Reproduction, Development and Ageing Flashcards
After what Carnegie stage is the embryo considered a foetus?
Stage 23
What is the length and weight of the developing foetus at the end of each trimester?
Trimester 1
Length: 5-8cm
Weight: 50g
Trimester 2
Length: 24-27cm
Weight: 1050g
Trimester 3
Length: 35-36cm
Weight: 2100g
What is the conceptus?
Everything produced from the fertilized egg
What causes regulation of cells during proliferation and differentiation of the developing foetus?
Paracrine and autocrine effect of hormones
How long is a normal pregnancy?
37-41 weeks
What is gastrulation? What is the result?
Formation of a 3-layer embryo Results in 3 germ layers - Ectoderm - Mesoderm - Endoderm
What is the fate of the different germ layers?
Endoderm: gut, liver, lungs
Mesoderm: Skeleton, muscle, kidney, heart, blood
Ectoderm: skin, nervous system
How is the CNS formed during neurulation?
Formed from the ectoderm
Neural groove does not undergo differentiation. Cells move and fuse to form the CNS
When does closure of the body cavity occur?
Begins at 21 days
Closes around 28 days
What development occurs in the second month PF?
- Limbs develop days 28-56
- Face develops
- Internal tissues develop (heart and lungs, gut)
- Looks like a foetus by day 56
What is the difference between PF and GA
Gestational age: Measured from day of last period
Post-fertilisation: Fertilisation occurs 2 weeks after the last day of period
What causes spina bifida?
When there is failure to complete neurulation; formation of a posterior neuropore
- Usually occurs towards the bottom of the spine
- Contents and location determines the outcome
- Vertebrae do not form correctly about the maformation. Neural tissue directs bone formation
Incidence: 1-2 per 1000 pregnancies
Surgery can hep anatomical but not functional problems
What are the different types of spina bifida?
Spina bifida occulta: Vertebrae do not form correctly. Superficially there are hairs above that part of the spine
Spina bifida meningocele: Pocket of CSF
Spina bifida myelomeningocele: More severe; part of the neural cord contained within the pocket
What is the incidence of anencephaly?
1-8 per 10,000 births
Female > male
How does the heart develop in utero?
- Heart tubes are at the greater edge of the blastocyst.
- Greater fold pushes heart tubes underneath and towards the cranial edge of the embryo
- The two heart tubes fuse to form the primitive heart tube
- Primitive atrium rotates around the primitive ventricle, whilst the primitive ventricle grows in size, until the atrium is sat behind the ventricle
- New connection forms between right atrium and ventricle
What is the ductus arteriosus?
Connection between aorta and pulmonary artery allows blood to bypass the lungs until birth
What changes occur to the heart after birth?
Before
- Deoxygenated blood from the upper body and oxygenated blood from the placenta enter the right atrium
- Goes to right ventricle
- Minimal blood goes to the lungs and most goes through the ductus arteriosus into the aorta
- Small amount of blood returns from lungs into right atrium, into ventricle then into the aorta
After
- Blood into right atrium is no longer a mix of oxygenated and deoxygenated, as no oxygen from placenta
- Ductus arteriosus closes so all blood from right ventricle goes to the lungs
How do the limbs develop?
- Forelimb bud appears at day 27/28
- Hindlimb bud appears at day 29
- Grow out from lateral plate mesoderm rapidly under control of special signalling regions
- Fully formed and patterned by day 56
What causes acondroplasia?
Gain of function mutation in FGFR3
What is Thalidomide? What effect does it have on foetal development?
- A drug used ~1958-1962 to treat morning sickness
- Currently used to treat leprosy and cancer
- Typically caused poor development of upper limbs
- In addition caused deformed eyes and heart, deformed alimentary and urinary tracts, blindness and deafness
- Interferes with blood vessel development
(Morning sickness peaks at 8 weeks- same time as limb development)
What is polydactyly?
Malformation of the hand causing 5 fingers and a thumb.
Cells direct development of each digit, extra cell present
No functional problems
How do the kidneys develop in utero?
Pronephros develops first. Precursor tissue that directs formation of the Mesonephros which connects to the cloaca. There are limited excretory functions.
Early fourth week: Uretetic bud appears
Sixth week: Metanephric blastema (metanephros = definitive kidney)
Eighth week: Differentiating metanephric tissue ascends
How do the kidneys ascend?
- The kidneys initially formed near the tail end of the embryo
- Vascular buds from the kidneys grow toward and invade the common iliac arteries
- Kidney position changes relative to:
a) adrenal glands
b) gonads - Rather than “drag” their blood supply with them as they ascend, the kidneys send out new and slightly more cranial branches and then induce the regression of the more caudal branches
What does the bladder develop from in utero?
Mostly endodermal, except the trigone (mesodermal) which develops from the mesonephric duct
(Trigone signals filling of the bladder to the brain)
What are the possible outcomes if development of the kidneys goes wrong?
- Renal agenesis
- Abnormal shaped kidneys
- Abnormal ureter
- Pelvic or horseshoe-shaped kidneys
- Bladder exstrophy
What causes renal agenesis?
- Early degeneration of ureteric bud
- Unilateral renal agenesis 1:1000 L>R
- Bilateral - Potter’s syndrome (oligohydramnios)
How do the gonads develop in utero?
- The gonads arise from intermediate mesoderm within the urogenital ridges of the embryo
- Primordial germ cells are the precursors to all gametes
- The genital ducts arise from paired mesonephric and paramesonephric ducts
- The mesonephric ducts give rise to MALE genital ducts (Wolffian duct)
- The paramesonephric ducts give rise to FEMALE genital ducts (Mullerian duct)
At what point does sexual differentiation occur in utero?
The gonads and reproductive tracts are indifferent up until 7 weeks of development; differentiation is determined largely by the presence or absence of SRY (on the Y chromosome)
Normally:
- If SRY+, then development proceeds along the male path (~7 weeks onwards)
- If SRY-, then development proceeds along the female path (~9 weeks onwards)
- If male is dysfunctional then female will take over
How does the male reproductive tract develop?
- SRY expression: a gonad develops into a testis containing spermatogonia, Leydig cells and Sertoli cells
- Leydig cells produce testosterone, which support growth of the mesonephric ducts (without testosterone, they regress)
- Some testosterone is converted into Dihydroxytestosterone (DHT), which supports development of the prostate gland, penis, and scrotum
- Sertoli cells produce anti-mullerian hormone (AMH, or mullerian inhibiting substances MIS), which induces regression of the paramesonephric ducts (absence of MIS, the paramesonephric ducts will persist)
What does the male genitalia differentiate from in utero?
- Ureteric bud: ureter
- Mesonephric ducts: rete testis, efferent ducts, epididymis, vas deferens, seminal vesicle, trigone of bladder
- Urogenital sinus: bladder (except trigone), prostate gland, bulbourethral gland, urethra
How does the female reproductive tract develop?
- In the absence of SRY, the gonad develops into an ovary with oogonia and stromal cells
- Since no testosterone is produced, the mesonephric (Wolffian) ducts regress
- Since there is also no AMH (MIS), the Mulleria (paramesonephric) ducts persist to give rise to the oviducts, uterus, and upper ⅓ of the vagina
- The urogenital sinus contributes to the formation of the bulbourethral glands and the lower ⅔ of the vagina
What does the female genitalia differentiate from in utero?
- Ureteric bud: ureter
- Mesonephric ducts: trigone of bladder
- Paramesonephric ducts: oviduct, uterus, upper ⅓ of vagina
- Urogenital sinus: bladder (except trigone), bulbourethral gland, urethra, lower ⅔ of the vagina
What causes the decent of the testes?
Due to tethering of the testes to the anterior body wall by the gubernaculum. With growth and elongation of the embryo coupled with shortening of the gubernaculum, the testes are pulled through the body wall, then the inguinal canal, and finally into the scrotum
What are the risks associated with undescended testes?
- Increased risk of cancer
- Do not function normally
How does external genitalia form?
- Male structures form under the control of testosterone
- In the absence of testosterone, female structures will form
What is hypospadias?
- Fusion of urethral folds is incomplete, so the urethra exits the penis other than at the tip. Primarily a structural complication
What is persistent Mullerian duct syndrome?
- Occurs in genetic males with mutations in AMH/MIS or the AMH/MIS receptor
- Because testosterone and DHT are produced, there are normal male external genitalia and male (Wolffian) genital ducts
- Because there is no inhibition, the paramesonephric ducts persist, i.e. there is a small uterus and paired fallopian tubes
- The testes may lay either in what would be the normal position for ovaries (i.e. within the broad ligament) or one or both testes may descend into the scrotum
What is androgen insensitivity syndrome?
- Occurs in genetic males (XY) with mutations in the androgen receptor (AR)
- Lack of virilisation of due to inability of AR to bind testosterone or DHT, so androgens have no effect
- Relatively normal female external genitalia (no functional androgens) but undescended testes
- Mesonephric ducts are rudimentary or lacking due to loss of testosterone signalling
- Normal progression of MIS from Sertoli cells causes Mullerian duct regression, so no oviducts, uterus, or upper ⅓ of vagina
What is Congenital Adrenal Hyperplasia?
- A female homologue to AIS
- Genetic females with decreased of lacking 21-hydroxylase enzyme activity, essential for cortisol synthesis
- Lack of cortisol feedback to pituitary causes overproduction of ACTH, and overactivity of the adrenal gland
- This leads to increased production of weak androgenic hormones from the adrenal gland, which results in weak virilisation of external genitalia, some male features:
- Enlarged clitoris
- Partial of complete fusion of labia majora
- The internal genitalia are female
During what time does formation of the face occur in embryogenesis?
Between 5 and 10 weeks
How does development of the lungs occur in utero?
Embryonic phase (~2-8 weeks) Pseudoglandular phase (~5-17 weeks) Canalicular phase (~16-27 weeks) Saccular phase (~24 weeks-birth) Alveolar phase (36 weeks-post-partum)
0-16 weeks: conducting zone: bronchi, bronchioles, terminal bronchioles
16 weeks+: transitional and respiratory zones: respiratory bronchioles, alveolar ducts, alveolar sacs
Surfactant production begins at 25 weeks and increases past birth
What causes Respiratory Distress Syndrome?
Babies born prematurely, before they have produced surfactant (1% of all births)
- ~100% at GA 24 weeks
- ~50% at GA 26-28 weeks
- ~25% at GA 30-31 weeks
Can be treated with artificial surfactant or supplemental oxygen
What is the composition of surfactant? What is the half-life, source and function?
- ~40-45% DP-PC
- ~40-45% other phospholipids, mainly other PC
- ~5% surfactant-associated proteins
- ~5% other proteins
- Cholesterol
- Trace components
Half-life: 5-10 hours
Source: Type II cells (pneumocytes)
Primary function: low surface tension in alveoli
What are teratogens?
Many different factors can act as teratogens (illegal drugs, medications, radiation, infections), but they all exert their main effects in the first trimester of pregnancy
What can be impacted the whole way through pregnancy by teratogens?
CNS
What is labour?
- Fundally dominant contractions (Starting at the top of the uterus and pushing down)
- Cervical ripening and effacement (changes from rigid to soft)
- Fetal membrane remodelling
- Lower segment relaxation
What is the process of labour? What are the phases?
Cervical ripening and effacement (increasing)
- Rigid to flexible structure
- Loss of ECM
- Recruitment of leukocytes (neutrophils)
- Inflammatory process (prostaglandin E2, local (paracrine) change in IL-8
Co-ordinated myometrial contractions (increasing)
- Fundal dominance
- Increased co-ordination of contractions
- Increased power of contractions
- Key mediators (Prostaglandin F2α (E2) levels increased from fetal membranes; oxytocin receptor increased; contraction associated proteins)
Rupture of fetal membranes
- Loss of strength due to changes in amnion basement component
- Inflammatory changes, leukocyte recruitment (exacerbated in preterm labour)
- Increased levels and activity of MMPs
- Inflammatory process in fetal membranes
- Delivery of infant
- Delivery of placenta
- Contraction of uterus
Phase 1 (many hours): Contractions, cervical changes Phase 2 (hours): Baby delivered Phase 3 (30 mins): Placenta delivered
What causes preterm initiation of labour?
- Intrauterine infections
- Intrauterine bleeding
- Multiple pregnancies
- Stress (maternal)
- Others
What is the main pro-inflammatory factor associated with labour? What evidence supports this?
NF-𝜅B
Almost all pro-labour genes have NF-𝜅B binding domain as their promoter
What is thought to control term labour?
CRH or PAF can upregulate inflammatory pathways i fetal membranes
What is the hypothesis for parturition?
- CRH from placenta causes release of ACTH from fetal pituitary, which then acts on adrenals to stimulate release of cortisol
- Cortisol stimulates the lungs to produce surfactant
- PAF in surfactant stimulates IL to activate prostaglandins, which induces labour
What effect does progesterone have on pregnancy?
Progesterone is needed to sustain pregnancy
- Progesterone receptor blockade: pregnancy loss
- Placenta produces high levels of progesterone
What is development?
Growth, increase in understanding, acquisition of new skills and more sophisticated responses and behaviour
What infectious agents can affect a foetus in utero?
T - Toxoplasmosis O - Others (syphilis, HIV etc) R - Rubella C - Cytomegalovirus H - Herpes simplex virus
What are the complications associated with spina bifida cystica?
- Neurogenic bowel incontinence
- Neurogenic bladder incontinence
- Lower limb paralysis
- Fractures
- Joint contractures
- Developmental deformities
- Learning impairment
- Hydrocephalus ↔︎ meningitis
What are the different domains of child development?
- Gross motor
- Vision and fine motor
- Hearing, speech and language
- Social, emotional and behavioural
What is a limit age for development? How is it different in prematurity?
The age by which a child should have achieved a milestone
(2 standard deviations from the mean)
Must be corrected for prematurity until 2 years of age (must subtract the number of months premature from the milestone)
What is the development of gross motor and posture in a child?
Newborn - limbs flexed, symmetrical posture - marked head lag on pulling up 6-8 weeks - raises head to 45° in prone - sits without support (at 6 months with round back, at 8 months with straight back) 8-9 months - crawling 10 months - cruises around furniture 12 months - walks unsteadily - broad gait, hands apart 15 months - walks steadily
What are the primitive reflexes?
- Stepping
- Moro
- Grasp
- Asymmetric tonic reflex (turn babies head one way and they will extend their limbs on that side, other sides remains flexed)
- Rooting (stroke next to mouth- baby will turn to face that side)
They should disappear by 4-6 months
When are the different protective reflexes developed in childhood?
Downward parachute reflex: 5 months
Sideward protective reflex: 6 months
Forward protective reflex: 7 months
Backward protective reflex: 9 months
What is the development of fine motor and vision in a child?
6 weeks - follows moving object or face by turning the head 4 months - reaches out for toys 4-6 months - palmar grasp 7 months - transfers toys from one hand to another 10 months - mature pincer grip 16-18 months - makes marks with a crayon 14 months-4 years - tower of 3 blocks (18 months) - tower of six blocks (2 years) - tower of eight or a train with four bricks (2½ years) - bridge (from a model) (3 years) - steps (after demonstration) (4 years) 2 to 5 years - line (2 years) - circle (3 years) - cross (3½ years) - square (4 years) - triangle ( 5 years - Ability to draw without seeing how it is done - Can copy 6 months earlier
What is the development of language and hearing in a child?
Newborn
- startles to loud noise
3-4 months
- vocalises alone or when spoken to, coos and laughs
7 months
- turns to soft sounds out of sight (Manchester rattle test)
7-10 months
- at 7 months, sounds used indiscriminately
- at 10 months, sounds used discriminately to parents
12 months
- two to three words other than ‘dada’ or ‘mama’
18 months
- 6-10 words. Shows two parts of the body
20-24 months
- uses two or more words to make simple phrases
2½-3 years
- talks constantly in 3-4 word sentences
What is the development of social, behaviour and play in a child?
6 weeks - smiles responsively 6-8 months - puts food in mouth 10-12 months - waves bye-bye, plays peek-a-boo 12 months - drinks from a cup with two hands 18 months - holds spoon and gets food safely to mouth 18-24 months - symbolic play* 2 years - dry by day, pulls off some clothing 2½-3 years - parallel play. Interactive play evolving. Takes turns*
*Affected in autism
What are the concerns if a child does not meet their development milestone by the limit age in the different domains?
Vision and fine motor development: occipital blindness or cataracts
Hearing, speech and language: If cannot join two words together- must assess hearing
Social: could be autism
What are the different types of delay in development of a child?
Consonant delay: all domains affected to same extent
Dissonant delay: domains affected to different extent
