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