16 – Parturition Flashcards
1
Q
Parturition definition
A
- Act of giving birth to young
- Ex. foaling, calving, farrowing, lambing, whelping, queening
2
Q
Key players involved in parturition
A
- Fetus (fetal hypothalamic-pituitary-adrenal (HPA) axis
- Fetoplacental unit
- Uterine musculature
3
Q
Fetal HPA provides a major input on
A
- Length of gestation
4
Q
Fetoplacental unit
A
- Fetal HPA and gonads
- Placenta
- Endometrium
5
Q
Uterine musculature (myometrium)
A
- Biochemical ripening of the cervix
- Transition from quiescent to powerfully coordinated contractile muscle
6
Q
Sheep model of parturition
A
- Factors that initiate birth and terminate pregnancy are likely MULTIFACTORIAL
- Major animal model used
o Mechanism not well understood in pig, horse, dog, cat
7
Q
Experiments in 1960s based on natural occurrences
A
- Herd of cows had prolonged pregnancy and a heritable disorder resulting in very small pituitaries and adrenal glands
- Pregnant sheep in Nevada mountains had no parturition or delivered at 200d (vs. 147d)=displacement or absence of pituitary
o Ingested a plant (Corn Lilly)=has teratogens (alkyloids)=cause malformations OF or WITHIN an embryo
8
Q
Activation of fetal HPA likely result of
A
- Development of critical synapses in hypothalamus
- Hypothalamus responding to placental hormones
- Fetal stressors (ex. BP, glucose)
9
Q
Increased cortisol concentrations in ewe within last 15-20 days of gestation
A
- Increased cortisol production from fetal adrenals that increase in size and response to ACTH
- **Fetal plasma ACTH levels rise in response to increased hypothalamic production of arginine vasopressin and CRH
o CRH can be produced by placenta
10
Q
2 ‘mechanisms’ of how increased fetal cortisol has implications for intrauterine prostaglandin synthesis
A
*cyclic fatty-acid hormone like compounds (starting block=AA)
- Estrogen-independent
- Estrogen-dependent
11
Q
Breakdown of AA by
A
- COX2: PGHS2(PG synthetase)
o Goes into PGF2 or PGE2
12
Q
Estrogen-independent prostaglandin synthesis
A
- Cortisol produced and stimulates placental trophoblast (PGHS 2) to produce PGE2
- PGE2 stimulates P450 enzyme
- Pregnenolone is converted into different steroids
o *DHEA: dehydroepiandrosterone
o Ultimately go into estrogen and get estrogen-dependent PG synthesis
13
Q
Estrogen-dependent prostaglandin synthesis
A
- Once estrogen produced by placenta (estrogen-independent PG synthesis) it will induce endometrium (maternal side): PGHS2
- Production of PGF2 produced=uterine contractility
14
Q
Feto-placental unit (pregnenolone ‘different’ pathways)
A
- Pregnenolone being used to get steroid hormones
- *shifting it from being produced to get progesterone to now get estradiol!
- *shift drives the drop in progesterone and increase in estradiol
15
Q
What is progesterone highly produced by in ruminants?
A
- CL
o So PGF2alpha may also luteolysis
o Also get PGF2alph from estrogen-dependent PG synthesis
16
Q
Estradiol production stimulates
A
- Production of CAPS (contraction associated proteins) including
o Gap junction proteins
o Oxytocin receptors
o Prostaglandin receptors
o Calcium channels
17
Q
Estrogens also stimulate and promote
A
- Stimulate cervical and vaginal mucous secretion for lubrication to aid birth
- Promotes cervical ripening
18
Q
Prostaglandin effects on myometrium and cervix
A
- Depends on which receptors it binds to (PGE2 and PGF2alpha)
o Slightly different pathways with different consequences - *different receptors in myometrium and cervix for both PGE2 and PGF2alpha)
19
Q
Receptors that cause increased myometrial contractility
A
- PGE2: EP1 and EP3
- PGF2alpha: FP
20
Q
Ferguson’s reflex
A
- Uterine contractions of parturition forces fetus toward cervix and vagina
- Stimulate pressure sensitive neurons in cervix which synapse with neurons in hypothalamus
o *leads to increased oxytocin secretion and cycle of greater contractions with greater pressure on cervix (+ FEEDBACK!)
21
Q
Oxytocin effects on uterus (myometrium and endometrium)
A
- Binds to myometrium receptors and stimulates myometrium to increase intracellular Ca levels=binding of actin-myosin=smooth muscle contraction
- Bind to receptors in endometrium=stimulate PGF2alpha synthesis and secretion=even more uterine contractions
22
Q
Myometrial contractile activation
A
- Needs to be electrically and metabolically coupled
o Increase in gap junction production and communication just prior to and during labour - *genetic studies how removal of Cx43 gap junction gene IMPAIRS parturition
23
Q
Fetal growth-induced uterine distension
A
- Growth distends uterus and stimulates expression of CAPs that aid parturition
o Cx43 (GJ protein)
o Oxytocin receptors
o Prostaglandin receptors - *primes myometrial cells to be properly adhered to one another and promote COORDINTED contractions
24
Q
Sow parturition
A
- Unclear of fetal participation
- Estrogens probably not involved in stimulating release of PGs
- Exogenous estrogens do NOT induce farrowing
25
Mare parturition
- Progesterone levels in last 3rd are very LOW
o Progestogens are responsible for uterine quiescence
- Progestogens in maternal plasma drop with increasing fetal cortisol levels
- Mare uses fetal gonads to a larger extent to supply androgens (DHEA) for estrogen biosynthesis
o NOT progesterone or pregnenolone
o Equine placenta lacks P450 C17 hydroxylase activity
- *fetal gonads are bigger contributor to fetoplacental unit than adrenals in equine
26
Progestogens
- Metabolites of P4 and pregnenolone
27
Dog parturition
- No fetal cortisol secretion data
- Rapid decline in maternal P4 prior to birth with increased released of PGF2alpha from placental trophoblast (PG may not be luteolytic)
- Maternal oxytocin levels indicate it is NOT responsible for initiating parturition
28
Cat parturition
- Domestic cats: PG levels in plasma unreported
- Wild cats: indicated increases (fetal levels) toward parturition
- Estradiol levels peak 1 week before parturition and decline markedly by labour
29
Overview of impact of endocrine events on parturition
- Fetal hypothalamus
o Receive signals to become mature (stressors, axis of hypothalamus, estrogens from placenta)
- Signals form hypothallus activate pituitary
- Get ACTH production
- Adrenals release steroids (ex. cortisol)
- Cortisol improves fetal maturation (ex. lungs) and decrease in placental PG production->shift to estrogen production
o Increased gap junctions and expressions
- Estrogen production effect on myometrium-> release of PGF2alpha (can bind to EP4 receptors in cervix=softening) (maybe also release relaxin)
o Effect on contractility and luteolysis of CL (species dependent)
o Fetus towards cervix and vagina (+ abdominal straining)
o Ferguson’s reflex (oxytocin production)
30
Impact of endocrine changes on fetal maturation
- Stimulate closure of ductus arteriosus and foramen ovale
- Maturation of fetal lungs
- Glucose homeostasis
- Maturation of thyroid gland
31
Maturation of fetal lungs (impact of endocrine changes on fetal maturation)
- Production of alveolar surfactant: stimulated by fetal cortisol form adrenals
- Resorption of fetal fluids by lungs stimulated by adrenaline from fetal adrenal glands
32
Glucose homeostasis (impact of endocrine changes on fetal maturation)
- Accumulation of liver glycogen stores in late gestation: stimulated by fetal cortisol
33
Maturation of thyroid gland (impact of endocrine changes on fetal maturation)
- THs altered to enhance biological activity
34
Phases of parturition
0. Quiescence (95%)
1. Activation
2. Stimulation
3. Involution
35
Quiescence period (phase 0)
- 95% of gestation marked by myometrial quiescence and non-dilated cervix
36
Activation period (phase 1)
- Softening of cervix
- Myometrium becoming prepared for contractions with increased CAPs (GJs, PG receptors) and uterine factors (PGs, E2)
37
Stimulation period (phase 2)
- Increased contractility
- Large surges of PG and oxytocin release
- Dilation of cervix
- Delivery of fetus
38
Involution (phase 3)
- Afterbirth delivered
- Uterus and cervix begin to be remodeled back to non-pregnant stage
39
Why would you need to terminate a pregnancy?
- Mismating
- Twins in mares
- Risk to dam’s health
- *straight forward in some species (ex. pigs and goats)
40
Pigs: pregnancy termination
- Terminated at any stage with PGF2alpha
o Repeated injections may be needed
41
Goats: pregnancy termination
- Terminated at any stage with PGF2alpha
42
Cows: pregnancy termination
- Terminated from 4-100d (maybe 150d?) post-ovulation with PFG2 alpha
- After 150-270d: long-acting corticosteroids +/- PGF2alpha required
o Due to placental contributions of progesterone
43
Sheep: pregnancy termination
- 4-12d: PGF2 effective
- 12-21d: resistant, maybe due to protective effects of IFN-tau
- Over 45d, placental progesterone production increase and predominates: progesterone antagonists OR corticosteroids would be necessary
44
Cat: pregnancy termination
- IM injection of estradiol cypionate within 40h of mating (inhibits tubal transport)
- PGF2alpha can be effective to induce abortion
- Aglepristone effective in mid-pregnancy
45
Dog: pregnancy termination
- Tactical use of estrogens within 5 days of mating inhibits transport of zygotes from oviduct to uterine horns
- PGF2alpha 10-14d
- Progesterone receptor antagonists are more effective and acceptable for termination
46
Horse: pregnancy termination
- 1-35d administer PGF2alpha or analogue to induce luteolysis
o Optimally: 10-15d after mating
47
Horse: TWIN pregnancy termination
- Surgical removal (high risk of remaining fetus and mare)
- Ultrasound guided injection of fetus
o Procaine Penicillin G (PPG) into fetal thorax or abdomen (30-60% success rate)
