RDA Flashcards
From where do oocytes develop?
The oocytes are formed from primordial germ cells arising in the yolk sac, which then migrate into the hindgut and to the embryonic gonadal ridge. From there, they become contained within the developing ovary.
What is the development of oocytes from their containment in the developing ovary to pre-pubescence?
In the ovary, they differentiate into diploid oogonia. This expands to a population of 7 million germ cells at 6 months gestation, which decreases to approx 1 million by birth
The population expands via mitosis, producing oocytes that undergo meiosis and arrest at prophase of meiosis 1. They stay this way until the follicle is activated, or die via a process called atresia
What is a follicle?
An oocyte surrounded by supporting structures, fibroblasts and a vascular network, located in the cortex
What is the general pathway of oocyte development after follicle activation?
Meiosis one gets completed by one primary oocyte per month, and then gives off a polar body (small nucleus extruded as a sort of daughter cell).
Follicles become primordial, then primary, secondary, mature and ovulated
How long does each oocyte spend in each developmental stage?
Primordial- 12-50 years
Primary- 2-3 months
Secondary- 2 weeks rapid growth
What features characterize the primordial follicle?
Oocyte surrounded by flattened layer of granulosa cells with a thin protein shell (zona pellucida). A second layer of theca cells is outside the granulosa cells
What features characterize the primary follicle?
Single layer of cuboidal granulosa cells that express FSH receptors, and form multiple layers
What features characterize the secondary follicle?
Granulosa cells immediately surrounding the oocyte separate from more distal ones, forming a fluid filled antrum.
What features describe the mature follicle?
The follicle and antrum enlarge, with dominant bulging from the ovarian surface, eventually gaining a size of approx. 20mm.
Describe the process of ovulation
The follicle ruptures, releasing the mature oocyte and its surrounding granulosa cells (cumulus oocyte complex). This is swept up by fimriae at the ends of the fallopian tubes. Ovulation occurs not due to pressure buildup but due to weakening of the follicular wall.
Describe the process of luteinisation
Residual follicle cells after ovulation grow inwards, forming the corpus luteum. These are responsive to LH and produce progesterone and oestrogen.
What are the components and functions of the zona pellucida?
It is a glycoprotein ‘shell’. ZP1 is the protein found in primordial follicles, while ZP2 & 3 are added when the follicle becomes activated. It is important for filtering normal sperm and preventing polyspermy or sperm from different species.
What is the conversion pathway of reproductive hormones?
Thecal cells convert progesterones androgens via aromatisation. This is in response to LH.
The Granulosa cells then convert the androgen to estrogens via aromatisation, and inhibin, as well as AMH (antimalaria hormone)- this blocks primordial follicle development and recruitment.
What stages of follicular development do and do not require involvement of gonadotrophins?
Primordial follicle development through to secondary stage does not require gonadotrophins, while secondary to antral cells do.
What does estrogen do for fertility?
- Promotes endometrial growth after menstruation
- At low levels suppresses LH and FSH, but at sustained high levels this switches to positive feedback
What does progesterone do for fertility?
Induces the decidual reaction in the endometrium, and renders the cervical mucus permissive to sperm
Enhances negative feedback of oestrogen, and blocks its positive feedback
How do levels of different hormones change across the menstrual cycle?
A small FSH surge begins the conversion of primordial to primary follicles. These develop and produce estrogen, which at sustained high levels causes a peak of LH. About 12-24h after this, ovulation occurs. The corpus luteum forms and begins producing progesterone, which inhibits FSH and LH. After it regresses, levels of progesterone drops and the FSH surge can come again.
Describe the parts of the uterus
Small pear shaped organ- 7.5cm long, 5-10 mL non pregnant volume. Normal pregnant volume is 5L, but can be up to 20.
Body is largest region
Fundus is the rounded part of the body, sup. to fallopian tube attachment. Normally anteverted and anteflexed
Cervix is the inf portion extending from isthmus to the vagina. Distal end forms a curving surface surrounding the external os
What are the layers of the uterus?
Outermost is the perimetrium, with a muscular myometrium and an inner glandular endometrium.
Muscular myometrium has longitudinal, circular and oblique layers.
Describe the endometrium
Has a functional and a basal layer
Contains glandular and vascular tissues. Its initial growth is due to estrogen, and stretches the existing cells. The glands, blood vessels and endothelium change with the menstrual cycle.
The functional zone contains most of the glands, with the basal zone attaching it to the myometrium and containing terminal gland branches and spiral arteries to regenerate the functional layer with
Describe the vascular components of the myometrium
COntains branches of the uterine arteries (arcuate arteries) that then form radial arteries at right angles. They supply the straight arteries to the basal zone, which go on to form spiral arteries.
What is the function of progesterone in the fallopian tubes?
It decreases muscle activity, decreases cilia numbers, but increases the beating frequency, and decreases secretion volume.
Describe the fallopian tubes
Not attached to the ovary. Starts at the infundibulum, then the ampulla, isthmus, and transmural portion. Less complex as it goes along.
Epithelial lining, then inner circular and outer longitudinal muscle layers, then serosal covering.
it contains some ciliated and some secretory epithelial cells. It responds to steroids.
What is the function of estrogen in the fallopian tubes?
Increases cilia, as well as secretory and muscular activity.
Describe the structure of the cervix
Endocervix is continuous with the body of the uterus, ectocervix with the vagina. It also has a transitional zone.
Therefore, the endocervix has columnar epithelium, but it changes to stratified squamous epithelium at the junctional area. This is the site of many neoplasms
What is the function of the cervix?
Secretes mucus into the cervical, which changes is response to hormones of the menstrual.
It is permissive to sperm transport only during a short window, becoming abundant and stretchy when exposed to estrogen. In contrast, high progesterone makes it hostile.
What is the function of estrogen in the uterus?
Stimulates epithelial and stromal cell proliferation Causes stromal oedema Increases glandular secretions Synthesizes progesterone receptors Stimulates myometrial activity
What is the function of progesterone in the uterus?
Stimulates glandular secretions in the luteal phase (with oestrogen background)
Causes stromal cell proliferation
Inhibits myometrial activity
How does an embryo implant and what is required for this to be successful?
It implants and sinks entirely into the wall of the uterus
To do this, the endometrium undergoes the decidual change, where the stroma becomes odematous, and fibroblasts and stroma fill with glycogen to give it energy.
This only occurs in women
Why are the glands and arteries of the endometrium tortuous?
They grow faster than the surrounding stroma, forcing them to coil
What phase can you see glandular mitoses in the uterus?
In the proliferative phase, as they grow so fast.
What is the hypothalamus?
A structure in the brain secreting hormones involved with fluid balance, smooth muscle, and controlling hormones of the ant. pituitary gland. Formed from the diencephalon
What is the pituitary gland?
Secretes multiple hormones that regulare the endocrine activities of the adrenal cortex, thyroid and reproductive organs, as well as melanin
Where does each lobe of the pituitary gland come from?
Anterior pituitary formed from the hypophyseal pouch, forming the adenohypophysis.
Posterior pituitary formed rom the neuroectoderm, forming the neurohypophysis. (from median eminence and pars nervosa.
What are the main nuclei of the hypothalamus and where are they?
Suprachiasmic nucleus: above the optic chiasm
Arcuate nucleus- most inferior
Ventromedial: above arcuate
Posterior: Most posterior
What are the components of each lobe of the pituitary gland?
Anterior: Pars tuberalis and anterior lobe
Posterior: Median eminence, hypothalamo-hypophyseal tract, stalk and posterior lobe
Describe infundibular circulation of the pituitary
Blood runs from the superior hypophyseal plexus, down the hypophyseal portal veins, to the secondary plexus on the ant. pituitary. These are drained by ant hypophyseal veins.
The post pituitary just has inf. hypo artery and post hypo veins
Why is the hypophyseal plexus so crucial for the ant pituitary function?
Hormones are produced in the hypothalamus that travel down the portal vein to the ant lobe, which then stimulate release of pituitary hormones.
What is the method of hormone release in the post pituitary?
Hormones are produced by the hypothalamus and passed into the post pituitary via the nerves, before being released into the blood
What is the histological profile of the ant vs post pituitary?
The posterior has many axonal processes, while the ant is mainly vascular and hormonal secretory cells.
In the ant pituitary, it is mainly acidophils, with somatotrophs and mammotrophs.
There are also some basophils, with corticotrophs, thyrotrophs and gonadotrophs.
Describe growth hormone
Stimulated by GHRH and inhibited by GHIH
Acts on epithelia, adipose tissue etc. to stimulate growth of cartilage, skeletal muscle and other tissues.
Describe prolactin
Inhibited by dopamine
Placental lactogens bypass feedback, and cause reduced dopamine, causing increased prolactin, as does sucking stimulus.
This causes an increased rate of prolactin transport to the brain
Describe the HPG axis
GnRH released from hypothalamus, triggering FSH and LH release from ant pituitary. Negative feedback from testosterone.
They may have long or short loop feed back (ie to ant pit or all the way to hypothalamus)
Why does GnRH not have a distinct hypothalamic nucleus?
It is critical for normal fertility, so it is scattered to help preserve it
Which female structures do LH and FSH act on?
FSH acts on granulosa cells, LH on thecal cells to stimulate androgen production
Estrogen and progesterone give long and short loop feedback
Estrogen at sustained high levels switches to positive feedback
What is the function of kisspeptin?
Kisspeptin regulates positive feedback and pulse synchronization of GnRH in the arcuate nucleus, which is the trigger for puberty
How are seminiferous tubules kept cool? Why is this important?
Due to migration of the testes from intra abdominal to an outside the body position
Development of a countercurrent venous plexus called the pampiniform plexus
What are the four main cell types in the testes?
Spermatogonia (germ cells, make gametes) Sertoli cells (epithelium, surround, support and nourish germ cells) Leydig cells (interstitial stromal tissue for making testosterone) Myoid cells (contractile)
What are the exocrine and endocrine functions of the testicles?
Exocrine: sperm
Endocrine: testosterone
Describe the process of spermiogenesis
It’s the differentiation of spermatids which become spermatozoa
Stem cells at the base of the germinal epithelium, proliferate by mitosis and meiosis to produce spermatocytes and spermatids. This then results in spermatozoa production. Daughter cells are linked by cytoplasmic bridges, so coordinated development occur
What is the transit time for spermatozoa from basal lamina to lumen and what is its cyclicality?
Transit time is 74 days
A new wave of sperm development occurs every 16 days
Describe spermatogonia and the cells the form
Have 46 chromosomes
When mitosis is complete, they move between sertoli cells into the adluminal compartment of the seminifferous tubules.
They then perform meiosis to become primary spermatocytes. At the end of meiosis they are secondary spermatocytes. These divide rapidly into 4 spermatids with 23 chromosomes each.
Cytodifferentiation occurs and the cells become sperm
Describe what happens during cytodifferentiation of sperm
Unnecessary cytoplasm is formed into residual bodies. Tails form and they move to the lumen
The acrosome and increased mitochondria also form
How do testes form and move in the antenatal body?
They ofrm in gonadal ridges in the lumbar area, between caudal and gaubernaculum ligaments. As the testes grow, they drag downwards. ISL-3 (from leydig cells) causes the migration of the gametes towards and dilation of the inguinal canal.
The two phases of testicular descent are the transabdominal abdominal, and the inguinoscrotal (where androgen is important)
What is the spermatogenic wave?
Presperm cells in adjacent sections of the tubule are retarded or advenced at the same time
Describe leydig cells
They produce testosterone. Their initial function (7-8 weeks gestational age) is not dependent on gonadotrophin stimulation, but from 14 weeks onwards it depends on LH
Empbryonic leydigs are derived from different progenitors to adult ones (derived from stem cells at puberty)
What are the functions of leydig cells?
They are responsible for minipuberty at 2 months postpartum
Also masculize neonatal brain
Trigger sertoli cell proliferation
Timing of orcidopexy (descent of testes)
Describe sertoli cells
They stretch from basement membrane to lumen of the seminiferous tubules.
Nourish the spermatogonia
Absorb excess cytoplasm into residual bodies
Produce seminiferous tubule fluid
Maintain spermatogonial stem cell niche
Form the blood-testis barrier (making the testes an immune prigvileged site).
Their number is proportional to sperm count
Why is the immune privelige of testes important?
The body’s innate immune learning occurs in utero- as sperm are produced after this they will be seen as foreign bodies and a reaction will occur.
The sertoli cells also actively secrete compounds that turn off the immune sytem, and so can be useful in transplant surgeries etc.
Describe the epididymis
A comma shaped organ superoposterior to the testes
Efferent tubules drain into the head. It is 7.5cm long, but 4-6m in length.
Describe the function of the epididymis
Concentration of sperm, some fluid resorption using the stereocilia
Describe the vas deferens and its function
A 45cm tube used for sperm storage.
It has an inner and outer longitudinal, middle oblique muscle layer, leading into an ampulla
Describe the feedback cycle of male hormones with the hypothalamus and pituitary gland
Hypothalamus releases GnRH, promoting release of LH and FSH
- FSH targets sertoli cells, causing them to secrete androgen binding protein
- LH targets leydig cells, causing them to secrete testosterone
- Testosterone binds to ABP on sertoli cells, stimulating spermatogenesis along with FSH
- Testosterone is also converted to dihydrotestosterone, which causes male embryonic development, secondary sex characteristics, anabolism and enlargement of male sex organs.
- Testosterone inhibits the ant pituitary and hypothalamus
- Inhibin from sertoli cells inhibits the ant pituitary
Describe the seminal vesicles
They are androgen and LH responsive
Produce 60% of seminal fluid, which includes fructose, semenogelin I (forms a coagulum in the vagina) antioxidants, and alkaline fluid to counteract vaginal pH
It contains smooth muscle for ejaculation, as well as forming part of the ejaculatory duct when joined to the vas
Describe the prostate gland
A donut shaped gland the size of a walnut. Secretes a slightly alkaline fluid as well as PSA, responsible for semen liquefication after coagulum formation
Four zones- Central 25% is resistant to carcinoma
Peripheral 70% is most at risk
Transitional 5% most commonly benign hyperplasia
Periurethral can also contribute to BPH
Describe the penis
2 corpora cavernosa
Corpus spongiosum prevents constriction of the penile urethra
Describe how an erection occurs, and how viagara can help
Parasympathetic stimulation causes ACh release, and this triggers NO release. This increased cGMP, causing vasodilation, so the cavernosa relax and increase blood flow, squashing the veins, and reducing outflow
Viagra helps this by blocking type V phosphodiesterases, which break down cGMP
Describe germ cells of the testis and how they migrate
Primordial germ cells first seen 3-4 weeks post conception
First found in the yolk sac of extraembryonic tissues, and migrate into gonadal ridges via the hindgut
Stem cell factor important for driving migration (PGCs die with insufficient levels)
Ectopic germ cells can be origins of germ cell tumours (ie in pancreas)
Germ cells become spermatogonia
Describe cryptorchidism
Failure of the testicles to descend into the scrotup
Affects up to 9% of full term and 30% of preterm boys
Most self correct in 3mos, with orchidopexy a surgical option
What are the consequences of cryptorchidism? What can help the testes to descend?
Infertility due to excess temperature
Testicular cancer (3-4 fold risk, assoc. with ethnicity (maori, then euro, the pacific/asian)
Breastfed infants are less likely to remain cryptorchid
Describe hyperpituitary-acromegaly
Often caused by a tumour on the pituitary. gland.
Presents as an enlarged pituitary gland with headche, visual disturbances, coarse facial features, hypertrophy of soft tissues, enlargement of small hand/feet bones
Describe idiopathic central precocious puberty
Mutation of autosominal dominant GPR4 leads to prolonged activation of signalling pathways in response to kisspeptin
This results in increased amplitude pulses of GnRH and development of pubertal changes before normal
Describe Kallmann Syndrome
GnRH deficiency, causing extremely low FSH, LH and estrogen, with amenorrhea, olfactory disturbances, reduced bone density etc.
Describe GnRH dependent precocious puberty
Can be due to 47XXX chromosomal abnormality, causing early activation of the HPG axis, and blunted ovarian function. It results in increased FSH and LH secretion, causing precocious puberty (as early as infancy)
Where do polar bodies removed by the oocytes go?
They sit in the zona pellucida
Describe the processes sperm must go through once they reach the vagina
Undergoes capacitation (removal of glycoprotein coat)
Matures- causes hyperexcitability
Acrosome reaction: Release of proteases and hyaluronidase. Allows it to penetrate zona pellucida and plasma membrane to fuse with the egg
Describe how sperm breach the cervix
Only achievable when mucus is penetrable
Mucus filters for poor sperm. Sperm vibrate in unison to break down the barrier- those that can’t do this don’t tend do succeed in getting through
How long can sperm survive in each region of the female tract?
2.5h in vagina
48h in cervix
24h in uterus
48h in oviducts (may slow tail beating to wait for an egg)
Describe the consequences of sperm entry for the femal
Sperm induce leukocytosis in the female, to help break down dead or dying sperm
Exposure to paternal antigens may also allow the mother to tolerate foreign antigens
Describe the processes of sperm entry into an egg
ZP3 binds to sperm heads via a receptor on the head of the sperm
This initiates the acrosome reaction as exposure to the zona pellucida causes Ca2+ release in the sperm, causing membrane fusion etc
Exposure of the acrosomal membrane reveals new binding sites for ZP2
Proteolytic enzymes are activated and begin to break down the ZP
Fusion with surface membrane of the egg leads to cortical granule release
ZP1 corsslinks ZP2 and 3, hardening the shell and making it impermeable.
Progesterone from the cumulus makes the acrosome leaky prior to the acrosome reaction
Hyaluronidase digests the cumulus basement membrane
How long does an oocyte last unfertilized?
24h
Describe the functions of the different ZP proteins
ZP3 is the primary sperm receptor and induces the acrosome reaction
What happens once the sperm crosses the zona pellucida?
Touches the oolemma, and enters, causing increased calcium, followed by regular calcium spikes, which induce resumption of meiosis
Describe what happens to the egg after fertilisation
Active mitotic division, and passage into the uterus 4-5 days after ovulation. Formation of morula (8-16 cells) and blastocyst- shows differentiation into trophoblast (future placenta) and inner cell mass (fetus)
This then hatches out of the zona pellucida, with the blastocyst attaching and sinking into the decidua.
What is the definition of infertility?
Failure to conceive after 12 months of unprotected intercourse
How can you assess male infertility?
Semen analysis, for count, motility, volume, total number and morphology
What are the lowest normal limits of male fertility parameters?
Sperm count: 15million/mL Motility: 40% need to be progressive Volume: Must be more than 1.5mL Total number of sperm: 39 million in an ejaculate Morphology: 4% with normal shape
How can you assess female infertility?
Ovulation- regularity of periods, with an estrogen spike at day 12, progesterone at day 21, FSH at day 2-4 with AMH levels above a certain parameter per age
Timing of intercourse for ovulation
STI presence
How do you deal with anovulation as a cause of female infertility?
Can treat with weight gain or loss
Treat with GnRH
Treat with clomiphene citrate, for selective estrogen receptor modulation
Treat with letrazole- prevents conversion of androgens to estrogen to increase monofollicular development
(THese should cause the body to produce more FSH)
Treat with FSH
How do you deal with polycystic ovarian syndrome as a cause for infertility?
Problem presents as infrequent or no periods, with overweightness as a consequence of the assoc metabolic syndrome and increased androgens
Treated with weight loss, letrozole, metformin to treat the metabolic syndrome, or with IVF
How do you treat tubal disease as a cause for infertility?
Surgery or IVF
What are some further causes of infertility in women and how are they managed?
Cervical problems: Treated with IUI (intrauterine insemination)
Endometriosis: Hormonal contraceptives, surgery, IVF
Premature menopause: Donor egg
No uterus: Surrogacy
What are the steps of IVF?
- Stimulate ovary with FSH. Prevent ovulation with GnRH antagonists until want to trigger- GnRH agonist. Then give progesterone for luteal support
- Egg released
- Sperm sample produced
- Egg and sperm combined for fertilisation
- Fertilised eggs introduced into uterus
- Embryo freezing if possible
When do you know when to trigger ovulation?
Need several follicles with estrogen at 1000 units per follicle, and progesterone at less than 6 picomol per L
How is timelapse photography used in fertility?
They can be used to take timelapses of morula development, to track cell division without disturbing the culture, and produce an algorithm for those with the best potential
What are some problems with male fertility, and how are they managed?
Oligospermia- Can have intra-cytoplasmic sperm injection (ICSI), donor sperm
Oligoasthenotetraspermia- triad of few sperm, slow sperm and abnormal sperm
Need ICSI or donor sperm
Can have azoospermia- due to Kallman’s syndrome (no GnRH/FSH/LH)- need donor insemination
No spermatogenesis- donor insemination
Obstruction/vasectomy- Testicular sperm aspiration (TESA)
Congenital absence of Vas (CAVD)- need TESA or ICSI or donor sperm
Describe TESA
Fine needle aspirates epididymis to take sperm
If doesn’t work, stick fine needle in testis and take testicular tissue
If doesn’t work, take chunk of testis
Describe the steps of icsi
- Select mobile, normal sperm
- Immobilize it by cutting tail
- Aspirate tail
- Position tail in needle
- Position egg and hold with suction pipette
- Insert needle into egg
- Rupture egg membrane by aspirating
- Expel egg
Describe unexplained infertility
Can be due to unknown aetiology, fertilisation issue or age. Can treat with midl ovarian stimulation with intrauterine insemination, or IVF
Why does age reduce fertility?
AMH decreases with age, reducing egg quality
Increased chromosomal abnormalities
Describe preimplantation genetic screening
- Make hole in ZP on day 3
- Select blastocysts with herniating cells at day 5
- Aspirate 8-10 cells with pipette and cut off with lazer
- Freeze biopsied embryos
- Wash biopsied cells
- Place in tube and store
- Lyse cells and PCR
- Genetic analysis
What are the pros and cons of egg freezing?
Less successful- need 10 eggs for a successful pregnancy
Can preserve fertility before chemo, radiation etc
Social egg freezing possible
What is pre-eclampsia and why is it important?
Pre-eclampsia refers to high maternal blood pressure with proteinuria in the second half of human pregnancy. More likely in first paternity pregnancies. It is so important as it is very closely linked to CVD, as women with early onset, and to some extent late onset, are at high risk of early CVD mortality.
If it develops into eclampsia, it can be fatal.
What are the functions of the placenta?
- Self maintenance/renewal
- Exchange/transfer/transport
- Separation of blood circuits
- Protection from maternal infections
- Protection from maternal immune reactions
The placenta brings maternal and fetal blood into close apposition, but does not allow the two to mix. Some fetal vessels are contained within the placenta.
What is the early placenta made up of?
When the embryo undergoes nidation, it implants with the inner cell mass at the leading edge. Trophectoderm starts to eat its way into the wall, and the embryo follows. The syncytiotrophoblast is at the leading edge.
Describe the structure of the ‘real’ placenta
Trophectoderm invades under the syncitiotrophoblast on the fetal side, now called cytotrophoblast which proliferates and invades the trabeculae, becoming primary villi. The lucanar system is now the intervillous space, containing pools of maternal blood
The syncytiotrophoblast covers the whole placental surface, made of only a single cell. Some mesencymal tissue comes from the embryo itself, and its presence indicates secondary villi. When endothelial cords (small fetal blood vessels in the villi) are seen, the villi are now called tertiary
How large can the syncytiotrophoblast be at term?
11-13m squared
Describe floating villi
Suspended in a pool of maternal blood, but don’t actually have contact with walls. Responsible for exchange and barrier functions of placenta
Describe how the placental structure changes during fetal development
Initially the villi form a sphere around the embryo. Those to the sides and luminal edge of the placenta regress, leaving the smooth chorion laeve. Those at the base of implantation form the chorion frondosum, with thickened villi.
Describe anchoring villi
Some cytotrophoblasts break through the syncytiotrophoblast, and spread laterally around the implantation site to form a shell. These contact maternal tissue throughout gestation. Through them exit cytotrophoblast columns, which invade the decidua and spiral arteries. These are called extravillous trophoblasts
What is the function of extravillous trophoblasts?
They enter the endometrium, eating the decidua and growing into the spiral arteries to replace endothelial cells and musculature. This keeps the arteries patent and gives a good blood supply through pregnancy. This prevents activation of the flight or fight response cutting off the baby’s blood supply
What can happen if there is an issue with extravillous trophoblasts?
They may not invade deeply enough, or can fail to invade some vessels. This can cause IUGR, where babies are more likely to be born prematurely or stillborn
What are trophoblast plugs and why are they important?
Trophoblasts are able to plug the spiral arteries, reducing maternal blood pressure reaching the placenta, preventing damage. Normal early fetal development occurs in less than 1% Oxygen.
Increased pressure in the placenta occurs in missed miscarriages.
What is the function of the uterine glands?
Produce glandular milk, rich in glycogen that sustains the embryo in terms of nutrition. This is the major energy source in the first few weeks after implantation.
Define villous cytotrophoblast
A progenitor cell type found in the first trimester, underlying the syncytiotrophoblast
Define syncytiotrophoblast
The surface layer of the placenta, made of a single cell. It is formed by the fusion of villous cytotrophoblasts into the syncytial layer. Replaced by fusion of further ones.
Define extravillous cytotrophoblasts
Differentiated cells that have migrated out of the villous placenta towards the maternal tissues
Describe how the villi change over gestational age.
Early pregnancy- the stroma become more cellular and vascularized. Fetal vessels sit deep within the villi, while maternal blood is covering them, so they need to thin
In the second trimester, their thinning is complete- the number of villi doesn’t increase, but the placenta grows
In the 3rd trimester, villous cytotrophoblast is sparse, with increased branching
What does the mother contribute to the placenta?
Beneath the implantation site is the decidua basalis, which comes away with the placenta
The part covering the luminal side of the embryo is the decidua capsularis, while the rest is the decidua peritalis.
Eventually, the capsualis fuses with the opposite side of the decidua peritalis, obliterating the uterine cavity.
What are the placental membranes?
The amnion is the avascular covering of the cord and placenta. The chorion covers the fetal vessels
The decidua is not a fetal membrane
What is contained within the umbilical cord?
2 umbilical arteries and 1 umbilical vein (O2 blood). Formed from the yolk sac and allantois (bit of gut sticking out).
Between the vessels and within the epithelium is Wharton’s jelly. This is a network of myofibroblasts, filled with mucopolysaccharides, helping to keep the cord turgid, even when knots form in the cord
How is the body adapted to increase placental transport?
- Villous structures are tortuous, with a large surface area
- The syncytiotrophoblast has a microvillous surface, which also slows maternal blood
- In the third trimester, most villi are tertiary, and fetal capillaries are close to the syncytiotrophoblast
What are the characteristics of fetal/maternal blood that make oxygen transport more efficient?
Fetal blood has a greater affinity for oxygen as it contains HbF. It is normally 80% saturated, compared to 50% in adults. It also has more haemoglobin- 20-25ml/dl vs 15.3 in adults
Maternal blood pH lowers as it picks up fetal metabolites, causing decreased oxygen affinity and allowing it to dissociated. The opposite of this happens in the fetus.
What is amniotic fluid?
It is an ultrafiltrate of maternal plasma, with a large contribution from fetal urine from midgestation. Aprox .5-1.2 mL are produced daily.
What is the function of amniotic fluid?
Gives the fetus buoyancy, allowing symmetrical growth
Cushions the embryo, preventing its adhesion to the membrane
Allows fetus to move for muscle tracts
Allows breathing movements and swallowing
How does amniotic fluid get cycled around?
Leaves by fetal swallowing
May also move across the skin prior to keratinization at 24w. Can move across fetal membrane into the maternal circulation, or into fetal vessels of placenta and umbilical cord.
Describe 2 conditions assoc with amniotic fluid
Polyhydramnios: Excessive amniotic fluid due to potential loss of swallowing. More common in diabetic pregnancy
Oligohydramnios: Lack of fluid potentially due to kidney issues
Describe how amniotic fluid can be used
Diagnosis of fetal genetic disease, using amniocentesis, chorionic villi sumpling.
What does the placenta block and permit in terms of disease and drugs?
It can prevent hepB, rabies, measles and malaria (although this clogs it). Transmits HIV, cytomegalovirus, small pox etc, rubella and toxoplasmosis
Lets through some drugs (most dangerous in 20-70day period of organogenesis).
Ethanol and recreational drugs can cross, causing IUGR and developmental delay
Heparin doesn’t cross, warfarin does (dangerous) and so does aspirin/paracetamol (safe)
Describe hCG
A two-chain hormone sharing its alpha chain with TSH, LH and FSH. All have unique beta chains
Produced exclusively by syncytiotrophoblast of preimplantation blastocyst and placenta. Proportional to how much syncytiotrophoblast there is
Binds to LH/hCG receptor, transmitting signals similar to LH, allowing progesterone production to occur in first 6-8 weeks of pregnancy, stopping CL regression
After 8 weeks, the placenta produces the progesterone
hCG prevents return to uterine cyclic pattern
Why is hCG important other than in prog production?
Can indicate a trophoblastic tumour
Important for male pregnancies, as it stimulates leydig cells to produce testosterone- responsible for the LH independent stage of testosterone production
Where is progesterone synthesized in pregnancy and what does it do?
Synthesized by the syncytiotrophoblast of the placenta after CL regression
Trophoblasts synthesize it from LDL cholesterol
it maintains uterine quiescence, maintains the uterine environment, induces decidua formation.
Receptors are found in the stroma and uterine glands
Describe how oestrogen conc changes during pregnancy?
Increases by 1000x, made by the feto-placental unit. Cannot produce testosterone de novo, but aromatises various androgens.
Fetal adrenal produce these androgens, but cannot convert them.
What CVS maternal changes occur during pregnancy?
CO increase by 10-15%, HR increase SV increase by 10% Reduced PVR esp in reproductive tissues. Alters type1:2 collagen in vessel walls. Progesterone induces vascular relaxation in reproductive tissues Increased angiotensin II and RAA system some NO vasodilation
What blood changes occur during pregnancy?
Expansion of blood and plasma volume (plasma faster, causing decreased haematocrit).
500mL loss in singleton birth- hypervolemia modifies this, not needing compensation
What immune changes occur during pregnancy?
Diminution of maternal immune response- white cell count rises due to more neutrophils, with more Th2 cells compared to Th1, allowing more antibody responses rather than cytotoxic
How does the uterus function in terms of the immune system
The decidua contains specialized killer cells
NK cells can act by antibody dependent cytotoxicity
Increased T cell density in placenta can cause repeated miscarriage
How does the skin change during pregnancy?
Increased blood flow- warm, clammy skin. Esp hands and feet
Pigmentation in skin, nipples are areola. Linea digra
Chloasma (areas of pigmentation) in the neck and face, lost after pregnancy (due to elevated melanocyte stimulating hormone)
Striae gravid arum (red depressed streaks in abdomen, thighs and breasts
Hair loss reduced, but excess gain is lost in the pueperium (immediately after birth)
What is the difference between primary and secondary amenorrhea?
Primary amenorrhea is the lack of ability to start a period
Secondary amenorrhea is when periods stop after a normal pattern
Describe the presentation of high prolactin causing secondary amenhorrea, and how this occurs
Can present with long cycles with no real blood, no other symptoms apart from milk expression on breast examination Diagnose using blood sample. High prolactin with normal others indicate the diagnosis
Lactotrophs reduce pulsatile GnRH secretion through negative feedback. Dopamine has negative feedback on this. Dopamine inhibitors can increase prolactin
May be due to a prolactinoma, psychotropic drugs, stress, lactation.
Can be treated with drugs or surgery depending on cause
List the possible causes of primary amenorrhea
Exclude pregnancy Hypothalamic issue Stress Exercise Anorexia Low body fat PCOS Tumour of ant pituitary Absent/atrophic endometrium Imperforate hymen Vaginal septum
Describe the possible presentation of premature ovarian insufficiency
Less frequent menses, normal smears, normal exam
Investigate with labs- find inadequate estrogen, causing decreased GnRH.
what is PCOS?
Oligo or Anovualation, evidence of hyperandrogenism, polycystic ovaries on ultrasound (need 2/3)
What are the possible symptoms of PCOS?
Hirtuism (facial hair)
Metabolid disorder- insulin resistance
Obesity
Acne
Large ovaries with multiple small follicles and stromal hyperplasia.
Increased androgens and free testosterone
Acanthrosis Nigracans (dark velvety skin)
LH to FSH ratio of 3
How can PCOS be managed?
Weight loss, medication for insulin, clomiphene citrate to increase FSH taken at the beginning of cycles, surgery
What are the consequences of anovulation?
No LH surge, causing no progesterone rise and no drop to allow menses
The endometrium proliferates, possibly leading to hyperplasia
Can induce a withdrawal bleed every 4-6 weeks, preventing endometrial proliferation
Why is fetal growth important?
Babies born small have increased chance of perinatal mortality, lower IQ, inattention, and behavioural issues
Almost half of stillborn babies have growth deficits
Large babies have increased chance of trauma, neonatal admission, and increased risk of noncommunicable disease in adulthood
What are the cutoffs for growth assessment in newborns?
LBW is <2500g VLBW is <1500g ELBW is <1000g HBW is >4500g SGA is less than 10th centile LGA is greater than 90th centile
What is fetal growth and what regulates it?
Increase in body size and mass from the end of organogenesis
Hyperplasia occurs more than hypertrophy- gain 16-17g/Kg/day
Normally constrained by maternal environment and substrate supply, provided minimal endocrine requirements (IGFs and insulin) are met
What are the four main substrates needed by developing fetuses?
- Glucose: Enters fetal circulation by facilitated diffusion. Gives energy and carbon for tissue accretion
- Amino acids: Enter fetal circulation by active transport. Allows metabolic balance of oxidation to growth
- Lactate: Produced by placenta. Mostly oxidised
- Fatty acids: Enter fetal circulation through diffusion. Form cell membranes and used as a store of energy
Describe the fetal supply line
Maternal nutrition, metabolic and endocrine status communicate with the maternal circulation. This then travels through uterine blood, placental transport and umbilical blood into fetal circulation, where it is taken up by tissues to determine fetal metabolic, nutrition and endocrine status.
What is poor fetal growth?
In utero growth potential is limited by bathology
Decreased fat and lean tissue with poor placental function
Increased risk of asphyxia, stillbirth etc.
Why is fetal insulin important and how does it get produced?
Allows increased glucose uptake, fat deposition, protein anabolism and promotion of placental growth
In early pregnancies, amino acids stimulate fetal insulin secretion. Then it is predominantly made up of already absorbed amino acids
Describe IGF and why it’s important in fetal growth
Growth hormones are present in high concs, with receptors everywhere but the liver. They affect length, but have minimal effect on weight.
Adrenal activation occurs near term, turning on the somatotrophic axis by inducing growth hormones in the liver. It promotes cell differentiation and maturation.
Describe how maternal constraint can limit size
Ability of the uteroplacental unit to supply oxygen and nutrients affects how large the fetus will be
Determined by maternal size, adolescence, parity, short inter pregnancy interval or macronutrient imbalance
Twins and periconceptual undernutrition can also trigger this
What is the cause of IUGR?
Placental insufficiency (idiopathic or vascular)
Trophoblast invasion insufficient
Maternal undernutrition (severe)
Fetal pathology (toxin, infection, congenital defects)
Switching off of paternal growth promoting allele
What is the cause of fetal overgrowth?
Called beckwith wiedemann syndrome.
Maternal imprinted allele not working, so paternal allele causes macrosomia, macroglossia, hemihypertrophy and omphalocoele, as well as embryonic tumours
What is Russell silver syndrome?
Short fetus, SGA, normal head
Due to underexpression of IGF2
What are the consequences of IUGR?
Phenotype is thrifty- low nephron mass, low lean mass, endothelial dysfunction, arterial stiffness, insulin resistance, dyslipidaemia, central adiposity, exaggerated stress response
Health risks including hypertension, IHD, stroke, diabetes, metabolic syndrome and osteoporosis
Describe gestational diabetes and its consequences
Glucose intolerance developing in pregnancy, causing excess fetal substrate and fetal insulin, causing excess growth
This results in LGA, resp distress, jaundice, hypoglycemia, polycythemia, hypocalcemia
Increased future diabetes risk, obesity, etc
Mother at higher risk of preeclampsia, birth trauma and type 2 diabetes
Define parturition
The process of giving birth- uterine and cervical activity acting to expel the conceptus (fetus, placenta and membranes) from the uterus, and prevention of hemorrhage so mother survives, breastfeeds and nurtures the newborn
