REB 11. Biochemical Synthesis of Steroid Hormones Flashcards
What type of disorder are Congenital Adrenal Hyperplasia (CAH)? How does it arise? What does it present as? What is the result of it?
- a group of inherited autosomal recessive disorders
- mutations in genes encoding enzymes in mineralcorticoids, glucocorticoids or sex steroids synthesis
- enlarged adrenal glands (hyperplastic adrenomegaly)
- results in reduced levels of cortisol + aldosterone with overproduction of androgen
What is the clinical presentation of classic CAH in infants?
- ambiguous genitalia in females
- enlarged genitalia in males
- poor weight gain
- adrenal crisis (dehydration, vomiting, hypoglycaemia and circulatory collapse)
What is the clinical presentation of classic CAH in children and adults?
- early onset of puberty
- rapid growth during childhood
- premature completion of growth (short stature)
- irregular menstrual cycles
- infertility in both sexes
What are glucorticoids?
regulates metabolism, mood, blood pressure, immunity, pain sensation
e.g. cortisol
What are mineralcorticoids?
electrolyte and fluid balance, blood volume
e.g. aldosterone
What are androgens?
male reproductive development
e.g. testosterone
What are estrogens?
female secondary sex characteristics; regulation of menstrual cycle
What are progestogens?
regulation of ovulation; maintains pregnancy
What are the 2 MAIN layers of the adrenal gland?
[1] Outer Cortex
[2] Medulla
What are the 3 sublayers of the cortex?
[1] Zona Glomerulosa - aldosterone [2] Zona Fasciculata - cortisol [3] Zona Reticularis - sex steroids (androgens)
Which layer of the cortex are mineralcorticoids made in?
Zona Glomerulosa
Which layer of the cortex are glucocorticoids made in?
Zona Fasciculata
Which layer of the cortex are the sex steroids (androgens) made in?
Zona Reticularis
Where are the catecholamines made?
Medulla
Which hormones are made in the adrenal glands?
- corticosteroids (mineralocorticoids + glucocorticoids)
- androgens
Which hormones are made in the ovaries?
- estrogens
- progesterone
Which hormones are made in the testis?
- androgen
What is the precursor for all steroid hormones?
Cholesterol (27 carbon structure)
Where is cholesterol synthesized? What is its structure and what type of molecule is it?
- synthesized in the liver
Structure:
- 4-linked hydrocarbon (steroid nucleus)
- hydroxyl group (OH)
- hydrocarbon side chain (hydrocarbon tail)
- Amphipathic Molecule: both hydrophilic and hydrophobic parts
What is the first step in steroid synthesis?
Cholesterol to Pregnenolone
Explain the steps and enzymes involved in converting Cholesterol to Pregnenolone. What type of step is this?
[1] Cholesterol taken up into mitochondria - mediated by StAR enzyme (steroidogenic acute regulatory protein)
[2] Cholesterol converted to Pregnenolone through side-chain cleavage (catalyzed by enzyme Cytochrome P450)
It is a rate-limiting step - NADPH and Oxygen are required
What is another name for the enzyme cytochrome P450?
- desmolase
- CYP11A1
What are the 3 possible locations that cholesterol may be converted to pregnenolone?
[1] Adrenal
[2] Ovary
[3] Testis
Explain the process by which Pregnenolone is converted into Progesterone. What enzymes are involved?
[1] 3-hydroxyl group (OH) is oxidized to 3-keto group via the enzyme:
- 3beta-OH Dehydrogenase
[2] 5th carbon double bond is isomerized to a 4th carbon double bond via the enzyme:
- Delta5,4 Isomerase
What are the enzymes involved in the synthesis of cortisol from progesterone? (in order!)
[1] 17 alpha-hydroxylase
[2] 21 alpha-hydroxylase
[3] 11 beta-hydroxylase
What are the enzymes involved in the synthesis of aldosterone from progesterone? (in order!)
[1] 21 alpha-hydroxylase
[2] 11 beta-hydroxylase
[3] aldosterone synthase
- this is made up of 2 enzymes
What are the metabolic functions of glucocorticoids?
[1] CARBOHYDRATE METABOLISM
- stimulates hepatic gluconeogenesis
- increases deposition of glycogen in the liver
- antagonizes the peripheral action of insulin on glucose uptake
[2] PROTEIN METABOLISM
- inhibits amino acid uptake and protein synthesis in extrahepatic tissues
- potent protein catabolic agent in peripheral tissues such as muscle, skin and bone
- stimulates amino acid uptake of the liver which are gluconeogenesis precursors
[3] FAT METABOLISM
- increases mobilisation of fatty acids
- stimulates the lipolysis in adipose tissue
- increases the deposition of fat in facial and truncal areas
What is the primary function of mineralocorticoids?
mineral and fluid balance
What is the primary function of gonadal steroids?
reproductive functions
What are some other roles that steroid hormones play a role in?
- carbohydrate regulation (glucocorticoids)
- mineral and fluid balance (mineralocorticoids)
- reproductive functions (gonodal steroids)
- inflammation
- stress responses
- bone metabolism
- cardiovascular function
- behaviour and mood
What is mineralocorticoids and what is it secreted in response to?
[1] Increase ECF
[2] High K+ Concentration
What is the actions of mineralocorticoids?
[1] stimulates transcription of the sodium-potassium ATPase
[2] increased numbers of sodium pumps in the basolateral membranes of tubular epithelial cells
[3] facilitates uptake of sodium (and with it, water) from the tubular lumen
[4] reabsorbs sodium in the kidney at the expense of potassium and H+ !!
What are the 4 main types of Congenital Adrenal Hyperplasia (CAH)?
[1] 3beta-Dehydrogenase Deficiency
[2] 17-alpha-Hydroxylase
[3] 21-Hydroxylase Deficiency
[4] 11beta-Hydroxylase Deficiency
When there is a deficiency of the 3beta-OH Dehydrogenase enzyme what happens?
- no glucocorticoids
- no mineralocorticoids
- no active androgens
- salt excretion in urine
- patients have female-like genitalia
- autosomal recessive with incidence (1:10 000)
When there is a deficiency of the 17-alpha-hydroxylase (CYP17) enzyme what happens?
- no androgens or cortisol
- increase in aldosterone (causes sodium and fluid retention and therefore, hypertension)
- patients have female-like genitalia
When there is a deficiency of the 21 alpha-hydroxylase enzyme what happens?
most common!
- no cortisol
- no aldosterone
- increase in androgen (leads to masculinization of external genitalis in females and early virilization in males)
- there are partially and virtually complete deficiencies are known
- mineralocorticoids and glucocorticoids are virtually absent (salt-wasting form) or completely deficient (non-classical form)
What is the most common type of Congenital Adrenal Hyperplasia (CAH)?
Deficiency in 21 alpha-hydroxylase
When there is a deficiency of the 11-beta-hydroxylase (CYP11B1) enzyme what happens?
- no cortisol
- no aldosterone
- overproduction of deoxycorticosterone (causes fluid retention due to its ability to supress the renin/angiotensin system – hypertension)
- overproduction of androgens (leads to masculinization of external genitalis in females and early virilization in males)
Cortisol deficiency leads to….?
- poor response to stress (both emotional and physical)
- hypoglycaemia
- hyperpigmentation (cortisol can directly affect the activity of melanin producing cells)
Aldosterone deficiency leads to….?
- hyperkalemia
- hyponatremia
- disturbs cardiac rhythm
- hypotension
A combined deficiency of both cortisol and aldosterone can lead to?
Vascular Collapse, Shock and Death
What is the treatment for CAH?
[1] daily glucocorticoid and mineralocorticoid replacement
[2] restore volume, electrolyte and glucose imbalances
- large volumes of 0.9% saline or 5% dextrose in saline
