Parturition

Question 1

Parturition

Answer 1

Process by which conceptus is expelled from the uterus

• Fetus dictates when it comes out, not the mother
• Conceptus consists of: foetus, placenta & foetal membranes
• Parturition requires: simultaneous cervical remodelling & Co-ordinated myometrial contractions

Question 2

Stages of Labour

Answer 2

• 1st stage: Regular uterine contractions, cervical mucous plug removed, cervical shortens & dilates- can be particularly long in human/ bitch
• Latent phase: cervix slowly dilates to 3cm (human)
• Active phase: rapid dilation of cervix
• 2nd stage: complete delivery of foetus, rupture of membranes & abdominal contractions
• 3rd stage: placental expulsion

Question 3

Myometrial Contractions

Answer 3

Myometrium consists of smooth muscle fibres, nerves, blood & lymph

In pregnancy, oestrogens induce muscle cell hypertrophy (50 to 500μm) ↑ force of contraction

Muscle cells behave as a syncytium being electrically coupled via gap junctions–> simultaneous activation of all the SM cells –> coordinated uterine contraction

Question 4

How the Myometrium contracts

Answer 4

• Progesterone hyperpolarises the myometrial membrane–> harder to reach threshold potential (-50 mV)
• Spontaneous depolarizing pacemaker potentials occur-If magnitude of these potentials > critical threshold–> burst of APs is superimposed on the pacemaker potentials–> ↑ in intracellular Ca+2 occurs which binds to regulatory sites on actin & myosin allowing expression of ATPase activity–> contraction

Question 5

Direct Regulation of Myometrial Contraction

Answer 5

• Oxytocin – Lowers the excitation threshold of muscle cells
• Prostaglandins – Stimulates liberation of Ca+2 from intracellular stores

Question 6

Contraction- Frequency

Answer 6

• At onset of labour large contractions occur which progressively ↑ in frequency & amplitude
• Pressure ↑ from 10mmHg between contractions to 50-100mmHg

Question 7

Brachystasis

Answer 7

• Contractions –> retraction of the lower uterine segment & cervix upwards –>Creating a birth canal
• Myometrial cells undergo brachystasis (contract & shorten, but don’t regain original relaxed length)
• Uterine muscles retract, uterine wall thickens & uterine volume ↓–> forces the fetus out
• Uterus divided into 2 segments: Upper segment (contractions), Lower segment (passive, no contractions)
• Retraction ring= Junction between 2 segments- palpation provides ongoing index of labour progression

Question 8

Cervical Remodelling

Answer 8

• Cervix has high CT content: Collagen fibre bundles & proteoglycan matrix
• CT resists stretch, allows distension of body of uterus whilst maintaining cervix in a closed state
• Collagen is made up of helical strands of amino acids bound together to form fibrils
• For delivery, cervical remodelling is needed, divided into 4 distinct, but overlapping phases:

- Softening–> Ripening –>Dilation–> Postpartum repair

Question 9

Cervical Softening

Answer 9

• The process of softening starts during the first trimester (a measurable decrease in tissue compliance)
• Softening involves a gradual change in the intercellular matrix – NOT very well understood!

1. Reduction of collagen fibres
2. Structural changes to collagen: ↑GAG as pregnancy proceeds –> ↓aggregation of collagen fibres

• keratin sulphate (which does not bind collagen) increases the most
• dermatan sulphate (which binds very tightly to collagen) ↓

Question 10

Cervical Ripening

Answer 10

• For the fetus to move out of the uterus, the softened cervix must “ripen“ & subsequently “dilate”
• Cervical ripening occurs rapidly in the days before birth = maximal loss of tissue compliance & integrity
• It seems “like” a pro-inflammatory reaction:
• ↑ vascularization, Influx of monocytes, ↑ level of IL6 & IL8
• A GAG, high molecular weight forms of hyaluronan (HA) ↑ during ripening & as dilation gets underway, the low molecular weight forms of HA ↑ due to an ↑ in hyaluronidase

Question 11

Cervical Dilation

Answer 11

• Involves ↑ in: viscoelastibility, tissue distensibility, hydration, disorganization of the collagen matrix & levels of matrix metaloproteinases

Question 12

Hormonal Control of Cervical remodelling

Answer 12

• Prostaglandins are thought to regulate cervical softening – mechanism= unknown
• The cervix produces: prostaglandin E2 (PGE2), prostacyclin (PGI2). prostaglandin F2α(PGF2α)
• Production of prostaglandin increases at term and during parturition
• Application of PGE2 & PGF2α to the vagina or cervix induces cervical compliance
• PGs might facilitate cervical compliance by:
• Inducing collagen breakdown
• Altering GAG/proteoglycan composition
• Inducing leucocytic migration by causing release of IL8
• Nitric Oxide- another possible agent that induces cervical ripening as inhibition of iNOS prevents ripening & NO induces release of PGs
• Relaxin- essential for cervical softening in the sow- not absolutely essential in other species (tends to be PGs)
• CL= Major source of relaxin (↑ risk of premature delivery in women with multiple CL after superovulation)

Question 13

Regulation of Prostaglandins

Answer 13

• Uterus important site of prostaglandin synthesis, ↑ synthesis is required for parturition
• Oestrogen induces liberation of PLA2 from lysosomes (labilises lysosomal membranes) & ↑ number of endometrial oxytocin receptors (contractions cannot occur without these)
• Progesterone inhibits release of PLA2 (stabilises lysosomal membranes)
• ↑ oestrogen/progesterone ratio–> ↑ prostaglandin production

Question 14

Regulation of Oxytocin

Answer 14

• “Ferguson reflex“- neuroendocrine reflex –>self-sustaining cycle of uterine contractions:
• Fetus causes pressure on the internal end of the cervix –>signals PVN & SON of the hypothalamus–>oxytocin released from P.pituitary stimulates uterine contractions, which in turn ↑ pressure on the cervix–> oxytocin release (positive feedback loop)
• Oxytocin acts to: ↑ myometrial contraction (+ve feedback loop) & ↑ prostaglandin release

Question 15

Onset of Parturition

Answer 15

Removal of progesterone–> ↑ in oestrogen: progesterone ratio–> parturition

Question 16

Goat, Cow, Dog, Pig and Rabbit

Answer 16

depend on CL to produce progesterone throughout pregnancy

• Goat foetus must stop progesterone production by the CL to start parturition
• The foetal pituitary-adrenal axis determines the timing of onset of parturition

As the foetus grows in a restricted space it becomes stressed–> ↑ in foetal ACTH –>↑ in cortisol–> DHEA (androgen) synthesised & aromatising enzymes released–> ↑ oestrogen production by placenta

• Oestrogen–> ↑ PGF2α –>luteal regression (also causes ↑ contractions & cervical softening)

Question 17

Sheep, Guinea-pig, Cat, (horse)

Answer 17

depend on placental progesterone in later pregnancy

• Similar method to above: foetus becomes stressed, foetal ACTH is released & cortisol ↑
• ↑ in foetal cortisol induces 3 enzymes: 17α-hydroxylase, C17-C20 lyase & aromatase- these convert progesterone produced by placenta–> oestrogen therefore ↑ the oestrogen: progesterone ratio

Question 18

Humans

Answer 18

• Obtain progesterone from placenta but lacks the enzymes: 17β hydroxylase & C17-C20-lyase ∴ can’t convert progesterone–> oestrogen, can use fetal adrenals to make androgen substrates instead
• Progesterone levels don’t fall at parturition but progesterone receptor complement levels change. ensures that despite the level of progesterone being the same, the progesterone present can’t inhibit myometrial contractions
• PGs act to soften the cervix & ↑ uterine contractions (as in goat and sheep)

Question 19

Mare

Answer 19

• Hormone profile in pregnancy is very different to that in other species – no surprise!
• Progestagens ↑ during end stages of gestation whereas total oestrogens ↑ during pregnancy but appear to ↓ before parturition
• Cortisol ↑ only 2-3 days before parturition (in ewe, it is the last few weeks) believed to be the trigger for onset of parturition & other maturational changes (lungs, liver, gut etc)
• PG concentrations= ↓ during pregnancy & ↑ slightly towards term: However, PGFM increases 50-fold during 2-stage of labour.

Progesterone- major hormone only in 1st trimester- from mid gestation, it’s concentration is <1 ng/ml

• Other progestagens increase markedly at this time reaching concentrations between 5-50 ng/ml
• Fetus produces large quantities of pregnenolone–> placenta where its converted into progesterone action of 5α reductase DHP (5α pregnane-3,20-dione)
• DHP= major biologically active progestagen in the mare (binds more avidly than P4 to uterine PRs)

Oestrogens- The ↑ during pregnancy is not down to classical estrogens (estradiol, estriol, estrone)

• Instead, it is due the synthesis of large quantities of equine unique estrogens, equilin & equilenin

(synthesized from farnesyl pyrophosphate)

• Despite this, classical estrogens remain essential for the initiation of labour

Question 20

Ecbolic Drugs

Answer 20

**Oxytocin release!**

• PGF2α analogues- (Dinoprost, cloprostenol) –> induce cervical dilation & uterine contractions
• Oxytocin- induces uterine contractions & delivery of placenta
• Used in conjunction with oestradiol benzoate (induces oxytocin receptors)
• Oestradiol inhibits uterine activity but sensitises uterus to oxytocin

Horse: Calcium levels above 40 mg/dl or 200 ppm indicate mare has ↑ probability of foaling in the next 48hours.

Thick waxy exudate accumulates on end of teats 24-48hours prior to foaling

• can give Oxytocin (90min), but not prostaglandins (abdominal pain) or corticosteroids

Cow:

-can give corticosteroids and after prostaglandins

Pig:

-can give prostaglandin with oxytocin following

Sheep:

-corticosteroids

Dog/cat:

can give oxytocin (+anti-progestin)