Lecture 4-Steroid Hormone Metabolism Flashcards
Steroid hormones are lipids, what are the consequences of this?
Transport in the blood
Corticosteroid-binding globulin Sex-hormone binding globulin Albumin
Target cells
Only the free steroid hormone enters the cells. Specific receptors are in the cytosol or nucleus.
Hormone degradation Target cells Only the free steroid hormone enters the cells. Specific receptors are in the cytosol or nucleus. Hormone regulation (some in bile and feces) mainly in the liver (some in kidney) Released in urine
De novo synthesis of ALL steroid hormones….
cleaves cholesterol (C27) to pregnenolone (C21)
The enzyme is a cytochrome P450 enzyme and is commonly known as P450scc, cholesterol side-chain cleavage enzyme or desmolase and lately as CYP11A.
In what cells does de novo synthesis of steroid hormones take place?
De-novo synthesis of steroid hormones takes place only in the following cells Adrenal Cortex: a. Cortisol b. Aldosterone c. Weak Androgens
Testes: Testosterone
Ovaries: Estradiol
Corpus luteum: Progesterone
What are steroid hormones?
Steroid hormones contain a sterol ring system and are grouped according to their functions
Glucocorticoids Mineralocorticoids Androgens Estrogens Progestins
Summarize hormonal control of the synthesis of adrenal corticosteroids
CRH is released by the hypothalamus in a circadian rhythm and at low blood glucose or psychological stress.
CRH is the abbreviation for corticotropin-releasing hormone. Corticotropin is also known as ACTH.
ACTH is the abbreviation for adrenocorticotropic hormone which stimulates synthesis of all adrenal corticoids.
Cortisol is the glucocorticoid that is the feed- back inhibitor for the release of ACTH and CRH.
What is the relevance of cholesterol in steroid hormones synthesis?
Cholesterol C27–>
Pregnenolone C21
Progesterone C21
Weak Androgens C19 formed from pregnolone and progesterone
Either of the following can be synthesized from progesterone
Mineralocorticoids C21 Glucocorticoids C21
Which zona of the adrenal cortex is aldosterone synthesized?
Z. Glomerulosa
Receptors for ACTH and for angiotensin II
Which zona of the adrenal cortex synthesizes Cortisol and DHEA and also contains some lipid droplets?
Z. Fasciculata
Which zona of the adrenal cortex is responsible for synthesizing DHEA and androstenedione?
Z. Reticularis
Where do each of the zones of the adrenal cortex get their names?
Glomerulus= cluster
Fasces= bundles of parallel cords
Reticular= tangled network
How is aldosterone synthesis in Z. Glomerulosa mainly regulated by the hormone angiotensin II?
Cholesterol —> Pregnenolone—> Progesterone—> 11-Deoxycorticosterone—> Corticosterone—> Angiotensin II leads to synthesis of aldosterone synthase (CYP 11B2) Aldosterone
How is angiotensin II formed?
Angiotensin II is formed in the blood involving a cascade of different enzymes.
Decrease in blood pressure, blood volume or low sodium ion concentration leads to release of the enzyme renin from the kidney. Renin cleaves in the blood angiotensinogen released by the liver (12 C) to angiotensin I (10 C).
The enzyme ACE1 is mainly released in the lungs and cleaves angiotensin I to angiotensin II (8 C).
How is Angiotensin II degraded?
Angiotensin II is degraded in the blood by the enzyme ACE2 to angiotensin (potential vasodilation). ACE2 is bound to cell membranes in the regions of the heart, lungs, kidney, intestines and arteries. Note: ACE2 is also known as ACE2 “receptor” as it binds COVID-19.
What is the action of angiotensin II?
Angiotensin II leads to increase of blood pressure directly by vasoconstriction of blood vessels and indirectly by synthesis of aldosterone.
How does Angiotensin II lead to aldosterone release?
Angiotensin II stimulates the synthesis of aldosterone synthase.
Angiotensin II binds to its receptor in the adrenal Z. glomerulosa and acts via the phosphoinositide calcium ion messenger system. This activates gene expression of aldosterone synthase (CYP 11B2).
What is the action of aldosterone?
Aldosterone leads to increase of blood pressure, Na+ reabsorption, K+ excretion.
The primary effect of aldosterone is on kidney tubules. Aldosterone increases renal tubular sodium ion reabsorption into the blood stream and secretion of potassium ion in urine.
Water follows sodium ions causing an increase in blood volume that will raise the blood pressure.
Outline Cortisol synthesis in the z. Fasciculata
Cholesterol—> pregnolone—> 17-OH pregnolone
Or pregnolone forms progesterone which would then form 17-OH progesterone
17-OH pregnolone can also form 17-OH progesterone
17-OH prelgesterone—> 11-Deoxycytidinecortisol—> Cortisol
How is Cortisol synthesis regulated?
StAR: hormonal regulated step. Transport of cholesterol into mitochondria
P450scc is regulated by cholesterol availability , this then forms pregnolone which is then transported out of the mitochondria then used to firm 11-Deoxycortisol in the cytoplasm
11-deoxycortisol is transported back in the mitochondria to firm cortisol
Where is cholesterol obtained for Cortisol synthesis?
Cholesterol is obtained from LDL (LDL-receptor), HDL (SRB-1 receptor) or de-novo synthesis and is
stored as cholesteryl esters in cytosol.
What is the impact of ACTH on Cortisol synthesis?
ACTH leads via protein kinase A (PKA) to activation of both cholesteryl esterase and StAR as well as
the gene expression of steroidogenic enzymes.
Cholesteryl esterase generates free cholesterol which is transported by StAR (steroidogenic acute
regulatory protein) into the mitochondrial matrix