Synthesis of cortisol Stress CRF: corticotropic releasing hormone Hypothalamus cortisol CRF Pituitary cortisol - Adrenocorticotropic hormone - ACTH cortisol Adrenal + Overproduction of ACTH= skin darkening ACTH First 13 aa of ACTH= MSH (melanocyte stimulating hormone) Addison’s disease Hypofunctioning of adrenal cortisol ACTH
High levels of ACTH (MSH activity: ↑pigmentation)
Synthesis of steroids: 17 hydroxylase 11 hydroxylase 21 hydroxylase 18 hydroxylase Cortisol 21 hydroxylase 17 hydroxylase 11 hydroxylase Aldosterone 21 hydroxylase 18 hydroxylase 11 hydroxylase Estradiol 17 hydroxylase Testosterone
Mechanism of action of steroids By being bound to plasma proteins Transport: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol Corticosteroid Binding Globulin (CBG) binds and transports cortisol Steroids act in only specific tissues and have specific functions due to the presence of an intracellular receptor specific for the hormone. Specificity
Steroid Hormone Receptor DNA binding domain hormone binding domain DNA binding domain: Zinc fingers bind to DNA
Coactivators- histoneacetyltransferase activity affect RNA Polymerase II
Patients whose breast tumors areER+ respond to hormone ablative therapy • Anti estrogens (such as taxmoxifen) 2) Aromatase inhibitors (letrozole) (aromatase – enzyme responsible for estradiol synthesis)
Peptides proteins (10-40,000 mw) membrane receptors act within minutes activate enzymes Steroids derived from cholesterol (~300 mw) cytoplasmic and nuclear receptors act within hours affect transcription !!!!