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Higher β-HCG concentrations and higher birthweights ensue from single vitrified embryo transfers

Keane KN, Mustafa KB, Hinchliffe P, Conceicao J, Yovich JL

Reprod Biomed Online, 2016 Aug;33(2):149-60.
PMID: 27209497 DOI: 10.1016/j.rbmo.2016.04.014

To examine the effect of cryopreservation on developmental potential of human embryos, this study compared quantitative β-HCG concentrations at pregnancy test after IVF-fresh embryo transfer (IVF-ET) with those arising after frozen embryo transfer (FET). It also tracked outcomes of singleton pregnancies resulting from single-embryo transfers that resulted in singleton live births (n = 869; with 417 derived from IVF-ET and 452 from FET). The initial serum β-HCG concentration indicating successful implantation was measured along with the birthweight of the ensuing infants. With testing at equivalent luteal phase lengths, the median pregnancy test β-HCG was significantly higher following FET compared with fresh IVF-ET (844.5 IU/l versus 369 IU/l; P < 0.001). Despite no significant difference in the average period of gestation (38 weeks 5 days for both groups), the mean birthweight of infants born following FET was significantly heavier by 161 g (3370 g versus 3209 g; P < 0.001). Furthermore, more infants exceeded 4000 g (P < 0.001) for FET although there was no significant difference for the macrosomic category (≥4500 g). We concluded that FET programme embryos lead to infants with equivalent (if not better) developmental potential compared with IVF-ET, demonstrated by higher pregnancy β-HCG concentrations and ensuing birthweights.
M2/ANXA5 haplotype as a predisposition factor in Malay women and couples experiencing recurrent spontaneous abortion: a pilot study

Thean Hock T, Bogdanova N, Kai Cheen A, Kathirgamanathan S, Bin Abdullah R, Mohd Yusoff N, et al.

Reprod Biomed Online, 2015 Apr;30(4):434-9.
PMID: 25682309 DOI: 10.1016/j.rbmo.2014.12.014

Recurrent spontaneous abortion (RSA) is a prevalent condition among the Malay population of Malaysia, where carriage risk of conventional hereditary thrombophilia factors has been generally ruled out. The contribution of M2/ANXA5, a common haplotype in the annexin A5 gene promoter, was evalauted for RSA in Malay. Seventy-seven women who had experienced two or more unexplained RSA and 41 available male partners were selected for study, with 360 population controls recruited from healthy Malay individuals. Incidence of M2 carriage and odds ratios were calculated between control and patient groups, and clinically defined subgroups and RSA risk was evaluated. M2/ANXA5, found in 42.2% of the general Malay population, was associated with greater risks for women with primary and secondary RSA with early (gestational week 5-15) losses. The risk was somewhat higher in Malay couples when both partners were carriers and a trend of higher prevalence was seen for the male partners patients who had experienced RSA. M2 carriage seems to be a risk factor with unusually high incidence in Malay women and couples with primary and secondary RSA with 'early' spontaneous abortions. The associated male partner risk confirms the proposed role of M2/ANXA5 as a genetic trait impeding embryonic anticoagulation.
Proteomics, oxidative stress and male infertility

Agarwal A, Durairajanayagam D, Halabi J, Peng J, Vazquez-Levin M

Reprod Biomed Online, 2014 Jul;29(1):32-58.
PMID: 24813754 DOI: 10.1016/j.rbmo.2014.02.013

Oxidative stress has been established as one of the main causes of male infertility and has been implicated in many diseases associated with infertile men. It results from high concentrations of free radicals and suppressed antioxidant potential, which may alter protein expression in seminal plasma and/or spermatozoa. In recent years, proteomic analyses have been performed to characterize the protein profiles of seminal ejaculate from men with different clinical conditions, such as high oxidative stress. The aim of the present review is to summarize current findings on proteomic studies performed in men with high oxidative stress compared with those with physiological concentrations of free radicals, to better understand the aetiology of oxidative stress-induced male infertility. Each of these studies has suggested candidate biomarkers of oxidative stress, among them are DJ-1, PIP, lactotransferrin and peroxiredoxin. Changes in protein concentrations in seminal plasma samples with oxidative stress conditions were related to stress responses and to regulatory pathways, while alterations in sperm proteins were mostly associated to metabolic responses (carbohydrate metabolism) and stress responses. Future studies should include assessment of post-translational modifications in the spermatozoa as well as in seminal plasma proteomes of men diagnosed with idiopathic infertility. Oxidative stress, which occurs due to a state of imbalance between free radicals and antioxidants, has been implicated in most cases of male infertility. Cells that are in a state of oxidative stress are more likely to have altered protein expression. The aim of this review is to better understand the causes of oxidative stress-induced male infertility. To achieve this, we assessed proteomic studies performed on the seminal plasma and spermatozoa of men with high levels of oxidative stress due to various clinical conditions and compared them with men who had physiological concentrations of free radicals. A variety of sperm and seminal plasma proteins were found to be expressed either in abundance (over-expressed) or in a lesser amount (underexpressed), while other proteins were found to be unique either to men with oxidative stress or to men with a balanced ratio of antioxidants/free radicals. Each study included in this review suggested several proteins that could possibly act as biomarkers of oxidative stress-induced male infertility, such as protein DJ-1, PIP, lactotransferrin and peroxiredoxin. Pathway analysis performed in these studies revealed that the changes in seminal plasma proteins in men with oxidative stress could be attributed to stress responses and regulatory pathways, while changes in sperm proteins were linked to stress responses and metabolic responses. Subsequent studies could look into post-translational modifications in the protein profile of men with idiopathic infertility. We hope that the information in this review will contribute to a better understanding of the main causes of idiopathic male infertility.
Successful pregnancy outcome following gamete intra-Fallopian transfer in a patient with Müllerian dysgenesis

Lee CS, Lie AT

Reprod Biomed Online, 2012 May;24(5):547-9.
PMID: 22410277 DOI: 10.1016/j.rbmo.2012.01.021

A 29-year-old lady with Müllerian dysgenesis was keen to have a baby. Clinically, she was medium built with well-developed secondary female sexual characteristics. There was a short and blind vagina. She had undergone surgery for an imperforated hymen. Her FSH and LH concentrations were normal. Laparoscopy revealed a patent right Fallopian tube, a rudimentary right uterus and extensive pelvic endometriosis. She subsequently underwent gamete intra-Fallopian transfer (GIFT). Oocyte retrieval was carried out laparoscopically and a total of nine oocytes were retrieved. Four of the oocytes were transferred together with motile spermatozoa into the right Fallopian tube and the remaining five oocytes were inseminated with spermatozoa for IVF. Three embryos resulted and were frozen. She subsequently developed moderate ovarian hyperstimulation syndrome. Serum β-human chorionic gonadotrophin concentration 14 days after GIFT was 1612 IU/l. Her antenatal care was relatively uneventful until 31 weeks of gestation when she was diagnosed to have intrauterine growth retardation and oligohydramnios. She then underwent an emergency Caesarean section at 32 weeks of pregnancy delivering a normal baby. This case study describes a successful pregnancy outcome following gamete intra-Fallopian transfer (GIFT) in a woman with malformation of the vagina (Müllerian dysgenesis). A 29-year-old lady with Müllerian dysgenesis diagnosed at 16 years of age was keen to become pregnant. Upon examination, a decision was made for a William's vulvovaginoplasty but as the patient was indecisive the surgery was deferred. Clinically, she is a medium-built lady with well-developed secondary female sexual characteristics. There was a short and blind vagina. Her serum FSH and LH concentrations were normal. Laparoscopy revealed a patent right Fallopian tube, a rudimentary right uterus and extensive pelvic endometriosis. She subsequently underwent GIFT. Nine oocytes were retrieved through laparoscopy. Four of the oocytes were transferred together with motile sperm into the right Fallopian tube and the remaining five oocytes were inseminated with sperm for IVF. Three embryos resulted and were frozen. Serum β human chorionic gonadotrophin concentration measured 14 days after GIFT was 1612 IU/l. An abdominal ultrasonography performed at 5 weeks showed one intrauterine gestational sac. Her antenatal care was uneventful until 31 weeks of gestation when she developed a deficiency of amniotic fluid in the amniotic sac. She then underwent an emergency Caesarean section at 32 weeks of pregnancy. She delivered a healthy, normal 1.24 kg baby boy. Her post-natal care was uneventful.
Role of Withania somnifera (Ashwagandha) in the management of male infertility

Sengupta P, Agarwal A, Pogrebetskaya M, Roychoudhury S, Durairajanayagam D, Henkel R

Reprod Biomed Online, 2018 Mar;36(3):311-326.
PMID: 29277366 DOI: 10.1016/j.rbmo.2017.11.007

To manage male infertility caused by hormonal imbalance, infections and other predicaments, multifarious treatment strategies are emerging worldwide. Contemporary treatments, such as assisted reproductive techniques, are costly with low success rates of only 10-30%; however, herbal remedies are gaining more attention as an alternative or supplementary therapeutic modality for male infertility. The beneficial effects induced by oral intake of the roots of a small evergreen shrub, Withania sominifera (Ashwagandha) on semen quality of infertile men have previously been studied. Oral intake of Ashwagandha roots has been found to inhibit lipid peroxidation, improve sperm count and motility, and regulate reproductive hormone levels. The molecular mechanisms of these effects, however, are yet to be unveiled. In this review, we will discuss the role of herbal medicines in male infertility; provide a detailed analysis of various human and animal studies involving Withania somnifera; describe a proposed direct oxidative mechanism involving mitigation of oxidative stress as well as an indirect mechanism consisting of a gamma-aminobutyric acid-like-mimetic pathway ameliorating hormonal balance through crosstalk among different endocrine glands to improve male fertility; and how Withania somnifera supplementation mitigates risk factor-induced male infertility as well as ameliorates male fertility.
Graph cluster approach in identifying novel proteins and significant pathways involved in polycystic ovary syndrome

Afiqah-Aleng N, Altaf-Ul-Amin M, Kanaya S, Mohamed-Hussein ZA

Reprod Biomed Online, 2020 Feb;40(2):319-330.
PMID: 32001161 DOI: 10.1016/j.rbmo.2019.11.012

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with diverse clinical implications, such as infertility, metabolic disorders, cardiovascular diseases and psychological problems among others. The heterogeneity of conditions found in PCOS contribute to its various phenotypes, leading to difficulties in identifying proteins involved in this abnormality. Several studies, however, have shown the feasibility in identifying molecular evidence underlying other diseases using graph cluster analysis. Therefore, is it possible to identify proteins and pathways related to PCOS using the same approach?
METHODS: Known PCOS-related proteins (PCOSrp) from PCOSBase and DisGeNET were integrated with protein-protein interactions (PPI) information from Human Integrated Protein-Protein Interaction reference to construct a PCOS PPI network. The network was clustered with DPClusO algorithm to generate clusters, which were evaluated using Fisher's exact test. Pathway enrichment analysis using gProfileR was conducted to identify significant pathways.
RESULTS: The statistical significance of the identified clusters has successfully predicted 138 novel PCOSrp with 61.5% reliability and, based on Cronbach's alpha, this prediction is acceptable. Androgen signalling pathway and leptin signalling pathway were among the significant PCOS-related pathways corroborating the information obtained from the clinical observation, where androgen signalling pathway is responsible in producing male hormones in women with PCOS, whereas leptin signalling pathway is involved in insulin sensitivity.
CONCLUSIONS: These results show that graph cluster analysis can provide additional insight into the pathobiology of PCOS, as the pathways identified as statistically significant correspond to earlier biological studies. Therefore, integrative analysis can reveal unknown mechanisms, which may enable the development of accurate diagnosis and effective treatment in PCOS.
Fulltext An artificial intelligence model correlated with morphological and genetic features of blastocyst quality improves ranking of viable embryos

Diakiw SM, Hall JMM, VerMilyea M, Lim AYX, Quangkananurug W, Chanchamroen S, et al.

Reprod Biomed Online, 2022 Dec;45(6):1105-1117.
PMID: 36117079 DOI: 10.1016/j.rbmo.2022.07.018

RESEARCH QUESTION: Can better methods be developed to evaluate the performance and characteristics of an artificial intelligence model for evaluating the likelihood of clinical pregnancy based on analysis of day-5 blastocyst-stage embryos, such that performance evaluation more closely reflects clinical use in IVF procedures, and correlations with known features of embryo quality are identified?
DESIGN: De-identified images were provided retrospectively or collected prospectively by IVF clinics using the artificial intelligence model in clinical practice. A total of 9359 images were provided by 18 IVF clinics across six countries, from 4709 women who underwent IVF between 2011 and 2021. Main outcome measures included clinical pregnancy outcome (fetal heartbeat at first ultrasound scan), embryo morphology score, and/or pre-implantation genetic testing for aneuploidy (PGT-A) results.
RESULTS: A positive linear correlation of artificial intelligence scores with pregnancy outcomes was found, and up to a 12.2% reduction in time to pregnancy (TTP) was observed when comparing the artificial intelligence model with standard morphological grading methods using a novel simulated cohort ranking method. Artificial intelligence scores were significantly correlated with known morphological features of embryo quality based on the Gardner score, and with previously unknown morphological features associated with embryo ploidy status, including chromosomal abnormalities indicative of severity when considering embryos for transfer during IVF.
CONCLUSION: Improved methods for evaluating artificial intelligence for embryo selection were developed, and advantages of the artificial intelligence model over current grading approaches were highlighted, strongly supporting the use of the artificial intelligence model in a clinical setting.
Poorly controlled type 1 diabetes mellitus seriously impairs female reproduction via immune and metabolic disorders

Zhang S, Liu Q, Yang C, Li X, Chen Y, Wu J, et al.

Reprod Biomed Online, 2024 Apr;48(4):103727.
PMID: 38402677 DOI: 10.1016/j.rbmo.2023.103727

RESEARCH QUESTION: Does type 1 diabetes mellitus (T1DM) affect reproductive health of female patients? What is the potential mechanism of reproductive dysfunction in female patients caused by T1DM?
DESIGN: Preliminary assessment of serum levels of female hormones in women with or without T1DM. Then histological and immunological examinations were carried out on the pancreas, ovaries and uteri at different stages in non-obese diabetic (NOD) and Institute of Cancer Research (ICR) mice, as well as assessment of their fertility. A protein array was carried out to detect the changes in serum inflammatory cytokines. Furthermore, RNA-sequencing was used to identify the key abnormal genes/pathways in ovarian and uterine tissues of female NOD mice, which were further verified at the protein level.
RESULTS: Testosterone levels were significantly increased (P = 0.0036) in female mice with T1DM. Increasing age in female NOD mice was accompanied by obvious lymphocyte infiltration in the pancreatic islets. Moreover, the levels of serum inflammatory factors in NOD mice were sharply increased with increasing age. The fertility of female NOD mice declined markedly, and most were capable of conceiving only once. Furthermore, ovarian and uterine morphology and function were severely impaired in NOD female mice. Additionally, ovarian and uterine tissues revealed that the differentially expressed genes were primarily enriched in metabolism, cytokine-receptor interactions and chemokine signalling pathways.
CONCLUSION: T1DM exerts a substantial impairment on female reproductive health, leading to diminished fertility, potentially associated with immune disorders and alterations in energy metabolism.
Fulltext Use of federated learning to develop an artificial intelligence model predicting usable blastocyst formation from pre-ICSI oocyte images

Hall JMM, Nguyen TV, Dinsmore AW, Perugini D, Perugini M, Fukunaga N, et al.

Reprod Biomed Online, 2024 Dec;49(6):104403.
PMID: 39433005 DOI: 10.1016/j.rbmo.2024.104403

RESEARCH QUESTION: Can federated learning be used to develop an artificial intelligence (AI) model for evaluating oocyte competence using two-dimensional images of denuded oocytes in metaphase II prior to intracytoplasmic sperm injection (ICSI)?
RESULTS: The oocyte AI model demonstrated area under the curve (AUC) up to 0.65 on two blind test datasets. High sensitivity for predicting competent oocytes (83-88%) was offset by lower specificity (26-36%). Exclusion of confounding biological variables (male factor infertility and maternal age ≥35 years) improved AUC up to 14%, primarily due to increased specificity. AI score correlated with size of the zona pellucida and perivitelline space, and ooplasm appearance. AI score also correlated with blastocyst expansion grade and morphological quality. The sum of AI scores from oocytes in group culture images predicted the formation of two or more usable blastocysts (AUC 0.77).
CONCLUSION: An AI model to evaluate oocyte competence was developed using federated learning, representing an essential step in protecting patient data. The AI model was significantly predictive of oocyte competence, as defined by usable blastocyst formation, which is a critical factor for IVF success. Potential clinical utility ranges from selective oocyte fertilization to guiding treatment decisions regarding additional rounds of oocyte retrieval.
DESIGN: In total, 10,677 oocyte images with associated metadata were collected prospectively by eight IVF clinics across six countries. AI training used federated learning, where data were retained on regional servers to comply with data privacy laws. The final AI model required a single image as input to evaluate oocyte competence, which was defined by the formation of a usable blastocyst (≥expansion grade 3 by day 5 or 6 post ICSI).