RESUMO
RESEARCH QUESTION: What is the discontinuation rate among patients with remaining cryopreserved embryos in Belgium and what are the reasons for discontinuation? DESIGN: Multicentre, cross-sectional study across 11 Belgian fertility clinics. Patients were eligible (nâ¯=â¯1917) if they had previously undergone an unsuccessful fresh embryo transfer (fresh group) or frozen embryo transfer (FET) (in-between group) and did not start a subsequent FET cycle within 1 year despite having remaining cryopreserved embryos. The denominator was all patients with embryos cryopreserved during the same period (2012-2017) (nâ¯=â¯21,329). Data were collected through an online anonymous questionnaire. RESULTS: The discontinuation rate for patients with remaining cryopreserved embryos was 9% (1917/21329). For the final analysis, 304 completed questionnaires were included. The most important reasons for discontinuing FET cycles were psychological (50%) and physical (43%) burden, effect on work (29%), woman's age (25%) and effect on the relationship (25%). In 69% of cases, the patient themselves made the decision to delay FET treatment. In 16% of respondents, the decision to delay FET was determined by external factors: treating physician (9%), social environment (4%), close family (3%) and society (3%). Suggested improvements were psychological support before (41%), during (51%) and after (51%) treatment, as well as lifestyle counselling (44%) and receiving digital information (43%). CONCLUSIONS: The discontinuation rate is remarkably high in patients with remaining cryopreserved embryos who have a good prognosis. Respondents stressed the need to improve the integration of psychological and patient-tailored care into daily assisted reproductive technology practice.
Assuntos
Transferência Embrionária , Técnicas de Reprodução Assistida , Gravidez , Feminino , Humanos , Taxa de Gravidez , Estudos Transversais , Técnicas de Reprodução Assistida/psicologia , Criopreservação , Estudos RetrospectivosRESUMO
PURPOSE: Ovarian stimulation for oocyte and embryo cryopreservation is the standard of care for fertility preservation in young breast cancer patients before gonadotoxic chemotherapy. The procedure should be started as soon as possible to avoid delay of treatment; thus, it is often performed concomitantly with tumor staging assessments. However, questions remain regarding the potential negative impact on oocyte quality that may occur due to exposure to scattered ionizing radiation from imaging techniques when staging assessment is conducted at the same time as ovarian stimulation. METHODS: We conducted a retrospective study on all breast cancer patients who performed ovarian stimulation for fertility preservation at our center between November 2012 and May 2020. RESULTS: Gynecologic and oncological characteristics were similar between patients exposed (n = 14) or not (n = 60) to ionizing radiation. Exposed patients started the ovarian stimulation sooner after diagnosis than non-exposed patients (11.5 vs 28 days, respectively, P < 0.01). Cycle parameters, including the median number of oocytes collected (10.5 vs 7, P = 0.16), maturation rates (92.5% vs 85.7%, P = 0.54), and fertilization rates (62.2% vs 65.4%, P = 0.70), were similar between groups. CONCLUSION: This study shows that scattered ionizing radiation due to staging assessment appears to be safe without compromising follicular growth and maturation. Larger studies on fertility and obstetrical outcomes are needed to confirm these preliminary data.
Assuntos
Neoplasias da Mama , Preservação da Fertilidade , Neoplasias , Neoplasias da Mama/radioterapia , Feminino , Humanos , Oócitos , Indução da Ovulação , Estudos RetrospectivosRESUMO
RESEARCH QUESTION: How do cumulative live birth rates (CLBR), cumulative multiple live birth rates (CMLBR) and dropout rates over six IVF and intracytoplasmic sperm injection (ICSI) cycles change over time? DESIGN: Prospective longitudinal cohort (nâ¯=â¯16,073 patients; 48,946 cycles) starting a first fresh assisted reproductive technology cycle between 1 January 2014 and 31 December 2016, with follow-up until 31 December 2017. Outcomes between the periods 2014-2017 and 2009-2012 were compared. RESULTS: Conservative estimates of CLBR after six complete cycles were significantly higher in women younger than 35 years after every cycle: one to three, adjusted P-value [p adj] < 0.0001; four, pâ¯=â¯0.01; five, p adjâ¯=â¯0.03; six, p adjâ¯=â¯0.04) and after the first cycle in women aged 35-37 years (p adjâ¯=â¯0.04) in 2014-2017 versus 2009-2012. For an optimal estimate, the CLBR was significantly higher after the first three cycles in women younger than 35 years (all p adj < 0.0001) and after the first cycle in women aged 35-37 years (p adjâ¯=â¯0.04). The CMLBR rate decreased from 5.1% ± 0.19 (SE) to 4.1% ± 0.16 for the conservative estimate and from 8.6% ±0.37 (SE) to 6.7% ± 0.30 for the optimal estimate after six complete cycles for the whole cohort. Dropout rates of complete cycles were 26.5% 29.4%, 33.4%, 38.9% and 47.3% after the first to fifth cycle, respectively. Compared with 2009-2012, the dropout rate in the current period was significantly higher for the first (P < 0.0001) and second (Pâ¯=â¯0.0124) cycle. CONCLUSION: Over six complete IVF/ICSI cycles, CLBR and dropout rates increased and multiple live birth rates decreased when 2014-2017 was compared with 2009-2012.
Assuntos
Coeficiente de Natalidade/tendências , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Injeções de Esperma Intracitoplásmicas/tendências , Feminino , Humanos , Estudos Prospectivos , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricosRESUMO
AIM: To assess the birthweight of neonates conceived after fresh and frozen embryo transfers (FET) and, if different, to investigate whether estradiol levels during the late follicular phase were associated with the observed difference. METHODS: Singleton pregnancies from fresh and FET transfers between January 1990 and December 2013 were compared retrospectively. A total of 2885 singleton pregnancies after fresh embryo transfer and 746 after FET were analyzed. Obstetric and neonatal outcomes were compared between fresh and FET cycles. RESULTS: The singletons born after FET were found to have a significantly higher birth weight (3313 g), compared to those born after fresh embryo transfer (3143 g); p < .001. The main predictor of this difference was found to be estradiol levels at the end of the follicular phase. The difference in birthweight was inversely correlated to estradiol levels considering all cycles together but also considering fresh and frozen cycles separately. CONCLUSIONS: Our study demonstrates a link between high estradiol levels and low birth weight of singletons after IVF both in fresh and frozen-thawed embryo transfer cycles. It provides additional support to the involvement of hyperestrogenemia in the process of implantation and on the subsequent fetal development.
Assuntos
Peso ao Nascer , Criopreservação/estatística & dados numéricos , Transferência Embrionária/métodos , Estradiol/sangue , Macrossomia Fetal/epidemiologia , Pré-Eclâmpsia/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Diabetes Gestacional/epidemiologia , Feminino , Fertilização in vitro , Fase Folicular/sangue , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Mortalidade Perinatal , Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: Fertility preservation (FP) protocols in case of breast cancer (BC) include mature oocyte cryopreservation following letrozole associated controlled ovarian hyperstimulation (Let-COH). To date, the impact of Let-COH on the follicular microenvironment has been poorly investigated, although a high androgen/estrogen ratio was previously associated with low oocyte quality. METHODS: In this prospective study, follicular fluid (FF) steroid levels (estradiol, testosterone, progesterone) and cumulus cell (CC) gene expression related to oocyte quality (HAS2, PTGS2, GREM1) were compared between 23 BC patients undergoing Let-COH for FP and 24 infertile patients undergoing conventional COH without letrozole. All patients underwent an antagonist COH cycle, and ovulation was triggered with hCG or GnRHa in both groups. RESULTS: FF estradiol levels were significantly lower while testosterone levels were significantly higher in the study group compared to controls irrespective of the trigger method. However, estradiol levels increased significantly with GnRHa triggering compared to hCG in the study group (median = 194.5 (95.4-438) vs 64.4 (43.8-152.4) ng/ml, respectively, p < 0.001), but not in the control group (median = 335.5 (177.5-466.7) vs 354 (179-511) ng/ml, respectively). After hCG trigger, Cumulus cell (CC) gene expression was lower in the study group compared to the control group, and difference was significant for PTGS2. Conversely, CC gene expression of PTGS2 and GREM1 was significantly higher in the study group compared to controls when ovulation was triggered with GnRHa. CONCLUSIONS: Let-COH triggered with hCG may negatively impact oocyte quality. However, ovulation triggering with GnRHa may improve the oocyte microenvironment and cumulus cell genes expression in Let-COH, suggesting a positive impact on oocyte quality in breast cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov - NCT02661932 , registered 25 January 2016, retrospectively registered.
Assuntos
Neoplasias da Mama , Preservação da Fertilidade/métodos , Infertilidade Feminina/terapia , Letrozol/uso terapêutico , Oócitos/efeitos dos fármacos , Indução da Ovulação/métodos , Adolescente , Adulto , Microambiente Celular , Estradiol/metabolismo , Feminino , Líquido Folicular/metabolismo , Marcadores Genéticos , Humanos , Letrozol/efeitos adversos , Oócitos/fisiologia , Progesterona/metabolismo , Testosterona/metabolismoRESUMO
BACKGROUND: Currently, there is no gold standard for monitored anaesthesia care during oocyte retrieval. OBJECTIVE: In our institution, the standard is a conscious sedation technique using a target-controlled infusion (TCI) of remifentanil, titrated to maintain a visual analogue pain score less than 30âmm. This protocol is well accepted by patients but is associated with frequent episodes of respiratory depression. The main objective of this study was to evaluate whether the addition of a continuous intravenous infusion of ketamine could reduce these episodes. DESIGN: Controlled, randomised, prospective, double-blinded study. SETTING: The current study was conducted in a tertiary-level hospital in Brussels (Belgium) from December 2013 to June 2014. PATIENTS: Of the 132 women undergoing oocyte retrieval included, 121 completed the study. INTERVENTION: After randomisation, patients received either a ketamine infusion (40âµgâkgâmin over 5âmin followed by 2.5âµgâkgâmin) or a 0.9% saline infusion in addition to the variable remifentanil TCI. MAIN OUTCOME MEASURES: The primary outcome was the number of respiratory depression episodes. Effect site target remifentanil concentrations, side effects, pain score, patient satisfaction and incidence of pregnancy were also recorded. RESULTS: No significant difference in the incidence of respiratory events was noted (pulse oximetry oxygen saturationâ<â95% was 49% in the ketamine group and 63% in the control group; Pâ=â0.121). No patient required ventilatory support. In the ketamine group, visual analogue pain score and remifentanil concentrations were significantly reduced, but the latter remained above 2ângâml. Postoperative nausea was less frequent in the ketamine group, 4 versus 15% (Pâ=â0.038). The addition of ketamine did not influence length of stay nor patient satisfaction. CONCLUSION: The addition of low plasma levels of ketamine to a TCI remifentanil conscious sedation technique did not decrease the incidence nor the severity of respiratory depression. Continuous monitoring of capnography and oxygen saturation is always required. TRIAL REGISTRATION: EUDRACT number 2013-003040-23.
Assuntos
Analgésicos/administração & dosagem , Sedação Consciente/métodos , Ketamina/administração & dosagem , Recuperação de Oócitos/métodos , Remifentanil/administração & dosagem , Adulto , Analgésicos/efeitos adversos , Analgésicos Opioides/administração & dosagem , Sedação Consciente/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infusões Intravenosas , Ketamina/efeitos adversos , Efeito Placebo , Estudos Prospectivos , Remifentanil/efeitos adversos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/epidemiologiaAssuntos
Síndrome de Hiperestimulação Ovariana , Feminino , Humanos , Letrozol , Indução da OvulaçãoRESUMO
The aim of this study was to evaluate whether pregnancies resulting from oocyte donation have a higher risk of preeclampsia compared with pregnancies after IVF using autologous oocytes. Propensity score matching on maternal age and parity was carried out on a one to one basis, and a total of 144 singleton pregnancies resulting in delivery beyond 22 gestational weeks, achieved by oocyte donation, were compared with 144 pregnancies achieved through IVF and intracytoplasmic sperm injection with the use of autologous oocytes. All pregnancies were achieved after fresh embryo transfer. Obstetric and neonatal outcomes were compared for each pregnancy. Singleton pregnancies after oocyte donation were associated with a significantly higher risk for preeclampsia (OR 2.4, CI 1.02 to 5.8; P = 0.046), as well as for pregnancy-induced hypertension (OR 5.3, CI 1.1 to 25.2; P = 0.036), and caesarean delivery (OR 2.3, CI 1.4 to 3.7; P = 0.001) compared with pregnancies using autologous oocytes.
Assuntos
Fertilização in vitro , Infertilidade/complicações , Doação de Oócitos , Oócitos/citologia , Pré-Eclâmpsia/epidemiologia , Adulto , Transferência Embrionária , Feminino , Humanos , Hipertensão Induzida pela Gravidez , Ovário/fisiologia , Pré-Eclâmpsia/diagnóstico , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Risco , Injeções de Esperma IntracitoplásmicasRESUMO
PURPOSE: The purpose of the present study is to study what is the best predictor of severe ovarian hyperstimulation syndrome (OHSS) in IVF. METHODS: This is a retrospective analysis of all consecutive IVF/intracytoplasmic injection cycles performed during a 5-year period (2009-2014) in a single university fertility centre. All fresh IVF cycles where ovarian stimulation was performed with gonadotrophins and GnRH agonists or antagonists and triggering of final oocyte maturation was induced with the administration of urinary or recombinant hCG were analyzed (2982 patients undergoing 5493 cycles). Because some patients contributed more than one cycle, the analysis of the data was performed with the use of generalized estimating equation (GEE). RESULTS: Severe OHSS was diagnosed in 20 cycles (0.36%, 95% CI 0.20-0.52). The number of follicles ≥10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles. The cutoff in the number of follicles ≥10 mm with the best capacity to discriminate between women that will and will not develop severe OHSS was ≥15. CONCLUSION: The presence of more than 15 follicles ≥10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles.
Assuntos
Biomarcadores/análise , Síndrome de Hiperestimulação Ovariana/etiologia , Indução da Ovulação/efeitos adversos , Indução da Ovulação/métodos , Adulto , Gonadotropina Coriônica/urina , Estudos de Coortes , Estradiol/sangue , Feminino , Fertilização in vitro/efeitos adversos , Hormônio Foliculoestimulante/farmacologia , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Técnicas de Maturação in Vitro de Oócitos/métodos , Modelos Logísticos , Hormônio Luteinizante/sangue , Folículo Ovariano/efeitos dos fármacosRESUMO
Ovarian insufficiency is a major long-term adverse event, following the administration of a myeloablative conditioning regimen, and occurring in >80% of children and adolescents receiving such treatment for malignant or non-malignant disease. Cryopreservation of ovarian tissue is currently offered to preserve the fertility of these young patients. At least 35 live births have been reported after transplantation of cryopreserved ovarian tissue in adult patients, but the procedure remains unproven for ovarian tissue harvested at a prepubertal or pubertal age. We report here the first live birth after autograft of cryopreserved ovarian tissue in a woman with primary ovarian failure after a myeloablative conditioning regimen as part of a hematopoietic stem cell transplantation performed for homozygous sickle-cell anemia at age 14 years. This first report of successful fertility restoration after the graft of ovarian tissue cryopreserved before menarche offers reassuring evidence for the feasibility of the procedure when performed during childhood.
Assuntos
Autoenxertos/transplante , Criopreservação , Preservação da Fertilidade/métodos , Nascido Vivo , Ovário/transplante , Adolescente , Adulto , Anemia Falciforme/terapia , Feminino , Humanos , Agonistas Mieloablativos/efeitos adversos , Gravidez , Insuficiência Ovariana Primária/induzido quimicamente , Transplante AutólogoRESUMO
PURPOSE: To compare two different vitrification methods to slow freezing method for cryopreservation of human cleavage stage embryos. DESIGN: Prospective randomised trial. SETTING: University assisted reproduction centre. PATIENT(S): 568 patients (mean age 33.4 ± 5.2) from April 2009 to April 2011. METHODS: 1798 supernumerary good-quality cleavage stage embryos in 645 IVF cycles intended to be cryopreserved were randomly allocated to three groups: slow freezing, vitrification with the Irvine® method, vitrification with the Vitrolife® method. MAIN OUTCOME MEASURE(S): Embryo survival and cleavage rates, implantation rate. RESULTS: A total of 1055 embryos were warmed, 836 (79.2%) survived and 676 were finally transferred (64.1%). Post-warming embryos survival rate was significantly higher after vitrification (Irvine: 89.4%; Vitrolife: 87.6%) than after slow freezing (63.8%) (p < 0.001). No differences in survival rates were observed between the two vitrification methods, but a significant higher cleavage rate was observed using Irvine compared to Vitrolife method (p < 0.05). Implantation rate (IR) per embryo replaced and per embryo warmed were respectively 15.8% (41/259) and 12.4% (41/330) for Irvine, 17.0% (40/235) and 12.1% (40/330) for Vitrolife, 21.4% (39/182) and 9.9% (39/395) for slow-freezing (NS). CONCLUSIONS: Both vitrification methods (Irvine and Vitrolife) are more efficient than slow freezing for cryopreservation of human cleavage stage embryos in terms of post-warming survival rate. No significant difference in the implantation rate was observed between the three cryopreservation methods.
Assuntos
Fase de Clivagem do Zigoto , Criopreservação/métodos , Vitrificação , Adulto , Implantação do Embrião , Feminino , Fertilização in vitro , Congelamento , Humanos , Gravidez , Taxa de Gravidez , Taxa de SobrevidaRESUMO
Background: Sperm quality at cancer diagnosis is often compromised by the disease and any given gonadotoxic treatment will further diminish fertility. Objectives: Here, we aim to analyze the cryopreserved sperm quality according to the cancer types as well as the fertility outcomes. Methods: Our study included all cancer patients who cryopreserved sperm over 20 years at Erasme Hospital Brussels (from 1999 to 2019). First sperm samples from 111 hematologic, 104 testicular, 19 prostate, 28 gastrointestinal, and 16 neurological cancer patients were compared. Results: Oligozoo-asthenozoospermia was observed in 30% of the samples, including 19.33% with severe oligozoospermia (<5 million/ml). Our results showed a significant reduction in sperm concentration among testicular cancer (p < 0.01). No significant differences in progressive motility, sperm volume, and number of frozen straws were observed. Significant correlations were found between sperm concentration and cancer type (p <0.01) as well as patients' age (p <0.01). Twenty-eight cancer survivors returned for using their cryopreserved sperm (9.33%), fertilization rate was 60.5% and implantation rate was 29.6%. There was no correlation between sperm concentration and fertility outcomes. Conclusion: Our results confirm the negative impact of cancer on sperm quality without affecting assisted reproductive technology (ART) success rate, which is utterly important as a male reproductive health perspective. All cancer patients should be counselled and offered fertility preservation options as a gold standard.
RESUMO
INTRODUCTION: Fertility preservation (FP) is recommended in young breast cancer (BC) patients before (neo)adjuvant treatment. Letrozole-associated controlled ovarian hyperstimulation (LetCOH) is used worldwide to collect mature oocytes for FP, but its efficacy and safety compared to conventional protocols (cCOH) are still debated. AIMS: To compare efficacy and safety of FP procedure using LetCOH or cCOH in BC patients in terms of oocyte maturation rate and disease-free survival rates after at least two years of follow-up. METHODS: This multicenter retrospective study compared outcomes of 107 cycles in 97 non-metastatic BC patients aged ≤40 years who underwent cCOH (n = 56) or LetCOH (n = 41) for FP in CHU-Lille and Erasme Hospital, respectively, between December 2012 and January 2017. RESULTS: Patients and oncological characteristics were similar except for tumor size and HER2 status which were less favorable in the LetCOH group. Patients underwent adjuvant chemotherapy in 96.4% and 48.8% of the cases in cCOH and LetCOH groups, respectively. Hence, 51.2% of LetCOH patients underwent neoadjuvant chemotherapy (p < 0.001). Estradiol peak at ovulation trigger was lower in LetCOH compared to cCOH group while oocyte maturation rates were significantly higher (p < 0.001), without impacting the final number of mature oocytes collected. Seven and four patients relapsed in LetCOH and cCOH groups, respectively, and one patient died in each group after a median follow-up of four years. CONCLUSION: LetCOH is as effective as cCOH for FP. At this time point, there were no safety concerns regarding cCOH in the adjuvant setting but a longer follow-up is warranted.
Assuntos
Preservação da Fertilidade , Neoplasias , Criopreservação , Estradiol , Feminino , Preservação da Fertilidade/métodos , Humanos , Letrozol/uso terapêutico , Neoplasias/etiologia , Indução da Ovulação/efeitos adversos , Indução da Ovulação/métodos , Estudos RetrospectivosRESUMO
We report on the results of array-CGH and Whole exome sequencing (WES) studies carried out in a Tunisian family with 46,XX premature ovarian insufficiency (POI). This study has led to the identification of a familial Xp22.12 tandem duplication with a size of 559.4 kb, encompassing only three OMIM genes (RPS6KA3, SH3KBP1and EIF1AX), and a new heterozygous variant in SPIDR gene: NM_001080394.3:c.1845_1853delTATAATTGA (p.Ile616_Asp618del) segregating with POI. Increased mRNA expression levels were detected for SH3KBP1 and EIF1AX, while a normal transcript level for RPS6KA3 was detected in the three affected family members, explaining the absence of intellectual disability (ID). To the best of our knowledge, this is the first duplication involving the Xp22.12 region, reported in a family without ID, but rather with secondary amenorrhea (SA) and female infertility. As EIF1AX is a regulatory gene escaping X-inactivation, which has an extreme dosage sensitivity and highly expressed in the ovary, we suggest that this gene might be a candidate gene for ovarian function. Homozygous nonsense pathogenic variants of SPIDR gene have been reported in familial cases in POI. It has been suggested that chromosomal instability associated with SPIDR molecular defects supports the role of SPIDR protein in double-stranded DNA damage repair in vivo in humans and its causal role in POI. In this family, the variant (p.Ile616_Asp618del), present in a heterozygous state, is located in the domain that interacts with BLM and might disrupt the BLM binding ability of SPIDR protein. These findings strengthen the hypothesis that the additional effect of this variant could lead to POI in this family. Although the work represents the first evidence that EIF1AX duplication might be responsible for POI through its over-expression, further functional studies are needed to clarify and prove EIF1AX involvement in POI phenotype.
Assuntos
Insuficiência Ovariana Primária , Feminino , Humanos , Heterozigoto , Fenótipo , Insuficiência Ovariana Primária/genética , RNA Mensageiro , Sequenciamento do Exoma , Cromossomos Humanos XRESUMO
Aggressive chemotherapy generally results in the loss of both endocrine and reproductive functions. If the patient has not undergone previous oocyte, embryo or ovarian tissue cryopreservation, orthotopic allotransplantation of fresh ovarian tissue from a genetically non-identical sister may be considered. Here, we describe a case report. The patient, aged 15 years and presenting with homozygous sickle cell anemia, underwent chemotherapy (busulfan, cyclophosphamide) and total body irradiation before bone marrow transplantation, the donor being her HLA-compatible sister. HLA group analysis later revealed complete chimerism. When the patient was 32 years old, ovarian allografting was performed, with the ovarian tissue donor being the same sister who had already donated bone marrow. The goal was to restore ovarian activity and natural fertility. No immunosuppressive therapy was administered. No sign of rejection was observed. Restoration of ovarian function was achieved 3.5 months after transplantation, as proved by the first estradiol peak and follicular development detected by ultrasound. After 9 months of regular ovulatory cycles, IVF was attempted because proximal tubal stenosis (unknown at the time of grafting) could not be repaired by tubal reanastomosis. After stimulation, three oocytes were retrieved. Two embryos were obtained. One embryo was frozen and the other was transferred, resulting in an ongoing pregnancy. The patient delivered a healthy baby girl weighing 3.150 g at 37 2/7 weeks of gestation.
Assuntos
Anemia Falciforme/terapia , Ovário/transplante , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Transplante de Medula Óssea/efeitos adversos , Feminino , Fertilização in vitro , Humanos , Recém-Nascido , Nascido Vivo , Ovário/fisiologia , Gravidez , Insuficiência Ovariana Primária/etiologia , Irmãos , Quimeras de Transplante , Transplante Homólogo , Irradiação Corporal TotalRESUMO
OBJECTIVE: To analyse treatment outcomes after SET law enforcement and to evaluate the contribution of cryopreservation in a SET policy. MATERIAL: Embryo transfer cycles performed after the law enforcement (SET period) was retrospectively compared to the cycles performed before the law enforcement (DET period). RESULTS: Pregnancy and delivery rates after fresh transfer of SET and DET periods were comparable (31.7% versus 33.3% and 24.5% versus 26.2%, respectively, NS). Overall twin delivery rate is significantly decreased after the law enforcement (11.3% versus 22.4%, p < 0.001) but not in patients aged 36 to 39 years (20.3% versus 24%, NS). Frozen-thawed embryo cycles allowed similar cumulative pregnancy rate (30.6%, NS). Taking into account all frozen embryos still to be transferred, SET period offers a better overall pregnancy rate than the DET period (36.1% versus 32.3%, p < 0.01). CONCLUSIONS: The Belgian law allowed a dramatic reduction of twin deliveries especially for patients under 39 years. Cryopreservation maintains a similar cumulative pregnancy rate.
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Criopreservação/estatística & dados numéricos , Aplicação da Lei , Gravidez Múltipla , Transferência de Embrião Único , Injeções de Esperma Intracitoplásmicas/legislação & jurisprudência , Adolescente , Adulto , Bélgica , Coeficiente de Natalidade , Feminino , Humanos , Gravidez , Taxa de Gravidez , Gravidez de Gêmeos , Adulto JovemRESUMO
BACKGROUND: Premature ovarian insufficiency (POI) is a heterogeneous clinical syndrome defined by a premature loss of ovarian function that associates menstrual disturbances and hypergonatropic hypogonadism. POI is a major cause of female infertility affecting 1% of women before the age of 40 and up to 0.01% before the age of 20. The etiology of POI may be iatrogenic, auto-immune or genetic but remains however undetermined in a large majority of cases. An underlying genetic etiology has to be searched in idiopathic cases, particularly in the context of a family history of POI. METHODS: Whole exome sequencing (WES) was performed in trio in a Belgian patient presenting POI and in her two parents. The patient presented delayed puberty and primary amenorrhea with hypergonadotropic hypogonadism. RESULTS: WES identified two novel compound heterozygous truncating mutations in the Newborn oogenesis homeobox (NOBOX) gene, c.826C>T (p.(Arg276Ter)) and c.1421del (p.(Gly474AlafsTer76)). Both mutations were confirmed by Sanger sequencing in the proband's sister who presented the same phenotype. Both variants were pathogenic and very likely responsible for the severe POI in this family. CONCLUSION: We report here for the first time compound heterozygous truncating mutations of NOBOX in outbred patients, generalizing biallelic NOBOX null mutations as a cause of severe POI with primary amenorrhea. In addition, our findings also suggest that NOBOX haploinsufficiency is tolerated.
Assuntos
Amenorreia/etiologia , Heterozigoto , Proteínas de Homeodomínio/genética , Mutação , Puberdade Tardia/etiologia , Irmãos , Fatores de Transcrição/genética , Adolescente , Alelos , Amenorreia/diagnóstico , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Linhagem , Fenótipo , Puberdade Tardia/diagnóstico , Sequenciamento do ExomaRESUMO
OBJECTIVE: To find the genetic etiology of premature ovarian insufficiency (POI) in a patient with primary amenorrhea and hypergonadotropic hypogonadism. DESIGN: Case report. SETTING: University hospital. PATIENTS: A Belgian woman aged 32 years with POI at the age of 17, her parents, and her sister whose POI was diagnosed at age 29. INTERVENTIONS: Analysis of a panel of 31 genes implicated in POI (POIGP) using next-generation sequencing (NGS), Sanger sequencing, and in vitro functional study. MAIN OUTCOME MEASURES: Gene variants, family mutational segregation, and in vitro functional impact of the mutant proteins. RESULTS: The analysis of the gene panel using NGS identified the presence of two novel follicle-stimulating hormone receptor (FSHR) missense mutations at a compound heterozygous state in the affected patient: c.646 G>A, p.Gly216Arg, and c.1313C>T, p.Thr438Ile. Sanger sequencing showed the presence of each mutation at heterozygous state in the patient's parents and at heterozygous compound state in the affected sister. Both substituted amino acids (Gly216 and Thr438) were conserved in FSHR of several vertebrate species as well as in other glycoproteins receptors (TSHR and LHCGHR), suggesting a potentially important role in glycoprotein receptor function. An in vitro functional study showed similar results for both variants with more than 90% reduction of their cell surface expression and a 55% reduction of their FSH-induced cyclic adenosine 3':5' monophosphate (cAMP) production compared with the wild-type FSHR. CONCLUSIONS: The analysis of a gene panel of 31 genes implicated in POI allowed us to identify two novel partially inactivating mutations of FSHR that are likely responsible for the POI phenotype of the proband and of her affected sister.
RESUMO
Sex differences are observed in the evolution of numerous inflammatory conditions. Women exhibit better clinical courses compared to men in acute inflammatory processes, yet worse prognosis in several chronic inflammatory diseases. Inflammatory markers are significantly different between prepubertal boys and girls, whose sex steroid levels are very low, suggesting genetics play a role. To evaluate the potential influence of the X chromosome, we studied cytokine production and protein phosphorylation following Toll-like receptor (TLR) activation in whole blood and purified neutrophils and monocytes of healthy adults of both sexes as well as subjects with Klinefelter syndrome. We recorded higher levels of inflammatory cytokines in men compared to both women and patients with Klinefelter syndrome following whole blood stimulation. In purified monocytes, production of inflammatory cytokines was also higher in men compared to women, while Klinefelter subjects expressed the same pattern of cytokine production as males, in contrast with whole blood analyses. These differences remained after adjusting for sex steroid levels. Our study revealed higher cytokine inflammatory responses in men than women, yet also compared to subjects with Klinefelter syndrome, who carry two copies of the X chromosome, like women, and thus potentially benefit from the cellular mosaicism of X-linked genes.