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)
AldosteroneHow 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
What are the hormone regulatory step and rate limiting step of Cortisol synthesis?
The action of StAR is considered the hormonal regulatory step of steroid hormone synthesis.
Cholesterol (27 C) is cleaved to pregnenolone (21 C) in the rate-limiting step by P450scc inside the mitochondria. P450scc is also known as cholesterol side-chain cleavage enzyme or desmolase and lately as CYP11A. Side-chain cleavage involves 3 enzymatic steps.
The enzyme activity is mainly regulated by the availability of cholesterol in mitochondria.
Summarize Cortisol synthesis in the brain
Circardian Rhythm
Blood cortisol levels highest in the morning (waking).
• Stress and low blood glucose lead to release of CRH and ACTH.
Hypothalamus has glucose-sensing neurons
Cortisol is released into the blood
Summarize the metabolic functions of Cortisol
Liver: Gluconeogenesis and release of glucose into blood. Note: low cortisol leads to hypoglycemia and high cortisol leads to hyperglycemia found in Cushing’s syndrome
Adipose tissue:
TAG degradation and release of free fatty acids and glycerol.
Skeletal muscle:
Protein degradation and release of amino acids into blood.
Anti-inflammatory:
Inhibition of PLA2 and reduced synthesis of eicosanoids.
Outline androgen synthesis
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 progesterone—> Androstenedione
Or 17-OH pregnolone—> DHEA—> androstenedione
What happens to adrenal androgens after they are released into the blood?
In adipose tissue:
Dehydroepiadrosterone + androstenedione uses CYP 19 Aromatase to form estrogens
In Extra-adrenal tissues:
Dehydroepiadrosterone + androstenedione uses 17-B hydroxysteroid DH-3
to form testosterone
Give an outline: Abnormal Cortisol synthesis
- Cortisol synthesis is reduced. A. Congenital Adrenal Hyperplasia (CAH):
One enzyme of cortisol synthesis is deficient. B. Addison Disease: Atrophy of adrenal cortex - Cortisol synthesis is increased. Cushing’s Syndrome: Hypercortisolism due to tumor
What is congenital adrenal hyperplasia?
CAH is a group of autosomal recessive disorders with different onset of clinical manifestations.
The low level of cortisol reduces the feed-back inhibition of ACTH and leads to overstimulation of the adrenal cortex.
What is the effect of 3-hydroxysteroid DH deficiency?
Low blood pressure
Low blood glucose
Androgens are variable generally
What are the effects of 17 a-hydroxylase deficiency?
High blood pressure
Blood glucose can be low
Androgens are low in general
What are the effects of 21 a-Hydroxylase deficiency?
Low blood pressure
Blood glucose- Can be low
Androgens are high in adrenals
What are the effects of 11B-hydroxylase?
Blood pressure- mildly elevated
Blood glucose can be low
Androgens are high in adrenals
What are the effects of 3B-hydroxysteroid DH deficiency?
rare and difficult to confirm.
Hypotension, low fasting blood glucose, high DHEA Test for 17-OH-Progesterone is negative
This results in less progesterone as pregnenolone cannot be converted
As progesterone is decreased, aldosterone and Cortisol is decreased
Pregnenolone increased DHEA but, less androstenedione as DHEA cannot be converted to androstenedione
Explain in detail the effects of 3B-hydroxysteroid DH deficiency
The rare deficiency of 3b-hydroxysteroid DH has 3 different forms.
In the most severe form there is a severe deficiency of all mineralocorticoids and glucocorticoids. This results in infants to have hypotension, low fasting blood glucose and salt excretion in urine.
(This rare CAH is difficult to confirm. It has similar clinical signs like CYP 21 deficiency (more common) but does not show increased levels of 17-OH-progesterone which is the tested marker for CYP 21 deficiency.)
There is a large clinical variability of ambiguous genitalia in newborns which results from the stimulated synthesis of the adrenal DHEA and at the same time the reduced sex hormone synthesis that occurs in the testes and ovaries.
Male newborns may have male or ambiguous, female-like genitalia. Female newborns may have female or ambiguous, male-like genitalia.
What are the effects of deficiency of CYP 17 (a-hydroxylase)?
Hypertension, often low blood glucose and decreased androgens
CYP17 is responsible for adding OH to the 17-C on pregnenolone and progesterone, without it, 11-deoxycosterone increases, corticosterone increases and aldosterone increases
How does CYP-17(17a-hydroxylase) lead to hypertension? What other effects may occur?
CYP 17 deficiency does not only reduce androgen synthesis in adrenals but also reduces the synthesis of sex hormones in testes and ovaries. This leads to female-like
external genitalia in males and females.
As ACTH is still activating the synthesis of corticoids this leads to hypertension from the high levels of the intermediates 11-deoxycorticosterone and corticosterone which can be measured in clinical tests.
The abnormal high levels of ACTH stimulate first the synthesis of aldosterone which leads to hypertension. This hypertension leads to low renin and the resulting low level of angiotensin II leads then to reduced gene expression of aldosterone synthase.
What is the most common Congenital adrenal hyperplasia?
CYP 21( 21a-hydroxylase)
Summarize the effects of deficiency of CYP 21?
Hypotension, often low blood glucose and increased androgens
Most common, Newborn screening test for elevated 17-OH Progesterone
What hormones are increased/decreased in CYP-21 deficiency?
Without CYP 21, 17-OH progesterone can’t be converted to 11-Deoxycortisol (leads to decreased Cortisol)and progesterone cannot be converted to 11-deoxycosterone(leads to decreased aldosterone)
17-OH pregnenolone –>increased DHEA
DHEA and 17-OH progesterone lead to increased ADD
Androgen synthesis is stimulated as it does not use CYP 21
What are the symptoms of CYP 21 deficiency?
Different age of onset and severity. Hypotension, hyponatremia and hyperkalemia.
Hypotension and possible “salt-wasting crisis”. Aldosterone and cortisol are virtually absent in the classic form. Infants two weeks old can become critically ill. Severe loss of sodium.
High potassium levels diminish cardiac output which can be fatal if not treated.
Female newborns: ambiguous male-like genitalia. Milder CYP 21 deficiency leads to virilization of females later in childhood.
Male newborns: external genitalia appear normal.
Virilization of males in early childhood.
What happens in deficiency of CYP 11B1 (11B-hydroxylase)?
Mild hypertension, low fasting blood glucose, increased
What hormones are increased/decreased in deficiency of CYP 11B1?
CYP 11B1 is responsible for 11-deoxycorticosterone —> corticosterone(subsequent decreased in aldosterone)
As well as 11-deoxycortisol (subsequent decrease in Cortisol in deficiency)
Increased DHEA(from 17-OH pregnolone )and increased ADD from increased DHEA and 17-OH progesterone
What is impact of sex hormones on Testes?
Hypothalamus releases GnRH
Anterior pituitary releases LH - FSH
LH causes Leydig cells to release testosterone into the blood
FSH stimulates spermatogenesis in Sertoli cells
Summarize testosterone synthesis in the leydig cell
Leydig cells contain 17b-hydroxysteroid DH3 which forms testosterone from androstenedione. The synthesis of DHEA and androstenedione is activated by LH and needs CYP 17. The pathway is similar to the one found in the adrenal cortex.
Testosterone and other androgens are released and can be taken up by sertoli cells or be distributed in the blood
Outline testosterone synthesis
Cholesterol—> pregnolone —>17-OH pregnolone
Pregnenolone—> progesterone —> 17 OH progesterone
17 OH pregnonolone —> 17 OH progesterone
17 OH pregnonolone —> DHEA—> androstenedione
17-OH progesterone —> androstenedione
17 B-hydroxysteroid DH-3–> testosterone
How is testosterone activated ?
Formation of dihydrotestosterone (DHT) by 5-alpha-reductase
Testosterone is mainly released by Leydig cells and then activated to dihydrotestosterone in prostate and hair follicles and other cells.
DHT has a considerably higher affinity for the androgen receptor.
Summarize sex hormone synthesis in ovaries
GnRH from hypothalamus to release anterior pituitary gland LH & FSH
LH stimulates theca cells to release testosterone
FSH stimulates follicle granulosa cells to release estradiol ( and released into the blood)
Follicle granulosa cells take up testosterone and use it for synthesis of estradiol which is released into the blood.
How do ovaries use androgens to form estrogens?
The theca cells have receptors for LH which activates synthesis and secretion of androgens, mainly testosterone and androstenedione.
The follicle granulosa cells have receptors for FSH and contain aromatase (CYP 19).
They use androgens for estrogen synthesis and secrete primarily estradiol formed from testosterone.
What is the special in the synthesis of estrogen?
Aromatase (CYP 19) uses
ID:
SOM.1ai.BPM2.1.ER.2.BCHM.EC.0508
CYP19
androgens for estrogen synthesis.
CYP 19 cuts carbon #19 and forms estrogens with 18C and an aromatic ring A.
The aromatic ring bends part of the molecule upward. This is needed for the recognition by the estrogen receptor.
Explain in detail the effects of Addison’s
Addison Disease: Primary adrenal insufficiency
All corticoids are low and high ACTH, Hypotension, Hyponatremia, Hyperkalemia
- Insufficiency and atrophy of the adrenal cortex due to: a. Autoimmune destruction or tumors.
b. Infections like HIV, tuberculosis, fungi. - Low level of cortisol lead to:
a. Low blood glucose during prolonged gluconeogenesis.
b. High level of ACTH which does not lead to CAH because of the
atrophy of the adrenal cortex. - Low level of aldosterone leads to:
a. Low blood pressure and salt craving.
b. Low sodium and high potassium blood levels.
What is Cushing’s syndrome?
Hyper cortisolism
Cushing’s Syndrome is a collection of signs and symptoms due to abnormally high levels of cortisol in the blood resulting from:
- Tumor in the Z. fasciculata leads to very high levels of cortisol and high adrenal androgens. The high cortisol level leads to a low ACTH level.
- Tumor in Pituitary (Cushing Disease) leads to very high ACTH release which results in very high cortisol levels.
- Prolonged administration of high doses of corticosteroidal drugs.
Outline the characteristics of patients with Cushing’s syndrome
- Characteristic fat distribution: a. Increased fat in upper body.
b. Fatty hump between the shoulders. c. Red round face. - Rapid weight gain with central obesity.
- Pink purple stretch marks in the skin (collagen).
- Hirsutism and early pubic hair development.
- Thin arms and legs, severe muscle weakness (cortisol stimulates muscle protein degradation).
- Elevated blood glucose up to twice normal (cortisol stimulates gluconeogenesis).
- High blood pressure from epinephrine or a mineralocorticoid effect of cortisol.
- Reduced inflammatory response (cortisol has anti-inflammatory action).
- Suppressed Immune System (reduced protein synthesis in lymphoid tissue)
What are the characteristics of patients with Addison Disease?
- Bronze pigmentation of skin and gum line is due to high level of melanocyte stimulating hormone. The lack of cortisol leads to increased release of CRH which stimulates the synthesis of the large precursor protein Proopio- melanocortin (POMC) which is cleaved to: ACTH, melanocyte stimulating hormone and others. Note: you find this also in Cushing’s disease.
- Failure to thrive.
- Weight loss.
- Muscle weakness and salt craving.
- Thinning of axillary and pubic hair in some females.
- Abdominal pain.
