Hormone and endocrine therapy Flashcards
What do oestrogen receptor positive breast cancers require?
Oestrogen to proliferate and metastisise.Oestrogen penetrates breast cancers and activates ER receptors promoting growth
What are used post- menopausal?
Aromatase inhibitors,Tamoxifen- non steroid antioestrogen, fulvestrant – steroidal antioestrogen.
What are used pre- menopausal?
Tamoxifen,Goserelin GnRH analougue, aromatase inhibitors
Expalin the diagram of how they affect oestrogen receptors?
Tamoxifen and fulvestrant prevent oestrogen from reaching oestrogen receptors.The others prevent the conversion by aromatase enzymes
What is the equation for the synthesis of oestrogen?
Cholesterol- progesterone- androstenedione- estrone/testosterone-oestradiol.
What does the source of oestrogen depend on?
Whether the patient is post or pre menopausal.
How is oestrogen made in pre-menopausal women- e2?
Most oestrigens are made in the overaries by testosterone, which is converted to oestradiol E2. Gonadotropi- releasing horme GnRH is a releasing hormone responsible for the release of follicle – stimulating hormone FSH and lutenizing hormone LH .FSH stimulates ovarian release of oestrogen.
How is oestrogen made in post menopausal women?
Most oestrogens are made outside the ovaries,adipose tissue is a major source. Androstenedione produces estrone E1.If a post menopausal woman with ER + and BRCA,their prognosis is worse because E1 is produced from adipose.E1 is required for tumour growth and proliferation.
What are gnrh analougues?
GnRH is responsible for the release of FSH,which is responsible for the ovarian release of oestrogen E2.Goserelin is a GnRH analogue acting as a potent inhibitor of GnRH secretion.This therefore decreases E2 levels to levels similar to a post menopausal state when medication is stopped, hormone levels return to normal.
What is an aromoatase inhibitor and how does it work?
so aromatase enzymes convert androgens into oestrogens – E1 – so inhibitors of aromatase therefore block the synthesis of oestrogen. Example of first gen aromatase inhibitor – Aminoglutethimide; It blocks all hormone synthesis – sortisol etc so supplemenst were needed. Anastrazole (NS) and exemestane (steroidal) are third gen aromatase inhibitors that are more specific to treating oestrogen dependent breat cancers.
Explain the process by which oestrogen receptors work?
Silimlar to steroid receptors, intracellular and effect gene transcription.ER alpha and ER beta are oestrogen receptors. ER alpha is dominant in the vagin, breast,bone,hypothalamus and blood vessels,ER Beta is dominant in the ovaries of females. Er alpha is slightly longer with a number of domains,The C region binds to DNA and the hinge region is where oestrogen binfs .When oestrogen binds to ER the receptors dimerise: ER ALPHA WITH ALPHA OR BETA WITH BETA = HOMODIMERS.ER Alpha with ER Beta – hetrodimers.
Explain the dna binding hinge
oestrodiol – e2- binds to receptors with equal affinity.Circulating E2 enters the cell and reaches ER receptor.Heat shock protein HSP90 is bound to ER so e2 dissociates HSP90 from ER.E2 then binds to receptors
which dimerise,Once dimerised ER enters the nucleus. Depending on the cell type,er binds directly to DNA and affects gene transcription or binds indirectly to DNAby binding to a transcription factor.There are extracellular nuclear receptors – G- coupled proteins GPR30 AND GPER – Oestradiol – they sit on the bottom of the membrane – coupled to the bottom by lipid tag.The secondary messanger system cAMP,which can cause gene transcription when G protein couples receptor is activated.
- Non genomic oestrogenic effects do not involve dna transcription – they cause direct physiological effects.Oestrogen receptors can also activate without oestrogen, Gf signalling leads to activation of ER via kinase phosphorylation.ER activation causes gene transcription.
What are 2 examples of oestrogen receptor antagonists?
Tamoxifen and fulvestrant
How does tamoxifen work?
A prodrug that requires activation by cytochromes P450 enzymes and CYP2D6 and 3A4 to generate the active metabolied,endotoxifen. It ia a selective oestrogen receptor modulator SERMs that acts as a competitive antagonist of oestrogen at ER – alpha in the breast .It causes conformational change in the receptor,modulating the xpression of eastrogen – dependent genes.The prolonged binding of tamoxifen results in reduced DNA polymerase activity,impaired thymidine utilisation,blockade of oestrodiol uptake and decreased oestrogen response. It is also a partial agonist at other oestrogen receptors,minimising the potential effects of oestrogen deprivation. Tamoxifen is not cytotoxic and does not cause a loss of bone marrow.
What is fluvestrant and how does it work?
Steroidal antioestrogen,used post menopausal women with disease progression following antioestrigen therapy – tamoxifen.It competitively and revesibily bings to the ER, downregulates ER so oestrogen is no longer able to bind to these receptors and degrading the ER.This inhibits the growth of the tumour as it is not able to utilise oestrogen.
