fertilization, pregnancy, embryonic development
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Fertilization, Pregnancy, Embryonic Development
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
• 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
• 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
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
• 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
• 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
• 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
• 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
• 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
Placenta
• Interface between maternal, fetal tissues– Maternal = decidua
• Endometrial lining
• Falls off at parturition
• Supplied by spiral arteries
– Fetal cells = trophoblasts
• Exchange organ
• Barrier
• “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
• 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
Fetoplacental Unit
• Sim to theca lutein, granulosa lutein cooperation in progesterone/E2 production
• 3 Main hormonal groups– Estrogens– Progesterone– Corticosteroids
• Estrogens– From androgens by fetal adrenal cortex– Fetus doesn’t express 3hydroxysteroid
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
• 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
• 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
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)
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
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)
• 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
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
• 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
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
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
• 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
Fetal Gonad Sex Steroid Synthesis
• 17 hydroxylase activity dominant– Pregnenolone 17 hydroxypregnenolone
and 17 hydroxyprogesterone androgen synth
• Testes testosterone
• Ovary androstenedione, testosterone precursors for estrogen Estradiol
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