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  • 更新日期:2019-12-30
  • 更新日期:2019-12-30
  • Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics?
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-11-27
    Leaver M, Wells D.

    BACKGROUNDPreimplantation genetic testing (PGT) encompasses methods that allow embryos to be tested for severe inherited conditions or for chromosome abnormalities, relevant to embryo health and viability. In order to obtain embryonic genetic material for analysis, a biopsy is required, involving the removal of one or more cells. This invasive procedure greatly increases the costs of PGT and there have been concerns that embryo viability could be compromised in some cases. The recent discovery of DNA within the blastocoele fluid (BF) of blastocysts and in spent embryo culture media (SCM) has led to interest in the development of non-invasive methods of PGT (niPGT). OBJECTIVE AND RATIONALEThis review evaluates the current scientific evidence regarding non-invasive genetic assessment of preimplantation embryos. The success of different PGT methodologies in collecting and analysing extra-embryonic DNA is evaluated, and consideration is given to the potential biological and technical hindrances to obtaining a reliable clinical diagnosis. SEARCH METHODSOriginal research and review papers concerning niPGT were sourced by searching PubMed and Google Scholar databases until July 2019. Searches comprised the keywords: ‘non-invasive’; ‘cell-free DNA’; ‘blastocentesis’; ‘blastocoel fluid’; ‘spent culture media’; ‘embryo culture medium’; ‘preimplantation genetic testing’; ‘preimplantation genetic diagnosis’; ‘preimplantation genetic screening’; and ‘aneuploidy’. OUTCOMESEmbryonic DNA is frequently detectable in BF and SCM of embryos produced during IVF treatment. Initial studies have achieved some success when performing cytogenetic and molecular genetic analysis. However, in many cases, the efficiency has been restricted by technical complications associated with the low quantity and quality of the DNA. Reported levels of ploidy agreement between SCM/BF samples and biopsied embryonic cells vary widely. In some cases, a discrepancy with respect to cytogenetic data obtained after trophectoderm biopsy may be attributable to embryonic mosaicism or DNA contamination (usually of maternal origin). Some research indicates that aneuploid cells are preferentially eliminated from the embryo, suggesting that their DNA might be over-represented in SCM and BF samples; this hypothesis requires further investigation. WIDER IMPLICATIONSAvailable data suggest that BF and SCM samples frequently provide DNA templates suitable for genetic analyses, offering a potential means of PGT that is less expensive than traditional methods, requires less micromanipulation skill and poses a lower risk to embryos. Critically, DNA isolation and amplification protocols must be optimised to reproducibly obtain an accurate clinical diagnosis, whilst minimising the impact of confounding factors such as contamination. Further investigations are required to understand the mechanisms underlying the release of embryonic DNA and to determine the extent to which this material reflects the true genetic status of the corresponding embryo. Currently, the clinic al potential of niPGT remains unknown.

    更新日期:2019-12-30
  • IUI for unexplained infertility—a network meta-analysis
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-05
    Danhof N, Wang R, van Wely M, et al.

    ABSTRACT BACKGROUNDIUI for unexplained infertility can be performed in a natural cycle or in combination with ovarian stimulation. A disadvantage of ovarian stimulation is an increased risk of multiple pregnancies with its inherent maternal and neonatal complication risks. Stimulation agents for ovarian stimulation are clomiphene citrate (CC), Letrozole or gonadotrophins. Although studies have compared two or three of these drugs to each other in IUI, they have never been compared to one another in one analysis. OBJECTIVE AND RATIONALEThe objective of this network meta-analysis was to compare the effectiveness and safety of IUI with CC, Letrozole or gonadotrophins with each other and with natural cycle IUI. SEARCH METHODSWe searched PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL and the Clinical Trial Registration Database indexed up to 16 August 2018. We included randomized controlled trials that compared a stimulation regimen with CC, Letrozole or gonadotrophins to each other or to natural cycle IUI among couples with unexplained infertility. We performed the network meta-analysis within a multivariate random effects model. OUTCOMESWe identified 26 studies reporting on 5316 women. The relative risk (RR) for live birth/ongoing pregnancy rates comparing IUI with CC to natural cycle IUI was 1.05 (95% CI 0.63–1.77, low quality of evidence), while comparing IUI with Letrozole to natural cycle IUI was 1.15 (95% CI 0.63–2.08, low quality of evidence) and comparing IUI with gonadotrophins to natural cycle IUI was 1.46 (95% CI 0.92–2.30, low quality of evidence). The RR for live birth/ongoing pregnancy rates comparing gonadotrophins to CC was 1.39 (95% CI 1.09–1.76, moderate quality of evidence), comparing Letrozole to CC was 1.09 (95% CI 0.76–1.57, moderate quality of evidence) and comparing Letrozole to gonadotrophins was 0.79 (95% CI 0.54–1.15, moderate quality of evidence). We did not perform network meta-analysis on multiple pregnancy due to high inconsistency. Pairwise meta-analyses showed an RR for multiple pregnancy rates of 9.11(95% CI 1.18–70.32) comparing IUI with gonadotrophins to natural cycle IUI. There was no data available on multiple pregnancy rates following IUI with CC or Letrozole compared to natural cycle IUI. The RR for multiple pregnancy rates comparing gonadotrophins to CC was 1.42 (95% CI 0.68–2.97), comparing Letrozole to CC was 0.97 (95% CI 0.47–2.01) and comparing Letrozole to gonadotrophins was 0.29 (95% CI 0.14–0.58).In a meta-analysis among studies with adherence to strict cancellation criteria, the RR for live births/ongoing pregnancy rates comparing gonadotrophins to CC was 1.20 (95% CI 0.95–1.51) and the RR for multiple pregnancy rates comparing gonadotropins to CC was 0.80 (95% CI 0.38–1.68). WIDER IMPLICATIONSBased on low to moderate quality of evidence in this network meta-analysis, IUI with gonadotrophins ranked highest on live birth/ongoing pregnancy rates, but women undergoing this treatment protocol were also at risk for multiple pregnancies with high complication rates. IUI regimens with adherence to strict cancellation criteria led to an acceptable multiple pregnancy rate without compromising the effectiveness. Within a protocol with adherence to strict cancellation criteria, gonadotrophins seem to improve live birth/ongoing pregnancy rates compared to CC. We, therefore, suggest performing IUI with ovarian stimulation using gonadotrophins within a protocol that includes strict cancellation criteria. Obviously, this ignores the impact of costs and patients preference.

    更新日期:2019-12-30
  • Age-related presence of spermatogonia in patients with Klinefelter syndrome: a systematic review and meta-analysis
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-10
    Deebel N, Galdon G, Zarandi N, et al.

    BACKGROUNDKlinefelter syndrome (KS) has been defined by sex chromosome aneuploidies (classically 47, XXY) in the male patient. The peripubertal timeframe in KS patients has been associated with the initiation of progressive testicular fibrosis, loss of spermatogonial stem cells (SSC), hypogonadism and impaired fertility. Less than half of KS patients are positive for spermatozoa in the ejaculate or testis via semen analysis or testicular sperm extraction, respectively. However, the chance of finding spermatogonia including a sub-population of SSCs in KS testes has not been well defined. Given the recent demonstration of successful cell culture for mouse and human SSCs, it could be feasible to isolate and propagate SSCs and transplant the cells back to the patient or to differentiate them in vitro to haploid cells. OBJECTIVE AND RATIONALEThe main objective of this study was to meta-analyse the currently available data from KS patients to identify the prevalence of KS patients with spermatogonia on testicular biopsy across four age groups (year): fetal/infantile (age ≤ 1), prepubertal (age 1 ≤ x ≤ 10), peripubertal/adolescent (age 10 < x < 18) and adult (age ≥ 18) ages. Additionally, the association of endocrine parameters with presence or absence of spermatogonia was tested to obtain a more powered analysis of whether FSH, LH, testosterone and inhibin B can serve as predictive markers for successful spermatogonia retrieval. SEARCH METHODSA thorough Medline/PubMed search was conducted using the following search terms: ‘Klinefelter, germ cells, spermatogenesis and spermatogonia’, yielding results from 1 October 1965 to 3 February 2019. Relevant articles were added from the bibliographies of selected articles. Exclusion criteria included non-English language, abstracts only, non-human data and review papers. OUTCOMESA total of 751 papers were identified with independent review returning 36 papers with relevant information for meta-analysis on 386 patients. For the most part, articles were case reports, case-controlled series and cohort studies (level IV-VI evidence). Spermatogonial cells were present in all of the fetal/infantile and 83% of the prepubertal patients’ testes, and in 42.7% and 48.5% of the peripubertal and adult groups, respectively were positive for spermatogonia. Additionally, 26 of the 56 (46.4%) peripubertal/adolescent and 37 of the 152 (24.3%) adult patients negative for spermatozoa were positive for spermatogonia (P < 0.05). In peripubertal/adolescent patients, the mean ± SEM level for FSH was 12.88 ± 3.13 IU/L for spermatogonia positive patients and 30.42 ± 4.05 IU/L for spermatogonia negative patients (P = 0.001); the mean ± SEM level LH levels were 4.36 ± 1.31 and 11.43 ± 1.68 IU/L for spermatogonia positive and negative, respectively (P < 0.01); the mean ± SEM level for testosterone levels were 5.04 ± 1.37 and 9.05 ± 0.94 nmol/L (equal to 145 ± 40 and 261 ± 27 and ng/dl) for the spermatogonia positive and negative groups, respectively (P < 0.05), while the difference in means for inhibin B was not statistically significant (P > 0.05). A similar analysis in the adult group showed the FSH levels in spermatogonia positive and negative patients to be 25.77 ± 2.78 and 36.12 ± 2.90 IU/L, respectively (mean ± SEM level, P < 0.05). All other hormone measurements were not statistically significantly different between groups. WIDER IMPLICATIONSWhile azoospermia is a common finding in the KS patient population, many patients are positive for spermatogonia. Recent advances in SSC in vitro propagation, transplantation and differentiation open new avenues for these patients for fertility preservation. This would offer a new subset of KS patients a chance of biological paternity. Data surrounding the hormonal profiles of KS patients and their relation to fertility should be interpreted with caution as a paucity of adequately powered data exists. Future work is needed to clarify the utility of FSH, LH, testosterone and inhibin B as biomarkers for successful retrieval of spermatogonia.

    更新日期:2019-12-30
  • Polymorphisms and endometriosis: a systematic review and meta-analyses
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-10
    Méar L, Herr M, Fauconnier A, et al.

    BACKGROUNDEndometriosis is an estrogen-dependent gynecological disorder that affects at least 10% of women of reproductive age. It may lead to infertility and non-specific symptoms such as chronic pelvic pain. Endometriosis screening and diagnosis are difficult and time-consuming. Late diagnosis (with a delay ranging from 3.3 to 10.7 years) is a major problem and may contribute to disease progression and a worse response to treatment once initiated. Efficient screening tests might reduce this diagnostic delay. As endometriosis is presumed to be a complex disease with several genetic and non-genetic pathogenic factors, many researchers have sought to identify polymorphisms that predispose to this condition. OBJECTIVE AND RATIONALEWe performed a systematic review and meta-analysis of the most regularly reported polymorphisms in order to identify those that might predispose to endometriosis and might thus be of value in screening. SEARCH METHODSThe MEDLINE database was searched for English-language publications on DNA polymorphisms in endometriosis, with no date restriction. The PubTator text mining tool was used to extract gene names from the selected publications’ abstracts. We only selected polymorphisms reported by at least three studies, having applied strict inclusion and exclusion criteria to their control populations. No stratification based on ethnicity was performed. All steps were carried out according to PRISMA guidelines. OUTCOMESThe initial selection of 395 publications cited 242 different genes. Sixty-two genes (corresponding to 265 different polymorphisms) were cited at least in three publications. After the application of our other selection criteria (an original case-control study of endometriosis, a reported association between endometriosis and at least one polymorphism, data on women of reproductive age and a diagnosis of endometriosis in the cases established by surgery and/or MRI and confirmed by histology), 28 polymorphisms were eligible for meta-analysis. Only five of the 28 polymorphisms were found to be significantly associated with endometriosis: interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695 and wingless-type MMTV integration site family member 4 (WNT4) rs16826658 and rs2235529. Six others showed a significant trend towards an association: progesterone receptor (PGR) PROGINS, interCellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamily A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285 and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282), and 12 showed a significant trend towards the lack of an association: tumor necrosis factor (TNF) rs1799964, interleukin 6 (IL6) rs1800796, transforming growth factor beta 1 (TGFB1) rs1800469, estrogen receptor 1 (ESR1) rs2234693, PGR rs10895068, FSH receptor (FSHR) rs6166, ICAM1 rs5498, CYP1A1 rs4646903, CYP19A1 rs10046, tumor protein 53 (TP53) rs1042522, X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) rs25487 and serpin peptidase inhibitor clade E member 1 (SERPINE1) rs1799889; however, for the 18 polymorphisms identified in the latter two groups, further studies of the potential association with the endometriosis risk are needed. The remaining five of the 28 polymorphisms were not associated with endometriosis: glutathione S-transferase theta 1 (GSTT1) null genotype, vascular endothelial growth factor alpha (VEGFA) rs699947, rs833061, rs2010963 and rs3025039. WIDER IMPLICATIONSBy carefully taking account of how the control populations were defined, we identified polymorphisms that might be candidates for use in endometriosis screening and polymorphisms not associated with endometriosis. This might constitute the first step towards identifying polymorphism combinations that predispose to endometriosis (IFNG (CA) repeat, GSTM1 null genotype, GSTP1 rs1695, WNT4 rs16826658 and WNT4 rs2235529) in a large cohort of patients with well-defined inclusion criteria. In turn, these results might improve the diagnosis of endometriosis in primary care. Lastly, our present findings may enable a better understanding of endometriosis and improve the management of patients with this disease.

    更新日期:2019-12-30
  • BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-10
    Turan V, Oktay K.

    BACKGROUNDOocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging. OBJECTIVE AND RATIONALEAlthough there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. SEARCH METHODSWe searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. OUTCOMESLaboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. WIDER IMPLICATIONSThe existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

    更新日期:2019-12-30
  • Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-23
    Gunning M, Sir Petermann T, Crisosto N, et al.

    BACKGROUNDWomen diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALEThe aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1–18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODSPubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as ‘offspring’ and ‘PCOS’ were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (β) as outcome. OUTCOMESNine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (β = 0.21(95%CI: 0.01–0.41), P = 0.05), insulin-resistance (β = 0.21(95%CI: 0.01–0.42), P = 0.04), triglycerides (β = 0.19(95%CI: 0.02–0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (β = 0.31(95%CI: 0.08–0.54), P < 0.01), but a reduced birthweight (β = −116(95%CI: −195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (βf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((βm) = −0.20(95%CI: −0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein–cholesterol differences in OPCOS versus controls were lower among females (βf = −0.39(95%CI: −0.62 to 0.16)), but comparable between male OPCOS and male controls (βm = 0.27(95%CI: −0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (βf = −0.31(95%CI: −0.57 to 0.06), βm = 0.28(95%CI: −0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (βf = 0.53(95%CI: 0.18–0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (βm = 0.13(95%CI: −0.05−0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: βf = −0.14(95%CI: −1.05 to 0.77)) or males (OPCOS versus controls: βm = 0.85(95%CI: −0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONSWe observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may—next to a genetic predisposition—influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.

    更新日期:2019-12-30
  • Ovarian stimulation for freeze-all IVF cycles: a systematic review
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-23
    Mizrachi Y, Horowitz E, Farhi J, et al.

    BACKGROUNDFreeze-all IVF cycles are becoming increasingly prevalent for a variety of clinical indications. However, the actual treatment objectives and preferred treatment regimens for freeze-all cycles have not been clearly established. OBJECTIVE AND RATIONALEWe aimed to conduct a systematic review of all aspects of ovarian stimulation for freeze-all cycles. SEARCH METHODSA comprehensive search in Medline, Embase and The Cochrane Library was performed. The search strategy included keywords related to freeze-all, cycle segmentation, cumulative live birth rate, preimplantation genetic diagnosis, preimplantation genetic testing for aneuploidy, fertility preservation, oocyte donation and frozen-thawed embryo transfer. We included relevant studies published in English from 2000 to 2018. OUTCOMESOur search generated 3292 records. Overall, 69 articles were included in the final review. Good-quality evidence indicates that in freeze-all cycles the cumulative live birth rate increases as the number of oocytes retrieved increases. Although the risk of severe ovarian hyperstimulation syndrome (OHSS) is virtually eliminated in freeze-all cycles, there are certain risks associated with retrieval of large oocyte cohorts. Therefore, ovarian stimulation should be planned to yield between 15 and 20 oocytes. The early follicular phase is currently the preferred starting point for ovarian stimulation, although luteal phase stimulation can be used if necessary. The improved safety associated with the GnRH antagonist regimen makes it the regimen of choice for ovarian stimulation in freeze-all cycles. Ovulation triggering with a GnRH agonist almost completely eliminates the risk of OHSS without affecting oocyte and embryo quality and is therefore the trigger of choice. The addition of low-dose hCG in a dual trigger has been suggested to improve oocyte and embryo quality, but further research in freeze-all cycles is required. Moderate-quality evidence indicates that in freeze-all cycles, a moderate delay of 2–3 days in ovulation triggering may result in the retrieval of an increased number of mature oocytes without impairing the pregnancy rate. There are no high-quality studies evaluating the effects of sustained supraphysiological estradiol (E2) levels on the safety and efficacy of freeze-all cycles. However, no significant adverse effects have been described. There is conflicting evidence regarding the effect of late follicular progesterone elevation in freeze-all cycles. WIDER IMPLICATIONSOvarian stimulation for freeze-all cycles is different in many aspects from conventional stimulation for fresh IVF cycles. Optimisation of ovarian stimulation for freeze-all cycles should result in enhanced treatment safety along with improved cumulative live birth rates and should become the focus of future studies.

    更新日期:2019-12-30
  • Do cancer therapies damage the uterus and compromise fertility?
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-12-20
    Griffiths M, Winship A, Hutt K.

    BACKGROUNDAs cancer survival rates improve, understanding and preventing the adverse off-target and long-term impacts of cancer treatments, including impacts on fertility, have become increasingly important. Cancer therapy-mediated damage to the ovary and depletion of the primordial follicle reserve are well characterised. However, our knowledge of the full extent of damage to the rest of the female reproductive tract, in particular the uterus, is limited. OBJECTIVE AND RATIONALEImproving our understanding of the off-target effects of cancer therapies on the entire female reproductive tract is a critical step towards developing truly effective strategies to protect the fertility of cancer survivors. The objective of this narrative review was to critically evaluate the available literature regarding the capacity for the uterus to sustain a healthy pregnancy following exposure to radiotherapy or chemotherapy. SEARCH METHODSThe authors performed PubMed (Medline) searches using the following key words: uterus, cancer survivors, radiotherapy, chemotherapy, pregnancy outcome, fertility preservation, infertility. There were no limits placed on time of publication. OUTCOMESOverall, there were major limitations to the current available literature, meaning that interpretations should be taken with caution. Despite these drawbacks, data suggest that the uterus may sustain off-target damage, with the extent of damage dependent on the type of cancer treatment and patient age. Specifically, uterine growth is stunted and resistant to hormone replacement therapy in prepubertal girls receiving abdominal, pelvic or whole-body radiotherapy. In contrast, females treated with radiotherapy post-puberty can benefit from hormone replacement therapy, as demonstrated by increased uterine volume and function. No live births have been reported in women previously exposed to radiotherapy after transplantation of cryopreserved ovarian tissue, even when menstruation returns. However, this technique has proven to be a successful fertility preservation method for women previously treated with chemotherapy. Obstetricians commonly report that women who maintain sufficient ovarian function can achieve pregnancy naturally following radiotherapy, but they have thin and/or fibrotic myometrium at delivery, compromising safe delivery and subsequent pregnancy. Furthermore, women exposed to either radiotherapy or chemotherapy have a higher prevalence of preterm birth and low birth weight infants, even in those with normal ovarian function or when oocyte donation is utilised. The mechanisms of potential uterine damage are poorly understood. While the myometrium, vasculature and endometrial progenitor cells are possibly targets, further studies are clearly required and well-controlled animal models could provide the best avenue for these types of future investigations. WIDER IMPLICATIONSFemale cancer survivors experience greater rates of early pregnancy loss and complications, suggesting that cancer therapy-induced damage to the uterus contributes to infertility. Despite clinical reports dating back to 1989, we highlight a surprising lack of detail in the literature regarding the precise nature and extent of off-target damage inflicted to the uterus in response to cancer therapies. Young women requiring cancer treatment, and the clinicians treating them, must be equipped with accurate information to aid informed decision-making regarding cancer treatment regimens as well as the development and use of effective fertility preservation measures. As the current literature on the impacts of cancer treatments is limited, we hope that our narrative review on this subject will stimulate more research in this important field.

    更新日期:2019-12-21
  • Human sperm ion channel (dys)function: implications for fertilization
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-30
    Brown S, Publicover S, Barratt C, et al.

    BACKGROUNDIntensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples. OBJECTIVE AND RATIONALEThis review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential. SEARCH METHODSRelevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate. OUTCOMESThere are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men. WIDER IMPLICATIONSRecent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order to help prevent failed ART cycles. Conversely, development of drugs that block calcium and/or potassium conductances in sperm is a plausible strategy for producing sperm-specific contraceptives.

    更新日期:2019-11-13
  • First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-23
    Wang R, Li W, Bordewijk E, et al.

    BACKGROUNDPolycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment–covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALEWe aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODSWe searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMESIPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17–1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23–1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38–2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01–1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00–1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00–1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87–1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01–1.06). WIDER IMPLICATIONSIn women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

    更新日期:2019-11-13
  • Fertility preservation for transgender adolescents and young adults: a systematic review
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-21
    Baram S, Myers S, Yee S, et al.

    BACKGROUNDMany transgender individuals choose to undergo gender-affirming hormone treatment (GAHT) and/or sex reassignment surgery (SRS) to alleviate the distress that is associated with gender dysphoria. Although these treatment options often succeed in alleviating such symptoms, they can also negatively impact future reproductive potential. OBJECTIVE AND RATIONALEThe purpose of this systematic review was to synthesize the available psychosocial and medical literature on fertility preservation (FP) for transgender adolescents and young adults (TAYAs), to identify gaps in the current research and provide suggestions for future research directions. SEARCH METHODSA systematic review of English peer-reviewed papers published from 2001 onwards, using the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P) guidelines, was conducted. Four journal databases (Ovid MEDLINE, PubMed Medline, Ovid Embase and Ovid PsychINFO) were used to identify all relevant studies exploring psychosocial or medical aspects of FP in TAYAs. The search strategy used a combination of subject headings and generic terms related to the study topic and population. Bibliographies of the selected articles were also hand searched and cross-checked to ensure comprehensive coverage. All selected papers were independently reviewed by the co-authors. Characteristics of the studies, objectives and key findings were extracted, and a systematic review was conducted. OUTCOMESIncluded in the study were 19 psychosocial-based research papers and 21 medical-based research papers that explore fertility-related aspects specific for this population. Key psychosocial themes included the desire to have children for TAYAs; FP discussions, counselling and referrals provided by healthcare providers (HCPs); FP utilization; the attitudes, knowledge and beliefs of TAYAs, HCPs and the parents/guardians of TAYAs; and barriers to accessing FP. Key medical themes included fertility-related effects of GAHT, FP options and outcomes. From a synthesis of the literature, we conclude that there are many barriers preventing TAYAs from pursuing FP, including a lack of awareness of FP options, high costs, invasiveness of the available procedures and the potential psychological impact of the FP process. The available medical data on the reproductive effects of GAHT are diverse, and while detrimental effects are anticipated, the extent to which these effects are reversible is unknown. WIDER IMPLICATIONSFP counselling should begin as early as possible as a standard of care before GAHT to allow time for informed decisions. The current lack of high-quality medical data specific to FP counselling practice for this population means there is a reliance on expert opinion and extrapolation from studies in the cisgender population. Future research should include large-scale cohort studies (preferably multi-centered), longitudinal studies of TAYAs across the FP process, qualitative studies of the parents/guardians of TAYAs and studies evaluating the effectiveness of different strategies to improve the attitudes, knowledge and beliefs of HCPs.

    更新日期:2019-11-13
  • In-utero stress and mode of conception: impact on regulation of imprinted genes, fetal development and future health
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-21
    Argyraki M, Damdimopoulou P, Chatzimeletiou K, et al.

    BACKGROUNDGenomic imprinting is an epigenetic gene regulatory mechanism; disruption of this process during early embryonic development can have major consequences on both fetal and placental development. The periconceptional period and intrauterine life are crucial for determining long-term susceptibility to diseases. Treatments and procedures in assisted reproductive technologies (ART) and adverse in-utero environments may modify the methylation levels of genomic imprinting regions, including insulin-like growth factor 2 (IGF2)/H19, mesoderm-specific transcript (MEST), and paternally expressed gene 10 (PEG10), affecting the development of the fetus. ART, maternal psychological stress, and gestational exposures to chemicals are common stressors suspected to alter global epigenetic patterns including imprinted genes. OBJECTIVE AND RATIONALEOur objective is to highlight the effect of conception mode and maternal psychological stress on fetal development. Specifically, we monitor fetal programming, regulation of imprinted genes, fetal growth, and long-term disease risk, using the imprinted genes IGF2/H19, MEST, and PEG10 as examples. The possible role of environmental chemicals in genomic imprinting is also discussed. SEARCH METHODSA PubMed search of articles published mostly from 2005 to 2019 was conducted using search terms IGF2/H19, MEST, PEG10, imprinted genes, DNA methylation, gene expression, and imprinting disorders (IDs). Studies focusing on maternal prenatal stress, psychological well-being, environmental chemicals, ART, and placental/fetal development were evaluated and included in this review. OUTCOMESIGF2/H19, MEST, and PEG10 imprinted genes have a broad developmental effect on fetal growth and birth weight variation. Their disruption is linked to pregnancy complications, metabolic disorders, cognitive impairment, and cancer. Adverse early environment has a major impact on the developing fetus, affecting mostly growth, the structure, and subsequent function of the hypothalamic–pituitary–adrenal axis and neurodevelopment. Extensive evidence suggests that the gestational environment has an impact on epigenetic patterns including imprinting, which can lead to adverse long-term outcomes in the offspring. Environmental stressors such as maternal prenatal psychological stress have been found to associate with altered DNA methylation patterns in placenta and to affect fetal development. Studies conducted during the past decades have suggested that ART pregnancies are at a higher risk for a number of complications such as birth defects and IDs. ART procedures involve multiple steps that are conducted during critical windows for imprinting establishment and maintenance, necessitating long-term evaluation of children conceived through ART. Exposure to environmental chemicals can affect placental imprinting and fetal growth both in humans and in experimental animals. Therefore, their role in imprinting should be better elucidated, considering the ubiquitous exposure to these chemicals. WIDER IMPLICATIONSDysregulation of imprinted genes is a plausible mechanism linking stressors such as maternal psychological stress, conception using ART, and chemical exposures with fetal growth. It is expected that a greater understanding of the role of imprinted genes and their regulation in fetal development will provide insights for clinical prevention and management of growth and IDs. In a broader context, evidence connecting impaired imprinted gene function to common diseases such as cancer is increasing. This implies early regulation of imprinting may enable control of long-term human health, reducing the burden of disease in the population in years to come.

    更新日期:2019-11-13
  • Ovarian damage from chemotherapy and current approaches to its protection
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-10
    Spears N, Lopes F, Stefansdottir A, et al.

    BackgroundAnti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage. Objective and rationaleThis paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed. Search methodsArticles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents. OutcomesRecent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed. Wider implicationsUnderstanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically.

    更新日期:2019-11-13
  • Sperm recovery and ICSI outcomes in men with non-obstructive azoospermia: a systematic review and meta-analysis
    Hum. Reprod. Update (IF 12.878) Pub Date : 2019-10-30
    Corona G, Minhas S, Giwercman A, et al.

    BACKGROUNDFactor affecting sperm retrieval rate (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in patients with non-obstructive azoospermia (NOA) have not been systematically evaluated. In addition, although micro-TESE (mTESE) has been advocated as the gold standard for sperm retrieval in men with NOA, its superiority over conventional TESE (cTESE) remains conflicting. OBJECTIVE AND RATIONALEThe objective was to perform a meta-analysis of the currently available studies comparing the techniques of sperm retrieval and to identify clinical and biochemical factors predicting SRR in men with NOA. In addition, PRs and live birth rates (LBRs), as derived from subjects with NOA post-ICSI, were also analysed as secondary outcomes. SEARCH METHODSAn extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR derived from cTESE or mTESE in patients with NOA and their specific determinants were included. Data derived from genetic causes of NOA or testicular sperm aspiration were excluded. OUTCOMESOut of 1236 studies, 117 studies met the inclusion criteria for this study, enrolling 21 404 patients with a mean age (± SD) of 35.0 ± 2.7 years. cTESE and mTESE were used in 56 and 43 studies, respectively. In addition, 10 studies used a mixed approach and 8 studies compared cTESE with mTESE approach. Overall, a SRR per TESE procedure of 47[45;49]% (mean percentage [95% CI]) was found. No differences were observed when mTESE was compared to cTESE (46[43;49]% for cTESE versus 46[42;49]% for mTESE). Meta-regression analysis demonstrated that SRR per cycle was independent of age and hormonal parameters at enrolment. However, the SRR increased as a function of testis volume. In particular, by applying ROC curve analysis, a mean testis volume higher than 12.5 ml predicted SRR >60% with an accuracy of 86.2% ± 0.01. In addition, SRR decreased as a function of the number of Klinefelter’s syndrome cases included (S = −0.02[−0.04;−0.01]; P < 0.01. I = 0.12[−0.05;0.29]; P = 0.16). Information on fertility outcomes after ICSI was available in 42 studies. Overall, a total of 1096 biochemical pregnancies were reported (cumulative PR = 29[25;32]% per ICSI cycle). A similar rate was observed when LBR was analysed (569 live births with a cumulative LBR = 24[20;28]% per ICSI cycle). No influence of male and female age, mean testis volume or hormonal parameters on both PR and LBR per ICSI cycle was observed. Finally, a higher PR per ICSI cycle was observed when the use of fresh sperm was compared to cryopreserved sperm (PR = 35[30;40]%, versus 20[13;29]% respectively): however, this result was not confirmed when cumulative LBR per ICSI cycle was analysed (LBR = 30[20;41]% for fresh versus 20[12;31]% for cryopreserved sperm). WIDER IMPLICATIONSThis analysis shows that cTESE/mTESE in subjects with NOA results in SRRs of up to 50%, with no differences when cTESE was compared to mTESE. Retrieved sperms resulted in a LBR of up to 28% ICSI cycle. Although no difference between techniques was found, to conclusively clarify if one technique is superior to the other, there is a need for a sufficiently powered and well-designed randomized controlled trial to compare mTESE to cTESE in men with NOA.

    更新日期:2019-11-13
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  • Adherence to review protocol and rigorous methodology are the pre-requisites of a well-conducted systematic review.
    Hum. Reprod. Update (IF 12.878) Pub Date : null
    Amerigo Vitagliano,Guido Ambrosini,Alessandra Andrisani,Mohan S Kamath,Attilio Di Spiezio Sardo

    更新日期:2019-11-01
  • The role of infection in miscarriage.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2015-09-20
    Sevi Giakoumelou,Nick Wheelhouse,Kate Cuschieri,Gary Entrican,Sarah E M Howie,Andrew W Horne

    BACKGROUND Miscarriage is the spontaneous loss of a pregnancy before 12 weeks (early miscarriage) or from 12 to 24 weeks (late miscarriage) of gestation. Miscarriage occurs in one in five pregnancies and can have considerable physiological and psychological implications for the patient. It is also associated with significant health care costs. There is evidence that potentially preventable infections may account for up to 15% of early miscarriages and up to 66% of late miscarriages. However, the provision of associated screening and management algorithms is inconsistent for newly pregnant women. Here, we review recent population-based studies on infections that have been shown to be associated with miscarriage. METHODS Our aim was to examine where the current scientific focus lies with regards to the role of infection in miscarriage. Papers dating from June 2009 with key words 'miscarriage' and 'infection' or 'infections' were identified in PubMed (292 and 327 papers, respectively, on 2 June 2014). Relevant human studies (meta-analyses, case-control studies, cohort studies or case series) were included. Single case reports were excluded. The studies were scored based on the Newcastle - Ottawa Quality Assessment Scale. RESULTS The association of systemic infections with malaria, brucellosis, cytomegalovirus and human immunodeficiency virus, dengue fever, influenza virus and of vaginal infection with bacterial vaginosis, with increased risk of miscarriage has been demonstrated. Q fever, adeno-associated virus, Bocavirus, Hepatitis C and Mycoplasma genitalium infections do not appear to affect pregnancy outcome. The effects of Chlamydia trachomatis, Toxoplasma gondii, human papillomavirus, herpes simplex virus, parvovirus B19, Hepatitis B and polyomavirus BK infections remain controversial, as some studies indicate increased miscarriage risk and others show no increased risk. The latest data on rubella and syphilis indicate increased antenatal screening worldwide and a decrease in the frequency of their reported associations with pregnancy failure. Though various pathogens have been associated with miscarriage, the mechanism(s) of infection-induced miscarriage are not yet fully elucidated. CONCLUSIONS Further research is required to clarify whether certain infections do increase miscarriage risk and whether screening of newly pregnant women for treatable infections would improve reproductive outcomes.

    更新日期:2019-11-01
  • Metabolic heterogeneity during preimplantation development: the missing link?
    Hum. Reprod. Update (IF 12.878) Pub Date : 2014-05-06
    Daniel R Brison,Roger G Sturmey,Henry J Leese

    BACKGROUND Most tissues in the body rely on the presence of gap junctions in order to couple their component cells electrically and metabolically via intercellular transport of ions, metabolites and signalling agents. As a result, cells within tissues achieve a high degree of, 'metabolic homogeneity' which enables them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues. Unusually, the developing mammalian preimplantation embryo does not form functional gap junctions until it has divided into 8 or more cells. We discuss the implications of this 'missing link' during the first few days of development for the maintenance of homogeneity between embryonic cells and for the co-ordination of the embryonic response to intrinsic genetic damage and external environmental signals. METHODS No systematic review has been carried out. The physiology of preimplantation development and the general nature of gap junctions have been reviewed briefly before examining experimental evidence which addresses the following points: (i) whether there are functional differences between early blastomeres; (ii) when during preimplantation development the embryo is most sensitive to environmental perturbation and (iii) the consequences for early embryos of ablating gap junction formation and function. RESULTS AND CONCLUSIONS General conclusions are confounded by species differences, especially in the timing of embryonic genome activation (EGA) and the extent of intrinsic genotypic and phenotypic variation (low in embryos from inbred mice; high in human embryos). Nevertheless, we propose that the absence of gap junctions requires cleavage stage mammalian embryos to behave cell autonomously in a metabolic sense, contributes to their heightened sensitivity to environmental perturbation compared with the later stages of preimplantation development and poses more problems in the early human embryo, where there is a high degree of heterogeneity between the blastomeres. We argue that the legacy of metabolic heterogeneity, in part generated by the absence of gap junctions, is 'rescued' by the onset of apoptosis following EGA. In the context of human-assisted conception, since early embryos lacking gap junctions are more sensitive to environmental stress during cleavage, this would support transfer to the natural environment as early as possible after fertilization.

    更新日期:2019-11-01
  • Oocyte activation, phospholipase C zeta and human infertility.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2010-06-25
    J Kashir,B Heindryckx,C Jones,P De Sutter,J Parrington,K Coward

    BACKGROUND Mammalian oocytes are activated by intracellular calcium (Ca(2+)) oscillations following gamete fusion. Recent evidence implicates a sperm-specific phospholipase C zeta, PLCζ, which is introduced into the oocyte following membrane fusion, as the responsible factor. This review summarizes the current understanding of human oocyte activation failure and describes recent discoveries linking certain cases of male infertility with defects in PLCζ expression and activity. How these latest findings may influence future diagnosis and treatment options are also discussed. METHODS Systematic literature searches were performed using PubMed, ISI-Web of Knowledge and The Cochrane Library. We also scrutinized material from the United Nations and World Health Organization databases (UNWHO) and the Human Fertilization and Embryology Authority (HFEA). RESULTS AND CONCLUSIONS Although ICSI results in average fertilization rates of 70%, complete or virtually complete fertilization failure still occurs in 1-5% of ICSI cycles. While oocyte activation failure can, in some cases, be overcome by artificial oocyte activators such as calcium ionophores, a more physiological oocyte activation agent might release Ca(2+) within the oocyte in a more efficient and controlled manner. As PLCζ is now widely considered to be the physiological agent responsible for activating mammalian oocytes, it represents both a novel diagnostic biomarker of oocyte activation capability and a possible mode of treatment for certain types of male infertility.

    更新日期:2019-11-01
  • Current knowledge of the aetiology of human tubal ectopic pregnancy.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2010-01-15
    J L V Shaw,S K Dey,H O D Critchley,A W Horne

    BACKGROUND An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common cause of maternal mortality in the first trimester of pregnancy. The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization. This review appraises the data to date researching the aetiology of tubal ectopic pregnancy. METHODS Scientific literature was searched for studies investigating the underlying aetiology of tubal ectopic pregnancy. RESULTS Existing data addressing the underlying cause of tubal ectopic pregnancy are mostly descriptive. There are currently few good animal models of tubal ectopic pregnancy. There are limited data explaining the link between risk factors and tubal implantation. CONCLUSIONS Current evidence supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur. Future studies are needed that address the functional consequences of infection and smoking on Fallopian tube physiology. A greater understanding of the aetiology of tubal ectopic pregnancy is critical for the development of improved preventative measures, the advancement of diagnostic screening methods and the development of novel treatments.

    更新日期:2019-11-01
  • Maternal metabolism and obesity: modifiable determinants of pregnancy outcome.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2009-12-08
    Scott M Nelson,Phillippa Matthews,Lucilla Poston

    BACKGROUND Obesity among pregnant women is highly prevalent worldwide and is associated in a linear manner with markedly increased risk of adverse outcome for mother and infant. Obesity in the mother may also independently confer risk of obesity to her child. The role of maternal metabolism in determining these outcomes and the potential for lifestyle modification are largely unknown. METHODS Relevant studies were identified by searching PubMed, the metaRegister of clinical trials and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words. RESULTS Maternal obesity and gestational weight gain have a significant impact on maternal metabolism and offspring development. Insulin resistance, glucose homeostasis, fat oxidation and amino acid synthesis are all disrupted by maternal obesity and contribute to adverse outcomes. Modification of lifestyle is an effective intervention strategy for improvement of maternal metabolism and the prevention of type 2 diabetes and, potentially, gestational diabetes. CONCLUSIONS Maternal obesity requires the development of effective interventions to improve pregnancy outcome. Strategies that incorporate a detailed understanding of the maternal metabolic environment and its consequences for the health of the mother and the growth of the child are likely to identify the best approach.

    更新日期:2019-11-01
  • Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2006-05-10
    Eric Jauniaux,Lucilla Poston,Graham J Burton

    Miscarriage and pre-eclampsia are the most common disorders of human pregnancy. Both are placental-related and exceptional in other mammalian species. Ultrasound imaging has enabled events during early pregnancy to be visualized in vivo for the first time. As a result, a new understanding of the early materno-fetal relationship has emerged and, with it, new insight into the pathogenesis of these disorders. Unifying the two is the concept of placental oxidative stress, with associated necrosis and apoptosis of the trophoblastic epithelium of the placental villous tree. In normal pregnancies, the earliest stages of development take place in a low oxygen (O2) environment. This physiological hypoxia of the early gestational sac protects the developing fetus against the deleterious and teratogenic effects of O2 free radicals (OFRs). In miscarriage, development of the placento-decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, with the time at which it occurs in the first trimester depending on the aetiology. In contrast, in pre-eclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero-placental circulation, predisposing to a repetitive ischaemia-reperfusion (I/R) phenomenon. We suggest that pre-eclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chronic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.

    更新日期:2019-11-01
  • Development of contraceptive vaccines for humans using antigens derived from gametes (spermatozoa and zona pellucida) and hormones (human chorionic gonadotrophin): current status.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-01-01
    R K Naz,A Sacco,O Singh,R Pal,G P Talwar

    Contraceptive research has entered a new phase of development with the advent of hybridoma and DNA recombinant technologies. During the past 5 years, significant advances have been made in this area and now it seems that realistic prospects exist for the development of contraceptive vaccines for use in humans and animals (veterinary, wild and domestic), applicable to both the female and male sexes. Contraceptive vaccines will be valuable supplements to the presently available methods of family planning, and, due to high specificity, the occurrence of limited side-effects if any, low cost and infrequent administration, contraceptive vaccines may have greater acceptability than the currently available methods. Mammalian reproduction starts with the unison of gametes contributed by the male and female partners. Both spermatozoon and oocyte have antigens on the cell surface that are unique, tissue-specific, immunogenic and accessible to antibodies, and binding of the antibodies to these antigens can cause inhibition of gamete function, resulting in a failure of fertilization. Fertilization is followed by embryogenesis, with the early embryo producing several proteins, some of which, e.g. human chorionic gonadotrophin (HCG), have a vital role in the establishment and maintenance of early pregnancy. Again, these proteins are accessible to antibodies, and their immunoneutralization can cause anti-fertility effects with loss of early embryo. Thus, the antigens derived from proteins on spermatozoa, oocyte and early embryo, especially HCG, constitute interesting molecules for the development of contraceptive vaccines. The aim of the present article is to review the current status of development of contraceptive vaccines based on antigens derived from sperm cell, oocyte zona pellucida and HCG, and to discuss their relative merits and future development.

    更新日期:2019-11-01
  • Reply: The two sides of the individualization of controlled ovarian stimulation.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2014-08-06
    Antonio La Marca,Sesk Kamal Sunkara

    更新日期:2019-11-01
  • Genetic variants in pre-eclampsia should be interpreted with caution.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2013-08-10
    A J Buurma,O M Dekkers,H J Baelde

    更新日期:2019-11-01
  • Human follicle-stimulating hormone produced by recombinant DNA technology: a review for clinicians.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-03-01
    E Loumaye,R Campbell,J Salat-Baroux

    Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH.

    更新日期:2019-11-01
  • CA125 and endometriosis.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-03-01
    M Muyldermans,F J Cornillie,P R Koninckx

    This review covers the literature on CA125 and endometriosis; data on CA125 and oncology are not discussed. In normal women, plasma concentrations of CA125 are increased slightly at ovulation and significantly during menstruation. Marked increases are observed during pregnancy and following peritoneal irritation by infection or surgery. These data are consistent with the concept that CA125 in normal women is mainly derived from the endometrium and the irritated peritoneum. Plasma concentrations of CA125 are markedly elevated in women with cystic ovarian endometriosis and/or deeply infiltrating endometriosis, but not, or only slightly, in the luteal phase of women with minimal or mild endometriosis. This is consistent with the recent concept which considers minimal endometriosis as a normal condition occurring intermittently in many women, in contrast with deep endometriosis and cystic ovarian endometriosis which are called 'endometriotic disease'. Serum CA125 is not a good marker for endometriosis but it is a helpful additional parameter to diagnose endometriotic disease in patients with chronic pelvic pain. Following treatment of endometriosis, elevated plasma concentrations of CA125 could be used as an argument that treatment has been incomplete, or that the condition has recurred. Assaying CA125 in peritoneal fluid requires high sample dilutions or a modified immunoradiometric assay, and until now, its clinical value has been questionable.

    更新日期:2019-11-01
  • Angiogenic growth factor expression in the uterus.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-03-01
    S K Smith

    更新日期:2019-11-01
  • Adaptive strategies regulating energy balance in human pregnancy.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-03-01
    A M Prentice,S D Poppitt,G R Goldberg,A Prentice

    更新日期:2019-11-01
  • Culture of preimplantation embryos: facts and artifacts.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1995-03-01
    B D Bavister

    Mammalian preimplantation embryos normally develop within the protected environment of the female reproductive tract, which virtually precludes studies on embryogenesis in situ. Information must therefore be derived from experiments on cultured embryos. Consequently, studies on the epigenetic regulation of embryogenesis have long been interwoven with efforts to formulate culture media capable of sustaining normal development. In this review, comparative information on epigenetic regulation of embryo development is discussed, including information on energy substrate and amino acid preferences of embryos. Advantages of simple versus complex culture media, and of substituting serum albumin or synthetic macromolecules for serum, are discussed. Some potential pitfalls of co-culture are described. Culture appears to induce anomalies in embryo metabolism, which may derive from disturbed intracellular pH. Rationales for selecting endpoints to evaluate the outcome of experiments are considered, including incorporation of timing of embryo development into the analysis. Poor experimental design and/or data analysis can detract from or even negate the value of data obtained from embryo culture; examples are examined to help correct this problem. All of these points are discussed with a view to using data on the needs of embryos for making improvements in the design of culture media, so that higher yields and increased viability of embryos are achieved.

    更新日期:2019-11-01
  • Ethics and reproductive medicine.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    D Schäfer,R Baumann,M Kettner

    This article surveys relevant moral and ethical implications of reproductive medicine, excluding any aspects of contraception. To maintain the methodological priority of a moral perspective, it focuses on moral theory and ethics in general before looking at the impact of ethics on the different techniques applied in reproductive medicine. We suggest that discourse ethics should be centre-stage among the moral perspectives, since it has a unique capacity to synthesize, gauge and emulate other moral perspectives without necessarily replacing them. Questions of spousal fidelity, parental identity, sexual relations, reshaping of family ties, preimplantation diagnosis, discarding of human life, up to the question of what kind of life is generally acknowledged as worth living, and which is not, all these are morally significant topics. As well as providing a description of the techniques used in reproductive medicine, our article presents a rationale for charting potentials for moral problems. This renders it possible to elucidate the moral costs of each of the options offered by reproductive medicine in the light of whatever moral view one identifies with.

    更新日期:2019-11-01
  • Diagnosis and management of organic ovarian cysts: indications and procedures for laparoscopy.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    C Chapron,J B Dubuisson,X Fritel,D Rambaud

    In the field of gynaecological surgery, the past few years have been significant due to the development of operative laparoscopy. Originally recommended for the diagnosis of female infertility, over the past 15 years laparoscopy has acquired the standing of a surgical discipline in its own right. Laparoscopic surgical treatment of ovarian cysts, whether conservative or radical, has now been completely standardized. The aim of this work is to specify the indications, procedures and risks involved with this surgery as applied to organic ovarian cysts. Only benign ovarian cysts are suitable for treatment by laparoscopic surgery; ovarian cancer must always be handled by classic surgery using a mid-line laparotomy. Given that clinical and other pre-operative investigations can give only an indication, ovarian lesions require surgical investigation to diagnose the histological type. Laparoscopy appears to be as reliable as laparotomy when assessing whether an ovarian tumour is malignant. The risk of parietal contamination and peritoneal dissemination if a malignancy is not recognized means that, if there are no signs of extra-ovarian extension, adnexectomy is mandatory whenever there is the slightest doubt. This adnexectomy must obey two important rules: it must be accomplished without rupturing the cyst, and the cyst must be placed, intact, inside an endoscopic bag before being extracted. Provided that all stages of the procedure, from pre-operative work-up to the initial diagnostic phase of the laparoscopy, are carried out meticulously, laparoscopic surgery is reliable for both the diagnosis and the management of benign organic-ovarian cysts.

    更新日期:2019-11-01
  • The assessment of tubal functional status by tubal perfusion pressure measurements.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    C V Karande,E D Pratt,N Gleicher

    The measurement of tubal perfusion pressures (TPP) is a recent advance in the field of gynaecoradiology. Measurement of TPP involves a standardized technique using transcervically placed tubal catheters which is reviewed in detail. TPP assesses the functional status of the Fallopian tubes, i.e. their ability to permit pregnancy. Infertile patients with normal TPP demonstrated a higher pregnancy rate (10 out of 23) than patients with elevated TPP (four out of 24, P < 0.05). Analysis of patients who had undergone a laparoscopy as well as measurement of TPP suggest that elevated TPP are highly indicative of tubal endometriosis. Tubal catheterization with wireguides was successful in reducing mildly elevated TPP. The impact of this procedure on pregnancy rates is not known. The use of the gynaecoradiological techniques discussed in this paper has reduced the need for diagnostic laparoscopy at our centre by >60%. This was achieved without compromise in pregnancy rates and has resulted in a considerable reduction in cost.

    更新日期:2019-11-01
  • Modern surgical approaches to female reproductive tract.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    T Tulandi

    Laparoscopic and hysteroscopic surgery have changed the management of many gynaecological disorders. Procedures that previously required a long duration of hospitalization can now be done on an outpatient basis or with a short hospital stay. Surgical treatment remains the definitive and universal treatment of ectopic pregnancy and it can be safely done by laparoscopy. Most reproductive operations are done by laparoscopy and the results appear to be similar to those obtained with laparotomy. Those needing a laparotomy will be better treated by in-vitro fertilization. Laparoscopic ovarian drilling is a viable alternative for infertile women with polycystic ovarian syndrome. Most ovarian cysts and endometriosis should be treated by laparoscopy. Although uterine myomas can be removed by laparoscopy, the uterine integrity after the procedure is questionable. Surgery should be reserved for women who have completed their family or those with pedunculated or shallow intramural myomas. Alternatively, a laparoscopically assisted myomectomy can be done. For laparoscopic hysterectomies for benign lesions, supracervical hysterectomy appears to be a good option. Hysteroscopy has changed our management, particularly for abnormal uterine bleeding. A submucous myoma and polyp can be removed by hysteroscopy and, as an alternative to hysterectomy, endometrial ablation can be done. In the future, most procedures will be done by endoscopy and laparotomy will be reserved only for selected cases.

    更新日期:2019-11-01
  • Development, structure and function of the cranial suspensory ligaments of the mammalian gonads in a cross-species perspective; their possible role in effecting disturbed testicular descent.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    P van der Schoot,J M Emmen

    The present review aims to present a perspectiveon a relatively unknown part of the mammalian internal genitalia: their cranial suspensory apparatus. This apparatus shows wide divergence of development when examined during the fetal period or during adulthood, in males or females, or in individuals across a variety of species. In rats and other mamalian species the apparatus undergoes a distinct patern of sexually dimorphic development and fetal testicular androgens are proposed to play a key role in this process. Extensive development of this suspensory apparatus in females is argued to be a part of the anatomical adaptations of the genital apparatus to support the internal genitalia throughout pregnancy, including the relatively enormous growth towards the time of parturition. Minor development of this apparatus in males is judged to be a part of the anatomical requirements allowing developing testes to become displaced from the dorsal abdominal wall during the first stage of testicular descent. Extensive development of this suspensory apparatus in males generally seems to hinder testicular descent. Accordingly, the apparatus is well developed in so-called testicond species which do not show testis descent as a part of their normal male genital development. Furthermore, arguments are adduced that inappropriate and extensive development in species with testis descent may be a key aetiological factor in the disturbance of this process. Diagnosis and treatment of human cryptorchidism might profit from including an analysis of the development and function of (remnants of) the cranial testicular and epididymal suspensory apparatus.

    更新日期:2019-11-01
  • The peritoneal environment in endometriosis.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    E Oral,D L Olive,A Arici

    The local environment of peritoneal fluid (PF) surrounding the endometriotic implant is immunologically dynamic and links the reproductive and immune systems. Peritoneal fluid contains a variety of free floating cells, including macrophages, mesothelial cells, lymphocytes, eosinophils and mast cells. Macrophages are attracted to the peritoneal environment more abundantly than any other cell type. These scavengers promote cellular growth and viability through secretion of growth factors and cytokines. It is now becoming evident that cytokines play an important role in reproduction at various levels, including gamete function, fertilization and embryo development, implantation and postimplantation survival of the conceptus. Peritoneal fluid has been shown to affect negatively ovum capture by the fimbria, sperm survival, spermatozoon-oocyte interaction and embryonic development. We have recently identified the presence of two pro-inflammatory chemoattractant cytokines for monocyte/macrophages (MCP-1) and for granulocytes (interleukin-8, IL-8) in the PF. Concentrations of both IL-8 and MCP-1 are not only elevated in PF of women with endometriosis compared to those without endometriosis, but they are related to the severity of the disease. Over the past 70 years, at least a dozen theories have been proposed to explain the histogenesis and aetiology of endometriosis. It appears that the aetiology is multifactorial, and today a composite theory of retrograde menstruation with implantation of endometrial fragments in conjunction with peritoneal factors to stimulate cell growth is the most widely accepted explanation for peritoneal endometriosis.

    更新日期:2019-11-01
  • Immunological aspects of endometriosis.
    Hum. Reprod. Update (IF 12.878) Pub Date : 1996-09-01
    D Vinatier,P Dufour,D Oosterlynck

    The immune system probably plays a role in the onset and development of endometriosis. A general picture can be proposed. In some women refluxing endometrial cells are not destroyed, either because the patient is genetically programmed not to respond to endometrial antigens, or because the reflux is so abundant that the scavenging capacity of the peritoneal immune cells is overloaded. Refluxing cells could be protected due to an abnormal adherence to the mesothelium which exceptionally expresses certain adhesive molecules. Undestroyed, these endometrial cells would cause an inflammation with activation of macrophages. Not only does the peritoneum protect these endometrial cells, but it also produces abnormal quantities of chemotactic and angiogenic cytokines (interleukin-8). Macrophages facilitate development via growth factors such as transforming growth factor P. Immunosuppressive factors block the cytotoxic activity of natural killer (NK) cells. Activated macrophages present antigens of endometrial cells to T cells which will co-operate with B cells to synthesize autoantibodies. Synthesized antibodies protect the ectopic endometrium and could worsen the dysfunction of local NK cells. A vicious circle is set up involving all the partners of the immune system. It is as yet impossible to pinpoint the triggering mechanism. The primary defect could be localized on the endometrium, macrophages already activated by an extrinsic factor (infection, spermatozoa, chemical substances), the uterus or the tubo-uterine junction. The two pathophysiological theories put forward to explain endometriosis are linked by a defective immune system. Indeed, once the vicious circle is set up, growth and angiogenic factors could induce metaplasia of the already irritated mesothelium.

    更新日期:2019-11-01
  • The development of cytogenetically normal, abnormal and mosaic embryos: a theoretical model.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    Frans J Los,Diane Van Opstal,Cardi van den Berg

    Assisted reproduction and preimplantation genetic diagnosis (PGD) involve various complicated techniques, each of them with its own problems. However, the greatest problem with PGD for chromosome abnormalities is not of a technical nature but is a biological phenomenon: chromosomal mosaicism in the cleavage stage embryo. Here, we present a hypothetical, quantitative model for the development of chromosomally normal, abnormal and mosaic embryos. The arising of mosaicism in 2-8-cell embryos was described by a binomial probability model on the occurrence of mitotic events inducing chromosomal changes in the blastomeres. This model converted the 'mean' rate of mosaicism found in cross-sectional studies (60%) into an equal rate of mosaic embryos at arrival at the 8-cell stage (59.8%). The disappearance of > 90% of the mosaic embryos or the mosaicism itself from surviving embryos during the morula stage was explained by mitotic arrest of most of the mitotically changed cells under increasing cell cycle control. In our model, 25.9 and 14.3% of the embryos at the 8-cell stage are normal and abnormal respectively. The remaining 59.8% of the embryo shows mosaicism: 34.6% of abnormal/normal cells and 25.2% of abnormal/abnormal cells. The high proportion of abnormal and mosaic embryos together explains the high rate of abnormal laboratory findings in PGD for chromosomal abnormalities and aneuploidy screening. The poor representation of a 1- or 2-cell biopsy for the 7- or 6-cell post-biopsy embryo in the case of mosaicism explains the high rate of false-negative and false-positive results.

    更新日期:2019-11-01
  • Neurobiological mechanisms of puberty in higher primates.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    Tony M Plant,Mandi L Barker-Gibb

    Puberty in humans is comprised of two developmental processes; namely, gonadarche and adrenarche. Of the two, gonadarche is fundamentally the most important, and this review examines the neurobiological mechanisms that first prevent, and later trigger, progression into this critically important phase of human development when the ability to first reproduce is established. The review draws extensively upon results obtained by studies of the rhesus monkey (Macaca mulatta), a representative higher primate which, like man, exhibits a postnatal pattern in activity of the hypothalamic-pituitary-gonadal axis that is characterized by a prolonged period of relative quiescence from late infancy until the initiation of the pubertal process. The proximate cause of the prepubertal quiescence in this neuroendocrine axis is the arrest or restraint of the pulsatile mode of hypothalamic GnRH release by a neurobiological brake that holds in check release of this decapeptide, without seeming to down-regulate the transcriptional activity of the gene encoding GnRH (GnRH-I). Thus, if neurogenomes control the onset of gonadarche, they must reside upstream from that of the GnRH neuron. The genetic and physiological factors (with a particular emphasis on leptin) that time the application and duration of the prepubertal brake on GnRH release are also considered.

    更新日期:2019-11-01
  • Electrical events during gamete maturation and fertilization in animals and humans.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    Elisabetta Tosti,Raffaele Boni

    Gamete cells are electrogenic, i.e. capable of responding to electrical stimuli and modifying their electrical properties during the crucial periods of maturation and fertilization. Ion channels have been widely demonstrated on the plasma membrane of the oocyte and spermatozoon in all animals studied, and electrical modifications in gametes are due to ion currents that are modulated via these ion channels. The modification of intracellular calcium levels in gametes has been extensively studied, and these modifications are recognized to be a second messenger system for gamete maturation and fertilization. Other ions also move through the plasma membrane, either in association with or independent of calcium, and these generate typical features such as fertilization currents and oscillation of resting potential. These modifications were first studied in marine invertebrates, and the observations subsequently compared with mammalian systems, including human. The precise role played by these currents in the processes of maturation and fertilization is still poorly understood; however, recent research opens new frontiers for their clinical and technological application.

    更新日期:2019-11-01
  • Role of caspases in male infertility.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    Tamer M Said,Uwe Paasch,Hans-Juergen Glander,Ashok Agarwal

    Apoptosis is characterized by a variety of changes resulting in the recognition and phagocytosis of apoptotic cells. Caspases (cysteinyl aspartate-specific proteinases) play a central role in the regulation of apoptosis in the human seminiferous epithelium. They are expressed as inactive proenzymes and participate in a cascade triggered in response to pro-apoptotic signals. To date, 14 caspases have been implicated in the human apoptotic pathway cascade. Among these, caspase-3 is considered to be a major executioner protease. Since apoptosis is a universal suicide system in almost all cells, a close control via molecular, endocrine and physical factors establishes homeostasis of cell growth and death. The proper regulation of the caspase cascade plays an important role in sperm differentiation and testicular maturity. However, caspases have been implicated in the pathogenesis of multiple andrological pathologies such as impaired spermatogenesis, decreased sperm motility and increased levels of sperm DNA fragmentation, testicular torsion, varicocele and immunological infertility. Future research may provide a better understanding of the regulation of caspases, which may help us to manipulate the apoptotic machinery for therapeutic benefits. In this review, we summarize the consequences of caspase activation, aiming to clarify their role in the pathogenesis of male infertility.

    更新日期:2019-11-01
  • Apoptosis in human endometrium and endometriosis.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    T Harada,A Kaponis,T Iwabe,F Taniguchi,G Makrydimas,N Sofikitis,M Paschopoulos,E Paraskevaidis,N Terakawa

    Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. The BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Similarities in characteristics of endometriosis at a molecular level with gynaecological tumours are also discussed. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.

    更新日期:2019-11-01
  • A review of ten years experience of ICSI.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    P Devroey,A Van Steirteghem

    This review summarizes the introduction of ICSI in the early 1990s as an assisted fertilization procedure in couples with severe male factor infertility, who could not be helped by conventional IVF. As for current practice, the indications for ICSI using fresh or frozen-thawed ejaculated, epididymal or testicular sperm are reviewed as well as some reports on the use of ICSI in non-male infertility. The main steps in an ICSI cycle are well standardized by now; it is rare that ICSI cannot be carried out and the results in terms of fertilization, embryo transfer and clinical pregnancy rate have been consistent for many years, indicating that a substantial number of couples can now have their own genetic child instead of having to use artificial insemination with donor sperm. This review also emphasizes the importance of assessing the risk of ICSI for the children: there is a slight increase in de novo chromosomal abnormalities, the major congenital malformation rate is similar for IVF and ICSI (between 3 and 4%), and at approximately 2 years of age the developmental outcome as assessed by the Bayley scale is similar for IVF and ICSI. Recent publications mention that a few children are affected by diseases caused by imprinting disorders. Future studies are needed to assess the association between assisted reproductive technologies and imprinting disorders. ICSI is frequently used in couples undergoing preimplantation genetic diagnosis. PGD stricto sensu as well as PGD for aneuploidy screening and for Klinefelter patients are reviewed using the ESHRE PGD Consortium data.

    更新日期:2019-11-01
  • Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-03-10
    Diana Lucifero,J Richard Chaillet,Jacquetta M Trasler

    Recent studies suggest a possible link between human assisted reproductive technology and genomic imprinting disorders. Assisted reproductive technology includes the isolation, handling and culture of gametes and early embryos at times when imprinted genes are likely to be particularly vulnerable to external influences. Evidence of sex-specific differences in imprint acquisition suggests that male and female germ cells may be susceptible to perturbations in imprinted genes at specific prenatal and postnatal stages. Imprints acquired first during gametogenesis must be maintained during preimplantation development when reprogramming of the overall genome occurs. In this review, we will discuss both new developments in our understanding of genomic imprinting including the mechanisms and timing of imprint erasure, acquisition and maintenance during germ cell development and early embryogenesis as well as the implications of this research for future epigenetic studies in reproduction and assisted reproductive technology.

    更新日期:2019-11-01
  • Terminology associated with vitrification and other cryopreservation procedures for oocytes and embryos.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    J M Shaw,G M Jones

    Over the past 30 years many cryopreservation procedures have been applied to oocytes, embryos, sperm, ovarian and testicular tissue. Over this time many, often specialized, terms have been developed for all aspects of these procedures. This can make it difficult for readers who are not familiar with the terminology or protocols to compare and evaluate different procedures. This paper describes the main cryopreservation procedures, the terminology associated with them, and briefly explains the underlying physical, chemical and biological processes. The aim is to help readers understand and interpret other papers on slow cooling, rapid cooling, ultrarapid cooling and vitrification.

    更新日期:2019-11-01
  • Chemically defined media and the culture of mammalian preimplantation embryos: historical perspective and current issues.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    Michael C Summers,John D Biggers

    Considerable advances in media development for the culture of preimplantation mammalian embryos have been made since mouse embryos were first cultured and successfully transferred to foster mothers. The purpose of this review is to detail the history of the development of chemically defined media for the culture of preimplantation embryos. Two approaches have been used to determine the composition of chemically defined media: the 'back-to-nature' approach and 'let the embryo choose' or empirical optimization approach. Recent developments, including the supplementation of media with amino acids and the use of sequential media for the extended culture of preimplantation embryos, are critically assessed. Importantly, it is recognized that even the best media currently used are not optimal and inevitably cause imbalances and stress to the embryos. Consequently, preimplantation embryos must adapt to the culture environment in order to survive. The adaptations to stress that occur when embryos are placed in a chemically defined environment are reviewed. The implications of these various stresses on the patterns of gene expression in the early embryo and their potential long-term effects are also emphasized. The scientific and ethical issues raised by the commercialization of human embryo culture media are briefly addressed.

    更新日期:2019-11-01
  • How to make a good oocyte: an update on in-vitro models to study follicle regulation.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    Fiona H Thomas,Kirsty A Walters,Evelyn E Telfer

    The ability to develop the technology to mature oocytes from immature oocytes in vitro is the ambition of many IVF clinics. If this can be successfully achieved then these techniques would be available to women with fertility problems. This would aid women at risk of premature ovarian failure, and possibly result in women no longer requiring an expensive drug regime and monitoring programme, which they currently have to undergo. The idea of harvesting immature oocytes for growth in vitro is not a new one, but progress has been slow in developing and optimizing techniques for use on humans and domestic species. At present, there are many technical reasons for the lack of progress in these species, such as length of culture and difficulty of follicle isolation. However, the major problem is our lack of knowledge of how the oocyte acquires developmental competence during its growth within the follicle. To date, culture systems have been developed that can support the growth and development of immature oocytes. These systems are beneficial in improving our knowledge of how autocrine/paracrine factors are involved in regulating and controlling oocyte development. However, only when we have a more in-depth understanding of what is required during development to make a viable oocyte, will we perhaps be able to develop in-vitro culture systems for clinical application. This review will focus on how analysis of early follicular growth and development, using in-vitro culture systems, has advanced our knowledge of the factors and process involved in the regulation of oocyte and somatic cell development.

    更新日期:2019-11-01
  • A comparison of placental development and endocrine functions between the human and mouse model.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    A Malassiné,J L Frendo,D Evain-Brion

    The placenta plays a key role in pregnancy, mediating exchanges between mother and fetus and maternal tolerance of fetopaternal antigens. In some species, it also produces hormones that ensure the maintenance of gestation and fetal well-being. This unique organ also has considerable potential for use as a model for various aspects of biology. Indeed, the use of transgenic mouse models has greatly improved our understanding of the genetic control of placental development in this species and has opened up new fields of investigation in developmental biology. Analogous cell types have been identified among human and murine trophoblasts: proliferative trophoblastic cells, invasive trophoblastic cells and cells differentiating into syncytium, but human and mouse placentas differ in both morphogenesis and endocrine function. Herein, the similarities and differences between the human and mouse models are reviewed, with a view to encouraging caution in the extrapolation of results from one model to the other.

    更新日期:2019-11-01
  • Clinical and molecular genetics of the human GnRH receptor.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    Beate Karges,Wolfram Karges,Nicolas de Roux

    A functional GnRH receptor (GnRH-R) in the anterior pituitary is critical for normal LH/FSH secretion, pubertal development and reproduction. Inactivating mutations of the GnRH-R have been identified in patients with idiopathic hypogonadotrophic hypogonadism. In this article we summarize phenotypic characteristics of these patients and focus on specific functional alterations of the human GnRH-R. In-vitro studies using recombinant receptor constructs demonstrate that GnRH-R missense mutations result in impaired ligand binding and reduced signal transduction, causing gonadotrophin deficiency. A detailed molecular understanding of receptor inactivation may help to design new GnRH agonists to therapeutically modulate GnRH-R function.

    更新日期:2019-11-01
  • The endometrium in stimulated cycles for IVF.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    Claire Bourgain,Paul Devroey

    Ovarian stimulation for IVF is known to affect luteal phase function. The endometrium in IVF cycles is thus subject to an altered endocrinological environment and to a possible direct effect of the ovarian stimulation therapy. Factors influencing the endometrial receptivity in such cycles are poorly understood. Studies comparing the endometrium in IVF cycles with natural cycles as controls have shown premature secretory changes in the post-ovulatory and early luteal phase of IVF cycles, followed by a large proportion of dyssynchronous glandular and stromal differentiation in the mid-luteal phase. These findings suggest a profound modification of luteal endometrial development in stimulated cycles. This hypothesis is further supported by the demonstration of a modified endometrial steroid receptor regulation and a profound antiproliferative effect in IVF cycles. The time of maximal endometrial receptivity is defined as the implantation window and is characterized by the expression of various endometrial products, among which pinopodes, integrins and leukaemia inhibitory factor are best described. Premature expression of pinopodes and integrins are in line with the observation of precocious luteal transformation following ovarian stimulation, although the clinical relevance with respect to the establishment of a clinical pregnancy awaits further validation. Studies exploring the endometrium within the cycle of embryo transfer have shown a deleterious effect of severe peri-ovulatory maturation advancement exceeding 3 days, as no clinical pregnancies were obtained in this condition. Further unravelling of molecules involved in the implantation mechanism is needed for a better comprehension of the link between altered endometrial development and receptivity in IVF cycles.

    更新日期:2019-11-01
  • Ultrasound assessment of the polycystic ovary: international consensus definitions.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2004-01-13
    Adam H Balen,Joop S E Laven,Seang-Lin Tan,Didier Dewailly

    The polycystic ovary syndrome (PCOS) is a heterogeneous condition, the pathophysiology of which appears to be both multifactorial and polygenic. The definition of the syndrome has been much debated. Key features include menstrual cycle disturbance, hyperandrogenism and obesity. There are many extra-ovarian aspects to the pathophysiology of PCOS, yet ovarian dysfunction is central. At a recent joint ASRM/ESHRE consensus meeting, a refined definition of the PCOS was agreed, encompassing a description of the morphology of the polycystic ovary (PCO). According to the available literature, the criteria fulfilling sufficient specificity and sensitivity to define the PCO should have at least one of the following: either 12 or more follicles measuring 2-9 mm in diameter, or increased ovarian volume (> 10 cm3). If there is a follicle > 10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area. The presence of a single PCO is sufficient to provide the diagnosis. The distribution of follicles and a description of the stroma are not required in the diagnosis. Increased stromal echogenicity and/or stromal volume are specific to PCO, but it has been shown that the measurement of ovarian volume (or area) is a good surrogate for quantification of the stroma in clinical practice. A woman having PCO in the absence of an ovulation disorder or hyperandrogenism ('asymptomatic PCO') should not be considered as having PCOS, until more is known about this situation. Three-dimensional and Doppler ultrasound studies may be useful research tools but are not required in the definition of PCO. This review outlines evidence for the current ultrasound definition of the polycystic ovary and technical specifications.

    更新日期:2019-11-01
  • Menstrual disorders in adolescence: investigation and management.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    Martha Hickey,Adam Balen

    Menstrual disorders in adolescence may present diagnostic and management challenges for the gynaecologist. This review will describe the common and uncommon menstrual disorders that may arise in early reproductive life, together with guidance on their investigation and management.

    更新日期:2019-11-01
  • Gestational surrogacy.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    Peter R Brinsden

    Gestational surrogacy is a treatment option available to women with certain clearly defined medical problems, usually an absent uterus, to help them have their own genetic children. IVF allows the creation of embryos from the gametes of the commissioning couple and subsequent transfer of these embryos to the uterus of a surrogate host. The indications for treatment include absent uterus, recurrent miscarriage, repeated failure of IVF and certain medical conditions. Treatment by gestational surrogacy is straightforward and follows routine IVF procedures for the commissioning mother, with the transfer of fresh or frozen-thawed embryos to the surrogate host. The results of treatment are good, as would be expected from the transfer of embryos derived from young women and transferred to fit, fertile women who are also young. Clinical pregnancy rates achieved in large series are up to 40% per transfer and series have reported 60% of hosts achieving live births. The majority of ethical or legal problems that have arisen out of surrogacy have been from natural or partial surrogacy arrangements. The experience of gestational surrogacy has been largely complication-free and early results of the follow-up of children, commissioning couples and surrogates are reassuring. In conclusion, gestational surrogacy arrangements are carried out in a few European countries and in the USA. The results of treatment are satisfactory and the incidence of major ethical or legal complications has been limited. IVF surrogacy is therefore a successful treatment for a small group of women who would otherwise not be able to have their own genetic children.

    更新日期:2019-11-01
  • Applications of ovarian tissue transplantation in experimental biology and medicine.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    E Torrents,I Boiso,P N Barri,A Veiga

    Nowadays, high-dose chemotherapy and radiotherapy treatments for cancer are more effective but can severely affect the ovarian follicular store, compromising the fertility of surviving young patients. A promising alternative to prevent fertility loss in these patients is the cryopreservation and transplantation of ovarian tissue. Slices of animal and human ovarian tissue have been shown to survive the cryopreservation process. After transplantation, follicular development and restoration of hormone secretion have been observed in animal and human studies. This review addresses recent developments on ovarian tissue transplantation in animals and humans. We also illustrate the indications and technical difficulties of the procedure and the ethical issues that should be considered.

    更新日期:2019-11-01
  • Oocyte freezing: here to stay?
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    Josiane Van der Elst

    Oocyte freezing is an established technology but, in contrast to embryo freezing, it has very limited application in clinical IVF programmes. Is there a chance that oocyte freezing will become an integrated routine in assisted reproductive technology? The delicate cytological architecture of the oocyte with a cold-sensitive spindle and a hardening zona have made the frozen oocyte 'unwanted' in assisted reproductive technology. Nevertheless, empirical improvements in freezing protocols and the use of ICSI for fertilization have led to an increasing number of live births. This mitigates against a simple ban on oocyte freezing. While efficiency of oocyte freezing can certainly be further improved by basic research, it is clear that there are humanitarian reasons for considering oocyte freezing as a future fully utilized assisted reproductive technology. The storage of the female genome as a particulate entity can provide an alternative in case of moral, ethical, legal or religious concerns about embryo freezing. Oocyte freezing can also offer hope for oocyte donation and preservation of fertility for women facing ovarian loss. The message is one of cautious optimism when looking for a place for oocyte freezing in routine assisted reproductive technology.

    更新日期:2019-11-01
  • Rethinking gamete/embryo isolation and culture with microfluidics.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    Ronald S Suh,Nandita Phadke,Dana A Ohl,Shuichi Takayama,Gary D Smith

    IVF remains one of the most exciting modern scientific developments and continues to have a tremendous impact on people's lives. Since its beginnings, scientists have studied and critically analysed the techniques in order to find ways to improve outcomes; however, little has changed with the actual technology and equipment of IVF. Semen is still processed in test tubes and fertilization and culture still occurs in culture dishes. New technological possibilities exist with the burgeoning advancement of microfluidic technology. Microfluidics is based on the behaviour of liquids in a microenvironment. Although a young field, many developments have occurred which demonstrate the potential of this technology for IVF. In this review, we briefly discuss the physical principles of microfluidics and highlight some previous utilizations of this technology, ranging from chemical analysis to cell sorting. We then present the designs and outcomes for microfluidic devices utilized thus far for each step in IVF: gamete isolation and processing, fertilization, and embryo culture. Finally, we discuss and speculate on the ultimate goal of this technology--development of a single, integrated unit for in-vitro assisted reproduction techniques.

    更新日期:2019-11-01
  • Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis.
    Hum. Reprod. Update (IF 12.878) Pub Date : 2003-12-03
    Annemarie G M G J Mulders,Joop S E Laven,Marinus J C Eijkemans,Edward G Hughes,Bart C J M Fauser

    A systematic review was conducted to determine whether initial screening characteristics of women with normogonadotrophic anovulatory infertility predict clinically significant outcomes of ovulation induction with gonadotrophins, and to obtain pooled estimates of their predictive value through meta-analysis. Only those studies in which pre-treatment screening characteristics (such as body mass index, serum LH and androgens, insulin sensitivity and ultrasound appearance of ovaries) were related to outcome parameters (such as total amount of FSH administered, cancellation, ovulation, pregnancy and miscarriage), were included in this analysis. Thirteen studies fulfilled the inclusion criteria. A positive association was seen in all studies between the level of obesity (definition applied as assessed by individual studies) and total amount of FSH administered [weighted mean difference (WMD) of 771 IU (95% confidence interval (CI): 700-842)]. Pooled odds ratios (OR) of 1.86 (95% CI: 1.13-3.06) and 0.44 (95% CI: 0.31-0.61) were found between obesity with cancellation and ovulation respectively. Pooled analysis did not show a significant association between obesity and pregnancy rate. The pooled OR for obese versus non-obese women and miscarriage rate was significant [3.05 (95% CI: 1.45-6.44)]. Association measures between insulin resistance (definition applied as assessed by individual studies) and total amount of FSH administered produced a WMD of 351 (95% CI: 73-630) IU. A pooled OR of 0.29 (95% CI: 0.10-0.80) was found for insulin resistance with pregnancy rate. The pooled OR for insulin resistance (hyperinsuliaemia versus normoinsuliaemia) and miscarriage rate was not significant. A pooled OR of 1.04 (95% CI: 1.01-1.07) was found for LH (IU/l) with pregnancy rate. The pooled OR for LH and miscarriage rate was not significant. Finally, pooled analysis did not find a significant association between testosterone and pregnancy rate. In conclusion, the best available evidence, though limited, suggests that the most clinically useful predictors of gonadotrophin ovulation induction outcome in normogonadotrophic women are obesity and insulin resistance.

    更新日期:2019-11-01
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