PLACENTAL HORMONES

steroid and protein hormones b-subunit antibody is used in most pregnancy tests

Human Chorionic Gonadotropin (hCG) Pregnancy hormone (the detection of hCG in blood or urine is almost always indicative of pregnancy) Biologic activity similar to LH Made by placenta and also fetal liver

Significance of abnormally high or low hCG HIGH 1. Multifetal pregnancy 2. Erythroblastosis fetalis ass. With fetal hemolytic anemia 3. Gestational trophoblastic diseases 4. Down syndrome LOW 1. Early pregnancy wastage 2. Ectopic pregnancy

Chemical Characteristics Highest carbohydrate content of any human hormone Sialic acid protects the molecule from catabolism T1/2=36 hours

Biosynthesis Single gene located on Ch 6 encodes the alpha-subunit for hCG, LH, FSH, and TSH. Seven separate genes on Ch 919 for the beta-hCG-beta-LH family {hcg (6), LH(1)}

Site of hCG synthesis Before 5 weeks, hcg is expressed in both syncytiotrophobast and cytotrophoblast. Later is solely produced by syncytitrophoblast.

Regulation of hCG synthesis - Placental GnRH regulates formation of hCG. - Primary GnRH production is regulated by inhibin(inhibits) and activin(stimulates) Renal clearance of hCG accounts for 30% and liver metabolism is 70%. BIOLOGIC FUNCTIONS OF hCG 1. Rescue and maintenance of corpus leuteum- i.e. continued progesterone production. 2. Stimulation of fetal testicular testosterone secretion 3. In the fetus, it acts as LH surrogate to stimulate replication of leydig cells and testosterone synthesis to promote male sexual differentiation. 4. Stimulate maternal thyroid gland: acidic isoforms stimulate thyroid

Notes: 1. level of hcg increases gradually and steadily until they plateau at about 36 weeks 2. Alpha-hCG secretion roughly corresponds to placental mass 3. Secretion of complete hCG molecule is maximal at 8-10 weeks 4. Decline: 10-12 weeks 5. Nadir: 16weeks

activity and basic isoforms stimulate iodine uptake 5. Promotion of relaxin secretion by corpus leuteum Human Placental Lactogen Prolactin like activity Concentrated in syncytiotrophoblast, demonstrated in cytotrophoblast before 6 weeks. Detected: 2nd or 3rd week after fertilization The production rate of hPL near term approx. 1g/day- is by far the greatest of any known hormone in humans, Demonstrable: 5-10days after conception Detected in maternal serum: 23weeks Rise steadily: 34-36weeks T1/2; 10-30 minutes

OTHER PLACENTAL PROTEIN HORMONES 1. Chorionic Adrencorticotropin - ACTH, lipotropin, beta-endorphin - ACTH helps in fetal lung maturation and timing of parturition 2. Relaxin - Demonstrated in human corpus leuteum, decidua and placenta - Structurally similar to insulin and ILGF. - Peaks:14-weeks and time of delivery - Relaxin with progesterone acts on myometrium to promote relaxation and quiescence in early pregnancy - Has autocrine-paracrine role in postpartum regulation of extracellular matrix degradation 3. Parathyroid hormone-related protein - Significantly elevated in pregnancy within maternal but not fetal circulation - Not produced in parathyroid glands of normal adults - Autocrine-paracrine role - Activate trophoblast receptors to promote calcium transport for fetal bone growth and ossification 4. Growth hormone variant - Detected: 21-26weeks - Peak:36weeks 5. Gonadotropin-releasing hormone - Found in cytotrophoblast only - Regulate trophoblast hCG production

Regulation of hPL biosynthesis The rate of hPL secretion is proportional to placental mass. hPL synthesis is stimulated by insulin and ILGF-1 and inhibited by PGE2 and PGF2alpha.

Metabolic actions of HPL 1. maternal lipolysis--inc. FFA - energy for maternal metabolism and fetal nutrition - HPL inhibits leptin secretion 2. Anti-insulin or diabetogenic - Inc. maternal insulin favours protein synthesis and provide source of AA to fetus 3. Potent angiogenic hormone formation of fetal vasculature

6. Corticotropin-releasing hormone - Increase trophoblast ACTH secretion - Induction of smooth muscle relaxation in vascular and myometrial tissue and immunosuppression. - Timing of parturition - Glucocorticoids act in Hypothalamus to inhibit its release and act in Trophoblast to stimulate its release 7. Growth hormone releasing hormone - Ghrelin is regulator of hCG secretion - Peaks: midpregnancy 8. Leptin Secreted by adipocytes Anti-obesity Regulates bone growth and immune function Also synthesiszed by syn and cytotrophoblast. Leptin inhibits apoptosis and promotes trophoblast proliferation. Contribute to Fetal birth weight

11. Activin - Not detectable in fetal blood before labor but detected after labor begins and decline rapidly after delivery. - GnRH synthesis Progesterone Progesterone: Synthesis Cholesterol pregnenolone (cytochrome P450)leaves the mitochondria and is converted to progesterone in the endoplasmic reticulum(3beta-hydroxysteroid dehydrogenase)diffusion Uses maternal circulating precursos vs. fetal circulating precursor (estrogen) Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cyle, pregnancy and embryogenesis. During the 6 to 7 weeks gestation, little progesterone is produced in the ovary. Surgical removal of corpus luteum during 7th to 10th week does not cause decrease in excretion of urinary pregnanediol,the urinary metabolite of progesterone However before that time, removal of corpus luteum will result in miscarriage. Exogenous progestin- given in place of an impaired progesterone production. After 8 weeks-placenta assumes progesterone secretion until term. 5000 times- progesterone increase compared to non pregnant woman.

9. Neuropeptide-Y - In cytotrophoblast - Cause CRH release 10. Inhibin - Inhibit pituitary FSH release - Produced by human testis and ovarian granulosa cells inc. corpus - Act with GnRH to regulate placental hCG syntheisis

250 mg-daily production for singleton,late and normal pregnancies 600 mg/day=for multifetal pregnancies

Metabolism during Pregnancy Metabolic clearance rate of progesterone in pregnant is similar to men and non pregnant women. During pregnancy, there is a disproportionate increase in plasma concentration of 5 alpha dihydroprogesterone from syncytiotrophoblast increases level of this metabolite Resistance to pressor agents during pregnancy Progesterone is converted to the potent mineralocorticoid deoxycorticosterone During implantation and gestation progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy. Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus making it thick and impenetrable to sperm If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding Progesterone decreases contractility of the uterine smooth muscle

In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production. A drop in progesterone levels is possibly one step that facilitates the onset of labor The fetus metabolizes placental progesterone in the production of adrenal steroids.

Estrogen Placenta produce huge amounts of estrogen using blood-borne steroidal precursors from maternal and fetal adrenal glands Near term, pregnant woman is in HYPERESTROGENIC STATE terminates abruptly after delivery Estrogen produced by syncytiotrophoblast during last few weeks of pregnancy is = 1 day of ovarian production of estrogen by 1000 ovulatory women

Estrogen Production 2-4 wks of pregnancy rising level of HCG maintain the production of estradiol in maternal corpus luteum 7th wk of pregnancy production of Pg & Eg by maternal ovaries luteal-placental transition >50% of Estrogen entering maternal circulation is produced in the placenta

Placental Estrogen Biosynthesis The pathways of estrogen synthesis in the human placenta differ from

those in the ovary of nonpregnant women Neither cholesterol nor progesterone can serve as precursor for estrogen biosynthesis in human trophoblast Steroid 17a hydroxylase (CP17) not expressed in plancenta

4. 17 -hydroxysteroid dehydrogenase type 1 (17 HSD1)

DHEA secreted by fetal adrenal glands converted to 16a OHDHEAS in the liver) Estradiol, (E2) and Estriol (E3)

Conversion of C21 steroid to C19 steroid not possible Estrogen precursors therefore are: C19 steroids Dehydroepiandrosterone (DHEA) & its Sulfate (DHEA-S) High capacity for placenta to convert C19 steroids to estrone and estradiol

By term , half of estradiol-17B (E2)is derived from fetal adrenal DS and half from maternal DS On the other hand-90% estriol (E3) in placenta from fetal 16 a-OHDS, 10% other sources. Increase metabolic clearance rapid use of substrate for placental estrogen Decrease plasma concentration of DHEAS as pregnancy progresses

Placental expression of 4 key enzymes

1. Steroid sulfatase (STS) 2. 3-hydroxysteroid dehydrogenase type 1 (3 -HSD) 3. Cytochrome p450 aromatase (CYP19)

Fetal adrenal glands are quantitatively most important source of placental Estrogen precursors in human pregnancy

Role of estrogen: pregnancy 1. Interacts with Prostaglandin and makes ovulation possible 2. Regulates production of Prostaglandin by placenta 3. Vital role in development of fetus. It stimulates maturation of different fetal organs- lungs, kidneys, liver, and regulates bone density. 4. Speed up the transformation of stem cells of placenta into mature cells. 5. Maintains pregnancy.