Steroid Biosynthesis Flashcards
How do you make steroid hormones from cholesterol?
cholesterol – desmolase –> pregnenolone –> progesterone
then either corticosteroids = aldosterone and cortisol
or sex hormones = testosterone and estradiol
How is progesterone related to pregnancy?
regulates voltage-gated Ca channels on spermatozoa
prepares uterus for implantation
causes smooth muscle relaxation
decreases maternal immune response
decrease in progesterone precedes menstruation, labor, and lactation
How are glucocorticoids linked to infant respiratory distress syndrome?
in normal-term babies: burst of glucocorticoids during delivery –> surfactant, normal lung expansion
in preterm babies, this is lost –> give mothers glucocorticoids to prevent
What is the significance of cortisone?
target tissues of mineralcorticoids have receptors w/ affinity for both gluco and mineralcorticoids
avoid excessive Na and H2O retention from cortisol by metabolizing cortisol – 11Beta-hydroxysteroid dehydrogenase –> cortisone = lower affinity
Why can licorice cause hypertension?
natural licorice has isoflavones = inhibitors of 11beta-dehydrogenase
cant convert cortisol to cortisone –> excess Na and H2O retention –> HTN
How is testosterone metabolized for signalling?
Testosterone – 5alpha-reductase –> DHT = higher affinity for T receptor, potentiates T effects
What does finasteride do?
inhibits 5alpha-reductase that converts T to DHT
used to treat male pattern baldness and benign prostate hyperplasia
What is CBG?
human corticosteroid-binding globulin
involved in the transport and release of the majority of plasma glucocorticoid hormones and also progesterone
What is SHBG?
sex hormone binding globuline
transports sex steroids (T, DHT, and estradiol)
only partially saturated in women
binding sites are mostly occupied by testosterone in men
How do glucocorticoids suppress the immune system?
induce i-KBA inhibitory protein –> sequestors NF-KB (needed for cytokines)
also promotes T cell apoptosis
decreased IL-2 and receptor –> inhibition of clonal expansion of B cells
What is significant about the CYP3A4 enzyme?
nearly 60% of all drugs are metabolized by it in the liver
have to consider interactions w/ this enzyme and how it might affect other drugs a pt is taking
What is significant about desmolase (cyp11A1)?
catalyzes cholesterol –> pregnenolone = 1st and rate limiting step of steroid synthesis
Positively regulated by ACTH
How does cortisol affect ACTH release?
negative feedback to hypothalamus and Ant pit = inhibits release
What are the short-term actions of ACTH?
stimulates lipoprotein uptake into cortical cells
increases bioavailability of cholesterol in adrenal cortex
What are the long-term actions of ACTH (hours)?
stimulation of transcription of the genes coding for steroidogenic enzymes
P450scc
11Beta-hydroxylase
associated e- transfer proteins
What type of receptor does ACTH bind?
Gs
What can occur in a tumor that secretes cortisol?
PKA that is normally signaled by ACTH binding Gs is always active –> get too much cortisol and cell proliferation
What in general, does cortisol do?
Binds and activates glucocorticoid receptor (GR)
increases gluconeogenesis and BP
anti-inflammatory
What, in general, does aldosterone do?
binds and activates mineralcorticoid receptor (MR)
increases Na and H2O retention
raises BP
What receptor does testosterone bind?
androgen receptor (AR)
What do women with congenital adrenal hyperplasia present with?
hirsuitism
general oligomenorrhea = infrequent or very light menstruation
infertility
What are the 3 main enzyme deficiencies that can lead to congenital adrenal hyperplasia?
21alpha-hydroxylase = 95%
11beta hydroxylase = 5%
17alpha-hydroxylase = unknown %
What occurs biochemically in CAH due to mutant 11-beta-hydroxylase?
cant do 11-deoxycorticosterone –> corticosterone (don’t make aldosterone)
can’t do 11-deoxycortisol –> cortisol
get buildup of precursors –> excess androgen production
increased DOC –> has mineralcorticoid activity –> high BP
low K+ (bc of water retention)
What occurs to cause hypertension in CAH w/ mutant 11-beta-hydroxylase?
get buildup of 11-deoxycortisol –> can bind to MR w/ high affinity –> HTN
What do you see clinically in CAH due to mutant 11-beta-hydroxylase?
masculinization
virilization
high BP
low potassium
What occurs biochemically in CAH due to mutant 21-alpha-hydroxylase?
can’t do progesterone –> 11-DOC (can’t make aldosterone)
can’t do 17-alpha-hydroxyprogesterone –> 11-DOC (can’t make cortisol)
get buildup of precursors –> shunted to androgen production
What do you see clinically in CAH due to mutant 21-alpha-hydroxylase?
low aldosterone and cortisol
increased androgens –> masculinization
low BP
high K
What occurs in CAH due to mutant 17-alpha-hydroxylase?
can’t do progesterone –> 17-alpha-hydroxyprogesterone –> can’t make cortisol
buildup of progesterone –> shifted to aldosterone synthesis
What do you see clinically in CAH due to mutant 17-alpha-hydroxylase?
high aldosterone
low cortisol
decreased androgens –> lack of secondary sex characteristics
high BP
low serum K
where are CBG and SHBG made?
in the liver
What do FSH and LH do in females?
promote production of estradiola and progesterone
What do FSH and LH do in men?
FSH –> stimulates inhibin production
LG –> stimulates testosterone production
What enzyme catalyzes Vit D3 –> 25 OH Vit D?
Where does this occur?
25-hydroxylase
in the liver
What enzyme catalyzes 25-OH Vit D –> 1,25 Vit D (calcitriol)?
Where does this occur?
1-alpha hydroxylase
in the kidneys
What occurs with an excess of vitamin D?
elevated blood and urine Ca
dazed, loss of apepetite
