Unit 6 - Steroid Hormones and Vitamin D Flashcards
what is the precursor and the 3 classes of steroid hormones?
cholesterol is precursor of…
- glucocorticoids (like cortisol)
- mineralcorticoids (like aldosterone)
- sex hormones (like androgens)
where does synthesis and secretion of steroid hormones occur? what do they make?
- adrenal cortex: cortisol (glucocorticoid), aldosterone (mineralcorticoid), androgens
- ovaries/placenta: estrogens, progestins
- testes: testosterone
how do steroid hormones travel in blood?
from point of synthesis to target
- nonspecific (albumin) is less often than specific (transcortin for cortisol) carrier PRO
- once they reach the target, the hormone enters thru membrane to bind receptor in cytoplasm or nucleus
- receptor binds both steroid hormone and specific DNA hormone response elements and (once homodimerized), causes altered transcription
what is the rate limiting step of steroid synthesis? what is the enzyme? what does it need?
conversion of cholesterol to 21C pregnenolone via cholesterol side-chain cleavage enzyme (desmolase, P450 SCC)
-P450 = CYP is a mixed function oxidase on IMM that needs NADPH
where does cholesterol move during synthesis?
starts within the cell, then moves to OMM, then IMM via StAR (steroidogenic acute regulatory protein)
what is 3-beta-hydroxysteroid dehydrogenase deficiency?
a congenital adrenal hyperplasia
- no pregnenolone to progesterone
- virtually no glucocorticoids, mineralcorticoids, active androgens, or estrogens
- salt excretion in urine (b/c no aldosterone)
- female like genitalia
- autosomal recessive with with incidence of 1:10,000
- absolutely no steroid hormones
what is 17-alpha-hydroxylase deficiency?
a congenital adrenal hyperplasia
- defect in CYP17; no progesterone to 17-alpha-hydroxyprogesterone
- virtually no sex hormones or cortisol
- increased production of mineralcorticoids causing Na+ and fluid retention and no HTN
- female-like genitalia
- still have aldosterone
what is 21-alpha-hydroxylase deficiency?
a congenital adrenal hyperplasia (most common form >90%)
- no progesterone to (11-deoxycorticosterone to aldosterone) or 17-alpha-hydroxyprogesterone (to 11-deoxycortisol to cortisol)
- partially (salt wasting) and virtually (nonclassic) complete deficiencies known
- overproduction of androgens causing masculinity of external genitalia in females and early virilization in males
what is 11-beta1-hydroxylase deficiency?
a congenital adrenal hyperplasia
- no 11-deoxycorticosterone to aldosterone or 11-deoxycortisol to cortisol
- -decrease in aldosterone and cortisol
- increased production of deoxycorticosterone causes fluid retention (b/c hormone represses RAS and causes low renin HTN)
- overproduction of androgens causes masculinization and virilization (like 21-alpha-hydroxylase deficiency)
where is cortisol produced? what is it controlled by? what does it do?
made in middle layer of adrenal cortex (zona fasciculata)
- production and secretion is controlled by hypothalamus attached to pituitary gland (CRH –> ACTH –> cortisol)
- helps body respond to stress thru effects on metabolism (increase gluconeogenesis) and inflammatory and immune responses
what is the mechanism of cortisol secretion?
- stress triggers corticotropin releasing hormone (CRH) from hypothalamus
- CRH travels thru capillaries to anterior lobe of pituitary
- CRH induces production and secretion of adrenocorticotropic hormone (ACTH; “stress hormone” polypeptide)
- ACTH causes adrenal cortex to synthesize and secrete glucocorticoid cortisol
how are CRH, ACTH, and cortisol related?
CRH –> ACTH –> cortisol
as [cortisol] rises, CRH and ACTH are inhibited
how does ACTH cause cortisol release?
- ACTH binds to GPCR –> increased cAMP –> activated PKA
- PKA phosphorylates and activates lipase (converts cholesterol ester to cholesterol) and StAR PRO (cholesterol moves to IMM)
- In IMM, cholesterol converted to pregnenolone
- pregnenolone returns to cytosol to become progesterone
- CYP17 and CYP21 in ER membrane hydroxylate progesterone into 11-deoxycortisol
- 11-deoxycortisol returns to IMM where CYP11B1 catalyzes beta-hydroxylation at C21 to make cortisol to ext the cell
where is aldosterone produced? what is it controlled by? what does it do?
made in outer layer of adrenal cortex (zona glomerulosa)
- stimulated by angiotensin II and decreases in plasma Na+/K+ ratio
- acts on kidney tubules to enhance Na+ and water uptake, and K+ efflux
- increases BP
what is the RAS system?
- angiotensinogen (liver) cleaved by renin (kidneys) in blood
- angiotensin I (in blood) converted to angiotensin II by ACE (lungs)
- angiotensin II stimulates aldosterone secretion from adrenal cortex
what are ACE inhibitors used for?
to decrease HTN b/c will stop the RAS system
where are androgens produced?
made by inner and middle layers of adrenal cortex (zona reticularis and fasciculata)
-adrenal androgens androsterone and androstenedione converted to testosterone and estrogen in peripheral tissues
what do the different layers of adrenal cortex make?
- inner
- middle
- outer
reticularis: androgens
fasciculata: androgens, cortisol
glomerulosa: aldosterone
what do testes and ovaries make? what are their effects?
make hormones for sexual differentiation and reproduction
- hypothalamic releasing factor gonadotropin-releasing hormone (GRH) stimulates anterior pituitary to release LH and FSH glycoproteins
- LH/FSH bind to GPCR to increase cAMP and stimulate PKA
- LH stimulate testes to make testosterone, and ovaries to make estrogens and progesterone (more hormones)
- FSH regulates growth of ovarian follicles and stimulates spermatogenesis in testes
how are estrogens made? inhibited?
produced from androstenedione, then testosterone by aromatase
-aromatase inhibitors are used as treatment for hormone positive (estrogen responsive) breast cancer in post menopausal women
how do steroid hormones act on a molecular level?
- diffuse thru plasma membrane to target cells
- bind to specific cytoplasmic or nuclear receptor
- if not already in nucleus, ligand-receptor complex will enter
- once in nucleus, will dimerize and, with coactivator PRO, bind to specific regulatory sequence HRE (hormone response element) - HRE in promotor or enhancer element for genes responsive to specific steroid hormone to ensire coordinated regulation of genes
- with coactivator PRO, mRNA transcription is increased for these specific genes - binding of ligand to receptor causes conformational change in receptor to expose DNA binding domain, which associates with DNA via zinc-finger motif in receptor
- superfamily of structurally related receptors binds the steroid hormones, thyroid hormone, retinoic acid, and vit D to function in similar fashion
how are steroid hormones metabolized and excreted?
- where?
- do they need PRO carriers?
- converted into inactive excretion products in liver
- reduction of unsaturated bonds, introduction of additional hydroxyl groups
- conjugation with glucuronic acid ro sulfate (from 3’-phospho-adenosyl-5’-phosphosulfate) makes excretion products water soluble - 20-30% of metabolites are secreted into bile and excreted in feces
- the rest are released into blood and filtered in kidney to go to urine
- since excretion products are water soluble, don’t need PRO carriers
what is the active vit D form? how does it interact? what are its most important functions?
most active is 1,25-dihydroxycholecalciferol (calcitriol) that binds to receptor PRO within cell
- ligand receptor complex interacts with DNA in manner similar to steroid hormones, and enhances/represses transcription of coordinated set of genes
- most important function is to regulate plasma levels of Ca and P
what is the endogenous source of vit D? where does it go once made?
7-dehydrocholesterol is intermediate in cholesterol biosynthesis
- converted to cholecalciferol in dermis/epidermis via UVs
- cholecalciferol is transported to liver while bound to vit D binding PRO
