Hormone Biosynthesis Flashcards

1
Q

Rate limiting steps in:

Steroidogenesis?
Prostaglandin production?
Melatonin synthesis?
FSH/LH/TSH synthesis?
Estrogen synthesis?

A

Steroid biosynthesis – StAR enzyme transport of cholesterol form the outer to the inner mitochondrial membrane

Prostaglandin formation – release of free arachidonic acid

Melatonin synthesis – increase in cAMP leading to N-acetyltransferase activity

FSH/LH/TSH synthesis – availability of β subunits

Estrogen synthesis – aromatase activity

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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

Which G subunit?

A

FSH, LH, HCG, ACTH, TSH, CRH

Gs-alpha

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10
Q

Calcium second messenger hormones

Which G subunit?

A

GnRH, TRH, GHRH, kisspeptin, oxytocin, vasopressin, AGII

Gq-alpha

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11
Q

Protein kinase/MAP kinase hormone

A

Oxytocin (here also, through PKC)

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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 ligands?

& what do ligands act by?

A

Activin, inhibin

  • Activin acts via Type I and Type II serine/threonine specific receptor kinases
  • Inhibin acts by blocking the Type II serine/threonine specific receptor kinase
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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
Q

F Carboxy Terminal

A

no notes

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26
Q

TAF1 location/function

A

(A/B, regulatory domain) can stimulate transcription in the absence of hormone when fused to DNA

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27
Q

TAF2 location/function

A

(E, hormone binding domain) must have hormone binding for full activity

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28
Q

TAF3 location/function

A

(B-upstream segment [BUS]) autonomously activates transcription OR synergizes w/ other TAFs

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29
Q

TAFs on ER’s

A

ERα has TAF1 and TAF2
ERβ only has TAF2

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30
Q

TAFs on PR’s

A

PRα has TAF1 and TAF2
PRβ has TAF1, TAF2, and TAF3

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31
Q

Steroid hormones with nuclear receptors

A

Estrogen, thyroid (alpha-chrom 17, beta-chrom3), retinol, vit D

maybe progesterone & androgens?

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32
Q

Steroid hormones with cytoplasmic receptors

(still called nuclear receptors because the action is done there)

A

Mineralocorticoids, glucocorticoids

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33
Q

ER receptor expression during menstrual cycle

A

Peak late proliferative (self induced by E2), declines in early secretory (increased P4), increased in mid- and late-secretory (decreased P4)

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34
Q

ER alpha dominant tissues

A

Uterus/cervix/vagina, ovarian STROMA, breast, bone, hypothalamus, pituitary, kidney / adrenal (E2 and EE most sensitive)

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35
Q

ER beta dominant tissues

A

Granulosa cells, brain, colon, bladder, prostate

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36
Q

ER alpha and beta tissues

A

ovary, breast (alpha in dev and fxn, beta as natural suppressor of alpha activity)

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37
Q

2 SERMS and MOA

A

Raloxifene, tamoxifen; competitive inhibitor of estrogen binding to ER

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38
Q

Tamoxifen SEs

A

VTE, vaginal bleeding, endometrial hyperplasia/cancer, hot flashes, cataracts

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39
Q

Raloxifene SEs

A

Hot flashes, vaginal dryness, VTE (less than tamoxifen), decreases LDL, increase HDL, no change in TG

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40
Q

Raloxifene location of estrogenic and antiestrogenic effect

A

Estrogenic effect on bone
Antiestrogenic effects on breast and uterus

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41
Q

Tamoxifen location of estrogenic and antiestrogenic effect

A

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

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42
Q

PR-alpha action and TAFs

A
Negative action (inhibits activity of PR-B) 
TAF1 on reg domain, TAF2 on hormone binding domain
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43
Q

PR-beta action and TAFs

A

Positive reg of progesterone response genes
TAF1 on reg domain, TAF2 on hormone binding domain, TAF3 in B-upstream segment (BUS) at 5’ terminal

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44
Q

PR receptor expression

A

Induced by E2, inhibited by P4
Peak late-proliferative phase, nearly undetectable by midpoint of secretory phase

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45
Q

First gen progestins

A

Estranes derived form testosterone
Pregnanes derived from 17-OHP

46
Q

Second gen progestins

A

Gonanes derived from testosterone

47
Q

Third gen progestins

A

Gonane (levonorgestrel) derivatives

48
Q

Fourth gen progestins

A

Non-ethylated estranes

49
Q

Estranes

A
Norethindrone (MIcronor) 
Niorethindrone acetate (Loestrin) 
Ethynodiol diacetate (Kelnor)
50
Q

Pregnanes

A

MPA, Megestrol acetate (Megace)

51
Q

Gonanes

A

Levonorgestrel (Seasonale)
Norgestrel (Ovral)

52
Q

Gonane derivatives (3rd gen)

A

Gestodene
Desogestrel (Kariva)
Norgestimate (OrthoCyclen)
Etenogestrel (NuvaRing, Implanon)

53
Q

Non-ethylated estranes

A

Drosperinone: progestin analogue of spironolactone; high affinity for the MC receptor and anti-androgenic activity

54
Q

Relative progestin potency

A

Levonorgestrel
Norgestimate
Desogestrel
NE
NEA
Drosperinone
MPA & Megace

*Most potent on primed endometrium = levonorgestrel

55
Q

Component that determines efficacy of OCPs

A

Progestin dose (inhibits LH surge, thickens mucus)

56
Q

Emergency contraception options (4)

A

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%

57
Q

Aromatase inhibitors SEs

A
  • Lower risk VTE, uterine ca, hot flashes and bleeding than tamoxifen
  • Higher risk fracture and joint pain/stiffness, vaginal dryness
58
Q

Androgen receptor forms

A

A (shorter) and B (full length)

59
Q

Androgen receptor chromosome location

A

Xq11-12 (only steroid receptor on X chromosome)

60
Q

Reason for Androgen and Progesterone receptor cross reactivity

A

Similar steroid binding

61
Q

Androgen receptor mutation diseases (2)

A

AIS (similar presentation to 17-B HSD (type 3) deficiency
Kennedy’s disease (X-linked spinobulbar muscular atrophy)

62
Q

Flutamide

A

Nonsteroidal androgen receptor antagonist, can cause severe hepatotoxicity; teratogenic

63
Q

Cyproterone acetate (CPA)

Derivative of? competes with what? similar profile to what drug?

A

1st gen progestin

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)

64
Q

Spironolactone

MOA?

Competive or non-competitive? and with what hormone?

A

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

65
Q

Finasteride

MOA?

why only limited action in hirsutism treatment?

A

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

66
Q

Danazol

A

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

67
Q

DHEA-S source

A

100% adrenal – [3-20 mg/day]

68
Q

DHEA source

A

50% adrenal, 20% ovary, 30% peripheral conversion of DHEA-S – [6-8 mg/day]

69
Q

Androstenedione source

A

50% ovary, 50% adrenal – [1.5-6 mg/day]

70
Q

DHT source

A

100% peripheral conversion

71
Q

Androgen potency of androgens

A

DHT (higher affinity/slower dissociation from AR)>Testosterone>Androstenedione>DHEA-S

72
Q

Testosterone source

A

50% from peripheral conversion of androstenedione, 25% adrenal, 25% ovary

73
Q

Most abundant circulating androgen

A

Testosterone (DHT is formed intracellularly)

74
Q

Measuring Peripheral Androgen Activity

A

 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
Q

Insulin/IGF-1 Receptors

A

Grossly elevated insulin levels stimulate ovarian androgen production in theca cells via insulin, IGF-1 and hybrid receptors

76
Q

Adrenal zonas

A

Zona glomerulosa: produces mineralocorticoids
Zona fasciculata: produces glucocorticoids
Zona reticularis: produces sex steroids

77
Q

Half life hCG

A

24 hours

78
Q

Half life FSH

A

2-4 hours

79
Q

Half life LH

A

20 minutes

80
Q

Half life GnRH

A

2-3 minutes

81
Q

SHBG

How many binding sites? What is necessary before binding of ligand?

A

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
Q

SHBG increased by…

A

Estrogen, pregnancy, hyperthyroidism, liver disease, anorexia

83
Q

SHBG decreased by…

A

Androgens

corticosteroids/anabolic steroids

GH

insulin, IGF1, obesity,

menopause

HYPOthyroidism

Cushing’s disease

prolactin

84
Q

SHBG affinity of hormones (% bound)

A
o Testosterone (70) 
o Estrogen (70) 
o DHT (30) 
o DHEA (8) 
o Androstenedione (8) 
o Progesterone (1)
85
Q

Cholesterol Metabolism (exogenous & endogenous)

A
  • Exogenous pathway
    i. Lipids absorbed in intestine via microsomal triglyceride transfer protein (MTP) and form chylomicrons (triglycerides)
    ii. Chylomicrons carried in bloodstream and broken down by lipoprotein lipase (LPL) into fatty acids and glycerol in peripheral tissues (also makes empty HDL)
    iii. Chylo-remnants enter liver via apoE and low density lipoprotein receptor (LDLR) binding
  • Endogenous pathway
    i. Newly synthesized triglycerides repackaged into VLDL
    ii. VLDL enter bloodstream and release fatty acids and glycerol in peripheral tissues via lipoprotein lipase – becoming IDL + HDL  then LDL
    iii. IDLs absorbed by the liver and broken down into LDL via hepatic lipase
86
Q

Main cholesterol carrier in blood: LDL, HDL or VLDL? (and facts of the other two)

A
  • LDL main cholesterol carrier in blood – low protein:cholesterol ratio
  • HDL carries cholesterol from tissues to liver for metabolism/excretion (reverse cholesterol transport) – high protein:cholesterol ratio
  • VLDL are triglyceride rich particles
87
Q

What happens if you have an LDL receptor mutation/defect? (and other s/sx)

A

CVD/atherosclerosis

Other symptoms:

i. Xanthelasma palpebrarum (yellowish patches around eyes)
ii. Arcus senilis corneae (cholesterol in iris)
iii. Tendon xanthoma (lumps in tendons)

88
Q

Best predictor of heart disease in women?

A

Low HDL

89
Q

How are steroids metabolized?

A

oxidized by cytochrome P450 oxidase enzymes

  • P450 enzymes introduce oxygen into the steroid ring
  • Byproducts of steroid breakdown then excreted as bile acids
90
Q

What is special of conjugated estrogens?

What is the “conjugation”?

A

conjugated to make them hydrophilic

serve as steroid hormone precursors; cannot bind the estrogen receptor as is

  • Conjugation groups
    o Sulfate – most common
    o Glucuronidase
  • Lengthens the ½-life of the compound
    o Allows transport via circulation
    o Increases solubility in bile
91
Q

Most abundant conjugated estrogen?

A

Estrone sulfate

92
Q

Which Progestin generation has:

low androgenic effects
increased risk of DVT/PE
little effect on lipids and glucose

A

3rd

93
Q

Which Progestin generation has:

a diuretic effect

A

4th

94
Q

Androgenic potency of progestins (highest to lowest)

A

i. Levonorgestrel
ii. Norgestrel
iii. Desogestrel
iv. Norgestimate
v. Norethindrone acetate
vi. Norethindrone
vii. Ethynodiol diacetate
viii. Drospirenone
ix. Medroxyprogesterone

easier: 2nd > 1st = 3rd > 4th

95
Q

Each progestin generation’s effect on cholesterols

A

1st gen GOOD: Increase HDL, decrease LDL, no change/increase TG

2nd gen BAD: Decrease HDL, increase LDL, increase TG

3rd gen: No change/neutral

4th gen GOOD: Increase HDL, decrease LDL, no change/increase (same as 1st)

96
Q

Inhibin

Production: increased by?

Secretion:
what increases it?
what decreases it?

A

FSH stimulates inhibin production from granulosa cells → suppresses FSH

Secretion increased by IGF-1

Secretion decreased by GnRH

97
Q

Inhibin:

Actions (2)
how?
what are low & high levels associated w/?

A
  1. Down-regulates FSH synthesis and inhibits FSH secretion
  2. Enhances LH stimulation of androgen synthesis in the theca to provide substrate for aromatization to E2 in the granulosa

Acts by blocking the Type II serine/threonine specific receptor kinase

Low = DOR

High = granulosa cell tumors

98
Q

Epidermal growth factor

structural analog?

function?

A

TGF-alpha - can bind to EGF receptors

decreases FSH induction of LH receptors on granulosa cell (opposite the TGF-b superfamily)

99
Q

TGF-b action on granulosa cells & theca cells

A

Granulosa: enhances FSH induction of LH receptors (positive)

Theca: negative action, inhibiting androgen production

100
Q

Types of nuclear steroid receptors

A

Type I - reside in cytoplasm, then move to nucleus (mineralcorticoid, glucocorticoid receptors)

Type II - reside in nucleus (Estrogens (most), progestins, and androgens (most) receptors, thyroid hormone receptor, Vit D)

101
Q

Most common HSPs in E region of steroid receptors that need to be dissociated before moving to nucleus

A

hsp 90 & 56

102
Q

Zinc Fingers:

  1. # of AAs? most important AA?
  2. Essential for what?
  3. Where is functional specificity localized?
A
  1. 100 AA’s w/ 9 cysteines in fixed positions
  2. activation of transcription
  3. second zinc finger in an area called the d(distal) box
103
Q

DNA sequences that are bound by steroid receptors called what?

Where is it in the gene? what is common about it?

A

steroid/hormone response element

Part of the promoter region of the gene

  • most commonly a pair of inverted repeats separated by three nucleotides, which also indicates that the receptor binds as a dimer.
104
Q

What aspect of binding is just as important as the dose?

give example (2)

A

Duration of exposure

  1. only small amounts of estrogen needed in circulation b/c long half-life of estrogen hormone-receptor complex. (Potency differences among the various estrogens related to length of time estrogen-receptor complex occupies the nucleus)
  2. Cortisol and progesterone must circulate in large concentrations because their receptor complexes have short half-lives
105
Q

What do IP3 & DAG activate?

A
  1. IP3 – activates calcium ion channels
  2. DAG – activates protein kinase C
106
Q

Mifepristone MOA

A
  • Progesterone receptor antagonist (affinity 5x greater than natural hormone)
  • Glucocorticoid receptor antagonist (but the circulating level of cortisol is so high, so doesn’t produce as much an effect)
107
Q

Positive & Negative feedback of estrogen

A

Negative: Occurs during follicular phase when E2 levels are low

Positive: Occurs at high E2 concentrations near the end of the follicular phase – E2 becomes a positive inducer of the anterior pituitary - triggers the anterior pituitary to release more FSH/LH to produce more E2 – resulting in a substantial rise that triggers the LH surge

108
Q

Progesterone receptor-A and B knock-out - what happens to:

Breast? Endometrium? Ovary?

A
  • Receptor-A knock-out (PR-A opposes E2-induced proliferation, required for fertility/ovulation)
  • Ovary - anovulation
  • Endometrium – epithelial cell proliferation in response to E2/P4 (because ONLY PR-B expression present)
  • Breast – no change in response of mammary gland to E2/P4
  • Progesterone Receptor-B knock-out (PR-B enhances E2-induced proliferation, required for mammary gland function)
  • Ovary – no change in response of ovary to E2/P4
  • Endometrium – no change in response of endometrium to E2/P4
  • Breast – Reduced mammary ductal morphogenesis and alveologenesis during pregnancy
109
Q

Elagolix

MOA?

A

non-peptide oral, short-acting competitive GnRH receptor antagonist

110
Q

Medroxyprogesterone Acetate risk in:

VTE / effect on lipids?

breast cancer?

CHD?

what is oral brand name?

A

all bad. the worst progestin when combined w/ estrogen

Provera

111
Q

Micronized Progesterone risk in:

VTE / effect on lipids?

breast cancer?

CHD?

what is brand name?

A

metabolically neutral, doesn’t seem to have effect.

Prometrium