Chronic superphysiologic AMH promotes premature luteinization of antral follicles in human ovarian xenografts.

Anti-Müllerian hormone (AMH) is produced by growing ovarian follicles and provides a diagnostic measure of reproductive reserve in women; however, the impact of AMH on folliculogenesis is poorly understood. We cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and downstream single-cell RNA sequencing of granulosa and theca/stroma cell fractions. A total of 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals (>10 weeks). In the context of exogenous AMH, follicles exhibited a decreased ratio of primordial to growing follicles and antral follicles of increased diameter. Transcriptomic analysis and immunolabeling revealed a marked increase in factors typically noted at more advanced stages of follicle maturation, with granulosa and theca/stroma cells also displaying molecular hallmarks of luteinization. These results suggest that superphysiologic AMH alone may contribute to ovulatory dysfunction by accelerating maturation and/or luteinization of antral-stage follicles.

Exogenous insulin-like growth factor 1 accelerates growth and maturation of follicles in human cortical xenografts and increases ovarian output in mice.

OBJECTIVE: To measure the influence of exogenous insulin-like growth factor 1 (IGF1) on follicle growth and maturation in human ovarian cortical xenografts. DESIGN: Xenotransplantation model. SETTING: University-based research laboratory. PATIENTS/ANIMALS: Ovarian tissue was donated with consent and institutional review board approval by brain-dead organ donors or patients undergoing ovarian tissue cryopreservation for fertility preservation. Cortical fragments were transplanted into immunocompromised mice. INTERVENTIONS: Cryopreserved ovarian cortical fragments from four women (aged 19, 25, 33, and 46 years) were transplanted into the gluteus muscle of immunocompromised mice in a fibrin matrix containing endothelial cells that were transduced with lentiviral particles encoding secreted IGF1. Xenografts were recovered after 3, 8, and 14 weeks. In addition, C57/Bl6 mice underwent intraovarian injection of saline or recombinant IGF1 (60 µg), followed by superovulation, analysis of ethynyl-deoxyuridine incorporation, and ribonucleic acid sequencing of the whole ovaries. MAIN OUTCOME MEASURES: For xenografts: follicle count and distribution; antral follicle count; and corpora lutea/albicans count. For mice: follicle count and distribution; oocyte yield, ethynyl-deoxyuridine incorporation (granulosa cell proliferation); and ovarian transcriptomic signature. RESULTS: At 3 weeks, xenografts in the IGF1 condition revealed a decreased percentage of primary follicles and increased percentage of secondary follicles that were concentrated in the preantral subtype; at 8 weeks, an increase in secondary follicles was concentrated in the simple subtype; after 14 weeks, primordial follicles were reduced, and while the number of advanced follicles did not power the experiment to demonstrate significance, antral follicles reduced and corpora lutea increased. Supporting experiments in mice revealed an increase in normal oocytes following intraovarian injection of recombinant IGF1 (60 µg) as well as increased proliferative index among follicles of secondary and preantral stages. Ribonucleic acid sequencing analysis of the whole ovaries following injection of recombinant IGF1 (25 µg) revealed an acute (24 hours) upregulation of transcripts related to steroidogenesis and luteinization. CONCLUSIONS: Exogenous IGF1 advances the pace of growth among primordial, primary, and secondary stage follicles but results in near absence of antral stage follicles in long-term (14 weeks) xenografts. In mice, acute administration of IGF1 promotes follicle advance and increased oocyte yield. The results suggest that while superphysiological IGF1 alone advances the pace of growth among early/preantral follicles, a sustained and/or later-stage influence undermines antral follicle growth/survival or promotes premature luteinization. These findings provide a temporal framework for interpreting follicle growth/mobilization and may be useful in understanding the clinical application of human growth hormone in the context of assisted reproduction.

Cardiac catheterization is underutilized after in-hospital cardiac arrest.

BACKGROUND: Indications for immediate cardiac catheterization in cardiac arrest survivors without ST elevation myocardial infarction (STEMI) are uncertain as electrocardiographic and clinical criteria may be challenging to interpret in this population. We sought to evaluate rates of early catheterization after in-hospital ventricular fibrillation (VF) arrest and the association with survival. METHODS: Using a billing database we retrospectively identified cases with an ICD-9 code of cardiac arrest (427.5) or VF (427.41). Discharge summaries were reviewed to identify in-hospital VF arrests. Rates of catheterization on the day of arrest were determined by identifying billing charges. Unadjusted analyses were performed using Chi-square, and adjusted analyses were performed using logistic regression. RESULTS: One hundred and ten in-hospital VF arrest survivors were included in the analysis. Cardiac catheterization was performed immediately or within 1 day of arrest in 27% (30/110) of patients and of these patients, 57% (17/30) successfully received percutaneous coronary intervention. Of those who received cardiac catheterization the indication for the procedure was STEMI or new left bundle branch block (LBBB) in 43% (13/30). Therefore, in the absence of standard ECG data suggesting acute myocardial infarction, 57% (17/30) received angiography. Patients receiving cardiac catheterization were more likely to survive than those who did not receive catheterization (80% vs. 54%, p<.05). CONCLUSION: In patients receiving cardiac catheterization, more than half received this procedure for indications other than STEMI or new LBBB. Cardiac catheterization was associated with improved survival. Future recommendations need to be established to guide clinicians on which arrest survivors might benefit from immediate catheterization.

Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest.

OBJECTIVE: We sought to evaluate current physician use of therapeutic hypothermia after cardiac arrest, to ascertain reasons for nonadoption of this treatment, and to determine current cooling techniques employed. DESIGN: Web-based survey. SETTING: International physician cohort in the United States, UK, and Finland. SUBJECTS: Physicians (MD or DO) caring for resuscitated cardiac arrest patients. INTERVENTIONS: An anonymous Web-based survey was distributed to physicians identified through United States-based critical care, cardiology, and emergency medicine directories and critical care networks in the UK and Finland. Recipients were queried regarding use of postresuscitation therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the final 13,272 surveys actually distributed to physicians, 2,248 (17%) were completed. Most respondents were attending physicians (82%) at teaching hospitals (76%) who practiced critical care (35%), cardiology (20%), or emergency medicine (22%). Of all replies, 74% of United States respondents and 64% of non-United States respondents had never used therapeutic hypothermia. United States emergency medicine physician adoption of cooling was significantly less than that of United States intensivists (16% vs. 34%, p < .05). The most often cited reasons for nonuse by respondents were "not enough data," "not part of Advanced Cardiac Life Support guidelines," and "too technically difficult to use." Factors associated with increased use included non-United States residence, critical care specialty, and larger hospital size. CONCLUSIONS: Physician utilization of cooling after cardiac arrest remains low. For improved adoption of therapeutic hypothermia, our data suggest that development of better cooling methodology and recent incorporation into resuscitation guidelines may improve use.