1 1/37 ch. 6. the placental hormones 부산백병원 산부인과 r1 손영실 ch. 6. the placental...

11/37Ch. 6. The Placental Hormones

부산백병원 산부인과

R1 손영실

Ch. 6.

The Placental Hormones


INDEX

HUMAN CHORIONIC GONADOTROPIN (hCG)1

HUMAN PLACENTAL LACTOGEN (hPL)2

HYPOTHALAMIC-LIKE RELEASING HORMONES4

ESTROGENS6

OTHER PLACENTAL PEPTIDE HORMONES5

OTHER PLACENTAL PROTEIN HORMONES3

FETAL ADRENAL GLANDS7

MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

8

PROGESTERONE9


◎ The human placenta synthesize an enormous amount of hormones

: hPL, hCG, ACTH, PTH-rP, GH variant, calcitonin, relaxin

hypothalamic-like releasing and inhibiting hormones (TRH, GnRH, CRH, somatostatin, GHRH)

inhibins, activins, ANP


HUMAN CHORIONIC GONADOTROPIN

◎ hCG

“• pregnancy hormones”

• produced almost exclusively in the placenta

• detection of hCG in blood or urine

- indication of pregnancy


• glycoprotein H - hCG, FSH, LH, TSH • two subunits

- α subunits – identical - β subunits – distinctly different

1. Chemical Characteristics

2. Biosynthesis • single gene (chromosome 6 at q12-q21)

- codes for α-subunit • eight separate gene (chromosome 19)

- Codes for β-hCG/β-LH family



- complete hCG molecule is synthesized primarily

in the syncytiotrophoblast

3. Cellular Sites of Origin

4. Regulation of hCG Subunit Biosynthesis- The amount of mRNA for hCG in syncytiotrophoblast

from the first trimester are greater than at term

→ the measurement of hCG in plasma

as a screening procedure to identify

abnormal fetuses



• 1st detection : 7 1/2 to 9 1/2 days

after the LH surge

• maximal levels : about 8 to 10 weeks

• begin to decline : about 10 to 12 weeks

• nadir : about 20 weeks

• maintained at this lower level

for remainder of pregnancy

5. Concentrations of hCG in Serum & Urine



• elevated : multiple fetuses, erythroblstotic fetuses,

hydatidiform mole, choriocarcinoma.

Down syndrome

• depressed : ectopic pregnancy impending

spontaneous abortion

6. Elevated or Depressed hCG Levels



- rescue and maintenance of function of corpus luteum- stimulate of fetal testis : to promote male sexual differentiation- stimulate of maternal thyroid : increases thyroid activity, stimulate iodine uptake- other : promote relaxin secretion

7. Biological Function



- single non-glycosylated polypeptide chain

- similar to hPRL (prolactin)

1. Chemical Characteristics

◎ hPL

- potent lactogenic and GH-like bioactivity

HUMAN PLACENTAL LACTOGEN


- hPL – on chromosome 17

- hPRL – on chromosome 6

2. Gene Structure

3. Serum Concentration

• demonstrable in placenta within 5 to 10 days

after conception

• detected as early as 3 weeks after fertilization

• rises until about 34 to 36 weeks



- stimulated : insulin, cAMP

- inhibited : PGE2, PGF2α

4. Regulation of hPL Biosynthesis

5. Metabolic Actions

① lipolysis and increase FFA

② anti-insulin action



1. Chorionic Adrenocorticotropin - ACTH, lipotropin, β-endorphin

2. Chorionic Thyrotropon

3. Relaxin - acts on myometrial smooth muscle

to promote uterine relaxation

4. PTH-rP

5. hGH-variant

OTHER PLACENTAL PROTEIN HORMONES


1. GnRH

HYPOTHALAMIC-LIKE RELEASING HORMONES

• immunoreactive GnRH was present

in cytotrophoblast

2. CRH • biological function

- fetal adrenal steroidogenesis

- smooth muscle relaxation

- immunosuppression



• level

- nonpregnant – 15 pg/mL

- early third trimester – 250 pg/mL

- last 5 to 6 weeks – 1000 to 2000 pg/mL

• cushing syndrome that developed during pregnancy

with spontaneous resolution after delivery

→ placental CRH stimulated pituitary

ACTH formation



• positive feedback

: placental CRH↑ → placental ACTH↑

→ glucocorticosteroid formation↑

→ placental CRH expression↑


1. Neuropeptide-Y

2. Inhibin and Activin

3. Atrial Natriuretic Peptide (ANP)

OTHER PLACENTAL PEPTIDE HORMONES


ESTROGENS

• placenta produce huge amounts of

estrogen, progesterone

• near tern : hyperestrogenic state

• produced by syncytiotrophoblast


ESTROGENS

1. Biosynthesis

1) nonpregnant : produced in the ovarian follicle

(in theca cell)acetate

cholesterolandrostenedione

(taken up granulosa cell)estradiol 17β synthesis


ESTROGENS

2) pregnant - neither acetate nor cholesterol, nor even progesterone can serve as precursor - C19-steroids convert to estrone and estradiol-17β

- C19-steroids : dehydroepiandrosterone, androstenedione, and testosterone - plasma C19-steroids are estrogen precursors


ESTROGENS

2. Placental Aromatase Enzyme

• enzyme complex that catalyze estrogen formation

from androstenedione

• - Cyt P-450 monooxygenase

- aromatase cytochrome P-450

- flavoprotein

- NADPH-cytochrome P-450 reductase


ESTROGENS

3. Secreted Estrogens • ovary

: androstenedione → estrone → estradiol-17β

• adipose tissue

: androstenedione → estrone

• human placenta

① estradiol-17β

② 16α-hydroxyandrostenedione

→ 16α-hydroxyesterone → estriol


FETAL ADRENAL GLANDS

◎ Fetal Adrenal Glands- compared with adult organs, the adrenal cortex is the largest organ of the fetus- more than 85% of fetal gland is normally composed of a peculiar fetal zone (not in adults)

1. Contribution to Placental Estrogen Formation • near term, estradiol-17β produced in placenta

- half from maternal - half from fetal plasma



2. Placental Estriol Synthesis

• nonpregnant

urine estriol : estrone + estriol-17β = 1 : 1

• near term, this ratio increases to 10 or more

• 16α-hydroxylated C19-steroids

- converted to estriol by placental tissue

- is synthesized by the fetal adrenal and liver

• near term, fetal source (90&)

maternal source (10%)



E2

E3

Adrenal

DS

Liver

16α-OH-DS

E2

Placenta

E3

E2Adrenal

DS16α-OH-DS

Liver

16α-OH-DS

E3

MaternalCompartmen

t Fetus



3. Fetal Adrenal Development

• in early embryo, adrenal cortex is composed of cells

- proliferate rapidly prior to vascularization

of pituitary gland

→ comprise fetal zone

• ACTH is secreted by

- fetal pituitary gland

- chorionic ACTH syncytiotrophoblast



4. Enzymatic Considerations

• deficiency of 3β-hydroxysteroid dehydrogenase

→ limit the conversion of

- pregnenolone → progesterone

- 17α-hydroxypregnenolone

→ 17α-hydroxyprogesterone

• very active steroid sulfotransferase



5. Fetal Adrenal Steroid Precursor

- LDL cholesterol

- is synthesized fetal adrenal

→ convert to 16α-OH C19 steroid in fetal liver

→ placenta



6. Fetal Conditions that Affect Estrogen Production

① fetal death

- striking reduction in the levels of

urinary estrogens

② fetal anencephaly (In the absence of the fetal zone)

- limited availability of C19-steroid precursors

→ rate of formation of placental estrogens is

severely limited



③ fetal adrenal hypoplasia - estrogen formation is very limited④ placental sulfatase deficiency - precludes the hydrolysis of C19-steroid sulfates (X-linked disorder)⑤ placental aromatase deficiency - androstenedione could not converted to estradiol-17β

⑥ down syndrome - serum unconjugated estriol levels were low - screening of 2nd trimester



⑦ deficiency in fetal LDL biosynthesis

- lead to no progesterone formation

- estriol levels were also lower than normal

⑧ fetal erythroblastosis

- estrogen levels in maternal plasma are elevated

⑨ decreased fetal adrenal use of LDL

- most common cause of decreased

placental estrogen formation


① glucocorticosteroid treatment

- inhibit ACTH secretion → maternal & fetal adrenal secretion is decreased → causes striking reduction in placental estrogen② maternal adrenal dysfunction

- estrone and estradiol-17β is decreased

③ maternal ovarian androgen-producing tumors

- precluding transplacental passage



④ maternal renal disease

- lower level of estriol in urine maybe observed

⑤ maternal HTN and DM

- decreased uteroplacental flow → fetal formation of dehydroepiandrosterone is impaired⑥ gestational trophoblastic disease - in H-mole or choriocarcinoma, there is no fetal adrenal source of C19-steroid precursor, estrogen formation is limited



PROGESTERONE

1. Source of Cholesterol for Placental Progesterone Biosyntheis

• cholesterol (in mitochondria) cytochrome P450 → pregnenolone → progesterone 3β-hydroxysteroid dehydrogenase

- 6 to 7 weeks of gestation

→ produced in the ovary


PROGESTERONE

2. Progesterone Synthesis and Fetal Well-Being

• relationship between fetal well-being and placental

estrogen cannot be demonstrated in the case of

progesterone

• thus, progesterone biosynthesis may persist

for long periods after fetal death


PROGESTERONE

3. Progesterone Metabolism During Pregnancy

① 5α-dihydroprogesterone↑

② progesterone is converted to the potent

mineralocorticosteroid deoxycorticosterone

in pregnant women and in the fetus


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1 1/37 ch. 6. the placental hormones 부산백병원 산부인과 r1 손영실 ch. 6. the placental...

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