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REI Written Boards 2024 - AK > Hormone Action and Clinical Pharmacology of Hormones > Flashcards

Hormone Action and Clinical Pharmacology of Hormones Flashcards

1
Q

Steroid vs peptide hormones

A

Steroid hormone (e.g. androgen) - 18-21 carbons (small)

Protein hormone (e.g. FSH) - large, multiple moieties, alpha/beta subunits (e.g. FSH alpha subunit 92 AAs!, beta subunit 118 AAs!)

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2
Q

Basics re: steroid hormones

A
  • Derived from cholesterol
  • 3 x 6-C rings + 1 x 5-C ring
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3
Q

Types of receptors

A
  1. Ion channels: simple, ion diffusion through gated channel
  2. G-protein coupled: transmembrane
  3. Intrinsic enzyme activity (e.g. tyrosine kinase): also transmembrane
  4. Intracellular (*steroid hormone receptors)
  5. Other (LDL, PRL)
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4
Q

Steroid hormone receptors mechanism of action

A
  1. Steroid hormone diffusion across cell membrane lipids
  2. Steroid hormone binds to receptor protein directly either:
    - In cytoplasm: glucocorticoid, mineralocorticoid, androgen receptors
    - In nucleus: estrogen and progesterone receptors
    *binding of steroid hormone to its receptor causes dissociation of heat shock protein 90 (hsp90) and subsequent conformational change in receptor

**Many hormones require dimerization of the receptor here for activation

  1. Steroid hormone-receptor complex travels to nucleus if not there already > binds directly to DNA at hormone-responsive element
  2. In nucleus: gene activation > transcription of mRNA > transport to ribosomes
  3. In cytoplasm: translation > protein synthesis > specific cellular activity
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5
Q

Basic structure of steroid hormone receptor
- A/B: regulatory domain
- C: DNA-binding domain
- D: Hinge region
- E: Hormone-binding domain/pocket
- F: F region

A
  • A/B: regulatory domain: most variable region, can bind transcription factor (TF) to activate receptor without ligand (steroid hormone) binding (e.g. TAF-1 on the estrogen receptor)
  • C: DNA-binding domain: essential to activate transcription, most homologous region, contains zinc fingers
  • D: Hinge region: localizes receptors to nucleus, a rotational site for conformational change
  • E: Hormone-binding domain (pocket): where ligand binds, also may be site of hs90 protein, dimerization, co-factor binding, TAF-2 for ER
  • F: F region: conformational change impacts receptor activity
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6
Q

Which region of the steroid hormone receptor is most variable? Most homologous?

A

Most variable - A/B regulatory domain (F region also variable)

Most homologous: C DNA-binding domain

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7
Q

Structure of ER alpha vs ER beta receptors

A

ER alpha (chromosome 6) - A/B region contains TAF-1 binding site, 1/2-life is 4-7 hours (found in uterus, bone, pituitary)

vs

ER beta (chromosome 14) (found in granulosa cells)

*Both contain on E-region (hormone-binding region): hs90 protein, TAF-2 binding region

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8
Q

TAF-1

A
  • Transcription activating function-1
  • Binds to A/B region of ER alpha receptor
  • Can activate transcription after binding to ER alpha receptor without estrogen binding
  • Helps explain how estrogen can have different actions in different tissues (depends on which receptor is present in the tissue)

SERM:
- E.g. tamoxifen binding to TAF-1 on ER alpha in breast, uterus, bone, pituitary > acts as agonist: stimulatory (effect of TAF-1 in these tissues overcomes TAF-2 inhibitory effects in these tissues)

Tamoxifen binding to TAF-2 > acts as competitive antagonist: inhibitory (normally overrides TAF-1 activation in most tissues)

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9
Q

Compare effects of SERMs on breast, uterus, bone, VTE, lipids, hot flushes:
- Estrogen
- Clomiphene
- Tamoxifen
- Raloxifene
- Bazedoxifene

A

Breast: Estrogen is + (all others are -)
Uterus: Estrogen and Tamoxifen are + (bazedoxifene is –)
Bone: All are +
VTE: All are +
Lipids: All are -
Hot flushes: Estrogen is - (all others are +)

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10
Q

Structure of progesterone receptor alpha vs beta

A

PR alpha - A/B regulatory domain contains TAF-3 binding region

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11
Q

Where is the androgen receptor gene located? How does this affect inheritance of certain disorders?

A

X chromosome (Xq11-12)

AIS is an X-linked recessive disorder because it involves defects in the androgen receptor gene on the X chromosome

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12
Q

Tissues derived from Wolffian ducts respond to ___

Hair follicles and UG sinus/tubercle respond to __

A

Tissues derived from Wolffian ducts respond to testosterone (internal male genitalia development)

Hair follicles and UG sinus/tubercle respond to DHT (testosterone must be converted > 5 alpha reductase > DHT) (external male genitalia development)

DHT has much higher affinity (more potent) for its receptor than testosterone

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13
Q

What is the mechanism of action of mifepristone?

A

Mifepristone (RU-486) is a selective progesterone receptor modulator (“SPERM”)

Mostly acts as a progesterone receptor ANTAGONIST (in the presence of progesterone); however, acts as an agonist in the absence of progesterone

Weak anti-glucocorticoid and anti-androgen activity

FDA-approved for medical abortion, non-FDA clinical use for miscarriage

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14
Q

Mechanism of action of ulipristal acetate?

A

SPERM (selective progesterone receptor modulator)

Works primarily as an ANTAGONIST at the uterus, cervix, ovaries, hypothalamus

Weak anti-mineralocorticoid and anti-androgen activity

FDA-approved for emergency contraception (30 mg dose), non-FDA approved for fibroids (5 mg dose)

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15
Q

Mechanism of action of spironolactone?

A

Aldosterone antagonist

Competitive inhibitor of testosterone at androgen receptor (but not completely antagonistic effect; dose-dependent competition, 20% affinity)

*Interferes with multiple cypP450 enzymes including 5-alpha reductase, SCC, 17 alpha hydroxylase, 17,20-lyase, 3 beta HSD, 11 beta hydroxylase, 21 hydroxylase, aldosterone synthase

*SE: HYPERkalemia (diuretic)
*Contraindications: teratogenic

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16
Q

Mechanism of action of flutamide?

A

Pure anti-androgen

Blocks androgen effect by competitive inhibition

*SE: liver toxicity
*Contraindications: teratogenic

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17
Q

Mechanism of action of finasteride?

A

5-alpha reductase inhibitor (inhibits conversion of testosterone > DHT)

Tx for: hirsutism

*Contraindicaitons: teratogenic

18
Q

Steroid analogues
- Ethinyl estradiol

A

Ethinyl estradiol: addition of ethinyl group to increase oral bioavailability and increase half-life, but prevents detection by standard estrogen assays
- Most common estrogen in OCP
- 5 mcg dose of EE = 1 mg 17-beta-E2 (Estrace)

19
Q

Norethinedrone
- Which generation?
- Androgenic/Estrogenic?
- What is it derived from?
- What is another name?
- Classified as?

A
  • One of the oldest synthetic progestins
  • Derived from testosterone
  • 19-nor testosterone (NO 19th C, unlike testosterone)
  • Addition of ethinyl group
  • 1st generation
  • Androgenic (binds to androgen receptor)
  • “Estrane”
20
Q

Levonorgestrel
- Which generation?
- Androgenic/Estrogenic?
- Compare to norethinedrone
- Classified as?

A
  • 2nd generation
  • Most potent and more androgenic than norethinedrone due to longer half-life > makes a good progestin for IUD (packaged small amount)
  • One additional C compared to norethinedrone
  • “Gonane”
21
Q

Norgestimate
Desogestrel > (and Etonogestrel metabolite)
Gestodene
- Which generation?
- Androgenic/Estrogenic?
- Concerns?

A
  • 3rd generation
  • Designed to be less androgenic
  • Some concern re: higher DVT risk
22
Q

Drospirenone
- Which generation?
- Androgenic/Estrogenic?
- Concerns?

A
  • 4th generation
  • Agonist at progesterone receptor
  • Antagonist at androgen and mineralocorticoid receptors > mild diuretic effect
  • Some concern re: higher DVT risk
23
Q

Medroxyprogesterone acetate (Provera)
- Derived from?
- Acts on which receptor?
- Concerns?
- Classified as?

A
  • NOT derived from androgen, but progesterone itself
  • Potent progesterone agonist at high doses
  • Can suppress FSH at high doses (negative feedback) > decrease E2 production, amenorrhea, bone loss (e.g. Depo-Provera)
  • “Pregnane”
24
Q

Megestrol acetate (Megace)
- Derived from?
- Acts on which receptor?

A
  • Derived from progesterone
  • Potent progesterone receptor agonist
  • Tx of endometrial hyperplasia
25
Q

Norethinedrone acetate (Aygestin)

A
  • Similar to norethinedrone with added acetyl group
  • Tx: 5 mg for AUB, lower doses in OCP
  • Metabolized at a low rate > ethinyl estradiol ! Therefore, can be used as sole HRT (for endo, for GnRH agonist add-back)
26
Q

Which region of the steroid hormone receptor contains zinc fingers?

A

C - DNA-binding domain

27
Q

G-protein coupled receptors

A
  • Peptide hormone receptor
  • 7 membrane spanning domains
  • 3 intracellular, 3 extracellular loops
  • Several subunits
28
Q

Describe cAMP 2nd messenger pathway for G-coupled protein receptors
- What types of G-protein receptors use this pathway?
- Name examples

A

Adenylate cyclase
cAMP
Protein kinase A

Gs (stimulatory) vs Gi (inhibitory)

FSH, LH, hCG, TSH, ACTH
CRH, Somatostatin, GHRH

29
Q

Describe phospholipase C 2nd messenger pathway for G-coupled protein receptors

A

Phospholipase C (PLC)
DAG
IP3
Protein kinase C (sustained response)
Calmodulin (acute response)
Ca2+ dependent reactions

Gq

GnRH (Ca2+ dependent), TRH, oxytocin, kisspeptin

30
Q

Pathophysiology of McCune Albright Syndrome

A
  • Constitutive activation of the Gs receptor (in absence of ligand)

Manifestations:
- Constitutively active FSH-R > increased estrogen production
- Constitutively active MSH-R > skin pigmentation

31
Q

Kisspeptin mutation leading to hypo/hypo and absent puberty is a mutation in what gene?

A

Kisspeptin receptor (GPR54) mutation in Gq receptor > prevents kisspeptin binding and downstream PLC pathway > hypo hypo / absent puberty

32
Q

Tyrosine kinase receptor
- Typical process
- Examples

A
  • Peptide binds to receptor
  • Often involves receptor dimerization
  • Receptors phosphorylate themselves (tyrosine residues) or are phosphorylated by other protein kinases > conformational change
  • Stimulate other intracellular signaling

Examples: insulin receptor, IGF-1, VEGF, EGF

33
Q

Pathophysiology behind insulin resistance?

A
  • Resistance: insulin continues to bind, but ceases to have the same biologic effect
  • Decreased phosphorylation of tyrosine residues vs
  • Increased phosphorylation of serine residues
34
Q

What effect does insulin have on the theca cells of the ovary?

A

Increases androgen production

35
Q

Cytokine receptor

A
  • JAK-STAT hormone pathway
  • Ex: growth hormone, prolactin, hPL, leptin
36
Q

Serine/threonine kinase

A

Activin
Inhibin

37
Q

Describe the structure of gonadotropins

A

FSH, LH, hCG, TSH - glycoprotein hormones

Heterodimers: common alpha subunit, unique beta subunit (alpha-beta subunits connected via disulfide bonds)

38
Q

Where does glycosylation of gonadotropins occur?

What is the effect of glycosylation?

A

Golgi apparatus

Adding carbohydrate > alters metabolic clearance/half-life (the higher sialic acid > the longer the half-life)

E.g. hCG has near identical beta subunit, but has much more sialic acid/glycosylation, so its half-life is significantly longer than LH

39
Q

Heterogeneity of glycoproteins

A

Multiple isoforms of gonadotropins exist (e.g. hyperglycosylated hCG in GTD) due to differences in DNA promoter action, RNA splicing, post-translational modifications (e.g. glycosylation)

Another example: recombinant (1 isoform, Follistim, Gonal-F from Chinese hamster ovary cells, need mammalian cells for post-translational modification in the Golgi apparatus, cannot use bacteria) vs purified gonadotropins (multiple isoforms, e.g. Menopur from urine). Clinical impact?

40
Q

Regulation of tropic hormones:

Describe desensitization
- Homologous
- Heterogeneous

vs

Down-regulation

A

DESENSITIZATION: Prolonged exposure to agonist > DECREASED RESPONSE via auto-phosphorylation of cytosolic portion of receptor > loss of signaling

  • Homologous desensitization: affects only single receptor
  • Heterogeneous desensitization: affects multiple receptors on the membrane

DOWN-REGULATION: Prolonged exposure to agonist > internalization of receptor via clathrin pits > decreased # of receptors / decreased response to hormone

**prolonged exposure causes both desensitization and down-regulation

41
Q

Describe structure of GnRH
How does it differ from GnRH agonist?
GnRH antagonist?

A
  • GnRH is a decapeptide
  • GnRH has a short half-life due to AA cleavage
  • GnRH agonist (leuprolide acetate or Lupron): replacement of AA at #6 position (Gly > Leu) > longer half-life > metabolic stability
  • GnRH antagonist: multiple AA substitutions > competitive blockade of GnRH receptor > immediate decline in gonadotropin levels with immediate therapeutic effect (70% suppression of LH, 30% suppression of FSH after only 6 hours)

REI Written Boards 2024 - AK (25 decks)

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