5.2 Hormones in pregnancy

Question 1

what is hCG produced by?

Answer 1

Syncytiotrophoblast cells of placenta

Question 2

When is hCG detectable?

Answer 2

Detectable 8 – 9 days post-conception (basis of all standard pregnancy tests → early appearance in blood and urine)

Question 3

what are the effects of hCG?

Answer 3

Maintains corpus luteum: maintains progesterone production (prevents shedding of uterine lining) until placenta takes over progesterone production at 6 – 8 weeks)

2. Immunoprotective (with cortisol and progesterone): suppress T cell mediated maternal immune response to the foetus
3. Thyrotrophic: shares common α subunit with LH, FSH, TSH (unique β subunit) → can activate TSH receptors (but far less potent) → only clinically significant with excessive increased hCG (e.g. molar pregnancy) → increases T3, T4 levels
4. Nausea: increases quickly (double every 48h) in first few weeks → peak at 80000 – 100000 between 8 – 10 weeks gestation → decrease to 10000 – 20000 for remainder → morning sickness (actually occurs at any time of day)

Question 4

what is hCS produced by?

Answer 4

Syncytiotrophoblast cells of placenta

Question 5

How does hcS change with time?

Answer 5

Rise proportionately with the placental mass

Question 6

what are the effects of hCS?

Answer 6

1. Anti-insulin: reduces maternal sensitivity to insulin (produces more sugar but does not inhibit insulin production)
2. Mobilisation of maternal fatty acids: promotes lipolysis and reduces maternal glucose use (increase use for foetal growth)
3. Stimulation of mammary glands
4. Increases erythropoiesis (by increasing EPO)
   * Similar structure to prolactin and growth hormone

Question 7

what is oestrogen produced by?

Answer 7

Ovaries & placenta

Question 8

How does oestrogen change with time?

Answer 8

Rise steadily throughout pregnancy (especially oestriol/E3 in the 1st trimester

Question 9

what are the effects of oestrogen?

Answer 9

1. Maintains uterine lining
2. Stimulates mammary gland growth
3. Strengthens myometrium
4. Promotes contractions
5. Stimulates the RAAS (increases sodium and water retention)
6. Increases CBG & TBG production
7. Inhibits hypothalamic GnRH release & pituitary LH/FSH release
8. Increases oxytocin receptor expression on uterine muscles (labour)
9. Prolongs anagen phase of hair (post-partum telogen effluvium)

Question 10

what is progesterone produced by?

Answer 10

Corpus luteum & placenta (from 8 weeks)

Question 11

How does progesterone change with time?

Answer 11

Rise steadily throughout pregnancy (especially oestriol/E3 in the 1st trimester

Question 12

what are the effects of progesterone?

Answer 12

Prevent spontaneous abortion:

1. Maintains uterine lining
2. Inhibits contractions
3. Reduces prostaglandin production (to maintain uterine lining)
4. Immunoprotective
5. Mucus plug
6. Inhibits insulin
7. Competes with aldosterone for mineralocorticoid receptors → reduces aldosterone effects

Question 13

The hypothalamus regulates endocrine function with input from various sources and outputs via the hypothalamic-pituitary axis:
• Involves positive and negative feedback loops, paracrine, and autocrine signalling
• Non-pregnant state: high levels of hormones are present and active in the ________________ but nearly undetectable in the rest of the circulation
• Pregnant state: placental hormone production causes elevated systemic levels of hormones or structurally similar hormones

Answer 13

portal circulation

Question 14

There are reduced levels of gonadotrophins, FSH and LH in pregnancy (helps to prevent ________________):
• Levels are significantly lower at 6 weeks gestation, and undetectable in serum by _____________ (due to negative feedback to the pituitary and hypothalamus from high levels of progesterone and oestrogen from the placenta → decreased GnRH)
• Most of the circulating GnRH in pregnancy is from the placenta (involved in placental
growth; not fully understood) → FSH/LH levels remain low despite placental GnRH (possibly due to ____________________)
• After childbirth: gonadotrophin levels remain low (___________________) → non-breastfeeding mothers have increased levels by 14 – 21 days post-delivery

Answer 14

menstruation and spontaneous abortion;

mid-pregnancy;

progressively reduced pituitary responsiveness to GnRH and increased inhibin from placenta

lactational amenorrhoea

Question 15

Normally, CRH is released by the hypothalamus in response to stress → corticotrophs produce ACTH → stimulates cortisol release (exerts negative feedback on CRH and ACTH):

• In pregnancy: CRH released from ___________________ increase exponentially → stimulates pituitary and placental ACTH release → cortisol release
o Positive feedback: cortisol stimulates further placental CRH release (involved in initiation of labour)
o Binding proteins of CRH drop from _____________ → allows increased CRH bioavailability to prepare for labour (early rise is linked to preterm labour)

• Plasma ACTH levels increases 2 – 4 times in pregnancy (despite high cortisol) → due to placental synthesis, pituitary desensitisation to cortisol negative feedback, and enhanced pituitary response to stimulating factors (__________________)

• ___________________ stimulates hepatic production of CBG → increased levels of bound cortisol in maternal blood:
o Reduces liver breakdown and clearance of cortisol (prolongs half-life)
o Increases free blood and urine cortisol levels → difficult to diagnose pituitary-adrenal pathologies in pregnancy (rely on blood/urine parameters) The state of relative hypercortisolism is important to meet the increased metabolic demand:
• Responsible for the increased tendency to develop abdominal striae, glycosuria, hypertension with increasing gestation
• Generally, no symptoms of hypercortisolism due to anti-glucocorticoid activity of __________________

Answer 15

placental cytotrophoblasts, amnion and decidua;

~34 weeks;

vasopressin and CRH;

Placental oestrogen;

increased progesterone concentration

Question 16

The foetal glucocorticoid levels are much lower than maternal levels (raised) due to the action of _____________________ (converts active to inactive form).

Answer 16

corticosteroid 11β-dehydrogenase isozyme 2

Question 17

Melanocyte stimulating hormone (MSH): Released in response to _______________ → same precursor as ACTH (POMC) → increased levels causes skin pigmentation

Answer 17

hypothalamic CRH

Question 18

GH variant: Produced by the placenta (exerts negative feedback on pituitary GH production):
• Similar to maternal GH (promotes _________________-)

Answer 18

gluconeogenesis and lipolysis

Question 19

RAAS is stimulated in pregnancy due to the reduced blood pressure and vascular resistance:
• 4-fold increase in plasma renin activity + markedly elevated aldosterone levels by week 8 post-conception despite increased extracellular fluid volume due to stimulation of renin release by _______________
• Increased angiotensin levels do not lead to vasoconstriction due to __________________ → failure causes pregnancy-induced hypertension
• ADH levels remain normal (no major role in pregnancy endocrine changes)

Answer 19

oestrogen and progesterone;

reduced sensitivity of maternal vasculatur

Question 20

How does oestrogen affect RAAS?

Answer 20

Stimulates hepatic synthesis of angiotensinogen → increased levels of angiotensin II and aldosterone → expansion of blood volume (required)

Question 21

How does progesterone affect RAAS?

Answer 21

Acts as mineralocorticoid receptor antagonist → competes with aldosterone → reduces renal sodium reabsorption → constrains the effects of increased aldosterone

Question 22

How does placental oestrogen increase total T3 and T4?

Answer 22

Stimulates maternal liver to produce double the amount of TBG → increases bound thyroid hormone levels → reduces free T4 levels → reduces negative feedback → increases pituitary TSH secretion → increases total T3 and T4

Question 23

How does hCG increase T3-T4?

Answer 23

Structurally similar to TSH → stimulates TSH receptors → provides most of receptor stimulation and suppression of TSH by the end of the 1st trimester (when hCG levels are the highest)
• May cause transient hyperthyroidism in some women (usually only clinically significant if hCG levels are markedly elevated e.g. in molar pregnancies → associated hyperemesis gravidarum)

Question 24

The increased thyroid activity causes higher iodine requirements in pregnancy → tendency for iodine deficiency due to ____________________ → thyroid increases uptake of iodine from blood.

Dietary iodine insufficiency in pregnancy: causes maternal goitre and foetal cretinism

• Maternal goitre: thyroid hypertrophies to trap sufficient iodine
• Foetal cretinism: severe maternal iodine deficiency causing __________________
• Prevention: increased iodine intake (from standard 100 150μg /day to at least 200μg/day ) during pregnancy–> iodine rich foods (e.g. dairy products, seaweed)

Answer 24

active transport of iodine across the placenta and increased renal iodine clearance

foetal brain damage (deaf mutism, spastic motor disorder, hypothyroidism)

Question 25

The parathyroid glands secrete PTH (increases serum Ca2+ by increasing bone resorption), which is opposed by calcitonin (lowers serum Ca2+ by increasing urinary excretion and preventing bone resorption):
• Foetus requires about __________________ to mineralise the skeleton and maintain normal physiology → requirement increases further with breastfeeding
• Maternal intestinal Ca2+ absorption doubles by week 12 and increases vitamin D levels → placenta makes _________ and releases ___________
• PTH is not transferred across the placenta → foetal PTH levels remain low (only increase after delivery)
• Foetal thyroid gland produces increased levels of _____________ → supports bone growth
• Maternal calcitonin levels remain unchanged in pregnancy

Answer 25

30g of calcium

active vitamin D; s PTH-rp ;

calcitonin

Question 26

Which hormones oppose labour?

Answer 26

Progesterone: inhibits uterine contractions → inhibits oxytocin and prostaglandin release

Relaxin: secreted towards the end of pregnancy by the placenta and ovaries → relaxes pelvic ligaments, dilates the cervix, inhibits uterine contractions

Question 27

Which hormones promote labour?

Answer 27

Oxytocin, oestrogen, prostaglandins

Question 28

The placental and foetal secretion of CRH increases cortisol production by foetal adrenal glands → increases _____________ → increases oxytocin receptors on ______________:
• Foetal cortisol also inhibits progesterone (reduces inhibitory effects on the uterus)

Answer 28

oestrogen;

uterine smooth muscle cell membrane

Question 29

How does oxytocin promote label?

Answer 29

Stimulates uterine contractions and enhances prostaglandin release from the decidua (promotes contractions)

Question 30

How does prostaglandins promote labour?

Answer 30

Soften the cervix, stimulate contractions and enhances oxytocin effects (increases oxytocin receptors and gap junctions between muscle cells):
• Gap junctions help to synchronise depolarisation

Question 31

Ferguson reflex: The positive neuroendocrine feedback loops perpetuate labour and uterine contractions:

1. _______________ stimulates mechanoreceptors
2. Mechanoreceptors signal to the brain to increase oxytocin secretion by the ________________
3. Oxytocin further stimulates _______________ (series of regular and more powerful contractions)
4. Further dilation of the cervix aids foetal descent

Answer 31

Contractions and increased pressure on cervix;

maternal posterior pituitary gland;

uterine smooth muscle contractions

Question 32

During pregnancy, the mammary glands enlarge and begin lactogenesis, allowing for milk ejection during suckling post-delivery:
• Oestrogen causes hypertrophy and hyperplasia of lactotrophs → increases prolactin 10-fold during pregnancy (mostly from maternal pituitary; some from placenta)
o Increased size of anterior pituitary could cause ______________________
• ____________________ levels remain elevated after delivery to allow breastfeeding → other hormones rapidly return to normal non-pregnant levels

Answer 32

transient hemianopia ;

Oxytocin and prolactin

Question 33

How does prolactin cause the growth of mammary glands?

Breast tissue made of ~20 functional units (each containing ductule and mammary gland lobule with several alveoli):
• Prolactin mediates the change in mammary gland structure from _______________

Answer 33

ductal to lobular-alveolar

Question 34

When is milk production (in alveoli) initiated?

Answer 34

Only initiated after sudden drop in oestrogen and progesterone (upon delivery of the placenta)

Question 35

Milk release (let down reflex):

Infant suckling → ________________ in hypothalamus stimulated → posterior pituitary releases oxytocin:
• Oxytocin → myoepithelial cells around alveoli and ducts contract → pushes milk out of alveoli → __________ →______________ → opens into the nipple
• Can be conditioned to visual/auditory stimuli (e.g. milk ejection occurs upon hearing the baby cry)
• Reflex is inhibited by stress

Answer 35

paraventricular nuclei & supraoptic nuclei;

ductules; lactiferous ducts

Question 36

There is a baseline elevation of prolactin in lactating mothers, which prevents __________________ release from the hypothalamus:
• More often/longer baby suckles → more prolactin released → more milk produced in subsequent feeds (alters milk production to meet changing needs of growing infant)
• Regular suckling inhibits _______________- → reduces FSH/LH → inhibits ovarian cycle (natural contraception of lactational amenorrhoea → allows child spacing and increases the chance of infant survival)
• Non-breastfeeding women: prolactin levels gradually fall → resumption of reproductive cycle within _________________

Answer 36

prolactin inhibiting factor

GnRH release;

14 – 21 days of delivery