Peptide & protein hormone ; hPL, hCG, ACTH, other products of POMC, chorionic
thyrotropin, GH variant, PTH-rP, calcitonin, relaxin, TRH, GnRH, CRH, somatostatin,
GHRH, inhibin, activins, ANP
Figure 6-1
II. Human Chorionic Gonadotropin
"Pregnancy hormone"
Glycoprotein hormone with biologic activity like LH, both of which act via plasma
membrane LH/hCG receptor.
Produced almost exclusively in the placenta (but, β-subunit is synthesized in fetal
kidney,& a number of fetal tissues produce the intact hCG molecules)
A. Chemical characteristics
Glycoprotein with the highest carbohydrate content
Carbohydrate component (esp, terminal sialic acid) ; protects the molecule from catabolism
Plasma half-life ; 24 hrs (cf. LH; 2 hrs)
Comprised of α &β subunit
-> noncovalently linked ; no intrinsic LH-like biologic activity of either separated subunit
Structurally, similar to hCG : LH, FSH, TSH ; α-subunit identical
B. Biosynthesis
Synthesis of the α-& β- chain ; regulated separately
* α-subunit ; single gene ( chromosome 6 at q12-q21)
* 8 separate genes ( chromosome 19 ) of β- hCG/β-LH family
7 genes -> code for β-hCG
1 gene -> code for β-LH
--> only 3 of the β-hCG genes are expressed.
7β-hCG genes likely evolved from an ancestral gene for LH.
* As with hCG, a number of genes that are expressed in human placenta seem to
have evolved from genes normally expressed in adult tissues.
ex) hPL <-- prolactin gene
CYP19 (aromatase, the enzyme required for estrogen synthesis)
: Promoters used to initiate gene transcription in trophoblast are different from the
promoters used to initiate transcription of the same gene in nontrophoblastic cells
(ex. granulosa & adipose tissue stromal cells)
α-&β-subunits of hCG : synthesized as larger molecular wt. precursors
--> Signal sequence are cleaved by microsomal endopeptidase.
--> Once intact hCG is assembled, the molecule is rapidly released from the cell.
Rate limiting step for hCG synthesis : synthesis β-subunits
Trophoblasts of normal placenta & tissue of H-mole & choriocarcinoma tissues secretes
free α-&β-subunits as well as intact hCG.
--> Excess of hCG α-subunits (+) in placenta & plasma of pregnant women but,
β-subunits : present in plasma in only small quantities.
C. Cellular Sites of Origin
Complete hCG molecule is synthesized primarily in the syncytiotrophoblast.
Immunoreactive hCG is present in cytotrophoblasts very early in pregnancy, before 6wks.
Cellular shift in the formation of hCG & hPL --> occurs at about 6wk
1. Regulation of HCG Subunit Biosynthesis
The amounts of mRNA for both the α-&β-subunits of hCG in syncytiotrophoblast
: 1st trimester >> at term. --> important consideration in the measurement of hCG in
plasma as a screening procedure to identify abnormal fetuses.
The finding of mRNA for the α-&β-subunits of hCG in cytotrophoblasts or in
intermediate trophoblasts --> hCG genes are expressed before full differentiation of
trophoblast. : treatment of cytotrophoblasts in culture with cAMP --> promote hCG
secretion without the formation of syncytium.
Supported by the fact that cytotrophoblasts begin to disappear from the placenta at
the end of the 1st trimester : but, in some abnormal pregnancy in which there is a
reappearance of cytotrophoblasts. -- hCG ↑
(ex. D-antigen isoimmunization * G-DM)
GnRH (produced in cytotrophoblast) --> may act on the syncytium to stimulate
hCG formation
D. Molecular Forms of HCG in Plasma & Urine
Multiple forms of hCG in maternal plasma & urine (+)
1. Enzymatic degradation
2. Modification during the normal cellular sequence of synthesis/processing of the
hCG molecule
1. β-Subunits
Plasma levels of the free α-&β-subunits in pregnant women : substantially differed
from those of the intact molecule. (result of rate-limiting synthesis of β-subunits)
Figure 2-4
2. Free α-Subunits
Free α &α-subunits of intact hCG : identical. but 2 forms of the α-subunits differ
in oligosaccharide structure.
↑ size of the oligosaccharide of free α: prevent dimerization with β-hCG.
Plasma levels of free α increase gradually, but steadily, until about 36wk, when a
plateau is attained that is maintained for the remainder of pregnancy.
(--> this pattern is similar to that of hPL)
α-hCG secretion : roughly correspondent to placental mass.
c.f. Rate of secretion of complete hCG molecule : maximal at 8~10wk
Always < 10% than that of intact hCG.
3. hCG Glycosylation.
4. Nicks in the HCG Molecule.
Nicks : missing peptide linkages
Site : between β-subunit amino acid 44 ~ 45 & 47 ~ 48
Extent of nicking in standard preparation from pooled urine.
: 10 ~ 20% but, in individual samples, (0 ~ 100%)
Origin : believed to be through enzymatic action on the molecule that occurs near the
cellular site of synthesis of the β-subunit (ex. reaction catalyzed by leukocyte elastase)
(--> severely attenuated but variable among different antibody)
--> Issue of some concern when monitoring changes in the levels of hCG as a
function of time, treatment or both, as in the clinical management of persons with
neoplastic trophoblastic Dz.)
5. The " β-core fragment" of HCG.
Composition : aminoacids 6-40 that are disulfide bonded to aminoacids 55-92
Not biologically active and not combine with the α-subunit to produce intact hCG.
More easily identified in urine because in plasma this moiety is bound to protein in a
manner that precludes ready identification/quantification by immunoassay.
E. Concentration of HCG in Serum & Urine
Intact hCG molecule : detectable in plasma about 7.5 ~ 9.5 days after the midcycle surge
of LH. --> enters maternal blood at the time of blastcyst implantation.
Max. level : about 8 ~ 10wks.
During day, rhythmicity of hCG secretion (-), but fluctuation (+).
Concentration in maternal urine --> closely parallel to that in plasma.
Figure 2-4
Pattern of appearance of hCG in fetal blood --> similar to that in the mother (but,
levels in fetal plasma --> only 3% in maternal plasma.)
Concentration in amniotic fluid early in pregnancy --> similar to that in maternal
plasma. but, at near term, only 1/5.
1. Elevated or Depressed HCG levels in Maternal Plasma. / Urine
Significantly higher plasma levels
Multiple fetus
Single erythroblastotic fetus resulting from maternal D-Ag isoimmunization
H-mole & choriocarcinoma.
Relatively higher levels
: in midtrimester, Down syndrome (reason : ?, placenta - less mature)
: Renal clearance as native molecule --> 30% of total MCR,
remainder --> liver & kidney
c.f MCR : β-subunit (*10), α-subunits (* 30)
G. Biological Factor of HCG
1. Rescue of the Corpus Luteum
Continued progesterone production
Progesterone synthesis by corpus luteum ↓ at 6wk despite continued & increasing
hCG production
2. HCG Stimulation of Fetal Testis.
Testosterone secretion (max, at max. levels of hCG)
At a critical time in sexual differentiation of the male fetus, entering fetal plasma
from syncytiotrophoblast acts as an LH surrogate, stimulating the replication of fetal
testicular Leydig cells & testosterone synthesis to promote male sexual differentiation.
Before about 110 days, no vascularization of the fetal ant. pituitary from hypothalamus.
→ little LH secretion from the pituitary
→ hCG acts as LH before this times
→ as hCG levels fall, pituitary LH maintains a lower level of fetal testicular stimulation
3. HCG Stimulation of the Maternal Thyroid.
In neoplastic trophoblastic disease → biochemical & clinical evidence of hyperthyroidsm
(+) (Past, d/t chorionic thyrotropins by neoplastic trophoblast. Later, some forms of hCG
bind to the TSH receptors of thyroid cells)
hCG stimulates thyroid activity via the LH/hCG receptor & by the TSH receptor as well
4. Other Proposed Function.
Promote relaxin secretion by the corpus luteum.
LH/hCG receptor are found in myometrium & in uterine vascular tissue
Potent lactogenic & GH-like bioactivity ( and an immunochemical resemblance to human
GH ), --> In past, called chorionic GH, chorionic somatomammotropin
In syncytiotrophoblast
Detected in the trophoblast as early as the 2nd or 3rd weeks after fertilization of the ovum.
A. Chemical Characteristics.
Single nonglycosylated polypeptide chain with a molecular Wt. 22.279d
<-- derived from a precursor of 25.000d than contains a 26aminoacids signal sequence.
2 of these genes, hCS-A & hCS-B --> both code for hPL.
C. HPL Secretion & Metabolism
2 of these genes, hCS-A & hCS-B --> both code for hPL.
MCR : 175L/day (>> hCG)
Production rate at near term : 1g/day --> the greatest (by far) of any known
hormone in humans.
1. HPL Serum Concentration.
Demonstrable in placenta within 5 ~` 10days after conception & detected in serum
as early as the 5th week after LMP.
In maternal plasma, : rises steadily until about 34th ~ 36th weeks & proportional to
placental mass.
Figure 2-4
Half-life : very short, 10 ~ 30MIN.
In fetal blood / urine of the mother / newborn : very little
c.f. in amniotic fluid, somewhat lower than that in maternal plasma.
(d/t, secreted primarily into the maternal circulation, with only very small amounts in
cord blood)
2. Regulation of HPL Biosynthesis
mRNA levels in syncytiotrophoblast : relatively constant throughout pregnancy.
Prolonged maternal starvation in the 1st half of pregnancy --> ↑ HPL
Synthesis ↑ : insulin, cAMP
Synthesis ↓ : PGE2 & PGF2
3. Metabolic Actions of HPL
Lipolysis & ↑FFA (--> providing a source of energy for maternal metabolism &
fetal nutrition)
Anti-insulin action, (leading to ↑maternal insulin level)
--> favors protein synthesis and provides a mobilizable source of aminoacid for
transports to the fetus.
4. Pregnancy with no Detectable HPL
Not required for a successful pregnancy outcome.
hPL deficiency : ca. 1/12.000 pregnancy
hPL function primarily as a fail-safe mechanism to ensure nutrient supply to the fetus,
possibly, in times of maternal starvation.