Sex Hormones and Disease Flashcards
What are the benefits of postmenopausal HRT?
Improved bone density (decreased resorption); relief from flushes, fatigue, vaginal dryness by re-estb feedback control; reversal of atrophy of vulva, vagina, and urethra; improved sleep and pattern; reduced incidence of colorectal cancers; +/-reduced incidence of CHD and Alzheimer’s
What are the risks of postmenopausal HRT?
breast tenderness, nausea, fluid retention; increased risk of breast or uterine cancer; increased risk of thromboembolism and stroke
What is the mechanism of action of estrogen?
oestrogen crosses the plasma membrane; binds estrogen receptor (ER) in cytoplasm; receptors form homodimers which bind to specific oestrogen response elements (ERE) to activate gene transcription to mRNA
T/F oestrogen bound to its ER can form heterodimers
True, with different transcription factors to up or downregulate gene transcription - may be related to different types of oestrogen (less abundant forms)
Tissue specific effects of oestrogen arise due to
receptor subtypes - ER alpha and ER beta with differential affinities; multiple co-factors; can cause gene activation or repression
Rapid effects of oestrogen eg neuronal actions where oestrogens cause rapid Ca2+ influx causing rapid dilation are attributed to
in certain tissues, there are ER on the cell membrane; oestrogen may also be able to act via GPR30, a GPCR
Oestrogen binding ER generally promotes
growth and expression of the progesterone receptor PR
Progesterone receptors are upregulated by
oestrogen binding ER
Progesterone binding PR stimualtes
growth and differentiation
What is significant about ER and PR expression post menopausal?
Expression of both receptors goes up post-menopause in patients with breast cancer
Tamoxifen, Raloxifene
ER partial agonists used in tx of breast cancer; both have antagonistic effects on ER receptors in breast tissue
Fulvestrant
ER antagonist in trials for tx of breast cancer; antagonistic effects in breast, uterus, bone, CV, and CNS tissue
Tamoxifen is used as
palliative tx of metastatic breast cancer and adjuvant following lumpectomy
Tamoxifen acts as
an antagonist in breast but partial agonist in bone and endometrium
What are the adverse effects of tamoxifen?
Endometrial hyperplasia, polyps, and cancer; thromboembolic events; thrombocytopaenia; ocular toxicity; menopausal symptoms (hot flushes, atrophic vaginitis)
T/F resistance can develop to tamoxifen
True; tumours can recur because there are multiple receptors and transcription factors in the mechanism of action
Aromatase is active in
breast adipose mesenchymal cells
Why are blood oestrogen levels in post-menopausal women inaccurate?
Oestradiol may act as a paracrine hormone therefore while plasma oestrogen may be low, cellular levels will be high due to aromatase activity
Exmenostane is
an aromatase inhibitor
Exmenostane is used in
tx of breast cancer because it reduces levels of all oestrogens by reducing their synthesis thus decreasing the potential of ER stimulation in breast tissue
What are the benefits of exemestane in tx of breast cancer?
improvement in disease-free survival after tamoxifen tx; reduced incidence of contralateral breast cancer, number of thromboembolic events, and incidence of endometrial cancer
What are the risks of using exemestane tx in breast cancer?
Increased bone loss & fracture risk; increased arthralgia and joint damage; potentially poorer lipid profile, hepatic steatosis, and metabolic syndrome with long term use; menopausal signs
Dihydrotestosterone is active in
prostate, seminal vesicles, epididymis and skin
Testosterone circulates in blood on
steroid hormone binding globulin
What is the mechanism of action of testosterone?
dissociates from SHBG in blood to cross the membrane; in some tissues 5a reductase converts it to dihydrotestosterone; DHT binds the androgen receptor; the receptor dimerizes and the complex translocates to the nucleus to alter gene transcription
What actions of testosterone are specific to the testosterone form?
Gonadotrophin release (-ve fbk)
Spermatogenesis
Sexual differentiation
Anabolic effects
What actions of testosterone are specific to the DHT form?
Prostate development
External virilisation
Sexual maturation
T/F testosterone can directly activate androgen receptors in the nucleus
True; there is an equilibrium between receptors in the cytoplasm and the nucleus - testosterone can bind both of these receptors
Therapeutic uses of androgens for androgenic effects include
hypogonadism
Therapeutic uses of androgens for anabolic effects include
senile osteoporosis to promote bone growth; speeding recovery from surgery and chronic debilitating diseases
Therapeutic uses of androgens for growth effects include
promoting skeletal growth in pituitary dwarfism
Androgen use in endometriosis aids
reduce pain and inflammation; may increase local oestrogen production to restore balance
What are the therapeutic uses of oestrogens?
Hypogonadism in children for development of sex characteristics and accelerating growth; primary amenorrhoea, contraception, and menopause in adults
Adverse coronary effects of androgens include
increased LDL and decreased HDL tf increasing risk of CHD
Adverse effects of androgens in females include
acne, facial hair, deepening of voice, male pattern baldness, excessive muscle development, menstrual irregularities
Adverse effects of androgens in males include
priapasm, impotence, decreased spermatogenesis, gynaecomastia
Adverse effects of androgens on children include
premature closure of epiphyses, abnormal sexual maturation
Adverse effects of androgens on athletes include
liver damage, increased aggression, psychotic episodes
Anti-androgen receptor antagonists include
cyproterone and flutamide
Cyproterone is a
steroidal antagonist with relative selectivity for androgen receptors
Cyproterone is used for
prostate cancer and androgenisation in females (PCOS)
What are the adverse effects of cyproterone?
cognitive changes, fatigue, oedema, reduced spermatogenesis
Flutamide is a
non-steroidal antagonist thought to selectively block androgen receptors in prostate rather than throughout the body
Flutamide is used in
metastatic prostate cancer
What are the adverse effects of flutamide?
Diarrhoea, anaemia, hepatic injury, odema, dizziness, blurred vision
5alpha reductase inhibitors
anti-androgen; blocks conversion of testosterone to dihydrotestosterone
Finasteride is a
5alpha reductase inhibitor that blocks conversion of testosterone to DHT
Finasteride is used in
benign prostatic hypertrophy (remember that DHT is abundant in prostate, SV, and epididymis); hair loss (assoc with high DHT) treatment
What are the adverse effects of 5alpha reductase inhibitor finasteride?
impotence, decreased libido, ejaculation disorder; breast enlargement and tenderness; breast cancer because testosterone is now converted to oestrogen in breast tissue instead of DHT
