis. Exosomes purified from either conditioned medium or human plasma could partially rescue the defects of HSCs and leukemia-initiating cells (LICs). VPS33B co-existed in exosomes with GDI2, VPS16B, FLOT1, and other known exosome markers. Mechanistically, VPS33B interacted with the GDI2/RAB11A/RAB27A pathway to regulate the trafficking of secretory proteins as exosomes. These findings reveal an essential role for VPS33B in exosome pathways in HSCs and LICs. Moreover, they shed light on the understanding of vesicle trafficking in other stem cells and on the development of improved strategies for cancer treatment.

Prognostic value of Musashi-1 in endometrioid adenocarcinoma.

AIMS: Musashi-1, a RNA-binding protein, is suggested to be a cancer stem cell-related marker; its high level of protein expression is reported to be associated with high histological grade in some tumors. The aim of this study was to investigate the prognostic value of Musashi-1 in patients with endometrioid adenocarcinoma (EAC). METHODS: We examined the Musashi-1 mRNA expression level in 35 fresh EAC tissue samples and 15 normal endometrium samples by real-time RT-PCR, and its protein expression level in 148 paraffin EAC tissue samples and 20 paraffin normal endometrium samples by immunohistochemistry. The correlation between Musashi-1 and overall survival (OS) used Cox proportional hazards regression. The prognostic accuracy of Musashi-1 compared with other clinicopathological risk factors by logistic regression. Furthermore, we examined whether Musashi-1 expression is correlated with another cancer stem cell marker CD133 by real-time RT-PCR. RESULTS: Musashi-1 mRNA expression of EAC is 2.8-fold higher than that of normal endometrium (P=0.0009). Musashi-1 protein expression level is correlated with tumor stage, grade and vascular invasion. Patients with higher protein expression level of Musashi-1 are associated with poor survival rate than those with negative or low level of expression (HR=2.073, P=0.001). The area under the curve (AUC) for Musashi-1 is 0.8, which is higher than other clinicopathological factors (P=0.000). In addition, Musashi-1 mRNA expression seems to be closely correlated with CD133 expression (r=0.7167, P<0.0001). CONCLUSIONS: Our results suggest high level of Musashi-1 protein expression is associated with poor survival in EAC patients, which may be an independent prognostic factor for EAC.

PTEN signaling is required for the maintenance of spermatogonial stem cells in mouse, by regulating the expressions of PLZF and UTF1.

BACKGROUND: Pten plays a crucial role in the stem cell maintenance in a few organs. Pten defect also causes the premature oocytes and ovary aging. We and other groups have found that the phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling regulates the proliferation and differentiation of spermatogonial stem cells (SSCs). PTEN functions as a negative regulator of the PI3K pathway. Thus, we thought that the fate of SSCs might be controlled by Pten. RESULTS: We report that promyelocytic leukaemia zinc finger (PLZF) and undifferentiated embryonic cell transcription factor 1 (UTF1), both of which are germ cell-specific transcriptional factors, are regulated by Pten. Conditional deletion of Pten leads to reduction in PLZF expression but induction of UTF1, which is associated with SSCs depletion and infertility in males with age. CONCLUSION: Our data demonstrate that Pten is required for the long-term maintenance of SSCs and precise regulation of spermatogenesis in mouse. The finding of a Pten-regulated GFRα1(+)/PLZF(-)/UTF1(+) progenitor population provides a new insight into the precise mechanisms controlling SSC fate.

Efficacy of the Levonorgestrel-Releasing Intrauterine System on IVF-ET Outcomes in PCOS With Simple Endometrial Hyperplasia.

OBJECTIVE: This study investigated the in vitro fertilization (IVF) outcome of levonorgestrel-releasing intrauterine system (LNG-IUS) pretreatment for simple endometrial hyperplasia (EH) in patients with polycystic ovary syndrome (PCOS) undergoing IVF embryo transfer (IVF-ET). METHODS: One hundred ninety patients with PCOS and simple EH without cytologic atypia were allocated randomly to 2 independent arms, that is, the LNG-IUS group (90 patients) and the non-LNG-IUS group (100 patients). Four hundred fourteen patients with PCOS without endometrial disease comprised the control group. Each patient was reevaluated by transvaginal ultrasonography (TVS) and endometrial biopsy after 6 months. For each patient, IVF outcome measures, such as number of recombinant follicle-stimulating hormone, endometrial thickness on human chorionic gonadotropin (HCG) day, hormone levels (progesterone, luetinizing hormone, and serum estradiol) on HCG day, number of oocytes, fertilization rate, clinical pregnancy rate, and miscarriage rate were compared among the 3 groups. RESULTS: In general, the 3 groups did not differ with respect to the main clinical and biochemical data. After 6 months, patients in LNG-IUS group had an EH resolution rate of 87.77%. In the non-LNG-IUS group, the resolution rate was 15.00%, and 3% of these patients showed progression of EH. The clinical pregnancy rates in the non-LNG-IUS group were significantly lower (28.04%) than that in the LNG-IUS group (46.06%) and the control group (44.65%). The miscarriage rate was highest in the non-LNG-IUS group, but no significant difference in miscarriage rate existed among the 3 groups. CONCLUSION: The study illustrates that the LNG-IUS can be safely used for 6 months as a treatment for patients with PCOS and simple EH. Additionally, use of the LNG-IUS can increase the clinical pregnancy rates and implantation rates of patients with PCOS and simple EH who undergo gonadotropin-releasing hormone agonist IVF-ET protocols.