PREGNANCY 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 PLACENTA

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 (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 pregnancy

HUMAN CHORIONIC GONADOTROPIN (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 wk. of gestation –  in multiple pregnancy –at 1,000-1,500 IU/L intrauterine gestation visible with TVG ultrasound

HUMAN CHORIONIC GONADOTROPIN (hCG) determination: –biologic assays –immunologic: radioimmunoassay (RIA, sensitivity 5mIU/ml) immunoradiometric assay (IRMA, sensitivity 150mIU/ml) ELISA (sensitivity mIU/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 hCG

HUMAN PLACENTAL LACTOGEN (hPL) 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 pregnancy

HUMAN PLACENTAL LACTOGEN (hPL) 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) structurally similar to pituitary ACTH  circulating maternal levels hypercortisolism CORTICOTROPIN RELEASING HORMONE (CRH) produced in cytotrophoblast (max. at term) stimulates placental ACTH release  circulating maternal levels

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  ( ng/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 STEROIDS

ESTRIOL 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 9 th wk. (0,05ng/ml) ; at term (30ng/ml) ESTRADIOL / 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 UNCONJUGATED 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 isoimmunisationESTRIOL

ESTROGENS - HORMONAL 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

PROGESTERONE production during pregnancy: –corpus luteum (only source till 6 th wk.) –placenta (6 th wk. -> 12 th wk. -> parturition ) luteoplacental shift: 7-8 th wk of pregnancy production independent of fetus conception cycle: sustained slow rise early pregnancy: 10-35ng/ml, 100mg/day at term: max ng/ml, 250mg/day

MATERNAL 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 - HORMONAL FUNCTION

Steroidogenesis in fetus & placenta

OVARIAN STEROIDOGENESIS