What are the physiological (vs. hormonal) mechanisms of intitiation of parturition in domestic & companion animals, involving especially the uterus.
Myometrial (uterine) hypertrophy of myometrial muscle - 50 to 500 micrometers
Myometrial contraction - lowering of action-potential threshold by oxytocin, increase of intracellular Ca++ by PGF2a, syncytium formation
Brachystasis - uterine muscles retrac & shorten, not regaining their original length, so uterine walls thicken but volume reduces
Cervix softens - more GAGs, less collagen caused by PGE2
Outline in brief the Ferguson Reflex.
Neuroendocrine reflex comprising the self-sustaining cycle of uterine contractions initiated by pressure at the cervix or vaginal walls by the stressed foetus. It is an example of positive feedback in biology.
In the mother: Pressure on the mother's cervix by the foetus triggers oxytocin synthesis by the mother's hypothalamus & secretion by the posterior pituitary gland. Oxytocin stimulates uterine contractions, which in turn increases pressure on the cervix (thereby increasing oxytocin production, etc.), until the baby is delivered.
Sensory information regarding mechanical stretch of the cervix is carried in a sensory neuron, which synapses in the dorsal horn before ascending to the brain, then via efferent fibre to the hypothalamus. The posterior pituitary releases oxytocin due to increased firing in the hypothalamo-hypophyseal tract.
Oxytocin acts on the myometrium, on receptors which have been upregulated by an increasing estrogen-progesterone ratio. This causes myometrial contraction and further positive feedback on the reflex.
The Ferguson Reflex is only concerned with what happens in the mother during parturition. The stressed foetus's release of ACTH & cortisol is considered separately, although it causes the increase in the oestrogen-progesterone ratio and upregulating of the OTRs in the myometrium.
How does the foetus initiate parturition and enable the physiological mechanisms that take places as a result of oxytocin release in the Ferguson Reflex?
Foetal stress due to pressure in the uterus causes the foetus's anterior pituitary to release ACTH, which triggers cortisol release by the foetal adrenal glands.
The rise in cortisol causes placenta via three enzymes to convert progesterone into androgen substrates that are converted again into oestrogen before they re-enter the mother's circulation.
Thus the oestrogen:progesterone ratio is increased, upregulating the expression of OTR in the mother's myometrium. These OTRs bind with oxytocin released by the mother.
Oxytocin reduces the membrane potential threshold needed to trigger an action potential, so myometrial contractions can occur more quickly (shorter refractory periods).
The increase in plasma oestrogen caused by the enzymatic conversions of placental progesterone also destabilize lysosomes, which then release phospholipase A2 in cell membranes for formation of prostaglandins PGE2, PGF2a & prostacyclin. NB progesterone stabilizes lysosomes.
The increase in prostaglandins increase intracellular calcium-ion concentrations, which bind to troponin-C and form many actin-myosin cross-bridges in myometrial muscles, increasing the force of contraction, leading to brachystasis & formation of retraction ring.
Prostaglandins, PGF2a & esp. PGE2, soften the cervix by increasing the GAG-collagen ratio in the proteoglycans matrix.
In animals such as goats, dogs, humans and cows in which the placenta doesn't take over the production of progesterone in pregnancy, how does the placenta convert progesterone to oestrogen?
The placenta converts progesterone produced by the CL in goats, pigs , dogs and cows into oestrogens.
In these cases, the placenta uses foetal DHA (dehydroepiandrosterone), formed by the foetus from conversion of CL progesterone, to make oestradiol and oestrone.
Foetus converts CL progesterone into foetal DHA → Placenta converts foetal DHA to oestrogen using aromatizing enzymes.
How does the placenta convert progesterone produced by itself in sheep, horses, cats & guinea pigs (the placenta takes over P4 production from the extended-life CL in these animals).
Under control of increased foetal cortisol, three enzymes convert placental & foetal progesterone or androgen substrates into oestrogen for the maternal circulation:
17a-hydroxylase - converts progesterone from placenta to 17a-hydroxyprogesterone in foetus
C17-C20-lyase - converts 17a-hydroxyprogesterone into Dehydroepiandrosterone (DHEA or DHA, from adrenal gland), which is converted to oestradiol & oestrone in the placenta.
Aromatase - converts 16a-hydroxyandrostenedione from the foetal liver into oestriol in the placenta.
What pharmacological intervention would you use to dilate a pregnant animal's cervix, increase uterine contractions or induce delivery of the placenta?
Normally, prostaglandins PGF2a & PGE2 soften the cervix by increasing the GAG content in proteoglycans matrix, preventing aggregation of collagen.
Both oxytocin & prostaglandings help increase myometrial contractions.
Cortisol increases oestrogen levels relative to progesterone, leading to more OTR in myometrium and prostaglandin production. So:
Dinoprost & Cloprostenol - used in sows & cows, not used in sheep, dogs, cats or guinea pigs; used after cortisol in cows
Used in cows & sheep; used prior to prostaglandins in cows
Oxytocin & analogues:
Oxytocin + oestradiol benzoate: Oestradiol inhibits uterine activity but sensitises uterus to oxytocin (↑ OTR); used in mare, dog, cat & guinea pig
Ergot alkaloids (act like oxytocin) - induce contraction; vasoconstrictors; not used in UK