Rebecca J. Chason

Environmental and epigenetic effects upon preimplantation embryo metabolism and development

In vitro fertilization has provided a unique window into the metabolic processes that drive embryonic growth and development from a fertilized ovum to a competent blastocyst. Post-fertilization development is dependent upon a dramatic reshuffling of the parental genomes during meiosis, as well as epigenetic changes that provide a new and autonomous set of instructions to guide cellular differentiation both in the embryo and beyond. Although early literature focused simply on the substrates and culture conditions required for progress through embryonic development, more recent insights lead us to suggest that the surrounding environment can alter the epigenome, which can, in turn, impact upon embryonic metabolism and developmental competence.

Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review.

OBJECTIVE To evaluate novel hormonal therapies in patients with unresectable benign metastasizing leiomyoma (BML) disease. DESIGN Case series. SETTING National Institutes of Health (NIH). PATIENT(S) Five subjects with the diagnosis of BML based on imaging and/or histopathologic diagnosis. INTERVENTION(S) Four patients were treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor. One patient was treated with an antiprogestin (CDB-2914). MAIN OUTCOME MEASURE(S) Response to therapy was measured by tumor burden on cross-sectional imaging employing RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 guidelines. RESULT(S) Four patients treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor demonstrated stable disease with reduction in tumor burden. The fifth patient treated with antiprogestin (CDB-2914) had degeneration of her tumor, progression of its size, and an improvement in symptoms. CONCLUSION(S) Hormone treatment with GnRH agonist and/or aromatase inhibition may be a therapeutic option to reduce tumor burden in unresectable BML disease or for those patients who wish to avoid surgical intervention. RECIST 1.1 guidelines, while traditionally used to evaluate tumor response to cancer therapeutics, may be useful in evaluating BML tumor burden response to hormone therapy.

GnRH antagonist rescue in high responders at risk for OHSS results in excellent assisted reproduction outcomes

Gonadotrophin-releasing hormone (GnRH) antagonist rescue is performed by replacing a GnRH agonist with a GnRH antagonist in patients with rapidly rising serum oestradiol who are at risk of ovarian hyperstimulation syndrome (OHSS) during stimulation. It results in a rapid reduction in serum oestradiol, allowing for the avoidance of cycle cancellation and the continuation of exogenous gonadotrophin administration. A total of 387 patients who underwent GnRH antagonist rescue for ovarian hyperresponse were compared with 271 patients who did not receive GnRH antagonist rescue and had oestradiol concentrations >4000 pg/ml on the day of human chorionic gonadotrophin (HCG) administration. GnRH antagonist rescue decreased the mean oestradiol concentration by 35% on the first day of use. There was no difference in oocyte maturity (82% versus 83%) or fertilization rate (69% versus 67%) between the antagonist rescue and comparison groups, respectively. The percentage of high-grade embryos on day 3 and the blastocyst development rate were also similar between groups. The live-birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy. Gonadotrophin-releasing hormone (GnRH) antagonist rescue is a protocol to reduce the risk of ovarian hyperstimulation syndrome (OHSS) in assisted reproduction treatment. Patients who have a hyperresponse to medication during their treatment cycle have their GnRH agonist discontinued and a GnRH antagonist started in its place. This causes a rapid reduction in oestrogen concentrations and allows for the continuation of stimulation medication. We evaluated the effectiveness of this protocol by comparing patients who had GnRH antagonist rescue against high-responding patients who did not receive GnRH antagonist rescue. GnRH antagonist rescue resulted in a 35% reduction in oestrogen concentration and only a 1.5% cycle cancellation rate. There were no differences in oocyte maturity or fertilization between the two groups. There were no differences in the quality of day-3 and day-5 embryos between the two groups. The live birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue reduced serum oestradiol concentrations and enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy.

Preconception stress and the secondary sex ratio: a prospective cohort study

OBJECTIVE To study the association between salivary stress biomarkers and the secondary sex ratio. DESIGN Prospective, longitudinal cohort study. SETTING Community setting in the United Kingdom. PATIENT(S) On discontinuation of contraception for purposes of becoming pregnant, 338 women aged 18-40 years with complete data (90%) were followed until pregnant or up to six menstrual cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Secondary sex ratio. RESULT(S) Human chorionic gonadotropin pregnancies were detected in 207 (61%) women of whom 130 (63%) delivered singleton infants with available gender data. The adjusted odds ratio for a male birth was decreased for women in the highest quartile (AOR = 0.26; 95% confidence interval = 0.09, 0.74) of salivary cortisol relative to women in the lowest quartile during cycle 1. An inverse relation was observed between α-amylase and the 2° sex ratio, though not statistically significant. CONCLUSION(S) Our findings are consistent with a reversal in the 2° sex ratio with increasing preconception salivary cortisol concentrations. This relation suggests that activation of the hypothalamus-pituitary-adrenal axis may have implications in sex allocation and requires further study.

Are intracytoplasmic sperm injection and high serum estradiol compounding risk factors for adverse obstetric outcomes in assisted reproductive technology

OBJECTIVE To evaluate whether intracytoplasmic sperm injection (ICSI) use and E2 on the final day of assisted reproductive technology (ART) stimulation are associated with adverse obstetric complications related to placentation. DESIGN Retrospective cohort study. SETTING Large private ART practice. PATIENT(S) A total of 383 women who underwent ART resulting in a singleton live birth. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Adverse placental outcomes composed of placenta accreta, placental abruption, placenta previa, intrauterine growth restriction, preeclampsia, gestational hypertension, and small for gestational age infants. RESULT(S) Patients with adverse placental outcomes had higher peak serum E2 levels and were three times more likely to have used ICSI. Adverse placental outcomes were associated with increasing E2 (odds ratio 1.36, 95% confidence interval 1.13-1.65) and ICSI (odds ratio 3.86, 95% confidence interval 1.61-9.27). Adverse outcomes increased when E2 was >3,000 pg/mL and continued to increase in a linear fashion until E2 was >5,000 pg/mL. The association of ICSI with adverse outcomes was independent of male factor infertility. Interaction testing suggested the adverse effect of E2 was primarily seen in ICSI cycles, but not in conventional IVF cycles. Estradiol >5,000 pg/mL was associated with adverse placental events in 36% of all ART cycles and 52% of ICSI cycles. CONCLUSION(S) ICSI and elevated E2 on the day of hCG trigger were associated with adverse obstetric outcomes related to placentation. The finding of a potential interaction of E2 and ICSI with adverse placental events is novel and warrants further investigation.

GnRH agonist reduces estrogen receptor dimerization in GT1-7 cells: Evidence for cross-talk between membrane-initiated estrogen and GnRH signaling

17β-estradiol (E2), a key participant on the initiation of the LH surge, exerts both positive and negative feedback on GnRH neurons. We sought to investigate potential interactions between estrogen receptors alpha (ERα) and beta (ERβ) and gonadotropin releasing hormone receptor (GnRH-R) in GT1-7 cells. Radioligand binding studies demonstrated a significant decrease in saturation E2 binding in cells treated with GnRH agonist. Conversely, there was a significant reduction in GnRH binding in GT1-7 cells treated with E2. In BRET(1) experiments, ERα-ERα dimerization was suppressed in GT1-7 cells treated with GnRH agonist (p < 0.05). There was no evidence of direct interaction between ERs and GnRH-R. This study provides the first evidence of reduced ERα homodimerization by GnRH agonist. Collectively, these findings demonstrate significant cross-talk between membrane-initiated GnRH and E2 signaling in GT1-7 cells.

Balloon fluoroscopy as treatment for intrauterine adhesions: a novel approach

OBJECTIVE To report a unique fluoroscopically guided approach to treat severe intrauterine adhesions and cervical stenosis using balloon hysteroplasty. DESIGN Case report. SETTING Military-based fertility center. PATIENT(S) A 33-year-old woman undergoing assisted reproductive technology whose uterus could not be cannulated because of the development of intrauterine synechiae and cervical stenosis after a post-IUI infection that was further complicated by a prominent lower uterine segment-filling defect in the location of a prior cesarean delivery scar. INTERVENTION(S) Fluoroscopic cannulation and balloon uterine dilation. MAIN OUTCOME MEASURE(S) Resolution of synechiae by hysterosalpingogram and successful uterine cannulation. RESULT(S) A postprocedure hysterosalpingogram demonstrated a normalized uterine cavity with the exception of a persistent prominent lower uterine segment-filling defect from a prior cesarean delivery. A frozen ET cycle was performed successfully. CONCLUSION(S) Hysteroplasty, using standard interventional radiographic techniques, may provide an alternative treatment modality for patients with intrauterine adhesions and lower uterine defects from prior cesarean deliveries in select cases. While treating intrauterine adhesions improves pregnancy outcome, the effect of lower uterine segment-filling defects from cesarean deliveries on pregnancy outcome in assisted reproductive technology cycles warrants further investigation.

Does the Presence of Blood in the Catheter or the Degree of Difficulty of Embryo Transfer Affect Live Birth

The technique used for embryo transfer (ET) can affect implantation. Prior research that evaluated the effect of postprocedural blood of the transfer catheter tip have yielded mixed results, and it is unclear whether this is actually a marker of difficulty of the transfer. Our objective was to estimate the effect of blood at the time of ET and the difficulty of ET on live birth rates (LBR). This retrospective cohort study utilized generalized estimating equations (GEEs) with nesting for repeated cycles for all analyses. Univariate modeling was performed and a final multivariate (adjusted) GEE model accounted for all significant confounders. Embryo transfers were subjectively graded (easy, medium, or hard) by a physician at the time of transfer. The presence of blood at ET was associated with more difficult ETs, retained embryos, and presence of mucous in the catheter. In the univariate analysis, ET with blood was not associated with live birth, while the degree of difficulty for ET had a negative impact on LBR. In the final multivariate GEE model, which accounts for repeated cycles from a patient, the only factors associated with an increased LBR were the degree of difficulty of the ET, female age, and blastocyst transfer. After controlling for confounding variables, the presence of blood in the transfer catheter was not associated with the likelihood of pregnancy and thus was not an independent predictor of cycle outcome. This indicates that the difficulty of the transfer itself was a strong negative predictor of pregnancy.The technique used for embryo transfer (ET) can affect implantation. Prior research that evaluated the effect of postprocedural blood of the transfer catheter tip have yielded mixed results, and it is unclear whether this is actually a marker of difficulty of the transfer. Our objective was to estimate the effect of blood at the time of ET and the difficulty of ET on live birth rates (LBR). This retrospective cohort study utilized generalized estimating equations (GEEs) with nesting for repeated cycles for all analyses. Univariate modeling was performed and a final multivariate (adjusted) GEE model accounted for all significant confounders. Embryo transfers were subjectively graded (easy, medium, or hard) by a physician at the time of transfer. The presence of blood at ET was associated with more difficult ETs, retained embryos, and presence of mucous in the catheter. In the univariate analysis, ET with blood was not associated with live birth, while the degree of difficulty for ET had a negative impact on LBR. In the final multivariate GEE model, which accounts for repeated cycles from a patient, the only factors associated with an increased LBR were the degree of difficulty of the ET, female age, and blastocyst transfer. After controlling for confounding variables, the presence of blood in the transfer catheter was not associated with the likelihood of pregnancy and thus was not an independent predictor of cycle outcome. This indicates that the difficulty of the transfer itself was a strong negative predictor of pregnancy.