Oxytocin, oxytocin receptors and the efficacy of labor arousal and labor stimulation

The major biological action of oxytocin in mammals, both in vivo and in vitro, is to stimulate contraction of the uterine muscles and the myoepithelial cells surrounding the alveoli of the mammary gland. Even before labeled oxytocin became available, it was found that the rate of excretion of exogenous oxytocin was significantly greater in lactating female rats than in non-lactating rats, and tissue distribution of ^eH -oxytocin in non-pregnant rats showed that the uterus exhibits a relatively high affinity for oxytocin. Specific oxytocin binding sites have been established in the uterus, mammary gland, and other target organs of this hormone. Thus, the binding sites are an integral part of the oxytocin-receptor systems of the uterus and mammary gland.

It is believed that almost nothing is known about the chemical nature of the oxytocin receptor. It is assumed that oxytocin acts on plasma membranes, since this hormone changes the electrophysiological status of the myometrium and milk ducts.

When studying the effect of estrogens on oxytocin receptors in the uterus, it was shown that estrogens cause an increase in spontaneous contractions of the uterus and the uterotonic activity of oxytocin. The sensitivity of the uterus to the action of oxytocin becomes maximal with an increase in the concentration of endogenous estrogens both at the stage of proestrus and estrus, which is probably due to an increase in the number of oxytocin-receptor sites in the uterus.

The woman's uterus responds to oxytocin throughout pregnancy. The uterus's sensitivity to this hormone increases as the pregnancy progresses, reaching a maximum just before or during labor. This may be due to the increase in blood estrogen during pregnancy, and the signal for labor to begin is not the increase in blood oxytocin itself, but the uterus's ability to respond to this increase.

Cyclic AMP and calcium obviously play a role in the mechanisms of oxytocin action. Oxytocin can increase the supply of extracellular Ca ²⁺ and stimulate the release of this ion from intracellular depots.

The source of Ca ²⁺ supply appears to be determined by the electrochemical state of the uterus. For example, extracellular Ca ²⁺ appears to stimulate contraction of depolarized myometrium, whereas intracellular Ca ²⁺ stimulates contraction of polarized myometrium. The precise mechanisms of oxytocin action remain to be determined.

In this regard, the level of exogenous oxytocin in the blood is of interest. Fuchs et al. compared oxytocin levels in spontaneous and oxytocin-induced labor. The levels of oxytocin in the blood plasma did not differ in both groups at uterine os dilation of 2 cm and 4 cm. Starting with uterine os dilation of 4-6 cm, 7-9 cm, and 10 cm, a statistically significant increase in the concentration of oxytocin in the blood plasma was noted both in spontaneous labor and in oxytocin-induced labor with an infusion frequency of 4-6, 7-9, and 10-16 milliunits/min (mU/min), respectively. Amico et al. (1984) studied the level of oxytocin in the blood plasma of 11 women in labor with weak labor. The basal oxytocin level fluctuated within the range of 0.4-5.94 pg/ml. These parturient women were administered synthetic oxytocin with a gradual increase in the infusion frequency by 1 milliunits/min, with a constant level of oxytocin in the blood plasma being achieved after 40 min. A linear relationship was found between the dose of infused oxytocin and the average level of oxytocin in the blood plasma in the corresponding units.

Along with determining the level of oxytocin in the blood plasma, an important point is determining the sensitivity of the uterus to oxytocin. The latter varies significantly in different patients and the sensitivity of the uterus to oxytocin gradually increases towards the end of pregnancy, reaching a maximum in full-term pregnancy and continues to increase even during labor. Thus, even with a relatively constant level of oxytocin in the blood plasma, uterine activity increases in the dynamics of pregnancy.

It has long been believed that oxytocinase in the mother's blood prevents circulating oxytocin from reaching the threshold level during pregnancy. However, this hypothesis has not been confirmed. C. N. Smyth in London developed an oxytocin test and showed that the maximum sensitivity of the uterus to oxytocin is reached on the day of delivery, which was parallel to the ripening of the cervix, although it is unknown whether there is a connection between uterine sensitivity and cervical ripening.

A connection has been established between the blood steroid level and the sensitivity of the uterus to oxytocin. Thus, cortisol, estradiol and dehydroepiandrosterone sulfate increase, and progesterone decreases the sensitivity of the uterus to oxytocin. It has been shown that steroid hormones, in particular estrogens, are capable of changing cell metabolism, membrane permeability, enzyme activity, affecting the genetic apparatus of target cells, and influencing lipid peroxidation, being antihypoxants. Biotransformation of steroid hormones of the estrogenic series in erythrocytes is possible by peroxidase reaction.

Oxytocin receptors. The uterus of some animal species (rats, rabbits) and humans contains oxytocin receptors. Despite the fact that oxytocin is the most powerful and specific uterotropic agent, the participation of oxytocin in activating the uterus in humans during labor has long been questionable, since many researchers have failed to detect an increase in the level of oxytocin in the blood of women in labor.

A marked increase in the number of oxytocin receptors in the myometrium may result in uterine activation without changing the plasma oxytocin level. At the onset of labor, the concentration of oxytocin receptors is significantly higher than without labor. Starting from the dilation of the uterine os by 7 cm or more, as well as in the absence of the effect of labor induction, a low concentration of oxytocin receptors was found. The lowest concentration of oxytocin receptors was found at the beginning of the second stage of labor. It is interesting to note that the concentrations of oxytocin receptors in the fundus, body, and lower segment of the uterus did not differ. The isthmus or lower part of the lower segment of the uterus had significantly lower concentrations of oxytocin receptors, and the cervix had even lower concentrations. The established distinct gradient in the concentration of oxytocin receptors from the fundus to the cervix provides a molecular basis for the direct organization of the contractile forces of the uterus. The relative inactivity of the lower segment can be explained by the low concentration of oxytocin receptors. In the decidual tissue, these were similar to the myometrium both in size and in their distribution. This is surprising, since the decidua is not a contractile tissue. However, the decidua is a very active synthesis of prostaglandins of the E2, F _2a series, and it has been established that oxytocin stimulates the synthesis of prostaglandins in the decidua. This effect, although there is little evidence, is still apparently mediated by a high concentration of oxytocin receptors.

It is believed that the sensitivity of the myometrium to oxytocin is greatly increased in the presence of small amounts of prostaglandins, and that oxytocin-stimulated myometrial contractions are accompanied by the release of prostaglandins; this effect is blocked by the prostaglandin synthetase inhibitor indomethacin. The absence of this mechanism may well account for the insensitivity of the uterus to oxytocin during pregnancy, and the release of prostaglandins may account for the high sensitivity to oxytocin during labor. It may also explain the marked increase in sensitivity to oxytocin that occurs with rupture of the membranes and is accompanied by local release of prostaglandins.

Although the clinical use of oxytocin should be well understood by now, several distinctive features need to be repeated as they are forgotten in the ever-changing environment of obstetric practice.

The human uterus is highly insensitive to oxytocin during pregnancy. This lack of sensitivity probably results from the presence of an intact placenta, which produces large amounts of progesterone, and may be due to very low levels of local prostaglandin synthesis. As a result, oxytocin is useless as a primary agent for inducing abortion or for treating hydatidiform mole or missed abortion. "Starter estrogen" is of no use in intrauterine fetal death that occurs with intact membranes; oxytocin becomes effective only 3 to 4 weeks after fetal death, when the placenta has ceased functioning, or after amniotomy, which activates local prostaglandin release. Similarly, oxytocin is ineffective in "ripening" the cervix before the membranes have ruptured. On the other hand, oxytocin may be effective in enhancing the action of ergometrine, promoting uterine contractions after abortion or childbirth. The effect of oxytocin on phosphoinositide metabolism in a contracting strip of isolated human myometrium was studied and it was found that this effect is universal and manifests itself both outside and during pregnancy. Spontaneous contractile activity of the myometrium is modulated by the phosphoinositide system.

Neomycin (0.5 mM), an inhibitor of phosphoinositide metabolism, decreased the amplitude of spontaneous and oxytocin-induced (10 IU/ml) contractions. However, increasing the oxytocin concentration (10 IU/ml) again caused contractions of the myometrial strip. A higher concentration of oxytocin (10 IU/ml) was required to work with strips from non-pregnant myometrium. Neomycin (0.5 mM) did not affect the effect of protein kinase C activators. Glycerol caused an increase in the frequency of contractions, and phorbol ester induced a prolonged tonic component. Staurosporine, a protein kinase C blocker, decreased the amplitude and frequency of both spontaneous and oxytocin-induced myometrial contractions. A competitive effect of staurosporine and phorbol ester on protein kinase C was revealed.

An increase in the intracellular Ca level is one of the consequences of phosphoinositide hydrolysis. When calcium channels were blocked by verapamil (1 μM) and Ca ions in the solution were reduced, spontaneous and oxytocin-induced myometrial contractions were always suppressed. These experimental data are also confirmed by clinical observations of labor anomalies in primiparous women. A high frequency of labor anomalies was found among primiparous women whose somatic and obstetric history was uncomplicated, which suggests changes in many links regulating uterine contractility. Clarification of the pathogenetic mechanisms of labor anomalies development in primiparous women requires in-depth scientific research, including hormonal, biochemical, and electrophysiological methods.

Studying the biomechanics of effective labor contractions, he believes that external work on the deformation reconstruction of the cervix in the first period of labor is an integral derivative of the interdependent interaction of a number of functional-morphological and physiological phenomena:

• complete removal of the “resting hypertrophy” blockade from myocytes with activation of their spontaneous contractile activity;
• functional homogeneity of the contractile units of the myometrium, which are in direct mechanical connection with each other;
• optimal degree of resistance of cervical tissue to deformation;
• the formation of two functionally isolated hydraulic cavities in the laboring uterus;
• deposition and exfusion of blood from the vascular reservoirs of the uterus with changes in the intracavitary volumes of its functional sections.

The sensitivity of the myometrium is known to increase in the last days of pregnancy and the biochemical equivalent of this increase in sensitivity is an increase in the number of oxytocin receptors in the myometrium. Thus, it can be postulated that oxytocin is involved in the processes responsible for the development of labor, with a sudden increase in oxytocin receptors in the myometrium and decidua observed shortly before the end of pregnancy. Using a specially developed technique of very thin strips of human myometrium with a cross-section of 2.2 - 10 ³ mm ² and 6.1 - 10 ^-3 mm ^2, it was found that the maximum amplitude of contractions caused by oxytocin was the highest compared to prostaglandin F _2a and somewhat less than that caused by prostaglandin E2.

A number of modern experimental studies have shown that the physiological significance of uterine activity in the early stages is unknown. Thus, in the early stages of pregnancy, a high concentration of oxytocin in the blood plasma of sheep was found, which does not lead to an increase in myometrium activity. This can be explained by the low level of oxytocin receptors in the myometrium at these stages. They stimulate uterine contractions in sheep and are primarily important in the process of labor, while oxytocin receptors in the endometrium of sheep mediate the humoral response - the release of prostaglandin F _2a.

The concentration of oxytocin receptors remains low throughout pregnancy and increases suddenly a few hours before delivery, remains at a maximum level during delivery, and then decreases to predelivery levels 1–2 days after delivery. A positive correlation has also been found between the concentration of oxytocin receptors and uterine activity measured in Montevideo units. Thus, the sensitivity of the uterus to oxytocin is regulated by the concentration of oxytocin receptors. In addition, the human uterus is relatively insensitive to oxytocin in early pregnancy but becomes very sensitive to it immediately before delivery. A 50–100-fold increase in the dose of oxytocin is required to induce uterine contractions at 7 weeks of pregnancy compared with full-term pregnancy.

In accordance with changes in the sensitivity of the myometrium to oxytocin, the concentration of oxytocin receptors was low in the non-pregnant uterus, then an increase in their concentration was noted at 13-17 weeks of pregnancy and then a 10-fold increase at 28-36 weeks of pregnancy. Immediately before labor, the level of oxytocin receptors additionally increases by 40%. In the early stages of pregnancy, there is only a 2-fold increase in their concentration, and during labor, the number of oxytocin receptors in the myometrium increases ISO times compared to that in non-pregnant women.

It is important to note that the concentration of oxytocin receptors was significantly lower in those pregnant women in whom induction of labor with oxytocin was ineffective, as well as in post-term pregnancies.

The cardiovascular side effects of oxytocin are minimal when given intravenously in large doses. However, water intoxication and encephalopathy still occur due to failure to recognize that oxytocin has an antidiuretic effect when given in large doses and that strict control of fluid intake and electrolyte balance is necessary when used. Water intoxication is characterized by nausea, vomiting, anorexia, weight gain, and lethargy. It is now generally accepted that intramuscular, nasal, and oral routes of oxytocin administration are unacceptable during labor and are associated with some risk of uterine rupture. The fact that prostaglandins greatly increase the sensitivity of the uterus to oxytocin is still not fully appreciated in obstetric practice, and cases of uterine rupture have been observed in women receiving full doses of oxytocin after prostaglandins have been administered to accelerate cervical ripening and dilation.

A very large number of oxytocin analogues have been synthesized and tested in experiments. None of them have shown clear advantages over oxytocin in clinical practice.

Contraindications for the administration of uterotonic drugs are:

• discrepancy between the size of the fetus and the mother's pelvis (anatomically and clinically narrow pelvis);
• the presence of a scar on the uterus after previous surgeries (cesarean section, enucleation of myomatous nodes, metroplasty, etc.);
• fatigue of the mother in labor;
• incorrect positions and presentations of the fetus;
• intrauterine fetal distress;
• complete placenta previa;
• detachment of normally and low-lying placenta;
• the presence of vaginal stenosis, a scar after a healed third-degree perineal rupture and other cicatricial changes in the soft birth canal;
• cervical dystopia, atresia and cicatricial changes;
• allergic intolerance to oxytotic agents.

Oxytocin administration should begin with 0.5-1.0 mIU/min, and if careful assessment does not reveal signs of hyperstimulation or a threatening condition of the fetus, then the dose of the drug can be periodically increased by 0.5 mIU/min with a break of 20-30 minutes. In most women in labor, the effect is observed with oxytocin doses not exceeding 8 mIU/min.