The physiology and pharmacology of oxytocin in labor and in the peripartum period.

Oxytocin is a reproductive hormone implicated in the process of parturition and widely used during labor. Oxytocin is produced within the supraoptic nucleus and paraventricular nucleus of the hypothalamus and released from the posterior pituitary lobe into the circulation. Oxytocin is released in pulses with increasing frequency and amplitude in the first and second stages of labor, with a few pulses released in the third stage of labor. During labor, the fetus exerts pressure on the cervix of the uterus, which activates a feedforward reflex-the Ferguson reflex-which releases oxytocin. When myometrial contractions activate sympathetic nerves, it decreases oxytocin release. When oxytocin binds to specific myometrial oxytocin receptors, it induces myometrial contractions. High levels of circulating estrogen at term make the receptors more sensitive. In addition, oxytocin stimulates prostaglandin synthesis and release in the decidua and chorioamniotic membranes by activating a specific type of oxytocin receptor. Prostaglandins contribute to cervical ripening and uterine contractility in labor. The oxytocin system in the brain has been implicated in decreasing maternal levels of fear, pain, and stress, and oxytocin release and function during labor are stimulated by a social support. Moreover, studies suggest, but have not yet proven, that labor may be associated with long-term, behavioral and physiological adaptations in the mother and infant, possibly involving epigenetic modulation of oxytocin production and release and the oxytocin receptor. In addition, infusions of synthetic oxytocin are used to induce and augment labor. Oxytocin may be administered according to different dose regimens at increasing rates from 1 to 3 mIU/min to a maximal rate of 36 mIU/min at 15- to 40-minute intervals. The total amount of synthetic oxytocin given during labor can be 5 to 10 IU, but lower and higher amounts of oxytocin may also be given. High-dose infusions of oxytocin may shorten the duration of labor by up to 2 hours compared with no infusion of oxytocin; however, it does not lower the frequency of cesarean delivery. When synthetic oxytocin is administered, the plasma concentration of oxytocin increases in a dose-dependent way: at infusion rates of 20 to 30 mIU/min, plasma oxytocin concentration increases approximately 2- to 3-fold above the basal level. Synthetic oxytocin administered at recommended dose levels is not likely to cross the placenta or maternal blood-brain barrier. Synthetic oxytocin should be administered with caution as high levels may induce tachystole and uterine overstimulation, with potentially negative consequences for the fetus and possibly the mother. Of note, 5 to 10 IU of synthetic oxytocin is often routinely given as an intravenous or intramuscular bolus administration after delivery to induce uterine contractility, which, in turn, induces uterine separation of the placenta and prevents postpartum hemorrhage. Furthermore, it promotes the expulsion of the placenta.

Pathophysiological Implications of Interstitial Cajal-like Cells (ICC-like) in Uterus: A Comparative Study with Gastrointestinal ICCs.

The main function of interstitial cells of Cajal (ICCs) is to regulate gastrointestinal peristalsis by acting as a "pacemaker" cell by generating spontaneous slow electrical waves. In 2005, electron microscopy revealed a cell type similar to ICCs (ICC-like) outside the gastrointestinal tract, with contractile activity and c-Kit+ immunohistochemistry shared with ICCs. Among the locations where ICC-like cells have been observed, it is in the uterus where they have a significant functional and pathophysiological role. These cells are involved in obstetric phenomena of contractile action, such as ascending sperm transport, embryo implantation, pregnancy, delivery, and the expulsion of menstrual debris. Within the pathophysiology related to these cells, we find obstetric alterations such as recurrent miscarriages, premature deliveries, abolition of uterine contractions, and failures of embryo implantation, in addition to other common conditions in the fertile age, such as endometriosis and leiomyoma.

Lipid-soluble fraction of Shakuyaku-kanzo-to inhibits myometrial contraction in pregnant women.

AIM: Shakuyaku-kanzo-to, a Kampo medicine composed equally of shakuyaku and kanzo, is an antispasmodic drug that can inhibit contraction of uterine smooth muscles in pregnant women and rats. We aimed to test the inhibitory effects of water- and lipid-soluble extracts of shakuyaku-kanzo-to, shakuyaku, and kanzo in order to identify the fraction responsible for inhibiting uterine smooth muscle contraction in pregnancy. MATERIAL AND METHODS: Myometrial tissues were obtained from pregnant women and rats. The water- and lipid-soluble fractions of shakuyaku-kanzo-to, shakuyaku, and kanzo were obtained using the method of Bligh and Dyer. Lipid-soluble fractions were also partially purified using thin-layer chromatography (TLC) with a chloroform : methanol : water (65:25:4 by volume) solvent system to yield four TLC fractions. The effect of each fraction on oxytocin-induced myometrial contraction was examined in vitro. RESULTS: Lipid-soluble fractions obtained from shakuyaku-kanzo-to and kanzo inhibited myometrial contraction; water-soluble fractions had no effect. Of the four TLC fractions, the inhibitory effect was greatest with TLC fraction 1 (0.75 < Rf value ≤ 1.0). Neither the water-soluble nor the lipid-soluble fraction from shakuyaku inhibited myometrial contraction. CONCLUSIONS: These results suggest that lipid-soluble substances with low polarity derived from kanzo are responsible for the inhibitory effect of shakuyaku-kanzo-to on myometrial contraction.

Why are We Waiting to Start Large Scale Clinical Testing of Human Chorionic Gonadotropin for the Treatment of Preterm Births?

Preterm births are an expensive global health problem. Despite the basic science and clinical research advances to better understand and prevent preterm births, the rates are increasing. There are several therapeutic options. While some options such as progestins work for selected women, others such as magnesium sulfate can only be used for delaying births for 24 to 48 hours so that the patients can be treated with corticosteroids to promote fetal lung maturity. Based on the scientific and clinical evidence, we recommend testing human chorionic gonadotropin in a large multicenter, randomized, double-blind, and placebo-controlled clinical trials in women with active preterm labor and those with a previous history of preterm births. Human chorionic gonadotropin is not only inexpensive but also has not shown any side effects so far in the infants or in the mothers.

Relaxant effects of metoclopramide and magnesium sulfate on isolated pregnant myometrium: an in vitro study.

BACKGROUND: Metoclopramide and magnesium sulfate are extensively used agents in obstetrics. In this study, the relaxant properties of metoclopramide and magnesium sulfate on pregnant myometrium, together with the possible reversing influences of oxytocin and cabergoline (a dopamine D2 receptor agonist), were investigated. METHODS: Myometrial strips from 24 parturients were randomly allocated to four groups: control (Group CON), magnesium sulfate and oxytocin (Group MSO), metoclopramide and oxytocin (Group MEO), and metoclopramide and cabergoline (Group MEC). Myometrial strips were mounted on a myograph bathed in Krebs buffer. Saline (Group CON) and five incremental doses of magnesium sulfate (Group MSO) or metoclopramide (Groups MEO and MEC) were sequentially microinjected into the bath. Subsequently, oxytocin (Groups CON, MSO and MEO) or cabergoline (Group MEC) was microinjected into the bath. The myometrial contractile characteristics after each drug injection, including contractile force, interval and duration, were analyzed. RESULTS: Magnesium sulfate was more potent for prolonging myometrial contractile interval than reducing contractile force. Metoclopramide relaxed myometrial contractions by inhibiting contractile force and prolonging contractile interval in a concentration-dependent manner. Oxytocin reversed both the inhibited contractile force and the prolonged contractile interval caused by a high concentration of magnesium sulfate but accelerated the contractile interval and had no significant effect on the contractile force suppressed by metoclopramide. The relaxant effects of metoclopramide were completely reversed by cabergoline. CONCLUSIONS: Both magnesium sulfate and metoclopramide relaxed myometrial contractions, and exhibited different responses to subsequent oxytocin treatment. The relaxant mechanism of metoclopramide may be via blockade of dopamine D2 receptor, which requires further investigation.