Steroid Hormones and Vitamin D Flashcards
1
Q
basics
A
- cholesterol is the precursor to all classes of steroid hormones:
1. glucocorticoids
2. mineralcorticoids
3. sex hormones - synthesis and secretion occurs in many organs
1. adrenal cortex-cortisol, aldosterone, androgens
2. ovaries and placenta
3. testes - travel in the blood from point of syn to target using nonspecific and specific carrier proteins
- once reaching target, enters through PM and binds receptor in cytosol or nucleus
- receptor binds the hormone and DNA- results in altered transcription
2
Q
synthesis of steroid hormones
A
- shortening of hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus
- rate limiting step is first one- cholesterol to 21C pregnenolone
- catalyzed by cholesterol side chain cleavage enzyme
- cytochrome p450 mixed function oxidase locatd on the inner mitochondrial membrane, requires NADPH and oxygen
- cholesterol in the cell moves to the mito outer membrane and then inner, this is mediated by StAR
3
Q
congenital adrenal hyperplasias
A
- pregnenolone is precursor for all steroid hormones
- oxidized and isomerized to progesterone
- then further modified by hydroxylation reactions in mito and ER
- primarily cyto p450 proteins
- defect in any steps can cause several diminished products at later steps and build up of substrates
4
Q
3-B-hydroxysteroid dehydrogenase deficiency
A
- progenolone to progesterone
- no glucocorticoids, mineralocorticoids, active androgens or estrogens
- salt excretion in urine
- female like genitalia
- AR with incidence of 1/10,000
5
Q
17-a-hydroxylase deficiency
A
- progesterone to 17-a-hydroxyprogesterone
- no sex hormones or cortisol
- increased production of mineralcorticoids, causing sodium and fluid retention and hypertension
- female like genitalia
6
Q
21-a-hydroxylase deficiency
A
-progesterone to 11-deoxycorticosterone
-also 17-a-hydroxyprogesterone to 11-deoxycortisol
-most common form of CAH
-partial and complete deficiencies known
-mineralcorticoids and glucocorticoids absent in salt wasting classic form or deficient in non-classic form
-overproduction of androgens, leading to masculinization of external genitalia in females and early virilization in males
Hypotension
7
Q
11-B1-hydroxylase deficiency
A
- 11-deoxycorticosterone and 11-deoxycortisol to aldosterone and cortisol
- decrease in serum cortisol, aldosterone, corticosterone
- increased production of deoxycorticosterone causes fluid retention because the hormone suppresses renin-low renin HTN
- overproduction of agdrogens-masculinization and early virulization
8
Q
secretion of adrenal cortical steroid hormones
A
- hormones secreted from their tissue of origin in response to hormonal signals
- corticosteroids and androgens are produced in different parts of adrenal cortex
9
Q
cortisol
A
- produced in zona fasciculata of the adrenal cortex
- its production and secretion is controlled by hypothal
- stress–>corticotropin releasing hormone–>anterior lobe pit (thru caps)–>induces production and secretion of ACTH–>adrenal cortex synthesizes and secretes cortisol–>stimulates gluconeo and IF and immune responses
- neg feedback from cortisol
10
Q
role of ACTH
A
- binds to Gs-increase cAMP and PKA
- activates lipase that converts CE to chol and StAR, so chol moves to inner mito membrane
- converted to pregnenolone
- pregnenolone returned to cytosol
- converted to progesterone
- two ER membrane located hydroxylation steps catalyzed by CYP17 and 21- progesterone to 11-deoxycortisol
- returned to inner mito membrane- CYP11B1 catalyzes B hydroxylation at C21, yields cortisol which can exit cell
11
Q
functions of aldosterone
A
- produced in outer layer of adrenal cortex-zona glomerulosa
- stimulated by a decrease in plasma Na/K ratio and by angiotensin II
- angiotensin II binds to G protein and activates PIP2 pathway (Gq), IP3, DAG, PKC, calcium
- aldosterones effect on kidney tubules
- enhances Na and water uptake and K efflux
- increases BP
- ACE inhibitors used to treat renin dependent hypertension
12
Q
angiotensin II
A
- peptide hormone (8)
- produced by cleavage of angiotensin I (10) by angiotensin converting enzyme (ACE)
- angiotensin I produced by cleavage of angiotensinogen, inactive precursor secreted by liver
- cleaved by renin-proteolytic enzyme from kidneys
**renin cleaves angiotensinogen to angiotensin I–>ACE cleaves I to II
13
Q
sex hormones
A
- zona reticularis (inner) and middle layers
- adrenal androgens (androsterone and androstenedione) are converted to testosterone and estrogen in peripheral tissues
14
Q
testes/ovaries
A
- synthesize hormones required for sexual differentiation and reproduction
- GRH (hypothal) stimulates ant pit (blood) to release LH and FSH
- LH and FSH binds to Gs
15
Q
LH
A
-testes to produce testosterone and ovaries to produce estrogens and progesterones
16
Q
FSH
A
regulates growth of ovarian follicles and stimulates spermatogenesis
17
Q
estrogens
A
- produced from androstenedione and then testosterone
- via aromatase
- aromatase inhibitors used for hormone positive breast cancer in post menopausal women
18
Q
steroid hormone at molecular level
A
- can cross PM because hydrophobic enough
- bind to cytoplasmic or nuclear receptor
- ligand bound receptor enters nucleus if not already there
- once in nucleus, complex dimerizes and binds to hormone response element on DNA with the help of co-activator proteins
- HRE is in promoter or enhancer for genes responsive to the hormone
- coordinated regulation of genes
- if co-activator is present, mRNA is increased
- can also decrease transcription with help of co-repressors
- binding of ligand causes a change in the conformation of the receptor, and exposes a DNA binding domain
- complex associates with DNA through a zinc finger motif
- super family of receptors binds steroid hormones, thyroid hormone, retinoic acid and vitamin D
19
Q
further metabolism and secretion of steroid hormones
A
- typically converted into inactive excretion products in the liver
- reactions involved include reduction of unsaturated bonds and additional OH groups
- conjugation with glucuronic acid or sulfate makes excretion products more water soluble
- 20-30% of these metabolites are secreted into the bile and excreted in feces
- remainder are released into the blood and filtered in kidneys
- all excretion products are water soluble and don’t need protein carriers
20
Q
vitamin D basics
A
- group of sterols that function like hormones
- active molecule (1,25 diOH-D3, cacitriol) binds to receptor proteins in the cell
- ligand receptor complex interacts with DNA in a manner similar to steroid hormones
- regulates plasma levels of calcium and phosphorous
21
Q
endogenous source of vitamin D
A
- 7-dehydrocholesterol
- intermediate in cholesterol synthesis
- converted to cholecalciferol (D3) in dermis and epidermis when we are exposed to sunlight
- cholecalciferol transported to liver while bound to a vitamin D binding protein
22
Q
exogenous source of vitamin D
A
- erogocalciferol (D2) which is found in plant
- cholecalciferol (D3) in animal tissues
- preformed vitamin D
- dietary vitamin D is packaged into chylomicrons
- supplementation is a dietary requirement in individuals with limited exposure to sunlight
23
Q
inactive to active vitamin D
A
- D2,3 not active on their own
- converted in vivo to 1,25-diOH-d3 by 2 reactions
- first OH added in liver by 25-hydroylase- give 25-hydroxycholecalciferol, (25-OH-D3 or calcidiol)
- major form of vitamin D in plasma and major storage form
- further hydroxylated at 1 position by 25-OH-D3-1 hydroxylase (calcidiol-1-hydroxylase)
- in kidney
- forms 1,25-diOH-D3
- both hydroxylases are cyto p450 proteins
24
Q
regulation of 25-OH-D3-1 hydroxylase
A
- increased directly by low plasma phosphate and indirectly by low plasma calcium
- low calcium–>PTH–>upregulates hydroxylase
- elevated levels of calcitriol inhibits hydroxylase and expression of PTH
25
regulation of plasma calcium levels by calcitriol
-low plasma calcium--> increased PTH-->increased calcitrol-->inc calcium mobilization from bone-->increased renal absorption of calcium-->decreased renal excretion of calcium-->increased absorption from intestine-->increased plasma calcium
26
intestinal calcium absorption
- calcitrol stimulates absorption
- enters cell and binds to vitamin D receptor (VDR) in cytoplasm
- VDR complex enters nucleus, forms heterodimer with retinoid-X receptor (RXR) and binds coactivators
- complex recognizes VDRE in promotor/regulatory element of gene
- can enhance or diminish cell type specific transcripts and influence expression of proteins
27
VDRE
- vitamin d response element in DNA
- two hexameric nucleotide half sites separated by 3 base pairs
- two half sites accommodate VDR-RXR heterodimer
28
calbindin-D9K
- in enterocytes
- mediates transport of calcium across apical side of cell
- TRPV5 allows entry of calcium into epithelial cell
- transport across enterocyte cytoplasm is rate limiting- calbindin increases amount of calcium crossing cell without raising the free concentration
29
vitamin D, calcium, bones
- low calcium increases calcitriol via PTH
- causes increased calcium absorption, decreased excretion, and increased demineralization
- high calcium stops PTH
- decreased PTH leads to more 24,25-diOH-D3 instead of 1,25 (decreased PTH decreases calcitriol)
- causes increase in calcitonin
- stops demineralization and increases excretion
- deficient D means demineralization of bone
- too much vitamin D can also cause demineralization
30
vitamin D requirements
- fatty fish, liver, egg yolkds
- measure calcidiol
- <30 is deficiency-rickets/osteomalacia
- 30-50 adequate
- over 50 to 125 ok
- more than 125 could be detrimental
31
vitamin D deficiency
- rickets
- osteomalacia
- soft and pliable vs hurting ones already formed-fractures
32
renal osteodystrophy
- chronic kidney disease causes decreased synthesis of active vitamin D and increased retention of phophate
- hypocalcemia aid hyperphosphatemia
- low calcium increases PTH and demineralization
- trt is supplement with calcitriol and reduce phosphate
33
hyperthyroidism
- lack of PTH cause hypocalcemia and hyperphosphatemia
| - treated with calcium and calcitriol
34
vitamin D toxicity
- fat soluble-stored and slowly metabolized
- excessive-loss of appetite, nausea, thirst, stupor
- enhanced calcium absorption and bone resorption results in hypercalcemia which leads to deposits in arteries and kidneys
- UL is 4000 IU/day for 9 years and older
* *see slide 9
