Fertilization, Pregnancy, Embryonic Development

1. Fertilization, Pregnancy, Embryonic Development

2. Fertilization • Human sperm fertilizable 48-72 h after ejac • Isthmic preparation • Human ova fertilizable 24-48 h after ov’n • Ampulla • Sperm hyaluronidase penetrates corona radiata

3. Ovum ZP3 • Glycoprotein • Recognition • Sperm membr FA-1 • Prot receptor tyr kinase • Act’n  autophosph’n  cell prot phosph’n •  Act’n voltage gated Ca channels  AR • Release, act’n acrosin (trypsin-like) • Penetration ZP

5. Sperm head fuses w/ oocyte • 2nd Meiotic div’n •  Mature oocyte + polar body • Mech’s to prevent polyspermy • Fusion male, female pronuclei  diploid zygote • Mitosis  morula  blastocyst • Blastocyst  uterus • Implantation  dev’t chorion, placenta

7. Implantation, Early Embryo Development • Implantation begins 5-6 d after fert’n (d 21 cycle) • Completed 11 fert’n d • Coincides w/ peak prod’n progesterone by CL (midluteal) • Progesterone impt to preparation decidual, secretory endometrium • If no fert’n, CL would begin decline now

8. Inner blastocyst cell mass  embryo proper • Outer cells = trophoblasts • Contact, signal uterine epith • EGF receptor on embryo nec • Uterine cell cytokine (LIF) nec • Two cell pop’ns • Syncytiotrophoblasts • Cytotrophoblasts

10. Syncytiotrophoblast – postmitotic surface layer • From fusion of cytotrophoblast plasma membr’s • Form initial chorionic shell • Erodes endometrial capillaries, veins • Perfused by maternal blood • Cytotrophoblast – mitotic cells • Inner cells = Langhans or villous • Form chorionic villi • Peripheral cells • Form trophoblastic shell • Form trophoblastic cell columns

15. Syncytiotrophoblast cells secrete hCG  maternal circ’n • Detectable w/in 24 h beginning implantation • Incr’s w/ incr’d trophoblast cell mass (peak end 1st trimester) • Functions: • Stim’s luteal function • Induces morning sickness • Stim area postrema of brain  n/v • Stim’s fetal androgen secr’n • Impt to masculinization of fetal genitalia

16. hCG stim’s luteal function • Incr’s hormone prod’n at CL • Progesterone uninterrupted • Mandatory until parturition • Functioning CL mandatory for maintenance first 7 wks • At 5 wks after fert’n, placental prod’n progesterone sufficient • Hormones @ sustained CL  strong neg feedback at ant pit • Plasma FSH, LH suppressed • Gonadotrophs unresponsive to GnRH

18. Chorionic villi dev by 2nd week after fert’n • Blood vessels here • Spiral endometrial arteries • Anchors to endometrium, placenta • Development her  umbilical cord • Definitive placenta at 11-12 fert’n wk • Structures can withstand high maternal blood pressure • Incr’d placental perfusion correlates w/ peak plasma hCG concent’s

21. Placenta • Interface between maternal, fetal tissues • Maternal = decidua • Endometrial lining • Falls off at parturition • Supplied by spiral arteries • Fetal cells = trophoblasts • Exchange organ • Barrier

25. “Incomplete twin of fetus” • GI, lung, kidney • Immunologic • Transfer immunoglobulins (exc IgG) • Prevent fetus rejection • Endocrine • Synth hormones, binding prot’s • Transport hormones • Degrade hormones

27. Placenta secretes variant of GH • GH-V • Replaces maternal GH @ 15-17 w gestation • May promote fetal growth • May be impt to pancreatic islet cells • Causes rising plasma IGF-1 • Neg feedback  suppression pit GH

28. Fetoplacental Unit • Sim to theca lutein, granulosa lutein cooperation in progesterone/E2 production • 3 Main hormonal groups • Estrogens • Progesterone • Corticosteroids

30. Estrogens • From androgens by fetal adrenal cortex • Fetus doesn’t express 3bhydroxysteroid dehydrogenase (isomerase) • So all pregnenolone  dehydroepiandrosterone (DHEA) • Placenta doesn’t express p450C17 • Can’t make 17-OH progesterone • Can’t make androstenedione • Can’t make DHEA • Impt to protection female fetus from androgens • Placenta makes mostly estriol • Sensitizes uterine smooth muscle to oxytocin

31. Progesterone • Syncytiotrophoblasts synth de novo • From cholesterol derived from maternal plasma • Placenta expresses much p450scc • Tubulovesicular mitochondria • Placenta can’t synthesize cholesterol • Pregnenolone  progesterone • Placenta doesn’t express p450C17 • So only progesterone • Enters both fetal, maternal circulations

32. Corticosteroids • In fetus, progesterone is precursor to adrenocortical hormones • Glucocorticoids • Gen’ly growth inhibitors, so minimized • Placental enz’s break down maternal glucocort’s • Uses maternal ACTH at fetal adrenal cortex • Diff enzymes expressed @ diff dev’l stages • 25th gestational week, rising corticosteroids • Impt to feedback mech’s • Impt to organ maturation

35. Embryonic Development/ Endocrinology • Innate bisexual potential  decision to male or female • Sex determination • Chromosomal (Y=male) • Gonadal (testis=male) • Genal (external genitalia) • Sexual/gender identity (psychosocial) • Sexual orientation (attraction)

36. Chromosomal Sex • Established during fert’n • Fusion male/female pronuclei  diploid chromosomal # • Oocyte – X sex chromosome • Sperm – X or Y sex chromosome • Female normal karyotype 46,XX • Male normal karyotype 46,XY

37. Gonadal Sex • Established during embryonic development • 5th week – urogenital ridge dev’d • Adjacent adrenal gland • 6th week – indifferent gonad from urogenital ridge • Requires expression WT-1 gene  zinc-finger transcription factor • Nec for gonad, kidney expression (mice) • Requires expression Steroidogenic Factor-1 (SF-1)

38. SF-1 • Impt to induction steroidogenic enz’s (mice) • Impt to dev’t adrenal glands, gonads, ventromedial nucleus hypothal (mice) • Impt to dev’t testis from indiff gonad • Stim’s testic differentiation  Sertoli cell appearance • Stim’s Sertoli prod’n AMH = AntiMullerian Hormone = MIF • Stim’s expression steroidogenic enzymes by dev’ng Leydig cells

39. Testis Development • Mandatory expression Sex determining Region Y (SRY gene)  SRY transcription factor (= Testis Determining Factor (TDF)) • Related to SOX genes that are impt to development cartilage, testis • SRY transcription factor probably suppresses Dosage Sensitive Sex reversal (DSS) gene • DSS suppresses SF1 • So SRY  disinhibition SF-1

40. Now SF-1  testicular differentiation • Sertoli cells • Steroidogenic enz’s in Leydig cells • AMH • Mullerian ducts would dev into female tract • AMH  inhibition dev’t Mullerian ducts

41. Sertoli Cells in Developing Testis • Secr’s AMH • 43-50 d embryonic life • Paracrine •  Involution Mullerian duct • Absence AMH  Mullerian duct dev’t regardless of sex steroid env •  Fallopian tubes, uterus, upper vagina • Normal condition in females

43. Leydig Cells in Developing Fetus • Secrete testosterone from embryonic d 60 (wk 8-9) • Not yet controlled by hypothal-hypophyseal system • hCG crucial • Rising during 1st trimester • Declines after wk 12 • Stim’s synth testosterone in developing Leydig cells

44. Testosterone • Stim’s dev’t Wolffian duct structures • Give rise to epididymis, vas deferens, seminal vesicles • Must be present before embryo wk 12 • Must be converted to DHT for masculinization external genitalia, prostate dev’t

46. Fetal Gonad Sex Steroid Synthesis • 17a hydroxylase activity dominant • Pregnenolone  17 a hydroxypregnenolone and 17 a hydroxyprogesterone •  androgen synth • Testes  testosterone • Ovary  androstenedione, testosterone precursors for estrogen •  Estradiol