2019 novel coronavirus disease has resulted in thousands of critically ill patients in China, which is a serious threat to people's life and health. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was reported to share the same receptor, angiotensin-converting enzyme 2 (ACE2), with SARS-CoV. Here, based on the public single-cell RNA-sequencing database, we analyzed the mRNA expression profile of putative receptor ACE2 and AXL receptor tyrosine kinase (AXL) in the early maternal–fetal interface. The result indicates that the ACE2 has very low expression in the different cell types of early maternal–fetal interface, except slightly high in decidual perivascular cells cluster 1 (PV1). Interestingly, we found that the Zika virus (ZIKV) receptor AXL expression is concentrated in perivascular cells and stromal cells, indicating that there are relatively more AXL-expressing cells in the early maternal–fetal interface. This study provides a possible infection route and mechanism for the SARS-CoV-2- or ZIKV-infected mother-to-fetus transmission disease, which could be informative for future therapeutic strategy development.

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Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis. It affects approximately 10% women of reproductive age. Although its etiology and pathogenesis remain poorly understood, it is characterized by the elevated local production of estrogen in the endometriotic tissues. In this paper, we review the mechanisms of estrogen biosynthesis and its regulation in endometriosis.

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Lack of the zona pellucida (ZP) is one of the manifestations of an oocyte maturation disorder. In recent years, genetic factors have attracted much attention as a possible cause of ZP anomalies. In this study, we report a form of primary infertility characterized by abnormal eggs that lack the ZP, which resulted from a compound heterozygous autosomal recessive mutation in ZP1. This compound heterozygous mutation has been reported for the first time, and our results may expand the spectrum of known mutations in ZP genes and provide evidence of oocyte maturation disorders during genetic counseling.

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Background: To study the effects of cryopreservation on human sperm glycocalyx. Methods: The lectin binding profilings of sperm after freeze-thaw were compared by lectin microarray. Results: CryoSperm™ and direct fumigation were confirmed to be the optimized cryoprotectant and method by comparing the sperm recovery rate. In 91 lectins, 33 lectins were significantly changed after sperm cryopreservation. Among them, 9 lectins greatly decreased and 24 lectins mainly increased. The binding signals of MAA, PSA, ABA, and AIA were verified by FACS, and the results were consistent with that of lectin microarray. Conclusions: Sperm glycocalyx had significant changes after cryopreservation. The sialic acid, playing an important role in protecting sperm, was greatly lost, which exposed the inner carbohydrates. Thus, the glycocalyx damage due to the cryopreservation might be one of the reasons for low sperm fertility.

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Objective: Spermatogenesis is a complex process which is of vital importance for sexual reproduction. In many studies of spermatogenesis, the mRNAs, protein-coding genes, as well as small noncoding RNAs (ncRNAs) have been well characterized. However, there remain numerous questions despite previously characterized molecular mechanisms. Long ncRNAs (lncRNAs) are a relatively new addition to our knowledge of ncRNAs. Limited studies have examined the function of lncRNAs in spermatogenesis. Therefore, we selected a testis-specific lncRNA, lncRNA4667, to analyze its potential role in spermatogenesis and male fertility. Methods: In situ hybridization and quantitative reverse transcription polymerase chain reaction analyses were used to confirm testis-specific expression of lncRNA4667. LncRNA4667 knockout mice were generated using CRISPR/Cas9 technology. Histology, sperm counts, sperm motility, body parameters, and fertility were compared between wild-type and knockout mice (n = 8/group). Results: Expression analysis showed that lncRNA4667 was testis specific and localized to round spermatids in seminiferous tubules of adult mouse testes. Mice homozygous for a null mutation of lncRNA4667 displayed normal spermatogenesis and fertility compared with wild-type mice. Conclusions: These data indicate that lncRNA4667 is dispensable for spermatogenesis and fertility in mice, and the localization of lncRNA4667 makes it a useful marker for the identification of round spermatids in mice.

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Objective: Endometriosis is a common gynecological disease with an enigmatic pathogenesis. Recent studies suggest that the behavior of normal endometrial stromal cells can dramatically change under hypoxic conditions, which effectively turns them into endometriotic stromal cells. Because menstrual debris is not only hypoxic but may also contain platelet aggregates, at present, we aimed to approve that activated platelets could induce hypoxia-inducible factor-1α (HIF-1α) expression in endometrial stromal cells, signaling the presence of hypoxia. Methods: We evaluated the gene and protein expression levels of HIF-1α and its target gene erythropoietin (EPO) in both human endometriotic stromal cells (HESCs) and a human endometrial stromal cell line (ESCL) cocultured with or without activated platelets for 48 h. Results: We found that the gene and protein expression levels of HIF-1α and EPO in both HESC and ESCL were significantly increased after coculture with activated platelets. We also found that neutralization of transforming growth factor-β1 completely abolishes this induction. Conclusions: Platelets can induce a hypoxic state in endometrial and endometriotic stromal cells, resulting in increased angiogenesis, as well as enhanced survival and proliferation. In conjunction with other roles that platelets play in the development of endometriosis, our findings further highlight the important roles of platelets in the development and initiation of endometriosis, shedding new light into the etiology of endometriosis.

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Endometriosis (EMS) is a common gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. It is commonly associated with pelvic pain and infertility. The exact pathogenesis remains unclear and many hypotheses have been suggested. In recent years, accumulating evidence indicates that oxidative stress (OS) plays a role in the development of EMS. The treatment of EMS remains a challenge. Antioxidant therapies for effective management of reactive oxygen species and inflammation have generated considerable research interest. Antioxidant agents such as Vitamins C and E, resveratrol, curcumin, melatonin, epigallocatechin-3-gallate, and others have been studied for the treatment of EMS. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.

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Objective: Polycystic ovary syndrome (PCOS), a heterogeneous endocrine disorder, affects female reproductive function, but its etiology has not been elucidated. In this study, we analyzed the differential genes related to ovarian steroid biosynthesis in patients with PCOS, to explore the mechanism of PCOS. Methods: The GSE59456 data were downloaded from the Gene Expression Omnibus database. We identified differentially expressed genes (DEGs) in ovaries between the female Sprague–Dawley rats those implanted with 5α-dehydrotestestrone (DHT) and those in control (CTL, implanted with empty capsule). Gene ontology, pathway enrichment analysis, and protein–protein interaction (PPI) network construction were subsequently performed. Results: In total, 530 upregulated DEGs and 522 downregulated DEGs were identified. The identified DEGs were mostly associated with steroid biosynthesis. In the PPI network, the module M1 was mainly related to steroid biosynthesis, and five genes (Hsd17b7, Tm7sf2, Idi1, Msmo1, and Sqle) of the module M1 were from the aforementioned group of upregulated genes. Furthermore, the 19 DEGs (Idi1, Cga, C1qb, Thy1, Gpx1, Ctss, Lpl, A2m, Cited2, Plppr4, Prkar2b, Slc44a1, Inha, Rbp4, Pla2g2a, Gata4, Fabp3, Cpa2, and Cpa1) between DHT and CTL groups were associated with the process of the transformation of primordial follicles to primary follicles. Conclusions: These DEGs, such as Hsd17b7, Tm7sf2, Idi1, Msmo1, Sqle, Rbp4, Gata4, Inha, and Cited2, may be used to elucidate the etiology of PCOS, which may provide new insights into the exploration of pathological mechanism and biomarkers for polycystic ovary.

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Objective: To evaluate the effect of recombinant human growth hormone (rhGH) supplementation during hormone-replacement therapy and frozen-thawed embryo transfer (FET) in patients with thin endometrium. Methods: A retrospective research was conducted on 225 patients, who underwent artificial cycle FET in Shanghai, China, between January 2016 and November 2017. Data from 245 FET cycles were analyzed, of which 184 cycles received rhGH (GH group) and 61 did not (control group). Results: Clinical pregnancy and implantation rates were significantly higher in the GH group than those in the control group (64.7% vs. 49.2%, P = 0.032; 44.8% vs. 32.8%, P = 0.019, respectively). After logistic regression analysis, rhGH was considered the only significant variable that influenced clinical pregnancy rate, increasing it by 1.89-fold. On the other hand, the presence of rhGH did not seem to affect the early pregnancy loss. Conclusions: Our results indicated that simultaneous addition of rhGH could improve clinical outcomes of FET in patients with thin endometrium, particularly in patients between 30 and 34 years of age.

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Objective: Villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix is a subtype of cervical adenocarcinoma. In the present study, we summarized the clinical features of VGPA of the uterine cervix and discussed the potential indications for a conservative treatment. Methods: A retrospective review of clinical characteristics and treatment aspects of 10 patients with VGPA at the Obstetrics and Gynecology Hospital of Fudan University was conducted between January 2007 and December 2016. Almost all of the existing 40 English papers on “villoglandular papillary adenocarcinoma [title/abstract]” identified from PubMed were obtained. Clinical data from these papers were analyzed in terms of age, International Federation of Gynecology and Obstetrics (FIGO) stage, recurrence rate, mortality, and conservation treatment aspects. Results: The median age of 10 patients with VGPA was 40 years. All cases had Stage IB 1 disease. Seven patients underwent human papillomavirus examinations, which revealed 6 positive and 1 negative case(s) of infection. Six patients underwent ThinPrep cytologic tests, which revealed 4 patients with atypical glandular cells, 1 with a high-grade squamous intraepithelial lesion, and 1 who tested negative for intraepithelial malignancy. None of the patients had lymph node metastases. During the 6–114 months of follow-up, no disease recurrence or death occurred. Of note, one patient who received conservative treatment successfully became pregnant. Conclusions: VGPA can be detected at an early FIGO stage with excellent prognosis. For young patients who do not exhibit poor prognosis factors, conservative treatment may be the first treatment choice based on overall assessment of clinical conditions.

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Primary dysmenorrhea (PDM) is the painful menses with spasmodic cramping in the lower abdomen in the absence of any discernable macroscopic pelvic pathology. The prevalence of dysmenorrhea changes between 16% and 91% in women. About 2%–29% of the women studied suffer from severe pain. This review focuses on the current knowledge, particularly with regard to the latest research on the etiology of PDM. Full-text manuscripts on PDM were searched on PubMed and Google Scholar. One or more of the following search terms were used to obtain articles published: PDM, pain, functional magnetic resonance imaging, brain image, etiology, epidemiology, metabolism, hormone, gene variation, and quality of life. In this review, we detailed four potential etiology aspects of PDM: brain abnormality, gene expression, metabolism, and hyperalgesia. We highlighted the latest brain research on PDM patients and investigated genetic aspects. We are dedicated to identifying more metabolic variations and expand the previous knowledge on the sensitive pain threshold.

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Objective: To analyze spontaneous abortion rate and its associated risk factors in patients with polycystic ovary syndrome (PCOS) after in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods: This was a retrospective cohort study on 2,231 PCOS patients undergoing IVF/ICSI treatment. For comparison, we enrolled another 2,231 patients with tubular factors in control group. Spontaneous abortion rate and chromosomal abnormality rate were compared between the two groups. Furthermore, clinical data were compared between the patients with spontaneous abortion and those with ongoing pregnancy using univariate and multivariate analysis for risk factors of spontaneous abortion in PCOS patients. Results: Patients in the PCOS group had significantly higher spontaneous abortion rate (24.15%) than that in the control group (12.75%, P < 0.001). Chromosomal abnormality rate was significantly lower in the PCOS group (36.05%, 31/86) than in the control group (55.56%, 50/90, P = 0.009). In the PCOS group, patients with spontaneous abortion had significantly elder age, higher body mass index (BMI), and homeostasis model assessment for insulin resistance (HOMA-IR) than those with ongoing pregnancy. The logistic regression analysis confirmed that the age, BMI, and HOMA-IR were the risk factors of spontaneous abortion in the PCOS patients. There were no significant differences between groups in the type of cycles, the quality of embryos transferred, the number of embryos transferred, fasting blood glucose, fasting insulin, and so on. Conclusions: Compared with non-PCOS patients, PCOS patients had higher spontaneous abortion rate, but the chromosomal abnormality was not a major factor for the high spontaneous abortion rate in the PCOS patients. Age, BMI, and HOMA-IR were risk factors for spontaneous abortion after IVF/ICSI-ET in PCOS patients.

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Objective: To establish the messenger RNA (mRNA) and long non-coding RNA (lncRNA) expression profiles in ectopic and eutopic endometrium and provide novel insights into endometriosis. Methods: The mRNA and lncRNA expression profiles were tested using high-throughput sequencing technology in ectopic and eutopic endometrium with endometriosis and normal endometrium without endometriosis. The potential targeted lncRNAs were annotated by analyzing the correlation between lncRNA and mRNA expression to better understand the pathogenesis of endometriosis. Results: In ectopic compared with normal endometrium, a total of 2,188 mRNAs and 1,200 lncRNAs were differentially expressed with a fold-change (FC) ≥2.5. In eutopic compared with normal endometrium, a total of 2,324 mRNAs and 695 lncRNAs were differentially expressed with an FC ≥1.5. In ectopic compared with eutopic endometrium, a total of 2,223 mRNAs and 511 lncRNAs were differentially expressed with an FC ≥2. Bioinformatic analysis indicated that the differentially expressed mRNAs were enriched in the biological processes and signaling pathways involved in endometriosis. In addition, we constructed a gene coexpression network based on the dysregulated lncRNAs in both ectopic endometrium and eutopic endometrium, combined with their coexpressed mRNAs to simulate the complex interactions. Conclusions: This study describes the first-to-integrate analysis of the differential expression profiles of mRNAs and lncRNAs, including analyses between ectopic and normal endometrium, eutopic and normal endometrium, and ectopic and eutopic endometrium, which provides new insights to investigate the pathogenesis of endometriosis and explore novel diagnostic biomarkers and therapeutic targets.

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Objective: Acupuncture can relieve pain by acting on the mitogen-activated protein kinase (MAPK) signal pathway, which plays a critical role in the balance between hyperalgesia and inflammation. Our previous studies have suggested that acupoint injection of Vitamin K3 (Vit K3) had an intensive analgesic effect on primary dyspareunia. However, the mechanism by which Vit K3 worked on nerve cells has not been elucidated. Methods: Cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) changes of PC-12 cells with Vit K3 treatment, for which the concentration gradient was 0, 5, 10, 20, 40, and 60 μmol/L, were quantified by flow cytometry. The expression and phosphorylation of c-Jun N-terminal kinase, p38, and extracellular-regulated protein kinase (ERK), the three critical molecules of the MAPK pathway, were further assessed using Western blotting. Results: The level of ROS first decreased and then increased with Vit K3 at 20 μmol/L, but no change in neither apoptosis nor MMP was evident. In addition, only ERK level decreased at 20 μmol/L and the relative phosphorylation level increased. Changes in ROS were negatively correlated with the expression of ERK. Conclusions: The rapid analgesic effect of Vit K3 acupoint injection may be through the reduction of ROS in nerve cells with a small dose of Vit K3 or by influencing the expression of ERK but without damaging the nerve cells themselves.

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Objective: Adequate extravillous trophoblast (EVT) invasion plays a crucial role in the establishment of successful pregnancy. Insufficient trophoblast migration and invasion can result in defective placentation, which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation. Methods: We utilized immortalized human first-trimester EVT cells (HTR8/SVneo) for our functional study. We examined the effects of Gal-9 on viability, proliferation, and invasion of HTR8/SVneo cells, as well as on matrix metalloproteinase-2 (MMP-2) production in HTR8/SVneo cells. Furthermore, we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells' invasion. Results: We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion. Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3, not CD44, and subsequently increased MMP-2 production. Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells. Conclusion: Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.

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Background: To examine the effects of dehydroepiandrosterone (DHEA) on in vitro fertilization (IVF) intracytoplasmic sperm injection (ICSI) and the levels of follicular fluid (FF) markers, namely, anti-Müllerian hormone (AMH), insulin-like growth factor (IGF)-1, bone morphogenetic protein (BMP)-15, and growth differentiation factor (GDF)-9, in patients with diminished ovarian reserves (DORs). Methods: 116 patients with DOR were randomized into two groups, DHEA group and control group. Each group contained 58 patients. The DHEA group received 75 mg/d of DHEA for 12 weeks prior to the start of IVF treatment, while the control group entered IVF treatment directly. All patients were treated with the same ovarian stimulation protocol. The primary outcome was high-quality embryo yield. Other IVF parameters, such as the clinical pregnancy rate, embryo survival rate, and intact blastomere rate, were compared between the two groups. FF samples from patients of both groups were collected to measure the levels of AMH, IGF-1, DHEA-sulfate, BMP-15, and GDF-9. Blood was also collected on day 3 of the menstrual cycle to define the baseline hormonal profile and to examine ovarian reserve markers. Results: The high-quality embryo yield was higher in DHEA group than that in control group (P = 0.033). AMH and IGF-1 concentrations in FF were significantly higher in DHEA group than that in the control group (2.83 ± 1.14 ng/L vs. 1.37 ± 0.55 ng/L, P = 0.000; 94.02 ± 38.28 ng/L vs. 74.03 ± 25.46 ng/L, P = 0.004, respectively). The BMP-15 level was also higher in DHEA group (relative expression were 1.80 ± 0.41) than that in control group (relative expression were 0.79 ± 0.16, P < 0.0001); however, there was no difference in GDF-9 expression between the two groups (relative expression were 1.29 ± 0.54 and 1.16 ± 0.50 respectively, P > 0.05) and in the clinical pregnancy rate between the two groups (13.79% vs. 7.27%, respectively, P > 0.05). Conclusions: In women with DOR undergoing IVF treatment, pretreatment with DHEA may increase the number of high-quality embryos, which may be due to increased levels of AMH, IGF-1, and BMP-15 in the FF. Trial Registration: NCT02866253.

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Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1 (FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency (POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5' untranslated region of the FMR1 gene. Before using the previously reported FragilEase polymerase chain reaction (PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women (0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.

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In clinical practice, early pregnancy loss has afflicted approximately 15%–25% women of reproductive age worldwide, which is partially attributed to defects associated with the endometrium. During pregnancy, the endometrial stromal cells experience remarkable tissue remodeling and transformation, termed as decidualization, to support embryonic development, placental formation, and the maintenance of normal pregnancy in both mice and human. During this process, a series of dynamic developmental events, including rapid stromal proliferation, increased stromal cell size, enhanced angiogenesis, taken place in a highly-ordered manner under the precise regulation of steroid hormones. Meanwhile, diverse molecules exhibit spatiotemporal-specific expression pattern, implying their unique roles in decidual development. To achieve a more comprehensive understanding of these biological events and explore the underlying causes of early pregnancy disorders, this review emphasizes on the detailed developmental progression of decidual transformation and patterning as well as related pregnancy complications at the early stage of pregnancy.

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Recurrent implantation failure (RIF) is a syndrome of complex etiology. Excluding the involvement of embryonic factors, RIF is characterized by women aged ≤40 years who fail to achieve clinical pregnancy after at least four high-quality embryos transfer in a minimum of three fresh or frozen cycles. However, current methods in the treatment of RIF are controversial. So far, there are no reports of any criteria or guidelines, and the mechanism of RIF is still not clear. Herein, we summarize the pathogenesis of RIF and highlight recent methods in its treatment, to provide reference for the basic and clinical research on RIF.

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Mammalian spermatogenesis is a complicated and precisely controlled process that requires spermatogonial stem cells (SSCs). SSCs maintain the stem cell pool, balance self-renewal–commitment with differentiation, and produce millions of sperm daily. Self-renewal and differentiation are controlled by intrinsic factors within SSCs and extrinsic factors from the “niche.” In this review, we discuss the biology of SSCs and the factors regulating their self-renewal and differentiation.

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DNA methylation and histone modification are two of the most characterized epigenetic modifications. With advanced detecting techniques, particularly single-cell sequencing, we can dissect epigenomic patterns and their regulatory roles in the growth and differentiation of gametes and early embryos in animals and humans. Assisted reproductive technology (ART) procedures have been shown to influence the methylation of certain genes. Aberrant epigenetic regulation may cause several developmental disorders and clinical diseases. Here, we describe some concepts in epigenetics and review recent researches on DNA methylation and the histone modification profile and their regulatory roles during early embryo development. We also summarize the recent progress in understanding the imprinting disorders associated with ART procedures.

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Fertility disorders have become a growing problem worldwide. It is well known that female fertility decreases with age, previous studies suggested that the age-related decline in female fertility potential was largely due to decrease in oocyte quality and mitochondrial dysfunction. Mitochondria play a crucial role during the process of oocyte maturation. Mitochondrial genetic, numerical and structural defects occur in oocyte aging process, mitochondrial abnormalities are believed to contribute to age-related infertility. Improvement of the mitochondrial function can lead to better fertility outcomes, and application of mitochondria replacement strategy or mitochondrial transfer to age-related infertility will be possible in the future. This review paper, we are trying to discuss current understanding about age-related changes in oocyte quality and mitochondrial dysfunction.

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Zearalenone (ZEA) is produced by Fusarium species and a common contaminant in food. ZEA and its metabolites, α- and β-zearalenol, α- and β-zearalanol, and zearalanone, are mycoestrogens that can interfere with estrogen signaling. High levels of mycoestrogens reduced female fertility in farm animals and rodents, in which adverse effects of mycoestrogens on major events in female reproduction, including ovarian folliculogenesis, ovulation, ovarian steroidogenesis, fertilization, preimplantation embryo development and transport, embryo implantation, placentation, parturition, and lactation, have been reported in different experimental settings. Here, we review the in vivo effects of mycoestrogens on the main events in female reproduction.

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Objective: The aim of this study is to evaluate the diagnostic accuracy of colposcopically directed biopsy (CDB) and loop electrosurgical excision procedure (LEEP) for cervical lesions and assess their ability to detect glandular involvement. Methods: This retrospective study reviewed 4689 cervical lesions that were tested by CDB and LEEP at a tertiary hospital. The sensitivity, specificity, and predictive value of CDB and LEEP and the ratio of glandular involvement detected by these two methods were analyzed. Results: CDB and LEEP had sensitivities of 95.4% and 80.0%, respectively, for diagnosing high-grade intraepithelial or more severe lesions (HSIL+) (P = 0.000) and 31.8% and 87.9%, respectively, for diagnosing adenocarcinoma in situ or more severe lesions (AIS+) (P = 0.001). CDB and LEEP had sensitivities of 18.1% and 90.2%, respectively, for diagnosing invasive squamous cell carcinoma (P = 0.000) and 5.9% and 98.0%, respectively, for diagnosing invasive adenocarcinoma (P = 0.000). The negative predictive values of CDB and LEEP for diagnosing HSIL+ were 88.6% and 64.4%, respectively (P = 0.000). The ratios of glandular involvement were 0.2% (CDB) and 2.4% (LEEP) in low-grade intraepithelial lesions (LSILs) and 8.9% (CDB) and 59.0% (LEEP) (P = 0.000) in HSIL+. Conclusions: LEEP is superior to CDB for diagnosing AIS and detecting early invasive cancer. It should be offered as an additional investigation to all patients with AIS, HSIL, or LSIL with glandular involvement on CDB.

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Objective: Female reproductive aging is characterized by reduced responsiveness of the hypothalamus to E₂-positive feedback, which can result in alterations of gene expression and luteinizing hormone (LH) surge dysfunction. We hypothesize that age-related changes in E₂-responsive gene expression are due to altered histone acetylation by histone deacetylases (HDACs) or estrogen receptor-alpha (ERα) coactivators with histone acetyltransferase (HAT) activity. Methods: In the present study, young and middle-aged female rats were ovariectomized (OVX) and treated with E₂ or oil once per day for 2 days. At the time of the expected LH surge, the anterior and posterior hypothalami were dissected, and gene expression of 11 HDACs and 4 ERα coactivators with HAT activity was measured using real-time polymerase chain reaction. Results: In the anterior hypothalamus, age affected the gene expression of 3 HDACs (Hdac3, Hdac5, and Hdac11) and 2 ERα coactivators (Src2 and Crebbp). E₂ treatment significantly decreased mRNA levels of 4 HDACs (Hdac4, Hdac5, Hdac10, and Hdac11) and 2 ERα coactivators (Src2 and Crebbp) in young females (3–4 months). However, none of the genes responded to E₂ in the middle-aged females (9–11 months), except Hdac10. In the posterior hypothalamus, age influenced Hdac5 and Src1 mRNA expression. E₂ treatment increased Hdac4 and Crebbp mRNA levels in the young but not middle-aged females. Conclusions: These data suggest that E₂ regulates HDACs and ERα coactivators with HAT activity in an age- and E₂-dependent manner, which may contribute to the age-related gene expression changes on the day of LH surge in female reproductive aging.

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