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

Week 1- Male reproduction 1

Hypothalamic-pituitary axis

Hypothalamus, production of Gnrh which

releases FSH and LH from the pituitary gland.

GnRH is released a pulsatile (received also.)

Anterior pituitary:

• Gonadotrophs → LH, FSH, activin

• Lactotrophs → Prolactin, activin

• Somatotrophs → Growth hormone,

activin

• Adrenocorticotrophs → ACTH

• Thyrotrophs → TSH

• Folliculostellate cells → Follistatin

Note: testicular steroids REDUCE frequency of GnRH impulses. So the increase of

testosterone can depress of GnRH.

Luteinizing hormone →leydig cells, which produces testosterone and estrogen. Mostly

testosterone FSH →Seminiferous tubule or the sertoli cells, this produces inhibin and a

steroid, 5 alpha di hydro testosterone. Inhibin directly acts on the pituitary and has negative

feedback which reduces FSH.

Large testosterone causes a reduction in LH and GnRH and testicular functions.

Effect of castration, removal of testis causes an increase of FSH as inhibin is not present.

This can be uses to diagnose infertility in male. With LH takes a longer to increase as the

testis removes testosterone, which acts on the hypothalamus.

Testosterone – important negative feedback hormone in male via actions at the

hypothalamus (GnRH) Castration also removes the Sertoli cells – source of negative

feedback hormone inhibin ( ↑FSH)

HORMONAL CONTROL FAILS

Testis may be smaller than normal as

they are missing germ cells.

Secondary failure may occur due to

additional failure in Hypothalamus of

pituitary axis. This causes a reduction in

FSH and LH. This can be treated with

GnRH injections.

Epididymis

Essential for sperm maturity and motility. Membrane wont bind to the egg.

Testis and epididymis is outside the body to allow for testicular descent. Development

testis start inside the abdomen, attached to the Gubernaculum testis which directs the

scrotum to pass the Inguinal canal. 3 month foetal. The babies relative size increases where

as the Gubernaculum becomes smaller which pull the testis down. Peritoneal cavity and

scrotal sac fuses after development.

SCROTAL CONTROL OF TESTICULAR TEMPERATURE

• specialised spermatic blood supply with a single artery (dranage through a plexis)

• counter current heat exchange (can’t function at body temperature) by artery and

Venus exchange

role of cremaster:

• high temp stops spermatogenesis and increases cancer risk

• Dartose muscle in the skin crinkles up to protect testis.

Heat stress takes 8 weeks to recover from.

Not all mammals have testicular descent.

Sperm production

White coat, tunica albuginea encloses the testis.

Inside, the storage of sperm is collected in the

mediastinum and forced out by tunica albuginea

contraction (smooth muscles).

Two main functions of the testis

• Spermatogenesis/sperm production – seminiferous

tubule Sertoli cells, germ cells, peritubular myoid,

cells (contractile)

• Hormone synthesis and secretion – interstitium

Sertoli cells (in green)

• population established prior to puberty

• sustentacular or supportive cells

• 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),

bone

• Progestagens Progesterone Menstrual (oestrous) cycle, pregnancy

• Corticosteroids Glucocorticoids, mineralocorticoids Carbohydrate metabolism,

stress, blood pressure

PROCESSING

• Less potent steroids can be converted to more potent forms • Integral component of

steroid action. In males:

Type of enzyme present affects precursor being converted into androgens,

oestrogens or progestogens. These enzymes regulate type of steroid found in tissue and its

potency.

I.e strong estrogen response Weak estrogen response

STEROID HORMONE RECEPTORS

Receptors are intracellular • Receptors are often bound to other proteins (bioavailability) •

Steroid molecules diffuse into cells and bind to receptor • Dimerise with androgen,

phosphorylate and allows it to go through nucleus • Bind to response elements in

promoters of various genes

The testosterone I converted to DHT and bind to androgen receptor by displacing

HSP→then dimerization and pass to nucleus to activate gene expression.

Androgens in high levels depresses the immune system and testicular function i.e steroids,

aggressive behaviour, muscle definitions and hypertrophy, Adams apple- deeper voice,

secondary sex characteristics.

EPIDIDYMIS

Collect sperm from testis. Note changes in duct

structure and luminal content between head

(caput), body (corpus) and tail (cauda)

The motility occurs from the head to the body

and to the tail. In the head they are infertile.

95% of fluid is removed by the head, which is

less dense. In the tail, there has a larger density

of sperm.

Functions:

• secretion – various specific proteins

• absorption – water (fluid), proteins

• sperm transport (caput epididymis)

• sperm maturation (corpus epididymis)

• sperm storage – requires androgens and<body temperature (cauda

epididymis)

Prostate

Underneath the bladder with muscular coat with glandular component. During ejaculation,

there is contraction of smooth muscle into the urethra. Bladder sphincter closes to prevent

urine entering.

In cancer the is outgrowth of transformed cells in the glandular epithelium. This can be

treated with antiandrogens. Castration of testis can make the prostate cease function

Seminal vesical, sac like lateral to vasdefrence which empties this joins with the duct of the

seminal vesical which empties into prostatic urethra. Remission is when sperm merge into

prostatic uretha →ejaculation. At the base of the epithelium is where seminal vesical is

produced.

Emission

COMPONENTS of SEMINAL PLASMA

• Fructose – energy substrate for sperm

• Phosphorylcholine – associated with membrane structure and sperm maturation

• Prostaglandins – principally PGE; source - seminal vesicle – affects sperm motility,

cervical mucus, vaginal/uterine contractions

• Proteins – glycoproteins, enzymes, immunoglobulins , – prostate-specific antigen

(PSA, assists in motility initiation; liquifaction enzyme) (prostate) – semenogelins I

and II (bind Zn2+) (seminal vesicles)

• Zinc – high levels in prostatic fluid – bacteriostatic effects in vagina – inactivates

proteases (eg PSA)

BULBOURETHRAL GLANDS (lubrication)

Paired glade on either side of prostate and produced a fluid High in sylic acid, a lubricant.

Human Ejaculate: Testis/Epididymis - ~10%; Prostate - ~30%; Seminal Vesicles - ~60%

QUIZ AT THE END OF THIS LECTURE.

Week 2- Male Reproductive Endocrinology

Definition: Collection of glands synthesise & secrete hormones into the bloodstream where

they act on target organs/tissues. The endocrine system has no ductal system (as such are

sometimes referred to as ductless glands) straight into blood stream. i.e testis. Contrast to

the exocrine glands, which secrete their products using ducts i.e prostate

The HPG axis: GnRH→gonadatrope

1. Hypothalamus → GnRH synthesis

2. Median eminence → GnRH storage/release

3. Portal blood vessels → GnRH transport (rapid)

4. Anterior pituitary → GnRH action

5. LH & FSH release into bloodstream

These are released in periodical pulses (GnRH,

and LH)

FSH is released passively (steady state), but is

still depended on GnRH amp and frequency.

Within the testis FSH→ sertoli cells which

nourish developing sperm cells to

spermatagonia→ spermatid. This produces

inhibin

LH→ leydig cells which are the steroidogenic

cells→ aromatases and testosterone.

Testostrone feedback to Hypothalamus to

↓GnRH.

Estrogen feedback to both Hypothalmus

and anterior pituitary ↓LH and GnRH

Inhibin feedback only to the anterior

pituitary ↓FSH.

Classes of Hormones.

• Peptides (eg GnRH) – Short chains of linked amino acids 10 amino acids

• Proteins/glycoproteins (eg LH & FSH) – Long chains of linked amino acids- FSH (2

polypeptide units, 96+110 amino acids)

• Steroids (eg testosterone & estradiol) – Derived from cholesterol

• Amino acid derivatives (eg norepinephrine) – Amino acids with modified groups

Steroid hormones

- 4 ring (tetracyclic) molecule

- Lipid soluble, enables passive diffusion into membrane

- All derived from cholesterol during steroidogenesis

All begins from cholesterol→ progestogens→androgens→estrogens

Note the enzymes: aromatase converts androgen into estrogen. 5 alpha reductase converts

testosterone into 5 alpha dihydro-tesostrone which is potent.

- Sex steroids: - androgens, oestrogens and progestogens - Have important roles in a range

of reproductive functions in both sexes - Feedback effects on the secretion and actions of

GnRH

Testosterone effects are mediated by the interaction with the androgen receptors.

Estradiol can signal through 2 different

receptors. ERbeta or ERalpha.

• Testosterone: levels decline at > 50

years of age

• LH: basal levels increase in older men

this is in response to less negative feedback

form testosterone at level of hypothalamus;

LH pulsatility is blunted (less effective)

• Leydig cells: steroidogenic capacity

decreases

• Spermatogenesis: lower fecundity at >40 years, 50% lower probability of achieving

pregnancy w/in 1 yr compared to men

In adulthood, there are variations across the year. Daily there is a diurnal secretion pattern,

highest in the morning and lowest in evening.

Male hypogonadism

Classical: testicular failure associated with androgen deficiency

Revised: decreased testicular function, as compared to what is expected for age, involving

impaired hormone secretion by Leydig cells

(androgens) and/or Sertoli cells (AMH, inhibin

B) and/or a disorder of spermatogenesis.

Primary (hypergonadotropic) hypogonadism –

Testicular disorder (eg, leydig cell hypoplasia)

Ethane dimethane sulphonate (EDS) Kills off

leydig cells – HIgh (hyper) gonadotrophin

levels

Central (hypogonadotropic) hypogonadism –

Disorder in hypothalamus/pituitary – Low

(hypo) gonadotrophin levels, error within the brain (understand the effects and mechanism

is important)

T feedback:

No evidence of direct T feedback on pituitary in humans (only hypothalimis), this because it

occurs animal models (rodent vs human)

Indirect via in situ T→E conversion in aromatase. Anterior pituitary and hypothalamus both

produce aromatase, potentially T in AP is converted to estrogen which is having a -ve effect

Testicular E synthesis. In human males, Leydig cells are the main source of testicular

estrogens. Sertoli cell only produce a small amount compared to leydig cells.

Signalling depends on the protein

polypeptide protein→signal via cell surface

Steroid→within nucleus or cell cytoplasm

Androgens (testosterone & DHT) – Androgen receptor

Estrogens (estradiol & estrone) – Estrogen receptors ERα ERβ

Each have a A/B, C, E, D and alpha has a F

domain. D contains the nuclear

localisation signal (brings receptor into

nucleus.) E domain location of ligand

binding to receptor. Variation is in A/B, relating to interaction with transcription. Signalling

is by classical signalling pathway.

Classical Nuclear receptor signalling

Steroid passes membrane encounters nuclear receptor bound to a HSP (originally to

protect it) disassociates in ligand presentsLigand and receptor dimerises and pass in

nucleases reacts with transcriptions causing an effect on the cell.

Note change of gene transcription and protein factors do not present for a while.

This pathway can be inhibited at any step. MDV3100 can be used to stop ligand from

binding. i.e in prostate cancer. Or the use of finasteride to block 5alpha reductase. Or target

HPG axis by using a GnRH agonist.

Non-classical nuclear response

Ligand binds to its receptor and the receptor is locked into the cell membrane. Or estrogen

can signal different receptor (g protein). This causes an effect on cytoplasmic kinases causes

rapid mediated effects (minutes.)

Hormone action is complex

• Administration of hormones to whole animals effect the endocrine system

– Reduction of other hormones and subsequent effects on target organs

• Also direct effects on target tissues themselves

Formally prostate cancer would be treated by estrogen to supress HPG axis (reducing

androgens) however this has local effects also. (rapid proliferations of epithelial cells).

(reduced testosterone hence smaller prostate???

Determining receptor may be to uses

- Stimulate with agonist

- Block with antagonist

- Knock-out (& transgenic) mice - (full, conditional, tissue specific)

Transgenic models

For estrogen effects in an animal

ArKO – no aromatase

AROM+ - excess aromatase

• αERKO – no ERα

• βERKO – no ERβ

• αβERKO – no ERα or ERβ

• NERKi – membrane signalling only

• AF2ERKi – AF2 mutation (ligand dependent transcription activation domain)

• 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.

Follicles

• Basic unit of female reproduction

• Roughly spherical cellular structure Comprises: Oocyte (egg) Granulosa cells Theca cells

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

division] – Mitozantrone [anthrocycline; anti-tumour antibiotic] – Cyclophosphomide

[alkylating agent]

Androgen independent (non-responsive to androgens) is not the same as castrate resistant

(still requires androgens to control growth, cells begin to shift and express different

enzymes) a drug being developed, Abiraterone Acetate – Enzyme Inhibitor, block pathway,

preventing the cancer from making its own androgens.

Enzalutamide (MDV3100) – AR Antagonist- stops interaction with testosterone preventing

changes in gene transcription.

Steroid Production in Castrate-Resistant Prostate Cancer (CRPC)

Androgen-independent does not = castrate-resistant prostate cancer • Tumours failed ADT

adapt to low androgen environments and make their own steroids i.e. prostate cancer is still

reliant on androgens • New drugs try to further block steroid metabolism

OBJECTIVES

1. Understand the basic cellular and molecular events associated with cancer – Hanahan

and Weinberg Interactions between cancer cells and microenvironment

2. Describe the disease progression of prostate cancer – Understand treatment resistance.

Genetic changes in the cancer cell and/or the tumour microenvironment. – Castrate-

resistant prostate cancer