Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

Significance of preventing developmental origins of diseases in improving population quality / 中华预防医学杂志

More studies show that various diseases, especially chronic non-infectious diseases, have developmental origin. Developmental origins of diseases are mainly due to gametes and early life development stage being exposed to adverse environment, resulting in abnormal modification of epigenetic and stable inheritance to the adult stage, which could make the risk of various long-term diseases of individuals high. The theory of developmental origin provides a new perspective for the occurrence and development of diseases, and also provides a theoretical basis for disease prevention. Attaching importance to maternal and child health care and life-cycle management is conducive to the prevention of developmental diseases and is of great significance to the improvement of population quality.

Risk factors for gestational diabetes mellitus among multiparae / 上海交通大学学报（医学版）

Objective·To investigate the risk factors for gestational diabetes mellitus (GDM) among multiparae. Methods?·?Women who had two consecutive pregnancies records in the International Peace Maternity and Child Health Hospital from January 2012 to January 2017 were included into this study. The case group (116 cases) and control group (464 cases) were matched at the ratio of 1:4 according to the pre-pregnancy age in index pregnancy. Clinical characteristics, biochemical parameters including oral glucose tolerance test (OGTT) and lipid profiles were took into consideration by virtue of their medical records. Multivariate Logistic regression analysis was used to compute the adjusted odds ratio (aOR) and 95%CI so as to identify the risk factors. Results?·?Compared with the control group, the case group was associated with greater body mass index (BMI) change between pregnancies (aOR=1.35, 95%?CI=1.07-1.69), greater postprandial 1 h glucose load (aOR=1.99, 95%?CI=1.55-2.55) and 2 h glucose load (aOR=2.02, 95%?CI=1.51-2.70) at OGTT in index pregnancy, and greater first-trimester fasting plasma glucose (aOR=1.96, 95%?CI=1.16-3.32), total cholesterol (aOR=1.37, 95%?CI=1.06-1.77) and triacylglycerol (aOR=1.53, 95%?CI=1.10-2.14) in subsequent pregnancy. Conclusion?·?The elevated BMI change between pregnancies, the abnormal glucose and lipid profiles persisting from index to subsequent pregnancy lead to the occurrence of GDM.

Roles of gut microbiota in the occurrence and development of polycystic ovary syndrome / 上海交通大学学报（医学版）

Polycystic ovary syndrome (PCOS) is a gynecologic endocrine disorder with complex etiology and pathogenesis.Many women of reproductive age are influenced by this disease due to infertility.The pathogenesis of PCOS remains unclear despite increasing studies in recent years.It is generally accepted that insulin resistance,hyperandrogenism and abnormal follicle development play a pivotal role in PCOS.Gut microbiota becomes a research hotspot in the aspect of infectious,immune and metabolic diseases recently.Previous studies have found that gut microbiota could modulate the synthesis and secretion of insulin,and affect metabolism of androgen and follicle development,providing us a new idea for unravelling the pathogenesis of PCOS.Based on these researches,fecal microbiota transplantation may be a promising treatment in rectifying intestinal microecology imbalance and improving metabolism.This paper reviewed recent research advances in the roles of gut microbiota in the occurrence and development of PCOS.

Research advances in the role of inflammatory factors in polycystic ovary syndrome / 上海交通大学学报（医学版）

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of childbearing age, which features oligo- or anovulation, polycystic ovaries, hyperandrogenism and the related clinical signs, such as acne and hirsutism. At present, PCOS patients are considered to be in a long-time condition of chronic inflammation. It is reported that increased expression of inflammatory factors and/or increased levels of inflammation exist in peripheral blood, granulosa cells, follicular fluid, ovarian stroma, adipocytes and endometrial cells in patients with PCOS. Studies on the role of inflammatory factors in the pathogenesis of PCOS suggest that inflammatory factors may have an influence on the clinical outcome through affecting follicular development, androgen levels and so on.

Comparison of the Reference Intervals Used for the Evaluation of Maternal Thyroid Function During Pregnancy Using Sequential and Nonsequential Methods / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Maternal thyroid dysfunction is common during pregnancy, and physiological changes during pregnancy can lead to the overdiagnosis of hyperthyroidism and misdiagnosis of hypothyroidism with nongestation-specific reference intervals. Our aim was to compare sequential with nonsequential methods for the evaluation of thyroid function in pregnant women.</p><p><b>METHODS</b>We tested pregnant women who underwent their trimester prenatal screening at our hospital from February 2011 to September 2012 for serum thyroid stimulating hormone (TSH) and free thyroxine (FT4) using the Abbott and Roche kits. There were 447 and 200 patients enrolled in the nonsequential and sequential groups, respectively. The central 95% range between the 2.5th and the 97.5th percentiles was used as the reference interval for the thyroid function parameter.</p><p><b>RESULTS</b>The nonsequential group exhibited a significantly larger degree of dispersion in the TSH reference interval during the 2nd and 3rd trimesters as measured using both the Abbott and Roche kits (all P < 0.05). The TSH reference intervals were significantly larger in the nonsequential group than in the sequential group during the 3rd trimester as measured with both the Abbott (4.95 vs. 3.77 mU/L, P < 0.001) and Roche kits (6.62 vs. 5.01 mU/L, P = 0.004). The nonsequential group had a significantly larger FT4 reference interval as measured with the Abbott kit during all trimesters (12.64 vs. 5.82 pmol/L; 7.96 vs. 4.77 pmol/L; 8.10 vs. 4.77 pmol/L, respectively, all P < 0.05), whereas a significantly larger FT4 reference interval was only observed during the 2nd trimester with the Roche kit (7.76 vs. 5.52 pmol/L, P = 0.002).</p><p><b>CONCLUSIONS</b>It was more reasonable to establish reference intervals for the evaluation of maternal thyroid function using the sequential method during each trimester of pregnancy. Moreover, the exclusion of pregnancy-related complications should be considered in the inclusion criteria for thyroid function tests.</p>

Instructional significance of HBV-DNA load in maternal milk on breastfeeding of postpartum women infected with HBV / 中华预防医学杂志

<p><b>OBJECTIVE</b>To study the instructional significance of HBV-DNA load in maternal milk on breastfeeding of postpartum women infected with HBV.</p><p><b>METHODS</b>HBV-DNA levels in serum and breast milk were detected by FQ-PCR in 152 postpartum women infected with HBV, and HBV-DNA ≥ 1.0 × 10(3) U/ml was defined as HBV positive. Correlation analysis was also conducted to estimate if there were relations in HBV levels in serum and breast milk.</p><p><b>RESULTS</b>HBV-DNA positive rate were 50.66% (77/152) and 36.18% (55/152) in serum and breast milk, respectively. When HBeAg was positive, HBV-DNA positive rate were 95.38% (62/65) and 76.92% (50/65) in serum and breast milk; however when HBeAg was negative, HBV-DNA positive rate were 17.24% (15/87) and 5.75% (5/87) in serum and breast milk. When the concentration of HBV-DNA was 3-4 lg U/ml in serum, HBV-DNA positive rate was 20.00% (5/25) in breast milk; However, when the concentration of HBV-DNA was higher than 5 lg U/ml in serum, HBV-DNA positive rate was 96.15% (50/52) in breast milk.</p><p><b>CONCLUSION</b>The HBV-DNA level in breast milk in postpartum women infected with HBV increased with the HBV-DNA levels in serum. Breastfeeding should be avoided when the concentration of HBV-DNA is higher than 1.0 × 10(3) U/ml in milk.</p>

Dynamic measurements of serum inhibin B and estradiol: a predictive evaluation of ovarian response to gonadotrophin stimulation in the early stage of IVF treatment / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>We dynamically measured serum inhibin B and estradiol in the early stage of hormonal stimulation to predict the ovarian response in in vitro fertilization (IVF) treatment.</p><p><b>METHODS</b>A total of 57 patients (<40 years of age) who underwent the first cycle of long protocol IVF or introcytoplasmic sperm injection (ICSI) treatment were included. Serum inhibin B, estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured four times: (1) on Day 3 of the menstrual cycle (basal); (2) on the day before the first administration of gonadotrophin (Gn) (Day 0); (3) on Day 1 of Gn therapy; and (4) on Day 5 of Gn therapy. Comparisons of these measurements with ovarian responses and pregnancy outcomes were made and analyzed statistically.</p><p><b>RESULTS</b>(1) On Day 1 and Day 5 of recombinant FSH (rFSH) stimulation, ovarian response, i.e., numbers of follicles, oocytes, fertilized oocytes, and embryos, had a positive correlation (r(s)=0.46~0.61, P=0.000) with raised inhibin B and estradiol concentrations, but a negative correlation (r(s)=-0.67~-0.38, P=0.000 or P<0.01) with total rFSH dose and total days of rFSH stimulation. (2) No significant variation (P>0.05) between the pregnant and non-pregnant groups on the basis of mean age or on all hormone concentrations at four times of the IVF cycle was observed. However, all the seven patients aged >35 years did not reach pregnancy.</p><p><b>CONCLUSIONS</b>(1) Serum inhibin B and estradiol concentrations obtained shortly after Gn therapy may offer an accurate and early prediction of ovarian response; (2) Low levels of serum inhibin B and estradiol obtained shortly after Gn stimulation indicate the need for a longer period of Gn treatment and a higher daily dosage; (3) No obvious pregnancy difference among patients of age <35 years was found; however, IVF pregnancy outcome is significantly lower in women of age >35 years.</p>

Adriamycin induces H2AX phosphorylation in human spermatozoa / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate whether adriamycin induces DNA damage and the formation of gammaH2AX (the phosphorylated form of histone H2AX) foci in mature spermatozoa.</p><p><b>METHODS</b>Human spermatozoa were treated with adriamycin at different concentrations. gammaH2AX was analyzed by immunofluorescent staining and flow cytometry and double-strand breaks (DSB) were detected by the comet assay.</p><p><b>RESULTS</b>The neutral comet assay revealed that the treatment with adriamycin at 2 microg/mL for different times (0.5, 2, 8 and 24 h), or for 8 h at different concentrations (0.4, 2 and 10 microg/mL), induced significant DSB in spermatozoa. Immunofluorent staining and flow cytometry showed that the expression of gH2AX was increased in a dose-dependent and time-dependant manner after the treatment of adriamycin. Adriamycin also induced the concurrent appearance of DNA maintenance/repair proteins RAD50 and 53BP1 with gammaH2AX in spermatozoa. Wortmannin, an inhibitor of the phosphatidylinositol 3-kinase (PI3K) family, abolished the co-appearance of these two proteins with gammaH2AX.</p><p><b>CONCLUSION</b>Human mature spermatozoa have the same response to DSB-induced H2AX phosphorylation and subsequent recruitment of DNA maintenance/repair proteins as somatic cells.</p>

Progress in the derivation, culture of human embryonic stem cells / 浙江大学学报·医学版

Human embryonic stem (hES) cells are considered to be a valuable resource for research in regenerative medicine, drug screening, and developmental studies. However, hES cells are usually established and maintained on mouse embryonic fibroblast feeder layers, and the risk of animal origin contamination from feeder layer generally excludes the clinical use of these hES cells. The main emphasis over the last several years has been in finding defined serum-and feeder layer-free system for derivation and culture of hES cells to enable the clinical use of hES cell for cell transplantation.

Accuracy of a combined score of zygote and embryo morphology for selecting the best embryos for IVF / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>To evaluate the accuracy of a scoring system combining zygote and embryo morphology in predicting the outcome of in vitro fertilization (IVF) treatment.</p><p><b>METHODS</b>In a study group, 117 consecutive IVF or intracytoplasmic sperm injection (ICSI) cycles with embryo transfer were carried out and 312 embryos were scored using a combined scoring system (CSS) of zygote and embryo morphology before transplantation. In a control group, a total of 420 IVF or ICSI cycles were carried out and 1176 embryos were scored using a cumulative embryo score (CES). The effects of the combined scoring system on the embryo implantation rate and pregnancy rate per cycle were analyzed.</p><p><b>RESULTS</b>Using the combined scoring system, the embryo implantation rate (27.6%) and the clinical pregnancy rate (48.7%) were significantly higher than those in the control group (20.8% and 38.6%, respectively). Also, the implantation rate of embryos scoring>or=70 (38.5%: 82 sacs/213 embryos) was significantly higher (P<0.001) than that of embryos scoring<70 (4%: 4 sacs/99 embryos). The pregnancy rate of patients with embryos scoring>or=70 using the combined scoring system (66.7%) was significantly higher (P<0.001) than that of patients with embryos scoring>or=20 using the cumulative embryo score (59.0%).</p><p><b>CONCLUSION</b>The results suggest that selecting embryos with a high score (>or=70) using the combined scoring system could increase the implantation rate and pregnancy rate, and that using a scoring system combining assessments of human zygotes and pre-implantation embryos might predict IVF outcomes more accurately than using a cumulative embryo score.</p>

Preimplantation genetic diagnosis for Down syndrome pregnancy / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>To evaluate the effect of preimplantation genetic diagnosis (PGD) conducted for women who had Down syndrome pregnancy previously.</p><p><b>METHODS</b>Trisomy 21 was diagnosed by using fluorescence in site hybridization (FISH) before embryo transfer in two women who had Down syndrome pregnancies. Each received one or two PGD cycles respectively.</p><p><b>RESULTS</b>Case 1: one PGD cycle was conducted, two oocytes were fertilized and biopsied. One embryo is of trisomy 21 and the other of monosomy 21. No embryo was transferred. Case 2: two PGD cycles were conducted, in total, sixteen oocytes were fertilized and biopsied. Four embryos were tested to be normal, six of trisomy 21, and one of monosomy 21. Five had no signal. Four normal embryos were transferred but no pregnancy resulted.</p><p><b>CONCLUSION</b>For couples who had pregnancies with Down syndrome previously, PGD can be considered, and has been shown to be an effective strategy.</p>

In vitro maturation--n vitro fertilization--embryo transfer--frozen-thawed of human oocytes / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the influence of different cycles, ovarian follicle size and IVM culture media on the number of retrieved immature oocytes, maturation rate, fertilization rate, embryo quality and implantation rate, pregnancy rate, delivery rate, survival and development of frozen-thawed embryos from IVM.</p><p><b>METHODS</b>The oocytes were obtained by follicular aspiration from 19 women undergoing oocyte retrieval for in vitro maturation due to the possible risk of ovarian hyperstimulation in IVF-ET program. One patient was in natural cycle, four patients were in ovulation induction cycles with gonadotropine and fourteen patients is controlled ovarian stimulated cycles. All the oocytes retrieved from follicles with 10.0 - 13.5 mm in maximumdiameter were allowed to culture in medium M-199 (TCM 199) or HTF supplemented with other substance.</p><p><b>RESULT</b>When there were nonuniform diameters of follicles and the diameter of largest oocyte exceeded 12 mm, the retrieval rate of oocytes, fertilization rate, and the number of high-quality embryos decreased. The high-quality embryos formation rate was higher for the oocytes cultured in TCM 199 medium than in HTF medium (P<0.01). After being frozen-thawed, the IVM embryos could achieve the same outcome when compared with the conventional IVF treatment. In addition, the offspring were healthy.</p><p><b>CONCLUSION</b>When the nonuniform diameters of follicles and the diameter of largest oocyte exceeds 12 mm,the retrieval rate of oocytes, fertilization rate, and the number of high-quality embryos decreased. TCM199-based medium is better to improve the developmental potential and implantation rate of embryos derived from in vitro matured oocytes. After being frozen-thawed, the IVM embryos could achieve the same outcome when compared with the conventional IVF treatment. In addition, the offspring are healthy.</p>

Expression of aquaporin 9 in granulosa cells of patients with polycystic ovary syndrome in IVF-cycles / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate aquaporin 9 (AQP9) mRNA and protein expression in antrum follicle and luteinizing granulosa cells of polycystic ovarian syndrome (PCOS) ovary, and its relation to follicular fluid steroids hormone levels during IVF cycles.</p><p><b>METHODS</b>AQP9 mRNA expression on luteinizing granulosa cells in IVF cycles was detected by RT-PCR. AQP9 protein expression in antrum follicles of PCOS ovary and luteinizing granulosa cells was measured by immunohistochemistry. The concentrations of estradiol (E2), progesterone (P) and testerone (T) in follicular fluid were measured by radioimmunoassay (RIA).</p><p><b>RESULT</b>The expression of AQP9 mRNA in luteinizing granulosa cells during IVF cycles was positive by RT-PCR. No significant differences in AQP9 mRNA levels in granulosa cells between PCOS and control group were found during IVF cycles. The expression level of AQP9 mRNA in large follicles was higher than that in small follicles, but not significantly. The immunoreactivity for AQP9 was localized in membrane and cytoplast of granulosa cells in antrum follicles from PCOS ovary and luteinizing granulosa cells during IVF cycles. Multiple regression analysis showed that AQP9 mRNA levels on granulosa cells were not correlated with E2, P and T levels in follicular fluid during IVF cycles.</p><p><b>CONCLUSION</b>AQP9 may play an important role in the follicle development and antrum formation through water transport and AQP9 may be involved in the mechanism of follicle development in PCOS.</p>

Genetic imprinting and embryonic development / 浙江大学学报·医学版

Erasure, establishment and maintenance of genetic imprinting are indispensable for normal embryonic development. All these processes depend on accurate expression and intimate cooperation of kinds of DNA methyltransferases. Many genetic syndromes and embryo developmental anomalies are caused by abnormality of genetic imprinting. Genetic imprinting is important for the nucleus totipotential of primordial germ cell, maturation of gamete,growth and development of embryo, structure and function of placenta as well as postnatal growth and development of individuals.

Research on minimal to mild endometriosis associated infertility / 浙江大学学报·医学版

Endometriosis is a common disease of reproductive age women and infertility is one of its clinical manifestations. Infertility of patients with severe endometriosis may be attributed to the anatomy alteration of pelvis.However, the infertility of patients with minimal to mild endometriosis whose pelvic anatomy remains intact is still hard to explain. It is considered that the infertility of patients with ninimal to mild endometriosis is associated with the alteration of the pelvic microenvironment. Several kinds of cytokines and proteins are involved in this process. They may disturb steps necessary to achieve successful pregnancy, such as ovulation,gamete transport, fertilization, embryo transport and implantation. Any disturbance to one of the steps mentioned above may lead to pregnant loss.

Progress in research on oocytes parthenogenetic activation / 浙江大学学报·医学版

Parthenogenetic activation is a procedure that an oocyte at meiosis II stage is activated into mitosis by some chemical or physical stimulation other than a sperm and the embryo is formed in the absence of any contribution from a male gamete. The activation of oocyte is the result of calcium ion oscillations and deactivation of some cytokines such as maturation promoting factor, mitogen-activated protein kinase and cytostatic factor. Parthenogenetic activation is artificially induced by various kinds of physical and/or chemical methods. The main activation method of human oocyte is chemical methods. The rates of activation and cleavage depend on the age, origin,and culture conditions of the oocyte.

Increased nitric oxide levels in peritoneal fluids of minor-endometriosis patients and its relation to IVF-ET outcomes / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the role of nitric oxide (NO) in the pathogenesis of early endometriosis-associated infertility.</p><p><b>METHODS</b>The volume of peritoneal fluids was recorded and the concentration of NO in peritoneal fluid and serum was measured with a fluorescence method using 4, 5-diaminofluorescein (DAF-2) as an indicator, in 60 patients with early endometriosis-associated infertility ( endometriosis group), 60 patients with tubal infertility (tubal infertility group) and 20 patients without infertility (control group). The IVF-ET outcomes between patients with endometriosis and tubal infertility were compared.</p><p><b>RESULT</b>The volume of peritoneal fluids from endometriosis group patients increased significantly compared with that in tubal infertility group patients and control groups. The concentration of NO in peritoneal fluid of the control group,the tubal infertility group and the endometriosis group was 9.98, 13.76 and 20.72, respectively (P<0.017). Furthermore the concentration of NO in serum of the patients of control group,tubal infertility group and endometriosis group was 12.25, 13.00, 13.60, respectively; there were no significant differences among these three groups. There were no significant differences in implantation rate, pregnancy rate and abortion rate of IVF-ET between endometriosis group patients and tubal infertility group patients. However, the fertilization rate was significantly lower in endometriosis group patients than that in tubal infertility group patients.</p><p><b>CONCLUSION</b>Changes of nitric oxide in peritoneal fluids may play an important role in the pathogenesis of early endometriosis-associated infertility and IVF-ET may serve as an alternative method for this type of infertility.</p>

Cathepsin D expression in ovaries from polycystic ovarian syndrome patients / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the expression of cathepsin D in ovary of patients with polycystic ovarian syndrome (PCOS).</p><p><b>METHODS</b>Western blot was performed to detect the expression of cathepsin D and immunohistochemistry was used to detect the protein distribution in ovarian tissue.</p><p><b>RESULT</b>Semi-quantity values of cathepsin D expression in PCOS and control group were 2.06 +/- 0.39 and 4.76 +/- 1.43 (P<0.05), respectively. Immunostaining for cathepsin D was obvious in both follicles and stromal cells, and the strongest immunostaining was seen in granulosa cells of follicles. Immunochemical study showed the protein was mainly located on the cytoplasm and cell membrane.</p><p><b>CONCLUSION</b>Cathepsin D expression is down-regulated in ovaries of PCOS patients, which may provide a clue for the abnormality of follicle development in PCOS.</p>

Expression profile of aquaporin 1 in patients with menorrhagia / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the expression of aquaporin 1 (AQP1) in endometrium of patients with menorrhagia.</p><p><b>METHODS</b>RT-PCR and immunohistochemistry were carried out in twenty women with normal menstrual cycle to confirm the expression of AQP1 in endometrium and locate it. Then 51 women with menorrhagia and 40 women with normal menstrual cycle were included in the study. RT-PCR and immunohistochemistry were used to examine the expression of AQP1.</p><p><b>RESULT</b>AQP1 mRNA was expressed in the human endometrium throughout menstruation cycle, which was mainly located in the endothelia of the capillaries and small blood vessels. Quantification of the immunostaining revealed higher density during secretary phase than that in proliferative phase (P<0.01). The staining intensity and density of AQP1-positive microvessel decreased significantly in simple hyperplasia group (P<0.01) and then gradually increased in complex hyperplasia and atypical hyperplasia groups (P<0.001).</p><p><b>CONCLUSION</b>Decreased expression of AQP1 may lead to disturbed endometrial vascular remodeling and may be involved in the occurrence of menorrhagia.</p>