Flashcards in RDA Deck (403):
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.
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?
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
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
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?
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
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?
1. Stimulate ovary with FSH. Prevent ovulation with GnRH antagonists until want to trigger- GnRH agonist. Then give progesterone for luteal support
2. Egg released
3. Sperm sample produced
4. Egg and sperm combined for fertilisation
5. Fertilised eggs introduced into uterus
6. 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
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
1. Select mobile, normal sperm
2. Immobilize it by cutting tail
3. Aspirate tail
4. Position tail in needle
5. Position egg and hold with suction pipette
6. Insert needle into egg
4. Rupture egg membrane by aspirating
5. 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
1. Make hole in ZP on day 3
2. Select blastocysts with herniating cells at day 5
3. Aspirate 8-10 cells with pipette and cut off with lazer
4. Freeze biopsied embryos
5. Wash biopsied cells
6. Place in tube and store
7. Lyse cells and PCR
9. 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
- 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?
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
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)
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
Low body fat
Tumour of ant pituitary
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
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
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
What is labour?
Uterine contractions using to cervical dilation and expulsion of the conceptus
What are the components of giving birth>
Quiescence of uterus: Growth, distension and pressure of fetus, but uterus remains relaxed
Timing of birth
Activation: Musculature is stimulated, cervical ripening, softening, shortening and effacing, membrane rupture
Birth: Fetal-neonatal transition
Involution: Haemostasis, retraction, lactation
What is the function of uterine contractions?
Effacement of cervix and widening of pelvis. Head drops down, waters break (presenting part important as head must move 90 degrees in the second stage of labour)
What determines the timing of the onset of partuition?
Ratio of activity of progesterone on receptors A and B causes a simulated progesterone withdrawal. Prostaglandins are also synthesized, and there is an increase in beta agonists.
The fetus has a central role in determining time.
The normal inflammatory response is activated in labour.
Once labour is established, ongoing cervical changes, membrane rupture and myometrial contractility occur
Can also be affected by ethnicity, parity, infection and stress
What are the differences between preterm and term onset of labour?
In preterm labour, one or more factors involved in the triggering of normal labour is changed. The inflammatory reaction is a potent trigger.
Timing, process and consequence is a key distinguisher
Describe uterine quiescence
Poorly synchronised contractions- cervix is firm and closed, with painless and low frequency contractions.
Progesterone is responsible for this, as it decreases Ca2+, (produced by corpus luteum and then placenta) Withdrawal of quiescence agents can start labour
Describe the role of oxytocin in labour
Not essential for initiation, and requires gap junctions to work. Can induce and augment labour, and prevents postpartum haemorrhage
Describe what is required for activation, and how this process occurs
You need a whole fetus, with ability to activate the fetal HPA axis. Need uterine stretch and membrane rupture
Increased prostaglandins, oxytocin receptors and gap junctions with high connectivity is needed to start coordinated labour
This causes increased contractility (due to actin and myosin- antagonised by Ca2+ channel blockers)
Increased excitability (Ca2+ voltage regulation, blocked with B2 sympathetic stim)
Increased connectivity- block with COX 1 & 2
What are the functions of the cervix, and how does it change due to birth?
It prevents ascending infection in pregnancy. It consists of fibroblasts, smooth muscle and blood vessels.
In birth, it softens due to the degradtion of collagen (triggered by prostaglandin trop, leukocyte inflammation etc.
What drugs help with activation, stimulation and involution of the uterus?
Activation: Mifepristone, PGs, NO- induces labour priming
Stimulation: PGs, oxytocin, causes augmentation and induction of labour
Involution: Oxytocin, PG analogues, tranexamic acid- causes prophylacctic treatment of haemorrhage
What are the membranes of the uterus and how do they change during birth
Amnion and chorion. Responsible for producing prostaglandins. Rupture is not essential for labour.
Zone of altered morphology is where ruptured occurs, and an amniotomy may help induce labour
What must happen after birth>
Establish continuous breathing- foramen ovale closes, so pulmonary vascular resistance must fall fast
The baby also needs to maintain heat- brown fat is more common here, allowing non shivering thermiogenesis. The baby must be dried.
Baby needs to feed- it also causes uterine contraction, as well as the letdown reflex of milk, in addition to bonding
Placenta separates from uterus, cleaved through the decidua basalis
Contraction prevents haemorrhage.
Helped by oxytocin, cord clamping
What is the definition of preterm and very preterm labour?
Preterm is labour before 37 weeks
Very preterm is before 32 weeks
What is preterm labour, and what are its consequences?
A failure of uterine quiescence, causing neonatal complications, individual, family and societal costs
What are the main triggers of preterm labour?
Fetal Endocrine activation
Describe how uterine over-distension causes preterm labour
Mechanical forces activate expression of genes involved in parturition. This can be due to multiple gestations, polyhydramnios, and fetal maturation
Describe how fetal endocrine activation causes preterm labour
Activation of the fetal HPA axis can lead to increased adrenal hormones, increased estrogen etc.
This can be caused by stress in early pregnancy. It can also cause increased estrogen receptors and decreased progesterone receptor activity, leading to decreased uterine quiescence.
Describe how intrauterine bleeding can lead to preterm labour
This can activate the clotting cascade leading to the release of thrombin, plasminogen activators, and plasmin. This can cause protease activation leading to cervical ripening and membrane rupture
Describe how intrauterine infection can lead to preterm labour
Pathogenic microbes may travel through the decidua or ascend through the cervix, initiating an inflammatory response accompanied by cytokines, leukocytes, MMp activity (causing tissue change) and membrane apoptosis. This can cause chorioamnionitis, fetal infection and premature rupture of membranes
Describe what occurs during cervical ripening
It is an active process, with inflammatory like features. Leukocytes, cytokines and MMPs increase
Fetal growth hormone release
Poor attachment of the placenta
Describe what other triggering factors can cause preterm labour
Damage to the cervix- congenital, surgery, previous birth
Fetal genome- including growth, HPA, and myometrial upregulation
What do prostaglandins do in the induction of labour?
They are produced by arachidonic acid for increaesd myometrial activity, cervical changes, and membrane rupture.
What factors can prevent preterm labour?
Progesterone- good for prior preterm birth and short cervixes
Stricturing the cervix
What are two major concerns in premature babies and how can these be minimised?
Once concern is the switching of gas exchange from the placenta to the lungs- lund development is the min limiting factor in viability due to atelectasis because of low surfactant (treated with antenatal glucocorticoids)
Increased risk of cerebral palsy- treat with MgSO4
What are risks for premature delivery, and how can these mothers be identified?
Risks include maternal infection, previous preterm birth, smoking, multiple gestation, previous surgery, polyhydramnios, anomaly, age, and lack of prenatal care
Can screen short cervixes, presence of fetal fibronectin in the vagina (glycoprotein holding membranes together- should have disappeared after first trimester). 30% of those detected deliver in 7-10 days
What do we need to know when taking a history of a pregnancy?
Family pregnancy health
Previous medical conditions
Screening or not
Baby's movements later in pregnancy
What physical exam tests should you perform on a pregnant woman?
- Blood pressure. Maternal pressure goes down in the second trimester and returns to normal in the third
- Radial pulse, check for oedema
- Ask friend whether they look 'puffy)
- IPPA (but no percussion)
- Feel symmetry of uterus, check its height (should be within a week of date in a less than 100kg person)
- Check whether fluid can be felt
What do you need to look for on ultrasound?
Bipyramidal head diameter- best for figuring out how far along the pregnancy is
Abdominal circumference is the most important measure
Fetal heart doppler and maternal blood doppler- determines whether enough blood is getting through to the placenta
Check amniotic fluid- at least 2cm
What are the components of the birth plan?
Why do we do prenatal screening?
Identify the at risk group in whom it is hoped to improve the health outcome
5% have chromosomal abnormalities
5% have IUGR
5% have preeclampsia
5% have diabetes
5% have obstetric problems
5% have historical problems
3% have fetal abnormalities
7% at risk of preterm birth
Although this is not diagnostic
Describe placental vasculopathy
Reduced vessels within the placenta, preventing adequate perfusion of the placenta. Causes very high resistance of blood flow, and lots of fibrous tissues
Describe how IUGR can be detected on doppler
It is caused by abnormal placental development with no diastolic velosity- an abnormal umbilical doppler will show forward flow only in systole. As a result, fetal hypoxemia occurs, redistributing blood to the brain, causing myocardial dysfunction, reversal in venous circulation, acidosis and death.
What are two main tips for sleep in pregnant women and in neonates?
Pregnant women should sleep on their side to reduce IVC compression
New parents should sleep the baby on its own, on the back
What are the two major hormones involved in Calcium regulation?
PTH is the most important, and provides minute to minute regulation of the ECF calcium
1,25(OH)2D (vitamin d) is also important, and partly regulated by PTH
How is calcium found within the body?
Can be bound to protein (mostly albumin)
Can be bound in ionic compounds
Can be ionized and free (active, regulates PTH)
What are the three organs involved in Calcium regulation, and how do they contribute?
The intestines are responsible for absorption through active and paracellular routes
The kidneys regulate excretion and respond to variations
The bones are a reservoir for Ca2+ and P
What are the functions of parathyroid hormone?
It stimulates bone resorption by osteogclasts
Stimulates renal tubular reabsorption of Ca2+
Stimulates hydroxylation to produce vitamin D, increasing Ca2+ absorption in the gut
It therefore increases serum calcium by acting on the bones and kidneys directly, and the intestine indirectly
What triggers PTH and where does it come from?
Formed by parathyroid glands made up of chief cells. There are 4 of these, though a fifth may occur in the mediastinum
Triggered by low serum calcium, high serum phosphate, or low vitamin D
If there is high binding of Ca2+ to the CaR, it inhibits formation and secretion of PTH
Where are CaRs found other than the parathyroid glands?
The renal tubules- these receptors sense serum calcium and either increase or decrease reabsorption from the kidneys as a result
How is vitamin D formed?
Calciferol comes from sunlight and the diet, converted into calcidiol and inactive biliary metabolites in the liver. The kidney then converts it to calcitriol with high PTH or low phosphate. This increased Ca2+ and P absorption in the gut
Describe parathyroid hormone related peptide
Important paracrine regulator of breast, skin and bone development, not normally involved in Ca2+ regulation due to extremely low levels at normal function
Produced in excess in some cancers, especially epithelial cell tumours, causing cancer-assoc hypercalcaemia
What are the causes of hypercalcaemia and how do you differentiate?
Can be PTH dependent, with increased serum calcium, and no change or increased PTH.
Examples are primary hyperparathyroidism, or FHH/ other mutations inactivating CaR
May be PTH independent, showing high serum calcium and low PTH
Due to cancer (PTHrP), lytic bone myelomas, or issues with vit D
Can also be vitamin D dependent, stimulating increased gut absorption- sarcoidosis, vit D intoxication
What are some causes of hypocalcaemia?
- Hypoparathyroidism, seen postsurgical, activating CaR mutations, autoimmune, infiltrative causes or hypomagnesaemia
- Parathyroid hormone resistance (pseudohypothyroidism)
- Vit D deficiency/ abnormal hydroxylation/renal failure/ resistance
What are the hormones involved in phosphate metabolism
What are the organs involved in phosphate metabolsim
What are the causes of hyperphosphatemia?
Increased input: IV phosphate, cell death
Decreased excretion: Renal failure, PTH resistance or deficiency
What are some of the causes of hypophosphatemia
Inadequate absorption, eg. vit D deficiency
Intracellular shift of P due to resp alkalosis, prolonged intense exercise, or refeeding malnourished patients
What do phosphotonins do>
FGF23 derived from osteoblasts in the bone is converted acts to inhibit conversion to vitamin D, resulting in decreased phosphate absorption
It also acts at transporters in the kidney to decrease reabsorption
This causes hypophosphatemia overall
FGF23 is converted to an inactive form in the liver
How does hypophosphatemia occur?
Phosphotonin inactivation is mediated by a gene called PHEX. If it is mutated, there is less inactivation, causing hypophosphatemia (x linked)
Defective Pi transport in the kidneys due to fanconi syndrome
Ectopic FGF23 beyond inactivation capacity, eg. due to osteomalacia
Abnormal FGF23 (eg autosomal dominant hypophosphatemic rickets)
Describe the presentation of primary hyperparathyroidism
No specific symptoms
May present with haematuria due to calcified renal stones
Can be due to parathyroid adenoma
Describe the presentation of a PTHrP secreting tumour
Chest pain, history of smoking, mass on CXR- squamous cell cancer
If progresses, can cause melaena, pyloric ulceration, with high calcium, low phosphate and low PTH
High levels of PTHrP
This stimulates calcium release from the bones, as we;; as increasing renal reabsorption of calcium and decreasing renal reabsorption of phosphate
Describe the presentation of osteomalacia due to coeliac disease
Uncontrolled coeliac disease can lead to villous atrophy, resulting in decreased ability to absorb iron, folate and calcium for vitamin D. Associated with sunlight deficiency, it can cause calciopenic osteomalacia, with low dietary calcium due to decreasd absorption
This causes the bone to be unable to properly mineralise, resulting in a lot of unmineralised osteoid.
Will show muscle wasting, bone pain and disability, with low calcium and phosphate, high phosphatase and low vitamin D.
Valgus/varus deformities, prominent costochondral joints, poor growth
How can vitamin D metabolism be impacted for the worse?
- Inadequate sunlight exposure
- Reduced dietary intake
- Induction of enzymes converting it to inactive biliary metabolites
- Impaired 1a hydroxylate
- GI disease preventing absorption
Describe the presentation of pseudohypoparathyroidism
Short 4h metacarpal
Due to mutations in signalling proteins, causing resistance to PTH
Describe ADHH and how it presents
Flu like illness, young patient, with muscle cramps, abdominal pain, n&v, afebrile, high BP, some neuromuscular irratability
low calcium, high phosphate- appears to be hypoparathyroidism
ADHH is autsosomal dominant hypercalciuric hypocalcaemia- constitutive activation of CaRs, meaning parathyroids read calcium as higher than it actually is. This means PTH secretion is low. Additionally, renal reabsorption is reduced as the CaRs there also read high serum calcium
What is the treatment of ADHH?
No treatment if asymptomatic- can cause nephrocalcinosis if vit D is given, as it will result in way too much calcium in the urine
Small doses of vitamin D if symptomatic
What is FHH?
Familial hypocaciuric hypercalcemia
Suspected if PTH is normal with family history of hypercalcemia
Diagnosed by screening immediate relatives, checking urinary creatinine to calcium, and CaR genotyping
What are the differences between ADHH and FHH?
ADHH has decreased PTH, very low sCa, and increased uCa. It causes the CaRs to think Ca2+ is high-decreased PTH and increased calcium wasting
FHH has normal or increased PTH, increased sCa and decreased uCa. It causes the CaRs to think calcium is low, increasing PTH and decreasing calcium wasting
Describe the pathology involving increased FGF23
Can be oncogenic, eg due to a mesenchymal tumour, and presenting with osteomalacia
The increased production of FGF23 causing renal phosphate wasting and osteomalacia, causing low phosphate, high PTH and poor bone mineralisation.
What is the function of the thyroid gland?
Necessary for normal growth and development, especially during pregnancy. For the first twenty weeks, the fetus is dependent on maternal thyroid hormone
Needed for metabolic activity and O2 requirements.
Regulates lipid and carbohydrate metabolism, and therefore weight
Controlled by the HP axis
Describe the development of the thyroid gland
By week 4 it is shown as endodermal cells
The gland decends through the thyroglossal duct from week 5, placing itself anterior to the trachea in week 7. In week 10, the thyroglossal duct disappears, and by 12-20 it is functional, but still dependent on maternal hormone.
Failure to migrate causes lingual thyroid, presenting as a child with hypothyroidism
Thyroglossal cysts can persist, and move upon tongue protrusion
Describe the anatomy of the thyroid gland
It is located deep to the sternohyoid muscle, and has two halves joined by an isthmus. Posterior to it are the recurrent laryngeal nerves, with the oesophagus to the left. It is supplied by the sup thyroid artery from the external carotid, and the inf thyroid artery from the subclavian.
It is innervated by the ANS
Describe the histological presentation of the thyroid
It is made up of follicles formed by a single layer of hormone producing cuboidal epithelium, which form a circle around the lumen. Newly formed hormone is stored in the lumen as colloid, made up mostly of thyroglobulin. When TSH is secreted, the cells become columnar with scalloped edges due to endocytosis of hormone containing colloid.
Cells between are called parafollicular cells responsible for secreting calcitonin. When there is medullary thyroid cancer, they cause increased calcitonin secretion.
How does the thyroid gland manage iodine?
Iodine is ingested in the diet and concentrated in the thyroid- approx 50 days' worth. This comes from fish, salt and bread, and is especially important during pregnancy to avoid fetal cretinism. Deficiency leads to compensatory thyroid enlargement called goitre.
Plasma iodine is low, and it is trapped by the sodium/iodine symporter called NIS. This is found on all thyroid cells, and can be used in treating cancer by giving radioactive iodine to be taken up.
Iodine is oxidised by thyroid peroxidase and moved into the colloid to form MIT and DIT
What is the downside to using radioactive iodine?
The NIS transporters are also found in the breast, gastric mucosa, ciliary body of the eye, salivary gland etc. Therefore you can get dry eye/mouth, increased risk of gastric cancer, and cannot give the compound to lactating mothers.
Describe the makeup of T3 and T4
T3 is made up of a monoiodotyrosine and a diiodotyrosine
T4 is made up of 2 dis.
Describe the process of releasing thyroid hormone
Thyroid hormone is found attached to the thyroglobulin in the lumen.
When it is needed, the colloid is endocytosed, separating T4 and T3 so that they can enter the bloodstream
Describe Pendred syndrome
Hypothyroidism as there is a deficiency in the iodine transporter. The I cannot reach the colloid. As this transporter is also involved in Cl- transport, it can cause deafness.
Describe the consequences of a range of thyroid conditions.
Ant pit tumor/ T3 receptor mutation: The body produces high levels of TSH and T4
Overactive thyroid: Low TSH, High T4
An ill patient will present with low T4 but no response from TSH
Thyroidectomy or primary hypothyroidism will show low T4 but high TSH
Secondary hypothyroidism will show low T4 and no TSH response
Describe the actions of Carbimazole
Blocks the peroxidase enzyme- used to treat thyrotoxicosis, when not due to thyroiditis
How is thyroid hormone regulated?
There is a negative feedback response between T3 and TSH. Although 80% of the hormones released are T4, these get converted to T3 at the tissues themselves.
After a thyroidectomy, enough T3 is needed to prevent TSH release
What does TSH do at the thyroid?
It stimulates production of thyroglobulins, iodine trapping, and T3 and 4 synthesis. It increases colloid endocytosis, proteolysis of Tg and T3/4 to increased their secretion. Also increases blood flow, increases thyroid peroxidase and H2O2
It also has the same alpha subunit as LH, FSH and hCG, causing thyroid stimulation. This also means TSH is lower in pregnancy, and regulation due to increased T3 is less effective.
What is graves disease?
Autoantibodies to the TSH receptor cause ongoing stimulation and thyrotoxicosis.
Pre-formed T4 & T3 is dumped into the blood, then causes hypothyroid as there is a long time taken for the T3 &4 stores to recover.
Presents with low TSH, high T3 and 4
Symptoms include nervousness, increased sweating, weight loss, vasodilation and heat sensitivity tachycardia and atrial fibrillation, and weakness due to hypokalemia
Signs include bruits over the thyroid and tachycardia due to increased blood flow. It also can show goitre, skin changes, tremor and eye signs
It may be caused by Graves disease, multinodular goitre (with some regions autonomous and hyperactive), thyroiditis, some drugs (eg. amnioderone) and toxic nodule, with a self-stimulating TSH receptor mutation
Shows low T4 and T3, with high TSH
Causes decreased energy metabolism and a slow adult onset
Called hashimotos disease
Shows weight gain, cold, hair loss and dry skin, constipation, fatigue and oedema
Describe thyroid eye disease
Increased glycosaminoglycans push the eyes forward, and cause the eyelids to retract.
The eye becomes very red and inflamed
treated with steroids.
Describe a possible presentation of Graves disease
Young female with: Weight loss, lots of hunger and deating. Leg weakness, eyelid retraction, tremor, temperature, shortened periods, palpitations and fatigue.
No neck pain
Likely graves disease as no neck pain, young age, sex
Treat with drugs for heart rate, carbimazole
Describe a possible presentation of toxic nodule
Palpitations, sweating, anxiety, weight loss, atrial fibrillation, loss of upper body strength, tremor, proximal myopathy
Lump in the neck. Shows toxic nodule
Treatment is Carbimazole
Can get radioactive iodine or surgery
What does thyroid hormone do?
Increases metabolic rate and head production
Increased HR and SV
Important for intrauterine CNS growth and development
What is the law surrounding the prescription of contraception in NZ?
Legal age of consent is 16, but there is no restriction on prescription of contraception to under 16s without parental consent, so long as they have sufficient understanding and maturity to comprehend the proposed treatment
What is conception vs contraception?
Conception is the union of egg and sperm, followed by implantation of the blastocyst
Contraception is a method of preventing pregnancy via interference with ovulation, fertilisation or implantation.
What are some methods of contraception available in NZ?
What are the most vs least effective methods of contraception?
Least: Fertility planning, spermicide
How does the combined pill work?
It suppresses ovulation
Reduces sperm transport in the upper genital tract
Alters the endometrium to inhibit implantation
Thickens cervical mucus
What are the advantages and disadvantages of the combined pill?
Advantages are that you can stop whenever you want, it's available almost everywhere, and there are also non contraceptive benefits including reduced ovarian and endometrial cancer.
Disadvantages are that there is a 9% failure rate, it is complicated to take, lots of things prevent its use, there is a very small breast cancer risk, and the pill free interval can cause the ovaries to wake up as the rising FSH can trigger an LH surve and ovulation
What conditions make the pill unsuitable for use?
Focal migraines (aura, flashing)
Personal and family history
How do you take the OCP?
If started on D1-5, protection is immediate. If started later, 7 days are needed as a precaution
Why can the progesterone only pill be better? How does it work?
Good for breastfeeding, or if you are unable to take the combined pill
Thickens cervical mucus, but must be taken within 3-4h of the same time every day. Some also suppress ovulation
How does depo provera work?
Suppresses hormones responsible for ovulation
Thickens cervical mucus
Can cause prolonged amenorrhea and weight gain
Delayed fertility return
What is LARC?
Long acting reversible contraception
Good as it is cost effecteive even after 1 year of use. Issues with training and accessibility
Describe the effects of jadelle
Alters the endometrium to prevent endometrial reception of sperm
Thickens cervical mucus
Bleeding is the main side effect, which may be prolonged or frequent
How does the copper IUD work?
Toxic to sperm
Creates an inflammatory response in the endometrium to prevent implantation
Can cause heavier periods
Gold standard for contraception
How does the mirena work? Why would it be indicated?
Creates an unfavourable uterine environment
Thins the endometrium
Thickens cervical mucus
Indicated for heavy bleeders, contraception, endometrial protection with HRT
Used for dysmenorrhea, endometriosis, endometrial hyperplasia
What are the options of emergency contraception?
ECP- up to 72 hours after upsi, efficiacy decreases with time. Postpones ovulation but cannot do anything if ovulation has already occured
Copper iud- >99% efficacy. Anti implantation as it takes 8 days for a blastocyst to implant.
What are the purpose of the breasts?
Nutrition of young
Spacing of pregnancies
Describe the mammary glands
Modified sweat glands derived from tissue identified in mammary crests that arise between the armpit and groin
Describe the development of the breasts
Downgrowth of the dermis to form the primary breast buds. Secondary buds develop from these, becoming the lactiferous ducts
Buds develop lumens and become canalized under the influence of estrogen and progesterone
By birth, 15-20 lactiferous ducts are present and the breasts could make milk under hormonal stimulus
Describe newborn lactation
The fetus hasbeen exposed to placental steroids and the maternal lactation hormones, which can cause it to produce a clostrum like secretion called witch's milk
What are the external structures of the breast?
- Body of the breast
- Nipple- raised cylindrical pigmented structure. Can be inverted. Point where lactiferous ducts join the skin
- Areola: Prominent circle of tissue surrounding the nipple, containing sebaceous glands without hair follicles, giving the surface a grainy structure
Describe the internal structures of the breast
Adipose tissue of the pectoral fat (texture and shape)
Cooper's ligaments support the breast- affected by age and childbearing
15-20 lobes made up of milk secreting lobules, each connected to a lactiferous duct, which leads to a lactiferous sinus
Describe how the breasts change at puberty
The breast ducts only develop alveoli under the influence of estrogen during pregnancy. The resting breast is dominated by the duct system and fat, but during the menstrual cycle, alveolar buds grow, and increase with successive cycles.
What are the changes that occur in the breast during pregnancy?
Oestrogen causes breast growth
Progesterone induces side branching of ducts
Prolactin causes alveolar development, and stimulates casein and alpha lactalbumin
Insulin and cortisol stimulate alveolar epithelial cell division
Ducts grow, branch and bud, causing potential quadrupling of breast weight
What is the function of prolactin in the breasts?
Promotes milk production, but is inhibited by high progesterone during pregnancy
Suckling of the infant induces prolactin secretion by the ant pituitary, through a neuroendocrine reflex
This also decreases dopamine which normally inhibits prolactin. Increases vasoactive intenstinal peptide secretion by the paraventricular nucleus
This induces milk protein production, correlated with duration and extent of suckling
What is the milk ejection reflex and what can cause it?
Suckling stimulates synthesis and secretion of oxytocin by the posterior pituitary. This induces contraction of myoepithelial cells of the alveoli, causing milk ejection from the ducts, and potentially from the nipple.
Stimulation such as baby smell, hungry crying and intercourse may cause it
Describe extramammary glands
Usually this additional breast tissue is found along the line of the embryonic milk ridge. Lactiferous ducts may exit the breast at sites outside the nipple.
What are the two stages of lactogenesis
Stage 1: Mid gestation to day 2 postpartum. Preparation, involving increasing alveoli, ducts. Capable of lactation, but normally doesn't occur until day2 postpartum
Stage 2: is postpartum day 3-8 with the start of large-scale milk production. There is increased alpha lactalbumin (for producing glucose) and decreased sodium and chloride in the milk due to tight junctions in alveolar epithelium
Define galactopoiesis and involution
- Galactopoiesis: Maintenance of established milk secretion
Involution: Reduction in breast size about 40 days after the last feed, due to buildup of inhibiting substances
Describe the colostrum
This contains less sugar and fat, so less energy. It is much more protein rich. It is especially rich in IgA antibodies (for the mucosal immune system) specific to the mother's exposure. Antibodies from the mother cross the placenta during pregnancy, but this is lost after birth
What is the timeline of gonad development?
Bipotential gonads emerge around 6 weeks, the internal genitalia at 7 weeks at external genitalia at 8
Describe the bipotential gonad
Equivalent to genial ridge. Arise as paired structures in the intermediate mesoderm and divide into three areas
Pronephros forms the adrenals
Mesonephros forms the gonads and internal structures
Metanephros forms the kidneys
Its development depends on nuclear transcription factor activation, which bind and form the protein complex aorund the DNA, altering gene transcription and expression.
As the adrenals, gonads and kidneys arise from here, mutations can affect more than one organ system.
What are the hormones necessary for the formation of a genital ridge?
WT1 (wills tumor- putation can result in pediatric renal cancer)
SF1 (steroidal factor)
Describe the overall process of gonadal determination
From the bipotential gonad, if it is exposed to SRY, SOX-9 and FGF9 it will become a testis. This is because earlier and greater gene activation occurs in testicular development. It is initated by the SRY gene.
SRY then triggers SOX9 etc. Testicular development suppresses ovarian development and vice versa.
The female ovary will form if not exposed to these, and exposed to FOXL2
Describe the development of male gonads
SRY determines male gamete development. In females where it has been transferred by recombination onto their X chromosome, they develop a testis
It is found only in the pre-sertoli cell in the testis, and activation precedes development of the sertoli cell, which precedes other testicular cell lines.
It stimulates SOX 9 to complete testicular differentiation. Initially SOX-9 is transcribed by SF1. SOX-9 up-regulates itself via a positive feedback loop, as well as being stimulated by prostaglandin D2 and FGF-9. These also inhibit ovarian transcription factors
Describe how leydig cells develop
They arise from the interstitium of the testis. They produce steroids. The initial leydig cells regress and are replaced by adult ones postnatally
Describe the development of primordial germ cells
These arise from the yolk sac and migrate to the genital ridges following Stem Cell factor
Once there they lose motility and aggregate. In the testis, germ cells enter cords and have mitotic errest. In the ovaries they continue into early meiosis before arresting
Spermatogenesis is determined soon after reaching the genital ridge. They are involved in ovarian development
If germ cells do not populate the ovary, only stromal tissue evolves
How do the internal genital structures evolve?
They develop from wolffian and mullerian ducts. Wolffian ducts form the internal male genitalia, while the mullerian ducts form as invaginations of these that become female internal genitalia.
This is determined by presence of leydig and sertoli cells, as testosterone stabilises wolffian structures at high local concentrations, and sertoli cells secrete antimullerian hormone, causing regression of mullerian structures
As there is no vasculature at this stage it is all paracrine signalling, meaning there can be bilateral differences
Describe the development of external genitalia
It can produce normal male or female genitalia
Male results if the genital tubercle is exposed to high concentrations of dihydrotestosterone. Lower concentrations can result in partial virilisation (eg. hyperspadius with the urethra low in the penis). Absence or resistance to androgens results in femal external genitalia
Note that Placental HCG takes the place of LH in the first trimester, allowing leydig cells to be activated.
Describe androgen resistance
Presence of a testis
Produces testosterone, but resistant
Lack of internal structures
Female external structures
All androgens converted to estrogen
No secondary sexual characteristics- no body odour, no pimples etc.
Describe the presentation of a virilised female
Normal female internal genitalia with the presence of a uterus
Male external genitalia
Can be due to prenatal androgen exposure
Fetal causes are congenital adrenal hyperplasia
Maternal causes are steroid ingestion, severe polycystic ovary disease and androgen secreting tumour
Describe the presentation of an undervirilised male
Presence of a testis
No female internal genitalia
Lack of prenatal androgen or inability to respond to it
(LH receptor mutation/enzyme defect/androgen receptor mutation)
Presents with a small normal phallus
Describe the presentation of a pre-bipotential gonad mutation
Shows presence of mullerian structures, with femal external genitalia and an XY karyotype. Testis has failed to develop
Describe how mutations in SRY, WT1, SF1 may present
SRY mutation causes campomelic dysplasia, with 75% of xy having sex reversal
WT1 mutation can result in kidney tumour in childhood
SF1 mutation regulates gonadal, adrenal, pituitary and steroidogenic functions. It is first released in the urogenital ridge, and then in fetal sertoli and steroidogenesis. Having only one copy leads to hyperspadia in men and women with early menopause
What are the glucocorticoids vs. the mineralocorticoids?
Glucocorticoids are cortisol
Mineralocorticoids are aldosterone
What does glucocorticoid do?
Regulates sodium, blood pressure and especially glucose in the body
Its loss can lead to hyponatremia, meaning water is unable to be excreted
Can cause hypoglycaemia due to to reduced hepatic gluconeogenesis
Can cause hypotension due to loss of cortisol effects of vascular tone
What does mineralocorticoid do?
Released in response to low blood volume
Regulates sodium balance
Regulates H+ balance
Regulates K+ balance
If not working, will see hyponatremia due to urine sodium loss and ADH secretion
Will also see hyperkalemia due to reduced K+ excretion
Can also reduce H+ excretion, causing metabolic acidosis
What are the causes of adrenal failure?
Can be primary (adrenal gland issue)
Can be secondary (pituitary/hypothalamic issue)
Describe how primary adrenal failure occurs, and why this causes pigmentation
The hypothalamus releases CRF, prompting to the pituitary to release ACTH- this acts on the adrenal cortex to produce cortisol, which has negative feedback on the ant pituitary and hypothalamus
However, ACTH is a product of POMC, which also produces MSH. ACTH also has the same alpha chain as MSH.
Increased POMC and ACTH produces increased MSH, increasing pigmentation. This is especially notable on skin flexures, mouth, freckles and nails
Describe how to distinguish between simple and pathological obesity in childhood
Check old photos for pattern of change- simple obesity is observable by 3-4 years old. Childhood glucocorticoid excess leads to generalized obesity, while in adulthood it leads to truncal
Simple obesity drives growth, so obese children are often tall for their age.
Describe the features of glucocorticoid excess
Short fat body
Thinning skin with bruising, v red marks
Androgen excess causing hirsutism and amenorrhoea
Myopathy causing proximal weakness
Glucose intolerance causing diabetes mellitus
Why does excess cortisol cause mineralocorticoid effects?
Cortisol also binds to mineralocorticoid receptors. While it has no mineralocorticoid effect at physiological state, it can cause it at excess levels
What can cause cushings syndrome?
-primary functional adrenal tumour
- ACTH secreting tumour (pituitary/ectopic)
- Exogenous glucocorticoid
What happens when you get partial loss of glucocorticoid receptor function (glucocorticoid resistance)
You get increased cortisol
Secondary mineralocorticoid effects including alkalosis, hypokalemia, and hypertension
This is because the brain thinks cortisol is low, so releases increased ACTH, causing hyperglycaemia
What do you get when you have loss of function of mineralocorticoid receptors?
Mineralocorticoid resistance (pseudohypoaldoseronism)
Causes high aldosterone and renin levels
Depletes ECF space
High serum K+ and low serum Na+
Increased urine osmolarity
What do you get when you have ACTH receptor loss?
Nonfunctioning zona reticularis and fasciculata
Cortisol deficiency from birth
Frequent collapsing and potential death
What can happen when an enzyme of cortisol is defective?
Defect in cotisol synthesis, leading to high ACTH with secondary stimulation of the adrenal precursors- these are androgens
Patients often also have mineralocorticoid deficiency and are salt wasting
Causes female internal genitalia with uterus, but male external genitalia
Describe conenital adrenal hyperplasia and its side effects
Due to defect in 11B hydroxylase. Causes low cortisol, high deoxycorticosterone, high 11deoxycortisol and old bone age
Very dark skin, very tall, large phallus, pubic hair, high BP and hypokalemia
Managed with glucocorticoid therapy to suppress ACTH. Also need to suppress central precocious puberty and treat the hypertension
Describe normal somatic growth
Depends on good general health
Normal nutrition and genetics
What can cause abnormal growth?
What are the phases of growth?
Infant- rapid growth at birth declining rapidly in the first 2 years of life
Childhood- constant annual growth- GH dependent
Puberty- Rapid growth dependent on sex steroids and GH release. The legs grow relatively faster than other areas
What is mid-parental height?
An estimate of height potential based on parental height
Boys it's Dad + (Mum +13) /2
Girls it's Dad - 13 + mum /2
What is height velocity?
The rate of change of height in children. It differentiates normal short stature from pathological
Normal has decreasing across childhood, rapid increase and then decrease at puberty.
Girls have earlier peaks
What is short stature
Common, may be normal or pathological
Normal short stature grows with normal height velocity
What are normal variants of short stature?
Familial short stature- within MPH. See same bone age
Constitutional delay- family history of delayed puberty. Slow late childhood height velocity and delayed bone age
What are the categories of pathological short stature?
Disproportionate (skeletal dysplasia)
How do you use bone age?
Picture of hand x ray matched with 'standard' x ray for that age. The age should be within a year of the age the child is at
Can tell based on epiphyseal growth plates etc
Describe growth hormone secretion
Pulsatile, low baseline
Primarily secreted at night
Increased by sleep, exercise stress, hypoglycemia, amino acids, malnutrition, sex steroids
Decreased by obesity, psychological issues, deprivation
Needs normal insulin and nutrition
What does growth hormone do?
Metabolic functions, inhibiting glucose uptake and promoting glycogenolysis
Stimulates protein synthesis
Functions as an endocrine, paracrine and autocrine hormone
Describe IGFs (somatomedins)
There are I and II varieties
Both have a great amount of homology with insulin, and have cross reactivity with each other
IGF I is the major postnatal growth promotor, bound to IGF binding proteins
It is prinicpally produced in the liver, and bone
It causes cell proliferation and differentiation
How does estrogen affect growth?
Has effects on the skeleton and body composition. Responsible for epiphyseal maturation and closure
If there is no estrogen growth does not stop
Describe how hypothyroidism affects growth
Thyroid hormone has a facilitatory role in growth, necessary for GH secretion and growth plate development
Without it, severe short stature, developmental delay and deafness can occur
How does insulin facilitate growth?
Provides the substrates for growth
Describe the growth promoting hormones in the fetus, child and pubertal person
Fetus needs IGF II, Insulin, PDGF, EGF and FGF
Infant needs GH, IGF-I and T4/T3
Pubescent needs GH, IGF-I, T4/3, E2 and Insulin
What are possible causes of short stature?
Proportionate may be cause by
Disproportionate may be caused by
Describe how IUGR can cause pathological short stature
Makes baby small for gestational age
Catch up growth above the 3rd percentile usually occurs by 6 months of age, but can drag on to two year
By 2 years it is normally assoc with short final height, and unlikely to reach MPHs
Describe how turner's syndrome can cause pathological short stature
Loss of X chromosome, normal Thyroid, but loss of some growth related areas of the X chromosome
May have short stature, failure to enter puberty, neck webbing, hand and food oedema, side spaced nipples, increased carrying angle, cardiac abnormalities, and renal/urinary tract abnormailities
Describe the body's need for glucose
The brain has an abligatory requirement, consuming approx. 80% of whole body glucose in the fasting state. Uptake is not insulin dependent. Blood cells account for the other 20%, with renal medulla accounting for the rest
Give the general overview of the function of insulin/glucagon
Insulin prevents uncontrolled rise in blood glucose after eating
Glucagon keeps blood glucose from falling into the hypoglycaemic range
What are the cell types within the islets of Langerhans?
Alpha cells produce glucagon
Beta cells produce insulin
Delta cells produce somatostatin
Also rich in capillaries- receives 20% of pancreatic blood flow, but makes up 1-2% of pancreatic mass
What is the innervation of the islets of langerhans?
ANS and peptidergic neurons
Describe how glucose enters the B cells of the pancreas
Facilitated transport. Most is Non-insulin mediated glucose uptake, and most of the rest is GLUT2 facilitated glucose uptake. GLUT-4 is the most important insulin sensitive transporter in muscle and fat
Describe the location of function for GLUT 2 and GLUT 4
GLUT2 functions in the pancreas and liver
GLUT 4 is primarily active in fat and muscle
Describe how the entry of glucose into B cells triggers the release of insulin
The glucose undergoes glycolysis to form ATP, thanks to an enzyme called glucokinase
This causes closure of ATP sensitive K+ channels
The cell depolarizes
Calcium enters via voltage gated channels
Increased calcium triggers insulin translocation and exocytosis
Describe what happens to insulin after its production, and the relevance of this
Insulin is first produced as pre-pro-insulin, and as it completes its transition to proinsulin and then insulin, each molecule releases a molecule of C peptide
C peptide can be used to distinguish people with type 1 vs type II diabetes as well as being able to tell whether people are injecting their own insulin or not
Type II diabetes will have normal levels of peptide C as they are producing insulin. Type I diabetics will have low peptide C as they are not.
People injecting insulin will have low peptide C as the insulin comes pre-formed
People with insulin secreting tumours will have high peptide C
What does insulin do once it binds to the insulin receptors?
Note that these receptors are not needed by the brain or red blood cells
Increased GLUT 4 vesicles travel to the cell surface, allowing glucose to enter muscle and fat cells, reducing blood glucose levels. It also increases fat and protein storage, and carbs stored as glycogen
What are the factors that regulate the release of insulin?
Insulin increases in respose to
Vagal nerve stimulation
Incretin hormones (GLP-1)
Describe how ingestion of food causes the release of insluin
When food is consumed, the GI tract releases incretin gut hormones. These act on the alpha cells of the pancreas to reduce glucagon, and the beta cells to increase insulin
As a consequence there is reduced hepatic gluconeogenesis, and increased peripheral glucose uptake
Describe regular secretion of insulin, and how it responds to high glucose
Baselin secretion is pulsatile
High glucose elicits a fast initial acute release, then a slower second phase. This causes a big peak, then regulation
Describe how insulin affects the glucose uptake and production, lipid synthesis, and ketones
Insulin increases glucose uptake in adipose tissue and muscle, increases glycogen sythesis in the liver and muscle, and decreases gluconeogenesis in the liver
It increases lipogenesis and decreases lipolysis in adipose tissue, increases lipid and protein sythesis in the liver
It also increase ketone uptake in the muscles, and decrease ketogenesis in the liver
How can diabetic patients' glucose levels change after exercise
Patients with diabetes may have an increase in blood sugar after exercise, as they are unable to shove glucose into their cells. They rely on other forms of glucose production- ie glycolysis
How is energy stored in the body?
50% of glucose is burned, 5% to glycogen and 45% stored as fat
Excess carbs are stored as glycogen- mainly in the muscle, but 70g in the liver Glycogenolysis results in glucose release. Excess energy is stored as fat
Fat is stored in adipocytes, which produce hormones like resistin, TNF alpha and adiponectin. Lipolysis results in glycerol release, to be transported to the liver into the krebs cycle. Associated free faty acids are oxidised to ketone bodies
Protein has no specific deposits and makes up about 20% of stored energy. It can be broken into amino acids to gluconeogenesis, oxidation to energy, or reincorporation to proteins
What happens to carbs stored as glycogen in the liver when glucose or energy is needed?
First converted to glucose - 6- phosphate, which can be converted to glucose
Alternatively, if energy is needed, it can be converted to pyruvate, then to acetylCoA which takes it through the krebs cycle, producing 38 ATP
Describe what happens to carbs stored as glycogen in the muscles when energy is needed
Converted to lactate, then given into the krebs cycle for 38ATP. However, lactic acid buildup can occur
Describe what happens to protein in the muscles when energy is needed
Can be broken down into alanine and used in the krebs cycle
Describe what happens to glycerol and free fatty acids from fat when energy is needed
Glycerol put into the krebs cycle, as are free fatty acids- although these come out of the cycle as ketones
Describe what can happen if too many ketones are produced
Can get ketoacidosis if insulin deficient- this is the result of uncontrolled protein hydrolysis, gluconeogenesis and inactive GLUT4
It presents as vomiting, abdominal pain, drowsiness and a high anion gap
Describe how hypoglycemia is prevented
Receptors sense low glucose, causing release of ACTH from the ant pituitary. This acts on the adrenal cortex to produce cortisol
The hypothalamus also stimulates the adrenal medulla to produce adrenaline
Along with SNS activation and hypothalamic innervation, the alpha cells of the pancreas produce glucagon
What are possible causes of hypoglycaemia?
Insulin in patients with diabetes
Sulphoylurea therapy (drug prevents K+ channel opening)
Severe hormone deficiency- eg. addison's disease where patient cannot produce cortisol
Why might somebody be recurrently hypoglycaemic?
The hypothalamus adjusts to low glucose, and stops activating at low levels. However, the brain doesn't adapt, so the patient is prone to random bouts of unconsciousness as their SNS doesn't activate in response to lowering glucose
Define insulin resistance
Subnormal glucose repsonse to a given concentration of insulin
High insulin with normal or high glucose. This starts before diabetes
It can be pre receptor or receptor, but most commonly it is a post receptor issue
What is the metabolic syndrome?
Clustering of multiple risk factors with obesity
Involves central obesity as well as two of
- Elevated triglycerides
- Reduced HDL cholesterol
- Abnormal glucose
What conditions are associated with insulin resistance?
Acanthrosis nigracans- black, velvety skin on the back of the neck due to increased IGF production
Describe how metabolic syndrome is associated with insulin resistance
Visceral adipocytes are metabolically active cells producing hormones and cytokines. They may get larger, and take up more fat. This means they don't stop performing lipolysis, and can't soak up glucose
This causes insulin resistance in muscles, liver and fat. It also causes release of non esterified fatty acids (NEFA), which causes toxicity at beta cells, and reduced insulin release.
High insulin prevents ketosis in most patients with type II diabetes.
What are other potential causes of insulin resistance?
Genetic components (eg. south asian populations)
May have Beta cell dysfunction, may be caused by drop in B cell mass or functionality
Intrauterine environment- SGA babies who become obese have increased diabetes risk
How do you treat insulin resistance?
Firstly, decrease glucose- too high levels may switch off B cells reversibly
Can also be treated with hyperinsulinaemia. This is because the liver increases its glucose output and triglyceride synthesis, which leads to fatty liver disease
Describe the development of type II diabetes
May be preceded by insulin resistance by many years. Causes hyperglucaemia due to loss of incretin response coupled with progressive B cell inability to produce insulin
Presents as high fasting and resting glucose
How do you test for diabetes?
Measure HbA1C- this is the portion of haemoglobin that binds to glucose. In a person with diabetes, the circulating high glucose triggers formation of increased HbA1c concentration
It can also assess average glucose levels
What are some of the consequences of type 2 diabetes
Microvascular disease- hyperglycaemia causes endothelial dysfunction, allowing retinopathy (oedematous, ischaemic retina), neuropathy and nephropathy to occur
Macrovascular disease- increased atherosclerosis acceleration leading to stroke, myocardial infarction and peripheral vascular disease
How do you treat type II diabetes?
Drugs that control hyperglycemia (metformin, sulphonylureas)
Drugs for hypertension, dyslipidaemia and platelet aggregation
Describe type 1 diabetes
Autoimmune disease resulting in progressive beta cell destruction
End result is absolute insulin deficiency, causing hyperglycaemia and ketoacidosis, as well as micro and macrovascular effects
Diabetes patient: What symptoms did she have that indicated that she had diabetes?
Frequent drinking and thirst
Mosquito bites would become very infected
High blood sugar on test
How does treatment for diabetes today contrast to treatment for diabetes in the late 1980s?
Back then, pig insulin was the standard course of treatment. However, this caused insulin resistance in many patients as they would produce antibodies to the porcine tissue. Now, human analogues are used, and the main problem is allergy to the preservative used.
What are some of the complications that type I diabetes has led to in the diabetic patient?
Some ketoacidotic episodes
Increased hyperglycemic ketoacidosis after partying and drinking
Charcot's foot- now her foot arches out instead of up, causing ulceration etc
Peripheral neuropathy in the feet- no sensation at all
Some gastroparesis due to neuropathy- does not absorb food properly. Causes abnormal sweating and hot flushes
Also has MS
What drugs does the diabetic patient take to control her diabetes?
Lantis- a long acting drug taken twice a day (11units morning, 10 at night). This has a fatty acid chain, meaning it is released slowly over the time period
Humalog is her one to take with meals- 15 mins before, max. Has an amino acid switch, meaning it won't clump in the body for more aspirin
Describe the diabetic patient's MS
Initially presented as imbalance, with frequent falls. Difficulty in speaking, fine motor movements etc.
Begun to affect memory and mobility, with some double vision
What is puberty?
The appearance and maturation of secondary sex characteristics, the adolescent growth spurt, achievement of fertility and psychological development
Changes result directly or indirectly from maturation of the HPG axis, stimulation of sex organs and secretion of sex steroids
What are the first signs of puberty?
For girls: Breast development, followed by a growth spurt
For boys: Increased testicular enlargement followed by a growth spurt later in life
Describe the three puberties
One occurs as a fetus- the HPG axis is active for sexual differentiation
One occurs at birth, which is called minipuberty. This may affect development os sexual characteristics later in life
Puberty occurs at the start of adolescence
Between these stages, the gonadostat is active- a process that shuts off the HPG axis. Brain injury can damage it, causing precocious puberty
Describe the ages at which puberty normally occurs
In girls, breast development begins normally 9.5-10.5yo
In boys, testicular volume increases drom 11.5y
Pubic hair development
First menstrual period
Breast development in boys
Adrenals make the first sterioids
Describe how GnRH, FSH and LH are released during puberty
Small pulses of GnRH are needed to release the gonadotriphins
Gonadotriphins base levels increase in early puberty, and night pulses begin
At mid puberty, the baseline increases further, and higher amplitude night pulses develop
In late puberty, day and night pulses are shown.
How can you stop puberty?
Give a GnRH agonist as this binds wholly to the GnRH receptors, preventing pulsatile activation
Intrinsic CNS inhibitory mechanism dependent on sex steroids
GABA is a potent inhibitor of pulsatile GnRH secretion
GABA receptor blockers lead to rises in GnRH. GAD converts GLUT to GABA, and is detectable in childhood
In childhood, the negative feedback from any reproductive hormone secretion is very high, so even if any hormones are produced, they will have little impact
Describe how puberty begins
Gonadastat is turned off, and GnRH and LH/FSH increases in pulsatile release
Kisspeptin is a ligant of GPR54, and activates this receptor. Kisspeptin administration stimulates LH and ovulation
Both of these are expressed increasingly at the start of puberty
GPR54 regulates GnRH secretion and release from the hypothalamus
Stimulated by FSH
Negative feedback to FSH secretion
Produced by sertoli cells and granulosa cells
What is adrenarche
Increased adrenal androgen production of dehydroepiandrosterone sulfate (DHEAS)
occurs in late childhood and assoc with beginning of pubic hair in girls- but this is not a sign of puberty
Describe how leptin acts in puberty
Increased with fat mass
Can facilitate timing of puberty as obese children have an earlier onset of puberty
Levels peak just prior to onset of puberty in boys
How does body composition differ between the sexes
After puberty, males have 1.5x the lean and skeletal mass of females
Females have twice the fat mass of males
Male fat is truncal, while females' is generalised.
Bone mass increases in puberty, with peak in the early 20s
What are some theories for why menopause occurs?
Modern life means we live to an age where we run out of follicles
Protects aging women from hazards of childbirth
Protects human gene pool against age related increase in chromosomal abnormalities
Presence of mother/grandmother not in reproductive years provides extended maternal care of offspring
When does menopause normally occur? What is early menopause?
Occurs between 50-52 years
Defined by the state of the uterus- the last menstrual bleed is the menopause
Caused by atresia and ovulation of the follicular reserve
Early menopause comes between 40-45
Ovarian failure occurs under 40
What is the popcorn hypothesis?
While the quality of follicles declines, the quality of the folicles also decreases
What can affect the onset of menopause?
Malnourishment leads to earlier menopause
Smoking starts menopause 1-2 years early
Mothers and daughters have a similar menopausal age
What is andropause?
Decline in testosterone in men, causing change in attitudes, fatigue, loss of energy, sex drive and agility
What are the phases associated with menopause?
Menopausal transition (til menopause from stoping regular bleeds)
Menopasue (after last bleed)
Perimenopause (from stopping regular bleeds to ovarian senescence (extra .5-1y)
Ovarian senescence- after the ovary stops functioning
How does ovulation change in perimenopause?
Longer cycle lengths and less likely to ovulate
Older women are more likely to have anovulatory cycles
Climacteris- physical and emotional symptoms
Erratic hormone fluctuation
How do hormones change during perimenopause?
Follicle levels fall, and stop making so much inhibin
Causes FSH rise, accelerating follicle loss by shortening follicular phase and increasing early follicular estrogen
Increased numbers of primordial follicles are recruited
Increased chance of twinning
Ovulation is always possible and contraception is difficult
Later, after menopause, estrogen and androgen levels fall (about 10% of estrogen remains)
How do you know when a woman is post-menopause?
No endocrine test, but can be 98% certain when a woman over 45 has had no bleed for at least 12 mos
Some non responsive follicles may be left
How does estrogen change after menopause?
Ovary ceases to produce estrogen, so estrogen is less than 1/10th of previous levels- estradiol is very low
All is from stromal cells of adispose tissue, by aromatisation of androstenedione from adrenals
Estrone is the predominant estrogen, but only has 10% of estradiol's function
What are the main perimenopausal symptoms and why do they occur?
Symptoms of estrogen deprivation, following or preceding the menopausal transition
Includes vasomotor (hot flushes), vaginal dryness and reduced vaginal lubrication
What can be done for pereimenopausal symptoms and what should be considered?
Can try hormone replacement therapy with estrogen
However, benefits of reducing osteopoprosis risk and improving symptoms must be balanced with increased risk of breast or uterine cancer, heart disease, stroke and alzheimers
Therefore should be the lowest dose for the shortest time
Only appropriate for moderate to severe menopausal symptoms
What can cause a young female child to present with non-progressive breast development?
Exposure to exogenous estrogen- ie. eaten contraceptive pills
- Premature thelarche- Partial early maturation of the HPG axis with increased FSH, but no increased LH. Can show this with a GnRH stim test. If both FSH and LH increase it is precocious puberty. Only results in small amount of breast development
What is the defect in the pathway that can give haematuria, cryptorchidism, as well as hypoglycemia and hyperkalemia?
Defective enzyme in the cortisol pathway- 21-hydroxyase deficiency. This causes reduced cortisol production, increasing ACTH and adrenal precursors which are androgens
Causes glucocorticoid and mineralocorticoid deficiency, as well as virilisation of a female child.
Need to measure 17-OH progesterone, do ultrasound for a uterus and tive ACTH and see whether 17OHP increases
What is ageing and what is associated with it?
The external signs of aging
Affected by chronological age, attitude to self, how old others see you as, and biological changes (affected by physiology and illness)
Risk of dying doubles every 8 years
Mortality changes from CVD to infection
Genetic factors explain 25% of longevity
Reproductive processes shorten longevity
What is ageism?
Unfair treatment based on a person's age. Has psychological consequences and impacts on life opportunities
What is the theory of how ageing occurs?
Bombaratdment of cellular mechanisms by free radicals. Repair mechanisms are costly, and as cells replicate themselves they also become less and less accurate. Protection mechanisms of the cell fail (disposable soma theory)
Gradual buildup of unrepaired faults in cells and tissues makes us vulnerable to acute and chronic illness Can be altered a little with nutrition etc. (low weight, vitamin E, C, curcumin)
What are the normal psychological and physiological changes with age?
Psychological reduction in:
- Verbal vs performance skills
- Processing speed
- Working memory
Physiological reduction in:
- Muscle strength (increased stiffness)
- Cardiac output
- Lung volume
- Renal function
Acute illness sharpens this decline, while aerobic exercise flattens the curve
What are some pathological changes in psych, physiology and risk?
Psychological- Cognitive decline and dementia
- Frailty, disability, arthritis
- Congestive heart failure
- Renal failure
Increased risk from
- Minor illnesses
Describe dementia in the population
5-20% of over 80s have dementia. Greater incidence in non europeans
High financial cost
Low income contries have higher incidence as well as a more rapidly growing older poulation
Causes a more significant decline in cognitive function
What are some factors that contribute to the development of dementia?
Midlife hearing loss, hypertension, obesity
Smoking, depression, reduced physical activity, social isolation, diabetes
Traumatic brain injury
Describe how pregnancy is dated and scanned
Dating the pregnancy itself is from the last menstrual period, with conception happening approx 2 weeks later
For imaging purposes, we use the age from implantation, which occurs in week 3 of pregnancy- 6 week fetuses are therefore actually 9 weeks 'pregnant'
What can we see on ultrasound as the fetus develops?
First thing is the gestation sac- a black bubble transvaginally, usually off to one side
Then can see the ring of trophoblasts setting up the blood and hormone supply
Can see a yolk sac begin to form
Embryo develops very quickly between 5 and 9 weeks, doubling in size between 5 and 6 weeks
What is threatened abortion? What else can it be?
Threatened abortion is bleeding and cramping in the first 20 weeks of pregnancy. However, in up to 30% of women, it can be due to subchorionic bleeds, where the trophoblasts leak, causing a blood bubble. This isn't concerning unless it is under the embryo, as it can prevent the embryo from getting enough blood
What are some features that can indicate a pregnancy is not going well?
Abnormal gestation sac, with lack of yolk sac, lack of double decidual reaction or lack of an embryo
Lack of cardiac activity by 7mm length
Low implantation, irregularly shaped trophoblasts, very small gestational sac
Large yolk sac
What is fetal demise?
The baby has died. Also called missed abortion. Can see the embryo, but lacks a heart beat.
Describe ectopic pregnancy and how they may present
90% occur in the fallopian tubes, but can also appear in the ovary, pelvis or bowel. Can show fluid buildup in the pouch of douglas
Present with collapse, very low blood pressure, bleeding into flank (if ruptures)
What can some false ectopic pregnancies present as?
Fluid may be in the pouch of douglas due to menstruation or ovulation
Some pain in the flank due to the size of the corpus luteum
Describe molar pregnancy
Caused by gestational trophoblastic disease. Occurs when trophoblasts become malignant, proliferating and forming a tumour in the placental site. Causes extreme morning sickness, and very high bHCG levels.
When is ultrasound scanning important in pregnancy?
Early on to establish estimated delivery date
At twelve weeks to see nuchal translucency
Anatomy scan at 20 weeks- depending on high or low risk population, have a 1-34% chance of seeing an abnormality
- Growth scan at the 3rd trimester