Oxytocin, oxytocin receptors, and the effectiveness of labor and delivery

The main biological effect of oxytocin in mammals, both in vivo and in vitro, is to stimulate contraction of the uterine muscles and myoepithelial cells surrounding the alveoli of the mammary gland. Even before the labeled oxytocin became available, it was found that the rate of excretion of exogenous oxytocin in lactating female rats was significantly greater than that of non-lactating rats, and the distribution of ^e H-oxytocin in the tissues of nonpregnant rats showed that the uterus exhibited a relatively high affinity for oxytocin . The presence of specific oxytocin binding sites in the uterus, mammary gland and other organs - targets of this hormone has been established. Thus, the binding sites are an integral part of the oxytocin-receptor systems of the uterus and mammary gland.

It is believed that little is known about the chemical nature of the oxytocin receptor. It is assumed that oxytocin affects plasma membranes, since this hormone changes the electrophysiological status of the myometrium and ducts of the mammary gland.

When studying the effect of estrogens on oxytocin receptors in the uterus, it has been shown that estrogens cause an increase in spontaneous contractions of the uterus and 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 uterus of a woman reacts to oxytocin throughout pregnancy. The sensitivity of the uterus to this hormone increases with the development of pregnancy, reaching a maximum immediately before childbirth or during childbirth. Perhaps this is due to an increase in the concentration of estrogens in the blood during pregnancy, and the signal for the onset of labor is not in itself an increase in the concentration of oxytocin in the blood, but the capacity of the uterus to respond to this increase.

Apparently, the role of cyclic AMP, as well as calcium, plays a role in the mechanisms of action of oxytocin. Oxytocin can increase the intake of extracellular Ca ²⁺ and stimulate the release of this ion from intracellular stores.

The source of intake of Ca ²⁺, apparently, is determined by the electrochemical state of the uterus. For example, extracellular Ca ²⁺ apparently stimulates a reduction in depolarization myometrium, whereas intracellular Ca ²⁺ stimulates a reduction in polarized myometrium. Exact mechanisms of action of oxytocin have yet to be established.

In this connection, the level of exogenous oxytocin in the blood is of interest. Fuchs et al. Compared levels of oxytocin in spontaneous and oxytocin-induced labor. At the same time, the levels of oxytocin in the blood plasma at opening of the uterine throat up to 2 cm and up to 4 cm did not differ in both groups. Since the opening of the uterine pharynx by 4-6 cm, 7-9 cm and 10 cm, there was a statistically significant increase in the concentration of oxytocin in the blood plasma both for spontaneous delivery and for oxytocin-induced infusion rates of 4-6.7-9, respectively 10-16 mn / min. Amico et al. (1984) studied the level of oxytocin in blood plasma in 11 parturient women with weakness of labor activity. The basal level of oxytocin ranged from 0.4-5.94 pg / ml. These parturients were injected with synthetic oxytocin with a gradual increase in infusion rate of 1 million / min, with a constant level of oxytocin in the blood plasma reached after 40 minutes. A linear relationship was established between the dose of infused oxytocin and the average level of oxytocin in the blood plasma in the appropriate units.

Along with the determination of the level of oxytocin in blood plasma, an important point is to determine the sensitivity of the uterus to oxytocin. The latter is significantly different in different patients and the sensitivity of the uterus to oxytocin is graded to the end of pregnancy, reaching a maximum at termed pregnancy and continues to increase even in childbirth. Thus, even with a relatively constant level of oxytocin in the blood plasma, the uterine activity in the dynamics of pregnancy increases.

For a long time it was believed that oxytocinase in the mother's blood protects circulating oxytocin from the threshold level during pregnancy. However, this hypothesis was not confirmed. S. N. Smyth in London developed the oxytocin test and showed that the maximum sensitivity of the uterus to oxytocin reaches the day of childbirth, it was parallel to the maturation of the cervix, although it is unknown whether there is a relationship between uterine sensitivity and maturation of the cervix.

A relationship was established between the level of steroids in the blood and the sensitivity of the uterus to oxytocin. So, cortisol, estradiol and dehydroepiandrosterone sulfate increase, and progesterone decreases the sensitivity of the uterus to oxytocin. It is shown that steroid hormones, in particular estrogens, are capable of altering cell metabolism, membrane permeability, enzyme activity, acting on the genetic apparatus of target cells, and affecting lipid peroxidation, being antihypoxic. The biotransformation of steroid hormones of the stromal series in erythrocytes is possible by a peroxidase reaction.

Oxytocin receptors. Uterus of some animal species (rats, rabbits) and humans contains oxytocin receptors. Despite the fact that oxytocin is the most powerful and specific uterotrophic drug, the involvement of oxytocin in the activation of the uterus in a human in labor has long been questionable, since many researchers failed to detect an increase in the level of oxytocin in the blood of women in labor.

A distinct increase in the number of oxytocin receptors in the myometrium can lead to activation of the uterus without changing the level of oxytocin in the blood plasma. At the onset of labor, the concentration of oxytocin receptors may be significantly higher than without a birth. Since the opening of the uterine pharynx by 7 cm or more, and also in the absence of the effect of induction, a low concentration of oxytocin receptors has been revealed. At the beginning of the II period of labor, the lowest concentration of oxytocin receptors was detected. It is interesting to note that the concentrations of oxytocin receptors in the bottom, 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 bottom to the cervix provides a molecular basis for the direct organization of contractile forces of the uterus. The relative inactivity of the lower segment can be explained by the low concentration of oxytocin receptors. In decidual tissue, this was similar to the myometrium both in size and distribution. This is surprising, since decidua is not a contractile tissue. However, in the decidua is very active series prostaglandins E2, F _2a, and found that oxytocin stimulates the synthesis of prostaglandins in decidua. This effect, despite the fact that there is little evidence, is apparently mediated by a high concentration of oxytocin receptors.

It is believed that the sensitivity of the myometrium to oxytocin greatly increases in the presence of small amounts of prostaglandins, and myometrial contractions stimulated with oxytocin are accompanied by the release of prostaglandins; this effect is blocked by an inhibitor of prostaglandin synthetase - indomethacin. The absence of this mechanism may well be the cause of insensitivity of the uterus to oxytocin during pregnancy, and the release of prostaglandins can cause high sensitivity to oxytocin during labor. This can also explain the significant increase in sensitivity to oxytocin that occurs when a fetal bladder is opened and is accompanied by local release of prostaglandins.

Although the clinical use of oxytocin should be well understood, several distinctive features need to be repeated, as they are forgotten in the constantly changing conditions of obstetric practice.

The woman's uterus is extremely insensitive to oxytocin during pregnancy. This lack of sensitivity probably depends on the presence of an intact placenta that produces large amounts of progesterone, and is possibly associated with a very low level of local synthesis of prostaglandins. As a result, oxytocin is useless as a primary substance for inducing abortion, as well as for the treatment of bladder skipping or abortion. "Fetal estrogen" does not help with intrauterine fetal death, which occurred with undamaged fetal membranes; Oxytocin is effective only after 3-4 weeks after fetal death, when the placenta stops functioning, or after an amniotomy that activates the local release of prostaglandin. Similarly, oxytocin is an ineffective substance for the "ripening" of the cervix before the rupture of membranes. On the other hand, oxytocin can be effective in enhancing the action of ergometrine, contributing to uterine contractions after abortion or childbirth. The effect of oxytocin on the phosphoinositide exchange of the contracting stria of isolated human myometrium has been studied and found that this effect is universal and manifests itself both outside and during pregnancy. The spontaneous contractile activity of the myometrium is modulated by the phosphoinositide system.

Neomycin (0.5 mM), inhibiting the metabolism of phosphoinositides, reduced the amplitude of spontaneous and induced oxytocin (10 IU / mL) contractions. However, an increase in the concentration of oxytocin (10 IU / ml) again caused a contraction of the myometrium band. A large concentration of oxytocin (10 IU / ml) was required to work with strips of non-pregnant myometrium. Neomycin (0.5 mM) had no effect on the effect of protein kinase C activators. Glycerol caused an increase in the contraction frequency, and phorbol ester induced a prolonged tonic component. Staurosporin, a blocker of protein kinase C, reduced the amplitude and frequency of both spontaneous and oxytocin-induced contractions of the myometrium. The competitive influence of staurosporine and phorbol ester on the protein protein was revealed.

An increase in the level of intracellular Ca is one of the consequences of the hydrolysis of phosphoinositides. With blockade of calcium channels with verapamil (1 μM) and with the decrease of Ca ions in solution, the suppression of spontaneous and oxytocin-induced contractions of the myometrium has always been observed. These experimental data are also supported by clinical observations of abnormalities of labor in the primitive. A high incidence of abnormalities of labor among the first-born, a somatic and obstetric anamnesis of which was uncomplicated, was identified, suggesting that there are changes in many links regulating the contractile activity of the uterus. Clarification of pathogenetic mechanisms of the development of abnormalities of labor in the primal areas requires in-depth scientific research, including hormonal, biochemical, electrophysiological methods.

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

• complete removal of the blockade "rest hypertrophy" from myocytes with the activation of their spontaneous contractile activity;
• functional homogeneity of the contractile units of the myometrium, which are in direct mechanical communication with one another;
• the optimal degree of cervical tissue resistance to deformation;
• formation of two functionally isolated hydraulic cavities in the uterus;
• deposition and exfusion of blood from vascular reservoirs of the uterus with changes in intracavitary volumes of its functional departments.

The sensitivity of the myometrium is known to increase in the last days of pregnancy and the biochemical equivalent of this sensitivity increase is the increase in the myometrium of the number of receptors for oxytocin. Thus, it can be postulated that oxytocin is involved in the processes responsible for the development of labor, while a sudden increase in oxytocin receptors in myometrium and decidua is noted shortly before the termination of pregnancy. Using the 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 established that the maximum amplitude of contractions caused by oxytocin was the highest in comparison with prostaglandin Ф _2а 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 early terms is unknown. Thus, early in pregnancy, a high concentration of oxytocin in the blood plasma in sheep, which does not lead to an increase in myometrium activity. This can be explained by the low level of oxytocin receptors in myometrium at these times. They also stimulate uterine contractions in sheep and are primarily important in the process of delivery, while oxytocin receptors in the sheep's endometrium mediate the humoral response-the release of prostaglandin F _2a.

The concentration of oxytocin receptors remains low throughout the pregnancy and suddenly rises a few hours before delivery and remains at the maximum level during labor and then decreases to pre-natal levels 1-2 days after delivery. A positive correlation was also 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 the early stages of pregnancy, but becomes very sensitive to it immediately before childbirth. At the same time, a 50-100-fold increase in the dose of oxytocin is required to induce uterine contraction in a 7-week pregnancy compared to a full-term pregnancy.

In accordance with the changes in the sensitivity of the myometrium to oxytocin, the concentration of oxytocin receptors was low in the nonpregnant uterus, then there was an increase in their concentration in the 13-17 weeks of pregnancy and then a 10-fold increase in the gestation period of 28-36 weeks. Immediately before birth, the level of oxytocin receptors is further increased by 40%. In the early stages of pregnancy there is only a 2-fold increase in their concentration, and in childbirth the amount of oxytocin receptors in myometrium increases in ISO times compared to that of non-pregnant women.

It is important to note that the concentration of oxytocin receptors was significantly lower in those pregnant women in whom the induction of labor with oxytocin was without effect, as well as with a pregnant pregnancy.

The side effects of oxytocin on the part of the cardiovascular system when administered intravenously in large doses are minimal. However, cases of the development of water intoxication and encephalopathy are still observed as a result of forgetting the fact that oxytocin has an antidiuretic effect when used in large doses and that it requires strict control of fluid intake and electrolyte balance. Water intoxication is characterized by nausea, vomiting, anorexia, weight gain and lethargy. It is now generally accepted that intramuscular, nasal and oral routes of administration of oxytocin during labor are unacceptable and involve some risk of uterine rupture. The fact that prostaglandins significantly increase the sensitivity of the uterus to oxytocin is still not fully taken into account in obstetric practice and there are cases of uterine rupture in women who received full oxytocin doses after they were given prostaglandins to accelerate the maturation and expansion of the cervix.

A very large number of oxytocin analogs was synthesized and tested in the experiment. None of them showed clear advantages over oxytocin in clinical practice.

Contraindications for the appointment of uterotonic drugs are:

• discrepancy between fetal and pelvic maternity size (anatomically and clinically narrow pelvis);
• presence of a scar on the uterus after the transferred operations (caesarean section, removal of myomatous nodes, metro-plastic, etc.);
• fatigue of the woman in childbirth;
• incorrect positions and presentations of the fetus;
• intrauterine fetal suffering;
• complete placenta previa;
• abruption of normal and low-lying placenta;
• presence of stenosis of the vagina, scar after a healed crotch rupture of the third degree and other cicatricial changes of the soft generic pathways;
• cervical dystopia, atresia and cicatricial changes;
• allergic intolerance to oxytocytics.

The administration of oxytocin should be started from 0.5-1.0 mU / min, and if there are no signs of hyperstimulation or a threatening condition of the fetus at a thorough evaluation, it can be periodically increased the dose by 0.5 mU / min with a break of 20-30 min. In most parturients, the effect is observed with doses of oxytocin not exceeding 8 mU / min.