Steroid Biosynthesis (Staudinger) Flashcards
What are some of the main biochemical pathways are centered around cholesterol ?
- steroid hormone biosynthesis
- steroid degradation
- primary bile acid biosynthesis
- vitamin D3 synthesis (from 7-dehydrocholesterol)
Where are steroid hormones synthesized?
adrenal cortex
What enzymes synthesizes pregneolone from cholesterol and how is it regulated?
- desmolase: enzyme that produces pregneolone from cholesterol
- regulation of desmolase: adrenocorticotropic hormone (ACTH), a hormonal signaling molecule that stimulates the prod of pregnenolone from cholesterol
(also called: P450scc, cholesterol desmolase, 20,22-desmolase)
What is the precursor molecule for corticosteroids and sex hormones?
progesterone
- enzyme found in all steroid producing tissue (adrenal, testes, ovary, and placenta)
- catalyzes the 1st and rate limiting step: cholesterol > pregnenolone
- regulated by ACTH
desmolase
(aka cytochrome P450(scc) or CYP11A1)
What is the biochemical intermediate for steroid hormone production and what hormones are produced from this intermediate?
- pregnenolone
- hormones: progesterone, aldosterone, cortisol, testosterone, estradiol
What is the pathway for aldosterone production?
(prod in zona glomerulose)
cholesterol
↓
(desmolase, (+) by ACTH)
↓
pregnenolone
↓
(3-beta-hydroxysteroid dehydrogenase)
↓
progesterone
↓
(21-alpha-hydroxylase)
↓
11-deoxycorticosterone
↓
(11-beta-hydroxylase, Addison’s dz)
↓
corticosterone
↓
(18-hydroxylase, (+) angiotensin II)
↓
aldosterone
What is the pathway for cortisol production?
(prod in the zona fasciculata)
cholesterol
↓
(desmolase, (+) by ACTH)
↓
pregnenolone
↓
(3-beta-hydroxysteroid dehydrogenase)
↓
progesterone
↓
(17-alpha-hydroxylase, Addison’s dz)
↓
17-alpha-hydroxyprogesterone
(pregnenolone can also be > 17-alpha-hydroxypregnenolone by 17-alpha-hydroxylase, then > 17-alpha-hydroxyprogesterone by 3-beta-hydroxysteroid dehydrogenase)
↓
(21-alpha-hydroxylase, Addison’s dz)
↓
11-deoxycortisol
↓
(11-beta-hydroxylase, Addison’s dz)
↓
cortisol
What is the pathway for sex hormone production?
(prod in the zona reticularis)
cholesterol
↓
(desmolase, (+) by ACTH)
↓
pregnenolone
↓
(17-alpha-hydroxylase, Addison’s dz)
↓
17-alpha-hydroxypregnenolone
↓
(17,20-lyase)
↓
dehydroepiandrosterone (DHEA)
↓
(3-beta-hydroxysteroid dehydrogenase)
↓
androstenedione
(17-alpha-hydroxypregnenolone can also be converted by 3-beta-hydroxysteroid dehydrogenase to 17-alpha-hydroxyprogesterone > androstenedione by 17,20-lyase)
↓
(17-beta-hydroxysteroid dehydrogenase)
↓
testosterone
↓
aromatase enzyme prod estradiol and 5-alpha-reductase enzyme prod dihydrotestosterone
(androstenedione can also be converted to estrone by aromatase)
How does aldosterone produce hormonal effects and what receptor does it target?
- aldosterone is produced in a tissue-specific manner
- binds and activates mineralocorticoid receptor (MR): important nuclear receptor superfamily member
What hormones utilize nuclear receptors for hormonal signaling?
- dihydrotestosterone
- estradiol
- thyroid hormone
- trans-retinoic acid
- 9-cis retinoic acid
- vitamin D
- cortisol
- aldosterone
- progesterone
What steroids activate MR receptor (which is most efficacious) and what common effect does this have on the body?
- aldosterone (highest efficacy)
- 11-deoxycorticosterone (very high efficacy)
- testosterone
- hydrocortisone (cortisol)
- cortisone
- all of these hormones increase Na+ retention > hypertension
- excessive secretion/levels of the hormone aldosterone prod by adrenal glands
- leads to loss of potassium and retention of sodium
- causes body to hold onto too much water, increase blood volume, and increase blood pressure (hypertension)
(in nml situation, aldosterone balances sodium and potassium in the blood)
Conn syndrome
(primary aldosteronism)
- both forms (classic and non-classic) of this condition are caused by deficiencies in adrenal enzymes that are used to synthesize glucocorticoids
- affects from 1:100-1:1000 persons in US, frequently eludes dx
- condition was previously that to be a rare inherited disorder w/ severe manifestations, however it is now known that mild form of condition is common
- causes: increased production from adrenal gland of cortisol precursors and androgens
- sx: life-threatening sinus/pulmonary infections, orthostatic syncope, shortened stature, severe acne, hirsutism (women), oligomenorrhea (women), and infertility (women)
- dx: in utero can determine using HLA haplotype and demonstration of excess cortisol precursors in amniotic fluid
- tx: hormone replacement therapy, recognition of the problem, timely replacement therapy (tx reduces morbidity and enhances quality of life)
adrenal hyperplasia
What enzyme mutations can lead to adrenal hyperplasia?
- 21-hydroxylase
- 11-β hydroxylase
What products will a mutation of 21-hydroxylase enzyme cause an accumulation and decrease in?
- accumulation: progesterone and 17-hydroxyprogesterone
- decrease: downstream products (aldosterone and cortisol)
What products will a mutation of 11-β hydroxylase enzyme cause an accumulation and decrease in?
- accumulation: 11-deoxycorticosterone and 11-deoxycortisol
- decrease: downstream products (aldosterone and cortisol)
How does 11-β hydroxylase deficiency lead to decreased aldosterone synthesis, yet it still produces hypertension?
- hydrocortisone (cortisol) and cortisone synthesis decreases b/c their synthesis is dependent on 11-β hydroxylase (aldosterone is also decreased b/c cortisone is a precursor for this hormone)
- however, 11-deoxycorticosterone and 11-deoxycortisol levels increase
- 11-deoxycorticosterone > relatively high affinity/efficacy for MR = produces hypertension
- decrease in serum cortisol, aldosterone, and corticosterone
- increased prod of deoxycorticosterone causes fluid retention; b/c this hormone suppresses the renin/angiotensin system, it causes low-renin hypertension
- overproduction of androgens causes masculinization and virilization as w/ 21-alpha-hydroxylase deficiency
11-β hydroxylase deficiency
Describe the feedback regulation of the hypothalamic-pituitary axis:
low levels of cortisol stimulate hypothalamus to produce corticotropin releasing hormone (CRH)
>
CRH acts on pituitary gland to produce adrenocorticotropic hormone (ACTH)
>
ACTH acts on adrenal glands to increase production of cortisol
>
high levels of cortisol provide negative feedback to hypothalamus to reduce CRH production and anterior pituitary to reduce ACTH production
What is the mechanism of action of ACTH?
- ACTH acts by binding to cell surface ACTH receptors within the zona fasciculata
- ACTH receptor: 7-membrane-spanning G-protein-coupled receptor (GPCR), located primary on adrenocortical cells of adrenal cortex
- receptor undergoes conformation changes
- stimulates the enzyme adenylyl cyclase (AC)
- leads to an increase in intracellular cyclic AMP (cAMP)
- activates protein kinase A (PKA) which causes cell proliferation and cortisol production
(in tumor cells, the activity of PKA is uncoupled from the GPCR, meaning cell proliferation and cortisol production continue unregulated)
What production of hormones does a CYP17A1 deficiency (17,20-lyase) cause accumulation and decrease in?
(isolated 17,20-lyase deficiency is rare condition causing deficient prod of androgens resulting in 46,XY disorders of sex development; prod of glucocorticoids is intact; several missense mutations in CYP17A1 gene are known to cause condition)
- accumulation: 17-α-hydroxypregnenolone and 17-α-hydroxyprogesterone > favors shift to cortisol production (glucocorticoids) and corticosterone > aldosterone production (mineralcorticoids)
- decrease: downstream sex hormone products (androstenedione, testosterone, estradiol, dihydrotestosterone, estrone)
Where is vitamin D absorbed and what are the specific enzymes/products a/w vitamin D in the liver and kidneys?
- absorbed in the skin and intestines
- liver: cholecalciferol (vit D3) > (25-hydroxylase, liver specific enzyme) > 25-hydroxycholecalciferol (found exclusively in the liver)
- kidneys: 25-hydroxycholecalciferol > (1-α-hydroxylase, (+) by PTH, low phosphate; (-) by calcitriol) > 1,25-dihydroxycholecalciferol
What is the role of tissues in vitamin D production?
- whether ingested or cutaneously synthesized, vit D is initially inert in the form of D2 or D3
- D3 is converted to its protein-bound circulating form in the liver > 25-hydroxy vitamin D
- 25-hydroxy vitamin D: transported to kidney, where under direction of circulating PTH, is converted by 1-α-hydroxylase to its active form 1,25-dihydroxy vitamin D (calcitriol)
