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Organ-level models are used to describe how cellular and tissue-level contractions coalesce into clinically observable uterine contractions. More importantly, these models provide a framework for evaluating the many different contraction patterns observed in laboring patients, ideally offering insight into the pitfalls of currently available recording modalities and suggesting new directions for improving recording and interpretation of uterine contractions. Early models proposed wave-like propagation of bioelectrical activity as the sole mechanism for recruiting the myometrium to participate in the contraction and increase contraction strength. However, as these models were tested, the results consistently revealed that sequentially propagating waves do not travel long distances and do not encompass the gravid uterus. To resolve this discrepancy, a model using 2 mechanisms, or a "dual model," for organ-level signaling has been proposed. In the dual model, the myometrium is recruited by action potentials that propagate wave-like as far as 10 cm. At longer distances, the myometrium is recruited by a mechanotransduction mechanism that is triggered by rising intrauterine pressure. In this review, we present the influential models of uterine function, highlighting their main features and inconsistencies, and detail the role of intrauterine pressure in signaling and cervical dilation. Clinical correlations demonstrate the application of organ-level models. The potential to improve the recording and clinical interpretation of uterine contractions when evaluating labor is discussed, with emphasis on uterine electromyography. Finally, 7 questions are posed to help guide future investigations on organ-level signaling mechanisms., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Preterm birth is the largest single cause of infant death in the United States. A cervical length of <2.5 cm, measured in the mid-trimester, has been shown to identify individuals at increased risk. Uterine electromyography is an emerging technology for noninvasively assessing uterine bioelectrical activity. With its ability to characterize nuanced differences in myometrial signals, uterine electromyography assessments during the mid-trimester may provide insight into the mechanisms of cervical shortening., Objective: This study aimed to characterize uterine bioelectrical activity in pregnant individuals with short cervices in the mid-trimester compared with that of pregnant individuals of the same gestational age with normal cervical lengths., Study Design: This is a prospective cohort study of subjects with singleton, nonanomalous pregnancies between 16 weeks and 0 days and 22 weeks and 6 days of gestational age. Subjects with normal cervical length (≥3.0 cm) were compared with subjects with short cervical length (<2.5 cm). The short-cervical-length cohort was further stratified by history of preterm birth. Multichannel uterine electromyography recordings were obtained for ∼60 minutes using proprietary, directional electromyography sensors on the abdomen. Uterine electromyography signals were observed and classified in groups as spikes, short bursts, and bursts. Primary outcomes were relative expression of spike, short-burst, and burst uterine electromyography signals. Subgroup analyses assessed each signal percentage by cervical length, history of preterm birth, and gestational age at delivery. Differences in percentage of uterine electromyography signals according to cervical length were analyzed using nonparametric tests of significance., Results: Of the 28 included subjects, 10 had normal and 18 had short cervical length. There were 9 subjects with short cervical length and a history of preterm birth. Spikes were the most commonly recorded signals and were higher in the normal-cervical-length cohort (96.3% [interquartile range, 93.1%-100.0%]) than the short-cervical-length cohort (75.2% [interquartile range, 66.7%-92.0%], P=.001). In contrast, median percentages of short-bursts and bursts were significantly higher in subjects with a short cervical length (17.3% [interquartile range, 13.6%-23.9%] vs 2.5% for normal cervical length [interquartile range, 0%-5.5%], P=.001 and 6.6% [interquartile range, 0%-13.4%] vs 0% for normal cervical length [interquartile range, 0%-2.8%], P=.014, respectively). Within subgroup analyses, cervical length was inversely proportional to percentage of observed short-bursts (P=.013) and bursts (P=.014). Subjects with short cervical length and history of preterm birth had higher burst percentages (12.8% [interquartile range, 9.0%-15.7%]) than those with short cervical length and no history of preterm birth (3.3% [interquartile range, 0%-5.0%], P=.003)., Conclusion: Short-burst and burst uterine electromyography signals are observed more frequently in mid-trimester patients with short cervical lengths. This relationship provides insight into abnormal myometrial activation in the mid-trimester and offers a plausible biophysiological link to cervical shortening., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model., Study Design: A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace., Results: Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth., Conclusion: Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The human uterus has no pacemaker or motor innervation, yet develops rhythmic, powerful contractions that increase intrauterine pressure to dilate the cervix and force the fetus through the pelvis. To achieve the synchronous contractions required for labor, the muscle cells of the uterus act as independent oscillators that become increasingly coupled by gap junctions toward the end of pregnancy. The oscillations are facilitated by changes in resting membrane potential that occur as pregnancy progresses. Reductions of potassium channels in the myocyte membranes in late pregnancy prolong myocyte action potentials, further facilitating transmission of signals and recruitment of neighboring myocytes. Late in pregnancy prostaglandin production increases leading to increased myocyte excitability. Also late in pregnancy myocyte actin polymerizes allowing actin-myosin interactions that generate force, following myocyte depolarization, calcium entry, and activation of myosin kinase. Labor occurs as a consequence of the combination of increased myocyte to myocyte connectivity, increased depolarizations that last longer, and activated intracellular contractile machinery. During labor the synchronous contractions of muscle cells raise intrauterine pressure to dilate the cervix in a process distinct from peristalsis. The synchronous contractions occur in a progressively larger region of the uterine wall. As the size of the region increases with increasing connectivity, the contraction of that larger area leads to an increase in intrauterine pressure. The resulting increased wall tension causes myocyte depolarization in other parts of the uterus, generating widespread synchronous activity and increased force as more linked regions are recruited into the contraction. The emergent behavior of the uterus has parallels in the behavior of crowds at soccer matches that sing together without a conductor. This contrasts with the behavior of the heart where sequential contractions are regulated by a pacemaker in a similar way to the actions of a conductor and an orchestra., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to characterize the oxytocin-induced desensitization of oxytocin-stimulated rises of intracellular calcium in cultured human myocytes., Study Design: Culture lines were begun from biopsy specimens of myometrium that had been obtained from women who underwent low transverse cesarean deliveries. Fluorescence changes of calcium green-1 were used to demonstrate the rises of intracellular free calcium. Cells were exposed to 10 nmol/L oxytocin for 1 to 6 hours before the experimentation, allowed to rest for 10 minutes, and then tested for the fluorescence increases that resulted from exposure to 10 nmol/L oxytocin and micromol/L prostaglandin F(2)(alpha). Subpopulations were defined as type 1 (responded to both oxytocin and prostaglandin F(2)(alpha)), type 2 (responded only to oxytocin), type 3 (responded only to prostaglandin F(2)(alpha)), or type 4 (responded to neither). The distribution of the subpopulations of cells was assessed by the determination of the response of every cell in every experimental run., Results: Pretreatment with oxytocin resulted in a decrease in the percentage of cells that responded to subsequent oxytocin exposure. The decrease was dependent on the duration of oxytocin exposure and was well fit with the Boltzmann sigmoid function. The duration of oxytocin exposure that yielded half-inactivation was 4.2 hours. Without oxytocin pretreatment, the distribution of subpopulations were 37.0% +/- 18.0% (type 1), 23.1% +/- 11.5% (type 2), 12.6% +/- 8.0% (type 3), and 27.3% +/- 22.9% (type 4). After 6 hours of oxytocin pretreatment, the percentage of type 1 and type 2 cells decreased to 2.4% +/- 3.8% and 2.6% +/- 2.4%, respectively, although the percentage of type 3 and type 4 cells increased to 20.4% +/- 18.9% and 74.6% +/- 22.1%, respectively., Conclusion: Oxytocin-induced desensitization of myocytes to oxytocin stimulation occurred over a clinically relevant time frame (4.2 hours). Continued responsiveness of the cells to prostaglandin F(2)(alpha) stimulation after 6 hours of oxytocin pretreatment indicated that postreceptor signaling pathways were maintained, which indicates that the oxytocin receptor likely is involved in the mechanism of myocyte desensitization to oxytocin stimulation.

Objective: The primary goal of this work was to determine the relative importance of sarcoplasmic reticulum inositol 1,4,5-triphosphate receptors and ryanodine receptors in the mechanism of intracellular calcium wave propagation in human uterine myocytes. A secondary goal was to identify the rate-determining step of calcium wave propagation., Study Design: Pregnant human myometrium was obtained at the time of cesarean delivery, enzymatically dispersed, and cultured through several passages. Intracellular calcium wave velocities were measured with video fluorescence microscopy and the calcium-dependent fluorescent dye calcium green 1. Experimental conditions were modified by exposure of the cells to ruthenium red (blocked ryanodine receptor), ryanodine (locked open ryanodine receptor), oxytocin (increased inositol-1,4,5-triphosphate), sodium butyrate (intracellular acidification), ammonium chloride (intracellular alkalinization), and elevation of temperature (from 19 degrees C to 30 degrees C)., Results: Wave velocities were found to be the same for spontaneously occurring (9.6 +/- 2.6 microm/s) and oxytocin-stimulated (10.3 +/- 3.4 microm/s) waves. Advance treatment of the cells with ryanodine or ruthenium red failed to change oxytocin-stimulated wave velocities from control values. The temperature dependence of calcium wave velocities was studied across the range 19 degrees C to 30 degrees C. Plots of wave velocities versus the inverse of the temperature yielded apparent activation energies that were the same for spontaneous (13.2 +/- 0.3 kcal/mol) and oxytocin-induced (14.3 +/- 1.6 kcal/mol) waves. After intracellular acidification by treatment with butyrate (20 mmol/L) wave velocities increased by 44%. Wave velocities decreased by 35% after treatment with ammonium chloride (20 mmol/L)., Conclusion: Propagation of intracellular calcium waves in cultured human uterine myocytes exhibited mechanisms of sarcoplasmic reticulum calcium release that could use either inositol 1,4,5-triphosphate receptors alone or ryanodine receptors alone, or both together. The rate-determining step for calcium wave propagation was diffusion of calcium though a highly buffered cytoplasm.

Objective: Indomethacin, an inhibitor of cyclooxygenase types 1 and 2, and nimesulide, a cyclooxygenase 2 selective inhibitor, are both well-known inhibitors of prostaglandin production. It has been assumed that the tocolytic mechanism of nimesulide and indomethacin is only through decreased prostaglandin production. The purpose of this study was to test the hypothesis that either nimesulide or indomethacin, or both, has a mechanism of action on human myocytes other than inhibition of prostaglandin production., Study Design: Human uterine myometrium was obtained from consenting patients during cesarean deliveries. Myocytes were cultured, plated, and loaded with a calcium-dependent fluorescent dye, calcium green 1. The relative concentrations of intracellular free calcium were determined by measurement of time-dependent fluorescence changes by means of a video fluorimeter. In all experiments, cells were stimulated with prostaglandin F2alpha, 30 micromol/L. Experiments were performed without pretreatment (control) or with pretreatment consisting of indomethacin, 10 micromol/L, or nimesulide, 30 micromol/L. The percentages of cells demonstrating calcium increases were counted and compared by means of the Fisher exact test. A P value =.05 was considered significant., Results: After prostaglandin F2alpha exposure, 33% of cells showed an increase in intracellular free calcium under control conditions. When pretreated with nimesulide, 39% of cells responded to prostaglandin F2alpha (P =.59). When pretreated with indomethacin, only 16% of cells responded to prostaglandin F2alpha (P =.019)., Conclusions: Pretreatment with nimesulide failed to reduce the fraction of cells that responded to prostaglandin F2alpha. In contrast, pretreatment with indomethacin significantly reduced the fraction of responding cells. These data suggest that, in vitro, indomethacin exhibits a mechanism of tocolysis other than inhibition of prostaglandin synthesis.

Objective: Our purpose was to characterize the types of voltage-activated calcium currents that are found in human uterine myocytes and to determine the effects of magnesium and nifedipine on these currents., Study Design: Electrophysiologic experiments were performed on freshly isolated human uterine smooth muscle cells by means of the nystatin modification of the whole-cell patch clamp technique., Results: Two types of voltage-activated calcium currents that are similar to the T-type and L-type calcium currents observed in cardiac myocytes were identified in freshly dispersed, pregnant human uterine myocytes. Magnesium at 8 mmol/L reduced uterine myocyte T-type currents by 68% +/- 17% but did not reduce L-type currents. Nifedipine at 10(-6) mol/L blocked the L-type currents but had no effect on T-type currents., Conclusion: Freshly isolated human uterine smooth muscle cells exhibit subtypes of calcium currents that are analogous to those found in cardiac myocytes. The uterine myocyte T-type current may be primarily involved with action potential transmission and the L-type current primarily with increasing intracellular free calcium by bulk calcium transport. The differing physiologic effects of magnesium and nifedipine on the calcium current subtypes suggest that for the treatment of preterm labor the primary effect of magnesium therapy is to decrease the frequency of contractions and of nifedipine the strength.

Human myometrium was obtained at the time of cesarean delivery by means of excisional biopsy from the upper margin of the uterine incision through the lower uterine segment. Isolated smooth muscle cells were obtained by collagenase treatment. With the whole-cell patch clamp technique, voltage-clamp and current-clamp experiments were performed. Regenerative action potentials were seen in 3 mmol/L calcium bathing solution. Voltage-clamp experiments demonstrated the presence of transient inward currents and large outward currents. Inward currents were isolated with the use of tetraethylammonium ion as a blocking agent of outward current. In 3 mmol/L calcium inward current began at -60 mV and maximum inward current occurred at -40 mV. Maximum inward current density during the rising phase of the action potential was 1.0 microA/cm2 in 3 mmol/L calcium and was unaffected by reduction of sodium concentration in the bathing solution.

Voltage-clamp studies using the whole-cell patch clamp technique were performed on single cells of cultured human uterine smooth muscle obtained from term pregnancies. The small size of the cells allowed time resolution of transient ionic currents as short as 3 msec. A large, voltage-activated inward current was identified as a sodium channel conductance by the following criteria: (1) Removal of sodium from the bath eliminated the current; (2) current was blocked by the sodium-channel-blocking agent tetrodotoxin; (3) current was observed in the absence of calcium. The sodium current was large (maximal inward current 7.2 microA/cm2) and of short duration (decayed within 10 msec). The onset of activation of this current was -40 mV, with peak inward current at -10 mV. Steady-state voltage inactivation of this channel demonstrated half-maximal inactivation at -67 mV, indicating that this channel is largely inactivated at normal resting potentials.

To characterize the effects of aminophylline and nifedipine on pregnant human myometrium, in vitro contractility studies were performed on myometrial strips obtained at cesarean section. The strips were stimulated with oxytocin (800 mU/L) to simulate labor and then were exposed to increasing concentrations of aminophylline (40, 100, and 400 mumol/L) or nifedipine (5, 10, and 20 micrograms/L). Both drugs produced a dose-related decrease in contraction strength, as measured by the time-integrated force of contraction. Aminophylline lengthened the period of contraction in a manner that was not dose dependent. Low-dose nifedipine (5 micrograms/L) increased the period of contraction, but higher doses had no effect on frequency. Both drugs produced a net reduction in the effectiveness of labor, as measured by the average force (time-integrated force divided by period). These results indicate that both aminophylline and nifedipine may be clinically useful tocolytic agents.

Myometrium was obtained from pregnant volunteers by biopsy of the upper margin of the uterine incision at the time of cesarean section. A multistep enzymatic digestion with collagenase, trypsin, protease, and deoxyribonuclease yielded viable cells capable of contraction. Primary monolayer culture was carried out in the presence of human pregnant serum. Electron microscopic examination of freshly isolated and cultured cells revealed an ultrastructure indicative of smooth muscle cells. Intracellular microelectrode studies were performed on freshly isolated cells. Passive membrane properties were: resting membrane potential, -49.4 mV; specific membrane resistance, 6.06 kohms-cm2; specific membrane capacitance, 1.57 microfarad per square centimeter. Outward-going rectification was observed in response to depolarizing current pulses. Regenerative action potentials were not observed; however, transient voltage responses were elicited after depolarizing, but not hyperpolarizing, current pulses. These studies characterize a human tissue preparation that is applicable to electrophysiologic investigation of the control of uterine function.

The results obtained from the routine use of peritoneoscopy in the initial evaluation and follow-up of 99 patients with ovarian cancer treated at the National Cancer Institute between 1970 and 1978 have been analyzed. Prior to treatment, peritoneoscopy documented new sites of involvement undetected by conventional radiologic and isotopic procedures in 42 patients (48%) and provided the only evidence for follow-up of disease in 25 patients (28%). Twenty-one percent of patients referred with Stages I and II disease were upstaged to Stage III on the basis of diaphragmatic disease detected at peritoneoscopy. In the 66 restaging (posttreatment) peritoneoscopies, residual disease was found in 33 (50%) and peritoneoscopic findings provided the only evidence for disease in 24 cases (36%). These patients were spared an unnecessary second-look laparotomy. Twenty-two patients with negative peritoneoscopies underwent laparotomy. Residual ovarian cancer was found in 12 (55%), mainly in the pelvis and mesentery. Thus, a negative peritoneoscopy must be followed by a laparotomy before a patient with ovarian cancer can be considered disease free. Peritoneoscopy was found to be a safe and feasible procedure, even in patients who had prior laparotomies. It could not be performed for technical reasons in only 6% of the patients. There were few serious complications and in only 2.5% of the cases was medical therapy required to deal with a complication. There were no deaths or perforations of the viscus and no patient required surgical exploration because of a peritoneoscopy complication.