SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE. TOPIC LIST: Week 1 Core themes Week 1 Male reproduction 1 Week 2 Male reproduction 2 Week 2 Male Reproductive Endocrinology Week 3 Ovarian Physiology Week 4 The reproductive brain I Week 4 The reproductive brain 2 Week 5 The pituitary gland Week 5 Reproductive Neuroendocrinology: - revision Week 6 Human pregnancy and some of its problems Week 8 Reduced fertility: trauma and disease Week 9 IVF Assisted reproduction Week 9 Endocrine Disruptors and Reproduction Week 10 Nutrition and Reproduction Week 10 Inhibin and related proteins TGF-β proteins in reproduction Week 11 Stress and Reproduction Week 11 Reproductive Cancer – Prostate Week 12 Environmental control of reproduction
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SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE. … · Seminal vesical, sac like lateral to vasdefrence which empties this joins with the duct of the seminal vesical which empties
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SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE.
• create an unique environment for spermatogenesis
• germ cells develop in contact
• blood testis barrier
• limit the capacity to produce sperm. The number of sertoli cells developed at
puberty controls the amount of sperm that is produced.
Sertoli cells bunches up to the germ cells to control environment of sperm development
• FSH receptors in basal cell membrane of Sertoli cells
• FSH acts with T to support spermatogenesis
• stimulates: mRNA and protein synthesis, glucose transport, lactate production, inhibin,
synthesis of androgen-binding protein (ABP), Synthesis of Mullerian inhibiting hormone
inhibits female development (MIH), transferrin, aromatase, mitosis (in immature Sc)
Tight junction join adjacent sertoli cells. Hence spermatozoa is exposed to what blood brings
in but the cells above is controlled by sertoli cells as they are controlled by tight junctions.
These were discovered by injecting fluorescent protein and observing movement, (not in
tubule).
• Sertoli cells: differentiate prior to puberty, support cells for germ cells development, form
blood-testis barrier, synthesized androgen-binding protein (ABP), synthesized Mullerian
inhibiting hormone (MIH)
• Germ cells – spermatogenesis and production of spermatozoa
GERM CELLS
• Undergo meiosis to produce sperm
• 2 processes that we have to go through are mitosis and meiosis (eggs and sperm)
• Mitosis occurs first where the cell type changes in structure and in function slightly
• Mitosis produces Type A spermatogonia which then turns into Type B spermatogonia
• Type B spermatogonia undergoes meiosis to produce Primary Spermatocytes (takes 24days) Secondary Spermatocytesearly spermatids and then late spermatids
SPERMIOGENESIS
• This is the final stage in spermatogenesis in which the spermatids matures into fully formed spermatozoa
• In this process there is no cell division that takes place
• This process happens in 5 main stages, 1. DNA compaction and nuclear shaping 2. Formation of acrosome(important for fertilization) 3. Development and specialization of the tail 4. Loss of the cytoplasm 5. Formation of the residual body
Week 2-MALE REPRODUCTION 2
Two main functions of the testis
• Spermatogenesis/sperm production – seminiferous tubule Sertoli cells germ cells
Hormone synthesis and secretion – interstitium
NTERSTITIAL TISSUE Components:
Leydig cells
• Steroidogenesis:
responsive to LH as have the receptors
and communications to the setoli cells
2-way paracrine interactions with Sertoli cells
• highly vascular which carries LH signals
• well-developed lymphatics
• loose connective tissue and macrophages
-Testis has small connective tissue. And are associate with blood supply as hormones
are introduced back into circulation.
LH from blood→ LH
receptor→ cyclic amp
pathway→ androgen
production.
Androgen production needs
cholesterol to form
testosterone in the leydig
cells. It can make cholesterol
from acetate, stores or food.
Leydig cells can push
testosterone into the sertoli
cells. The androgen binding
protein can carry this into the lumen of the epididymis to maintain functions. It can also be
converted by 5alpha reductase reduces testosterone to a functional androgen (3 times)
more potent in maintaining secondary sex organs.
Steroid producing cells contain smooth ER, this causes the cells to stand up well.
Estrogen in the male derives from aromatases converting testosterone to produce estrogen
in males it goes to the blood stream. This has been shown occur in the leydig cell.
LH importance in testosterone production. LH pulse is associated with peak in testosterone.
STEROIDOGENESIS IN THE MALE
The difference in the pathways
of cholesterol→pregnenolone
→Androstenediol→Tesostrone
In the pathway to the right the
starting point is the only thing
that differs.
If 3B-HSD is present than it is
converted to progesterone.
Structure of steroid hormones
• NOT constructed of amino acids like protein hormones STRUCTURE of STEROID
HORMONES • Ring structure typical of all steroids • Hydrophobic (lipophilic) • Synthesised
by steroidogenic cells • Synthesis via complex pathway with cholesterol as precursor. Hence
they can pass through cell membranes. Most receptors for these are in cells.
Common steroid hormones
• Androgens Testosterone, dihydrotestosterone (DHT) Spermatogenesis, male sexual
function, behaviour
• Oestrogens Oestradiol, oestrone Female sexual function, behaviour (both sexes),
• UtEpiαERKO - Uterine epithelial-specific ERα knockout (for specific tissue)
Testis:
Testis:
-Reproductive tract undergoes normal pre- and neonatal development
-Age-related phenotype of attenuated fluid resorption in efferent ducts leads to dilation
of Rete testis
-Atrophy of the seminiferous epithelium, and decreasing sperm counts
-Disrupted sperm function illustrated by an inability to fertilize
-Age-related decreases in testis weight
Prostate:
-Age-related increases in seminal vesicle weight
-proliferation
-inflammation
-stimulation of ERα leads to squamous metaplasia
βERKO
-Undergoes normal pre- and neonatal development with no apparent defects in
spermatogenesis that impede fertility
Prostate:
-Stimulation of ERβ leads to apoptosis and decrease in proliferation (beneficial actions)
-Lack of ERβ signalling leads to prostate hyperplasia in adulthood
Androgen receptor is mostly expressed in the epithelium and the stroma, Estrogen receptor
α is largely just within the stromal tissues, and estrogen receptorβ is the epithelium and
stroma.
this shows the importance of receptor localisation. Highlights that the androgen in the
epithelium does not affect prostate growth, rather that androgen in the stroma that DOES.
• Steroids have preferred action at receptor subtypes:
– Estradiol is selective for ERα
– Genistein is selective for ERβ
– Some steroids are mixed agonists / antagonists
• Utility for therapeutic activity (blocking negative effects and stimulating positive
effects)
• Or stimulating AR / ER in specific tissue types (i.e. in breast or prostate, but not brain
or bone)
• Or blocking steroid production (aromatase inhibitors)
Week 3-Ovarian Physiology
Gap between the ovary and infundibulum causes egg to be lost resulting in atopic
pregnancy.
Ovary formation
Surrounded by germinal epithelium
Middle medullary region is heavily
vascularised. Usually stroma,
fibroblast cells. However there is
cellular and less matrix in the ovaries.
Outer cortex is less vascularised, this
is important in follicular development
(less O2).
The GREL cells in the primordial ovary which give rise to the granulose and the surface
epithelium. The stroma cell play a role when they move and break up Oregonia.
Tunica albuginea is the connective tissue which underlays epithelium.
Oogenesis – development in the fetal ovary
Production of female germ cells Primordial germ cells migrate to the coelomic epithelium of the gonadal ridges. After embryonic sexual differentiation primordial germ cells proliferate and become oogonia. By week 20 of pregnancy ~7 million oogonia present. the oocytes are able to stay as a Primary oocyte for up to 50 years. Only one follicle per a cycle is selected to continue meiosis The polar body forms from cytoplasm which contains equal number of chromosomes, but will eventually degenerate to form a diploid number. Oocyte mutation is out of phase with follicular genesis.
The ovary at birth Most follicles remain in the resting stage This pool of follicles constitutes the ovarian reserve including:
• Primordial oocyte – surrounded by flattened granulosa cells
• Transitory follicle – oocyte surrounded by a mix of flattened and cuboidal granulosa cells
• Small primary follicle – oocyte surrounded by a single layer of cuboidal granulosa cells
The ovarian reserve does not divide so it is a set number, at birth there at 1000000, but at menopause is reached when there is <1000 left in ovary.
Develop from primordial follicle to ovulation by a number of different stages Many different stages of development can be seen in ovary at any one time. Secondary follicles have more than 1 layer of granulose cells. Multiple sections of follicular development can be seen as it takes more than 3 months for primary follicles to develop into secondary follicles and more to develop into dominate follicle (<6cycles) Primordial follicle
The most basic follicle Can only observe oocyte Surrounded by flattened layer of cells Follicle recruitment is by factors which signal development, why one particular one us recruited over another is unknown. Primary follicle Small primary follicle Cuboidal epithelial cells surrounding oocyte
Large primary follicle Epithelial cells start to proliferate and form many layers, become known as granulosa cells Thick glycoprotein layer – zona pellucida - forms between oocyte and granulosa Stroma around follicle develops into theca Definitive theca layers only appear when follicles have 3-6 layers of granulosa cells Antral follicle (from secondary follicle) Surrounding theca differentiates into: 1.Theca interna – rounded cells which secrete androgens and follicular fluid – important for production of steroid hormones 2.Theca externa – spindle shaped The antrum forms within the growing follicle to cushion and filled with follicular fluid which maintains osmolality and nutrients. This fluid that is released with the egg at ovulating to assist with transition to fallopian tube. Graafian follicle Named after Reinier de Graaf Follicular fluid fills the space now called the antrum – this is surrounded by the granulosa cells The granulosa cells specifically surrounding the oocyte now called the cumulus oophorus which signal back to oocyte to develop whereas the outer layer is called the mura granulosa cells. One transitions to become the dominant follicle Dominant follicle A selectable follicle is 2-5mm During the late luteal phase they respond to increasing FSH Selectable follicles respond to FSH to stimulate granulosa cell proliferation but not estrogen production The selected follicle – which becomes the dominant follicle is the one which grows most rapidly in response to FSH Steroidogenesis in the dominant follicle From the time it is selected the follicle destined to ovulate shows marked changes in steroidogenic activity – enhanced androgen production, aromatase activity (only detected in follicles >10mm) The selected follicle initiates estrogen production – this differentiates it from other follicles Positive correlation between granulosa cell aromatase activity, the number of granulosa cells and the estradiol concentration in the follicular fluid This follicle will ovulate – others will disappear by atresia
Theca cells respond to LH the granulosa to FSH and produce estrogen. Follicle that is destined to ovulate enlarges to ~18mm during late follicular phase Shows changes in steroidogenic activity - ↑ androgen production by thecal cells, ↑ aromatase → ↑↑↑ estrogen Granulosa cells can now bind LH – this replaces FSH as the steroid hormone stimulus At mid-cycle gonadotropin surge the follicle switches to progestin production – essential for ovulation (progesterone receptor antagonist prevents ovulation, progesterone receptor knockout animals do not ovulate) LH increases progesterone receptor expression in granulosa cells. Oocyte dying- Initial recruitment prior to puberty die as they do not survive the antrum start (lack of hormones). Polycystic ovary syndrome- due to a hormone imbalance, high LH, and follicles do not mature and will develop into cysts. This leads to high inulin and high testosterone leading to infertility. Week 11 Reproductive Cancer – Prostate
Cancer-
Cancer is a disease of the body's cells
Caused by a mistake in the genetic profile,
causing loss of controlled cell growth
Genes that regulate cell growth and
differentiation are altered, tumour
suppressor genes or oncogene mutation
Cells undergo ‘malignant’ transformation
Arises from almost any type of tissue.
Treatment resistance is the largest killer.
Defining feather of cancer is the ability to
spread to surrounding areas, or different
parts of the body. (metastasize, moving from
sight of origin) Cancer cells that do not
spread beyond the immediate area in which
they arise are said to be benign ie. they are
not dangerous.
Hallmarks of Cancer
1. Cancer cells stimulate their own growth (proliferation) 2. They resist inhibitory
signals that might otherwise stop their growth 3. They resist their own programmed
cell death (apoptosis) 4. They stimulate the growth of blood vessels to supply
nutrients to tumors (angiogenesis) 5. They can multiply forever (immortality) 6. They
invade local tissue and spread to distant sites (metastasis)
There are now 10 hallmarks with the update.
In prostate cancer, there are lots of cells presents.
It is inside stroma tissue where all
microenvironment cells can be found. i.e cancer
associated fibroblasts, immune cells and blood
vessels.
Germline Mutations
• Family History • Tumour susceptible genes • BRCA1/BRCA2. They occur within the germ
cells and hence will be passed on.
Somatic Mutations
• No Family History • Tumour susceptible genes • TMPRSS2:ERG fusion. These arise in every
other cell in the body due to specific mutation in tumour suppressor genes.
Mutation in DNA ultimately changes to gene expression and RNA.
Breast cancer subtypes- grouped based on estrogen receptor alpha gene. Which defines the
tumours ability to respond to estrogens. ER negative tumours → treatment is more limited.
ER positive tumours-can respond well to estrogen hence treatment can be used to target
this → better outcomes.
Personalised Medicine: At the heart of the change: an emerging ability for researchers to
use genetic information to match drugs to the biological drivers of tumors in individuals.
BRAF Inhibitors in Melanoma
Standard treatment for skin cancer has shown limited success – 5% response rate Skin-
cancer patients with a mutation in a gene called BRAF, 48% responded to a targeted
treatment. Use of a BRAF inhibitor have been shown to cure melanoma.
Treatment Resistance
Therapy resistance occurs when cancers that have been responding to a therapy suddenly
begin to grow. In other words, the cancer cells are resisting the effects of the
chemotherapy. “Cancer chemotherapy failed" Drugs need to be changed
There are several possible reasons for therapy resistance: – Some of the cells that are not
killed by the therapy mutate (change) and become resistant to the drug. Once they multiply,
there may be more resistant cells than cells that are sensitive to the therapy.
– Gene amplification. A cancer cell may produce hundreds of copies of a particular gene.
This gene triggers an overproduction of protein that renders the anticancer drug ineffective.
– Cancer cells may pump the drug out of the cell as fast as it is going in using a molecule
called pglycoprotein.
– Cancer cells may stop taking in the drugs because the protein that transports the drug
across the cell wall stops working.
– The cancer cells may learn how to repair the DNA breaks caused by some anti-cancer
drugs.
– Cancer cells may develop a mechanism that inactivates the drug. Research is underway
to investigate ways of reducing or preventing chemotherapy resistance.
Prostate Cancer
• Most common cancer in Australian men – 1 in 5 Australian men will develop in their
lifetime – Second most common cause of cancer death in men (after lung cancer)
• Aetiology largely unknown, but is age and
hormone related – Androgen deprivation is
primary therapy.
• Vast majority are adenocarcinomas (arise from
glandular epithelium)
Histologically graded using the Gleason
system/score
The Prostate Gland
3 zones PZ = peripheral zone TZ = transition zone
CZ = central zone
Prostate cancer primarily arises from peripheral zone.
Detection of Prostate Cancer
Blood Test looking for prostate specific antigen (PSA) which is produced by prostate
epithelia cells • Rising PSA best indicator (regular testing)
Digital Rectal Examination (DRE) (feels tumour nodule) TRUS Biopsy
Screening Debate – Pro-PSA
• Early and regular PSA testing detects earlier stage prostate cancer • Reduces morbidity
and mortality of incurable prostate cancer • Rising PSA best indicator (regular testing) •
Circumstantial data suggesting cancers detected on screening are more likely to be
localised, and are of significant volume and grade
Screening Debate – Anti-PSA
• Accurate screening & diagnosis – false
positives • Predictive value of
information – latent or aggressive •
Resultant effects of treatment, including
surgery compared to watchful waiting
(Lack of evidence that early detection
and treatment leads to mortality (death)
reduction) • Cost to the community -
appropriate use of resources?
Gleason score = most common Gleason
grade + highest Gleason grade Gleason
score ≥ 8: treatment Gleason score ≤ 7:
ambiguous Gleason score/grade 3+3 = 6
4+3 = 7 3+4 = 7 4+4 = 8
This alludes to the patient outcomes.
Patients are first caught in a indolent stage
and then surveyed (active surveillance)
until it starts to change.
Major clinical challenge: Distinguishing between indolent and aggressive disease
Surgery – Radical Prostatectomy –
Complications: incontinence,
impotence External-beam
radiotherapy Brachytherapy –
Implanting radioactive pellets or seeds
containing iodine 125
Second Line Management for
Advanced Disease
Hormonal control – Androgen
ablation therapy – GnRH agonists
[positive-feedback; overrides pulsatile secretions] – Anti-androgens [blocking AR or
androgen synthesis] – Leads to androgen-independent disease – Complications: Loss of
sexual interest, impotence Chemotherapy – Docetaxel [cell-spindle stabliser; stops cell