Lecture 9: Steroid Biosynthesis Flashcards
Where does steroid hormone synthesis occur?
Adrenal Cortex
What are the classic and non-classic forms of Adrenal Hyperplasia caused by?
Deficiencies in the adrenal enzymes that are used to synthesize glucocorticoids
Women with mild congenital adrenal hyperplasia often present with?
- Hirsutism
- Excessive body hair in men and women on parts of the body where hair is normally absent or minimal, such as on the chin or chest in particular
Other than Hirsutism what else do female patients with Adrenal Hyperplasia present with?
General oligomenorrhea = infrequent (or, in occasional usage, very light) menstruation
- Menstrual periods occuring at intervals of >35 days
- Infertility
How is it determined if a fetus is at risk for congenital adreanl hyperplasia?
- Using human leukocyte antigen halotype
- Demonstration of excess cortisol precursors in amniotic fluid
What is the treatment for Adrenal Hyperplasia?
Carefully monitored hormone replacement therapy (HRT)
What occurs in 21-hydroxylase deficiency?
- Accumulation of progesterone and 17-hydroxyprogesterone
- Results in shunting of substrates to the pathway for the production of testosterone
What accumulates as a result of 11-β hydroxylase deficiency?
- Accumulation of Deoxycorticosterone and 11-Deoxycortisol
- Both of which have MR activity
The production of aldosterone from corticosterone occurs in which part of the adrenal cortex?
Zone Glomerulosa
Aldosterone is a mineralcorticoid that binds what; and regulates?
- Binds mineralocorticoid receptor
- Promotes the retention of Na+ and H2O in the kidneys, as well as excretion of H+ and K+
Increased levels of aldosterone are seen in what pathology; what dpo these patients experience?
Conn syndrome = increased blood volume and hypertension
An 11-β-hydroxylase deficiency leads to what?
- Decrease in serum cortisol, aldosterone, and corticosterone
- Increased production of 11-deoxycorticosterone causes fluid retention because this hormone suppresses the renin/angiotensin system, it causes low-renin hypertension
- Overproduction of androgens causes masculinization and virilization as with 21-α-hydroxylase deficiency
Which substrate that buildsup from 11-β-hydroxylase deficiency has the greatest MR affinity?
11-deoxycorticosterone
Which molecule signals and stimulates production of steroid hormones from cholesterol; what is the first step in this pathway?
- ACTH signals and regulates Desmolase activity
- Desmolase is the enzyme that produces pregnenolone from cholesterol
What happens when cortisol levels are low; describe the pathway?
- Signals to the hypothalamus to produce CRH
- CRH stimulates the anterior pituitary gland to produce ACTH (polypeptide tropic hormone - 39 AA’s long)
- ACTH stimulates the production of cortisol
What type of receptors does ACTH bind and where does the production of glucocorticoids occur?
- Binds a GPCR located on adrenocortical cells of the adrenal cortex
- Zone Fasciculata
What is the significance of a tumor cell in terms of its ACTH activity?
- Does not require ACTH as a signal
- Uncoupling occurs and PKA is stuck in active state
- Leads to cell proliferation and increased cortisol production
What are the short-term mechanisms of ACTH binding its receptor in the adrenal cortex?
- Stimualtion of cholesterol delivery to the mitochrondria where the P450scc enzyme is located
- P450scc catalyzed the first step of steroidogenesis that is cleavage of the side-chain of cholesterol
What are the long-term actions of ACTH binding its receptor on the adrenal cortex?
- Stimulation of the transcription of the genes coding for steroidogenic enzymes (feed-forward loop):
- P450scc
- Steroid 11-β-Hydroxylase
- Associated electron transfer proteins
What is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens (sex hormones)?
17, 20-lyase = CYP17A1
What do mutations of 17, 20-lyase (CYP17A1) lead to?
- Pseudohermaphroditism
- Adrenal Hyperplasia
What 2 ways is cholecalciferol (D3) obtained?
1) Via the diet-Ergocalcifrol (Vitamin D2) is absorbed in the intestine
2) Converted from 7-dehydrocholesterol in the skin via UV radiation
What is found exclusively in the liver pertaining to vitamin D and what does it do?
- 25-hydroxylase (CYP2R1) only found in LIVER
- Converts Cholecalciferol (D3) to 25-hydroxycholecalciferol
