Basic endocrinology of pregnancy: reviews on progesterone role in early and late pregnancy

Kanadi Sumapradjakanadisuma@yahoo.com

Department of Obstetrics and GynecologyFaculty 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 STEROIDOGENESIS

Cholesterol

Mineralo corticoid Glucocorticoid

Androgen

Estrogen

Progesterone

Cholesterol (C27)

Pregnan (C21)

Androstan (C19)

Estran (C18)

Glucocorticoid (C21)

Mineralocorticoid (C21)

How steroidogenesis happens during pregnancy?

Implantation occurs about 5-6 days after ovulation

EstrogenProgesterone

hCG

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

The production of progesterone in early pregnancy

Fertilization

Ovulation

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

Fetu

s (S

emi-a

lloge

neic

) Maternal-fetal interface

HLA-G – inhibition of NK cell

Maternal immune system

Th

NK

B

Tr

Edited from Aluvihare VR, et al. J Mol Med 2005;83:88-96

Progesteron

Th2 > Th1

Less cytotoxic more regulating

Asymmetric antibodies

Endometrial receptivity

The role of progesterone in early pregnancy

Lin YS., Liu CH. Int J Gynecol Obstet 1995;51:33-8

Progesterone as a predictor of early pregnancy outcomes

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

Preeclampsia 7 (9.8%) 3 (6.6%) NS

IUGR 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

El-Zibdeh MY., et al. Maturitas 2009;65S:S43-6

El-Zibdeh MY. J Steroid Biochem Mol Biol 2005;97:431-4

Outcomes on P treated recurrent miscarriages

Pre Post0

50

100

150

200

250

300

350

400

450

500

Pre Post0

50

100

150

200

250

300

350

400

450

500Didrogesteron + Asam folat (n=20) Asam folat (n=20)

PlGF(pg/mL)

PlGF(pg/mL)

Pre Post p

Asam folat 40.80 89.60 0.01

Asam folat + Didrogesteron 48.80 186.20 <0.05

Karlina D., Sumapradja K. (Penelitian tesis), 2012

P supplementation on first trimester increases PlGF (angiogenic factor)

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.

Luteo-Placental shift

Steroidogenesis in the fetoplacental unit does not follow the conventional mechanisms of hormone production within a single organ.

The final products result from critical interactions and interdependence of separate organ systems that individually do not possess the necessary enzymatic capabilities.

Feta

l co

mpa

rtm

ent

Mat

erna

l co

mpa

rtm

ent

Plac

enta

l co

mpa

rtm

ent

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

Progesterone production of placenta

the

fetu

s co

ntrib

utes

ess

entia

lly n

o pr

ecur

sor

Precursor

3BHSD Regulating factors?hCGEstradiol

Progesterone serves as the substrate for fetal adrenal gland production of glucocorticoids and mineralocorticoids

virtual absence of 17a-hydroxylation and 17-20 desmolase (lyase) activity (P450c17) in the human placenta

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

the vast majority of maternal estrogen is derived from fetal androgens

Rapid and extensive conjugation of steroids with sulfate

blocking the biologic effects of potent steroids present in such great quantities

Sulphatase

Estrone and estradiol production

Estriol is the estrogen produced in greatest quantity during pregnancy;

The fetal adrenal, with the aid of 16a-hydroxylation in the fetal liver, provides the 16a-hydroxydehydroepiandrosterone sulfate for placental estriol formation

Estriol production

Estrone and estradiol are derived equally from fetal and maternal precursors

Higher in maternal

Higher in fetal

Aromatase

AromataseSu

lpha

tase

Sulp

hata

se

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

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.

During pregnancy, estrogens have several actions:

Hypoxia combined with 2-ME induces the invasive phenotype of cytotrophoblasts, which invade the uterine wall, and allows the utero-placental circulation to develop, thus restoring oxygen levels

Aromatase deficiency of placenta

Hertig A., et al. Am J Obstet Gynecol 2010;203:e1-9

Aromatase deficiency of placenta

The second finger is shorter relative to the fourth finger in men, resulting in a reduced finger length ratio compared to women

Finger length pattern

Cattrall FR., et al. Fertil Steril 2005;84:1689-92

15 weeks

hCGno ACTH

Fetal ACTH

Cortisol

Cortisone

Fetal adrenal maturationSteroid and IGF-II production

Negative feedback

11-bHSDPlacental Estrogen

The tropic support of the fetal adrenal gland by ACTH from the fetal pituitary is protected by placental estrogen

LDL receptor LDL uptake steroidogenesis

Smoking, preeclampsia

Placental CRH

Progesterone

Lipoxigenase

GCR

Infection

ACTHR

ACTHR = ACTH receptor; GCR = Glucocorticoid receptor

Adrenal growth

Maternal cortisol

High cortisolIUGR, insulin resistance, abnormal lipid, hypertension

Fetal ACTH

Corticotrophin Releasing Hormone (CRH)

Adrenocorticotropic hormone (ACTH)

CortisolDHEAS

Aldosterone

High cortisol

Increases Placental CRH

High estrogen

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 2010;16:529-31

Aromatase

Aromatase

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 - Gap junctions

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.

Mesiano S., et al. Semin Cell Dev Biol 2007;18:321-31Astle S., et al. Eur J Obstet Gynaecol 2003;108:177-81

CAP = Contraction Associated Protein

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

Endogenous anti-progestin which prevents the physiological action of P

Concept of P withdrawal

Myometrium relaxation

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 ?

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 hydroxy- methylcellulose gel containing 50 mg

17P-oestradiol or the same gel without oestradiol applied

within the cervical canal in the afternoon. The next morning

a 1 mg 16,16-dimethyl-trans-A’-prostaglandin E, methyl ester

pessary

Average 17 wga (15-21 wga)P = Primi; M = Multi; E = Estradiol treated; C = control

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

PRE

GN

ANCY

EARLY PREGNANCY

Effects on embryo allogeneic antigen, endometrium and maternal immune modulation

SUMMARY