Physiology of the uterine muscle during labor

The uterus in prepared for labor by progressive morphological and functional changes during pregnancy (chapter 13). Hypertrophy and dilatation (with limited appearance of new muscle cells) as well as changes in connective tissue, blood vessels, lymphatics and nerves have, beyond accommodation of fetus, one major aim: to make ready the organ for the work and mechanics of delivery. There is a high degree of morpho-functional integration: muscular cells are changed, the whole environment is adapted and the connective tissue ensures the transmission of contraction.

Estrogens stimulate uterine hyperplasia / hypertrophy. Together with progesterone and chronic myometrial stretching (due to the fetal growth), they stimulate actomyosin and collagen synthesis in a synergic manner.

I. Myometrial cell at term

At term, the myometrial cell is hypertrophied (500m in length), has an ectopic nucleus and, importantly, myofilaments consisting of actin and myosin. The plasma membrane contains gap functions (for intercellular communication for synchronization) and 3 type of receptors:

Type I   - ion channels;

Type II   - GTP-binding protein as transducer; inositol triphosphate, diacylglyceride or arachidonic acid as second messenger;

Type III   - enzymatic.

II. Cellular bases of contractile activity

Myosin is made of multiple light and heavy chains disposed in thick myofilaments. Calmodulin (a calcium-binding regulatory protein) binds Ca²⁺. The resulting complex activates the myosin light-chain kinase, which phosphorylates inactive light-chain myosin (20kd) into the active P-myosin light chain (fig. 18.1).

Myosin light chain

Myosin light-chain kinase

(Ca²⁺ activated - calmodulin)

P-Myosin light chain

Ca²⁺ Troponin Tropomyosin Actin

P-Actomyosin (ATPase)

ATP ADP

Figure 18.1. Molecular bases of contraction

Ca²⁺ stimulates conversion of troponin in tropomyosin, which prepares actin. P-myosin interacts with actin. The resulting molecule, P-actomyosin, is an ATPase that catalyses ATP hydrolysis and liberation of energy, therefore contraction force.

III. Control of myometrial contractility

There is a multifactorial initiation and control of uterine contraction:

Intracellular free Ca²⁺ Ca²⁺ _i) is essential for myometrial contraction: modulation of myosin light-chain kinase and conversion of troponin. The decrease of calcium concentration promotes myometrial relaxation. Ca²⁺ _i is regulated by:

cell membrane channels-receptor / voltage-mediated;

cell membrane Na⁺-Ca²⁺ exchange pump;

cell membrane calcium ATPase system;

cell membrane and sarcoplasmic reticulum active Ca²⁺ pumps;

cAMP and cGMP, which decrease Ca²⁺ _i

Estrogens are necessary for myometrial receptor expression and intracellular calcium release. On the opposite, progesterone stimulates calcium uptake by the sarcoplasmic reticulum.

Oxytocin is a nanopeptide - the most specific uterotonic hormone. It is synthesized in the magnocellular neurons of the supraoptic and paraventricular neurons and transported, as prohormone, bound to the carrier protein (neurophysin), through neural axons to the posterior pituitary gland. During transport, the prohormone is converted enzymatically to oxytocin. It is, consecutively, stored in membrane-bound vesicles for later release. Oxytocin has a specific receptor, which is present in myometrial cells after 12-13 weeks and increases to its maximum at term. Oxytocin opens voltage-mediated calcium channels and prevents the sarcoplasmic calcium uptake, thus increasing Ca²⁺ _i and promoting contraction. It also stimulates prostaglandin release.

Endothelin-1 acts similarly in way and magnitude with oxytocin, by opening the voltage-mediated calcium channels and promoting prostaglandin release.

Prostaglandins have two ways of action:

PGE₁, PGE₂ and PGF_2a (each with a specific receptor) alter membranes permeability for calcium and increase Ca²⁺ _i. On the opposite, PGD₂ and PGI₂ (through specific receptors which use GTP-binding proteins) activate intracellular adenyl cyclase, which increases CAMP and, subsequently, reduces Ca²⁺ _i

Concerning modulation of the gap junction formation, PGE₁, PGE₂ and PGF_2a promote it (whereas PGI₂ inhibit it).

Gap junctions play a key role in the coordination (thereby increasing the force) of the contraction. Their structure has been described in chapter 13. They significantly increase before labor (promoted by estrogens, PGE₁, PGE₂ and PGF_2a). Progesterone antagonizes estrogen effect.

Parathyroid hormone-related protein is increased, especially in the uterine horns at term. It may stimulate local blood irrigation and uterine contraction, through activation of adenylcyclase.

Calbindin D - 9 K is increased and plays a role in calcium transport.

Transforming growth factor- is increased and stimulates PTH-rP.

IV. Initiation of labor

During the last trimester of pregnancy, the process of cervical maturation is accelerated, under the influence of the relaxin, placental hormones and PGE₂. During the last weeks of gestation, there is an increased production of PGE₂ and oxytocin receptors. The concentration of oxytocin receptors increases with uterine distention. Concomitantly, there is increase in the number of myometrial gap junctions. As a result of the increase in oxytocin receptors and myometrial gap junctions, the myometrium becomes more reactive to the oxytocin pulses secreted by the posterior pituitary, which then causes an augmentation in the frequency and intensity of the contractions. The uterine contractions generate greater pressure on the cervix, which further increases the production of PGE₂. This results in an increased frequency of oxytocin pulses with subsequent more frequent contractions (Ferguson reflex). The decidua also reacts to oxytocin by secreting PGF₂, which increases the myometrial response to oxytocin.

At this point, placental and fetal maturational changes - as well as, possibly, the stress of the transient fetal hypoxia related to the higher uterine contractility - induce the secretion of a high number of substances, from several organs. This includes epidermal growth factor, platelet-activating factor, adrenocorticotropic hormone, stress hormones, vasopressin and increased amounts of oxytocin. There is a resulting greater mobilization of arachidonic acid from the uterine phospholipids with a subsequent increase in prostaglandin secretion from the placental membranes, especially during the contractions. Prostaglandins, in turn, further stimulate the uterine contractility. The circle closes - and this continuous self-enhancing cycle results in the initiation and sustaining of labor.

V. Myometrial contractility

Cellular, anatomical and physiological characteristics of myometrial muscle induce unique features for increasing the efficiency of uterine contractions and of the delivery mechanics:

The contraction may be of one order of magnitude greater than that attained in striated muscle cells;

Forces can be exerted in any direction;

Intracellular arrangement of thin and in thick filaments / long, random bundles induces greater shortening / higher force-generating capacity;

The network disposal and the spindle shape of the myometrial cells allow multidirectional force generation.

VI. Uterine contractions during labor.

During labor, uterine contractions have some unique characteristics among physiological muscular contractions, which represent some main labor diagnostic and monitoring criteria:

Uterine contractions of labor are painful. The causes of the pain are:

hypoxia of the contracted myometrium (as in angina pectoris);

compression of nerve ganglia in the lower uterus and cervix;

stretching of the cervix during dilatation;

stretching of the peritoneum overlying the fundus.

Uterine contractions are involuntary.

The interval between contractions diminishes gradually from about 15-20 minutes before labor (false labor), 10 minutes at the onset of the first stage of labor to as little as 2 minutes or less during the second stage.

The duration of each contraction progressively increases and ranges, in the active phase, 30-90 seconds, averaging about 50 seconds.

The intensity of uterine contractions gradually rises (on average). From around 20 mmHg before labor (Braxton Hicks), the intensity (25 mmHg at the beginning of labor) augments to about 40 mmHg, with variation from 20 to 60 mmHg. It is elevated to 100-140 mmHg during expulsion (also increased by maternal abdominal muscles during pushing) and even more, to 250 mmHg, in the immediate puerperium.

Uterine relaxation between contractions is essential to the fetal welfare, as it significantly influences uteroplacental and fetalplacental blood flow. Baseline pressure increases from latent labor (less than 5 mmHg), but it should remain beneath certain values: less than 12 mmHg during the active phase and less than 20 mmHg during the second stage of labor.

VII. Differentiation of uterine activity during labor

Uterine contractions have a necessary downward direction. The decreasing contractile activity from fundus to cervix is necessary for a greater contractile force and for the obvious directing of fetus towards the birth channel. From this point of view, the uterus expresses two morpho-functional different parts:

The upper, active, segment contracts, retracts and becomes thicker as labor advances. Successive contractions begin where the previous ones finished and, through progressive retraction, uterine walls keep contact with the fetus. The upper uterine segment becomes maximally thickened immediately after fetal expulsion.

The lower, passive, portion is made of the lower uterine segment and the cervix. It progressively develops during pregnancy from the isthmus, to a thin (few millimeters in the thinnest part), distended channel for the fetus. The relaxation is, however, not complete - and the progressive stretching with subsequent lengthening is accompanied by a constant tension in the muscular fibers.

The synchronism between the two uterine portions during labor is essential. While the lower segment is distended because of the pressure exerted by the fetus - pushed by the upper segment, this latter one can only contract / retract if the lower uterine portion allows it. It follows, by lower segment distension / cervical dilatation, the fetal passage.

Because of the significantly different morphological changes in the two portions, the physiological retraction ring (a ridge between the two segments) appears on the inner uterine surface.