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Objective: To determine the prevalence of sperm suitable for intracytoplasmic sperm injection (ICSI) in fresh ejaculated semen samples provided by men scheduled for a microdissection testicular sperm extraction (mTESE) procedure. Secondary objectives included an evaluation of the effect of a short abstinence period on semen quality and ICSI outcomes for men with cryptozoospermia., Design: Retrospective cohort study., Setting: Academic medical center., Patients: All men were scheduled to undergo a mTESE procedure by a single, high-volume surgeon at an academic center from September 1, 2015, to May 1, 2021., Intervention: Presence of sperm suitable for ICSI in the ejaculate on the day of scheduled mTESE., Main Outcome Measures: Prevalence of sperm suitable for ICSI in the ejaculate among previously diagnosed men with azoospermia. Secondary outcomes included changes in semen parameters, clinical pregnancy rate, and live birth rate., Results: Of 727 planned mTESE procedures, 69 (9.5%) were canceled because sperm suitable for ICSI were identified in a fresh ejaculated sample produced on the day of scheduled surgery (typically one day before oocyte retrieval). Overall, 50 men (50/727, 6.9%) used these rare, ejaculated sperm for ICSI. Semen samples obtained with <24 hours of abstinence were more likely to have better motility than the sample initially provided on the day of the planned mTESE. The live birth rate per ICSI attempt using these rare, ejaculated sperm was 36% (19/53)., Conclusion: Providing a fresh ejaculated semen sample on the day of mTESE allows nearly 10% of men with azoospermia to avoid surgery with satisfactory ICSI outcomes. Providing multiple ejaculated samples over a short period of time does not adversely affect sperm concentration and may enhance sperm motility in men with cryptozoospermia., Competing Interests: Declaration of interests J.A.M. has nothing to disclose. A.B. has nothing to disclose. C.K. has nothing to disclose. N.P. has nothing to disclose. P.X. has nothing to disclose. N.Z. has nothing to disclose. G.D.P. has nothing to disclose. Z.R. has nothing to disclose. P.N.S. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The human sperm centrosome, comprising the two morphologically distinct centrioles and associated pericentriolar materials, plays a crucial role in fertilization and early embryonic development after fertilization. Once inside the oocyte, the sperm centrosome serves as a microtubule-organizing center, orchestrating mitotic spindle formation, chromosome segregation, and syngamy. Abnormalities of the sperm centrosome can lead to abnormal embryonic development and embryonic chromosomal instability, and are associated with pregnancy loss. Recent research has shed light on the molecular composition, regulation, and function of this vital organelle. Understanding the intricacies of the sperm centrosome is crucial for elucidating the mechanisms underlying successful fertilization and early embryonic development, as well as addressing infertility and developmental disorders associated with centrosomal defects., Competing Interests: Declaration of interests P.X. has nothing to disclose. O.M.K. has nothing to disclose. S.C. has nothing to disclose. L.N. has nothing to disclose. D.F.A. has nothing to disclose. Z.R. has nothing to disclose. G.D.P. has nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To obtain de novo male gametes capable of inducing full preimplantation blastocyst development using a novel three-dimensional (3D) culture system., Design: Mouse embryonic stem cells (mESCs) were spherified by plunging in sodium alginate followed by calcium chloride, delineating a 3D environment that simulates the seminiferous tubule. As a control, mESCs cultured on two-dimensional plates were used. Plates and spheres containing mESCs from both methods were exposed to Activin-A, bFGF, and KSR followed by exposure to BMP4, LIF, SCF, and EGF to promote differentiation into male germ-like cells., Main Outcome Measures: Cells were assessed for VASA, DAZL, and BOULE on days 3 and 10. Cells were later injected into activated oocytes and monitored using time-lapse imaging on days 15, 22, 29, and 36. Control conceptuses generated using mature epididymal spermatozoa were also monitored via time-lapse imaging., Results: On day 3, cells differentiated on plates expressed VASA at 1% and DAZL at 29%. In spheres, VASA was expressed at a rate of 15% and DAZL at a rate of 45% (P<.001). On day 10, cells differentiated on plates had VASA expression of 7%, DAZL of 23%, and BOULE of only 0.5%. Cells differentiated into spheres expressed VASA at a rate of 20%, DAZL at 43%, and BOULE at 10% (P<.001). Subsequent differentiation in spheres on day 3 exhibited a DAZL (expressed in spermatogonia) expression of 43% and a VASA (further spermatogenesis progression) expression of 15%. On day 10, DAZL and VASA expressions were reassessed and increased to 45% and 18%, respectively. BOULE, a marker expressed solely in postmeiotic spermatocytes, was expressed at 8%, whereas acrosin was expressed in spermatids at 2%. On day 15, VASA expression plateaued at 17%, BOULE peaked at 10%, and acrosin reached 5%. On day 22, expression of VASA increased to 19%, BOULE decreased to 8%, and acrosin peaked at 7%. On day 29, VASA expression peaked at 20%, BOULE dropped to 2%, and acrosin remained stable at 7%. On day 36, VASA expression remained at 13%, whereas BOULE and acrosin expression decreased to 0% and 1%, respectively. The control cohort attained 88.4% fertilization and 76.9% blastocyst rates. De novo gametes achieved fertilization rates of 35.0%, 61.1%, 81.8%, and 50.0% on days 15, 22, 29, and 36, respectively. Neogametes-generated blastocyst rates were 5.0%, 16.7%, 36.4%, and 8.3% for days 15, 22, 29, and 36, respectively., Conclusion: Our novel 3D differentiation model can generate functional gametes and is aimed at obviating the need for allogeneic/xenogeneic transplantation. The decreased overall marker expression and the reduced blastocyst development indicated that intrasphere germ cell differentiation correlated with the length of mouse spermatogenesis at approximately 30 days. Future experiments will be conducted to confirm the reproducibility of our findings and the eventual generation of offspring., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify specific germline mutations related to sperm reproductive competence, in couples with unexplained infertility., Design: In this retrospective study, couples were divided according to whether they had successful intracytoplasmic sperm injection outcomes (fertile) or not (infertile). Ancillary sperm function tests were performed on ejaculates, and whole exome sequencing was performed on spermatozoal DNA. Sperm aneuploidy and gene mutation profiles were compared between the 2 cohorts as well as according to the specific reasons for reproductive failure., Setting: Center for reproductive medicine at a major academic medical center., Patient(s): Thirty-one couples with negative infertility workups and normal semen parameters., Intervention(s): Couples with mutations on fertilization- or embryo development-related genes were subsequently treated by assisted gamete treatment or microfluidics, respectively., Main Outcome Measure(s): Intracytoplasmic sperm injection cycle outcomes including fertilization, clinical pregnancy, and delivery rates., Result(s): Sperm aneuploidy was lower in the fertile group (4.0% vs. 8.4%). Spermatozoa from both cohorts displayed mutations associated with sperm-egg fusion (ADAM3A) and acrosomal development (SPACA1), regardless of reproductive outcome. The infertile cohort was then categorized according to the reasons for reproductive failure: absent fertilization, poor early embryo development, implantation failure, or pregnancy loss. Spermatozoa from the fertilization failure subgroup (n = 4) had negligible PLCζ presence (10% ± 9%) and gene mutations (PLCZ1, PIWIL1, ADAM15) indicating a sperm-related oocyte-activating deficiency. These couples were successfully treated by assisted gamete treatment in their subsequent cycles. Spermatozoa from the poor early embryo development subgroup (n = 5) had abnormal centrosomes (45.9% ± 5%), and displayed mutations impacting centrosome integrity (HAUS1) and spindle/microtubular stabilization (KIF4A, XRN1). Microfluidic sperm processing subsequently yielded a term pregnancy. Spermatozoa from the implantation failure subgroup (n = 7) also had abnormal centrosomes (53.1% ± 13%) and carried mutations affecting embryonic implantation (IL9R) and microtubule and centrosomal integrity (MAP1S, SUPT5H, PLK4), whereas those from the pregnancy loss subgroup (n = 5) displayed mutations on genes involved in trophoblast development (NLRP7), cell cycle regulation (MARK4, TRIP13, DAB2IP, KIF1C), and recurrent miscarriage (TP53)., Conclusion(s): By assessing the sperm genome, we identified specific germline mutations related to various reproductive processes. This information may clarify elusive factors underlying reproductive competence and enhance treatment for couples with unexplained infertility., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if increasing paternal age has an adverse effect on pregnancy outcomes in paired donor egg recipients who received oocytes from the same donor in the same stimulation cycle., Design: Retrospective cohort study., Setting: Reproductive Medicine Center., Patient(s): The study included 154 recipients who received oocytes from a split donor oocyte cycle and received sperm from men in discrepant age groups (group A: <45 years old; group B: ≥45 years old)., Intervention(s): None., Main Outcome Measure(s): Implantation rate, pregnancy loss rate, pregnancy rate, and live birth rate., Result(s): The median paternal age was 41 years old for group A and 48 years old for group B. The pregnancy rate was 81% in group A compared with 69% in group B. The live birth rate was 65% in group A compared with 53% in group B. The rate of pregnancy loss was 19% in group A and 23% in group B. The implantation rate was 69% in group A compared with 66% in group B. The adjusted odds of pregnancy were found to be 65% lower for patients in the older partner age group (95% confidence interval [CI], 0.13, 0.95). The adjusted odds of live birth rate (odds ratio [OR], 0.45; 95% CI, 0.20, 1.00), implantation rate (OR, 0.91; 95% CI, 0.43, 1.92), and rate of pregnancy loss (OR, 1.5; 95% CI, 0.5, 4.5) favored the younger partner age group; however, these results were not statistically significant., Conclusion(s): In this model that controlled for oocyte quality to the greatest degree possible by using paired recipients from the same donor from the same stimulation cycle, we found that increased paternal age had a negative effect on pregnancy rates., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this article is to gather 9 thought leaders and their team members to present their ideas about the future of in vitro fertilization and the andrology laboratory. Although we have seen much progress and innovation in the laboratory over the years, there is still much to come, and this article looks at what these leaders think will be important in the future development of technology and processes in the laboratory., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The in vitro fertilization and andrology laboratories are at the center of assisted reproductive technologies and the place where technicians and embryologists manipulate gametes and preimplantation-stage embryos with the goal of achieving the best embryo for transfer. Through the years, these laboratories have seen developments in technique, technology, and testing. The goal of this Views and Interviews series is to bring together the thought leaders in the field and envision what the laboratories will look like in the next 10 years., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report the utility of combined transvaginal and transabdominal oocyte retrieval in a patient with an ectopic ovary and unicornuate uterus., Design: Video case report with demonstration of oocyte retrieval technique., Setting(s): University-affiliated fertility center., Patient(s): A 35-year-old woman, gravida 0, with a 6-month history of infertility who presented to our center for fertility evaluation. Hysterosalpingography revealed a left unicornuate uterus and patent left fallopian tube magnetic resonance imaging and laparoscopy showed a right ectopic ovary located in the upper abdomen. Her partner was a 36-year-old male with isolated teratozoospermia. The couple did not conceive with intrauterine insemination., Intervention(s): Ovarian stimulation for in vitro fertilization (IVF). Transvaginal retrieval of oocytes from the right ovary was not deemed possible due the anatomic location of the ovary, intervening blood vessels, and limited mobility of the ovary. Institutional review board approval was not required for this case report as per our institution's policy; patient consent was obtained for publication of the case., Main Outcome Measure(s): Transabdominal retrieval of oocytes from the right ovary and transvaginal retrieval of oocytes from the left ovary., Result(s): The couple underwent two IVF cycles. Nine oocytes were retrieved during the first IVF cycle: seven transabdominal (right ovary) and two transvaginal (left ovary). All oocytes were mature, and five blastocysts were cryopreserved. Eight oocytes were retrieved during the second IVF cycle, of which five oocytes were retrieved transabdominally from the right ovary, and three oocytes were retrieved transvaginally from the left ovary. All oocytes were mature, and four blastocysts were cryopreserved. A single thawed embryo was transferred in the natural menstrual cycle, which resulted in the live birth of a full-term baby boy weighing 2,410 grams., Conclusion(s): The current case highlights the safety and feasibility of combined transvaginal and transabdominal oocyte retrieval in patients with an ectopic ovary located in the upper abdomen., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if the time from oocyte retrieval to frozen embryo transfer (FET) in the natural cycle affects reproductive or neonatal outcomes., Design: Retrospective cohort., Setting: Not applicable., Patient(s): Five hundred and seventy-six consecutive freeze-all cycles from January 2011 to December 2018 followed by natural cycle FET of a single blastocyst., Intervention(s): None., Main Outcome Measure(s): Primary outcome of live birth; secondary outcomes of preterm delivery (24-37 weeks) and small for gestational age (SGA) with a multivariable logistic regression performed with adjustment for age, infertility diagnosis, ovulatory trigger type, and preimplantation genetic testing (PGT)., Result(s): Before adjustment for confounding, we found a statistically significantly different live-birth rate (57.7% vs. 48.6%) for natural cycle FET occurring in the first versus second menstrual cycle, respectively. In a multivariate analysis, performing a natural cycle FET of a single blastocyst in the second compared with the first menstrual cycle did not statistically significantly impact the odds of live-birth rate. After adjustment for age, diagnosis, and ovulatory trigger type, only PGT was associated with statistically significantly increased odds of live birth compared with no PGT. There were no differences in the incidence of SGA (male, 6.6% vs. 2.3%; female, 9.8% vs. 11.1%) or preterm delivery (1.6% vs. 5.6%) between both groups., Conclusion(s): Performing a natural cycle FET of a single blastocyst in the second compared with the first menstrual cycle after ovarian stimulation did not statistically significantly impact the odds of live birth or neonatal outcomes., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the optimal lead follicle size for hCG trigger in clomiphene citrate (CC)-intrauterine insemination (IUI) cycles., Design: Retrospective cohort study., Setting: University-affiliated center., Patient(s): Patients <40 years of age with ovulatory dysfunction or unexplained infertility undergoing their first CC-IUI cycle., Intervention(s): Ovulation induction, hCG trigger, and IUI., Main Outcome Measure(s): Clinical pregnancy rate (CPR) was the primary outcome and was plotted against lead follicle size in increments of 1 mm. Odds ratios with 95% confidence intervals for associations between lead follicle size and CPR were calculated from a multivariable logistic regression model. A receiver operating characteristic (ROC) curve was generated for CPR as a function of lead follicle size., Result(s): 1,676 cycles were included. The overall CPR was 13.8% (232/1,676). There was no difference in baseline demographics or ovulation induction parameters of patients who did or did not conceive. The odds of clinical pregnancy were 2.3 and 2.2 times higher with lead follicle sizes of 21.1-22.0 mm and >22.0 mm, respectively, compared with the referent category of 19.1-20.0 mm. Lead follicle size was an independent predictor of CPR, even after accounting for confounders. A lead follicle size of 22.1 mm corresponded to a sensitivity and specificity of 80.1% and 90.4% for clinical pregnancy, respectively, with an area under the ROC curve of 0.89., Conclusion(s): hCG administration at a lead follicle size of 21.1-22.0 mm is associated with higher odds of clinical pregnancy in patients undergoing their first CC-IUI cycles for ovulatory dysfunction or unexplained infertility., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has resulted in paradigm shifts in the delivery of health care. Lockdowns, quarantines, and local mandates forced many physician practices around the United States to move to remote patient visits and adoption of telemedicine. This has several long-term implications in the future practice of medicine. In this review we outline different models of integrating telemedicine into both male and female fertility practices and recommendations on performing video physical examinations. Moving forward we foresee two general models of integration: one conservative, where initial intake and follow-up is performed remotely, and a second model where most visits are performed via video and patients are only seen preoperatively if necessary. We also discuss the impact THAT telemedicine has on coding and billing and our experience with patient satisfaction., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Artificial intelligence (AI) systems have been proposed for reproductive medicine since 1997. Although AI is the main driver of emergent technologies in reproduction, such as robotics, Big Data, and internet of things, it will continue to be the engine for technological innovation for the foreseeable future. What does the future of AI research look like?, (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

As the world becomes increasingly reliant on computers, it is not surprising that medicine has embraced the computer age with enthusiasm. This is also true in the field of reproductive medicine, where we are witnessing exciting applications of digital technologies and artificial intelligence (AI). It is anticipated that AI-guided approaches will become more objective, more accurate, and more rapid, resulting in greater precision, standardization, and automatization in our field. This month's Views and Reviews contains five thought-provoking contributions addressing the contemporary and futuristic applications of AI in reproductive medicine and the assisted reproductive technologies., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Embryo evaluation and selection embody the aggregate manifestation of the entire in vitro fertilization (IVF) process. It aims to choose the "best" embryos from the larger cohort of fertilized oocytes, the majority of which will be determined to be not viable either as a result of abnormal development or due to chromosomal imbalances. Indeed, it is generally acknowledged that even after embryo selection based on morphology, time-lapse microscopic photography, or embryo biopsy with preimplantation genetic testing, implantation rates in the human are difficult to predict. Our pursuit of enhancing embryo evaluation and selection, as well as increasing live birth rates, will require the adoption of novel technologies. Recently, several artificial intelligence (AI)-based methods have emerged as objective, standardized, and efficient tools for evaluating human embryos. Moreover, AI-based methods can be implemented for other clinical aspects of IVF, such as assessing patient reproductive potential and individualizing gonadotropin stimulation protocols. As AI has the capability to analyze "big" data, the ultimate goal will be to apply AI tools to the analysis of all embryological, clinical, and genetic data in an effort to provide patient-tailored treatments. In this chapter, we present an overview of existing AI technologies in reproductive medicine and envision their potential future applications in the field., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify and treat the gamete responsible for complete fertilization failure with intracytoplasmic sperm injection (ICSI) using a newly proposed assisted gamete treatment (AGT)., Design: Prospective cohort study., Setting: Center for reproductive medicine., Patient(s): One-hundred and fourteen couples with an adequate number of spermatozoa for ICSI and a fertilization rate of ≤10%, after controlling for maternal age., Intervention(s): Couples with an oocyte-related oocyte activation deficiency (OAD) underwent a subsequent cycle with a modified superovulation protocol; couples with sperm-related OAD had an additional genetic and epigenetic assessment to identify mutations and expression levels of the corresponding genes., Main Outcome Measure(s): Treatment cycle outcome for couples undergoing ICSI with either a modified superovulation protocol or AGT compared with their historical cycle., Result(s): A total of 114 couples matched the inclusion criteria, representing approximately 1.3% of the total ICSI cycles performed at our center, with age-matched controls. Fifty-two couples were confirmed negative for sperm-related OAD by the phospholipase Cζ (PLCζ) assay, indicating oocyte-related factors in their failed fertilization cycles. Couples were treated by one of two AGT protocols, AGT-initial or AGT-revised, in a subsequent attempt that was compared with their historical cycle. Subsequent ICSI cycles with a tailored superovulation protocol yielded significantly higher fertilization (59.0% vs. 2.1%) and clinical pregnancy (28.6% vs. 0) rates. In 24 couples (mean ± standard deviation: maternal age, 35.6 ± 5 years; paternal age, 39.8 ± 6 years) sperm-related OAD was confirmed; in four men, a deletion on the PLCZ1 gene was identified. Additional mutations were also identified of genes supporting spermiogenesis and embryo development (PIWIL1, BSX, NLRP5) and gene deletions confirming a complete absence of the subacrosomal perinuclear theca (PICK1, SPATA16, DPY19L). Subsequent AGT treatment provided higher fertilization (42.1%) and clinical pregnancy (36% vs. 0%) rates for couples with a history of impaired (9.1%) fertilization. A comparison of the two AGT protocols, AGT-initial or AGT-revised, revealed that the latter yielded even more favorable fertilization (37.6% vs. 45.9%) and clinical pregnancy (21.1% vs. 83.3%) rates., Conclusion(s): In couples with an oocyte-related OAD, tailoring the superovulation protocol resulted in successful fertilization, term pregnancies, and deliveries. In couples with a sperm-related OAD as determined by PLCζ assay, mouse oocyte activation test, and the assessment of gene mutations and function, AGT was successful. The AGT-revised protocol yielded an even higher fertilization rate than the AGT-initial protocol, resulting in the birth of healthy offspring in all couples who achieved a clinical pregnancy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To study whether patients exhibiting poor ovarian response have abnormal levels of serum insulin-like growth factor (IGF)-1 on cycle day 2 when compared with age-matched normal and high responders., Design: Retrospective cohort., Setting: University-based practice., Patient(s): All women between the ages of 21 and 42 years who underwent in vitro fertilization treatment cycle without estrogen pretreatment at our institution between 2013 and 2015., Intervention(s): Patients were separated into three groups: poor responders (≤4 oocytes retrieved/cycle cancellation), normal responders (8-12 oocytes), and high responders (≥18 oocytes). Subanalysis focused on the next cycle for poor responders adjacent to the nonpretreated index cycle, in which estrogen pretreatment was implemented., Main Outcome Measure(s): Serum cycle day 2: IGF-1, insulin-like growth factor-binding protein (IGFBP)-3 levels, and IGF-1:IGFBP3 ratio, number of eggs retrieved, number of two pronuclei embryos, cumulative pregnancy rate, and live birth., Result(s): A total of 184 patients met the inclusion criteria. The poor responder group exhibited a more than twofold increase in the cycle day IGF-1 serum levels when compared with normal responders and a threefold increase when compared with the high responders. Cycle day 2 IGF-1 level >72 ng/mL in poor responders had 70% sensitivity and 78% specificity for a negative controlled ovarian hyperstimulation cycle outcome with an area under the curve of 0.83. Luteal estrogen pretreatment in the poor responder group was associated with a significant reduction in IGF-1 levels. Significantly, more retrieved and mature oocytes, as well as two pronuclei embryos, were achieved in the pretreated poor responder group when compared with the yield from their adjacent nonpretreated index cycles. Furthermore, cumulative rates were higher for intrauterine pregnancies, and lower for negative pregnancy outcome., Conclusion(s): Patients who respond poorly to controlled ovarian stimulation, despite normal cycle day 2 follicle-stimulating hormone levels, have significantly higher serum cycle day 2 IGF-1 levels when compared with age-matched normal and high responders. Cycle day 2 IGF-1 level >72 ng/mL in poor responders was predictive of a negative cycle outcome. Luteal estrogen pretreatment in the poor responder group was associated with a significant reduction in IGF-1 levels, improved response to stimulation, and higher cumulative rates for intrauterine pregnancies, and lower for negative pregnancy outcome., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether BRCA carriers with and without malignancy have decreased ovarian reserve at baseline compared with BRCA noncarriers., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Seven-hundred and ninety-five oocyte cryopreservation patients, comprising BRCA carriers with and without malignancy (n = 57) and BRCA noncarriers (n = 738)., Intervention(s): Fertility preservation with oocyte cryopreservation., Main Outcome Measure(s): Antral follicle count (AFC), antimüllerian hormone (AMH) concentration, day-3 follicle-stimulating hormone (FSH) level, number of harvested oocytes, and number of mature/cryopreserved oocytes., Result(s): In the cancer cohort we compared BRCA-positive breast cancer (n = 38) with BRCA-negative breast cancer (n = 53) and with non-breast-cancer malignancies (n = 85). In the cancer-free cohort we compared BRCA carriers (n = 19) with women undergoing elective egg freezing (n = 600). We also compared the BRCA1 (n = 31) versus the BRCA2 carriers (n = 18). The patients' mean ages were 32.4 ± 3.6 years and 35.5 ± 4.3 years in the BRCA carrier and noncarrier cohorts, respectively. BRCA status was associated with a higher day-3 FSH level in the cancer cohort, but we found no changes in the other outcomes compared with the BRCA-negative cancer groups. BRCA carriers without cancer exhibited a higher AFC and number of mature oocytes compared with the patients undergoing planned egg freezing. Overall (cancer and cancer-free cohorts), the BRCA carriers had an increased AFC (15.5 ± 4.6 vs. 12.6 ± 5.7) and number of mature/cryopreserved oocytes (14.0 ± 7.9 vs. 10.4 ± 6.9) compared with the BRCA noncarriers but had no differences in other outcomes., Conclusion(s): BRCA carriers with and without malignancy exhibit comparable ovarian reserve and responses to ovarian stimulation compared with women with BRCA-negative cancers and cancer-free controls., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Congenital adrenal hyperplasia, an endocrine autosomal recessive disorder caused by several deficiencies of enzymes and/or proteins involved in adrenal cortisol biosynthesis, is often associated with reproductive dysfunction. While the most common disorder is due to 21-hydroxylase deficiency, several other enzymes in the steroidogenesis pathway have been described, all of which can result in a range of reproductive disorders in both males and females. Although for many enzymes the phenotypic presentation is associated with a particular genotype, the severity of disease cannot always be predicted., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Nonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder., (Copyright © 2018. Published by Elsevier Inc.)

With the first successful report of an IVF pregnancy achieved via donor oocytes in 1984, the applications of assisted reproductive technology (ART) were further expanded to include women unable to conceive with their own oocytes. Today, oocyte donation makes up an increasingly large percentage of all ART cycles worldwide. Oocyte donation presents several unique challenges to clinicians as two separate interests, those of the donor and those of the recipient, must be represented. These challenges include successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation while maximizing donor safety. Facing these challenges has not only allowed for the creation of successful donor egg programs but has also provided insights into many aspects of ART. Much of what we know about the window of implantation, frozen ET procedures, triggering of oocyte maturation, and fertility preservation has been learned through experience and investigations with donor egg cycles. Not only has oocyte donation, through its optimization and wide use, provided new treatment opportunities for patients, it has also become a critical scientific tool to study many aspects of menstrual cycle dynamics and implantation. Concomitantly, with its increased efficiency, it has also raised several clinical and ethical challenges., (Copyright © 2018. Published by Elsevier Inc.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

In commemoration of 40 years of in vitro fertilization (IVF), herein we describe the early evolution of the first IVF program at the Eastern Virginia Medical School in Norfolk, Virginia. The birth of the first American IVF baby was the result of the work of many investigators, both in experimental animal models and in humans, heavily relying on the experience of Robert Edwards and Patrick Steptoe in Great Britain. Although their first IVF baby was the result of the retrieval of a single oocyte in the natural cycle, duplicating their methods was not successful in Norfolk. It turns out that the achievement of the first pregnancy in the United States was associated with introducing ovarian stimulation with gonadotropins, establishing the appropriate timing for egg retrieval after hCG administration, retrieving multiple mature oocytes, determining the ideal time for in vitro insemination, and optimizing embryo culture media., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether the blastocyst development rate, as assessed by the day of trophectoderm biopsy (day 5 vs. day 6), affects the live birth rate (LBR) of similarly graded euploid blastocysts., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Patients who underwent frozen-thawed single euploid blastocyst transfers from 2013 to 2016 were included. Blastocyst morphologic grading was performed on day 5 or day 6 before the biopsy, with embryos designated into the following groups: good (3-6AA, 3-6AB, and 3-6BA), average (2-6BB), and poor (2-6BC and 2-6CB)., Intervention(s): Frozen-thawed embryo transfer., Main Outcome Measure(s): Implantation rate (IR) and LBR., Result(s): A total of 701 frozen-thawed single euploid blastocyst transfer cycles were included. Cycles in which day 5 blastocysts were transferred (n = 366) were associated with a significantly higher LBR than those in which day 6 blastocysts were transferred (n = 335; 60.4% vs. 44.8%). The odds ratio remained significant after controlling for all confounders, including the blastocyst grading. Furthermore, there was a significant difference in LBRs between good-quality, average-quality, and poor-quality blastocysts (67.8%, 53.4%, and 29.5%, respectively). Embryos reaching good-quality blastocysts on day 5 yielded significantly higher LBR (72.8% vs. 56.5%) and IR (77.7% vs. 58.7%) compared with those reaching similar quality blastocysts on day 6. Similarly, day 5 average-quality embryos conveyed a significantly higher IR compared with day 6 embryos of the same quality (64.4% vs. 53.4%)., Conclusion(s): In addition to aneuploidy assessment, the speed of embryo development to the blastocyst stage and an evaluation of blastocyst morphology are critical to selecting the best embryo., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Tumor protein 53 (TP53) and its related family of p63 and p73 are tumor suppressor genes that regulate cellular activity to enhance longevity. p53 binds to specific response elements in DNA, modulating the transcription of genes that govern the major defenses against tumor growth. Additional members of the p53 family are involved with male and female germ cell survival. Although the majority of studies have focused on p53 as a tumor suppressor gene, little is known about its function in normal cellular processes. Polymorphisms of TP53 codon 72 that alter activity levels have been studied with respect to implantation in both the murine and human models. TP53 codon 72 (arginine) exhibits higher rates of apoptosis and leukemia inhibitory factor expression, whereas the C allele (proline) reduces leukemia inhibitory factor expression. Here, we review the role of p53 and the family of p53 proteins, along with the potential effect of p53 polymorphisms on reproduction., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Infertility has been increasingly recognized as a possible biomarker for cancer risk. There is significant data linking these two seemingly disparate diseases in infertile men and burgeoning data linking them in infertile women. Here we investigate the possible mechanisms whereby one shared genetic or epigenetic insult could confer increased risk for both infertility and cancer., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Over the past four decades we have witnessed great progress and increasing pregnancy success rates with in vitro fertilization. However, this apparent success has been accompanied by the burden of multiple pregnancies. While efforts to reduce the number of embryos transferred have had a salutary impact on the incidence of high order multiple pregnancies, twin gestations have not diminished significantly. Thus, the search for a marker of embryo quality with the goal of selecting the single best embryo for transfer continues to be the major challenge facing our field. The four contributions in this Views and Reviews present several contemporary approaches, both invasive and non-invasive, for evaluating embryo viability. Each group makes the case that recent techniques, including time-lapse microscopy, biomechanical markers for oocytes and embryos, novel non-invasive methods of evaluating embryo metabolism and function as well as measurement of mitochondrial DNA, will allow the identification of the single best embryo for transfer. They describe several promising markers of embryo viability, although the goal of finding the "holy grail" of embryo selection has not yet been realized., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the association between ABO blood type and live-birth outcomes in patients undergoing IVF with day 5 single-embryo transfer (SET)., Design: Retrospective cohort study., Setting: University-affiliated center., Patient(s): Normal responders, <40 years old, undergoing their first IVF cycle with fresh SET., Intervention(s): None., Main Outcome Measure(s): Live-birth rate was the primary outcome. Secondary outcomes were birth weight and gestational age at delivery. Univariate and multivariable logistic regression was used to examine the association between blood type and live birth, while controlling for confounders. Odds ratios (OR) with 95% confidence intervals (CI) for live birth were estimated., Result(s): A total of 2,329 patients were included. The mean age of the study cohort was 34.6 ± 4.78 years. The distribution of blood types was as follows: A = 897 (38.5%); B = 397 (17.0%); AB = 120 (5.2%); and, O = 1,915 (39.3%) patients. There was no difference in the baseline demographics, ovarian stimulation, or embryo quality parameters between the blood types. The unadjusted ORs for live birth when comparing blood type A (referent) with blood types B, AB, and O were 0.96 (95% CI, 0.6-1.7), 0.72 (95% CI, 0.4-1.2), and 0.96 (95% CI. 0.6-1.7), respectively. The adjusted ORs for live birth remained not significant when comparing blood type A to blood types B, AB, and O individually. No difference in birth weight or gestational age at delivery was noted among the four blood types., Conclusion(s): Our findings suggest that ABO blood type is not associated with live-birth rate, birth weight, or gestational age at delivery in patients undergoing IVF with day 5 SET., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the oocyte and embryo yield associated with GnRH-agonist triggers vs. hCG triggers in cancer patients undergoing controlled ovarian stimulation (COS) for fertilization preservation., Design: Retrospective cohort study., Setting: Academic center., Patient(s): Cancer patients undergoing COS with letrozole and gonadotropins or gonadotropin-only protocols for oocyte or embryo cryopreservation., Intervention(s): Gonadotropin-releasing hormone agonist or hCG trigger., Main Outcome Measure(s): Number of metaphase II (MII) oocytes or two-pronuclei (2PN) embryos available for cryopreservation were primary outcomes. Separate multivariate linear regression models were used to assess the effect of trigger type on the primary outcomes, after controlling for confounders of interest., Result(s): A total of 341 patients were included, 99 (29.0%) in the GnRH-agonist group and 242 (71%) in the hCG group. There was no difference in the baseline demographics of patients receiving GnRH-agonist or hCG triggers. Within the letrozole and gonadotropins group (n = 269), the number (mean ± SD, 11.8 ± 5.8 vs. 9.9 ± 6.0) and percentage of MII oocytes (89.6% vs. 73.0%) available for cryopreservation was higher with GnRH-agonist triggers compared with hCG triggers. Similar results were noted with GnRH-agonist triggers in the gonadotropin-only group (n = 72) (i.e., a higher number [13.3 ± 7.9 vs. 9.3 ± 6.0] and percentage of MII oocytes [85.7% vs. 72.8%] available for cryopreservation). Multivariate linear regression demonstrated approximately three more MII oocytes and 2PN embryos available for cryopreservation in the GnRH-agonist trigger group, irrespective of cancer and COS protocol type., Conclusion(s): Utilization of a GnRH-agonist trigger increases the number of MII oocytes and 2PN embryos available for cryopreservation in cancer patients undergoing COS for fertility preservation., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report a case of ex vivo oocyte retrieval from oophorectomized specimens in a BRCA1 mutation carrier undergoing surgical staging for ovarian cancer., Design: Video case report and literature review., Setting: University-affiliated center., Patient(s): A 37-year-old single woman, gravida 0, with a known BRCA1 mutation, presented to her oncologist with a complex right ovarian mass and elevated CA-125 level. Ovarian cancer was suspected, and the patient consented to complete surgical staging. Although she desired to cryopreserve oocytes for fertility preservation, conventional oocyte retrieval was deemed unsafe because follicular puncture would compromise the integrity of the ovarian capsule, thereby increasing the risk of malignant cell spillage and cancer upstaging., Intervention(s): Luteal-phase ovarian stimulation with gonadotropins and letrozole was performed. Surgical staging was initiated 34 hours after the administration of the ovulatory trigger., Main Outcome Measure(s): Ex vivo retrieval of oocytes from bilateral oophorectomized specimens under direct visualization at the time of surgical staging., Result(s): Seven mature oocytes were retrieved and vitrified. Concomitant surgical staging was completed., Conclusion(s): The present case highlights the feasibility of ex vivo or extracorporeal retrieval of mature oocytes from oophorectomized specimens in patients with ovarian cancer. By avoiding follicular puncture within the pelvic cavity, it minimizes the risk of malignant cell spillage and cancer upstaging., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether blastocyst grading can predict pregnancy outcomes in the frozen-thawed embryo transfer (FET) of euploid blastocysts., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Women who underwent FET of euploid embryo(s) between January 2013 and December 2015, with blastocysts were divided into four groups based on their morphologic grading before cryopreservation: excellent (≥3AA), good (3-6AB, 3-6BA, 1-2AA), average (3-6BB, 3-6AC, 3-6CA, 1-2AB, 1-2BA), and poor (1-6BC, 1-6CB, 1-6CC, 1-2BB)., Intervention(s): FET., Main Outcomes Measure(s): Ongoing pregnancy rate (OPR)., Result(s): A total of 417 FET cycles (477 embryos) were included. Excellent-quality embryos (n = 38) yielded a statistically significantly higher OPR than poor-quality embryos (n = 106) (84.2% vs. 35.8%; adjusted odds ratio 11.0; 95% confidence interval, 3.8-32.1) and average-quality embryos (n = 197) (84.2% vs. 55.8%; adjusted odds ratio 4.8; 95% confidence interval, 1.7-13.3). Good-quality embryos (n = 76) were associated with a statistically significantly higher OPR than poor-quality embryos (61.8% vs. 35.8%). These odds ratios were adjusted for patient's age, body mass index, number of transferred embryos, type of frozen cycle, peak endometrial thickness, day of trophectoderm biopsy (5 or 6), and total number of euploid embryos for each patient. An inner cell mass grade of A yielded a statistically significantly higher OPR than ICM grade C (76.2% vs. 13.5%) or grade B (76.2% vs. 53.6%) after controlling for all confounders., Conclusion(s): Contrary to prior published studies, the current data suggest that blastocyst morphologic grading and particularly inner cell mass grade is a useful predictor of OPR per euploid embryo. Morphologic grading should be used to help in the selection among euploid blastocysts., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of prolonged ovarian stimulation on pregnancy outcomes in IVF cycles with fresh day 3 ET., Design: Retrospective cohort study., Setting: University-affiliated center., Patient(s): All patients initiating their first IVF cycle with fresh day 3 ET. Prolonged ovarian stimulation was defined as a duration of more than two standard deviations (95th percentile) for the study cohort (i.e., >13 days)., Intervention(s): None., Main Outcome Measure(s): Live birth rate was considered the primary outcome and was compared between patients undergoing ovarian stimulation for ≤13 days and >13 days. Odds ratios (OR) with 95% confidence intervals (CI) for all pregnancy outcomes after day 3 ET were calculated. The OR for live birth was adjusted using logistic regression., Result(s): A total of 6,410 and 339 patients underwent ovarian stimulation for ≤13 days and >13 days, respectively. There were no differences in the demographics or mean number of day 3 embryos transferred between the two groups. Ovarian stimulation ≤13 days was associated with increased odds of clinical pregnancy (OR 2.15, 95% CI 1.19-3.89) and live birth (OR 2.35, 95% CI 1.25-4.43). The increased odds for live birth in the ≤13-day group remained unchanged after logistic regression. Patients with clinical pregnancies in the >13-day group were younger (34.6 ± 4.91 years) compared with those who did not conceive (38.2 ± 4.72 years)., Conclusion(s): Our findings suggest that ovarian stimulation ≤13 days is associated with increased odds of clinical pregnancy and live birth. In patients undergoing ovarian stimulation >13 days, younger age is associated with live birth., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare IVF outcomes between women undergoing frozen transfers of blastocysts verified as euploid by preimplantation genetic screening (PGS) with patients undergoing fresh nonbiopsied blastocyst transfers., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): All patients undergoing IVF-PGS cycles between January 2010 and November 2014 were included (n = 274). Patients were compared with a control group consisting of all fresh blastocyst transfers that occurred during the same period (n = 863)., Intervention(s): Patients underwent IVF-PGS with 24-chromosome screening. Patients with euploid embryos had transfer of one to two embryos in a subsequent frozen ET cycle., Main Outcome Measure(s): Implantation, clinical intrauterine gestation (CIG), miscarriage, biochemical pregnancy (BC), and live birth (LB) rates were compared., Result(s): Odds ratios (ORs) were estimated for outcomes in women undergoing PGS versus controls. Among patients ≤37 years old, there were no differences in CIG and LB rates for single (adjusted ORs [aORs], 1.20 [95 %confidence interval {CI}, 0.66-2.21]; 1.21 [95% CI, 0.66-2.2]) and double ETs (aORs, 1.09 [95% CI, 0.54-2.18]; 0.87 [95% CI, 0.44-1.7]). BC and miscarriage rates were also similar. For patients >37 years old, CIG and LB rates were increased for single (aORs, 3.86 [95% CI, 1.25-11.9]; 8.2 [95% CI, 2.28-29.5]) and double ETs (aORs, 9.91 [95% CI, 2.0-49.6]; 8.67 [95% CI, 2.08-36.2]) with no difference in BC and miscarriage rates. A per-retrieval analysis of the >37 group failed to demonstrate any difference in CIG or LB rates., Conclusion(s): Among patients ≤37, IVF-PGS does not improve CIG, LB, and miscarriage rates. IVF-PGS in women >37 improved CIG and LB rates. However, per cycle, the PGS advantage in this age group does not persist., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)