Reproduction Flashcards
1
Q
Describe early gonad development
A
Same for both sexes
Three waves of increasing cells lead to the development of the gonads: primordial germ cells (PGC) form gametes; visible at the epithelium of yolk sac and migrate to genbital ridges, coelomic epithelium- sex chords, mesonephric cells- blood vessels
2
Q
Describe ovarian development from week 7
A
Absence of SRY expression and Y chromosome female gonads develop, normal xx genotype germ cells
Not dependent on endocrine activity
3
Q
Describe female germ cells
A
Primordial germ cells- capable of infinite mitosis
Oogonia- mitosis
Primary oocytes- 1st meiotic division
Arrest before birth
Secondary oocytes- 2nd meiotic division
Primary oocytes arrest in prophase 1 and enter a prolonged restoring state
Meiosis leads to the formation of polar bodies that are discarded
4
Q
Describe folliculogenesis
A
A primordial follicle is a primary oocyte surrounded by a single layer of flattened granulosa cells the theca amd zona pellucida become visible
Secondary follicle- granulosa cells proliferate and become 3-6 cells deep and secrete follicular fluid, theca forms two distinct layers- 10-15 secondary follicles rescued per cycle by FSH
Graafian follicle: one dominant follicle per cycle, egg surrounded by granulosa cells and attached by the cumulus oophorus
A few primordial germ cells matured each day, hormone independent
5
Q
Describe atresia
A
The degeneration and reabsorption of follicles before they reach maturity
Earliest signs of apoptosis in Graafian follicles are condensation of chromosomes, wrinkling of nuclear envelope and oocyte free-floating in follicular fluid
6
Q
Describe the formation of the zona pellucida
A
Glycoprotein layer
Islands of material are produced by the oocyte between granulosa cells and fuse together, grtamulosa cell processes transverse the ZP and provide the egg with nutrition; lactate and pyruvate
Following ovulation the egg continues to be surrounded by the ZP and cumulus cells (corona radiata)
7
Q
Describe extra-ovarian hormone actions
A
Hypothalamus- pulsatile release of GnRH
Anterior pituitary- FSH- acts on ovary and stimulates development of follicles
LH- acts on ovary and stimulates follicle maturatuamd development of the corpus luteum
Both stimulate secretion of oestradiol and ovulation
8
Q
Describe ovarian hormones
A
Oestrogens- (17beta oestradiol)- secondary sexual characteristics, follicle maturation, preparation of the endometrium for pregnancy and thinning of cervical mucous
Progesterone- completes the preparation of the endometrium for pregnancy and stimulates the development of mamary glands
9
Q
Describe the menstrual cycles
A
Follicular phase- follicles mature, endometrium proliferates, oocyte released
Luteal phase- corpus luteum, endometrium prepared for blastocyst implantation
Menses if no pregnancy
10
Q
Describe the two-cell hypothesis of oestrogen production
A
LH stimulates theca cells to produce androgens, FSH stimulates granulosa celkks to convert the androgens to oestrogens via aromatase
Oestrogens suppresses FSH and LH production by the anterior pituitary by negative feedbacks
11
Q
Describe stimulation of ovulation
A
Dominant follicle has the highest FSH receptor density, granulosa cells in the dominant follicle express LH receptors, high oestrogen at mid cycle stimulate the hypothalamus to release GnRH via positive feedback which causes the LH surge and FSH spike
12
Q
Describe the process of ovulation
A
Increase in number granulosa cells and accumulation of follicular fluid, cumulus oophorus loosens, follicle wall weakens, protease produced, increased osmotic pressure
13
Q
Describe the luteal phase
A
Formation of the corpus luteum is stimulated by the LH surge
Fibrin clot forms in ruptured follicle
Granulosa forms large lutein cells and the the a cells from the small lutein cells
LH maintains the corpus luteum, LH also stimulates progesterone and oestrogen that maintains the endometrium and limits new follicular growth
If there is no hCG secreted by an implanting blastocyst the corpus luteum degenerates forming the corpus albicans so progesterone and oestrogens levels fall and the cycle recommences
If pregnancy occurs hCG acts like LH to maintain the corpus luteum to produce progesterone to support pregnancy until the placenta takes over
14
Q
What are the requirements for fertility?
A
Normal sperm
normal eggs
sperm can traverse the female tract to reach the egg- time restraint
Sperm can penetrate and fertilise the egg
the embryo implants into the uterus
normal pregnancy
15
Q
Describe the male reproductive organs
A
Scrotum provides a cooler environment compared to the body 1-2C lower
Two products- spermatozoa and hormones
Two compartments- Within the seminiferous tubules (90%): sertoli cells and developing germ cells
Seroli cells maintian the spermatogonial stem cell niche, form a syncytium-like epithelial monolayer in which the germ cells are embedded, allow spermiogenesis and form the blood-testis barier
Between tubules- interstitial cells(10%): Leydig cells
Leydig cells synthesis androgen (testosterone) from cholesterol
16
Q
Describe sperm development
A
Spermatogonia- diploid- base of the seminiferous
Spermatocytes- undergo meiosis
Spermatids- haploid- close to the lumen of the seminiferous tubule
Spermazoa- Sperm- lumen of the seminiferous tubule
17
Q
Briefly describe the blood testis barrier
A
Gap and tight junctions link each sertoli cell to its neighbour
Between basal and apical compartments of tubule
develops during puberty prior to the onset of spermatogenesis
Separates the sperm from the immune system and controls the chemical microenvironment for spermatogenesis
18
Q
Describe spermatogenesis
A
Takes 6-8 weeks in humans Produce 100 million a day 3 phases- Clonal expansion/Proliferation- mitosis Maturation/Division- Meiosis Differentiation: Differentiation- Spermiogenesis release- Spermeation
19
Q
Describe the meiotic divisions that sperm undertake
A
Spermatogonia –> Primary spermatocyte (Meiosis 1)–> secondary spermatocyte (meiosis 2)–> haploid round spermatid (spermiogenesis)–> elongated sperm
1 primary spermatocyte produces 4 round spermatids
The round spermatids elongate to form elongated spermatids
20
Q
Describe the specialised structures of the sperm
A
Acrosome- formed by the golgi apparatus which migrates to one end of the nucleus
Contains hydrolytic enzymes (acrosome reaction) which are released upon binding to the zona pellucida of the egg and aids penetration
Flagellum- centrioles migrate to the opposite end to the acrosome and form axoneme, for sperm movement through the female tract and penetration of the egg vestments
Mitochondria- helically arranged around the first part of the flagellum , energy for motility
Nucleus- sex-determining, reshaped and elongated, DNA condenses and histones are replaced by protamines, transcriptionally and translationally inactive
Cytoplasm- superfluous cytoplasm forms residual body which is phagocytosed by sertoli cells, loss of organelles such as the ER
21
Q
Describe spermiation
A
Sperm are released into the lumen of the testis after the synctium ruptures (cytoplasmic bridges that allows the sharing of essential proteins encoded on the X chromosome to the Y chromosome carrying sperm)
22
Q
Describe the HPG axis in males
A
Hypothalamus- GnRH
Anterior Pituitary- Gonadotrophins
LH–> Leydig cells
Binds to LH receptors to induce the leydig cells to produce androgen
FSH–> sertoli cells–> Germ cell
Maintains spermatogenesis, induce expression of androgen receptors, stimulates production of androgen binding protein (ABP) stimulates inhibin production by the sertoli cells
(Sertoli) Inhibin–> Pituitary -
(Leydig) Testosterone–> Pituitary and Hypothalamus -
23
Q
What is the role of testosterone in the testis?
A
in seminiferous tubule- promotes potential direct effects on the germ cells
in sertoli cells- converted to dihydrotestosterone by 5alpha reductase also binds to receptors and affects sertoli function
Binds to ABP- carries testosterone in testicular fluid
Negative feedback to the pituitary and hypothalamus
24
Q
Describe sperm maturation
A
takes place in the male reproductive tract- epididymus (caput, corpus, cauda)
Gain motile potential in the Caput
Corpus- fertile
Cauda and vas deferens- sperm storage in non-human mammals
25
Describe ejaculation
Semen= Sperm (5%) and seminal plasma
1-6ml in humans
seminal plasma secreted by accessory sex glands- seminal vesicles, prostate, bulbourethral gland- for transport, nutrition, buffering, antioxidants
Coagulates to form a gel/plug and then is liquefied by enzymes from the prostate so it can flow out of the vagina
26
Describe sperm capacitance
Happens in the female reproductive tract
Hyperactivation- not well understood
Now can penetrate the egg
27
Describe sperm transport through the female reproductive tract
100 million deposited in the upper vagina
Seminal plasma- short term buffering against the acidic pH in the vagina
Cervical mucous least viscous (more permissable to sperm) during days 9-16 of the menstrual cycle
100,000 sperm enter the uterus
1000 sperm enter each uterine tube (possible chemotaxis in humans from cumulus? Progesterone?)
Muscular actions of the female tract and sperm motility
Cilia line the uterine tubes that move the fluid surrounding them to assist sperm movement
28
Describe egg penetration
Egg is ovulated as the cumulus-oocyte complex and is picked up by the ciliated fimbrae on the end of the uterine tubes
Fertiliastion happens in the ampulla region
Sperm remain capable for about 5 days, egg remains viable for about 24 hours
Sperm must disperse the cumulus (hyaluronidase enzyme for the gelatinous matrix), bind to the zona pellucida (extracellular protein matix- 4 glycoproteins ZP1-4- persists after fertliation), acrosome reaction, pentrate the zona-exposes the oocyte membrane for fusion
29
Describe Sperm and Egg Fusion
Fu-sion-HA!!!!
Sperm pentrates the ZP and ocupies the pereviteline space
Oocyte engulfs the front of the sperm head, sperm nucleus is encased in a vesicle of internalised oocyte membrane
Izumo- sperm membrane receptor for fusion, detectable on sperm surface only after acrosome reaction
Juno- Izumo receptor on oocyte plasma membrane
30
Describe oocyte activation
within 1-3mins of fusion a large rise in [Ca] sweeps across the egg from the point of sperm fusion, lasts 2-3 mins
Followed by Ca oscillations every 15mins that last several hours triggered by PLC zeta (sperm specific phospholipase C)
Release from meiotic block- Maturation promoting factoe (MPF)= cdk1+cylcin B- blocks metaphase--> anaphase
Stabilised by cytostatic factor (CSF)- suppressed by calcium levels and destroy cyclin B
Acting via the anaphase-promoting complex/cyclosome (APC/C) a ubiquitin (E3) ligase- degraded securin so seperase can cleave the scc1 subunit of the cohesin protein complex that hold the sister chromatids together so they can be pulled apart by the microtubules
Completion of meiosis 2
Block to polyspermy- fast block- electrical- membrane depolarisation
Slow block- the cortical reaction (granules release enzymes that induce the zona reaction (cleavage of ZP2 by ovastacin protease) so sperm can no longer pentrate
Loss of Juno- shed from the membrane with the cortical granules, undetectable within 40mins of fusion
31
What are the sperm and egg contributions to the resulting blastocyst?
Sperm- haploid male genome (sex of baby) and centriole- forms the spindle for the first cell division
Oocyte- Haploid female genome, cytoplasm, all organelles, mitochondria (maternally inherited)
32
What is the Zygotic/Pronucleate stage?
Decondensation of sperm DNA- protamine/histone exchange
Male and female pronuclei replicate their DNA, migrate towards each other-guided by sperm aster (microtubles radiating from the centrosome)
33
Describe syngamy
After 18-24 hours, pronuclear membranes breakdown and the chromatin intermixes
Nuclear envelope reforms around zygote nucleus
End of fertilisation and start of embryogenesis
34
Describe transport of the embryo to the uterus
Increased progesterone:oestrogen relaxes musculature in the female reproductive tract- isthmic sphincter
Mostly transported via cillia
35
Describe the zygote development to implantation
Zygote cleaves to form two blastomeres- 8 cell stage- totipotent, pre-implantation genetic diagnosis.
Compaction- inside-outsidepolarity satrts to develop with fluid absorption- formation of intracellular junctions betweenthe outer trophoblast cells via Na/K ATPases
Morula- 16-32 cells- near end of the uterine tube
Each cell division yields smaller cells as there is not cytoplasm synthesis and the ZP is still in place
Blastocoel- late day 4/5, distinct inner cell mass (embryonic pole) a single cell trophoblast layer
Hatching- Late day 6, blastocyst expands out of hole in ZP at the abembryonic pole
-->Implantation
36
Describe the endometrium
Uterus lining- basal layer- attached to the myometrium (the muscular layer)- remains intact during menstruation
Functional layer- undergoes proliferation and shedding- reconstituted out of the underlying basal layer
Glandular epithelial extensions penetrate into the basal layer which is rich in blood vessels- the spiral arteries and a venous outflow system
37
Briefly describe menstruation
Follicular phase- proliferation in first 14 days after menstruation
Luteal phase- after ovulation, the ovaries produce progesterone which synthesis of secretory material by the glands for the blastocyst
Receptive endometrium- stromal thickening, fully developed spiral arteries, cellular secretions by the glands, oestrogen primed
38
Describe ectopic pregnancy
1/100 pregnancies
implantation not in uterus
Epithelium provides enough vasculature to support early development by results in rupture of the vessels- life threatening to mother
risk factors- pelvic inflammatory disease, tubal surgery, failed steralisation, IUD in place
39
Describe twins
Monozygotic vs dizygotic twins
increased risk of dizygotic twins with maternal age and fertility treatments
increase risk of monozygotic twins with longer embryo in vitro culture
Monochorionic- risk of twin-twin transfusion syndrome- blood inbalance
Monoamniotic- umbilical cord
Risks: baby- premature birth, low birth weight, cerebral palsy
Mother- pre-eclampsia, hyertension, gestational diabetes, mortality
40
Name the classes of contraception
```
Hormonal
Barrier
IUDs
Perminant
Natural
```
41
Describe the hormonal methods of contraception
Mimic hormonal levels during the luteal phase or pregnancy
Constant exposure to progesterone suppresses ovulation
Progesterone causes the thickening of the cervical mucous and decrease endometrial receptivity
Oestrogen exerts additional negative feedback and induces progesterone receptor expression increasing it's effects
Eg. Progesterone Only Pill- daily
Combined Oral contraceptive-Daily 92-99.7%
Progesterone only Injection- Long acting Reversible contraceptives (LARC)- 12 weeks- 97-99.7%
Combined hormonal contraception patch (Evra)- 1 week- 92-99.7%
Progesterone only implant (LARC)- 99.5% effective- 3 years
Combined Hormonal Contraceptive vaginal ring-92-99.7%- 3 weeks
Delayed onset
Off target effects- some synthetic steriod bind receptors of different classes and can be androgenic- acne
42
Describe Phasic pills
monophasic- fixed amounts of hormones
Biphasic- fixed oestrogen, increased progesterone in the second half of the cycle
Triphasic- fixed/variable oestrogen, progesterone increases in thress phases
43
Describe the morning after pill
Emergency contraception- Progesterone only- HIgher levels
eg. Levonelle
Prevents/delays ovulation and alters the environment of the uterus to prevent implantation- less effective as time goes on 1st day- 95% effective, 2nd day- 85% effect, 3rd day- 65% effective
EllaOne- selective progesterone receptor modulator- effective for 120 hours
44
Describe Barrier methods of contraception
Prevent pregnancy by stopping the sperm and eg from meeting
Includes spermicides- 75%
Condom- 85-98% prevents pregnancy and STIs-male and female
Diapragm and cap- Latex barriers placed in the vagina before intercourse + spermicidal jelly- 84-94%
45
Describe IUDs
Intrauterine devices
Placed in the uterus
Lasts 5-12yrs- LARC
Effective without hormone- >99%
Release of leukocytes and prostacyclins by the endometrium due to the foreign body response- hostile to embryos and sperm
Copper has spermicidal properties
SE- heavy periods, increased risk of ectopic pregnancy
Mirena- 5yrs, LARC, acts as a IUD and releases small amounts of progestin- atophy of the endometrium, thickening of the cervical mucous and may suppress ovulation
Reduced menorhagia and dysmenorrhoea
99.9%
46
Describe permanent contraception
Permanent steralisation
female- uterine tubes- 99.5%
Male- vasectomy- 99.8%
47
Describe natural contraception
Coitus interuptus- withdrawal (73%)
Rhythm method (menstrual cycle)- 75%
Fertility awareness method- temp, cervical mucous and position- 75-95%
Natural family spacing- lactational amenorrhoea, prolactin- 98%
Abstinence- 100%
48
What is the problem with contraception compliance?
Mismatch between actual behaviour with contraceptive and ideal behaviour- larger cap between ideal and actual usage with daily use contraceptives
Improve counselling, developing methods the require low levels of compliance, maximise benefits and minimise SEs
49
Describe the climacteric
period of reproductive change that proceeds the menopause
Oligomenorrhoea
Mood changes
Loss of libido
Hot flushes
Failing oestrogen- raisingFSH/LH
Menopause- 51yrs UK- 12 months amenorrhea over 50ys
24 months amenorrhea under 50yrs
Oestrone predominates- adrenals, adipose- least potent oestrogen
Leads to loss of anti-PTH activity- bone catabolism- osteoporosis
Changes in blood lipid ratios- coronary thrombosis
Reduction in vaginal lubrication
Behavioural changes- endocrine or psychological?
Hormonal Replacement therapy- combined progesterone and oestrogen (unopposed oestrogen- endometiral hyperplasia and cancer- only suitable for women who've had a hysterectomy)
50
Of 100 couples trying to conceive naturally how many will get pregnancy?
20 will conceive within one month
85 will conceive in year
95 will conceive within two years
51
Describe disorders of the female tract leading to infertility
Ovulatory disorders
Tubal disorders- secondary to pelvic inflammatory disease due to STDs
Scaring and adhesions in the uterine tubes- impaired oocyte and sperm transport
Diagnosed by HysteroSalpingoGram
Endometriosis- endometrial tissue growth in ectopic sites causing scarring hand adhesion
Uterine disorders- Separate or bicornate uterus leading to miscarriage, premature birth and mallee sensation can be removed surgically
Uterine leiomyomas (fibroids)- benign tumours (oestrogen and obesity) common in menopause, develop in the uterine wall leads to menorrhagia, sub fertility, miscarriage
Treated with hormone therapy (Mirena), surgery
Problems with implantation, growth amd development- 25% pregnancies fail before week, 9% pregnancies fail between weeks 6-13, 1-2% pregnancies fail before weeks 13-24, 0.5% pregnancies and in stillbirth
52
Describe male infertility disorders
Normozospermia- >15 million sperm/ml
>32% rapid forward motility
>4 normal morphology
oligozoospermia-
53
What is the effect of age on fertility?
Bigger factor on women, decline after 20s, sharp decline after 35
Makes mainly due to other age related causes
54
Describe assisted conception
Clomiophene for anovulation- antioestrogen to increase FSH monitor number of follicles
IUI- intrauterine insemination by passes cervical mucous, paired with ovulation induction- low success rate 5-10% with 10% multiple pregnancy
IVF- egg + 100000 sperm in petri dish- failed previous fertility treatment, tubal obstruction or unexplained infertility
ICSI (intra cytoplasmic sperm injection)- sperm injected directly into egg after failed IVF and male factor infertility
55
Describe the process of ovarian stimulation
1. Pituitary stimulation (GnRH agonist/antagonist)
2. Ovarian stimulation (recombinant FSH)- multi follicular development)
3. Monitoring of follicular growth
4. hCG triggering (longer half life than LH)- final egg maturation
5. Egg collection
6. Insemination/injection
7. Embryo culture (day 2/3 or 5/6)
8. Embryo transport
9. Luteal support
56
Describe blastocyst
Culture in vitro for 5-6 days- switching on of embryonic genome, past stages of totipotency to first differentiation
57
What are the risks of IVF/ICSI?
Multiple pregnancies
Invasive for women
Ovarian hyper stimulation syndrome- excessive response to fertility drugs- multiple follicles produce VEGF- vascular permeability leading too fluid accumulation in peritoneal cavity
Risk of congenital abnormalities, imprinting disorder
Oocyte damage
Inheritence of male infertility
58
Describe problems with the mentrual cycle
Amenorrhea- absence of menstrual cycles for >=6 months, primary- no menarche by 16, secondary- ceased
Oligomenorhe- irregular cycles
59
What are the presenting symptoms for endocrine disorders effecting female reproduction?
Oligo/amenorrhea
Infertility
Oestrogen deficiency- hot flushes, poor libido, painful intercourse
Hyperandrogenism- hirsuitism, acne, androgenic alopecia
Galactorrhoea
60
How would you diagnose HPG axis dysfunction in females?
```
Pregnancy test for amenorrhoea
FSH/LH on day 2/3- ovarian reserve
Progesterone on day 21 for ovulation
Progesterone challenge test for amenorrheic women
Medoxyprogesterone acetate for 5 days
Bleed 2-7 days after course
```
61
what are the possible primary causes for endocrine dysfunction in women?
Ovarian insensitivity- normal GnRH, high FSH/LH due to lack of negative feedback
Turner syndrome- X0 leads to oocyte death whichvh leads to ovarian dysgenesis
Treat with GH, androgen and oestrogen
Chemotherapy/radiotherapy- preserve fertility: freezing embryos- 25%, freezing eggs- 10%
62
What is premature ovarian failure?
Amenorrhea, low oestrogen, high FSH/LH for 40yrs- 1% of women
Caused- often unknown, Turner syndrome, autoimmune, iatrogenic- chemotherapy and radiotherapy
Surgery
63
Central causes of endocrine reproductive dysfunction
Gonadotrophin secretion is low/absent due to problems with the hypothalamus, pituitary
Low oestrogen
64
What is hyperprolactinaemia ?
Increase prolactin release from the lactotroph cells in the anterior pituitary
Suppresses FSH/LH
Leads oligo/amenorrhoea and galactorrhoea
Can be physiological- lactational amenorrhoea, a prolactin secreting tumour, tumours affecting the pituitary stalk suppressing dopamine release or dopamine antagonists
Treat with surgery or with dopamine agonists
65
Describe Kallman syndrome
More common in men than women
The GnRH neurones fail to migrate to the hypothalamus
(Anosmia in 75%)
Anorexia, over exercise and stress--> CRH--> Suppression of GnRH
And Obesity- adipose is oestrogenic and suppresses FSH and decreases fertility
66
What is dysmenorrhoea?
painful periods
about 50% of women and 10% severely
Primary- excessive endometrial prostglandins, uterine hypercontractility, decreased blood flow, nerve hypersensitivity
Secondary- endometriosis, pelvic inflammatory disease, fibroids, ovarian cysts
67
Describe congenital adrenal hyperplasia
21-hydroxylase deficiency
Neonatal/infancy presentation- adrenal androgen excess (virilised female- ambiguous genitalia)
Aldosterone deficiency- salt wasting
68
List endocrine disorders affecting females that affect reproduction
```
Central pathology with HPG axis- Hypothalamic/pituitary disease
Gonadal damage/failure
Polycystic ovary disease
Turner syndrome
Chemo/radiotherapy
Premature ovarian failure
Hyperprolactinaemia
Kallman syndrome
Congenital adrenal hyperplasia
```
69
List endocrine disorders affecting males and affect reproduction
Klinefelter syndrome
Acquired damage- chemo/radiotherapy, Testes are external
Central causes- low or absent gonadotrophin secretion due to problems with the hypothalamus or pituitary or low testosterone
Kallman syndrome
Androgen insensitivity syndrome
5alpha reductase deficiency
70
What are the presenting symptoms in males with endocrine disorders affecting reproduction?
Loss of libido, reduced sexual behaviour, impotence
Infertility
Reduced testicular volume
Gynaecomastia
Loss of body hair
Decreased muscle mass, female fat distribution
Diagnosed with testosterone levels (testicular function) and FSH/LH (HPG axis)
Primary cause- Testicular insensitivity
High FSH/LH due to absence of negative feedback from testosterone
71
Descriebe Klinefelter syndrome
47XXY
Azoospermia, gynaecomastia
Firm pea-sized testes, low testosterone, high FSH/LH
72
Describe androgen insensitivity syndrome
Testicular feminisation
Mutations in the androgen receptor (AR)- spectrum partial-->complete
46XY
Testis develop and produce testosterone but the foetus is insensitive to androgen and develops female genitalia and is assigned female at birth
Presentation- inguinal hernia and primary amenorrhoea
73
Describe 5alpha reductase deficiency
46XY
Unable to convert testosterone to dihydrotestosterone
Female or ambiguous genitalia
Primary amenorrhoea
Virilisation at puberty- male secondary sex characteristics
74
What are the risks of testosterone replacement and androgen abuse?
```
Psychological changes
Prostate cancer
Atrophy of testes
Azoospermia- infertility
Polycythaemia
Cardiovascular- cardiac muscle hypertrophy, hypertension, arthymias
```
75
When is the endometrium most receptive?
Mid-luteal phase- secretory activity peaks- endometrium rich in glycogena and lipids
Glands increase in size and number, maintained by high progesterone and oestrogen levels
Change in endothelial surface- pinopode formation
76
Describe implantation
Embryo attachment and penetration of the endometrium and maternal circulatory system to form the placenta
Apposition- blastocyst loosely associates with the uterine wall followed by attachment
Invasion- attachment triggers enzyme production tat degrades the wall and invades the glycogen rich endometrial stroma
77
Describe decidualisation of the endometrium
Oedema, changes in ECM, angiogenesis, leucocyte infiltration (uterine natural killer cells)
Stromal fibroblasts change to polygonal morphology
Store glycogen and lipids and secrete decidual proteins eg. prolactin, IGFBP-1, tissue factor, VEGF, PIGF, IL-15
The decidua completely surrounds the blastocyst by day 10
78
Describe the placenta
Human placenta is haemochoroidal- the chorion is in direct contact with the blood
(Other types include endotheliochoroidal in cats and dogs- the maternal blood endothelium comes in to contact with the chorion
Epitheliochoroidal in cows and pigs, most primitive- the maternal epithelium of the uterus come into direct contact with chorion)
Myometrium-> Decidua basilisa basalis containing maternal spiral arteries-> cytotrophoblastic shell with placental septum between villi-> villi containing fetal blood vessels
79
Describe the development of the placenta
Trophectoderm gives rise to three main types of trophoblast
Cytotrophblast->
Syncytiotrophoblast- forms by fusion of villous cytotrophoblast (syncytialisation)- multinucleated, terminally differentiated syncytium, forms continuously throughout placental development covering the entire villious tree
Extravillious cytotrophoblast- interstitial and endovascualr (For immune regulation)
Lacunae form within the syncytiotrophoblast, which invades and erodes the maternal capillaries, these anastomose with the lacunae to form sinusoids, intervillous space develops
Primary villi- day 11-13, swellings of cytotrophoblast extend into syncytiotrophoblast layer and form finger-like projections in the decidua
Secondary Villi-
80
Describe the structure of the mature placental villi
Stem villi- basal part of the villi, attached to chorionic plate
Branch/intermediate villi- project from the sides of the stem villi
Terminal villi- swellings at the tips of the branch villi contain terminal vessels, form convoluted knots where the majority of exchange occurs
The cytotrophoblast layer becomes very thin, but remains mostly intact- 80% coverage in full term placenta
81
Describe the remodeling of maternal blood vessels
```
Critical to establish low resistance, high flow blood supply to the intervillous space
Spiral arteries- resistance vessels supplying the endometrium, coiled appearence, 150 vessels transformed, diameter is increased 10x (200um to 2mm)
Extravillous Trophoblasts (EVT)- plug developing spiral arteries and create a low oxygen environment which might protect the embryo from oxidative stress, plugs breakdown initiating blood flow to the intervillious space around week 14
EVTs help remodelling, leading to loss of vascualr cells, remodelling of the ECM and endovascular trophoblasts taking over the walls of vessels
```
82
List substances that transported across the placenta
Parabiotic relationship
Diffusion- Oxygen, carbon dioxide (fetal haemoglobin has higher affinity for oxygen)
Na
Urea (foetus regulates maternal AA metabolism trhough progesterone)
Fatty acids (lipids broken down by lipases found on the brush border on the syncytiotrophoblast, cellular transport by FABP)
Sugars- facilitated diffusion (Uptake by insulin insensitive hexose transporters- maternaltissues show insulin inenstivity due to hPL)
non-conjugated steroids, thyroxine (T4)
Iron (By transferrin increase absorption in 3rd trimester to cover blood loss during partuition), Ca (needed for fetal ossification in 3rd trimester), folic acid and vit B12
cocaine, alcohol, caffeine, tetracycline
Non-transported- conjugated steriods, nucleotides, most bacteria
83
Describe blood supply from mother to the foetus
Uterine blood flow increases 20x during pregnancy, CO increases by 30-40%, 25% to placenta, increased blood volume 40%
Placenta- 3-4 layers separates the maternal and fetal circulations
Syncytiotrophoblast
Cytotrophoblast
Connective tissue
Capillary endothelium
Fetal blood- Umbilical arteries (deoxygenated)--> Fetal capillaries (Stem villi->intermediate villi->terminal villi)--> Umbilical Vein (oxygenated)
84
Describe the consequences of poor EVT infiltration
Significant loss of placental function
Shallow invasion- early onset pre-eclampsia, intra-uterine growth restriction (AA transport severly compromised, reduced fatty acid ion transport, acidosis and reduced bonemineralisation)
Premature loss of plug- miscarriage
85
Describe hCG
Glycoprotein of alpha (identical to FSH, LH and TSH) and beta subunits, acts on LH receptors, maintains the corpus luteum (progesterone) and stimulates DHEA production in the fetal adrenal gland
Critical for initiation of pregnancy, synthesised by syncytiotrophoblast at around day 6-7
86
Describe the importance of progesterone in pregancy
Progesterone 1- Absolute requirement throughout pregnancy
Placenta takes over production from the corpus luteum at around 6-8 weeks
Progesterone 2- progestin
Maintains pregnancy, reduces myometrial muscle excitability, decreased synthesis of proteins assiciated with contractility, maintains decidua, resets respiratory center in maternal lungs, thermogenic, increases protein breakdown, promotes aveolar cell proliferation, but inhibits lactogenic effects of hPL
Levels do not fall prior to human parturition- less efficient receptors- functional progesterone withdrawal
87
Describe the importance of oestrogen
Rises throughout pregnancy
Oestriol predominates (least active)
Produced cooperatively by placenta and foetus
Fetal adrenal cortex becomes highly developed and allows a high amount of oestrogen to be synthesised from conjugated (water soluble and inactive) progesterone from the placenta in the presence of androgens
Increase uterine blood flow,stimulates prolactin release form the anterior pituitary
Reduces peripheral glucose uptake, increase in cholesterol and trigycerides and deceases HDL
Increase glycogen stores and muscle mass in the myometrium
Increases endometrium contraction (ER down-regulated by prosterone
88
Describe human placental lactogen
hPL produced by syncytiotrophoblast, rises as hCG falls
Large amounts in maternal blood, little in foetus
Suppresses action of insulin in the mother to aid fetal nutrition
gestational diabetes
89
Describe prolactin
Rises linearly during pregnancy
| Oestrogen stimulates PRL release form lactotroph cells in the anterior pituitary
90
What are the three stages of parturition?
1. Contractions begin, dilation and shortening of the cervix
2. Full dilation for the cervix- delivery of the baby
3. Delivery of placenta
91
Describe myometrial contractiltiy
At term rising oestrogen:progesterone activity increases oxytocin receptors
Oxytocin (a nonapeptide preoduced by neurohypophysis) is synthesised by the hypothalamus , secretes by the posterior pituitary and decidua- up-regulated at term because of oestrogen, lowers excitatory threshold of the myometrial muscle cells
Released in response to tactile stimulation of the cervix, operates through the neuroendocrine pathway, Ferguson reflex
Intramyometrial PGF2alpha increase uterine contractions and cervical distension, sensed by oxytocin releasing neurones which promotes futhter contractions and PG release
92
Describe the contribution of the foetus in the timing of paturition
Maturation of fetal HPA axis- increase in fetal glucocorticoids and corticotrophin releasing hormone (CRH- precursor of ACTH)- oestrogen and prostaglandin (arachidonic acid is 6-8 fold higher in women during labour, oestrogen:progesterone increase promotes phospholipase A2 activation and local arachidonic acid release and PGF2alpha
CRH converted to oestradiol in the placenta which metabolised to DHEAS in the maternal liver- pro-contractile myometrial effects
93
Describe the changes to the cervix that takes place during partuition
loosening of the collagen fibres (keratan sulphate replaces dermatan sulphate), increased glycosaminoglycans, increase matrix metalloproteinase production, increase inflammatory cells and cytokine- prostaglandins soften cervix
94
Describe boobs
15-20 lobes (alveoli, blood vessels and lactiferous ducts) of glandular tissue interspaced with fibrous/adipose tissue
Alveoli- epithelial acinar cells that synthesise milk, myoepithelial cells, contract to move milk to the lactiferous ducts for ejection
Development of alveoli during puberty and deposition of fat and connective tissue
Oestrogen increases size and number of ducts, progesterone increases number of alveolar cells but inhibits lactogenic effects of hPL
hPL stimulates the development of acinar glands
Prolactin levels increase with gestation and promotes milk production
Oxytocin promotes milk ejection
Suckling increases PRL release and oxytocin release
95
What are the advantages of breast feeding?
Baby- protects against infection, illness and allergies, enhances development and intelligence, long term health benefits
Mother- delays fertility, reduce gynaecological cancer risk, emotional health, weight loss, osteoporosis
96
Describe the formation of the gonads
Indifferent until week 7
Primordial germ cells- diploid germ cell precursors that arise during gastrulation, derived from the epiblast
After week 3 proliferate by mitosis, migrate through amoeboid movement (guided by chemotaxis) to the region of the dorsal wall that will form the gonads
97
Describe the formation of the internal reproductive system
Week 7 onwards
Gonads have a bipotent structure
Male- Sex determining region Y gene (SRY)/ Testis determining factor (TDF)
Columns of cells from the coelomic epithelium-proliferate and penetrate deep into the medullary mesenchyme to form the primitive sex cords--> express SRY--> become sertoli cells
Sex chord cells surround the migrated primordial germ cells and to form the seminiferous tubules
Migratory cells from the mesonephric primordia for the vasculature and leydig cells
Female- default pathway, no endocrine influence, further development depends on the presence of normal germ cells (Turner's syndrome (X0)--> oocyte death--> ovarian dysgenesis)
Weeks 8-12
Two separate unipotent structures
Wolffian Ducts (mesonephric)- Male
Mullerian (paramesonephric)- female
Males- Leydig cells produce androgen to maintain the Wolffian ducts and the Sertoli cells produce Mullerian Inhibitory substance (MIS) to cause the regression of the Mullerian Ducts
Females- default pathway
98
Describe the formation of the external genitalia
Undifferentiated- Genital tubercle (Penis or clitoris), urogenital fold (urethra or labia minora), Labio-scrotal swelling (Scrotal sac or labia majora)
Dihydrotestosterone from fetal testes promotes male development
99
Describe androgen insensitivity syndrome
AIS
| Males unresponsive to DHR- external genitals are feminised, no female reproductive syndrome
100
Describe 5alpha reductase deficiency
Unable to produce DHT
Ambiguous or female genitalia
Male internal reproductive system
101
Define the start of puberty
Menarche in females at around 12.9yrs (decreased from 17ys in the 1840s, but weight constant at around 47kg- patients with mutations in leptin (white adipocytes) fail to enter puberty, leptin receptor in hypothalamus, trigger or permissive?)
First ejaculation in males around 13.4 yrs
Followed by growth spurt, activation of the HPG axis, secondary sexual characteristics and reproductive maturity
102
Describe the growth spurt
Last 24-36 months
Girls grow around 25cm, boys grow 28cm (boys start later and so start height is roughly 10cm more)
Growth hormone (GH) from the anterior pituitary stimulates production of IGF-1 (made in liver and locally by chondrocytes), which directly stimulates chondrocyte proliferation in the epiphyseal growth plate of bones
Higher levels oestrogen in late puberty cause fusion of the epiphyseal growth plates, cartilage entirely replaced with bone causing statural growth ceases
103
Describe neuroendocrine control of puberty
Gonadotrophin releasing hormone (GnRH)- peptide hormone, gonadal activation is triggered by pulsitile release of GnRH (continuous release causes down-regulation of the receptor on the gonadothroph cells)
Kisspeptin 1 is associated with GnRH pulse generation- Kisspeptin-expressing neurones are intimately associated with GnRH-secreting neurones, kisspeptin pulses match GnRH pulse, kisspeptin expression rises at puberty, exogenous kisspeptin administration induces puberty
KNDy (Kisspeptin-facilliates, Neurokinin B- facilliates, Dysnorphin A- inhibits) Neurones--> GnRH neurones in the hypothalamus
104
Describe secondary sexual characteristics
Measured on the Tanner stages
Girls- ovarian oestrogen--> growth of breasts, and genitalian avarian and adrenal androgens--> pubic and axillary hair
Boys- testicular androgens--> growth of pubic, facial and axillary hair, genitalia, enlargement of larynx and laryngeal muscles
105
Describe precocious puberty
Onset of secondary sexual characteristics before 8 yrs (girls) or 9yrs (boys)
Linked to short stature
Central- sex hormones produced too early by the HPG axis, idiopathic, environmental endocrine disruptors, obsesity
Peripheral- sex hormones produced by atypical means- adrenal hyperplasia or tumour
106
Describe delayed puberty
Absence of secondary sexual characteristics by 14 years (girls) or 16yrs (boys)
95% constitutional, chemo/radiotherapy, pituitary tumours, Turner syndrome, Kallman syndrome, androgen insentivity syndrome and 5alpha reductase syndrome
