RESUMO
Recent advances in developing polygenic scores have made it possible to screen embryos for common, complex conditions and traits. Polygenic embryo screening (PES) is currently offered commercially, and though there has been much recent media and academic coverage, reproductive specialists' points of view have not yet been prominent in these discussions. We convened a roundtable of multidisciplinary experts, including reproductive specialists to discuss PES and its implications. In this Opinion, we describe four clinically relevant issues associated with the use of PES that have not yet been discussed in the literature and warrant consideration.
Assuntos
Programas de Rastreamento , Herança Multifatorial , Atenção , Embrião de Mamíferos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , FenótipoRESUMO
PURPOSE: To evaluate whether adjusting timing of modified natural cycle frozen embryo transfer (mNC-FET) 1 day earlier in the setting of a spontaneous LH surge has an impact on pregnancy outcomes. METHODS: This retrospective cohort study evaluated all mNC-FET with euploid blastocysts from May 1, 2016 to March 30, 2019, at a single academic institution. Standard protocol for mNC-FET included ultrasound monitoring and hCG trigger when the dominant follicle and endometrial lining were appropriately developed. Patients had serum LH, estradiol, and progesterone checked on day of trigger. If LH was ≥ 20 mIU/mL, trigger was given that day and FET was performed 6 days after surge (LH/HCG+6), with the intent of transferring 5 days after ovulation. If LH was < 20 mIU/mL, FET was performed 7 days after trigger (hCG+7). Primary outcomes included clinical pregnancy and live birth rates. To account for correlation between cycles, a generalized estimating equation (GEE) method for multivariable logistic regression was used. RESULTS: Four hundred fifty-three mNC-FET cycles met inclusion criteria, of which 205 were in the LH/HCG+6 group and 248 were in the HCG+7 group. The overall clinical pregnancy rate was 64% and clinical miscarriage rate was 4.8%, with similar rates between the two groups. The overall live birth rate was 60.9% (61.0% in LH/HCG+6 group and 60.9% in HCG+7 group). After implementing GEE, the odds of CP (aOR 0.97, 95% CI [0.65-1.45], p = 0.88) and LB (aOR 0.98, 95% CI [0.67-1.45], p = 0.93) were similar in both groups. CONCLUSIONS: In our study cohort, mNC-FET based on LH/HCG+6 versus HCG+7 had similar pregnancy outcomes.
Assuntos
Aborto Espontâneo/epidemiologia , Criopreservação , Transferência Embrionária , Hormônio Luteinizante/genética , Aborto Espontâneo/etiologia , Aborto Espontâneo/fisiopatologia , Adulto , Coeficiente de Natalidade , Blastocisto/patologia , Blastocisto/fisiologia , Endométrio/crescimento & desenvolvimento , Endométrio/patologia , Feminino , Humanos , Ovulação/genética , Ovulação/fisiologia , Indução da Ovulação , Gravidez , Resultado da Gravidez/epidemiologia , Taxa de Gravidez , Progesterona/genética , Estudos RetrospectivosRESUMO
Recurrent pregnancy loss (RPL) occurs in â¼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.
Assuntos
Aborto Habitual/genética , Aborto Habitual/imunologia , Decídua/metabolismo , Implantação do Embrião/genética , Regulação da Expressão Gênica no Desenvolvimento , Adulto , Movimento Celular/genética , Decídua/citologia , Regulação para Baixo , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Retardo do Crescimento Fetal , Perfilação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1/genética , Interleucina-8/genética , Metaloproteinases da Matriz/biossíntese , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Pré-Eclâmpsia , Gravidez , Complicações na Gravidez/genética , Proteínas Secretadas Inibidoras de Proteinases/biossíntese , Regulação para CimaRESUMO
IGF binding protein-1 (IGFBP-1) is a major product of decidualized human endometrial stromal cells and decidua, and as a modulator of IGF action and/or by independent mechanisms, it regulates cell growth and differentiation and embryonic implantation in these tissues. IGFBP-1 secretion is primarily stimulated by progesterone and cAMP and is inhibited by insulin and IGFs. The signaling pathways mediating the latter are not well defined, and the current study was conducted to determine which pathways mediate the effects of insulin on IGFBP-1 mRNA and protein expression by human endometrial stromal cells decidualized in vitro by progesterone. Cells were cultured and treated with different combinations of insulin; wortmannin, an inhibitor of the phosphatidylinositide-3-kinase (PI3-kinase) pathway; and PD98059, an inhibitor of the MAPK pathway. IGFBP-1 mRNA was determined by real-time PCR, and protein secretion in the conditioned medium was measured by ELISA. Activation of the PI3-kinase and the MAPK pathways was assessed by the detection of phosphorylated AKT and ERK in Western blots, respectively. Insulin inhibited IGFBP-1 mRNA and protein secretion in a dose-dependent fashion, with an ED(50) for the latter 0.127 ng/ml (21.6 pm). Inhibitor studies revealed that at low doses, insulin acts through the PI3-kinase pathway, whereas at higher levels it also activates the MAPK pathway in the inhibition of IGFBP-1. The data demonstrate that human endometrium is a target for insulin action in the regulation of IGFBP-1. At physiological levels insulin likely plays a homeostatic role for energy metabolism in the endometrium, and in hyperinsulinemic states, insulin action on the endometrium may activate cellular mitosis via the MAPK pathway and perhaps predispose this tissue to hyperplasia and/or cancer.
Assuntos
Endométrio/citologia , Hipoglicemiantes/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Células Estromais/metabolismo , Adulto , Células Cultivadas , Relação Dose-Resposta a Droga , Endométrio/fisiologia , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , RNA Mensageiro/análise , Células Estromais/citologiaRESUMO
Recombinant DNA technology makes it possible to produce large amounts of human gene products for pharmacologic applications, supplanting the need for human tissues. The genes for the alpha and beta subunits of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (hCG) have been characterized and cloned. Recombinant FSH (rFSH) has been shown to be safe and effective in the treatment of fertility disorders. In comparison with the urinary gonadotropin products, human menopausal gonadotropins (HMG), and urinary follitropins (uFSH), rFSH is more potent and better tolerated by patients. Recombinant HCG appears to be as efficacious as urinary HCG with the benefit of improved local tolerance. Recombinant LH (rLH) is likely to be recommended as a supplement to rFSH for ovulation induction in hypogonadotropic women. It may also benefit in vitro fertilization patients undergoing controlled ovarian hyperstimulation with rFSH combined with pituitary suppression, with a gonadotropin-releasing hormone agonist or antagonist.