The Placental Glucocorticoid Barrier

Brendan Waddell (Room 103; bwaddell@anhb.uwa.edu.au)

HUMAN REPRODUCTION 316

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!

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)

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

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

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

Adrenal weight across development

Human Fetal Adrenal 20 weeks

Definitive zone(cortisol production)

Fetal zone(androgen production)

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)

Maternalblood

The Placental Glucocorticoid Barrier

Cortisol

Cortisone(inactive)

11β-HSD

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

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

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)

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

The Rat Placenta

Basal Zone(major site of

hormone synthesis)

Labyrinth Zone(site of maternal -fetal exchange)

(23-day pregnancy)

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

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??