27 - Steroid Hormones Flashcards
Steroid hormones are derived from cholesterol. Name the six major steroid hormones and their precursors.
Precursor: pregnenolone (C21)
- Progesterone (C21)
Precursor: Progesterone (C21)
- Cortisol (eg. glucocorticoid, C21)
- Testosterone (C19)
- Corticosterone/mineralocorticoids (C21)
Precursor: corticosterone (C21)
- Aldosterone (mineralocorticoid, C19)
Precursor: testosterone (C19)
- Estradiol (C18)
What do the following steroid hormones effect:
- Cortisol
- Aldosterone
- Estradiol
Cortisol
- Protein and carb metabolism
- Suppresses immune response
- Inflammation/allergies
Aldosterone
- Reabsorption of Na, Cl, HCO3 in the kidneys
Estradiol
- Male and female sex hormones
Give the broad steps of hormonal stimulation of steroid hormone biosynthesis
- Hormone binds to receptor on membrane and activates stimulatory G-protein (adenylate cyclase activated)
- Ca levels are directly or indirectly activated by the usual ways (IP3 intracellular, DAG channels)
- Increase in cAMP activates protein kinase A
- PKA phosphorylation causes increased hydrolysis of cholesterol esters to free cholesterol
- Cholesterol is transported into the mitochondria
- Elevated Ca and protein phosphorylation induces StAR, which incrases side chain cleavage and steroid hormone synthesis
How is cholesterol converted to pregnenolone?
- mixed function oxidase converts cholesterol to 20,22-dihydroxycholesterol with the help of Cytochrome P450 as an electron carrier (converts 2 NADPH to 2 NADP+). Also needs electron transferring protein adrenodoxin and adrenodoxin reductase (found in mitochondria of adrenal cortex, the site of active steroid production)
- 20,22-hydroxycholesterol is converted to pregnenolone by desmolase and the addition of isocaproaldehyde (isoprene) units
Pregnenolone is the precursor of all other steroid hormones!
Give the carbons and enzymes involved in the conversion of cholesterol to the steroid hormones
17-OH pregnenolone
- C17 is hydroxylated
- CYP17
- Another CYP17 reaction (lyase) gives rise to DHEA (Δ5 pathway)
Progesterone
- C3
- 3β-hydroxysteroid dehydrogenase and isomerase
Androstenedione
- C17 hydroxylation
- CYP17
- Another CYP17 reaction (lyase) gives rise to androstenedione (Δ4 pathway)
11-deoxycorticosterone
- C21
- CYP21 or 21 hydroxylase
- Deficiency in CYP21 leads to excess androgen and masculinization
Corticosterone/cortisol
- CYP11B or 11beta-hydroxylase
- C11
Aldosterone
- CYP11B2
What are the Δ4 and Δ5 pathways of testosterone biosynthesis?
Δ4: Androstenedione from progesterone
Δ5: Dehydroepiandosterone (DHEA) from pregnenolone
Androstenedione and DHEA become testosterone
What is dihydrotestosterone? How is this targeted in prostate cancer treatment?
DHT: a more potent form of testosterone.
Testosterone is converted to DHT by 5α reductase isozymes
5α reductase inhibitors (finasteride and dutasteride) block DHT production
How are estrogens biosynthesized?
Estradiol is main circulating oestrogen in females
- Testosterone (C19) is converted to 17β-estradiol (C18)
- Estradiol is then converted to estrone and other metabolites
OR
- androstenedione (from Δ4 pathway) is converted to estrone via aromatase
- Estrone is converted to estriol via 16α-hydroxylase
How is breast cancer treated?
- Estrogen receptor antagonists (eg. tamoxifen)
- Aromatase inhibitors block conversion of testosterone to 17β-estradiol in adrenal glands
- Other receptor antagonists used: progesterone receptor and epidermal growth factor receptor with monoclonal antibody trastuzumab
How are steroid hormones involved in the regulation of gene expression?
Glucocorticoids
- Bind to receptor in cytoplasm complexed with hsp90
- Binding causes dissociation of hdp and conformational change in receptor
- Activated receptor enters nucleus and binds DNA at glucocorticoid response elements (GREs) to trigger assembly of transcriptional coregulators and enhanced transcription ensues
Thyroid hormones and retinoic acid directly enter nucleus to stimulate gene transcription
- Receptors already bound to response elements and are associated with transcription repressor complex
- Ligand binding results in dissociation of repressor complex from receptor, allowing an activator complex to assemble and allow the gene to be transcribed
Give the conserved domains of a typical steroid hormone receptor (5)
- Transcription activation subdomain
- Zinc fingers
- Nuclear localization signal
- Transcription activation subdomain
- Heat shock protein binding site
