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Molecular and Cellular Princples of Medicine > Unit 6 - Steroid Hormones and Vitamin D > Flashcards

Unit 6 - Steroid Hormones and Vitamin D Flashcards

1
Q

what is the precursor and the 3 classes of steroid hormones?

A

cholesterol is precursor of…

  1. glucocorticoids (like cortisol)
  2. mineralcorticoids (like aldosterone)
  3. sex hormones (like androgens)
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2
Q

where does synthesis and secretion of steroid hormones occur? what do they make?

A
  1. adrenal cortex: cortisol (glucocorticoid), aldosterone (mineralcorticoid), androgens
  2. ovaries/placenta: estrogens, progestins
  3. testes: testosterone
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3
Q

how do steroid hormones travel in blood?

A

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
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4
Q

what is the rate limiting step of steroid synthesis? what is the enzyme? what does it need?

A

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

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5
Q

where does cholesterol move during synthesis?

A

starts within the cell, then moves to OMM, then IMM via StAR (steroidogenic acute regulatory protein)

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6
Q

what is 3-beta-hydroxysteroid dehydrogenase deficiency?

A

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
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7
Q

what is 17-alpha-hydroxylase deficiency?

A

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
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8
Q

what is 21-alpha-hydroxylase deficiency?

A

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
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9
Q

what is 11-beta1-hydroxylase deficiency?

A

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)
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10
Q

where is cortisol produced? what is it controlled by? what does it do?

A

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
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11
Q

what is the mechanism of cortisol secretion?

A
  1. stress triggers corticotropin releasing hormone (CRH) from hypothalamus
  2. CRH travels thru capillaries to anterior lobe of pituitary
  3. CRH induces production and secretion of adrenocorticotropic hormone (ACTH; “stress hormone” polypeptide)
  4. ACTH causes adrenal cortex to synthesize and secrete glucocorticoid cortisol
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12
Q

how are CRH, ACTH, and cortisol related?

A

CRH –> ACTH –> cortisol

as [cortisol] rises, CRH and ACTH are inhibited

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13
Q

how does ACTH cause cortisol release?

A
  1. ACTH binds to GPCR –> increased cAMP –> activated PKA
  2. PKA phosphorylates and activates lipase (converts cholesterol ester to cholesterol) and StAR PRO (cholesterol moves to IMM)
  3. In IMM, cholesterol converted to pregnenolone
  4. pregnenolone returns to cytosol to become progesterone
  5. CYP17 and CYP21 in ER membrane hydroxylate progesterone into 11-deoxycortisol
  6. 11-deoxycortisol returns to IMM where CYP11B1 catalyzes beta-hydroxylation at C21 to make cortisol to ext the cell
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14
Q

where is aldosterone produced? what is it controlled by? what does it do?

A

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
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15
Q

what is the RAS system?

A
  1. angiotensinogen (liver) cleaved by renin (kidneys) in blood
  2. angiotensin I (in blood) converted to angiotensin II by ACE (lungs)
  3. angiotensin II stimulates aldosterone secretion from adrenal cortex
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16
Q

what are ACE inhibitors used for?

A

to decrease HTN b/c will stop the RAS system

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17
Q

where are androgens produced?

A

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

18
Q

what do the different layers of adrenal cortex make?

  • inner
  • middle
  • outer
A

reticularis: androgens
fasciculata: androgens, cortisol
glomerulosa: aldosterone

19
Q

what do testes and ovaries make? what are their effects?

A

make hormones for sexual differentiation and reproduction

  1. hypothalamic releasing factor gonadotropin-releasing hormone (GRH) stimulates anterior pituitary to release LH and FSH glycoproteins
  2. LH/FSH bind to GPCR to increase cAMP and stimulate PKA
  3. LH stimulate testes to make testosterone, and ovaries to make estrogens and progesterone (more hormones)
  4. FSH regulates growth of ovarian follicles and stimulates spermatogenesis in testes
20
Q

how are estrogens made? inhibited?

A

produced from androstenedione, then testosterone by aromatase
-aromatase inhibitors are used as treatment for hormone positive (estrogen responsive) breast cancer in post menopausal women

21
Q

how do steroid hormones act on a molecular level?

A
  1. diffuse thru plasma membrane to target cells
  2. 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)
  3. 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
  4. 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
  5. superfamily of structurally related receptors binds the steroid hormones, thyroid hormone, retinoic acid, and vit D to function in similar fashion
22
Q

how are steroid hormones metabolized and excreted?

  • where?
  • do they need PRO carriers?
A
  1. 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
  2. 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
23
Q

what is the active vit D form? how does it interact? what are its most important functions?

A

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
24
Q

what is the endogenous source of vit D? where does it go once made?

A

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
25
Q

what is the exogenous source of vit D?

A

from diet; ergocalciferol (D2; plants) and cholecalciferol (D3; animals and preformed vitamins)
-dietary vit D packaged in chylomicrons

26
Q

how to convert inactive vit D to active vit D

A
  1. liver 25-hydroxylase makes 25-hydroxycholecalficerol (calcidiol)
    - major form of vit D in plasma, major storage form, and what is measured in labs
  2. kidney 1-hydroxylase makes calcitriol
    - calcitriol negatively inhibits 1-hydroxylase

both enzymes are cytochrome P450 PRO

27
Q

how is 1-hydroxylase regulated?

A

increased by low plasma P and low plasma Ca++, PTH (from low Ca)

decreased by calcitriol (negative feedback loop)

28
Q

what does hypocalcemia do to calcitriol levels?

A

insufficient dietary Ca causes elevated calcitriol levels

29
Q

how does low plasma calcium right itself?

A
  • increases PTH, Ca++ mobilization from bone, renal reabsorption of Ca
  • decreases renal excretion of Ca++
  • PTH increases calcitriol production, which also increases mobilization from bone, renal absorption, and absorption from intestine
  • this will all icnrease plasma calcium levels
30
Q

how does vitamin D-receptor interaction for intestinal Ca absorption occur? what regions of DNA are utilized?

A
  1. calcitriol enters enterocyte and binds to ligand binding domain in vit D receptor (VDR) in cytoplasm of intestinal cell
  2. ligand-VDR compelx enters nucleus, forms heterodimer with retinoid-X-receptor (RXR) to bind various coactivator PRO
  3. VDR and coactivators in the large mediator complex recognize specific DNA sequence (vit D response element VDRE) in promotor/regulatory element of genes it will regulate
    - VDRE is made of 2 hexameric nucleotide half-sites separated by 3 base pairs
    - half-sites accommodate binding of VDR-RXR heterodimer
  4. ligand-VDR heterodimer enhances or diminishes cell type specific transcripts influencing specific PRO
31
Q

what is calbindin-D9K?

A

ehnaced PRO in enterocytes (member of S100 family of Ca binding proteins)
-mediates transport of Ca across enterocytes from apical side

32
Q

what is TRPV5?

A

calcium transport protein in enterocytes

  • allows entry of Ca into epithelial cell
  • rate-limiting for Ca++ absorption in intestine
  • presence of calbindin increases amount of Ca++ crossing the cell without raising free concentration (so can still increase Ca++ absorption)
33
Q

what happens if low serum calcium?

A

serum calcium is increased by bone demineralization (PTH, calcidiol) and increased dietary absorption (calcidiol)
-serum Ca++ and D3 from liver act on kidney to decrease Ca++ in urine (PTH) and increase calcitriol production (PTH)

34
Q

what happens if high serum Ca?

A

decreased dietary absorption, and increased bone mineralization (inhibited slightly by calcitonin)

  • increased Ca++ acts on kidney to increase Ca++ excretion (calcitonin)
  • blocks production of PTH, which converts 25-OH-D3 to 24,25-diOH-D3
35
Q

what happens if low vit D?

A

demineralization of bone (PTH), but NO increased dietary Ca absorption
-kidney does inhibit Ca++ excretion in urine (PTH)

36
Q

what are the 4 levels of vit D “intakes”? (in nmol/L VS ng/mL)

A

50 (>20): adequate for health

>125 (>50): potential adverse effects

37
Q

what is the major form of vit D measured?

A

25-OH-D3

-measured clinically to determine vit D levels

38
Q

what is rickets characterized?

A

formation of collagen matrix, but insufficient mineralization so soft and pliable

39
Q

what is osteomalacia characterized by?

A

demineralization of existing bones makes more susceptible to fracture

40
Q

what is renal osteodystrophy? how is it treated?

A

chronic kidney disease causes decreased synthesis of active vit D and increased phosphate retention, causing hypocalcemia and hyperphosphatemia

  • low blood Ca increases PTH and bone demineralization
  • treat with calcitriol supplementation and decreasing phosphate
41
Q

what is hyperthyroidism? how is it treated?

A

lack of PTH causes hypocalcemia and hyperphosphatemia

-can be treated with Ca and calcitirol

42
Q

vit D toxicity

-what’s the UL?

A

if excessive supplements of >100,000 IU over weeks/months, will have loss of appetite, nausea, thirst, and stupor

  • enhanced Ca++ absorption and bone resorption causes hypercalcemia that deposits in many organs, especially arteries and kidneys
  • UL is 4000 IU/day for 9 years and older (and lower levels for younger kids)

Molecular and Cellular Princples of Medicine (42 decks)

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