Embryology Part 3/ Reproductive Endocrinology Flashcards
What two hormones are important in neural tube development?
Chordin and Noggin
Presence inactivates BMPs and particularly BMP4 (meaning patterning of neural tube and somites can occur, as if BMP 4 was present this would be inhibited).
What is the neural groove?
The depression formed within the ectoderm when the lateral edges of the plate fold inwards.
This groove forms the neural tube
What germ layer forms the neural tube and which forms the notochord?
Neural tube- Ectoderm (although mesoderm influences the thickening of ectoderm to become neuroectoderm)
Notochord- Mesoderm
What mechanical forces help control the bending of the neural plate?
Cell Wedging- microtubules and microfilaments changing cell shape, cell cycle Hinge Points (most important)- median and dorsolateral hinge points Extrinsic forces- Pushing of the surface ectoderm, adhesion point with notochord.
What are neural crest cells?
Highly migratory cells forming at time of neurulation
Give rise to craniofacial structures, teeth, melanocytes, dorsal root ganglia
When does neural tube closure occur, in days?
Week 4 (anterior by day 25, posterior by day 27)
Briefly describe the process of neural tube closure
Noggin inhibits BMP which allows for hinge point formation (dorsolateral and median hinge points). Cell wedging and extrinsic factors also aid in neural bending.
Fusion begins at cervical region and moves in cephalic/caudal directions
Open ends form anterior and posterior neuropores (connect to overlying amniotic cavity)
Closure occurs at week 4
What is a neural tube defect, and when do they occur?
Result of failure or incomplete closure of the neural tube
Occurs during week 4
What are the two types of neural tube defects, what do they typically cause, and where along vertebrae do they most commonly occur?
Failure at anterior neuropore- anencephaly
Failure at posterior neuropore- spina bifida
Most common at lumbosacral region
What factors increase risk of developing neural tube defects?
Not enough folate
Certain medication (anti-epileptics)
Ethnic Background (Celtic origin)
Genetics (unusual sonic hedgehog signalling, 1 child with spina already)
What determines the severity of spina bifida?
Severity depends on where the failure to close occurs, but all result in a loss of neural functioning
Give examples of different types of spina bifida.
Occulta (hidden) is least severe- hidden, typically only found when vertebral scanning is done (or tufts of hair seen)
Meningocele - Sac protruding containing meninges and spinal fluid, but not neural tissue
Myelomeningocele- spinal cord protrudes through the opening. Can result in paralysis and nerve damage
How is spina bifida diagnosed?
Ultrasound at 20 weeks
Raised alpha-feto protein can indicate higher risk, but not diagnostic
How is spina bifida prevented?
Folate prior to and during first 12 weeks of pregnancy
Its a co-factor enzyme involved in DNA/RNA biosynthesis (lack of it can impact cell proliferation)
Folic acid is the oxidized, most active form
What anti-epileptic drug poses a 4 in 10 chance of developmental disorders, and 1 in 10 chance of birth defects?
Valproate
Lamotrigine and Levetiracetam are the safest options for pregnancy
Why is Sonic Hedgehog so important, how does its release start, and how does it influence nearby structures?
It is the closest to a master genes
Helps with patterning of neural tube, and somite patterning (sclerotome formation)
Notochord sends out sonic hedgehog, and it passes to developing neural tube, ventral area of tube is the responder, and its response is differentiation into the floor plate of the neural tube.
Once floor plate is differentiated, it can produce SHH, which causes nearby cells to form motor neurons.
How is sonic hedgehog potentially related to spina bifida?
Increased expression of sonic hedgehog in lower neural tube prevents the formation of the dorsolateral hinges, preventing closure of the tube.
This is because SHH inhibits noggin, and noggin works to inhibit BMP, and BMP (particularly BMP 4) is what prevents hinge point formation.
So with SHH in cephalic end increasing, more BMP is left un-inhibited, meaning it can prevent the dorsolateral hinge points from forming, which means the neural tube cant close (spina bifida).
This isn’t as much of a problem at the caudal end as cervical vertebrae don’t need the dorsolateral hinge points to close.
What are the four manifestations of abnormal development?
Death, malformation, growth retardation, and functional deficit
What factors influence teratogenesis?
Genotype of conceptus
Developmental stage at time of exposure
Dosage
What is a teratogen?
An “agent that can disturb the development of an embryo or foetus”. Teratogens can come in many forms, exposure to teratogens during pregnancy can have a range of effects ranging from very mild to severe, or causing death of the embryo/foetus.
What are the 5 types of teratogens?
Drugs and chemicals Industrial pollutants Hormones Infectious Agents Mechanical Factors
What is thalidimide? What are the critical time points impacted by the drug, and what will it impact?
An anti morning-sickness drug for pregnant women
Caused blood vessels in early progress zone of limbs buds to leak, resulting in complete absence (amelia) or partial absence (meromelia) of limbs
Days after conception Affected system
21-22 Ears, cranial nerves
24-27 Upper limbs
27-35 Lower limbs
34-36 Thumbs, rectum
What are examples of antibiotics that are teratogens? Give a very brief explanation of their impact.
Tetracyclines- cross placenta and deposit at sites of calcification in bones and teeth, impacts enamel formation and colour.
Streptomycin- Can cause inner ear defects.
What painkillers are thought to be teratogens, and what may they be impacting?
Paracetamol- male reproductive development
Ibuprofen- first trimester, reduction in germ line numbers of future children/grandchildren
Aspirin- heart defects
What are examples of prescribed drugs that act as teratogens?
Anti-epileptic drugs (particularly valproate)- folate inhibitor
Methotrexate- used in lupus, rheumatoid arthritis, psoriasis- works as folate inhibitor
Antineoplastic drugs- designed to kill rapidly dividing cells
Vitamin A for acne- Deformities for structures derived from neural crest cells
Warfarin- issues with bone development
What hormones can act as teratogens? Briefly touch on what they impact
Androgens- masculinization of female genitalia Endocrine disruptors (synthetic oestrogens from the environment)- increased vaginal/cervical carcinoma incidence, testis malformations and abnormal sperm
What are the characteristics of foetal alcohol syndrome?
Facial deformities Low birth weight small head circumference Developmental delay Memory problems Behavioural problems Poor motor skills Difficulty socializing
What is the mechanism behind how alcohol impacts a fetus?
Alcohol easily crosses placenta
Alcohol cannot be metabolized by foetal liver, resulting in high blood alcohol levels
Alcohol impairs white matter development and reduces oxygen and nutrient levels
How does radiation work as a teratogen?
Radiation kills rapidly dividing cells
Highly fatal and causes severe birth defects
How do cigarettes work as a teratogen?
Intrauterine growth retardation
In terms of the pre-embryonic stage of development, what sort of impact will teratogens have?
Weeks 1-2
All or nothing impact typically, will either cause spontaneous abortion, or no effect at all (as the regulative development can make up for the 1 or 2 cells impacted/killed)
Thought to cause 50% of miscarriages
In terms of the embryonic stage of development, what sort of impact will teratogens have? State the weeks of this stage
Weeks 3-8
Organogenesis is occurring
Teratogens have very high impact on developing foetus
Malformations (i.e. heart defects) are most common
Type of defect seen depends on which organ system is developing at the time of exposure
In terms of the foetal stage of development, what sort of impact will teratogens have? State the weeks of this stage
Weeks 9-38
Susceptibility to teratogens are reduced
Mostly functional defects occurring
Urogenital and nervous system are still vulnerable
What germ layer(s) form the amnion?
Somatic mesoderm and ectoderm
What germ layer(s) form the umbilical vein?
Somatic mesoderm and ectoderm
What germ layer(s) form the yolk sac?
Lined with the endoderm (from the hypoblast) and splanchnic mesoderm
Describe the process of extra-embryonic haematopoiesis and what component is responsible for it.
The yolk sac
Produces blood from weeks 4-6 until foetal liver is produced
Yolk sac also helps with GI development
When does the yolk sac disappear?
18 weeks
What is the chorion? Include germ layer derivatives.
Foetal part of the placenta
Combines with maternal side of placenta to form complete placenta
Its a layer of trophoblast (cytotrophoblast), plus a layer of extraembryonic mesoderm that sits outside of the amnion
What is the allantois? Include germ layer derivatives.
Foetal membrane laying below chorion
Some vasculature that gets incorporated into umbilical chord
Derived from the yolk sac which comes from the endoderm (hypoblast) and splanchnic mesoderm
What is the decidua reaction?
Progesterone causes stromal cells of uterus to enlarge and accumulate glycogen
Invading cells of blastocyst erode endometrium allowing for it to burrow into endometrium for implantation
Endometrial vessels become dilated around implantation
Where does they decidua come from?
Come from endometrium
What are the different regions of the decidua?
Basalis- area interacting with foetal membranes
Capsularis- Area growing around the embryo bulging into the uterine lumen
Parietalis- The outside edge, essentially the rest of the decidua. Will fuse with the capsularis around 20 weeks
What are the chorionic villi and what do they form?
Emerges from the chorion and invade into the decidua early in pregnancy.
Foetal chorion in contact with the basalis becomes known as the chorion frondosum (this will become the foetal placenta)
When do we start to see small spaces occurring within the Syncytiotrophoblast, and what are they called? What else occurs at this point?
Day 12 after fertilization
Small spaces, called trophoblastic lacunae, form.
Decidual reaction also begins (can be see by enlarging endometrial vessels)
What occurs at day 13 following fertilization?
Villi begin to form
They are stalks of cytotrophoblasts
What are secondary villi, and when do they form?
Day 16, extra-embryonic mesoderm (chorionic) invades core of primary villi
Secondary villi line the entire surface of the chorion
Called secondary when they have a mesenchymal core
What are the tertiary villi and when do they form?
When blood vessels develop in the mesenchyme of the secondary villi
It connects to the umbilical vessels of the embryo
Form by end of week 3 (21 days)
What is the placental barrier and what does it consist of?
Does it change at all?
Partition between maternal and foetal circulation
4 layers:
foetal capillary endothelium
Connective tissue of the villi
Cytotrophoblast
Syncytiotrophoblast
Reduces to 3 layers from the 4th month (lose cytotrophoblast cells as they were only used to produce Syncytiotrophoblast)
What are the functions of the placenta?
Metabolism- synthesizes glycogen, cholesterol, fatty acids, nutrients, and produces energy
Transfer:
Passive diffusion- O2, CO2, urea, uric acid, bilirubin, electrolytes, fatty acids, and carbs
Active facilitated diffusion- Glucose and amino acids use
Vit B, C, D cross readily (Lipophilic)
Endocrine- oestrogen, progesterone, HCG, placental growth factors
Immune Barrier- maternal immune tolerance
What area of the fallopian tube does fertilization typically take place?
Ampulla
What system has the longest critical period of development, and therefore is most susceptible to a wide range of teratogenic insults?
CNS
What is compaction and when does it happen?
Day 4
The process that occurs when the dividing cell becomes the morula
Cells fatten on each other, and the outlines of individual cells become hard to distinguish
What components make up the umbilical cord?
Wharton’s Jelly- protects vessels from damage
2 Arteries- carry blood away from foetus
1 Vein- carries blood towards foetus
What make up the lobes of the placenta?
Cotyledons- contain many villus trees which are bathed in maternal blood (allows for close proximity of maternal/foetal circulation)
How do the cyto and Syncytiotrophoblast differ? Include important characteristics and roles in development.
Cytotrophoblast- Mononuclear cell layer, high proliferation rates, replenish syncytio layer, forms chorion.
Syncytiotrophoblast- Formed by fusion of cytotrophoblast layer, multinucleated, where the lacunae form allowing for formation of intervillous space (area that becomes filled with maternal blood), hCG production
What are uterine glands and what do they do?
Within decidua
Produce histiotrophic secretions which support the placenta and embryo in early pregnancy prior to fully formed placenta (fluid fills space between placenta and uterine cavity, later phagocytosed by trophoblast cells)
What is the basal plate?
Maternal side of placenta
What are the extro-villus trophoblast cells and what do they do?
Were originally cytotrophoblast cells, but migrated to plug and/or remodel the maternal blood vessels
Invade the maternal decidua and myometrium and plug the spiral arteries causing the formation of wider, high flow, low resistance vessels to aid in blood flow
This helps with a more developed villus space surrounding the more branched villus trees (increasing surface area for exchange)
What is foetal growth restriction and what risks are associated with it?
Impacts 5-10% of births
Failure to reach your genetically pre-determined growth potential
Often look at parents, but in clinic use below 5th percentile as cut-off
Increases risk of stillbirth, childhood morbidities, and adult disease
No treatment- placental disfunction plays a role in this
What is pre-eclampsia
Proteinuria and elevated BP occurring after 20 weeks gestation
Can occur with/without foetal growth restriction
No treatment option, can treat symptoms but not cause
High rates of morbidity
What causes pre-eclampsia?
Incomplete remodelling of the spiral arteries, reducing blood supply to placenta.
Can result in ischemic reperfusion injury (periods of low blood flow to placenta)
All contribute to poor nutrient delivery
What screening tests are given during pregnancy and after birth for the foetus?
First 10 weeks- sickle cell, thalassemia
8-12 weeks- blood test for HIV, hep B, and syphilis
Diabetics offered eye screening
10-14 weeks- combined test (ultrasound and blood) looks for Down’s syndrome, Edwards Syndrome, and Patau’s Syndrome (could get quadruple test for Downs up until 20 weeks)
18-20 weeks- Ultrasound looking for 11 physical conditions (bones, heart, brain structure)
Physical exam within 3 days of birth- looks at conditions impacting eyes, hip, testicles, heart. Also get hearing test
Within 5 days of birth- Heal quick test, blood test test from heel looking at things like CF.
What are the 3 main classes of hormones?
Proteins/ polypeptides
Steroids
Derivatives of the amino acid tyrosine (end in ine)
What organs release protein and polypeptide hormones?
Anterior/Posterior pituitary
Pancreas
Parathyroid
and more..
What organs release steroids?
Adrenal cortex
Ovaries
Testes
Placenta
What organs release tyrosine deriviatives?
Thyroid gland
Adrenal Medulla
What is the solubility of the different hormone types in lipids?
Proteins- hydrophilic
Steroids- hydrophobic
Tyrosine Derivatives- hydrophilic
Hydrophobic=Lipophilic and hydrophilic=Lipophobic
Where (within cells) does steroid synthesis occur, and when is this hormone released?
Synthesis occurs in mitochondria and then smooth endoplasmic reticulum
Not stored as they are lipid soluble, so immediately released following synthesis
What are the 6 main steps involved in the mechanism of action of steroid drugs?
- Steroid enters target
- Binds steroid hormone receptor
- Hormone-receptor complex is generated and will travel into nucleus
- Complex will bind DNA and activate transcription
- New mRNA is made and moves to cytoplasm
- Translation produces new proteins
What are the types of oestrogen and what are it’s primary roles?
Oestrone, oestradiol (most prevalent), and oestriol.
Involved in development of female secondary sex characteristics, control menstrual cycle, and pregnancy
How are the different types of oestrogens produced? Include any enzymes needed for production
Oestrone- secreted by ovary or converted from androstenedione
Oestradiol- produced by ovary, and derived by direct synthesis in developing follicles, or through conversion of oestrone or testosterone
Aromatase is responsible for testosterone and androstenedione conversions
What are androgens and how are they produced?
Synthesized from cholesterol in testes, ovaries, and adrenal gland
Regulate development of male primary sex organs, male secondary sex characteristics, important in libido and sexual arousal
Include; testosterone, dihydrotestosterone, and androstenedione
What are progesterone’s, why are they important, and how are they synthesized?
Synthesized from cholesterol via pregnenolone.
Produced primarily by corpus luteum, adrenal glands, and placenta.
Important for endometrial development, maintenance of pregnancy, mammary gland development
Where is the hypothalamus found?
Anterior and inferior to thalamus, within diencephalon region of brain
Where are the pituitary glands found?
Cradles under hypothalamus, within the Sella turcica of the sphenoid bone
What glands form the pituitary and where do these glands stem from?
Posterior pituitary- neural tissue
Anterior pituitary- more glandular develops in primitive digestive track
What joins the hypothalamus and pituitary gland?
Infundibulum (or pituitary stalk)
What hormones are secreted by the 2 regions of the pituitary gland?
Posterior: Anti-diuretic hormone Oxytocin Anterior: FSH/LH Growth hormones Thyroid Stimulating Hormone Adrenocorticotrophic Hormone Prolactin
Describe the hypothalamic-pituitary-gonadal axis.
Works to regulate reproduction
Hypothalamus secrete gonadotropin releasing hormone (GnRH)
GnRH stimulates anterior pituitary gland to release follicle stimulating hormone (FSH)and luteinising hormone (LH)
Ovary or testis (and placenta) respond to levels of gonadotropin and secrete steroid sex hormones (androgens, oestrogens, etc)
What is GnRH, how is it secreted and delivered to its target?
Neurosecretory cells in hypothalamus secrete GnRH
10 amino acid with short half life
Secretes in pulsatile manner into portal vessels
Transported through hypophysial portal system to pituitary (to gonadotroph cells) causing gonadotropic hormone release
What is the role of FSH in males and females?
Males:
stimulates primary spermatocytes to undergo meiosis
Enhances production of androgen binding protein in Sertoli cells of the testis
Females:
Initiates recruitment and supports growth of ovarian follicles (granulosa cells)
What is the role of LH in males and females?
Males: Acts on Leydig cells of testis to regulate production of testosterone Females: Supports ovarian Theca cells Surge triggers ovulation
What are examples of positive feedback?
Oestrogen levels at mid-menstrual cycle allowing for ovulation
Prolactin during breast feeding
Oxytocin stimulates its own production and release as well during breastfeeding
How is feedback utilized in the HPG axis?
Oestrogen and progesterone released in female ovaries have negative feedback on hypothalamus and pituitary (oestrogen also has positive feedback during a short window in menstrual cycle allowing for ovulation)
Testosterone released by male testes does the same
What is precocious puberty?
Early onset of puberty
Prior to 8 for females, and 9 for males
How active is the HPG axis during foetal development and birth?
High as it needs to encourage differentiation (due to sex hormone production by gonads) and maturation of foetal reproductive tract
Activity is dampened closer to birth due to increase sex hormone production and negative feedback, but this axis becomes active following birth due to GnHR surge, but then quite swiftly turned off due to negative feedback.
What is happening to the HPG axis prior to puberty?
Inhibited due to GABA (and many other signals not understood) which prevents neurosecretory cells in the hypothalamus from creating GnHR.
Why is HPG axis inhibition prior to puberty important?
It allows for somatic growth is favoured, and growth hormones can really encourage growing in height and weight
What occurs within the HPG axis to allow for puberty?
Kisspeptin is released from hypothalamus and stimulates neurosecretory cells within the hypothalamus to produce GnRH, allowing for anterior pituitary stimulation of LH/FSH production/secretion
Kisspeptin increase is accompanied by decline in GABA
How does GnHR release change during puberty?
Pulsatile release increases
It is released at night.
This is why regulation of the menstrual cycle takes time to develop.
What are first clinical signs of puberty in females?
Presence of a breast bud
What are first clinical signs of puberty in males?
Testicle size increases to greater than 2.5cm
What are the secondary signs of puberty?
Axillary hair
Body Odour (sebaceous glands are more active)
Pubic hair
Acne
Growth Spurt
Changes in body composition
Menarchy in females and facial hair growth in males
When does puberty start?
Females- typically 10.5 years (8-13 years). Most girls should be in puberty or completing puberty by 16
Males- 11 years (9-14) with completion around 17 years
What are the tanner stages and how long do they take?
System consists of 5 stages that represent both complete and final appearance of both sexes.
Females,- growth of breasts and pubic hair, with hair growth occurring in the first half
Males- growth of pubic hair (second half of puberty) and testicular size
About 3-5 years to move from stage 1 to 5
What is delayed puberty?
When puberty has not begun within typical ages.
13 in girls (often picked up with there is no menstruation by 16), 14 in boys
What are the types of precocious puberty? Explain both types as well as giving examples as to what causes each.
Gonadotropic Dependent:
Breast/testicular development before 8/9
Means HPG axis is reactivated before it should, and increases in GnHR, Gonadotropins, and sex steroid production
Caused by: tumours on hypothalamus or pituitary, cerebral malformations, injuries to CNS, idiopathic, genetic
Gonadotropic Independent:
Only pubic/axillary hair before 8
No stimulation by gonadotropins or input by HPG. Sex steroid hormones production due to other inputs (like steroids) and aren’t regulated causing puberty sequence to be out of order
Caused by: tumours on gonads or liver, adrenal gland hyperplasia, exogenous androgenic or oestrogenic steroids, genetic
What is the most common cause of precocious puberty?
Idiopathic
What are reasons for delayed puberty?
Hypergonadotropic hypogonadism: High concentrations of gonadotropins typically due to bilateral gonadal insufficiency (typically genetic, or autoimmune disorders, trauma, infection, cancer treatment)
Hypogonatropic hypogonadism: Low levels of gonadotropins. Can be due to abnormal hypothalamus or pituitary gland resulting in dysfunction of GnHR/LH/FSH release, OR HPG axis isn’t working properly. Typically due to systemic illness, physical/psychological stress, anorexia nervosa.
Constitutional delay of growth- Most common, just a temporary delay in skeletal growth resulting in delay of puberty onset. Typically genetic inheritance or can occur idiopathically, or low body weight (not associated with eating disorder- puberty onset is associated with body fat)
What are genetic causes of hypergonadotropic hypogonadism?
Women: Turner’s Syndrome when women only have 1 X chromosome and ovaries do not form properly
Men: Klinefelter’s Syndrome where an extra X chromosome in inherited and testes don’t form properly. Typically present with low testosterone and smaller testes. Typically start puberty but don’t finish it
What are physical exams that can be used when assessing someone with delayed puberty?
Tanner Stage
Height and weight (bone growth and body fat)
Malnutrition
Visual Field Exams (tumours)
Dysmorphic Features (inherited chromosomal abnormalities)
Why is kisspeptin important?
It regulates the entire HPG axis by acting directly on the hypothalamus to cause GnHR release, and LH/FSH therefore as well.
What controls kisspeptin?
Feedback from gonads. They have oestrogen, progesterone and androgen steroid receptors on their surface.
Positive feedback causing increased kisspeptin secretion is due to secretion of oestrogen and progesterone in blood stream, resulting in ovulation and LH surge.
Neg feedback is result of oestrogen and testosterone secretion to help control reproduction
How do we know the role kisspeptin plays? Explain using examples of women from different phases of life.
Single injection if kisspeptin increases LH levels in adult females
In post-menopausal women where oestrogen levels are lower, kisspeptin injection causes LH levels to become much higher as negative feedback (via oestrogen production) is lost.
Those on oestrogen pills have lower levels of LH, due to ‘reinforced’ oestrogen negative feedback
What neurological changes are important when evaluating kisspeptin’s role in puberty? Which sex in more impacted by these changes and why?
Kisspeptin neuron numbers increase in the hypothalamus, and start to make contact with GnRH neurons (happens at the start of puberty)
GnHR neurons increase number of kisspeptin receptors on their surface (which happens prior to puberty)
Changes occur at higher level in female tract (higher exposure of male tract to testosterone and its role in negative feedback)
What happens if there is a mutation of kisspeptin?
Most mutations inactivate kisspeptin causing puberty is delayed (causing idiopathic hypogonatropic hypogonadism)
R386 mutation activates kisspeptin leading to precocious puberty
