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REI Written Boards SKORY > Hormone Biosynthesis > Flashcards

Hormone Biosynthesis Flashcards

1
Q

Rate limiting step in steroidogenesis

A

Transfer of cholesterol from outer mitochondrial membrane to inner

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2
Q

Responsible for cholesterol transport across mitochondrial membrane

A

STAR

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3
Q

Congenital lipoid adrenal hyperplasia (mutation, location, inheritance, functional change)

A

Loss of function mutation in STAR, chromosome 8, AR, limited intracellular transport of cholesterol 000? intracellular lipid accumulation 00> cellular destruction

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4
Q

Locations of steroid synthesis

A

Mitochondrial membrane, cytoplasm, endoplasmic reticulum

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5
Q

Locations of steroid receptor

A

Nucleus, cytoplasm

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6
Q

Mechanism of steroid hormone transport across cell membrane

A

Simple diffusion

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7
Q

Characteristics of steroid hormones

A

Small, non-polar, lipophilic

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8
Q

G-protein receptors

A

cAMP, calcium messenger, protein kinase/MAP kinase

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9
Q

cAMP second messenger hormones

A

FSH, LH, HCG, ACTH, TSH, CRH

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10
Q

Calcium second messenger hormones

A

GnRH, TRH, LH, kisspeptin

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11
Q

Protein kinase/MAP kinase hormone

A

Oxytocin

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12
Q

cAMP receptor function

A

o Hormone binds cell membrane receptor
o Adenylate cyclase activated
o Gα-GTP subunit binds catalytic unit forming active enzyme converting ATP to cAMP
o Forms cAMP-receptor protein complex which activates protein kinase A (PKA)
o Inactive form: tetramer, 2 regulatory subunits and 2 catalytic subunits
o Bound: Catalytic units released, regulatory units form dimer
o Catalytic units phosphorylate serine and threonine residues of cellular proteins (enzymes and mitochondrial, microsomal, and chromatin proteins) (energy-producing)
o Physiologic effect
o Enzyme activity terminated by hydrolysis of GTP to GDP returning the enzyme to its inactive state

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13
Q

Calcium messenger receptor function

A

o Phospholipase C (PLC) catalyzes hydrolysis of polyphosphatidylinositols (IPI2) into two intracellular messengers: IP3 (inositol triphosphate) and DAG (diacylglycerol)
o IP3 binds with a receptor in the smooth ER and mitochondria and opens the Ca2+ channel
o DAG activates protein kinase C
o Calmodulin binding Ca2+ causes a conformational change
o Modifies calcium transport, enzyme activity, calcium regulation of cyclic nucleotide and glycogen metabolism and secretion and cell motility

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14
Q

Single transmembrane domain receptor types

A

Tyrosine kinase, cytokine, serine/threonine kinase

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15
Q

Tyrosine kinase receptor hormones

A

Insulin, IGF, EGF, PDGF, FGF

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16
Q

Cytokine receptor hormones

A

GH, PRL, hPL, leptin

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17
Q

Serine/threonine kinase

A

Activin, inhibin

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18
Q

Tyrosine kinase receptor function

A

o 3 domains: extracellular domain for ligand binding, single transmembrane domain, cytoplasmic domain
o Receptor has 2 alpha and 2 beta subunits (each w/ 3 domains as above) linked by disulfide bridge
o Ligand specificity determined by unique AA sequence that determines 3D conformation
o Ligand binding –> conformational change of cytoplasmic domain –> autophosphorylation

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19
Q

Cytokine receptor second messenger

A

JAK-STAT

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20
Q

Serine/threonine kinase receptor second messenger

A

SMAD4 –> FOXH1

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21
Q

A/B Regulatory Domain

A

 Amino acid terminal
 Most variable in superfamily (i.e. only 18% homology between ERα and ERβ)
 In ER-α contains TAF1 which can stimulate transcription in absence of hormone binding

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22
Q

C DNA Binding Domain

A

 Most homologous
 Hormone binding induces conformational change in the 3 helices allowing binding to HRE (hormone responsive elements) of target genes
 Contains 2 zinc fingers: determine specificity for binding to enhancer site in gene promoter

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23
Q

D HInge REgion

A

Contains nuclear localization signal

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24
Q

E Hormone Binding Domain

A

Harbors TAF2 which requires hormone binding for full activity
Functions:
o Pocket for hormone binding
o Sites for cofactor binding
o Responsible for dimerization
o Harbors TAF-2
o Binding site for HSP (when no hormone bound)

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25
F Carboxy Terminal
no notes
26
TAF1 location/function
(A/B, regulatory domain) can stimulate transcription in the absence of hormone when fused to DNA
27
TAF2 location/function
(E, hormone binding domain) must have hormone binding for full activity
28
TAF3 location/function
(B-upstream segment [BUS]) autonomously activates transcription OR synergizes w/ other TAFs
29
TAFs on ER's
ERα has TAF1 and TAF2 | ERβ only has TAF2
30
TAFs on PR's
PRα has TAF1 and TAF2 | PRβ has TAF1, TAF2, and TAF3
31
Steroid hormones with nuclear receptors
Estrogen, progesterone, androgens, thyroid (alpha-chrom 17, beta-chrom3), retinol, vit D
32
Steroid hormones with cytoplasmic receptors
MIneralocorticoids, glucocorticoids
33
Steroid hormones with receptors in cytoplasm which move to nucleus after hormone binding
Corticosteroid
34
ER receptor expression during menstrual cycle
Peak late proliferative (self induced by E2), declines in early secretory (increased P4), increased in mid- and late-secretory (decreased P4)
35
ER alpha dominant tissues
Uterus, breast, bone, hypothalamus, pituitary, adrenal (E2 and EE most sensitive)
36
ER beta dominant tissues
Granulosa cells, brain, CV system, colon
37
ER alpha and beta tissues
ovary, breast (alpha in dev and fxn, beta as natural suppressor of alpha activity)
38
2 SERMS and MOA
Raloxifene, tamoxifen; competitive inhibitor of estrogen binding to ER
39
Tamoxifen SEs
VTE, vaginal bleeding, endometrial hyperplasia/cancer, hot flashes, cataracts
40
Raloxifene SEs
Hot flashes, vaginal dryness, VTE (less than tamoxifen), decreases LDL, increase HDL, no change in TG
41
Raloxifene location of estrogenic and antiestrogenic effect
Estrogenic effect on bone | Antiestrogenic effects on breast and uterus
42
Tamoxifen location of estrogenic and antiestrogenic effect
Estrogenic: liver (decrease AT3, total chol, LDL, increase binding globulins, stimulates P4-R synthesis), bone, vaginal mucosa, endometrium Antiestrogenic: cystostatic at breast, cytotoxic with breast ca
43
PR-alpha action and TAFs
``` Negative action (inhibits activity of PR-B) TAF1 on reg domain, TAF2 on hormone binding domain ```
44
PR-beta action and TAFs
Positive reg of progesterone response genes | TAF1 on reg domain, TAF2 on hormone binding domain, TAF3 in B-upstream segment (BUS) at 5' terminal
45
PR receptor expression
Induced by E2, inhibited by P4 | Peak late-proliferative phase, nearly undetectable by midpoint of secretory phase
46
First gen progestins
Estranes derived form testosterone | Pregnanes derived from 17-OHP
47
Second gen progestins
Gonanes derived from testosterone
48
Third gen progestins
Gonane (levonorgestrel) derivatives
49
Fourth gen progestins
Non-ethylated estranes
50
Estranes
``` Norethindrone (MIcronor) Niorethindrone acetate (Loestrin) Ethynodiol diacetate (Kelnor) ```
51
Pregnanes
MPA, Megace
52
Gonanes
Levonorgestrel (Seasonale) | Norgestrel (Ovral)
53
Gonane derivatives (3rd gen)
Gestodene Desogestrel (Kariva) Norgestimate (OrthoCyclen) Etenogestrel (NuvaRing, Implanon)
54
Non-ethylated estranes
Drosperinone: progestin analogue of spironolactone; high affinity for the MC receptor and anti-androgenic activity
55
Relative progestin potency
Gestodene > Levonorgestrel > Norgestimate > Desogestrel > NE > NEA > Drosperinone > MPA & Megace *Most potent on primed endometrium = levonorgestrel
56
Component that determines efficacy of OCPs
Progestin dose (inhibits LH surge, thickens mucus)
57
Emergency contraception options (4)
Levonorgestrel: 0.75mg given twice 12h apart or in combined single dose (1.5mg) Mifepristone: 600mg single dose, same efficacy/SE as levonorgestrel Ullipristal: 30mg single dose, slightly more effective and similar SE to levonorgestrel ParaGard: up to 5-10d after unprotected intercourse, failure rate as low as 0.1%
58
Aromatase inhibitors SEs
Lower risk VTE, uteirne ca, hot flashes and bleeding than tamoxifen Higher risk fracture and joint pain/stiffness, vaginal dryness
59
Androgen receptor forms
A (shorter) and B (full length)
60
Androgen receptor location
Xq11-12 (only steroid receptor on X chromosome)
61
Reason for Androgen and Progesterone receptor cross reactivity
Similar steroid binding
62
Androgen receptor mutation diseases (2)
AIS (similar presentation to 17-B HSD (type 3) deficiency | Kennedy's disease (X-linked spinobulbar muscular atrophy)
63
Flutamide
Nonsteroidal androgen receptor antagonist, can cause severe hepatotoxicity; teratogenic
64
CPA
17-α-OHP derivative with potent progestational activity that inhibits gonadotropin secretion, competes with DHT for binding to AR and reduces serum LH and ovarian androgen concentrations, shares similar pharmacological profile to RU486 (mifepristone)
65
Spironolactone
Aldosterone and androgen receptor antagonist structurally similar to progestins, competes with DHT for binding to AR and inhibits enzymes involved in androgen biosynthesis, can increase potassium
66
Finasteride
Inhibits type 2 5α-reductase, enzyme converting T to DHT, only partial inhibitory effect when used for hirsutism because enhanced 5alpha reductase activity involves both type 1 (skin) and type 2 (reproductive tissues) enzymes
67
Danazol
isoxazol derivative of 17α-ethinyl testosterone o Mechanism of action: • Weak-moderate binding to androgen receptor (also weak binding to PR and ER=least) • Inhibits the midcycle urinary LH surge and induces a chronic anovulatory state • Inhibits a number of steroidogenic enzymes (by inhibiting ovarian steroidogenesis) • Increases free testosterone levels (by displacing from SHBG) • Decreases serum estrogen levels o Side effects: weight gain, acne, hirsutism, fluid retention, fatigue, reduced breast size, oily skin, atrophic vaginitis, hot flashes, muscle cramps, emotional lability, can irreversible deepen the voice, unfavorable lipid profile changes (total cholesterol and LDL increased, HDL lowered) o Associated with virilization of female fetus in utero o First drug approved for treatment of endometriosis in the United States
68
DHEA-S source
100% adrenal – [3-20 mg/day]
69
DHEA source
50% adrenal, 20% ovary, 30% peripheral conversion of DHEA-S – [6-8 mg/day]
70
Androstenedione source
50% ovary, 50% adrenal – [1.5-6 mg/day]
71
Androgen potency
DHT (higher affinity/slower dissociation from AR)>Testosterone>Androstenedione>DHEA-S
72
Testosterone source
50% from peripheral conversion of androstenedione, 25% adrenal, 25% ovary
73
Most abundant circulating androgen
Testosterone (DHT is formed intracellularly)
74
Measuring Peripheral Androgen Activity
 3α-androstanediol glucuronide is peripheral metabolite of DHT  Marker of target tissue cellular activity; 3AG correlates w/ 5α reductase activity in skin  BUT, 3AG also reflects hepatic conjugation activity, and impact of precursors (androstenedione and T) derived from adrenal gland – not just from peripheral sources  3AG is not SOLELY a measure of cutaneous androgen metabolism
75
Insulin/IGF-1 Receptors
Grossly elevated insulin levels stimulate ovarian androgen production in theca cells via insulin, IGF-1 and hybrid receptors
76
Adrenal zonas
Zona glomerulosa: produces mineralocorticoids Zona fasciculata: produces glucocorticoids Zona reticularis: produces sex steroids
77
Half life hCG
24 hours
78
Half life FSH
2-4 hours
79
Half life LH
20 minutes
80
Half life GnRH
2-3 minutes
81
SHBG
Contains single binding site for androgens and estrogens (even though homodimer composed of two monomers) Dimerization is believed necessary to form single steroid binding site
82
SHBG increased by...
Estrogen, pregnancy, hyperthyroidism
83
SHBG decreased by...
Androgens, corticosteroids/anabolic steroids, GH, insulin/IGF1, obesity/GH, menopause
84
SHBG affinity of hormones (% bound)
``` o Testosterone (70) o Estrogen (70) o DHT (30) o DHEA (8) o Androstenedione (8) o Progesterone (1) ```

REI Written Boards SKORY (20 decks)

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