Phenanthroline relaxes uterine contractions induced by diverse contractile agents by decreasing cytosolic calcium concentration.

Uterine contractions during labor and preterm labor are influenced by a complex interplay of factors, including hormones and inflammatory mediators. This complexity may contribute to the limited efficacy of current tocolytics for preterm labor, a significant challenge in obstetrics with 15 million cases annually and approximately 1 million resulting deaths worldwide. We have previously shown that the myometrium expresses bitter taste receptors (TAS2Rs) and that their activation leads to uterine relaxation. Here, we investigated whether the selective TAS2R5 agonist phenanthroline can induce relaxation across a spectrum of human uterine contractions and whether the underlying mechanism involves changes in intracellular Ca2+ signaling. We performed experiments using samples from pregnant women undergoing scheduled cesarean delivery, assessing responses to various inflammatory mediators and oxytocin with and without phenanthroline. Our results showed that phenanthroline concentration-dependently inhibited contractions induced by PGF2α, U46619, 5-HT, endothelin-1 and oxytocin. Furthermore, in hTERT-infected human myometrial cells exposed to uterotonics, phenanthroline effectively suppressed the increase in intracellular Ca2+ concentration induced by PGF2α, U46619, oxytocin, and endothelin-1. These results suggest that the selective TAS2R5 agonist may not only significantly reduce uterine contractions but also decrease intracellular Ca2+ levels. This study highlights the potential development of TAS2R5 agonists as a new class of uterine relaxants, providing a novel avenue for improving the management of preterm labor.

Bitter taste receptors in the reproductive system: Function and therapeutic implications.

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single-cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

Intrapartum continuous subcutaneous insulin infusion vs intravenous insulin infusion among pregnant individuals with type 1 diabetes mellitus: a randomized controlled trial.

BACKGROUND: Intrapartum glucose management is critical to reducing neonatal hypoglycemia shortly after birth. Although it is known that insulin is required for all pregnant individuals with type 1 diabetes mellitus, the optimal mode of intrapartum glycemic control is not known. OBJECTIVE: This study aimed to compare the effect of intrapartum use of continuous subcutaneous insulin infusion with that of intravenous insulin infusion for glucose management among pregnant individuals with type 1 diabetes mellitus on neonatal blood glucose levels. STUDY DESIGN: This was a randomized controlled trial of pregnant participants with type 1 diabetes mellitus. After written informed consent, participants were randomly allocated to 1 of 2 intrapartum insulin administration strategies: continuation of their continuous subcutaneous insulin infusion or intravenous insulin infusion. The primary outcome was the first neonatal blood glucose level. RESULTS: Between March 2021 and April 2023, 76 participants were approached, and 70 participants were randomized (35 participants in the intravenous insulin infusion group and 35 participants in the continuous subcutaneous insulin infusion group). The groups were similar in terms of age, race/ethnicity, pregravid body mass index, nulliparity, and gestational age at delivery. There was no statistically significant difference in the first neonatal glucose measurement between the 2 groups (50.1±23.4 vs 49.2±22.6; P=.86). In addition, there were no statistically significant differences in any secondary neonatal outcomes. Approximately 57.1% of neonates in the continuous subcutaneous insulin infusion group required either oral, intravenous, or both treatments for hypoglycemia, whereas 51.4% of neonates in the intravenous infusion group required treatment. In both groups, 28.6% of neonates required intravenous treatment for hypoglycemia. CONCLUSION: Pregnant individuals with type 1 diabetes mellitus using either intravenous insulin infusion or continuation of their continuous subcutaneous insulin infusion for intrapartum insulin administration had no difference in the primary outcome of neonatal hypoglycemia. Patients should be given the option of both glycemic management strategies intrapartum.

Trends in Screening for Diabetes in Early Pregnancy in the United States.

Objective: The aim of this study was to characterize current diabetes screening practices in the first trimester of pregnancy in the United States, evaluate patient characteristics and risk factors associated with early diabetes screening, and compare perinatal outcomes by early diabetes screening. Methods: This was a retrospective cohort study of US medical claims data of persons diagnosed with a viable intrauterine pregnancy and who presented for care with private insurance before 14 weeks of gestation, without pre-existing pregestational diabetes, from the IBM MarketScan® database for the period January 1, 2016, to December 31, 2018. Univariate and multivariate analyses were used to evaluate perinatal outcomes. Results: A total of 400,588 pregnancies were identified as eligible for inclusion, with 18.0% of persons receiving early screening for diabetes. Of those with laboratory order claims, 53.1% underwent hemoglobin A1c testing, 30.0% underwent fasting glucose testing, and 16.9% underwent oral glucose tolerance testing. Compared with those who did not undergo early diabetes screening, those who did were more likely to be older; obese; having a history of gestational diabetes, chronic hypertension, polycystic ovarian syndrome, or hyperlipidemia; and having a family history of diabetes. In adjusted logistic regression, history of gestational diabetes (adjusted odds ratio 3.99; 95% confidence interval 3.73-4.26) had the strongest association with early diabetes screening. Adverse perinatal outcomes, including a higher rate of cesarean delivery, preterm delivery, preeclampsia, and gestational diabetes, occurred more frequently among women who underwent early diabetes screening. Conclusions: First-trimester early diabetes screening was mostly commonly performed by hemoglobin A1c evaluation, and persons who underwent early diabetes screening were more likely to experience adverse perinatal outcomes.

Screening test characteristics and comparison of diabetes outcomes among pregnant patients with prediabetes.

This study sought to compare test characteristics of hemoglobin A1c, oral glucose tolerance test and fasting plasma glucose for the development of gestational diabetes among women with prediabetes. Diabetes outcomes were compared by screening test used for prediabetes diagnosis among a retrospective cohort of pregnant patients between 2017-2021. During the study, 8132 patients received diabetes screening and 14.0% met criteria for prediabetes. By screening test, 75.1% were screened with hemoglobin A1c, 10.0% with fasting plasma glucose and 14.9% with a 75-g oral glucose tolerance test. Hemoglobin A1c had the highest positive predictive value (67.2%). Use of hemoglobin A1c was significantly more likely to identify women with GDM than oral glucose tolerance test (aOR 3.94, 95% CI 2.30-6.73). In this study cohort, hemoglobin A1c was able to identify patients that were more likely to develop GDM in an at-risk population.IMPACT STATEMENTWhat is already known on this subject? Prediabetes is becoming more common in the general population; however little is known about prediabetes in pregnancy. Women with prediabetes in pregnancy appear to be at increased risk of developing gestational diabetes mellitus, however there is minimal information about various screening tests performance in pregnancy for detection of prediabetes and subsequent gestational diabetes.What do the results of this study add? The results of this study compare three commonly used screening tests for screening for diabetes. When identifying women with prediabetes, they are at increased risk for developing gestational diabetes mellitus if identified by hemoglobin A1c.What are the implications of these findings for clinical practice and/or further research? The clinical implication of this study is that women can be screened with hemoglobin A1c in early pregnancy for both overt diabetes, but also may be identified as high risk with prediabetes. Among women with prediabetes by hemoglobin A1c, they remain at high risk for developing gestational diabetes mellitus.

Early Diagnosis of Prediabetes among Pregnant Women that Develop Gestational Diabetes Mellitus and Its Influence on Perinatal Outcomes.

OBJECTIVE: Purpose of this study was to determine whether early identification of impaired glucose tolerance consistent with prediabetes among pregnant women with gestational diabetes mellitus (GDM) in the first trimester impacts maternal and neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of patients who were screened for pregestational diabetes in early pregnancy at a large academic tertiary care center from October 1, 2017, to January 31, 2021, and who subsequently developed GDM. Demographic and perinatal outcomes were compared among women with GDM with a positive early diabetes screen consistent with prediabetes to women who screened negative in the first trimester. Multivariable logistic regression was performed to adjust for baseline demographic differences. RESULTS: During the study period, 260 women screened had negative first trimester diabetes screening and subsequently developed GDM, while 696 screened positive for prediabetes and developed GDM. Women with prediabetes were more likely to require insulin treatment for their GDM compared with those that screened negative (79.5 vs. 45.4%, p < 0.001), while those who screened negative were more likely to take an oral medication of metformin or glyburide for GDM management than those with prediabetes (41.5 vs. 16.4%, p < 0.001). Infants born to mothers who screened positive for prediabetes were more likely to require neonatal intensive care unit (NICU) admission compared with those who screened negative even when adjusted for type of GDM treatment used (adjusted odds ratio [aOR] = 8.5, 95% confidence interval [CI]: 1.5-49.9). CONCLUSION: Women identified as having early impaired glucose tolerance consistent with prediabetes that subsequently develop GDM are more likely to be prescribed insulin treatment and may be at increased risk of adverse neonatal outcomes leading to NICU admission than women with negative first trimester diabetes screening. Future studies should focus on whether different methods of early treatment and/or intervention improve perinatal outcomes. KEY POINTS: · Prediabetes in early pregnancy is associated with higher rates of insulin treatment for GDM.. · Prediabetes in pregnancy increases the risk of developing GDM.. · Prediabetes in early pregnancy is associated with higher rates of NICU admission..

Bitter taste receptors as targets for tocolytics in preterm labor therapy.

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here we report that myometrial cells from human and mouse express bitter taste receptors (TAS2Rs) and their canonical signaling components (i.e., G-protein gustducin and phospholipase C ß2). Bitter tastants can completely relax myometrium precontracted by different uterotonics. In isolated single mouse myometrial cells, a phenotypical bitter tastant (chloroquine, ChQ) reverses the rise in intracellular Ca2+ concentration ([Ca2+]i) and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin and by genetic deletion of α-gustducin. In human myometrial cells, knockdown of TAS2R14 but not TAS2R10 inhibits ChQ's reversal effect on an oxytocin-induced rise in [Ca2+]i Finally, ChQ prevents mouse PTBs induced by bacterial endotoxin LPS or progesterone receptor antagonist mifepristone more often than current commonly used tocolytics, and this prevention is largely lost in α-gustducin-knockout mice. Collectively, our results reveal that activation of the canonical TAS2R signaling system in myometrial cells produces profound relaxation of myometrium precontracted by a broad spectrum of contractile agonists, and that targeting TAS2Rs is an attractive approach to developing effective tocolytics for PTB management.-Zheng, K., Lu, P., Delpapa, E., Bellve, K., Deng, R., Condon, J. C., Fogarty, K., Lifshitz, L. M., Simas, T. A. M., Shi, F., ZhuGe, R. Bitter taste receptors as targets for tocolytics in preterm labor therapy.

Obstetricians and their role in cord blood banking: promoting a public model.

Umbilical cord blood, the blood remaining in the umbilical cord at birth, can be collected at birth and be a source of stem cells for a patient in need of a bone marrow transplant. Obstetricians and other health care practitioners are recognized as a patient's primary source for medical information affecting the mother and her neonate and frequently are asked to provide education and guidance regarding options of private and public cord blood banking. As the use of cord blood continues to grow in medicine and research uncovers more potential for cord blood, cord blood banking has become an important resource. The Stem Cell Therapeutic and Research Act has provided funding to expand public banking initiatives in the United States and to create a more ethnically diverse inventory of units. Private storage is not advocated unless there is an identified need in the family such that banked cord blood would offer a benefit. A recent report outlined the challenges of increasing participation and inventory, particularly among minority groups. Obstetricians and other health care practitioners should have a primary role in efforts to increase awareness of umbilical cord blood donation and be involved in initiatives to expand current public banking activities.

Association of fetal hormone levels with stem cell potential: evidence for early life roots of human cancer.

Intrauterine and perinatal factors have been linked to risk of childhood leukemia, testicular cancer, and breast cancer in the offspring. The pool of stem cells in target tissue has been suggested as a critical factor linking early life exposures to cancer. We examined the relation between intrauterine hormone levels and measurements of stem cell potential in umbilical cord blood. Cord blood donors were 40 women, ages >/=18 years, who delivered, from August 2002 to June 2003, a singleton birth after a gestation of at least 37 weeks. We assayed plasma concentrations of estradiol, unconjugated estriol, testosterone, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3. For stem cell potential, we measured concentrations of CD34(+) and CD34(+)CD38(-) cells and granulocyte-macrophage colony-forming unit (CFU-GM). We applied linear regression analysis and controlled for maternal and neonatal characteristics. We found strong positive associations between IGF-I and stem cell measures, 1 SD increase in IGF-I being associated with a 41% increase in CD34(+) (P = 0.008), a 109% increase in CD34(+)CD38(-) (P = 0.005), and a 94% increase in CFU-GM (P = 0.01). Similar associations were observed for IGF binding protein-3. Among steroid hormones, estriol and testosterone were significantly positively associated with CD34(+) and CFU-GM. These findings indicate that levels of growth factors and hormones are strongly associated with stem cell potential in human umbilical cord blood and point to a potential mechanism that may mediate the relationship between in utero exposure to hormones and cancer risk in the offspring.