Steroid Biosynthesis Flashcards
Describe endocrine signaling
long distance signaling through bloodstream
freely diffusible
long lasting
What is the site of synthesis, distribution and effects of progesterone?
synthesized in adrenal glands, ovaries and testes
Distributed to uterus
mediates implantation and maintenance of pregnancy
What is the site of synthesis, distribution and effects of glucocorticoids?
(e.g. cortisol)
Synthesized in adrenal glands
distributed to large # of tissues and organs
increases blood pressure and Na up-take in kidneys
affect brain development
Mediates response to stress by increasing protein catabolism and gluconeogenesis (fight or flight) and reducing inflammation (suppress immune)
What is the site of synthesis, distribution and effects of aldosterone and other mineralocorticoids?
synthesized in adrenal glands
distributed to kidney tubules, colon, and parotid gland
Increases Na/H2O retention, K excretion and BP
What is the site of synthesis, distribution and effects of estrogens?
Synthesized in ovaries, placenta, and adipose tissue
Distributed to primary and secondary reproductive organs
mediates feminization, estrous cycle, and inhibits testosterone synthesis
What is the site of synthesis, distribution and effects of androgens (testosterone, DHEA)?
Synthesized in adrenal glands, ovaries, and testes (major)
distributed to primary and secondary reproductive organs and muscle
mediates spermatogenesis, secondary male characteristics, bone maturation, and virilization
Endocrine cell signaling occurs with ________.
ligands
*can be proteins, small peptides, aa derivatives, hydrophobic molecules even gases like NO
What are the main categories of signaling molecules?
Small lipophilic molecules: steroid hormones
Water soluble molecules - hydrophilic
What are the lypophilic signaling molecules Dr. Theisen wants us to know?
Steroid hormones: progesterone, estradiol, testosterone, cortisol, aldosterone, Vit D
What are steroids synthesized from?
cholesterol in smooth ER of adrenal cortex, ovaries, and testes
What is the affinity of signaling receptors?
high affinity - bind to ligands with great specificity (concentration of ligand in bloodstream is low)
What are the general two types of receptors?
Intracellular receptor: small hydrophobic/steroid receptor - alters gene expression in nucleus
(majority) Cell surface receptors: cytoplasmic domain initiates signal by change in confirmation
Steroid signaling is a fast or slow response?
slow because it takes longer to interact with gene expression
What are the domains commonly found with intracellular receptors?
Transcription-activating domain
DNA-binding domain
Ligand-binding domain
Where do tissues that synthesize steroids obtain cholesterol from?
Circulating LDL, from de novo synthesis from acetyl CoA, or from cholesterol esters stored in cytoplasmic lipid droplets (fatty acids)
How is Vit D synthesized from acetyl CoA?
3 acetyl CoA form IPP
6 IPP come together - 30 carbons
modified to become 27 carbon Vit D
What is the rate limiting step of steroid hormone synthesis?
Desmolase: incorporates a carbonyl group (C=O) on the D ring of cholesterol and cleaves off a six-carbon piece of its side chain to form pregnenolone
What does pregnenolone act as?
a modulator of neurotransmitter signaling in the brain w/o being converted to other steroids
Effects the NMDA glutamate receptor (memory and learning)
What must pregnenolone by converted to first for synthesis of other progestrogens?
progesterone
by 17-alpha-hydroxylase and 3-beta-hydroxysteroid dehydrogenase
What are the 4 types of progestrogens?
mineralocorticoids, glucocorticoids, estrgens and androgens
________ have affinity for mineralocorticoid receptors and are ____ times more concentrated than mineralocorticoids
glucocorticoids
100
What are the synthetic forms of anabolic steroids used for?
PEGs - performing enhancing drugs
affecting natural testosterone signaling pathways
the arm of Androgens and estrogens pathway synthesis in the adrenal cortex is the ______ pathway
minor
The mineralocorticoid and glucocorticoid pathways are exclusive in what tissue? What enzyme would you expect to find exclusively with these pathways?
adrenal cortex
21-alpha hydroxylase
Aldosterone (a mineralocorticoid) is converted from progesterone in what tissue?
Zona glomerulosa - adrenal cortex
Progesterone is converted to cortisol (a glucocorticoid) in what tissue?
zona fasciculata - adrenal cortex
Progesterone is converted to estradiol (an estrogen) in what tissue?
in ovaries from testosterone!
minor amount in adrenal cortex
Progesterone is converted to testosterone (an androgen) in what tissue?
in testes
also dihydrotestosterone (more potent) formed
Minor amount in adrenal cortex
Where is desmolase only found?
in tissues that produce steroid hormones (gonads and adrenal cortex)
What is the expression and activity of desmolase stimulated by?
peptide hormones
- ACTH: activates expression
- LH: increases activity
- FSH: activates aromatase
What happens if there is a defect in 21-hydroxylase?
salt wasting (hyponatremia) and hypotension due to decreased porduction of aldosterone, and hypoglycemia due to decreased production of cortisol
In females: cuases virilism (dev of male secondary characteristics) due to increased flow of intermediates into adrenal androgens
Describe the deficiency of 17-a-hydroxylase
rare
causes loss of cortisol as well as sex steroids
Decrease in cortisol compensated for by increased production of corticosterone
Describe what occurs with defect in 11-beta-hydroxylase
causes hypertension due to accumulation of 11-decoxycorticosterone, which has mineralocorticoid activity
Reduced levels of aldosterone =
Excessive levels =
Loss of too much salt
Conn syndrome - increase blood volume, hypertension
What is cortisol also known as?
hydrocortisone
Elevated levels of cortisol =
Cushing syndrome, a condition marked by the accumulation of fat on face and trunk
Pituitary or adrenal tumors or chronic administration of corticosteroids
Cortisol has an important affect on ____ feedback inhibition
ACTH
How does cortisol cause immunosuppresion?
inhibits both cellular and humoral immune response
induce production of i-kBa inhibitory protein
NF-kB sequestered: no synthesis of many cytokines
Promotes T cell apoptosis - decreased IL-2
Inhibition of donal expansion of B cells
Must metabolize cortisol to cortisone through action of _________
11 beta-hydroxysteroid dehydrogenase
Mineral corticoid target tissues such as the kidneys, colon, and parotid gland contain a receptor that has equal affinity for ______
both mineralo- and glucocorticoids
What food can inhibit 11b-hydroxysteroid dehydrogenase? what could this lead to?
real licorice
hypertension due to salt retention
(cortisol/cortisone) has much lower affinity for mineralocorticoids
cortisone
-dehydroxylated form
How is the androgenic potency of testosterone amplified?
by its conversion to dihydrotestosterone DHT mediated by enzyme 5 alpha -reductase
*DHT has much higher affinity than testosterone for androgen receptor
What is finasteride? What is it used for?
An inhibitor of 5 alpha - reductase
prevents potentiation
Used to treat benign prostatic hyperplasia
Treat male pattern baldness - caused by DHT in scalp
What is the active form of Vitamin D?
Calcitriol (1,25 - dihydroxycholecalciferol)
Technically not classified as a steroid
Alters expression of target genes containing VDRE seq
What are the inactive forms of Vitamin D? Where are they derived from?
Vitamin D2 (ergocalcifrol) and Vitamin D3 (cholecalciferol) Found in liver, eggs, fish, plants, and vitamin D fortified foods like milk and cereal
VD3 also produced in skin with sunlight
How is the inactive form of Vit D (cholecalciferol D3) produced?
In skin from photochemical cleavage of B ring of 7-dehydrocholesterol (via UV irradiation in the skin)
In intestinal cells from ergocalciferol (Vit D2)
What converts inactive Vit D into 25-hydroxycholecalciferol? where does this take place?
25-hydroxylase
Liver
What converts 25-hydroxycholecalciferol into 1,25 - dihydroxycholecalciferol? Where does this take place?
1-alpha hydroxylase
Kidney (proximal tubules) when PTH is present and low PO4
Inhibited by calcitriol
What does calcitriol stimulate in the body? What positively regulates and what inhibits this process?
intestinal cells to increase absorption of Ca and PO4
Increase reabsorption of Ca by kidneys
Promote resorption of Ca from bone
Elevate blood Ca and PO4 levels
+ PTH
- Calcitonin
What can cause deficiencies in Vit D?
conditions that disrupt the absorption of lipids, inadequate dietary intake and poor functioning of liver and kidneys
Hypoparathyroidism
Lack of sunlight
Leads to brittle bones (ricketts, osteomalacia)
hypocalcamic tetany: low blood calcium
