human reproduction 316 · human reproduction 316. the placenta maternal-fetal interface ... in...
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The Placental Glucocorticoid Barrier
Brendan Waddell (Room 103; [email protected])
HUMAN REPRODUCTION 316
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The Placenta
Maternal-Fetal interface – intimate association of maternal and fetal circulations
Key functions:– Nutrient and oxygen supply to fetus
– Waste and CO2 removal from fetus
– Hormone production
– Selective passage of everything!
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Placental Endocrine Function
Steroids:ProgesteroneOestrogens (feto-placental unit)
Peptides / Proteins:
human choionic gonadotrophin (hCG)human chorionic somatomammotrophininsulin-like growth factors (IGFs)leptin (support for fetal growth?)corticotrophin releasing hormone (CRH)
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PROGESTERONE AND OESTROGENIN HUMAN PREGNANCY
Weeks of Pregnancy0 6 12 18 24 30 36
Plas
ma
prog
este
rone
(ng/
ml)
0
30
60
90
120
150
Plas
ma
oest
radi
ol (n
g/m
l)
0
3
6
9
12
15
18
21
Progesterone
Oestradiol
Time of luteal-placental shift
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The Feto-Placental Unit
• Placenta is main source of oestrogen after theluteal-placental shift
• But, placenta lacks 17α-hydroxylase(required for androgen formation)
• Fetal adrenal has specialized ‘fetal zone’
• Produces vast quantities of androgensdehydroepiandrosterone (DHEA) and DHEAS
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FETAL ADRENAL WEIGHT AND FETAL PLASMA DHAS
Feta
l adr
enal
wei
ght (
mg)
0
2
4
6
8
Weeks of Pregnancy6 12 18 24 30 36
Feta
l pla
sma
DH
AS
(ng/
ml)
0
500
1000
1500
2000
2500
Fetal adrenal weight
Fetal DHAS
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Adrenal weight across development
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Human Fetal Adrenal 20 weeks
Definitive zone(cortisol production)
Fetal zone(androgen production)
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Glucocorticoids in PregnancyGlucocorticoids in Pregnancy
• Glucocorticoids provide potent differentiationsignals for late fetal maturation
• Excess glucocorticoids associated with intrauterine growth retardation (IUGR)
• Glucocorticoid-induced IUGR associatedwith advanced organ maturation
• Glucocorticoid programming of the adult phenotype (Barker Hypothesis)
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Maternalblood
The Placental Glucocorticoid Barrier
Cortisol
Cortisone(inactive)
11β-HSD
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The Placental The Placental GlucocorticoidGlucocorticoid BarrierBarrier
• 1970s: Human feto-placental cortisol metabolism(Pasqualini et al, 1970; Bietins et al, 1973)
• 1980s: Placental 11β-HSD regulation in primates(Pepe & Albrecht, 1984; Pepe et al, 1988)
• 1960s: Recognition of placental glucocorticoid barrierinvolving 11β−hydroxysteroid dehydrogenase
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Gestational Changes in Baboon Placental 11Gestational Changes in Baboon Placental 11ββ--HSDHSD
Pepe et al (1988) Endocrinology 122:78
0
10
20
30
40
50
*
*
FF→→EE FF→→EE FF→→EEEE→→FF EE→→FFEE→→FF
Control Control -- MIDMID E2 E2 -- MIDMID Control Control -- TERMTERM
F: cortisolE: cortisone
* P<0.05 compared with E * P<0.05 compared with E →→F at same stageF at same stage
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The Placental The Placental GlucocorticoidGlucocorticoid BarrierBarrier
• 1970s: Human feto-placental cortisol metabolism(Pasqualini et al, 1970; Bietins et al, 1973)
• 1980s: Placental 11β-HSD regulation in primates(Pepe & Albrecht, 1984; Pepe et al, 1988)
• 1960s: Recognition of placental glucocorticoid barrier(Osinski, 1962)
• 1990s: Recognition of barrier’s role in fetal programming(Benediktsson et al, 1993; Lindsay et al, 1996)
Cloning of 11β-HSD-1 & -2 enzymes(Agarwal et al, 1994; Albiston et al, 1994)
Placental 11β-HSD-1 & -2 expression patterns(eg, Burton et al, 1996; McTernan et al, 2001)
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Human Placental 11Human Placental 11ββ--HSDHSD--2 mRNA 2 mRNA Increases with Advancing PregnancyIncreases with Advancing Pregnancy
0
10
20
30
40
50
60
Fold
incr
ease
in m
RN
A e
xpre
ssio
n
Earlyfirst
Latefirst Second Early
third Term TermIUGR
Stage of Normal Gestation (trimester)McTernan et al (2001) JCEM 86:4979
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The Rat Placenta
Basal Zone(major site of
hormone synthesis)
Labyrinth Zone(site of maternal -fetal exchange)
(23-day pregnancy)
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1111ββ--HSDHSD--11(activating)(activating)
1111ββ--HSDHSD--22(inactivating)(inactivating)
Day 16Day 16
Day 22Day 22
1111ββ--HSDHSD--1 and 1 and --2 mRNA in rat placenta2 mRNA in rat placenta
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Placental Glucocorticoid BarrierPlacental Glucocorticoid Barrier
• Increases in human and baboon pregnancy
• Decreases in rodent pregnancy
Near term pregnancy….
Linked to evolution of the feto-placental unit for estrogen synthesis??