The Placental Hormones (1)

Chapter 6. The Placental Hormones ( I )


Jan. 17, 1997 2nd year resident J. W. Lee. M.D.





I. Overview




  • Halban (1905), Placenta ; "endocrine organ
  • Steroid hormone : Table 6-1
  • 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.



  1. 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)



  2. 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. 1. Enzymatic degradation
  2. 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)


  • Biological importance of nicked hCG.

    : unknown, but. bioactivity ↓ (20%) & immunoreactivity to monoclonal antibody


    (--> 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)



  • Relatively lower levels

    Ectopic pregnancy

    Impending spontaneous abortion.



F. Regulation of HCG Synthesis



    By: 1. placental GnRH, 2. placental inhibin

    (c.f. In vitro)



    1. Butyrated derivatives of cAMP
    2. Hypothalamic - like hormone ( GnRH, CRH )
    3. IL-1 & IL-6
    4. TNF-α
    5. GF ( TGF-β & fibroblast GF )
    6. Colony-stimulating factors
    7. Thyroid hormone.


1. Metabolic Clearance of HCG




  • MCR (Metabolic Clearance Rate) : 3ml/min, (4L/day)

    : 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

    --> promote uterine vascular dilatation & myometrial smooth muscle relaxation.



III. Human Placental Lactogen




  • 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.


  • 191 aminoacid residues (GH: 94%, hPRL: 67% --> aminoacids sequence homology)

    <-- ? genes for hPL, hPRL, hGH evolved from a common ancestral gene (probably)
    by repeated gene duplication


  • Production Site :

    Trophoblast

    Direct radioimmunoassay in sera from men & women with varies malignancy

    --> broncogenic carcinoma, hepatoma, lymphoma, pheochromocytoma.


B. HPL Gene Structure & Expression.




  • 5 genes on chromosome 17.
  • 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.



IV. Other Protein Hormones of the Placenta



1. Chorionic Adrenocorticotropin




  • Pro-opiomelanocortin(POMC) --> ACTH, lipotropin, β-endorphin
  • Dexamethasone Tx -> not alter the levels of ACTH in placental tissue
  • Physiologic role ; unclear
  • Plasma level in pregnancy (before labor); lower than those in men and nonpregnant

    ; increase as pregnancy advances
  • Not cross the placenta


2. Chorionic Thyrotropin




  • Significant biologic role
  • Thyroid-stimulating activity in GTN; by hCG , not thyrotropin


3. Relaxin



  • Corpus luteum, decidua, placenta
  • Structually similar to insulin, nerve growth factor
  • Two relaxin genes; H1, H2

    i) corpus luteum; H2

    ii) decidua, placenta, fetal membrane; H1, H2
  • Act on myometrial smooth muscle to stimulate adenyl cyclase -> uterine relaxation


4. Parathyroid Hormone-related protein (PTH-rP)




  • Synthesis in uterus, corpus luteum, lactating mammary tissues, fetal parathyroid, placenta,
    kidney.
  • Not produced in the normal parathyroid gland of adults.
  • may serve as the parathromone of fetus
  • Synthesis/ secretion by cytotrophoblast
  • Responsive to the extracellular calcium concentration


5. Growth Hormone-variant ( hGH-v)



  • Placental growth hormone
  • hGH-v is in maternal plasma by 21-26 wks --> increasing concentration to 36 wks
  • Correlation with IGF-1 level.
  • Biologic action is similar to hPL




V. Hypothalamic-like Releasing Hormones



A. Gonadotropin-releasing Hormone (GnRH)




  • Present in cytotrophoblast
  • Stimulate the secretion of hCG from placenta
  • 1st trimester trophoblasts; more responsive to GnRH than term placenta
  • Inhibin, activin ; regulate GnRH synthesis


B. Corticotropin-releasing Hormone (CRH)




  • CRH gene is also expressed in trophoblast, amnion, chorion laeve, & decidua.


  • Plasma levels of CRH


    i) nonpregnant ; 15 pg/ml

    ii) early 3rd trimester ; 250 pg/ml

    iii) term ; 1-2 ng/ml

    iv) after delivery ; undetectable (half life; 1 hr)


  • Conditions of ↑ CRH : PIH, preterm labor, fetal asphyxia, fetal growth retardation,
    twin pregnancy, during the course of labor


1. CRH-binding protein (BP) in human plasma




  • Inactivate the CRH
  • Inhibit CRH-induced ACTH release by pituitary cells
  • CRH-BP levels decrease during last few weeks of pregnancy at a time when CRH
    increase
  • Deficiency --> Cushing syndrome


2. Placental CRH



  • Biologic function is not so unclear.


  • Receptors for CRH ; placenta, adrenal, sympathetic ganglia, lymphocyte, GI tract,
    pancreas, gonads, myometrium


  • Local action in paracrine or neuroendocrine fashion


  • Many suggestions of its role in pregnancy


    i) act to modify pituitary- adrenal function

    ii) induction of smooth muscle relaxation and immunosuppression

    iii) induction of myometrial contraction (i.e, initiation of parturition)

    iv) PG formation


3. Regulation of placental CRH synthesis



  • (+) feedback loop in placenta

    (--> glucocorticosteroid stimulation -> CRH gene expression)


C. Thyrotropin-releasing Hormone




  • Little known of the biologic role


D. Growth Hormone-releasing Hormone



    = somatocrinin

    ·Function ; not known



VI. Other Peptide Hormones Synthesized in Placenta



1. Neuropeptide-Y



  • Small peptide that distributed in brain, sympathetic neuron
  • Isolated from placenta, and localized in cytotrophoblast.
  • Potassium in high concentration NPY↑
  • Treatment of placental cells with NPY --> release of CRH


2. Inhibin and Activin




  • Produced by testis, granulosa-cells of ovary (including Corpus luteum)
  • Structure



    1) Inhibin ; composed of α- and β- subunit (βA of βB)

    2) Activin; combination of two β-subunits



  • Inhibin ; inhibit FSH secretion --> preclude ovulation during pregnancy ( greatest levels in term)


    * synthesis ; cytotrophoblast

    * storage ; syncytiotrophoblast

    * hCG and cyclic AMP analogue --> stimulate secretion

    * inhibin may act via GnRH to regulate hCG synthesis/ secretion in placenta


3. Atrial Natriuretic Peptide




  • Natriuresis, diuresis, vasorelaxation
  • Produced in atrial myocytes, placenta
  • ANP receptors are found in placenta, myometrium-> vasorelaxation by increasing
    cellular levels of cGMP
  • Promoting uterine relaxation during first 95% of pregnancy