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부산백병원 산부인과 R1 손영실

Ch. 6. The Placental Hormones. 부산백병원 산부인과 R1 손영실. HUMAN CHORIONIC GONADOTROPIN (hCG). 1. HUMAN PLACENTAL LACTOGEN (hPL). 2. OTHER PLACENTAL PROTEIN HORMONES. 3. HYPOTHALAMIC-LIKE RELEASING HORMONES. 4. OTHER PLACENTAL PEPTIDE HORMONES. 5. ESTROGENS. 6. FETAL ADRENAL GLANDS. 7.

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부산백병원 산부인과 R1 손영실

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

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

  3. ◎ 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. HUMAN CHORIONIC GONADOTROPIN ◎ hCG • “pregnancy hormones” • produced almost exclusively in the placenta • detection of hCG in blood or urine - indication of pregnancy

  5. HUMAN CHORIONIC GONADOTROPIN 1. Chemical Characteristics • glycoprotein H - hCG, FSH, LH, TSH • two subunits - α subunits – identical - β subunits – distinctly different 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

  6. HUMAN CHORIONIC GONADOTROPIN 3. Cellular Sites of Origin • complete hCG molecule is synthesized primarily • in the syncytiotrophoblast 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

  7. HUMAN CHORIONIC GONADOTROPIN 5. Concentrations of hCG in Serum & Urine • 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

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

  9. HUMAN CHORIONIC GONADOTROPIN 7. Biological Function - 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

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

  11. HUMAN PLACENTAL LACTOGEN 2. Gene Structure - hPL – on chromosome 17 - hPRL – on chromosome 6 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

  12. HUMAN PLACENTAL LACTOGEN 4. Regulation of hPL Biosynthesis - stimulated : insulin, cAMP - inhibited : PGE2, PGF2α 5. Metabolic Actions ① lipolysis and increase FFA ② anti-insulin action

  13. OTHER PLACENTAL PROTEIN 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

  14. HYPOTHALAMIC-LIKE RELEASING HORMONES 1. GnRH • immunoreactive GnRH was present in cytotrophoblast 2. CRH • biological function - fetal adrenal steroidogenesis - smooth muscle relaxation - immunosuppression

  15. 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. HYPOTHALAMIC-LIKE RELEASING HORMONES • positive feedback : placental CRH↑ → placental ACTH↑ → glucocorticosteroid formation↑ → placental CRH expression↑

  17. OTHER PLACENTAL PEPTIDE HORMONES 1. Neuropeptide-Y 2. Inhibin and Activin 3. Atrial Natriuretic Peptide (ANP)

  18. ESTROGENS • placenta produce huge amounts of estrogen, progesterone • near tern : hyperestrogenic state • produced by syncytiotrophoblast

  19. ESTROGENS 1. Biosynthesis 1) nonpregnant : produced in the ovarian follicle (in theca cell) acetate cholesterol androstenedione (taken up granulosa cell) estradiol 17β synthesis

  20. ESTROGENS 2) pregnant - neither acetate nor cholesterol, nor even progesterone can serve as precursor - C19-steroids convert to estrone and estradiol-17β - C19-steroids : dehydroepiandrosterone, androstenedione, and testosterone - plasma C19-steroids are estrogen precursors

  21. 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. 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. 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. 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. Maternal Compartment Fetus E2 E2 Adrenal DS 16α-OH-DS E2 Adrenal DS Placenta Liver 16α-OH-DS Liver 16α-OH-DS E3 E3 E3 FETAL ADRENAL GLANDS

  26. 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. 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. FETAL ADRENAL GLANDS 5. Fetal Adrenal Steroid Precursor - LDL cholesterol - is synthesized fetal adrenal → convert to 16α-OH C19 steroid in fetal liver → placenta

  29. 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 C19-steroid precursors → rate of formation of placental estrogens is severely limited

  30. FETAL ADRENAL GLANDS ③ fetal adrenal hypoplasia - estrogen formation is very limited ④ placental sulfatase deficiency - precludes the hydrolysis of C19-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. 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. MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION 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

  33. MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION 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 C19-steroid precursor, estrogen formation is limited

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

  35. 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. 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. 감사합니다.

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