1. 1 1/37 Ch. 6. The Placental Hormones 부산백병원 산부인과 R1 손영실 Ch. 6. The Placental Hormones

2. 2 2/37 Ch. 6. The Placental Hormones INDEX HUMAN CHORIONIC GONADOTROPIN (hCG) 1 HUMAN PLACENTAL LACTOGEN (hPL) 2 HYPOTHALAMIC-LIKE RELEASING HORMONES 4 ESTROGENS 6 OTHER PLACENTAL PEPTIDE HORMONES 5 OTHER PLACENTAL PROTEIN HORMONES 3 FETAL ADRENAL GLANDS 7 MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION 8 PROGESTERONE 9

3. 3 3/37 Ch. 6. The Placental Hormones ◎ The human placenta synthesize an enormous amount of hormones : hPL, hCG, ACTH, PTH-rP, GH variant, calcitonin, relaxin hypothalamic-like releasing and inhibiting hormones (TRH, GnRH, CRH, somatostatin, GHRH) inhibins, activins, ANP

4. 4 4/37 Ch. 6. The Placental Hormones HUMAN CHORIONIC GONADOTROPIN ◎ hCG “pregnancy hormones” produced almost exclusively in the placenta detection of hCG in blood or urine - indication of pregnancy

5. 5 5/37 Ch. 6. The Placental Hormones glycoprotein H - hCG, FSH, LH, TSH two subunits - α subunits – identical - β subunits – distinctly different 1. Chemical Characteristics 2. Biosynthesis single gene (chromosome 6 at q12-q21) - codes for α-subunit eight separate gene (chromosome 19) - Codes for β-hCG/β-LH family HUMAN CHORIONIC GONADOTROPIN

6. 6 6/37 Ch. 6. The Placental Hormones - complete hCG molecule is synthesized primarily in the syncytiotrophoblast 3. Cellular Sites of Origin 4. Regulation of hCG Subunit Biosynthesis - The amount of mRNA for hCG in syncytiotrophoblast from the first trimester are greater than at term → the measurement of hCG in plasma as a screening procedure to identify abnormal fetuses HUMAN CHORIONIC GONADOTROPIN

7. 7 7/37 Ch. 6. The Placental Hormones 1st detection : 7 1/2 to 9 1/2 days after the LH surge maximal levels : about 8 to 10 weeks begin to decline : about 10 to 12 weeks nadir : about 20 weeks maintained at this lower level for remainder of pregnancy 5. Concentrations of hCG in Serum & Urine HUMAN CHORIONIC GONADOTROPIN

8. 8 8/37 Ch. 6. The Placental Hormones elevated : multiple fetuses, erythroblstotic fetuses, hydatidiform mole, choriocarcinoma. Down syndrome depressed : ectopic pregnancy impending spontaneous abortion 6. Elevated or Depressed hCG Levels HUMAN CHORIONIC GONADOTROPIN

9. 9 9/37 Ch. 6. The Placental Hormones - rescue and maintenance of function of corpus luteum - stimulate of fetal testis : to promote male sexual differentiation - stimulate of maternal thyroid : increases thyroid activity, stimulate iodine uptake - other : promote relaxin secretion 7. Biological Function HUMAN CHORIONIC GONADOTROPIN

10. 10 10/37 Ch. 6. The Placental Hormones - single non-glycosylated polypeptide chain - similar to hPRL (prolactin) 1. Chemical Characteristics ◎ hPL - potent lactogenic and GH-like bioactivity HUMAN PLACENTAL LACTOGEN

11. 11 11/37 Ch. 6. The Placental Hormones - hPL – on chromosome 17 - hPRL – on chromosome 6 2. Gene Structure 3. Serum Concentration demonstrable in placenta within 5 to 10 days after conception detected as early as 3 weeks after fertilization rises until about 34 to 36 weeks HUMAN PLACENTAL LACTOGEN

12. 12 12/37 Ch. 6. The Placental Hormones - stimulated : insulin, cAMP - inhibited : PGE 2, PGF 2α 4. Regulation of hPL Biosynthesis 5. Metabolic Actions ① lipolysis and increase FFA ② anti-insulin action HUMAN PLACENTAL LACTOGEN

13. 13 13/37 Ch. 6. The Placental Hormones 1. Chorionic Adrenocorticotropin - ACTH, lipotropin, β-endorphin 2. Chorionic Thyrotropon 3. Relaxin - acts on myometrial smooth muscle to promote uterine relaxation 4. PTH-rP 5. hGH-variant OTHER PLACENTAL PROTEIN HORMONES

14. 14 14/37 Ch. 6. The Placental Hormones 1. GnRH HYPOTHALAMIC-LIKE RELEASING HORMONES immunoreactive GnRH was present in cytotrophoblast 2. CRH biological function - fetal adrenal steroidogenesis - smooth muscle relaxation - immunosuppression

15. 15 15/37 Ch. 6. The Placental Hormones HYPOTHALAMIC-LIKE RELEASING HORMONES level - nonpregnant – 15 pg/mL - early third trimester – 250 pg/mL - last 5 to 6 weeks – 1000 to 2000 pg/mL cushing syndrome that developed during pregnancy with spontaneous resolution after delivery → placental CRH stimulated pituitary ACTH formation

16. 16 16/37 Ch. 6. The Placental Hormones HYPOTHALAMIC-LIKE RELEASING HORMONES positive feedback : placental CRH↑ → placental ACTH↑ → glucocorticosteroid formation↑ → placental CRH expression↑

17. 17 17/37 Ch. 6. The Placental Hormones 1. Neuropeptide-Y 2. Inhibin and Activin 3. Atrial Natriuretic Peptide (ANP) OTHER PLACENTAL PEPTIDE HORMONES

18. 18 18/37 Ch. 6. The Placental Hormones ESTROGENS placenta produce huge amounts of estrogen, progesterone near tern : hyperestrogenic state produced by syncytiotrophoblast

19. 19 19/37 Ch. 6. The Placental Hormones ESTROGENS 1. Biosynthesis 1) nonpregnant : produced in the ovarian follicle (in theca cell) acetate cholesterol androstenedione (taken up granulosa cell) estradiol 17β synthesis

20. 20 20/37 Ch. 6. The Placental Hormones ESTROGENS 2) pregnant - neither acetate nor cholesterol, nor even progesterone can serve as precursor - C 19 -steroids convert to estrone and estradiol-17β - C 19 -steroids : dehydroepiandrosterone, androstenedione, and testosterone - plasma C 19 -steroids are estrogen precursors

21. 21 21/37 Ch. 6. The Placental Hormones ESTROGENS 2. Placental Aromatase Enzyme enzyme complex that catalyze estrogen formation from androstenedione - Cyt P-450 monooxygenase - aromatase cytochrome P-450 - flavoprotein - NADPH-cytochrome P-450 reductase

22. 22 22/37 Ch. 6. The Placental Hormones ESTROGENS 3. Secreted Estrogens ovary : androstenedione → estrone → estradiol-17β adipose tissue : androstenedione → estrone human placenta ① estradiol-17β ② 16α-hydroxyandrostenedione → 16α-hydroxyesterone → estriol

23. 23 23/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS ◎ Fetal Adrenal Glands - compared with adult organs, the adrenal cortex is the largest organ of the fetus - more than 85% of fetal gland is normally composed of a peculiar fetal zone (not in adults) 1. Contribution to Placental Estrogen Formation near term, estradiol-17β produced in placenta - half from maternal - half from fetal plasma

24. 24 24/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS 2. Placental Estriol Synthesis nonpregnant urine estriol : estrone + estriol-17β = 1 : 1 near term, this ratio increases to 10 or more 16α-hydroxylated C19-steroids - converted to estriol by placental tissue - is synthesized by the fetal adrenal and liver near term, fetal source (90&) maternal source (10%)

25. 25 25/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS E2 E3 Adrenal DS Liver 16α-OH-DS E2 Placenta E3 E2 Adrenal DS 16α-OH-DS Liver 16α-OH-DS E3 Maternal Compartment Fetus

26. 26 26/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS 3. Fetal Adrenal Development in early embryo, adrenal cortex is composed of cells - proliferate rapidly prior to vascularization of pituitary gland → comprise fetal zone ACTH is secreted by - fetal pituitary gland - chorionic ACTH syncytiotrophoblast

27. 27 27/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS 4. Enzymatic Considerations deficiency of 3β-hydroxysteroid dehydrogenase → limit the conversion of - pregnenolone → progesterone - 17α-hydroxypregnenolone → 17α-hydroxyprogesterone very active steroid sulfotransferase

28. 28 28/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS 5. Fetal Adrenal Steroid Precursor - LDL cholesterol - is synthesized fetal adrenal → convert to 16α-OH C 19 steroid in fetal liver → placenta

29. 29 29/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS 6. Fetal Conditions that Affect Estrogen Production ① fetal death - striking reduction in the levels of urinary estrogens ② fetal anencephaly (In the absence of the fetal zone) - limited availability of C 19 -steroid precursors → rate of formation of placental estrogens is severely limited

30. 30 30/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS ③ fetal adrenal hypoplasia - estrogen formation is very limited ④ placental sulfatase deficiency - precludes the hydrolysis of C 19 -steroid sulfates (X-linked disorder) ⑤ placental aromatase deficiency - androstenedione could not converted to estradiol-17β ⑥ down syndrome - serum unconjugated estriol levels were low - screening of 2nd trimester

31. 31 31/37 Ch. 6. The Placental Hormones FETAL ADRENAL GLANDS ⑦ deficiency in fetal LDL biosynthesis - lead to no progesterone formation - estriol levels were also lower than normal ⑧ fetal erythroblastosis - estrogen levels in maternal plasma are elevated ⑨ decreased fetal adrenal use of LDL - most common cause of decreased placental estrogen formation

32. 32 32/37 Ch. 6. The Placental Hormones ① glucocorticosteroid treatment - inhibit ACTH secretion → maternal & fetal adrenal secretion is decreased → causes striking reduction in placental estrogen ② maternal adrenal dysfunction - estrone and estradiol-17β is decreased ③ maternal ovarian androgen-producing tumors - precluding transplacental passage MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

33. 33 33/37 Ch. 6. The Placental Hormones ④ maternal renal disease - lower level of estriol in urine maybe observed ⑤ maternal HTN and DM - decreased uteroplacental flow → fetal formation of dehydroepiandrosterone is impaired ⑥ gestational trophoblastic disease - in H-mole or choriocarcinoma, there is no fetal adrenal source of C 19 -steroid precursor, estrogen formation is limited MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

34. 34 34/37 Ch. 6. The Placental Hormones PROGESTERONE 1. Source of Cholesterol for Placental Progesterone Biosyntheis cholesterol (in mitochondria) cytochrome P450 → pregnenolone → progesterone 3β-hydroxysteroid dehydrogenase - 6 to 7 weeks of gestation → produced in the ovary

35. 35 35/37 Ch. 6. The Placental Hormones PROGESTERONE 2. Progesterone Synthesis and Fetal Well-Being relationship between fetal well-being and placental estrogen cannot be demonstrated in the case of progesterone thus, progesterone biosynthesis may persist for long periods after fetal death

36. 36 36/37 Ch. 6. The Placental Hormones PROGESTERONE 3. Progesterone Metabolism During Pregnancy ① 5α-dihydroprogesterone↑ ② progesterone is converted to the potent mineralocorticosteroid deoxycorticosterone in pregnant women and in the fetus

37. 37 37/37 Ch. 6. The Placental Hormones 감사합니다.