Stress and Pregnancy Flashcards
What happens during pregnancy to stress hormones and precursors? Where is it produced?
CRH increases thousand fold from 8-10 weeks. The CRH produced is not from the hypothalamus, but from the placenta, decidua and fetus. The rise in maternal plasma CRH leads to increased maternal cortisol.
What happens to the accompanying CRH binding protein?
• CRH binding globulin is also raised until the 2nd or 3rd semester which limits the free CRH. Binding protein sequesters the hormone as it stops it from binding to its receptor. Corticosteroid binding globulin (CBG) is stimulated by estrogen, so levels are raised during pregnancy
What happens towards the end of pregnancy?
• Towards the end of pregnancy the ratio of CBG to free cortisol changes – probably due to displacement by progesterone and 17-OH-progesterone
What happens literally just before birth?
• A transient peak is seen in free cortisol just prior to birth – may signal the onset of parturition
What is the effect of cortisol on progesterone and other effects?
Cortisol is an endogenous inhibitor of the activating effect of progesterone upon prostaglandin-degrading enzymes.
Prostaglandins interfere with the maternal uterus and can be used to initiate abortions.
The peak in cortisol may allow the activation of prostaglandin signalling for the onset of parturition.
What evidence is there for the effect of cortisol on parturition?
Evidence: Intravenous infusion of antalarmin (a CRH receptor antagonist) to fetal sheep significantly delayed parturition
What does the peak in cortisol just before birth allow? Why is this clinically important
• 36/37 weeks foetal lungs not mature, glucocorticoids play a key role in developing them
• In the lungs, surfactant decreases surface tension in the alveoli and allows efficient gas exchange
• The peak in GCs seen during late gestation is essential for lung maturation, as they promote surfactant production
• The primary cause of death for premature infants is respiratory distress (RD) due to insufficient surfactant
• Antenatal GCs, given 2-7 days before preterm delivery, significantly decrease the incidence of infant RDS and death
• Synthetic GC treatment is now routine - 10% of all births
Glucocorticoids are needed for differentiation
In rats, what happens just after birth? Evidence?
- Just after birth until post natal day 14, rats have very low basal corticosterone
- Stressfull stimuli that would cause a full response in adults have a blunted effect in neonates, e.g. injecting LPS versus saline
- Serum ACTH concentrations in immature and adult rats determined 20 min after laparatomy stress or in untreated controls, n = 6-8
- The SHRP is not a stress non-responsive period - an increase in circulating corticosterone can still be induced by a sufficiently powerful stimulus
- Rats are precocious, i.e. significant brain development occurs after birth
- The SHRP is a protective phase which ensures that the developing individual is not s hazardous and may have important long-term consequences to health
Why is the stress hyporesponsive period important in rats?
- Rats are precocious, i.e. significant brain development occurs after birth
- The SHRP is a protective phase which ensures that the developing individual is not s hazardous and may have important long-term consequences to health
What are three potential mechanisms of the SHRP in rats?
Pituitary ACTH Release
Hypothalamic lesion
Enhanced glucocorticoid feedback
What happens in the rat model of pituitary ACTH release for SHRP?
Pituitary ACTH release increases linearly with age. Pituitary CRH binding sites – actually seems to decrease with age and neonates seem to have more than more developed. The ability of Pituitary to bind CRH is maintained throughout puberty and adulthood. Have ACTH and the pituitary is responsive to it.
What about in the hypothalamic lesion theory of SHRP in rats?
The hypothalamic PVN CRH mRNA content in rats decreases at birth then increases the first week afterwards. Hypothalamic CRH content remains low during the SHRP and then increases with age. During this period, stress in the form of a saline injection can still stimulate a CRH response in the hypothalamus in the absence of any increase in plasma of ACTH or corticosterone.
Generally what happens in the early stages of pregnancy versus the late stage?
Early is growth, late is maturation/ differentiation
What three ways is the foetus protected?
a) Cortisol binding globulin (Maternal)
b) Placental 11β-hydroxysteroid
dehydrogenase (Maternal/Foetus interface)
c) GR levels (Foetus)
What is prematurity in terms of the UK
<37 weeks, 13% pregnancy. Increasing perhaps due to increasing maternal age/ number of pregnancies
How does enhanced glucocorticoid feedback in the SHRP work?
Injection of a subcutaneous GR antagonist during the SHRP causes a dramatic increase in ACTH and corticosterone release (no negative feedback) implying there is increased sensitivity of the axis. Administration of a GR antagonist during the mouse SHRP:
Decreased GR expression in the PVN
Decreased GR expression in the hippocampus
Increased POMC expression in the anterior pituitary
Suggests a high, tonic level of negative feedback inhibition by GCs during the SHRP
Low corticosterone + low corticosteroid binding globulin
= high free corticosterone
Young rats have much more sensitive pituitary glands:
- IC 50 – the amount of dexamethasone required to reduce ACTH secretion by 50% through negative feedback.
How can the mother affect the SHRP?
• 24 hours of maternal deprivation led to a significantly increased corticosterone response to ACTH injection compared with non-deprived pups during the SHRP
• Increasing periods of maternal deprivation on P7 led to steadily rising basal corticosterone, and a proportionately greater stress response to saline injection
• Separation has been shown to have significant effects in the brain at P9
- Decreased GR and MR expression in the hippocampus and hypothalamus
- Increased basal ACTH and corticosterone
• Stroking pups reversed the effects of maternal separation on ACTH and MR mRNA, but had no effect on GR – suggesting a role for maternal contact
Do humans have a SHRP?
- Most of the experiments done have been in rats that are precocious animals meaning a large part of their development occurs after birth
- Unclear whether that humans have an SHRP
- Vast majority of human organ development occurs during pregnancy. SHRP could potentially occur in utero
Why can steroids readily cross the placenta? Protected by? Positive and negative regulators
Because they are lipophilic. placental trophoblasts of the enzyme 11β-hydroxysteroid dehydrogenase type 2. • The barrier to maternal GCs provided by 11β-HSD II is not complete – some maternal GCs can get across
• If the mother is stressed, 11β-HSD II can become saturated, and the fetus can be exposed to high levels of GCs since the barrier becomes saturated
• The efficiency of human and rat placental 11β-HSD II varies considerably, and seems to correlate with birth weight, although whether this is cause or effect is unclear
Some of the most important negative regulators are: Estrogen, Inflammatory cytokines, Hypoxia. Positive regulators include maternal stress and GCs
How do maternal and foetal blood come into contact with each other?
Intervilla space: Have maternal spiral arteries interweaving with intervilla space, as well as terminal villa of the placenta. Allows the transfer between maternal and foetal blood. Cortisol very lipid soluble meaning cortisol can easily diffuse across.
What are the problems with synthetic glucocorticoids?
Synthetic GCs;
- Do not bind to CBG
- Poor substrates for 11b-HSD II
Therefore foetus may be exposed to high levels of
glucocorticoid
What evidence is there for long term effects of glucocorticoids crossing the placenta?
Looking at PEPCK levels (important in gluconeogenesis), much higher in foetus exposed to dexamethasone controls
What happens with glucocorticoid receptors in the foetus during pregnancy?
High numbers of GR means very high negative feedback, meaning very small amounts of cortisol
GR only in brain
As you approach term, amount of glucocorticoid increases for differentiaion so GR in brain numbers decrease later in term.
At term in guinea big, decrease in GR dramatic
This is for Foetal HPA activation, ↑ foetal adrenal GC production
How does glucocorticoids in utero affect blood pressure?
Males are far more responsive and increase BP, and recover far more slowly.females, also take longer to recover. INJECTED AMPHETAMINE TO INDUCE A SNS RESPONSE/ RESTRAINING RATS THEN POST RESTRAINT
- ↑ renal Na/K-ATPase (so more sodium reabsorbed, water follows osmotic gradient)
- ↑ AT1 and AT2 receptor expression
- Altered coronary responsiveness
What effect does GC in utero have on 11bHSD?
Increases 11bHSD relative mRNA expression in subcutaneous fat that is linked to visceral adiposity
What are the effects of GC in utero on behaviour?
Higher GC during pregnancy are linked to increased anxiety in adulthood, seen by less time/ grid crossings spent in the open field.
Additionally, more CRHmRNA (anxiolytic hormone) in the fear centre of the brain, the AMYGDALA.
What happens in pituitary ACTH content with age?
Increases linearly from throughout pregnancy.
What is the risk for the foetus in terms of centiles and birth weight?
Baby at increased risk if it moves up centiles as grows. This implies that baby was genetically programmed to be larger, but was born in a stressful/ low nutrition period and thus fetal programming would have occurred. Also increased risk are babies who are born very long but not very wide, implying that their growth in utero was compromised. But it is a U-shaped curve with increased risk for very large babies as well.
Other than endogenous glucocorticoids, how might a mother in pregnancy be affected?
Women have more symptoms of depression and anxiety during pregnancy than post natally, not much media attention compared to post natal depression. 10-15% of mothers affected.
How common are neurodevelopmental disorders?
More than 1 million children in UK suffer from neurodevelopmental disorders, 8% of females and 11% of males.
How might some of the changes be happening in utero?
More than 1 million children in UK suffer from neurodevelopmental disorders, 8% of females and 11% of males.
What behavioural outcomes are associated with maternal stress?
If mother stressed, child more likely to be bullied at school – victimization. Many behavioural issues, but also mixed handedness (involved in many neurodevelopmental disorders), altered finger print pattern, decreased telomere length (leading to reduced longevity), ASTHMA, ALTERED IMMUNE FUNCTION, reduced birthweight and gestational age.
What was a key study for glucocorticoids in utero and pregnancy?
ALSPAC – large prospective birth cohort about 14000 pregnant women recruited around Bristol 1990-1991 and then detailed information on the children up to 13. Maternal anxiety and 18 and 32 weeks of pregnancy, compared children of 15% most anxious or depressed mothers with the rest. Good because has data for all the confounders eg maternal postnatal anxiety and depression as well as paternal, parenting, maternal age, birth weight, gestational age, smoking, alcohol and psychosocial factors such as crowding.
A clinical doubling of the risk after all the confounders have been taken into account . For top 15% of most anxious/depressed women in pregnancy, rate of probable mental disorder
• doubled from about 6 to 12% at age 13 years (after multivariate analysis allowing for a wide range of possible confounders).
What is one estimate of attributable load of probable mental disorder in whole population due to prenatal anxiety/stress?
10-15%
What is a way of assessing cognitive function in early life?
Bayley score
What evidence of the role of genes in stress?
COMT breaks down the catecholamines (such as dopamine, noradrenalin) – looking at genetic variants of this gene with ADHD. A single nucleotide (GG) polymorphism linked to maternal stress in pregnancy – WORSENED WORKING MEMORY AGE 8. Gene environment interaction.
What is a study for diabetes and Barker hypothesis?
Relative risk of type 2
diabetes
US Nurses’ Study (n=69,526)
What studies are there for the mechanisms of high stress transmitting to foetus?
Recruited day before elective caesarian and did anxiety questionnaire. Later collected the placenta and was found that the more stressed, the less 11bHSD2 present in placenta, allowing more cortisol to pass through (was proposed).
Queen Charlotte, measured amniotic fluid for cortisol then at 18 months did Bayley test. The more cortisol there was in the amniotic fluid, the worse the child did in the Bayley test.
What is the evolutionary value of prenatal stress?Potential benefits
Protective value of prenatal stress?
Eg in ADHD help survival, notice a danger and readily shifted attention
Anxious – more vigilant
Impulsive - more willing to explore new environments
Females – more anxious and vigilant, males more aggressive, ADHD.
In males, what are LH and FSH required for? What is like throughout males life?
• FSH→ sertoli cells and spermatogenesis
• LH→ Leydig→ Androgens (testosterone, DHEA and androstenedione)→ Secondary sexual characteristics
It is reasonably consistent throughout life.
What is gonadotrophin secretion like?
• Pulses every 30 mins, many tissues do not like a continuous exposure. If was released more steadily then there would be a down regulation of the receptors. Hence GnRH agonists being used for prostate and breast cancer
Mini summary of the menstrual cycle?
- E2 gradual rise that becomes exponential, positive feedback. The rising levels of oestrogen triggers LH surge. before is a negative feedback.
- Ovulation – one graffian follicle becomes dominant. Second half of the cycle rising levels of progesterone. If implantation occurs, the hcg produced will have a similar action to lh and fsh and cause progesterone to be elevated so that uterus lining does not decline
When oestrogen becomes positive regulator, increases frequency and amplitude of GnRH pulses.
FSH+LH→ graffian follicles
LH→ corpus luteum
What happens when oestrogen becomes the positive regulator?
When oestrogen becomes positive regulator, increases frequency and amplitude of GnRH pulses.
FSH+LH→ graffian follicles
LH→ corpus luteum
What is the difference between sex and gender?
Sex: Distinguishes male or female subjects according to the reproductive organs and functions that derive from the chromosomal complement (male XY or female XX sex chromosomes)
Gender: A [human] subject’s self-representation as male or female
