The control of labor.
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Contraindications↗
Biomedical subjects
E R Norwitz
Publications and source records attributed to E R Norwitz.
Identification and characterization of the gonadotropin-releasing hormone response elements in the mouse gonadotropin-releasing hormone receptor gene.
The response of the pituitary gonadotrope to gonadotropin-releasing hormone (GnRH) correlates directly with the concentration of GnRH receptors (GnRHR) on the cell surface, which is mediated in part at the level of GnRHR gene expression. Several hormones have been implicated in this regulation, most notably GnRH itself. Despite these observations and the central role that GnRH is known to play in reproductive development and function, the molecular mechanism(s) by which GnRH regulates transcription of the GnRHR gene has not been well elucidated. Previous studies in this laboratory have identified and partially characterized the promoter region of the mouse GnRHR gene and demonstrated that the regulatory elements for tissue-specific expression as well as for GnRH regulation are present within the 1.2-kilobase 5'-flanking sequence. By using deletion and mutational analysis as well as functional transfection studies in the murine gonadotrope-derived alphaT3-1 cell line, we have localized GnRH responsiveness of the mouse GnRHR gene to two DNA sequences at -276/-269 (designated Sequence Underlying Responsiveness to GnRH-2 (SURG-2), which contains the consensus sequence for the activating protein-1-binding site) and -292/-285 (a novel element designated SURG-1), and demonstrated that this response is mediated via protein kinase C. By using the electrophoretic mobility shift assay, we further demonstrate that a member(s) of the Fos/Jun heterodimer superfamily is responsible in part for the DNA-protein complexes formed on SURG-2, using alphaT3-1 nuclear extracts. These data define a bipartite GnRH response element in the mouse GnRHR 5'-flanking sequence and suggest that the activating protein-1 complex plays a central role in conferring GnRH responsiveness to the murine GnRHR gene.
Animals↗
Episiotomy, operative vaginal delivery, and significant perinatal trauma in nulliparous women.
OBJECTIVES: The aim of this study was to determine whether choice of obstetric instrument at operative vaginal delivery is associated with any differences in the rate of significant perineal trauma and whether this rate is modified by the use of episiotomy. STUDY DESIGN: The occurrence of significant perineal trauma among 323 consecutive operative vaginal deliveries was evaluated according to type of instrument used and performance of episiotomy. These findings were compared with spontaneous vaginal deliveries during the same period. RESULTS: Among forceps deliveries the use of episiotomy was not associated with a difference in the occurrence of significant perineal trauma (55% vs 46%; relative risk, 1.2; 95% confidence interval, 0.8-1.9). Among vacuum extraction deliveries an increased rate of such trauma was noted when episiotomy was used (34.9% vs 9. 4%; relative risk, 3.7; 95% confidence interval, 1.2-11.2). There was no difference in the rate of significant perineal trauma according to type of forceps used. In a logistic regression analysis forceps delivery with or without episiotomy was associated with an increase of >10-fold in the rate of significant perineal trauma with respect to vacuum extraction deliveries without episiotomy. CONCLUSIONS: Our data suggest that in forceps delivery neither the type of forceps nor episiotomy influences the risk of significant perineal trauma. When vacuum extraction delivery is performed, the use of episiotomy is associated with a higher risk of significant perineal trauma.
Adult↗
Epidural analgesia and third- or fourth-degree lacerations in nulliparas.
OBJECTIVE: To determine if epidural analgesia is associated with differences in rates of severe perineal trauma during vaginal deliveries. METHODS: We studied 1942 consecutive, low-risk, term, vaginal deliveries in nulliparas, including spontaneous and induced labors, at a single institution from December 1994 to August 1995. The rate of third- and fourth-degree lacerations was compared for women who had and did not have epidural analgesia for labor-pain relief. Statistical significance was determined using chi2. Logistic regression analyses were used to evaluate associations while controlling for possible confounding variables. RESULTS: Overall rates of third- and fourth-degree lacerations were 10.8% (n = 210) and 3.4% (n = 63), respectively. Epidural analgesia was given to 1376 (70.9%) women. Among women who had epidurals, 16.1% (221 of 1376) had severe perineal lacerations compared with 9.7% (n = 55) of the 566 women who did not have epidurals (P < .001; odds ratio [OR] 1.8, 95% confidence interval [CI] 1.3, 2.4). When controlling for birth weight, use of oxytocin, and maternal age in logistic regression analysis, epidural remained a significant predictor of severe perineal injury (OR 1.4, 95% CI 1.0, 2.0). Epidural use is consistently associated with increased operative vaginal deliveries and consequent episiotomies, so we constructed a logistic regression model to evaluate whether the higher rates of those procedures were responsible for the effect of epidurals on severe perineal traumas. With operative vaginal delivery and episiotomy in the model, epidural was no longer an independent predictor of perineal injury (OR 0.9, 95% CI 0.6, 1.3). CONCLUSION: Epidural analgesia is associated with an increase in the rate of severe perineal trauma because of the more frequent use of operative vaginal delivery and episiotomy.
Adult↗
Prevention of preeclampsia: is it possible?
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Aspirin↗
Thyroid hormone response elements differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor coactivator-1.
Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). SRC-1 contains three such motifs in the central (nuclear receptor binding domain-1, NBD-1) and a single one in the C-terminal (NBD-2) regions. To define the nature and role of the two NBDs in SRC-1, interaction studies between the two NBDs and thyroid hormone receptor (TR) were performed. Although NBD-1 and NBD-2 showed similar ligand- and AF-2-dependent interactions with TR in solution, these two NBDs possessed distinct interaction properties with TR when TR is bound to a thyroid hormone-response element (TRE). Both in vitro and in vivo interaction studies demonstrate that NBD-1, but not NBD-2, exhibits ligand-dependent interaction with TR in the presence of TREs. In addition, a natural isoform of SRC-1, SRC-1E, which lacks NBD-2, preserved TR as well as progesterone receptor-mediated coactivator function on reporter gene expression. Finally, we found that NBD-1 failed to interact with a TR and retinoid X receptor heterodimer complex on a transcriptionally inactive direct repeat +4 TRE in electrophoretic mobility shift assays. These observations indicate that DNA-induced, as well as ligand-induced, conformational change(s) of TR may influence the nature of its binding to SRC-1, and that the two NBDs of SRC-1 may play different roles to regulate ligand-dependent transactivation of TRs.
Animals↗
Birth weight as a predictor of brachial plexus injury.
OBJECTIVE: To examine the relationship between birth weight and brachial plexus injury and estimate the number of cesareans needed to reduce such injuries. METHODS: All 80 neonatal records coded for brachial plexus injury from October 1985 to September 1993 at the Brigham and Women's Hospital in Boston, Massachusetts, were studied along with linked maternal files. Birth weight, method of delivery, presence or absence of shoulder dystocia, and any diagnosis of maternal gestational or nongestational diabetes were abstracted. Data for the group with brachial plexus injury were compared with data for live-born infants without this injury during the same period. The sensitivity and specificity of birth weight as a predictor of brachial plexus injury were calculated. Further, the number of cesarean deliveries necessary to prevent a single brachial plexus injury was estimated using various weight cutoffs (4000, 4500, and 5000 g) for elective cesarean delivery. RESULTS: Among 77,616 consecutive deliveries, there were 80 brachial plexus injuries identified, for an incidence of 1.03 per 1000 live births. The incidence of brachial plexus injury increased with increasing birth weight, operative vaginal delivery, and the presence of glucose intolerance. In the group of women without diabetes, between 19 and 162 cesarean deliveries would have been necessary to prevent a single immediate brachial plexus injury. Among women with diabetes, between five and 48 additional cesareans would have been required. CONCLUSION: Although birth weight is a predictor of brachial plexus injury, the number of cesarean deliveries necessary to prevent a single injury is high at most birth weights. Because of the large number of cesarean deliveries needed to prevent a single brachial plexus injury in infants born to women without diabetes, it is difficult to recommend routine cesarean delivery for suspected macrosomia in these women.
Birth Injuries↗
Prostaglandin production by human peripheral blood monocytes changes with in vitro differentiation.
To investigate the influence of in vitro culture on prostaglandin (PG) production, human monocyte enriched peripheral blood mononuclear cells were isolated and incubated on gelatin-coated plates. On days zero, five and eleven of culture, the cells were examined microscopically and the production of PGF1 alpha, PGE2, PGD2, F metabolite (PGFM) and E metabolite (PGEM) were measured by radioimmunoassay. Differences in PG output were analyzed using the Wilcoxon and Friedman tests. Freshly isolated human peripheral blood monocytes produced mainly PGE2. In vitro, however, PGE2 production decreased from 196 (48-288) fmol/10(6) cells per 3h on day zero of culture to 28 (6-51) on day eleven (p = 0.04); median (range), n = 7. Prostaglandin D2 and PGEM output decreased similarly, but these differences failed to reach significance. Prostaglandin F2 alpha and PGFM output, on the other hand, increased from 32 and 19 fmol/10(6) cells per 3h, respectively, on day zero of culture to 127 (p < 0.05) and 58 (p = 0.01) on day eleven. Changes in PG output were associated with in vitro differentiation as evidenced by changes in cellular morphology. These result suggest that differentiation of human peripheral blood monocytes in vitro is accompanied by a shift in PG output from PGE2 and PGD2, towards PGF2 alpha.
Adult↗
Tumor necrosis factor-alpha selectively stimulates prostaglandin F2 alpha production by macrophages in human term decidua.
OBJECTIVE: Our objective was to investigate the effect of tumor necrosis factor-alpha on prostaglandin production by human term decidual cell subtypes in vitro. STUDY DESIGN: We measured the effect of tumor necrosis factor-alpha on prostaglandins F2 alpha, E2, D2, F metabolite, and E metabolite production by decidual cells (n = 4) with radioimmunoassay. We used flow cytometry after labeling with an antibody to histocompatibility antigen DR, L243, which is specific for macrophages in this tissue, to prepare pure populations of decidual macrophages (n = 3). Differences in prostaglandin output were analyzed by Wilcoxon and Kruskal-Wallis tests. RESULTS: Tumor necrosis factor-alpha stimulated prostaglandin F2 alpha output by unfractionated decidual cells, without altering the output of any other prostaglandins. Tumor necrosis factor-alpha (10 nmol/L) increased prostaglandin F2 alpha production from decidual macrophages (HLA-DR-positive cells) by about threefold: from a median of 727 (range 423 to 1226) to a median of 1974 (range of 1550 to 2201), fmol/10(6) cells per 18 hours, as compared with a 1.4-fold increase from nonmacrophages from a median of 247 fmol/10(6) cells per 18 hours (range 125 to 611) to a median of 340 fmol/10(6) cells per 18 hours (range 201 to 505). CONCLUSION: Stimulation of decidual prostaglandin F2 alpha production by tumor necrosis factor-alpha may be important in the etiology of spontaneous labor at term or preterm labor associated with infection.
Adult↗
Prostaglandin D2 production by term human decidua: cellular origins defined using flow cytometry.
OBJECTIVE: To measure prostaglandin (PG) D2 output by human decidua at term and to identify the cell population(s) responsible for its production. METHODS: Decidual cell suspensions were prepared enzymatically and the cells were labeled with either of two monoclonal antibodies: F10/89/4, which recognizes the leukocyte common antigen (CD45), or L243, which labels HLA-DR and is specific for macrophages in this tissue. Cells were sorted on a Coulter EPICS 541 flow cytometer. Prostaglandin levels were measured by radioimmunoassay. RESULTS: Human decidua is an important intrauterine source of PGD2 at term. Twenty-nine percent (median) of decidual cells were CD45-positive and 12% were HLA-DR-positive; sorted cell populations were 95% pure. Prostaglandin D2 output (fmol/10(6) cells per 3 hours) by bone marrow-derived (CD45-positive) cells was significantly higher than that by non-bone marrow-derived cells: median 63 (range 35-67) versus 20 (13-21), respectively; HLA-DR-positive cells (macrophages) had the highest PGD2 production rate (186, range 97-288 fmol/10(6) cells per 3 hours). Under basal conditions, PGD2 production by unsorted term decidual cells was not influenced by labor. CONCLUSION: Bone marrow-derived cells (macrophages) are the major source of decidual PGD2 at term. Further studies are required to investigate the possible role of PG production by human decidual macrophages in the mechanism of term and/or preterm labor.
Cell Separation↗
Expression of intermediate filament in endometrial glands changes with the onset of pregnancy and in endometriosis.
Appropriate endometrial differentiation is believed to be a prerequisite for pregnancy success. This study investigates the expression of two intermediate filament proteins, cytokeratin and vimentin, in human endometrium and first trimester decidua and in ectopic endometrium from women with endometriosis. Stromal elements, including vascular endothelial cells, were consistently vimentin-positive and cytokeratin-negative. Surface and glandular epithelial cells of human endometrium co-expressed vimentin and cytokeratin during all stages of the menstrual cycle, but failed to express vimentin after the onset of pregnancy. This suggests that intermediate filaments, and especially vimentin, may have a role to play in the proliferation and/or differentiation of the endometrial glands during decidualization. Ectopic endometrium showed a staining pattern similar to normal endometrium.
Decidua↗
Identification by flow cytometry of the prostaglandin-producing cell populations of term human decidua.
Human term decidua produces prostaglandins (PGs) which have been implicated in the initiation of human parturition. Using flow cytometry to isolate pure cell populations, we have investigated the cell types responsible for decidual PG production. Cell dispersions were prepared enzymatically from decidua vera isolated from term placentae, and were incubated in Dulbecco's Modified Eagle's Medium containing 0.25% bovine serum albumin at 37 degrees C. PGF2 alpha and PGE2 output were measured by radioimmunoassay of the conditioned medium. Production of PGF2 alpha (fmol/10(6) cells per 3 h) exceeded that of PGE2 at 273 (108-322) versus 97 (38-127) respectively (median (range]. The decidual cell dispersions were then incubated with monoclonal antibodies (anti-CD45 which labels the leukocyte common antigen or anti-human leukocyte antigen class II (HLA-DR) which is specific for macrophages in this tissue) and sorted by flow cytometry. The resultant antibody-positive and -negative cell populations were incubated and PG production was measured. Controls showed that antibody labelling and sorting did not alter PG production. PGF2 alpha and PGE2 output by bone marrow-derived (CD45-positive) cell populations exceeded that of non-bone marrow-derived (CD45-negative) cells. Furthermore, we were able to demonstrate that the HLA-DR-positive macrophage population had the highest PGF2 alpha and PGE2 production rates in human term decidua in vitro.
Antibodies, Monoclonal↗
Molecular mechanisms of gonadotropin-releasing hormone receptor gene regulation.
GnRH plays a critical role in regulating mammalian reproductive development and function. At the level of the anterior pituitary, GnRH binds to the GnRH receptor (GnRHR) on the cell surface of pituitary gonadotropes. Here, it activates intracellular signal transduction pathways to effect both the synthesis and intermittent release of the gonadotropins LH and FSH. These hormones then enter the systemic circulation to regulate gonadal function, including steroid hormone synthesis and gametogenesis. The response of pituitary gonadotropes to GnRH correlates directly with the concentration of GnRHR on the cell surface, which is mediated, at least in part, at the level of gene expression. A number of endocrine, paracrine, and autocrine factors are known to regulate GnRHR gene expression. This article reviews in detail the role of the GnRHR in the hypothalamic-pituitary-gonadal axis and the factors mediating expression of this gene. A better understanding of the molecular mechanisms that regulate transcription of the GnRHR gene will further our knowledge about the role of this receptor in mammalian reproductive physiology in health and disease.
Animals↗
Preeclampsia prevention and management.
Preeclampsia is a multisystem disorder specific to pregnancy with a high maternal and perinatal morbidity and mortality. The cause of this disorder is unknown. Preeclampsia likely represents the clinical end point of multiple contributory factors, and it is unlikely that any single cause will be found. The blueprint for the development of preeclampsia is laid down early in pregnancy, and delivery of the fetus and placenta remains the only effective treatment. Efforts to prevent preeclampsia in women at high risk have been largely unsuccessful. Until the pathogenesis of preeclampsia is well defined, it is unlikely that effective preventive strategies will be developed.
Female↗