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Human Reproduction Update Nov 2022To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones...
BACKGROUND
To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may be fertilized in the fallopian tubes, and the resulting zygote is transported toward the uterus, where it can implant and continue developing. The cervix acts as a physical barrier to protect the fetus throughout pregnancy, and the vagina acts as a birth canal (involving uterine and cervix mechanisms) and facilitates copulation. Fertility can be compromised by pathologies that affect any of these organs or processes, and therefore, being able to accurately model them or restore their function is of paramount importance in applied and translational research. However, innate differences in human and animal model reproductive tracts, and the static nature of 2D cell/tissue culture techniques, necessitate continued research and development of dynamic and more complex in vitro platforms, ex vivo approaches and in vivo therapies to study and support reproductive biology. To meet this need, bioengineering is propelling the research on female reproduction into a new dimension through a wide range of potential applications and preclinical models, and the burgeoning number and variety of studies makes for a rapidly changing state of the field.
OBJECTIVE AND RATIONALE
This review aims to summarize the mounting evidence on bioengineering strategies, platforms and therapies currently available and under development in the context of female reproductive medicine, in order to further understand female reproductive biology and provide new options for fertility restoration. Specifically, techniques used in, or for, the uterus (endometrium and myometrium), ovary, fallopian tubes, cervix and vagina will be discussed.
SEARCH METHODS
A systematic search of full-text articles available in PubMed and Embase databases was conducted to identify relevant studies published between January 2000 and September 2021. The search terms included: bioengineering, reproduction, artificial, biomaterial, microfluidic, bioprinting, organoid, hydrogel, scaffold, uterus, endometrium, ovary, fallopian tubes, oviduct, cervix, vagina, endometriosis, adenomyosis, uterine fibroids, chlamydia, Asherman's syndrome, intrauterine adhesions, uterine polyps, polycystic ovary syndrome and primary ovarian insufficiency. Additional studies were identified by manually searching the references of the selected articles and of complementary reviews. Eligibility criteria included original, rigorous and accessible peer-reviewed work, published in English, on female reproductive bioengineering techniques in preclinical (in vitro/in vivo/ex vivo) and/or clinical testing phases.
OUTCOMES
Out of the 10 390 records identified, 312 studies were included for systematic review. Owing to inconsistencies in the study measurements and designs, the findings were assessed qualitatively rather than by meta-analysis. Hydrogels and scaffolds were commonly applied in various bioengineering-related studies of the female reproductive tract. Emerging technologies, such as organoids and bioprinting, offered personalized diagnoses and alternative treatment options, respectively. Promising microfluidic systems combining various bioengineering approaches have also shown translational value.
WIDER IMPLICATIONS
The complexity of the molecular, endocrine and tissue-level interactions regulating female reproduction present challenges for bioengineering approaches to replace female reproductive organs. However, interdisciplinary work is providing valuable insight into the physicochemical properties necessary for reproductive biological processes to occur. Defining the landscape of reproductive bioengineering technologies currently available and under development for women can provide alternative models for toxicology/drug testing, ex vivo fertility options, clinical therapies and a basis for future organ regeneration studies.
Topics: Animals; Female; Humans; Pregnancy; Bioengineering; Embryo Implantation; Genitalia, Female; Reproduction; Uterus
PubMed: 35652272
DOI: 10.1093/humupd/dmac025 -
Human Reproduction (Oxford, England) Nov 2013Does a luteal estradiol (LE) stimulation protocol improve outcomes in poor responders to IVF? (Meta-Analysis)
Meta-Analysis Review
STUDY QUESTION
Does a luteal estradiol (LE) stimulation protocol improve outcomes in poor responders to IVF?
SUMMARY ANSWER
LE priming is associated with decreased cycle cancellation and increased chance of clinical pregnancy in poor responders
WHAT IS KNOWN ALREADY
Poor responders to IVF are one of the most challenging patient populations to treat. Many standard protocols currently exist for stimulating these patients but all have failed to improve outcomes.
STUDY DESIGN, SIZE, DURATION
Systematic review and meta-analysis including eight published studies comparing assisted reproduction technology (ART) outcomes in poor responders exposed to controlled ovarian hyperstimulation with and without LE priming. A search of the databases MEDLINE, EMBASE and PUBMED was carried out for studies in the English language published up to January 2012.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Studies evaluating women defined as poor responders to ART were evaluated. These studies were identified following a systematic review of the literature and data were analyzed using the DerSimonian-Laird random effects model. The main outcomes of interest were cycle cancellation rate and clinical pregnancy. Although the definition of clinical pregnancy varied between studies, the principal definition included fetal cardiac activity as assessed by transvaginal ultrasonography after 5 weeks of gestation.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 2249 publications were identified from the initial search, and the bibliographies, abstracts and other sources yielded 11 more. After excluding duplications, 1227 studies remained and 8 ultimately met the inclusion criteria. Compared with women undergoing non-LE primed protocols (n = 621), women exposed to LE priming (n = 468) had a lower risk of cycle cancellation [relative risk (RR): 0.60, 95% confidence interval (CI): 0.45-0.78] and an improved chance of clinical pregnancy (RR: 1.33, 95% CI: 1.02-1.72). There was no significant improvement in the number of mature oocytes obtained or number of zygotes obtained per cycle.
LIMITATIONS, REASONS FOR CAUTION
These findings are limited by the body of literature currently available. As the poor responder lacks a concrete definition, there is some heterogeneity to these results, which merits caution when applying our findings to individual patients. Furthermore, the increased clinical pregnancy rate demonstrated when using the LE protocol may be principally related to the decreased cycle cancellation rate.
WIDER IMPLICATIONS OF THE FINDINGS
The LE protocol may be of some utility in the poor responder to IVF and may increase clinical pregnancy rates in this population by improving stimulation and thereby decreasing cycle cancellation.
STUDY FUNDING/COMPETING INTERESTS
NIH K12 HD063086 (ESJ, MGT), NIH T32 HD0040135-11 (KAR), F32 HD040135-10 NIH (KRO), 5K12HD000849-25 (PTJ). No competing interests.
Topics: Adult; Estradiol; Female; Fertilization in Vitro; Humans; Luteal Phase; Pregnancy; Pregnancy Rate
PubMed: 23887073
DOI: 10.1093/humrep/det306 -
Journal of Reproductive Immunology Aug 2022The fallopian tubes (FT) play a key role in fertility by facilitating the movement of gametes to promote fertilisation and, subsequently, passage of the zygote for... (Review)
Review
The fallopian tubes (FT) play a key role in fertility by facilitating the movement of gametes to promote fertilisation and, subsequently, passage of the zygote for implantation. Histologically, the FT mucosa consists of three main cell types: secretory, ciliated and peg cells. In addition, several studies have reported the presence of immune cells. This systematic review aims to present a comprehensive analysis of the immune cell populations in the human FT, both in health and benign pathology, to promote a better understanding of tubal pathologies and their influence on infertility. A comprehensive literature search was conducted across five databases and augmented with manual citation chaining. Forty-two eligible studies were selected in accordance with PRISMA guidelines. Following screening, risk of bias assessments were conducted, data extracted and the findings presented thematically. T lymphocytes, predominantly CD8 T cells, represent the most abundant immune cell population within the healthy FT, with B lymphocytes, macrophages, NK cells and dendritic cells also localised to the tubal mucosa. There is evidence to suggest that lymphocyte and macrophage populations are susceptible to changes in the concentration of reproductive hormones. Tubal ectopic pregnancy, salpingitis, hydrosalpinx and endometriosis are all characterised by an increased population of macrophages in comparison to healthy FT. However, given the inconsistent evidence presented between studies, and the lack of studies examining all immune cell subtypes in tubal pathologies, only limited conclusions can be formulated on pathology-specific immune cell populations, and further research is required for validation.
Topics: CD8-Positive T-Lymphocytes; Fallopian Tubes; Female; Humans; Mucous Membrane; Pregnancy; Pregnancy, Tubal; Salpingitis
PubMed: 35644062
DOI: 10.1016/j.jri.2022.103646 -
Clinical Gastroenterology and... Aug 2020Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer... (Review)
Review
BACKGROUND & AIMS
Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer (CRC) and polyposis syndromes. We performed a systematic review to provide a comprehensive overview of somatic mosaicism in patients with CRC and polyposis syndromes.
METHODS
We searched PubMed through March 2018 to identify reports of mosaicism in patients with CRC or polyposis syndromes. We divided the final set of studies into 3 subgroups describing APC mosaicism, mosaicism in other CRC susceptibility genes, and epigenetic mosaicism.
RESULTS
Of the 232 articles identified in our systematic search, 46 met the criteria for further analysis. Of these, 35 studies described mosaic variants or epimutations in patients with CRC or polyposis syndromes. Nineteen studies described APC mosaicism, comprising a total of 57 patients. Six described mosaicism in genes associated with familial CRC syndromes, such as Lynch and Cowden syndromes. Ten studies described epigenetic mosaicism, sometimes resulting from a germline variant (such as deletion of EPCAM).
CONCLUSIONS
We found that somatic mosaicism is underdiagnosed but critical for determining the clinical management of patients with de novo polyposis who possibly carry mosaic APC variants, and present a decision tree for the clinical management of these patients. Mosaicism in genes associated with susceptibility to CRC contributes to development of other familial CRC syndromes. Heritable epigenetic mosaicism is likely underestimated and could have a dominant pattern of inheritance. However, the inheritance of primary mosaic epimutations, without an underlying genetic cause, is complex and not fully understood.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Genetic Predisposition to Disease; Humans; Mosaicism; Neoplastic Syndromes, Hereditary
PubMed: 32147591
DOI: 10.1016/j.cgh.2020.02.049 -
Journal of Assisted Reproduction and... Oct 2016The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the blastocyst stage in clinical IVF.
METHODS
We searched the Cochrane Central, PubMed, Scopus, ClinicalTrials.gov, Current Controlled Trials and WHO International Clinical Trials Registry Platform to identify randomized controlled trials comparing single versus sequential media for blastocyst culture and ongoing pregnancy rate. Included studies randomized either oocytes/zygotes or women. Eligible oocyte/zygote studies were analyzed to assess the risk difference (RD) and 95 % confidence intervals (CI) between the two media systems; eligible woman-based studies were analyzed to assess the risk ratio (RR) and 95 % CI for clinical pregnancy rate.
RESULTS
No differences were observed between single and sequential media for either ongoing pregnancy per randomized woman (relative risk (RR) = 0.9, 95 % CI = 0.7 to 1.3, two studies including 246 women, I = 0 %) or clinical pregnancy per randomized woman (RR = 1.0, 95 % CI = 0.7 to 1.4, one study including 100 women); or miscarriage per clinical pregnancy: RR = 1.3, 95 % CI = 0.4 to 4.3, two studies including 246 participants, I = 0 %). Single media use was associated with an increase blastocyst formation per randomized oocyte/zygote (relative distribution (RD) = +0.06, 95 % CI = +0.01 to +0.12, ten studies including 7455 oocytes/zygotes, I = 83 %) but not top/high blastocyst formation (RD = +0.05, 95 % CI = -0.01 to +0.11, five studies including 3879 oocytes/zygotes, I = 93 %). The overall quality of the evidence was very low for all these four outcomes.
CONCLUSIONS
Although using a single medium for extended culture has some practical advantages and blastocyst formation rates appear to be higher, there is insufficient evidence to recommend either sequential or single-step media as being superior for the culture of embryos to days 5/6. Future studies comparing these two media systems in well-designed trials should be performed.
Topics: Adult; Blastocyst; Cleavage Stage, Ovum; Embryo Culture Techniques; Embryo Transfer; Embryonic Development; Female; Fertilization in Vitro; Humans; Live Birth; Oocytes; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic
PubMed: 27491772
DOI: 10.1007/s10815-016-0774-5 -
Fertility and Sterility Jan 2012To evaluate the current available data regarding ovarian performance of patients diagnosed with malignant disease undergoing controlled ovarian hyperstimulation (COH)... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To evaluate the current available data regarding ovarian performance of patients diagnosed with malignant disease undergoing controlled ovarian hyperstimulation (COH) for fertility preservation, before radio/chemotherapy, compared with age-matched, healthy patients undergoing COH for in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI).
DESIGN
Meta-analysis of the data available from a systematic review of the literature.
SETTING
Academic centers of infertility and IVF.
PATIENT(S)
Patients with malignant disease, before radio/chemotherapy, undergoing COH for fertility preservation within comparative studies with healthy, age-matched controls.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Peak estradiol levels on day of human chorionic gonadotropin administration, number of oocytes retrieved, fertilization rate, incidence of low ovarian response, and cycle cancellation.
RESULT(S)
Only seven retrospective, case-controlled studies were found to match our objective. Overall, the results of the meta-analysis indicate that the number of retrieved oocytes rate was statistically significantly lower compared with age-matched healthy IVF patients. The incidence of poor ovarian performance and risk of cycle cancellation as well as the calculated number of two pronuclei zygotes achieved among patients with cancer were comparable with their age-matched controls.
CONCLUSION(S)
Women with malignant disease should expect a lower number of oocytes retrieved after COH for fertility preservation, compared with healthy, age-matched patients. Presently, there is paucity of evidence to assess the effect of a specific malignant disease on ovarian response to COH before IVF for fertility preservation. Multicentric studies should be conducted to resolve these important issues.
Topics: Female; Fertility Preservation; Humans; Infertility, Female; Neoplasms; Oocyte Retrieval; Ovulation Induction; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted
PubMed: 22078784
DOI: 10.1016/j.fertnstert.2011.10.014 -
Frontiers in Plant Science 2022Plants have amazing regenerative properties with single somatic cells, or groups of cells able to give rise to fully formed plants. One means of regeneration is somatic...
Plants have amazing regenerative properties with single somatic cells, or groups of cells able to give rise to fully formed plants. One means of regeneration is somatic embryogenesis, by which an embryonic structure is formed that "converts" into a plantlet. Somatic embryogenesis has been used as a model for zygotic processes that are buried within layers of maternal tissues. Understanding mechanisms of somatic embryo induction and development are important as a more accessible model for seed development. We rely on seed development not only for most of our caloric intake, but also as a delivery system for engineered crops to meet agricultural challenges. Regeneration of transformed cells is needed for this applied work as well as basic research to understand gene function. Here we focus on a MADS-domain transcription factor, AGAMOUS-Like15 (AGL15) that shows a positive correlation between accumulation levels and capacity for somatic embryogenesis. We relate AGL15 function to other transcription factors, hormones, and epigenetic modifiers involved in somatic embryo development.
PubMed: 35419012
DOI: 10.3389/fpls.2022.861556 -
Journal of Ovarian Research Sep 2013The current systematic review was aimed to assess the effectiveness of the zygote morphology evaluation in fresh in vitro fertilization (IVF) and intracytoplasmic sperm...
The current systematic review was aimed to assess the effectiveness of the zygote morphology evaluation in fresh in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. All available studies reporting on zygote morphology and clinical and/or biological outcomes were analyzed. Forty studies were included in the final analysis. Fourteen different zygote scoring systems were employed. Zygote morphology correlated significantly with embryo quality and cleavage, blastocyst stage, embryonic chromosome status, in a high proportion of the studies which assessed the specific outcome [15/25 (60%), 15/20 (75%), 7/8 (87.5%), 6/6 (100%), respectively]. On the other hand, only a reduced proportion of papers showed a statistically significant relationship between implantation, pregnancy and delivery/live-birth rates and zygote morphology score [12/23 (52.2%), 12/25 (48%), 1/4 (25%), respectively]. In conclusion, our findings demonstrate the lack of conclusive data on the clinical efficacy of the zygote morphology evaluation in fresh IVF/ICSI cycles, even if biological results showing a good relationship with embryo viability suggest a role in cycles in which the transfer/freezing is performed at day 1.
PubMed: 24028277
DOI: 10.1186/1757-2215-6-64