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Basic endocrinology of

pregnancy: reviews on
progesterone role in early and
late pregnancy
Kanadi Sumapradja
kanadisuma@yahoo.com
Department of Obstetrics and Gynecology
Faculty of Medicine Universitas Indonesia

OBJECTIVES
-

To understand the basic principles of steroid


hormones production

To understand steroid hormones production


during pregnancy (Progesterone, Estrogen,
Cortisol)

To understand the role of Progesterone during


early pregnancy and how to apply in clinical
setting

To understand the role of Progesterone, Estrogen


and Cortisol in parturition and how to apply in
clinical setting

BASIC
STEROIDOGENESI
S

Choleste
rol
Androge
n

Progesteron
e

Mineralo
corticoid

Estrogen
Glucocorticoid

Cholesterol
(C27)
Pregnan
(C21)
Glucocorticoid
(C21)

Androstan
(C19)
Estran (C18)

Mineralocorticoi

How
steroidogenesis
happens during
pregnancy?

The production of progesterone in early


pregnancy
Fertilizatio
n

Implantation
occurs about 56 days after
ovulation

Ovulation

hCG
must appear by the
10th day after ovulation
to rescue the corpus
luteum

Estrogen
Progesteron
e

In the first 5-6 weeks of pregnancy, hCG stimulation of the corpus


luteum results in the daily secretion of about 25 mg of progesterone
and 0.5 mg of estradiol

The role of progesterone in early


pregnancy

Fetus (Semiallogeneic)

Maternal-fetal Maternal
interface
immune system
Th

HLA-G inhibition
of NK cell

Endometrial
receptivity

Edited from Aluvihare VR, et al. J Mol Med


2005;83:88-96

Tr

NK

B
Progeste
ron

Th2 >
Th1
Less
cytotoxic
more
regulating

Asymmet
ric
antibodie
s

Progesterone as a predictor of early


pregnancy outcomes

Lin YS., Liu CH. Int J Gynecol Obstet


1995;51:33-8

Threatened
micarriage

Qureshi NS., et al. Maturitas


2009;65S:S35-41

Outcomes on P treated threatened


miscarriage
Treated by P (n=86)

Untreated (n=60)

Miscarriage

15 (17.5%)

15 (25%)

Preterm labour

6 (7%)

5 (8.3%)

Full term delivery

65 (75.5%)

40 (66.6%)

Treated by P
(n=71)

Untreated
(n=45)

P value

7 (9.8%)

3 (6.6%)

NS

5 (7%)

4 (8.8%)

NS

Ante-partum
hemorrhage

4 (5.6%)

3 (6.6%)

NS

Pre-term labour

6 (8.4%)

5 (11.1%)

NS

Congenital
abnormality

2 (2.8%)

2 (4.4%)

NS

Preeclampsia
IUGR

El-Zibdeh MY., et al. Maturitas


2009;65S:S43-6

Outcomes on P treated recurrent


miscarriages

El-Zibdeh MY. J Steroid Biochem Mol Biol


2005;97:431-4

PlGF
(pg/m
L) 500

450

P supplementation on first trimester increases PlGF


(angiogenic
PlGFfactor)
Didrogesteron + Asam folat
(n=20)

(pg/m
L) 500

450

400

400

350

350

300

300

250

250

200

200

150

150

100

100

50

50

0
Pre

Asam folat (n=20)

0
Pre

Post
Pre

Post

Post

Asam folat

40.80

89.60

0.01

Asam folat +
Didrogesteron

48.80

186.20

<0.05

Karlina D., Sumapradja K. (Penelitian

Luteo-Placental
shift

Progesterone is largely
produced by the
corpus luteum until
about 10 weeks of
gestation

At term, progesterone levels


range from 100 to 200 ng/mL,
and the placenta produces about
250 mg/day.

Steroidogenesis in the fetoplacental unit does not


follow the conventional mechanisms of hormone
production within a single organ.

Maternal
compartme
nt

Placental
compartme
nt

Fetal
compartme
nt

The final products result from critical interactions


and interdependence of separate organ systems
that individually do not possess the necessary
enzymatic capabilities.

Progesterone production of
placenta
Most of the progesterone produced in the placenta
enters the maternal circulation
Progesterone production by the placenta is largely
independent of the:

quantity of precursor available


the utero-placental perfusion
fetal well being
the presence of a live fetus

the fetus contributes essentially no precursor

Precur
sor

3BHS
D

Regulating
factors?

Progesterone serves as the substrate for fetal


adrenal gland production of glucocorticoids and
mineralocorticoids

hCG
Estradi
ol

Estrone
and
estradi
ol
product
ion
Rapid and
extensive
conjugation of
steroids with
sulfate
blocking the
biologic effects
of potent
steroids present
in such great
quantities

the vast majority of maternal


estrogen is derived from fetal
androgens

virtual absence of 17a-hydroxylation


and 17-20 desmolase (lyase) activity
(P450c17) in the human placenta

Sulphat
ase

21-carbon products (progesterone and


pregnenolone) cannot be converted to
19-carbon steroids (androstenedione
and dehydroepiandrosterone)

Aromat
ase

Sulphat
ase

The fetal adrenal,


with the aid of 16ahydroxylation in the
fetal liver, provides
the 16ahydroxydehydroepia
ndrosterone sulfate
for placental estriol
formation

Sulphat
ase

Estriol
product
ion

Higher in
maternal
Estrone and estradiol are derived
equally from fetal and maternal
precursors
Estriol is the estrogen produced in
greatest quantity during pregnancy;

Aromat
ase

Higher in
fetal

A rise in estradiol begins in weeks 6-8 when


placental function becomes apparent.2 Individual
estradiol values vary between 6 and 40 ng/mL at
36 weeks of gestation and then undergo an
accelerated rate of increase

Estriol is first detectable at 9


weeks when the fetal adrenal
gland secretion of precursor
begins. Estriol concentrations
plateau at 31-35 weeks and then
increase again at 35-36 weeks
A rise in estrone begins at 6-10
weeks, and individual values range
from 2 to 30 ng/mL at term

During pregnancy, estrone and estradiol production is increased about 100 times over
non-pregnant levels. However, the increase in maternal estriol excretion is about a
thousand-fold

During pregnancy, estrogens have


several actions:
1. Enhance receptor-mediated
uptake of LDL cholesterol, which is
important for normal placental
steroid production.
2. Increase utero-placental blood flow.
3. Increase endometrial prostaglandin
synthesis.
4. Prepare the breasts for lactation.

Aromatase deficiency of placenta

Hypoxia combined with 2-ME induces the invasive phenotype of


cytotrophoblasts, which invade the uterine wall, and allows the uteroplacental circulation to develop, thus restoring oxygen levels
Hertig A., et al. Am J Obstet Gynecol
2010;203:e1-9

Aromatase deficiency of placenta

Finger length pattern


The second finger is shorter relative to the fourth finger in
men, resulting in a reduced finger length ratio compared to
women
Cattrall FR., et al. Fertil Steril
2005;84:1689-92

ACTHR = ACTH receptor; GCR =


Glucocorticoid receptor

LDL
uptake

LDL
receptor

Adren
al
growt
h

ACTH
R
15
weeks

Maternal
cortisol
Placent
al
Estroge
The tropic support of n
the
fetal adrenal gland by
ACTH from the fetal
pituitary is protected by
placental estrogen
IUGR, insulin resistance,
abnormal lipid,
hypertension

Fetal adrenal maturation


Steroid and IGF-II
production

Fetal
ACTH

hCG
no ACTH
Cortiso
l
11bHSD
Cortison
e

steroidogene
sis

Negative
feedback

Smoking,
preeclampsia
High
cortisol

Fetal
ACTH

Placent
al CRH
GCR

Progestero
ne
Lipoxigena
se
Infectio
n

Corticotrophin
Releasing Hormone
(CRH)

Adrenocorticotro
pic hormone
(ACTH)

Cortisol
DHEAS
Aldostero
ne

High
estrogen

High
cortisol
Increases Placental
CRH

Young IR., et al. The comparative physiology of parturition in mammals: hormones and
parturition in mammals

Endocrinology of
parturition

Hirota Y., et al. Nature Med

Aromata
se

Aromata
se

Estrogen - Gap
junctions
Myometrium cells is a single unit smooth
muscle cell

Action potentials generated in one cell can activate adjacent cells by ionic
currents spreading rapidly over the whole organ and securing a co-ordinated
contraction as though the tissue were a single unit or a syncytium

Estrogen Oxytocin receptor

R: oxytocin G-protein coupled receptor; G: G-protein; PLC: phospholipase C; PIP2:


phosphatidyl-inositol biphosphate; IP3: inositol tri-phosphate; ER: endoplasmic
reticulum; VOCC: voltage operated calcium channels; Ca2+: ionised calcium; Ca2+i:
free intracellular ionised calcium; MCLK-P myosin light chain kinase phosphate.

Concept
of P
withdraw
al

Endogenous antiprogestin which


prevents the
physiological action of
P

A change in the number,


affinity, or distribution of
the progesterone
receptor (PR)
A change in local
synthesis, metabolism
or sequestration by a
binding protein

CAP = Contraction Associated


Protein

Myometrium
relaxation

Mesiano S., et al. Semin Cell Dev Biol


2007;18:321-31
Astle S., et al. Eur J Obstet Gynaecol

Young IR., et al. The comparative physiology of parturition in mammals: hormones and
parturition in mammals

Young IR., et al. The comparative physiology of parturition in mammals: hormones and
parturition in mammals

NO

Estrogen for labor


induction?

Hofmeyr GJ., et al. Best Pract Res Clin Obstet Gynecol


2003;17:777-94

The patients were randomly allocated to


pretreatment by either 3 ml hydroxymethylcellulose gel containing 50 mg 17Poestradiol or the same gel without oestradiol
applied within the cervical canal in the afternoon.
The next morning a 1 mg 16,16-dimethyl-transA-prostaglandin E, methyl ester pessary

P = Primi; M = Multi; E = Estradiol treated; C =


control
Average 17 wga (15-21 wga)
Allen J., et al. Eur J Obstet Gynecol Reprod Biol
1989;32:123-7

Mazaki-Tovi S., et al. Semin Perinatol


2007;31:142-58

Dydrogesterone 80mg/d for


10 days
Hudic I., et al. J Reprod Immunol
2011;92:103-7

LATE
PREGNANCY

SUMMA
RY

Effects on embryo allogeneic antigen,


endometrium and maternal immune
modulation

EARLY