Cervical Softening

Introduction

The basic function of the cervix during pregnancy is to retain the foetus within the uterus and to maintain the internal environment of the uterus by preventing the external environment accessing the uterus. Therefore the cervix regulates the passage to and from the uterine cavity. This ensures that any micro-organisms within the external environment are unable to enter the uterus. During pregnancy the uterine body becomes distended whilst stretch resistant tissues allow the cervix to be maintained in a closed state. For the foetus to move out of the uterus, the cervix must soften or 'ripen'.

Cervix Structure

The cervix has only a small amount of musculature and is mainly composed of collagen fibre bundles and proteoglycan matrices. The collagen fibres are helical strands of amino acids bound together to form fibrils whilst the proteoglycan matrix are made up of a protein core with glycosaminoglycan branches or GAGs. GAGs determine the degree of collagen fibre aggregation. An increased GAG content reduces collagen aggregation and vice versa.

The texture of the cervical tissues is influenced by the relative levels of oestrogen and progesterone and therefore are changable dependant on the stage of the oestrous cycle. The mucous membrane of the cervix is highly folded and contains mucin producing cells. Mucin production increases under the influence of oestradiol and helps to lubricate the vagina in preparation for copulation. Mucin is also responsible for the transport of bacteria and foreign bodies away from the uterus. During the luteal phase and during pregnancy small levels of mucin are produced under the influence of progesterone to help form a 'cervical plug'. This plug ensures that the external environment is unable to penetrate the uterus.

Cervical Species Differences

In ruminants the cervical mucus is expelled from the vagina during oestrous and is known as 'bulling string'. Bulling string therefore indicates that animal is in oestrous and should be mated. For further differences between species please see; mares, ewe, goat, sow, bitch and the queen.

A number of variables during pregnancy lead to the initiation of contractions of the myometrium including oxytocin, prostaglandins and neural inputs from the autonomic nervous system. These contractions of the myometrium lead to an increased pressure within the amniotic fluid and trigger a series of events that lead to the cervix becoming flexible and gradually beginning to dilate. As the force of the contractions increases, the cervix will open completely. Much of the activity related to the initiation of contractions is begun by fetal stress resulting in an increased production of fetal cortisol. The effects listed below are all linked to the initial increase in fetal cortisol in some way.

Endocrinology

Immediately prior to birth, the pre-parturition cervix loses firmness. Cervical softening involves two changes in the intracellular matrix; firstly a reduction in the number of collagen fibres and secondly an increase in GAGs to decrease aggregation of the remaining collagen fibres.

Several hormones are known to exhibit an effect on the cervix resulting in pre-parturition softening; 'prostaglandins' and 'relaxin'. Prostaglandin levels increase markedly in the days prior to parturition, peaking at parturition. There are three main types and sources of prostaglandin that are important in cervical softening; prostaglandin E2 (PGE2), prostacyclin (PGI2) and Prostaglandin F2α (PGF2α).

PGF2α is produced by the placenta in response to the production of fetal corticoids. (PGF2α also helps to remove the progesterone block pre-parturition.) PGF2α is not thought to act directly on the cervix and instead causes the myometrium of the uterus to become more active resulting in increased cervical stimulation and therefore softening and dilation.

PGE2 is maternally derived and is the main driver of cervical softening. The production of PGE2 coincides with reductions in progesterone levels. PGE2 also acts on the uterus resulting in increased myometrial contractions, increased uterine pressure and therefore also cervical stimulation.

PGI2 is also maternally derived and acts as a vasodilator and as an anticoagulant, playing another important role in cervical relaxation.

With all types of prostaglandin, isoforms are produced locally and act locally and are therefore not strictly classed as hormones.

Relaxin is produced by the ovaries and the placenta and together with progesterone prevent uterine contractions throughout the pregnancy. However, relaxin also aids in the loosening of tissues in the cervix and pelvic ligaments to loosen pre-parturition. Relaxin and PGE2 work in combination on the cervix.

Progesterone Production

The initiation of myometrial contractions via fetal cortisol results in cells within the uterus and the placenta undergoing a degree of stretch. This stretching is thought to activate several systems within the cells resulting in the production of progesterone. Stretching can increase the availability of cyclo-oxygenase 2 or COX-2, which is part of a chain of reactions converting arachadonic acid to PGE2 and PGF2α resulting in an increased cellular output. Both of these types of prostaglandin potentiate oxytocin once outside the cell and this in turn potentiates an increase in the level of arachidonic acid, thus scaling up production in the entire system. Secondly the stretching within the cell also results in increased expression of oxytocin receptors in the cell surface resulting in a greater impact on the cell for a given level of oxytocin, further upregulating the system.

Outside the cell, levels of oestradiol are also increasing and this also has an impact on the systems behind the production of prostaglandins. Oestradiol increases the availability of COX-2 within the cell and also the expression of oxytocin receptors providing a further mechanism to increase the total prostaglandin output of the cell.

Softening Mechanisms

It is thought that prostagladins together with relaxin may induce cervical softening by inducing collagen breakdown within the tissues and/or by altering the GAG/proteogylcan composition. Collagen breakdown within the tissue would facilitate a higher degree of movement and stretch in the tissue which is required for softening. Similarly, an increase in the GAG content of the tissues stimulated by prostaglandin would result in a decrease in collagen fibril agglutination therefore reducing the stretch-resistance of the remaining collagen.

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