PREGNANCY PROTEINSPREGNANCY PROTEINS

• Early pregnancy factor (EPF)• Placental proteins: – pituitary-like hormones: hCG, hPL, ACTH, hCT– hypothalamic-like hormones: GnRH, CRH, TRH,

SRIF– growth factors: inhibin, activin, IGFs, EGF– other peptides: SP-1, PAPP-A, PP-5

• Decidual proteins: PRL, relaxin, IGFBP, PP-14

• Fetal proteins: AFP

HUMAN PLACENTAHUMAN PLACENTA

Early pregnancy factor (EPF)Early pregnancy factor (EPF)

• immunosupressive protein produced by maternal ovaries stimulated by PAF

• earliest known indicator of fertilization (48hr)

• maximum production 0- 4 weeks then • function: – prevents rejection of an embryo (binds to

lymphocytes)– growth factor (?)

• clinical applications : to be evaluated

HUMAN CHORIONIC GONADOTROPIN HUMAN CHORIONIC GONADOTROPIN (hCG)(hCG)

• glycoprotein hormone, two chains – alpha-subunit (chromosome 6) : identical – beta-subunit (chromosome 19) : unique

activity and specificity

• trophoblastic tissue (syncytiotrophoblast)

– normal placenta (also multiple placenta)– gestational trophoblastic disease (hydatiform

mole and choriocarcinoma; x 3-100)– ectopic pregnancy

hCG levels during pregnancyhCG levels during pregnancy

HUMAN CHORIONIC GONADOTROPIN HUMAN CHORIONIC GONADOTROPIN (hCG)(hCG)

• control of secretion: placental GnRH secreted by cytotrophoblast ( activin, inhibin)

• normal pattern of secretion : 8 days post conception, dbl time 2-3 days– peak value 8-10 wk. of gestation ( 120,000 IU/L) and reach plateau 20,000 IU/L at 18-20 wk. of

gestation in multiple pregnancy– at 1,000-1,500 IU/L intrauterine gestation visible

with TVG ultrasound

HUMAN CHORIONIC GONADOTROPIN HUMAN CHORIONIC GONADOTROPIN (hCG)(hCG)

• determination:

– biologic assays

– immunologic:• radioimmunoassay (RIA, sensitivity 5mIU/ml)• immunoradiometric assay (IRMA, sensitivity 150mIU/ml)• ELISA (sensitivity 25-150mIU/ml)• fluoroimmunoassay (sensitivity 1mIU/ml)• latex agglutination inhibition tests (urine)• radioreceptor assay

• high sensitivity pregnancy tests (<1mIU/ml) - sometimes false positive because of endogenous pituitary hCG

• maintains corpus luteum

• stimulates:

– progesterone production by the corpus luteum

– Leydig cells of male fetus to produce testosterone (?)

– fetal adrenal steroidogenesis

• immunosupressive (lymphocyte modulator)

• thyrotropic activity

• induction of ovulation

FUNCTION OF hCGFUNCTION OF hCG

HUMAN PLACENTAL LACTOGEN (hPL)HUMAN PLACENTAL LACTOGEN (hPL)HUMAN SOMMATOMAMMOTROPHIN (hCS)HUMAN SOMMATOMAMMOTROPHIN (hCS)

• single chain polypeptide

• produced 3 wk. post conception; detected in serum 5-6 wk. post conception

• highest levels III trimester, disappears after delivery

• production proportional to placental mass

• determination: RIA

Role of hPL during pregnancyRole of hPL during pregnancy

HUMAN PLACENTAL LACTOGEN (hPL)HUMAN PLACENTAL LACTOGEN (hPL)HUMAN SOMMATOMAMMOTROPHIN (hCS)HUMAN SOMMATOMAMMOTROPHIN (hCS)

Growth hormone (GH and PRL-like effects) :

– induces lypolysis, plasma FFA

– inhibits glucose uptake and gluconeogenesis, glucose intolerance

– insulinogenic effect ( insulin)

–hyperinsulinemia plasma IGF-I

ADRENOCORTICOTROPIN (ACTH)ADRENOCORTICOTROPIN (ACTH)

• structurally similar to pituitary ACTH

circulating maternal levels

• hypercortisolism

CORTICOTROPIN RELEASING HORMONE (CRH)CORTICOTROPIN RELEASING HORMONE (CRH)

• produced in cytotrophoblast (max. at term)

• stimulates placental ACTH release

circulating maternal levels

DECIDUAL PROLACTIN (PRL)DECIDUAL PROLACTIN (PRL)

• similar to pituitary prolactin

• regulates fluid and electrolyte flux through fetal membranes

• secreted independently of fetal/maternal dopaminergic control

• ALSO maternal and fetal pituitary PRL

• maternal serum PRL (100-200ng/ml)

• AF PRL until 20wk. (1000ng/ml) then

PLACENTAL PROTEIN 14 (PP14)• immunosupresive peptide• secreted in decidualized endometrium • circulating marker of decidual growth

ALPHA-FETALPROTEIN (AFP)• synthesized in YS, GI and fetal liver

• osmoregulator of fetal intravascular volume AFAFP and MSAFP in neural tube defects MSAFP in pregnancies with Down syndrome

• Estrogens:– estradiol– estriol– estrone

• Progestogens:– progesterone– 17alpha-OHprogesterone

• Adrenocorticoids:– cortisol

PREGNANCY STEROIDSPREGNANCY STEROIDS

ESTRIOLESTRIOL• 1000 x more than in non pregnant state• 90% of all estrogens in pregnancy• exclusively produced by placenta (conversion of

16alpha-DHEA-S) - only living fetus • detectable at 9th wk. (0,05ng/ml) ; at term (30ng/ml)

ESTRADIOL / ESTRONEESTRADIOL / ESTRONE• produced by maternal sources (estradiol-ovaries: 5-6

wk.; estrone-ovaries, adrenal: 4-6wk.), gradually placenta, after I trimester major source (conversion of circulating DHEA-S)

• after conception range 5-30ng/ml

MATERNAL PLASMA MATERNAL PLASMA UNCONJUGATED ESTROGENSUNCONJUGATED ESTROGENS

Estradiol

Estriol

Estrone

• extremly low levels or no estriol:– fetal demise, anencephaly– CAH– placental sulfatase deficiency– hydatidiform moles

• decline in estriol production or failure to rise:– maternal renal disease, PIH, preeclampsia or eclampsia– IUGR

• large quantities:– multiple pregnancy – Rh isoimmunisation

ESTRIOLESTRIOL

ESTROGENS - ESTROGENS - HORMONAL FUNCTIONHORMONAL FUNCTION

• augment uterine blood flow

• placental steroidogenesis: regulation of progesterone synthesis

• parturition:– ripen the cervix– initiate uterine activity– augment established labor sensitivity of myometrium to oxytocin

PROGESTERONEPROGESTERONE

• production during pregnancy:– corpus luteum (only source till 6th wk.)– placenta (6th wk. -> 12th wk. -> parturition )

luteoplacental shift: 7-8th wk of pregnancy

• production independent of fetus

• conception cycle: sustained slow rise

• early pregnancy: 10-35ng/ml, 100mg/day

• at term: max. 100-300ng/ml, 250mg/day

MATERNAL PLASMA PROGESTERONEMATERNAL PLASMA PROGESTERONE

• modulates tubal motility (preimplantation conceptus)

• inhibits maternal-fetal tissue rejection

• antagonizes estrogen-augmented uterine blood flow

• induces uterine relaxation (stabilization of lysosomal membranes and inhibition of PG production)

PROGESTERONE - PROGESTERONE - HORMONAL FUNCTIONHORMONAL FUNCTION

Steroidogenesis in fetus & placentaSteroidogenesis in fetus & placenta

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