Endocrinology of Pregnancy: The Placenta

1. Endocrinology of Pregnancy: The Placenta Tasmia Q. Henry, MD PGY-6 Maternal-Fetal Medicine Fellow Harbor-UCLA Medical Center July 3, 2007

2. Objectives • Background • Hormones • Questions

3. Trophoblast • Cytotrophoblast: • inner layer composed of individual rapidly proliferating cells • Syncytiotrophoblast: • outer & thicker layer comprised of a continuous mass of cell plasma containing multiple nuclei w/ indistinct cell borders

4. Hormonal Overview

6. Human Chorionic Gonadotropin(hCG) • Aka: “Pregnancy hormone” • Structure: • Glycoprotein(Mr ~36,700) w/ highest carbohydrate content of any human horm(~30%) • 2 subunits A & B • Structurally related to LH, FSH, &TSH • A subunits identical, B subunits diff • Properties: Acts via plasma membrane LH/hCG receptor • Location: Complete molecule synth mainly in syncytiotrophoblast

7. hCG • Detection in pregnancy: • In plasma ~7 ½ -9 ½ days post midcycle LH surge (precedes ovulation) • Maternal urine ~ 6wks after LMP • Rate of secretion of complete molecule is max @ 8-10wk • Clinical • Increased plasma hCG • Multiple gestation, erythroblastic fetus from Rh dz,hydatidform mole, choriocarcinoma, T21 • Low levels hCG • Ectopic, SABs

8. hCG • Functions: • Best known function “rescue” & maintenance of corpus luteumcontinues progesterone prod’n • Sexual df’tn male fetus • hCG acts as LH surrogatestimulates replication of fetal testicular Leydig cells & testosterone synth to promote male df’tn • ?stimulates thyroid activity via LH/hCG receptor & TSH receptor • In vivo: promotes relaxin secretion by corpus luteum • May act to promote uterine vasodilation & myometrial smooth muscle relaxation

9. hCG • The physiological roles of human chorionic gonadotropin (hCG) during the course of human pregnancy form conception to term.

10. Human Placental Lactogen(hPL) • Aka: chorionic somatomammotropin (hCS) • Structure: • Single nonglycosylated polypeptide chain (MW 22,279 d) • Structurally similar to human prolactin(hPRL) • Location: • Concentrated in syncytiotrophoblast • Identified in cytotrophoblast from < 6wks • Detection in pregnancy: • Detected in trophoblast ~ 2nd or 3rd wk after ovum fertilization

11. hPL • Production: Prod’n rate near term is greatest of any known hormone in humans • Functions: • Has potent lactogenic & growth hormone-like bioactivity • Lipolysis & incr in levels of circulation free fatty acids • Anti-insulin action

12. Placental Adrenocorticotropin(ACTH) • Structure: Similar in struct to pituitary ACTH • Location: Prod by syncytiotrophoblast • Function: Stimulates increase in circulating maternal free cortisol resistant to dexamethasone suppression

13. Gonadotropin-Releasing Hormone(GnRH) • Class: Hypothalamic-like hormone • Location: Localized to cytotrophoblastic cells • Activity: peaks @8wks then decreases w/ advancing gestational age • Function: Stimulates hCG release in dose-dependent paracrine manner

14. Corticotropin-Releasing Hormone(CRH) • Class: Hypothalamic-like horm • Location: • Located on long arm of chromosome 8 • Present in cytotrophoblast • Detection in pregnancy: Concentration increases sharply @ 20wks, highest conc @ term • Activity: Most intense activity in 1st trimester, diminishes towards term

15. CRH • Functions: • Stimulates placental ACTH release • Potent uteroplacental vasodilator • Releases into fetal circulation in response to fetal stress & condns leading to growth restriction • Clinical: Often elevated in preeclampsia, fetal asphyxia, preterm labor, & various conditions causing growth restriction

16. Inhibin • Class: Growth Factors • Location: • localized to syncytiotrophoblast • Secreted by corpus luteum & detected in decidua • Detection in pregnancy: • Increases @ 5wks gestation, peaks @ 8-10wks; subsequent decrease seen @13 wks, stabilizes until 30wks, then rises towards term • Early fluctuationslikely reflect corpus luteum release • 3rd trimester reflect inhibin originating from placenta & decidua • Function: • Inhibit release of chorionic GnRH &hCG • Inhibits FSH release by pituitaryprecludes ovulation during pregnancy

17. Parathyroid Hormone-Related Protein(PTH-rP) • Locations: • Synthesis in adult • noted in myometrium, endometrium, corpus luteum & lactating mammary tissue • Synthesis in fetus • parathyroid, kidney & placenta • Regulated by calcium concentration in the placenta only

18. Growth Hormone-Variant (hGH-V) • Aka: placental growth hormone • Location: Synthesized in placenta • Detection in pregnancy: Present in maternal plasma by 21-26weeks, increases in conc to ~36 wks, then remains relatively constant • Function: Biological activity profile similar to hPL

19. Other HPT-like Releasing Hormones • Thyrotroping-Releasing Hormone(cTRH) • Unknown role • Growth Hormone-Releasing Hormone(GHRH) • Aka somatocrinin • Expressed in selected human tumors • Implicated in development of acromegaly • Placental fcn unknown

20. Other Hormones • Activin • Function: • Stimulates release of GnRH & hCG • Human Chorionic Thyrotropin(HCT) • Structure: • Structurally similar to pituitary TSH, but w/o A subunit

21. Relaxin • Class: Decidual protein • Location: • Expressed in human corpus luteum, decidua & placenta • Structure: similar to insulin & nerve growth factor • Function: Acts on myometrial smooth muscle to stimulate adenylyl cyclase & promote uterine relaxation

22. Other Placental Peptide Hormones • Neuropeptide-Y(NPY) • Widely distributed in the brain • Localized in cytotrophoblast • Tx of placental cells w/ NPY causes release of CRH • Atrial Natriuretic Peptide(ANP) • Effects natriuresis, diuresis, & vasorelaxation • Produced in atrial myocytes • Synth in placental cytotrophoblast-like cells • Receptors found in placenta myometrial tissues

23. Corpus Luteum • LDL cholesterol is key regulatory precursor of progesterone prod’n • Principal steroid products • Progesterone • 17a-hydroxyprogesterone • Estradiol • Androstenedione

24. Pregnancy Steroids • Decidual cortisol • Likely suppresses the maternal immune rejection response • Confers immunologic “privilege” to implanted conceptus • Estrogen • Progesterone

25. Estrogens • Detection in pregnancy: As early as 7th wk, >50% of estrogen entering maternal circulation is produced by placenta • Location: • Nonpregnant: • occurs in ovarian follicle(granulosa cells) • Human corpus luteum(luteinized granulosa cells): • accomplished by preformed cholesterol taken up in LDL particles from plasma

26. Estrogens • Properties: Steroid 17a-hydroxylase/17,20 desmolase(encoded by CYP17 gene) is NOT expressed in human placenta • Functions: • Placenta can convert C19 steroids(dehydroepiandrosterone, androstenedione & testosterone) to estrone & estradiol-17B • Syncytiotrophoblast secretes 2 estrogens: • Estadiol-17B • Estriol • Fetal adrenal glands are the quantitatively imp source of placental estrogen precursors in human pregnancy

27. Maternal, placental and fetal compartments for estrogen and progesterone synthesis in human pregnancy.

28. Progesterone • Detection in pregnancy: Gradual increase in plasma levels as pregnancy advances • Synthesis • Also synthesized from cholesterol • Placental progesterone synthesis is proceeded by using maternal precursor, LDL cholesterol • Rate of synthesis largely dependent on # of LDL receptors on plasma memb of trophoblasts • Independent of uteroplacental blood flow

29. Fetal Adrenal Glands • Structure: • Adrenal cortex is largest organ of fetus(disproportionately large) • Outer or definitive zone, accounts for only about 15% of the fetal gland • The unique inner or fetal zone comprises 80-85% of the volume of the adrenal in utero, and is largely responsible for the tremendous secretory capacity of this organ • Properties: Daily prod’n of steroids near term ~100-200mg/day • Principal secretory products • Pregnenolone sulfate • DHEAS

30. Steroid Hormone Synthesis

31. Fetal Adrenal Glands • Functions: • Dehydroepiandrosterone sulfate(DHEAS) in maternal plasma is converted to estrogen in placenta • Maternal plasma DHEAS16a-hydroxyDHEA in maternal liverestriol by placenta • Precursor for fetal adrenal steroidgenesis: • Cholesterol • Near term, the fetus is the source of 90% of placental estriol precursor in NL human pregnancy

32. Fetal Adrenal Glands ACTH • Properties: Doesn’t cross placenta • Functions: • Acts to promote hypertrophy, not hyperplasia of adrenal cells • Ensures adequate activity of cholesterol side-chain cleavage enzyme(rate-limiting step in adrenal steroidgenesis)

33. Fetal Adrenal Glands • Clinical: • Most common cause of decreased placental estrogen fmtn(aside from fetal death) • Acquired reduction in fetal adrenal use of plasma LDL • Reduces rate of fmtn of DHEASreduces placental estrogen precursor availability • Seen in HTN & severe DM pregnancies

34. FINALLY…QUESTIONS!!

35. 1-Which of the following is NOT true of the chemical characteristics of hCG? • A- glycoprotein • B-highest carbohydrate content of any human hormone • C- both a and B subunits are necessary for bioactivity • D- the B subunit is functionally most like the B-subunit of FSH

36. 7-In which of the following are relatively low levels of hCG detected in maternal blood? • A- Down’s syndrome • B-hydatidiform mole • C-multiple gestation • D-impending abortion

37. 8-The control of hCG synthesis is primarily regulated by what organ? • A-Fetal adrenal gland • B-fetal pituitary gland • C-maternal ovaries • D-not known at present

38. 9- The hCG receptor is also the receptor for what other hormone? • A-estriol • B-FSH • C-LH • D-progesterone

39. 10-What is the best known function of hCG? • A- maintenance of corpus luteum • B-protection against paternal antibodies • C- stimulation of human placental lactogen(hPL) • D-stimulation of fetal ovaries to produce estrogen

40. 11-Other actions of hCG include which of the following? • A-stimulation of thyroid activity • B-promotion of relaxin secretion by corpus luteum • C- promotion of sexual differentiation of male fetus • D- all of the above

41. 17-What is the probable role of placental inhibin? • A-suppresses FSH • B-suppresses thyroxine-releasing hormone • C- suppresses gonadotropin-releasing hormone • D-suppresses CRH

42. 18-What is the immediate precursor for estrogen biosynthesis in the human placenta? • A- acetate • B-cholesterol • C-progesterone • D-DHEAS

43. 19-What is the quantitatively important source of placental estrogen precursor in the human? • A- maternal adrenal gland • B-syncytiotrophoblast • C-cytotrophoblast • D- fetal adrenal gland

44. 27-What is the major source of fetal plasma LDL cholesterol? • A-maternal transfer • B-placental synthesis • C- fetal liver • D- fetal adrenal gland

45. 32-Which of the following hormones demonstrates levels that are most sensitive to the state of fetal well being? • A-estriol • B-hPL • C-inhibin • D-progesterone

46. 26-What is the precursor used for steroid biosynthesis in the fetal adrenal? • A-cholesterol • B-acetate • C-progesterone • D-pregnenolone

47. 30-What is the precursor for the biosynthesis of progesterone by the placenta? • A-placental acetate • B-maternal cholesterol • C-fetal pregnenolone • D-fetal C-19 steroids

48. 1-D 7-D 8-D 9-C 10-A 11-D 17-A 18-D 19-D 27-C 32-A 26-A 30-B ANSWERS

49. REFERENCES • Cunningham FG. Williams Obstetrics & Study Guide; 21st Edition. New York, McGraw-Hill, 2001. • Gabbe SG. Obstetrics: Normal and Problem Pregnancies; 4th Edition. New York, Churchill-Livingstone, 2002. • www.google.com