SERMS Flashcards
excessive exposure to osteorgen is associated
with risk of breast cancer
early menarche
late menopause
nulliparty
ERa
always an activator
more important in breast and uterus
ERb
sometimes a repressor and more important in CVS
both ERa and ERb are important for
for bone health and CVS protection
nucelar receptos bind DNA via
response elements
NR associated co-factors
do the transcriptional modulating
lots of cofactors
have tissues restricted expression patterns, results in increased complexity and tissue specific activity
ERb may
modulate Era function in breast and uterus
Era appears oncogenic while ERb has tumour suppressor functions
oestrogens and bone health
Era and ERb are expressed in bone and BM cells
increase in estradiol at puberty triggers long bone growth
estradiol maintains bone mineral density in adults
protective effects of estradiol
maintains bone miner density in adults
inhibits osteoclasts and promoting osteoblasts and osteocyte survival
SERMS
compounds that exhibit tissue-specific ER agonist or antagonist activity
non steroidal
all SERMs are nonsterodal except
fulvestrant
effects off SERMS
varying effects in different tissues but often
- anti-oostrogenic effect on breast epithelium
- oestrogenic effect on bone
SERMS mechanism of action
often bigger
prevent helix 12 from closing
co activators can’t bind - pure antagonist
net agonist/antagonist activity of ER ligands
depends on ligand-induced ER conformational changes, ER isoform (a or B) and recruited co-factors
SERMS act as
oestrogens on some tissues but anti oestrogens on others
first generation SERMS
clomiphene
tamoxifen
second generation SERMS
raloxifene
SERMS are used for
prevention and treatment of breast cancer
prevention and treatment of osteoporosis
infertility (clomiphene)
adjuvant hormone therapy
all women with oestrogen receptor positive breast cancer should be considered for adjuvant hormone therapy following surgery
in early breast cancer, its used to eradicate micro metastasis
in advanced breast cancer it is used to improve survival in low volume, bone only metastasis
used to prevent breast cancer in high risk women
tamoxifen
triphenylethylene
antagonises oestrogen effects on proliferation in breast cancer cells
used to treat oestrogen receptor positive breast cancer
tamoxifen in treating breast cancer
in metastatic, improved survival
reduction in recurrence
prevention in high risk women
tamoxifen in other tissues
antagonist in the breast - anti-oestrogen
partial agonist in bone which maintains bone density
cardioprotective - decreases LDL
agonist effect on the epithelium - increased effect of breast cancer
causes iatrogenc menopause
ca=ontraindications of tamoxifen
do not prescribe if pregnant or breastfeeding, smoker, or history of DVT/PE, stroke
raloxifene
treat and prevent breast cancer
not as effective as tamoxifen in preventing breast cancer
doesn’t stimulate endometrial proliferation
effects on reproductive tissues vary
breast epithelium - ER antagonist
endometrial epithelium - ER neutral
main use of raloxifene
osteoporosis
raloxifene in bone
ER agonist
used to treat osteoporosis n post menopausal women who can’t tolerate biphosphonates
aromatase inhibitors
anastrozole, letrosole and exemestane
block conversion of androgens to oestrogen
used to treat oestrogen receptor positive breast cancer
survival benefit is greater than tamoxifen
side effects of aromatase inhibitor
hot flushes
arthralgia
accelerated osteoporosis
so increase n DVTs or endometrial cancer
aromatase inhibitor contraindicated in
premenopausal women
ovarian function suppression
continuous GnRH shuts down FSH and LH because those are only triggered when GnRH is pulsatile
goserelin is a GnRH agonist implantat
used in pre menopausal women
BC prevention in high risk women
tamoxifen
BC women in pre menopausal women
tamoxifen 10 years
BC in post menopausal women low risk
tamoxifen
BC in post menopausal women high risk
aromatase inhibitors
