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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
Cholesterol (C27)
Pregnan (C21)
Androstan (C19)
Estran (C18)
Glucocorticoid (C21)
Mineralocorticoid (C21)
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
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
Pre Post0
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Pre Post0
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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
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
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
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
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
LATE
PRE
GN
ANCY
EARLY PREGNANCY
Effects on embryo allogeneic antigen, endometrium and maternal immune modulation
SUMMARY