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Oocyte stimulation parameters influence the number and proportion of mature oocytes retrieved in assisted reproductive technology cycles

Gonullu, Damla C; McCulloh, David H; Robinson, LeRoy G; Oh, Cheongeun; Keefe, David L
PURPOSE/OBJECTIVE:Whether differences in stimulation parameters alter the number and proportion of MII oocytes retrieved. METHODS:Records of 2546 patients were examined, looking at age, day 2/3 follicle-stimulating hormone (FSH) and estradiol (E2) levels, total dose of gonadotropins administered (including FSH and human menopausal gonadotropin [hMG]), fraction of hMG administered, number of days of treatment with gonadotropins, and the dose of gonadotropins administered per day. We segregated the patients into 3 different classes depending on the trigger method used and 2 groups based on egg freeze vs. ICSI. Multiple regression methods were used to examine associations between stimulation parameters and the total number of eggs, number of immature oocytes (Poisson regression), and the fraction of retrieved oocytes that were immature (Logistic regression). RESULTS:After adjustments for different triggers and egg freeze versus ICSI, both the #immature oocytes and the immature fraction of oocytes were associated with the total gonadotropin dose (inversely) and the gonadotropin dose/day (positively). Other parameters were associated with the number of immature oocytes but were also associated with the number of oocytes retrieved. CONCLUSIONS:Stimulations using less total gonadotropin and more gonadotropin per day were associated with more immaturity. The type of trigger method used for final maturation was associated with immaturity but was believed to be predominantly due to trigger assignment to patients based on response. The association between use of ICSI and less immaturity was believed to be due to additional time for maturation in the ICSI group.
PMID: 34125361
ISSN: 1573-7330
CID: 4911362

Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development

Kohlrausch, Fabiana B; Wang, Fang; Chamani, Isaac; Keefe, David L
Importance/UNASSIGNED:It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction. Objective/UNASSIGNED:In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos. Evidence Acquisition/UNASSIGNED:We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development. Results/UNASSIGNED:Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos. Conclusions and Relevance/UNASSIGNED:Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.
PMID: 34324695
ISSN: 1533-9866
CID: 4949972

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants

Rojas, Rebecca A; Kutateladze, Anna A; Plummer, Lacey; Stamou, Maria; Keefe, David L; Salnikov, Kathyrn B; Delaney, Angela; Hall, Janet E; Sadreyev, Ruslan; Ji, Fei; Fliers, Eric; Gambosova, Katarina; Quinton, Richard; Merino, Paulina M; Mericq, Veronica; Seminara, Stephanie B; Crowley, William F; Balasubramanian, Ravikumar
PURPOSE/OBJECTIVE:SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. METHODS:Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. RESULTS:Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD. CONCLUSION/CONCLUSIONS:SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
PMID: 33442024
ISSN: 1530-0366
CID: 4747062

Control of LINE-1 Expression Maintains Genome Integrity in Germline and Early Embryo Development

Kohlrausch, Fabiana B; Berteli, Thalita S; Wang, Fang; Navarro, Paula A; Keefe, David L
Maintenance of genome integrity in the germline and in preimplantation embryos is crucial for mammalian development. Epigenetic remodeling during primordial germ cell (PGC) and preimplantation embryo development may contribute to genomic instability in these cells, since DNA methylation is an important mechanism to silence retrotransposons. Long interspersed elements 1 (LINE-1 or L1) are the most common autonomous retrotransposons in mammals, corresponding to approximately 17% of the human genome. Retrotransposition events are more frequent in germ cells and in early stages of embryo development compared with somatic cells. It has been shown that L1 activation and expression occurs in germline and is essential for preimplantation development. In this review, we focus on the role of L1 retrotransposon in mouse and human germline and early embryo development and discuss the possible relationship between L1 expression and genomic instability during these stages. Although several studies have addressed L1 expression at different stages of development, the developmental consequences of this expression remain poorly understood. Future research is still needed to highlight the relationship between L1 retrotransposition events and genomic instability during germline and early embryo development.
PMID: 33481218
ISSN: 1933-7205
CID: 4761002

Molecular Features of Polycystic Ovary Syndrome Revealed by Transcriptome Analysis of Oocytes and Cumulus Cells

Li, Jie; Chen, Haixia; Gou, Mo; Tian, Chenglei; Wang, Huasong; Song, Xueru; Keefe, David L; Bai, Xiaohong; Liu, Lin
Polycystic ovary syndrome (PCOS) is typically characterized by a polycystic ovarian morphology, hyperandrogenism, ovulatory dysfunction, and infertility. Furthermore, PCOS patients undergoing ovarian stimulation have more oocytes; however, the poor quality of oocytes leads to lower fertilization and implantation rates, decreased pregnancy rates, and increased miscarriage rates. The complex molecular mechanisms underlying PCOS and the poor quality of oocytes remain to be elucidated. We obtained matched oocytes and cumulus cells (CCs) from PCOS patients, compared them with age-matched controls, and performed RNA sequencing analysis to explore the transcriptional characteristics of their oocytes and CCs. Moreover, we validated our newly confirmed candidate genes for PCOS by immunofluorescence. Unsupervised clustering analysis showed that the overall global gene expression patterns and transposable element (TE) expression profiles of PCOS patients tightly clustered together, clearly distinct from those of controls. Abnormalities in functionally important pathways are found in PCOS oocytes. Notably, genes involved in microtubule processes, TUBB8 and TUBA1C, are overexpressed in PCOS oocytes. The metabolic and oxidative phosphorylation pathways are also dysregulated in both oocytes and CCs from PCOS patients. Moreover, in oocytes, differentially expressed TEs are not uniformly dispersed in human chromosomes. Endogenous retrovirus 1 (ERV1) elements located on chromosomes 2, 3, 4, and 5 are rather highly upregulated. Interestingly, these correlate with the most highly expressed protein-coding genes, including tubulin-associated genes TUBA1C, TUBB8P8, and TUBB8, linking the ERV1 elements to the occurrence of PCOS. Our comprehensive analysis of gene expression in oocytes and CCs, including TE expression, revealed the specific molecular features of PCOS. The aberrantly elevated expression of TUBB8 and TUBA1C and ERV1 provides additional markers for PCOS and may contribute to the compromised oocyte developmental competence in PCOS patients. Our findings may also have implications for treatment strategies to improve oocyte maturation and the pregnancy outcomes for women with PCOS.
PMCID:8450412
PMID: 34552933
ISSN: 2296-634x
CID: 5012632

Posthumous assisted reproduction policies among a cohort of United States' in vitro fertilization clinics

Trawick, Emma; Sampson, Amani; Goldman, Kara; Campo-Engelstein, Lisa; Caplan, Arthur; Keefe, David L; Quinn, Gwendolyn P
Objective/UNASSIGNED:To assess the presence and content of policies toward posthumous assisted reproduction (PAR) using oocytes and embryos among Society for Assisted Reproductive Technology (SART) member clinics in the United States. Design/UNASSIGNED:Cross-sectional questionnaire-based study. Setting/UNASSIGNED:Not applicable. Patients/UNASSIGNED:A total of 62 SART member clinics. Interventions/UNASSIGNED:Questionnaire including multiple choice and open-ended questions. Main Outcome Measures/UNASSIGNED:Descriptive statistics regarding presence and content of policies regarding PAR using oocytes and embryos, consent document content regarding oocyte and embryo disposition, and eligibility of minors and those with terminal illness for fertility preservation. Results/UNASSIGNED:Of the 332 clinics contacted, 62 responded (response rate 18.7%). Respondents were distributed across the United States, and average volume of in vitro fertilization (IVF) cycles per year ranged from <250 to >1,500, but 71.2% (n = 42) reported a volume of <500. Nearly one-half (42.4%, n = 25) of clinics surveyed reported participating in any cases of posthumous reproduction during the past 5 years, and 6.8% (n = 4) reported participation in >5 cases. Participation in cases of posthumous reproduction was not significantly associated with practice type or IVF cycle volume among those surveyed. Only 59.6% (n = 34) of clinics surveyed had written policies regarding PAR using oocytes or embryos, whereas 36.8% (n = 21) reported they did not have a policy. Practice type, IVF cycle volume, fertility preservation volume, and prior participation in cases of PAR were not significantly associated with the presence of a policy among respondent clinics. Of those with a policy, 55.9% (n = 19) reported they had used that policy, 59.1% (n = 13) without a policy reported they had considered adopting one, and 63.6% (n = 14) reported they had received a request for PAR services. Only 47.2% (n = 25) of clinics surveyed specified that patients not expected to survive to use oocytes due to terminal illness are eligible for oocyte cryopreservation, whereas 45.3% (n = 24) did not specify. Conclusions/UNASSIGNED:Respondent clinics reported receiving an increasing number of requests for PAR services, but many also lacked PAR policies. Those with policies did not always follow ASRM recommendations. Given the low response rate, these data cannot be interpreted as representative of SART clinics overall. As PAR cases become more common, however, this study highlights poor reporting of PAR and institutional policies toward PAR, suggesting that SART clinics may not be equipped to systematically manage the complexities of PAR.
PMCID:8244314
PMID: 34223220
ISSN: 2666-3341
CID: 4932912

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

Davis, Erica E; Balasubramanian, Ravikumar; Kupchinsky, Zachary A; Keefe, David L; Plummer, Lacey; Khan, Kamal; Meczekalski, Blazej; Heath, Karen E; Lopez-Gonzalez, Vanesa; Ballesta-Martinez, Mary J; Margabanthu, Gomathi; Price, Susan; Greening, James; Brauner, Raja; Valenzuela, Irene; Cusco, Ivon; Fernandez-Alvarez, Paula; Wierman, Margaret E; Li, Taibo; Lage, Kasper; Barroso, Priscila Sales; Chan, Yee-Ming; Crowley, William F; Katsanis, Nicholas
Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen families (twelve autosomal dominant, and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome; KS) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12; and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD; highlight the genetic links between craniofacial patterning and GnRH dysfunction; and begin to assemble the functional network that regulates the development of the GnRH axis.
PMID: 32620954
ISSN: 1460-2083
CID: 4518222

Characteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers

Khoury, Rasha; Bernstein, Peter S; Debolt, Chelsea; Stone, Joanne; Sutton, Desmond M; Simpson, Lynn L; Limaye, Meghana A; Roman, Ashley S; Fazzari, Melissa; Penfield, Christina A; Ferrara, Lauren; Lambert, Calvin; Nathan, Lisa; Wright, Rodney; Bianco, Angela; Wagner, Brian; Goffman, Dena; Gyamfi-Bannerman, Cynthia; Schweizer, William E; Avila, Karina; Khaksari, Bijan; Proehl, Meghan; Heitor, Fabiano; Monro, Johanna; Keefe, David L; DʼAlton, Mary E; Brodman, Michael; Makhija, Sharmila K; Dolan, Siobhan M
OBJECTIVE:To describe the characteristics and birth outcomes of women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as community spread in New York City was detected in March 2020. METHODS:We performed a prospective cohort study of pregnant women with laboratory-confirmed SARS-CoV-2 infection who gave birth from March 13 to April 12, 2020, identified at five New York City medical centers. Demographic and clinical data from delivery hospitalization records were collected, and follow-up was completed on April 20, 2020. RESULTS:Among this cohort (241 women), using evolving criteria for testing, 61.4% of women were asymptomatic for coronavirus disease 2019 (COVID-19) at the time of admission. Throughout the delivery hospitalization, 26.5% of women met World Health Organization criteria for mild COVID-19, 26.1% for severe, and 5% for critical. Cesarean birth was the mode of delivery for 52.4% of women with severe and 91.7% with critical COVID-19. The singleton preterm birth rate was 14.6%. Admission to the intensive care unit was reported for 17 women (7.1%), and nine (3.7%) were intubated during their delivery hospitalization. There were no maternal deaths. Body mass index (BMI) 30 or higher was associated with COVID-19 severity (P=.001). Nearly all newborns tested negative for SARS-CoV-2 infection immediately after birth (97.5%). CONCLUSION/CONCLUSIONS:During the first month of the SARS-CoV-2 outbreak in New York City and with evolving testing criteria, most women with laboratory-confirmed infection admitted for delivery did not have symptoms of COVID-19. Almost one third of women who were asymptomatic on admission became symptomatic during their delivery hospitalization. Obesity was associated with COVID-19 severity. Disease severity was associated with higher rates of cesarean and preterm birth.
PMID: 32555034
ISSN: 1873-233x
CID: 4485172

Telomere erosion as a placental clock: From placental pathologies to adverse pregnancy outcomes

Kohlrausch, Fabiana B; Keefe, David L
The placenta provides nutritional and gas exchange between fetus and mother. Early in pregnancy, placental trophoblasts proliferate rapidly and invade aggressively. As pregnancy progresses, placental cells begin to age. Indeed, pregnancy itself has a tightly regulated duration, determined in large part by placental lifespan. Late in pregnancy, placental cells reach a senescent apoptotic state, activated by a number of intrinsic and extrinsic factors, including oxidative stress (OS), and DNA damage. Pregnancy complications, stillbirths and neonatal deaths have been related to OS and abnormal placental aging. Telomeres, the protective nucleoprotein structures at the ends of linear chromosomes, shorten both from cell replication and from exposure to OS. When telomeres become critically short they trigger cell cycle arrest and eventually cell death. Telomere attrition thus provide an intrinsic mechanism to explain tissue senescence and aging. Mounting evidence suggests that senescence of placental and fetal membrane cells results from telomere attrition. We review the studies that have addressed the role of telomere length (TL) in placentas from normal and complicated pregnancies, including pre-eclampsia, intrauterine growth restriction, gestational diabetes, and stillbirth. To date studies have uncovered associations between TL and a number of obstetrical complications. Future research is needed to determine whether these associations are causative, i.e. whether these clinical conditions result from telomere dysfunction, and whether particular features of telomeres, e.g. mean or shortest length, etc. could serve as clinically useful biomarkers of placental health.
PMID: 32792055
ISSN: 1532-3102
CID: 4556702

Telomere Length and Telomerase Activity in Immature Oocytes and Cumulus Cells of Women with Polycystic Ovary Syndrome

Pedroso, Daiana C C; Santana, Viviane P; Donaires, Flavia S; Picinato, Maria C; Giorgenon, Roberta C; Santana, Barbara A; Pimentel, Ricardo N; Keefe, David L; Calado, Rodrigo T; Ferriani, Rui A; Furtado, Cristiana L M; Reis, Rosana M
Metaphase II oocytes (MII) from polycystic ovary syndrome (PCOS) frequently have impaired oocyte competence. Since telomere maintenance is important for folliculogenesis, oocyte maturation, and early embryonic development, we sought to verify the implications of PCOS on telomere length and telomerase activity in immature oocytes and cumulus cells. 43 PCOS and 67 control women were included, and anthropometric, biochemical, and hormonal characteristics were evaluated. The telomere length in germinal vesicle stage (GV) and in metaphase I (MI) oocytes, as well as in the cumulus cells of immature (CCI) and mature oocytes (CCM), and in leukocytes was measured by qPCR. The telomerase activity in reproductive cells was evaluated by the TRAPeze® XL Kit. The body mass index (p = 0.001), LH (p = 0.015), estradiol (p = 0.004), insulin (p = 0.002), testosterone (p < 0.0001), androstenedione (p = 0.001), free androgen index (p < 0.0001), and c-reactive protein (p = 0.003) were greater, while the FSH (p = 0.0002) was lower in the PCOS group. The telomere length in the CCI (p = 0.649) and CCM (p = 0.378) did not differ between the PCOS and the control groups. On the other hand, telomerase activity in the CCI (p = 0.003) and CCM (p = 0.022) was higher in the PCOS group. In the leukocyte's cells, the telomere length was reduced in the PCOS group (p = 0.025). In the GV and MI oocytes, no differences were observed in telomere length and telomerase activity between the groups. We showed that telomere length is not altered in reproductive cells from PCOS. However, higher telomerase activity in the CCI and CCM may be required for telomere length maintenance.
PMID: 32046456
ISSN: 1933-7205
CID: 4304322