Synthesis of cortisol Stress Hypothalamus Pituitary Adrenal cortisol - ACTH + Adrenocorticotropic hormone - CRF CRF: corticotropic releasing hormone ACTH First 13 aa of ACTH= MSH (melanocyte stimulating hormone) Overproduction of ACTH= skin darkening Addison’s disease Hypofunctioning of adrenal cortisol ACTH cortisol

2 High levels of ACTH (MSH activity: ↑pigmentation)

CORTISOL SYNTHESIS

SYNTHESIS OF ALDOSTERONE

SYNTHESIS OF TESTOSTERONE AND ESTRADIOL

Synthesis of steroids: 17 hydroxylase11 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 Transport: By being bound to plasma proteins Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol Corticosteroid Binding Globulin (CBG) binds and transports cortisol Specificity Steroids act in only specific tissues and have specific functions due to the presence of an intracellular receptor specific for the hormone.

Steroid Hormone Receptor DNA binding domain DNA binding domain: Zinc fingers bind to DNA hormone binding domain

Coactivators- 1.histone acetyltransferase activity 2.affect RNA Polymerase II

Patients whose breast tumors are ER+ respond to hormone ablative therapy 1)Anti estrogens (such as taxmoxifen) 2) Aromatase inhibitors (letrozole) (aromatase – enzyme responsible for estradiol synthesis)

Peptides 1.proteins (10-40,000 mw) 2.membrane receptors 3.act within minutes 4.activate enzymes Steroids 1.derived from cholesterol (~300 mw) 2.cytoplasmic and nuclear receptors 3.act within hours 4.affect transcription !!!!