Publications by authors named "Raymond H W Li"

25 Publications

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Effect of serum vitamin D level before ovarian stimulation on the cumulative live birth rate of women undergoing in vitro fertilization: a retrospective analysis.

Endocr Connect 2022 Jan 1. Epub 2022 Jan 1.

E Ng, Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong.

Objective: Vitamin D receptors are present in the female reproductive tract. Studies on the association between serum vitamin D level and pregnancy rate of in vitro fertilization (IVF) showed inconsistent results and focused on a single fresh or frozen embryo transfer cycle. The objective of our study was to evaluate if serum vitamin D level before ovarian stimulation was associated with the cumulative live birth rate (CLBR) of the first IVF cycle.

Design: Retrospective cohort study.

Methods: Women who underwent the first IVF cycle from 2012 to 2016 at a university-affiliated reproductive medicine center were included. Archived serum samples taken before ovarian stimulation were analyzed for 25(OH)D levels using liquid chromatography-mass spectrometry.

Results: 1,113 had pregnancy outcome from the completed IVF cycle. The median age (25th-75th percentile) of the women was 36 (34-38) years and serum 25(OH)D level was 53.4 (41.9-66.6)nmol/L. The prevalence of vitamin D deficiency (less than 50nmol/L) was 42.2%. The CLBR in the vitamin D deficient group was significantly lower compared to the non-deficient group (43.9%,208/474 vs 50.9%,325/639, p=0.021, unadjusted), and after controlling for women's age, body mass index, antral follicle count, type and duration of infertility. There were no differences in the clinical/ongoing pregnancy rate, live birth rate and miscarriage rate in the fresh cycle between the vitamin D deficient and non-deficient groups.

Conclusions: Vitamin D deficiency was prevalent in infertile women in subtropical Hong Kong. The CLBR of the first IVF cycle in the vitamin D deficient group was significantly lower compared to the non-deficient group.
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http://dx.doi.org/10.1530/EC-21-0444DOI Listing
January 2022

Comparison of the number of oocytes obtained after ovarian stimulation between Chinese and Caucasian women undergoing in vitro fertilization using a standardized stimulation regime.

J Ovarian Res 2021 Dec 11;14(1):175. Epub 2021 Dec 11.

Department of Obstetrics and Gynecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.

Background: In vitro fertilization (IVF) is a well-established method to treat various causes of infertility. Some previous retrospective studies suggested a lower ovarian response in Asian women compared to Caucasian women. However, the ovarian stimulation regimens were not standardized, potentially confounding the findings. The objective of this study is to compare the number of oocytes obtained after ovarian stimulation between Chinese and Caucasian women undergoing IVF using a standardized stimulation regimen.

Methods: This is a prospective cohort study conducted in two tertiary IVF units in Hong Kong, China and Sydney, Australia from October 2016 to August 2019. A total of 192 women aged 18-42 years with a body weight > 60 kg underwent IVF with a standard ovarian stimulation regimen of 150 micrograms corifollitropin alfa (Elonva®) followed by 200 IU follitropin beta (Puregon®) per day. The number of oocytes retrieved in Chinese women treated in the Hong Kong center was compared to that of Caucasian women treated in the Australian center.

Results: Serum AMH levels were similar between the two groups. Although women in the Chinese cohort were older and had a higher body mass index (BMI), longer duration of infertility and lower antral follicle count (AFC) than those in the Caucasian cohort in this study, no differences in the number of oocytes retrieved [11 (8-17) vs. 11 (6-17), p=0.29], total dosage and duration of stimulation and number of follicles aspirated were noted between the two ethnic cohorts. The peak estradiol level was greater in Chinese women than in Caucasian women. After controlling for age, BMI and AFC, ethnicity was a significant independent determinant of the number of oocytes obtained.

Conclusions: Chinese women had a higher number of oocytes after ovarian stimulation using a standardized stimulation regimen compared with Caucasian women undergoing IVF after controlling for age, BMI, AFC and AMH despite presenting later after a longer duration of infertility.

Trial Registration Number: NCT02748278.
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http://dx.doi.org/10.1186/s13048-021-00928-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666011PMC
December 2021

Simulating nature in sperm selection for assisted reproduction.

Nat Rev Urol 2022 01 5;19(1):16-36. Epub 2021 Nov 5.

Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.

Sperm selection in the female reproductive tract (FRT) is sophisticated. Only about 1,000 sperm out of millions in an ejaculate reach the fallopian tube and thus have a chance of fertilizing an oocyte. In assisted reproduction techniques, sperm are usually selected using their density or motility, characteristics that do not reflect their fertilization competence and, therefore, might result in failure to fertilize the oocyte. Although sperm processing in in vitro fertilization (IVF) and intrauterine insemination (IUI) bypasses many of the selection processes in the FRT, selection by the cumulus mass and the zona pellucida remain intact. By contrast, the direct injection of a sperm into an oocyte in intracytoplasmic sperm injection (ICSI) bypasses all natural selection barriers and, therefore, increases the risk of transferring paternal defects such as fragmented DNA and genomic abnormalities in sperm to the resulting child. Research into surrogate markers of fertilization potential and into simulating the natural sperm selection processes has progressed. However, methods of sperm isolation - such as hyaluronic acid-based selection and microfluidic isolation based on sperm tactic responses - use only one or two parameters and are not comparable with the multistep sperm selection processes naturally occurring within the FRT. Fertilization-competent sperm require a panel of molecules, including zona pellucida-binding proteins and ion channel proteins, that enable them to progress through the FRT to achieve fertilization. The optimal artificial sperm selection method will, therefore, probably need to use a multiparameter tool that incorporates the molecular signature of sperm with high fertilization potential, and their responses to external cues, within a microfluidic system that can replicate the physiological processes of the FRT in vitro.
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http://dx.doi.org/10.1038/s41585-021-00530-9DOI Listing
January 2022

TLR5 Supports Development of Placental Labyrinthine Zone in Mice.

Front Cell Dev Biol 2021 28;9:711253. Epub 2021 Jul 28.

State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Toll plays an important role in innate immunity and embryonic development in lower-ranked animals, but in mammals, the homolog toll-like receptors (TLR) are reported to facilitate postnatal development of immunity only. Here, we discovered a role of TLR5 in placental development. was highly transcribed during the placenta-forming and functional phases. TLR5 deletion led to a smaller placental labyrinthine zone and lower embryo weight, and the smaller size of embryo was overcorrected, resulting in a higher postnatal body weight. Examination of TLR5-deficient conceptus revealed a decrease in nuclear cAMP-response element-binding protein (CREB), mechanistic target of rapamycin (mTOR) and insulin growth factor-1 receptor (IGF1R) abundances in the placenta-forming phase. Non-flagellin-based TLR5 ligands were detected in serum of female mice and the overexpression of TLR5 alone was sufficient to induce CREB nuclear translocation and mTOR transcriptional activation in trophoblasts. Taken together, we uncovered the participation of TLR5 in the early placental formation in mice, unveiling a role of TLR in embryonic development in higher-ranked animals.
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http://dx.doi.org/10.3389/fcell.2021.711253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356041PMC
July 2021

A retrospective analysis of artificial oocyte activation in patients with low or no fertilisation in intracytoplasmic sperm injection cycles.

J Obstet Gynaecol 2021 Aug 12:1-6. Epub 2021 Aug 12.

Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.

Intracytoplasmic sperm injection (ICSI) is commonly used to treat severe male factor infertility in assisted reproduction. A small percentage of patients face suboptimal fertilisation rate or even fertilisation failure despite having ICSI. Artificial oocyte activation (AOA) has been proposed as a suitable method to overcome their problem. This is a retrospective cohort analysis of ICSI cycles undergoing AOA. Injected metaphase II oocytes were exposed to either calcium ionophore (A23187) after ICSI or injection of calcium chloride during ICSI followed by incubation with A23187 after ICSI. The previous ICSI cycles of the patients formed the historical control group. Thirty-four AOA cycles were analysed. The normal fertilisation rate (52.1%) was significantly improved in the AOA group. The percentage of failed fertilisation cycles (11.8%) were significantly reduced in the AOA group. The cumulative clinical pregnancy rate (47.1%) and live birth rate (29.4%) were significantly increased when compared to the previous cycles. Subgroup analysis revealed that the performance of the A23187 only protocol and the concomitant injection of calcium chloride protocol were comparable in terms of laboratory parameters and pregnancy outcomes. AOA is an effective method to improve the fertilisation rate and pregnancy outcome of infertile couples with previous fertilisation problem after ICSI.IMPACT STATEMENT A failed and low fertilisation rate after ICSI is not uncommon in assisted reproduction. AOA is normally used to improve fertilisation but there are discrepancies in the efficacy of the treatment. AOA improves the fertilisation rate and pregnancy outcomes of couples with suboptimal fertilisation rate and fertilisation failure in previous ICSI cycles. The efficacies of two AOA protocols were comparable. The A23187 only protocol was recommended because of its simplicity. AOA should be considered as a routine procedure for infertile couples with compromised fertilisation rates in previous ICSI cycles.
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http://dx.doi.org/10.1080/01443615.2021.1922878DOI Listing
August 2021

Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles.

Cells 2021 06 13;10(6). Epub 2021 Jun 13.

Shenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong-Shenzhen Hospital, Haiyuan First Road 1, Shenzhen 518053, China.

The mammalian ovary has two main functions-producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation.
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http://dx.doi.org/10.3390/cells10061491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231864PMC
June 2021

The male germline-specific protein MAPS is indispensable for pachynema progression and fertility.

Proc Natl Acad Sci U S A 2021 02;118(8)

Shenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong-Shenzhen Hospital, 518053 Shenzhen, Guangdong, China;

Meiosis is a specialized cell division that creates haploid germ cells from diploid progenitors. Through differential RNA expression analyses, we previously identified a number of mouse genes that were dramatically elevated in spermatocytes, relative to their very low expression in spermatogonia and somatic organs. Here, we investigated in detail one of these genes, and independently conclude that it encodes a male germline-specific protein, in agreement with a recent report. We demonstrated that it is essential for pachynema progression in spermatocytes and named it male pachynema-specific (MAPS) protein. Mice lacking ( ) suffered from pachytene arrest and spermatocyte death, leading to male infertility, whereas female fertility was not affected. Interestingly, pubertal spermatocytes were arrested at early pachytene stage, accompanied by defects in DNA double-strand break (DSB) repair, crossover formation, and XY body formation. In contrast, adult spermatocytes only exhibited partially defective crossover but nonetheless were delayed or failed in progression from early to mid- and late pachytene stage, resulting in cell death. Furthermore, we report a significant transcriptional dysregulation in autosomes and XY chromosomes in both pubertal and adult pachytene spermatocytes, including failed meiotic sex chromosome inactivation (MSCI). Further experiments revealed that MAPS overexpression in vitro dramatically decreased the ubiquitination levels of cellular proteins. Conversely, in pachytene cells, protein ubiquitination was dramatically increased, likely contributing to the large-scale disruption in gene expression in pachytene cells. Thus, MAPS is a protein essential for pachynema progression in male mice, possibly in mammals in general.
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http://dx.doi.org/10.1073/pnas.2025421118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923350PMC
February 2021

The novel male meiosis recombination regulator coordinates the progression of meiosis prophase I.

J Genet Genomics 2020 08 26;47(8):451-465. Epub 2020 Aug 26.

Shenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong - Shenzhen Hospital, Shenzhen, 518000, China; Department of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China. Electronic address:

Meiosis is a specialized cell division for producing haploid gametes in sexually reproducing organisms. In this study, we have independently identified a novel meiosis protein male meiosis recombination regulator (MAMERR)/4930432K21Rik and showed that it is indispensable for meiosis prophase I progression in male mice. Using super-resolution structured illumination microscopy, we found that MAMERR functions at the same double-strand breaks as the replication protein A and meiosis-specific with OB domains/spermatogenesis associated 22 complex. We generated a Mamerr-deficient mouse model by deleting exons 3-6 and found that most of Mamerr spermatocytes were arrested at pachynema and failed to progress to diplonema, although they exhibited almost intact synapsis and progression to the pachytene stage along with XY body formation. Further mechanistic studies revealed that the recruitment of DMC1/RAD51 and heat shock factor 2-binding protein in Mamerr spermatocytes was only mildly impaired with a partial reduction in double-strand break repair, whereas a substantial reduction in ubiquitination on the autosomal axes and on the XY body appeared as a major phenotype in Mamerr spermatocytes. We propose that MAMERR may participate in meiotic prophase I progression by regulating the ubiquitination of key meiotic proteins on autosomes and XY chromosomes, and in the absence of MAMERR, the repressed ubiquitination of key meiotic proteins leads to pachytene arrest and cell death.
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http://dx.doi.org/10.1016/j.jgg.2020.08.001DOI Listing
August 2020

Adrenomedullin insufficiency alters macrophage activities in fallopian tube: a pathophysiologic explanation of tubal ectopic pregnancy.

Mucosal Immunol 2020 09 13;13(5):743-752. Epub 2020 Mar 13.

Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 1, Haiyuan 1st Road, Futian District, Shenzhen, Guangdong, China.

Ectopic pregnancy is the major cause of maternal morbidity and mortality in the first trimester of pregnancy. Tubal ectopic pregnancy (TEP) accounts for nearly 98% of all ectopic pregnancies. TEP is usually associated with salpingitis but the underlying mechanism in salpingitis leading to TEP remains unclear. Adrenomedullin (ADM) is a peptide hormone abundantly expressed in the fallopian tube with potent anti-inflammatory activities. Its expression peaks at the early luteal phase when the developing embryo is being transported through the fallopian tube. In the present study, we demonstrated reduced expression of ADM in fallopian tubes of patients with salpingitis and TEP. Using macrophages isolated from the fallopian tubes of these women, our data revealed that the salpingistis-associated ADM reduction contributed to aggravated pro-inflammatory responses of the tubal macrophages resulting in production of pro-inflammatory and pro-implantation cytokines IL-6 and IL-8. These cytokines activated the expression of implantation-associated molecules and Wnt signaling pathway predisposing the tubal epithelium to an adhesive and receptive state for embryo implantation. In conclusion, this study provided evidence for the role of ADM in the pathogenesis of TEP through regulating the functions of tubal macrophages.
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http://dx.doi.org/10.1038/s41385-020-0278-6DOI Listing
September 2020

Myometrial Cells Stimulate Self-Renewal of Endometrial Mesenchymal Stem-Like Cells Through WNT5A/β-Catenin Signaling.

Stem Cells 2019 11 8;37(11):1455-1466. Epub 2019 Oct 8.

Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China.

Human endometrium undergoes cycles of proliferation and differentiation throughout the reproductive years of women. The endometrial stem/progenitor cells contribute to this regenerative process. They lie in the basalis layer of the endometrium next to the myometrium. We hypothesized that human myometrial cells provide niche signals regulating the activities of endometrial mesenchymal stem-like cells (eMSCs). In vitro coculture of myometrial cells enhanced the colony-forming and self-renewal ability of eMSCs. The cocultured eMSCs retained their multipotent characteristic and exhibited a greater total cell output when compared with medium alone culture. The expression of active β-catenin in eMSCs increased significantly after coculture with myometrial cells, suggesting activation of WNT/β-catenin signaling. Secretory factors in spent medium from myometrial cell culture produced the same stimulatory effects on eMSCs. The involvement of WNT/β-catenin signaling in self-renewal of eMSCs was confirmed with the use of WNT activator (Wnt3A conditioned medium) and WNT inhibitors (XAV939 and inhibitor of Wnt Production-2 [IWP-2]). The myometrial cells expressed more WNT5A than other WNT ligands. Recombinant WNT5A stimulated whereas anti-WNT5A antibody suppressed the colony formation, self-renewal, and T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activities of eMSCs. Moreover, eMSCs expressed FZD4 and LRP5. WNT5A is known to activate the canonical WNT signaling in the presence of these receptor components. WNT antagonist, DKK1, binds to LRP5/6. Consistently, DKK1 treatment nullified the stimulatory effect of myometrial cell coculture. In conclusion, our findings show that the myometrial cells are niche components of eMSCs, modulating the self-renewal activity of eMSCs by WNT5A-dependent activation of WNT/β-catenin signaling. Stem Cells 2019;37:1455-1466.
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http://dx.doi.org/10.1002/stem.3070DOI Listing
November 2019

Measuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader.

Nat Commun 2019 02 20;10(1):852. Epub 2019 Feb 20.

School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Normal reproductive functioning is critically dependent on pulsatile secretion of luteinising hormone (LH). Assessment of LH pulsatility is important for the clinical diagnosis of reproductive disorders, but current methods are hampered by frequent blood sampling coupled to expensive serial immunochemical analysis. Here, we report the development and application of a Robotic APTamer-enabled Electrochemical Reader (RAPTER) electrochemical analysis system to determine LH pulsatility. Through selective evolution of ligands by exponential enrichment (SELEX), we identify DNA aptamers that bind specifically to LH and not to related hormones. The aptamers are integrated into electrochemical aptamer-based (E-AB) sensors on a robotic platform. E-AB enables rapid, sensitive and repeatable determination of LH concentration profiles. Bayesian Spectrum Analysis is applied to determine LH pulsatility in three distinct patient cohorts. This technology has the potential to transform the clinical care of patients with reproductive disorders and could be developed to allow real-time in vivo hormone monitoring.
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http://dx.doi.org/10.1038/s41467-019-08799-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382769PMC
February 2019

Knowledge, attitude and ethical consideration of Chinese couples requesting preimplantation genetic testing in Hong Kong.

J Obstet Gynaecol Res 2019 Jun 11;45(6):1096-1105. Epub 2019 Feb 11.

Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.

Aim: Increasing preimplantation genetic testing (PGT) cycles are being performed in Hong Kong. This study aims to evaluate the knowledge, attitude and ethical consideration of Chinese couples toward PGT.

Methods: Couples requesting PGT between June 2013 and March 2014 were invited to complete a questionnaire.

Results: Total 49 couples (49 women, 47 men) completed the questionnaires. Eighteen couples (37%) were waiting for PGT (pre-PGT group), 15 couples (31%) were undergoing PGT (PGT group) and 16 couples (32%) had completed at least one PGT cycle (post-PGT group). Only 53% of the couples could tell the recurrent risk, and 31% (with monogenic disorders) could tell the mode of inheritance of their condition. The acceptability of PGT (>80%) and attitude toward the embryo fate (58-78%) were good. The post-PGT group had more concern than the PGT and pre-PGT groups on the prenatal diagnostic testing (**P = 0.007). 12.5% of the couples worried about the transfer of healthy embryos with carrier state and they all had monogenic disorders. If the prenatal testing confirmed an affected fetus, a higher percentage (32%) in the Post-PGT group disagreed to terminate the pregnancy in contrast to a much lower 6% in the pre-PGT group (**P = 0.02). Three-quarter of the couples opted to tell their child about their conception through PGT.

Conclusion: Chinese couples in Hong Kong had an overall good acceptability and positive attitude toward PGT. We appreciate the difficulties the couples have gone through PGT. A checklist on what to cover pre-during-post-PGT in the counseling process is needed.
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http://dx.doi.org/10.1111/jog.13940DOI Listing
June 2019

Alteration of the immune cell profiles in the pathophysiology of tubal ectopic pregnancy.

Am J Reprod Immunol 2019 04 18;81(4):e13093. Epub 2019 Feb 18.

Department of Obstetrics & Gynaecology, The University of Hong Kong, Hong Kong, SAR, China.

Tubal ectopic pregnancy (TEP) refers to implantation of conceptus in the fallopian tube. It makes up over 98% of ectopic pregnancy (EP), which is the leading cause of maternal morbidity and mortality in the first trimester of pregnancy. Immune cells at the maternal-fetal interface play important roles in the process of embryo implantation, stroma decidualization, and early placental development. Alterations in the composition, phenotype, and activity of the immune cells in the fallopian tubes contribute toward the onset of TEP. In this review, we compare the leukocytic proportions in decidua of normal pregnancy, and in decidua and fallopian tubes of TEP. The possible functions of these immune cells in the pathophysiology of TEP are also discussed.
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http://dx.doi.org/10.1111/aji.13093DOI Listing
April 2019

Glycodelin-A stimulates the conversion of human peripheral blood CD16-CD56bright NK cell to a decidual NK cell-like phenotype.

Hum Reprod 2019 04;34(4):689-701

Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, 7/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong.

Study Question: Does glycodelin-A (GdA) induce conversion of human peripheral blood CD16-CD56bright natural killer (NK) cells to decidual NK (dNK) cells to facilitate placentation?

Summary Answer: GdA binds to blood CD16-CD56bright NK cells via its sialylated glycans and converts them to a dNK-like cells, which in turn regulate endothelial cell angiogenesis and trophoblast invasion via vascular endothelial growth factor (VEGF) and insulin-like growth factor-binding protein 1 (IGFBP-1) secretion, respectively.

What Is Known Already: dNK cells are the most abundant leucocyte population in the decidua. These cells express CD16-CD56bright phenotype. Peripheral blood CD16-CD56bright NK cells and hematopoietic precursors have been suggested to be capable of differentiating towards dNK cells upon exposure to the decidual microenvironment. These cells regulate trophoblast invasion during spiral arteries remodelling and mediate homoeostasis and functions of the endothelial cells. GdA is an abundant glycoprotein in the human decidua with peak expression between the 6th and 12th week of gestation, suggesting a role in early pregnancy. Indeed, GdA interacts with and modulates functions and differentiation of trophoblast and immune cells in the human feto-maternal interface. Aberrant GdA expression during pregnancy is associated with unexplained infertility, pregnancy loss and pre-eclampsia.

Study Design, Size, Duration: CD16+CD56dim, CD16-CD56bright and dNK cells were isolated from human peripheral blood and decidua tissue, respectively, by immuno-magnetic beads or fluorescence-activated cell sorting. Human extravillous trophoblasts were isolated from first trimester placental tissue after termination of pregnancy. Biological activities of the cells were studied after treatment with GdA at a physiological dose of 5 μg/mL. GdA was purified from human amniotic fluid by immuno-affinity chromatography.

Participants/materials, Setting, Methods: Expression of VEGF, CD9, CD49a, CD151 and CD158a in the cells were determined by flow cytometry. Angiogenic proteins in the spent media of NK cells were determined by cytokine array and ELISA. Blocking antibodies were used to study the functions of the identified angiogenic proteins. Endothelial cell angiogenesis was determined by tube formation and trans-well migration assays. Cell invasion and migration were determined by trans-well invasion/migration assay. Binding of normal and de-sialylated GdA, and expression of L-selectin and siglec-7 on the NK cells were analysed by flow cytometry. The association between GdA and L-selectin on NK cells was confirmed by immunoprecipitation. Extracellular signal-regulated protein kinases (ERK) activation was determined by Western blotting and functional assays.

Main Results And The Role Of Chance: GdA treatment enhanced the expression of dNK cell markers CD9 and CD49a and the production of the functional dNK secretory product VEGF in the peripheral blood CD16-CD56bright NK cells. The spent media of GdA-treated CD16-CD56bright NK cells promoted tube formation of human umbilical vein endothelial cells and invasiveness of trophoblasts. These stimulatory effects were mediated by the stimulatory activities of GdA on an ERK-activation dependent production of VEGF and IGFBP-1 by the NK cells. GdA had a stronger binding affinity to the CD16-CD56bright NK cells as compared to the CD16+CD56dim NK cells. This GdA-NK cell interaction was reduced by de-sialylation. GdA interacted with L-selectin, expressed only in the CD16-CD56bright NK cells, but not in the CD16+CD56dim NK cells. Anti-L-selectin functional blocking antibody suppressed the binding and biological activities of GdA on the NK cells.

Large Scale Data: N/A.

Limitations, Reasons For Caution: Some of the above findings are based on a small sample size of peripheral blood CD16-CD56bright NK cells. These results need to be confirmed with human primary dNK cells.

Wider Implications Of The Findings: This is the first study on the biological role of GdA on conversion of CD16-CD56bright NK cells to dNK-like cells. Further investigation on the glycosylation and functions of GdA will enhance our understanding on human placentation and placenta-associated complications with altered NK cell biology.

Study Funding/competing Interest(s): This work was supported by the Hong Kong Research Grant Council Grant 17122415, Sanming Project of Medicine in Shenzhen, the Finnish Cancer Foundation, Sigrid Jusélius Foundation and the Finnish Society of Clinical Chemistry. The authors have no competing interests to declare.
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http://dx.doi.org/10.1093/humrep/dey378DOI Listing
April 2019

Human chorionic gonadotropin stimulates spheroid attachment on fallopian tube epithelial cells through the mitogen-activated protein kinase pathway and down-regulation of olfactomedin-1.

Fertil Steril 2015 Aug 18;104(2):474-82. Epub 2015 May 18.

Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China; Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China; ShenZhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China. Electronic address:

Objective: To study the effect of human chorionic gonadotropin (hCG) on olfactomedin-1 (Olfm1) expression and spheroid attachment in human fallopian tube epithelial cells in vitro.

Design: Experimental study.

Setting: Reproductive biology laboratory.

Patient(s): Healthy nonpregnant women.

Intervention(s): No patient interventions.

Main Outcome Measure(s): Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and Olfm1 expression in fallopian tube epithelium cell line (OE-E6/E7 cells). OE-E6/E7 cells treated with hCG, U0126 extracellular signal-regulated kinase (ERK) inhibitor, or XAV939 Wnt/β-catenin inhibitor were analyzed by Western blotting, real-time polymerase chain reaction, and in vitro spheroid attachment assay.

Result(s): Human chorionic gonadotropin increased spheroid attachment on OE-E6/E7 cells through down-regulation of Olfm1 and activation of Wnt and mitogen-activated protein kinase (MAPK) signaling pathways. U0126 down-regulated both MAPK and Wnt/β-catenin signaling pathways and up-regulated Olfm1 expression. XAV939 down-regulated only the Wnt/β-catenin signaling pathway but up-regulated Olfm1 expression.

Conclusion(s): Human chorionic gonadotropin activated both ERK and Wnt/β-catenin signaling pathways and enhanced spheroid attachment on fallopian tube epithelial cells through down-regulation of Olfm1 expression.
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http://dx.doi.org/10.1016/j.fertnstert.2015.04.030DOI Listing
August 2015

Two-dimensional versus three-dimensional laparoscopy: evaluation of physicians' performance and preference using a pelvic trainer.

J Minim Invasive Gynecol 2015 Mar-Apr;22(3):421-7. Epub 2014 Nov 21.

Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.

Study Objective: To compare the proficiency and preference of physicians in performing standard tasks in a box trainer using 2-dimensional (2D) versus 3-dimensional (3D) laparoscopy.

Design: Prospective randomized controlled trial.

Design Classification: Prospective, randomized controlled trial (Canadian Task Force classification I).

Setting: Tertiary care teaching hospital.

Participants: Thirty physicians from the Department of Obstetrics and Gynecology.

Intervention: Participants were randomly assigned to perform a set of 3 to 4 tasks in a pelvic trainer using 2D laparoscopy first and then 3D laparoscopy, and vice versa.

Main Results And Measurements: The time taken to complete the tasks and side effects experienced were noted. Participants were asked to complete a modified Global Operative Assessment of Laparoscopic Skills (GOALS) form at the end of their tasks to evaluate their experiences and to assess their own proficiency with both visual modalities.

Results: The time taken for peg transfer, duct cannulation, and suturing was significantly faster using 3D laparoscopy compared with 2D laparoscopy. There were no significant differences in the time taken for pattern cutting with both visual modalities. Participants experienced more dizziness using 3D laparoscopy (6.9% vs 37.9%; p = .004). The GOALS self-evaluation score was significantly higher for 3D compared with 2D laparoscopy. After the study, 11 of 29 (37.9%) participants preferred 2D, 16 of 29 (55.2%) preferred 3D, and 1 of 29 (8.3%) had no preference.

Conclusion: Although 3D laparoscopy scored higher on self-evaluation and was preferred by more participants, it only gave better objective performance in the completion of some selected tasks by participants with intermediate skill levels and was associated with more dizziness. Further studies are needed to determine the value of 3D laparoscopy, especially when used in the clinical setting.
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http://dx.doi.org/10.1016/j.jmig.2014.11.007DOI Listing
August 2015

Caesarean scar pregnancy: a 10-year experience.

Aust N Z J Obstet Gynaecol 2015 Feb 28;55(1):64-9. Epub 2014 Oct 28.

Department of Obstetrics and Gynecology, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China.

Aims: To review the management and outcome of all women with caesarean scar pregnancy (CSP) at a single centre.

Methods: A retrospective review of women diagnosed with CSP between January 2004 and December 2013 was performed. Women were identified from the admission and Early Pregnancy Assessment Clinic records.

Results: Twenty-two cases of CSP were identified during the study period. The median gestational age at diagnosis was 6.7 weeks (range 4.7-11.8 weeks). All diagnoses were made by ultrasound, the most common finding of which was a heterogeneous mass at the site of the caesarean scar (100%). The median duration for human chorionic gonadotropin to return to undetectable level was 10 weeks (range 2-20 weeks), although the duration for sonographic resolution of the CSP can take much longer. The success rate of intralesional methotrexate was 80% in our series.

Conclusion: There is no consensus regarding the method of choice for managing CSP. Medical management using intralesional methotrexate appears to be an acceptable treatment in clinically stable women.
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http://dx.doi.org/10.1111/ajo.12273DOI Listing
February 2015

Live birth rate, multiple pregnancy rate, and obstetric outcomes of elective single and double embryo transfers: Hong Kong experience.

Hong Kong Med J 2014 Apr 14;20(2):102-6. Epub 2014 Feb 14.

Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong.

Objective: To compare the live birth rate, multiple pregnancy rate, and obstetric outcomes of elective single and double embryo transfers.

Design: Case series with internal comparisons.

Setting: University affiliated hospital, Hong Kong.

Participants: Between October 2009 and December 2011, 206 women underwent their first in-vitro fertilisation cycle. Elective single embryo transfer was offered to women who were aged 35 years or below, and had endometrial thickness of 8 mm or more and at least two embryos of good quality.

Main Outcome Measures: Live birth rate, multiple birth rate, and obstetric outcomes.

Results: Among the 206 eligible women, 74 underwent an elective single embryo transfer and 132 a double embryo transfer. The live birth rate was comparable in the two groups, being 39.2% in the elective single embryo transfer group and 43.2% in the double embryo transfer group, while the multiple pregnancy rate was significantly lower in the elective single embryo transfer group than the double embryo transfer group (6.9% vs 40.4%; P<0.001). Gestational ages and birth weights were comparable in the two groups. There was no significant difference between the two groups with respect to the rate of preterm delivery and antenatal complications (27.6% vs 43.9%, respectively; P>0.05).

Conclusion: In this selected population, an elective single embryo transfer policy decreases the multiple pregnancy rate without compromising the live birth rate. The non-significant difference in antenatal complications may be related to the small sample size.
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http://dx.doi.org/10.12809/hkmj134065DOI Listing
April 2014

Management of heterotopic cesarean scar pregnancy by repeated transvaginal ultrasonographic-guided aspiration with successful preservation of normal intrauterine pregnancy and complicated by arteriovenous malformation.

Eur J Obstet Gynecol Reprod Biol 2014 Apr 13;175:209-10. Epub 2014 Jan 13.

Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.

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http://dx.doi.org/10.1016/j.ejogrb.2013.12.042DOI Listing
April 2014

The use of sex hormones in women with rheumatological diseases.

Hong Kong Med J 2011 Dec;17(6):487-91

Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.

A number of rheumatological diseases predominantly affect women of reproductive age. There has always been concern that the use of oestrogen-containing agents such as combined hormonal contraception and hormone therapy might aggravate these conditions. This article reviews the up-to-date evidence regarding the safety of using these agents in women with various rheumatological diseases, with emphasis on systemic lupus erythematosus and rheumatoid arthritis. In the absence of antiphospholipid antibody or other prothrombotic risk factors, combined hormonal contraception is not contra-indicated in most rheumatological conditions including inactive systemic lupus erythematosus. Moreover, hormone therapy is generally not contra-indicated except for women with active systemic lupus erythematosus disease where its effect on disease flare is less clear and individual judgement is required.
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December 2011

Frozen-thawed embryo transfer cycles.

Hong Kong Med J 2009 Dec;15(6):420-6

Department of Obstetrics and Gynaecology, Centre of Assisted Reproduction and Embryology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.

Objective: To review the outcomes of frozen-thawed embryo transfer cycles. DESIGN. Retrospective review.

Setting: Tertiary assisted reproduction centre, Hong Kong.

Patients: Subfertile patients undergoing frozen-thawed embryo transfer between July 2005 and December 2007.

Main Outcome Measures: Clinical and ongoing pregnancy rates.

Results: A total of 983 frozen-thawed embryo transfer cycles performed during the study period were reviewed. The clinical pregnancy and ongoing pregnancy rates were 35% and 30%, respectively. Factors associated with successful outcome included younger maternal age (<=35 years) and 4 or more blastomeres at replacement, but not the method of insemination, the cause of subfertility, or the type of frozen-thawed embryo transfer cycle. The overall multiple pregnancy rate was 18%. For cycles with a single embryo replaced, embryos having 4-cell or higher stages at replacement gave an ongoing pregnancy rate of 25%, whereas those with less than 4 cells had a significantly lower ongoing pregnancy rate of 5% only. Blastomere lysis after thawing significantly reduced the clinical pregnancy and ongoing pregnancy rates of cycles with one embryo replaced.

Conclusions: Clinical pregnancy and ongoing pregnancy rates of frozen-thawed embryo transfer cycles were 35% and 30%, respectively. Higher pregnancy rates were associated with younger maternal age (<=35 years), blastomere numbers of 4 or more, and no blastomere lysis after thawing.
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December 2009

Impact of common contraceptive methods on quality of life and sexual function in Hong Kong Chinese women.

Contraception 2004 Dec;70(6):474-82

Department of Obstetrics and Gynaecology, New Territories East Cluster, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

The combined oral contraceptive (COC) pills, injectables, intrauterine contraceptive device (IUCD) and female sterilization are the most common contraceptive methods used by women. Women's choice, compliance and satisfaction with specific contraceptive methods are influenced by any impact of the method on their quality of life and sexual function. Anxiety regarding possible adverse effects of the contraceptive methods on their quality of life and sexual function is one of the common concerns. The aim of this prospective observational study was to determine the impact of the abovementioned contraceptive methods on the quality of life and sexual function of the users. A sample of 361 Hong Kong Chinese women who were first-time users of the following contraceptive methods completed the study: COC pills (n=87), injectables (n=67), IUCD (n=96) and female sterilization (n=111). Quality of life and sexual function of the subjects were assessed before and 3-4 months after use of the method by a standardized questionnaire. The questions were adopted from the validated Chinese versions of the World Health Organization Quality of Life (WHOQOL) questionnaire and the Derogatis Sexual Functioning Inventory (DSFI). In the female sterilization group, we found a significantly higher score for sexual satisfaction (p=.004) and sexual drive (p=.003) 3-4 months after sterilization, as well as an improved WHOQOL social domain score (p=.009). However, the other DSFI subscale scores and WHOQOL domain scores were not significantly different (p>.05). No significant difference was demonstrated in all the WHOQOL domain scores and DSFI subscale scores after use of COC pills, injectables and IUCD (p>.05). We conclude that the COC pills, injectables, IUCD and female sterilization all do not have significant adverse impact on quality of life and sexual function. After female sterilization, there is a significant improvement in sexual satisfaction and sexual drive.
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http://dx.doi.org/10.1016/j.contraception.2004.06.010DOI Listing
December 2004

Expression of leptin and leptin receptors in gestational trophoblastic diseases.

Gynecol Oncol 2004 Nov;95(2):299-306

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

Objectives: To investigate the expression profile of leptin and leptin receptors in gestational trophoblastic diseases (GTDs).

Methods: Using immunohistochemical staining on archival paraffin-embedded tissue sections, we studied the expression of leptin and leptin receptor in hydatidiform moles, with gestational age-matched normal first-trimester placenta used as control. A total of 38 cases of hydatidiform moles were studied, including 20 complete moles (CHMs) and 18 partial moles (PHMs). Among them, 10 cases of the CHM group and 8 cases of the PHM group subsequently developed residual trophoblastic disease (RTD). In addition, two cases of choriocarcinoma and three cases of placental site trophoblastic tumor (PSTT) were also studied. Reverse transcriptase-polymerase chain reaction (RT-PCR) was further performed using RNA extracted from frozen tissue (five CHMs, four PHMs and nine normal first-trimester placenta) to study the expression of leptin and individual leptin receptor isoforms at the transcription level.

Results: In all tissue sections, immunostaining signal was shown in the cytoplasmic compartment of cytotrophoblasts and syncytiotrophoblasts, with much stronger staining in the former. Significantly higher immunostaining intensity was shown for both leptin (P < 0.05) and leptin receptor (P < 0.001) in both CHMs and PHMs compared to normal first-trimester placenta. There was no significant difference between those cases subsequently developing RTD and those which did not (P > 0.05). In the choriocarcinoma and PSTT cases, intense immunostaining was found in the tumor cells. RT-PCR revealed that the expression of leptin and all leptin receptor isoforms were significantly higher in both CHMs and PHMs than in normal placenta (P < 0.05).

Conclusions: There is up-regulated expression of leptin and leptin receptor in GTDs. However, there is no obvious correlation with the development of RTD. The exact role played by leptin and its receptors in the pathogenesis of GTDs awaits further investigations.
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http://dx.doi.org/10.1016/j.ygyno.2004.06.040DOI Listing
November 2004

Expression of placental leptin and leptin receptors in preeclampsia.

Int J Gynecol Pathol 2004 Oct;23(4):378-85

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.

This study investigated the expression profile of placental leptin and leptin receptor isoforms in preeclampsia, using placental tissue from normal pregnancies that were matched in gestational age and birth weight as controls. A total of 29 cases of preeclampsia were studied by immunohistochemistry, including 16 severe and 13 mild preeclampsia cases. Reverse transcriptase-polymerase chain reaction (RT-PCR) was further performed using RNA extracted from frozen tissue (10 severe preeclampsia, 10 mild preeclampsia, and 20 normal third trimester placentas). In all tissue sections, immunostaining signal was shown in the cytoplasmic compartment of the trophoblastic cells. Both the severe and mild preeclampsia groups showed significantly higher immunostaining for leptin compared with normal controls (p < 0.05), but there was no significant difference between the severe and mild preeclampsia groups (p > 0.05). There was no significant difference in immunostaining for leptin receptor between both severe and mild preeclampsia compared with controls (p > 0.05). RT-PCR showed significantly higher levels of mRNA transcripts of leptin in severe preeclampsia (p < 0.05), but not mild preeclampsia (p > 0.05), compared with normal controls. No significant difference in expression of all the receptor isoforms was demonstrated between both severe and mild preeclampsia groups compared with controls (p > 0.05). In conclusion, we confirmed an up-regulated expression of leptin in placental tissue in preeclampsia. However, there was no difference in the expression of all leptin receptor isoforms in placental tissue between preeclamptic and normal pregnancies. The leptin signal probably does not play a major primary role in the pathogenesis of preeclampsia.
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http://dx.doi.org/10.1097/01.pgp.0000139647.40620.c8DOI Listing
October 2004
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