OESTROGEN RECEPTORS
OESTROGEN RECEPTORS
• Part of the steroid hormone super-family which includes the androgen receptor, progesterone and glucocorticoid receptor, aldosterone receptor, thyroid and retinoic acid receptor
• Nuclear transcription factor with binding domains for DNA and oestrogens
• Two sub-types - alpha and beta - the alpha sub-type has a half life of 4-7h.
• Located in the nucleus even without ligand binding - the androgen, mineralocorticoid and glucocorticoid receptors on the other hand localise to the nucleus only after hormone binding
• The oestrogen receptor, however, does undergo nucleocytoplasmic shuttling and is degraded in the cytoplasm
• Have similar binding affinities for oestradiol but different tissue expression and distribution. Phytoestrogens, however, have a greater affinity for the beta receptor
• Prior to ligand binding, the receptor is bound to a number of proteins including Heat Shock Protein 90 - dissociation of HSP 90 leads to activation of the receptor
• Following oestradiol binding, the receptor dimerises and undergoes conformational changes with permit binding to oestrogen response elements which regulate the transcription of oestrogen-sensitive genes
• Phosphorylation of the receptor and other peptides associated with it is an important mechanism of regulation - cAMP and protein kinase A pathways increase the transcriptional activity of the oestrogen receptor
• Activated by growth factors such as epidermal growth factor, insulin-like growth factor-1 and TGF - alpha
• Oestradiol, tamoxifen and raloxifene are agonists in bone; tamoxifen is an agonist in uterine tissue and tamoxifen and raloxifene are antagonists in breast
PROGESTERONE RECEPTOR
• Expression is induced by oestrogen at the transcriptional level and inhibited by progesterone at the transcriptional and translational level
• Two major forms - A & B
• The inactive receptor is bound to heat shock protein 90
• Progesterone binding leads to dimerisation with homodimers (AA) or heterodimers (AB)
• The activated receptor binds DNA and regulates transcription of progesterone responsive genes
• In most cell types, the B receptor is the positive regulator of progesterone sensitive genes
• The A sub-type inhibits the activity of the B sub-type
ANDROGEN RECEPTOR
• Exists as a full length B form and a shorter A form
• Gene located on the X-chromosome - androgen insensitivity syndrome is an X-linked disorder
• Similar to the progesterone, mineralocorticoid and glucocorticoid receptor - most similar to the progesterone receptor
• Progestogens compete with androgens for the receptor and for the 5-alpha reductase system - dihydroprogesterone which is produced competes with testosterone and dihydrotestosterone
• Has a greater affinity for dihydrotestosterone
• Lower affinity for cyproterone acetate or spironolactone (~20%) compared to testosterone
Androgens produce biological effects by:
1) Direct actions of testosterone - endocrine effects
2) Intracellular conversion to dihydrotestosterone
3) Intracellular conversion of testosterone to oestradiol (aromatization)
• Tissues derived from the Wollfian duct respond exclusively to testosterone
• Hair follicles and derivatives of the urogenital sinus / tubercle require conversion to dihydrotestosterone by 5-alpha reductase
• The hypothalamus actively converts androgens to oestrogens
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