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Androgens & Anti-Androgens Flashcards

1
Q

Androgens

A

19C compound derived from cholesterol

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2
Q

Androgenic Precursors

A
  • DHEA: dehydroepiandrosterone
  • Androstnedione
  • inactive; must be converted
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3
Q

DHEA: dehydroepiandrosterone

A
  • androgenic precursor
  • adrenal cortex; testes
  • inactive
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4
Q

Androstenedione

A
  • androgenic precursor
  • adrenal cortex; testes
  • inactive
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5
Q

Androgens

Name two

A
  • Testosterone

- DHT: dihydrotestosterone

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6
Q

Testosterone

A
  • testes

- MOST ABUNDANT

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7
Q

DHT

Dihydrotestosterone

A
  • androgen target cells and tissues
  • – paracrine/autocrine manner
  • MOST POTENT natural androgen
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8
Q

Adult male [testosterone]

A

[T]testes 100x > [T]serum

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9
Q

17-B-hydroxysteroid dehydrogenase (17B-HSD)

A
  • converts DHEA and androstenedione to testosterone

- expressed in testicular leydig cells

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10
Q

5-a-reductase

A

testosterone -> DHT

  • androgen-responsive target tissues
  • most DHT production occurs outside the testes
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11
Q

How much testosterone is produced in the adrenal cortex?

A

<5%

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12
Q

Aromatase (CYP19)

A

androgens are OBLIGATE precursors to estrone and estradiol

- more fat = more estradiol

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13
Q

Androgen Receptor: males express

A

only 1

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14
Q

Regulation of Androgen Production from Testes

A
  • Hypothalamus = pulse generator
  • – GnRH: hypothalamus -> pituitary (+)
  • FSH: pituitary -> testes/seminiferous tubules (+)
  • LH: pituitary -> testes/Leydig cells
  • – C -> T
  • Testosterone: testes -> pituitary & hypothalamus (-)
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15
Q

Testosterone secreted by Leydig cells play critical role in ____

A

spermatogenesis

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16
Q

Androgen Signaling Pathways

A

1) ligand binding triggers loss of heat shock proteins
2) nuclear localization
3) coactivators lead to transcription

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17
Q

T -> DHT

A

5-a-reductase

- DHT binds 5x more tightly to AR

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18
Q

T -> Estradiol

A

Aromatase

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19
Q

Androgen Actions

Developmental (males)

A
  • Embryonic/Fetal: masculinize internal and external male genitalia
  • Puberty
  • – regulate growth and development of male reproductive tract
  • – regulate linear growth and physical development
  • – imprint male behavior and libido
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20
Q

Androgen Actions
Metabolic Adult Males
Bone

A
  • maintains and strengthens bone mass by increasing osteoblast proliferation and decreasing bone resorption by osteoclasts
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21
Q

Androgen Actions
Metabolic Adult Males
Muscle

A
  • increases protein synthesis
  • increases size and length of muscle fibers
  • increases muscle mass
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22
Q

Androgen Actions
Metabolic Adult Males
Blood

A
  • increases erythropoietin
  • increases maturation of erythrocytes
  • increases number of red blood cells
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23
Q

Androgen Actions
Metabolic Adult Males
skin

A

increases sebum production in sebaceous glands

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24
Q

Androgen Actions
Metabolic Adult Males
Liver

A
  • increases LDL
  • decreases HDL
  • implications for CV function
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25
Q

Androgen Actions
Metabolic Adult Males
Reproduction

A
  • maintains and regulates the male reproductive tract
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26
Q

Androgen Actions
Metabolic Adult
Females

A
  • normal patterns of body hair growth, muscle growth, libido

- maintain bone density

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27
Q

Breakdown of Creation of Androgens in Females

A

50% adrenal cortex

50% ovaries

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28
Q

Therapeutic uses of ANdrogens

A
  • Male Hypogonadism

- Andropause

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29
Q

Male Hypogonadism

A
  • defect in testicular function that leads to testosterone deficiency
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30
Q

Andropause

A
  • male senescence; late onset hypogonadism; LOH
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31
Q

Androgen Replacement Therapy for Andropause

A

CONTROVERSIAL

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32
Q

Therapeutic Androgenic Drug Preparations

A
  • when oral, rapidly degraded by liver, limiting oral bioavailability

Effective androgen therapy requires:

1) testosterone in a slow continuously absorbed form
2) chemically modified testosterone derivatives that bypass metabolism in the body

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33
Q

3 types of T modifications

A

1) Type A: esterification of C17 hydroxyl group
2) Type B: alkylation of the C17a position
3) Type C: modifications of the A, B, or C rings

Type B+C= very effective

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34
Q

Type A Modifications

Esterification of C17 Hydroxyl Group

A
  • make more hydrophobic/lipophilic
  • allows slow and continuous release into the bloodstream
  • the longer the ester carbon chain, the more prolonged the action
  • T esters must be hydrolyzed back into free testosterone to become biologically active
35
Q

Testosterone undecanoate

A
  • Type A Modification
  • lasts the longest because longest C chain
  • intramuscular injection every 6-8 weeks
36
Q

Type B Modifications

Alkylation of the C17a position

A
  • increases oral availability; VERY TOXIC to liver
  • inhibits hepatic catabolism = higher bioavailability
  • Drawback: prolonged use is associated with liver toxicity
37
Q

Methyltestosterone

A

Type B Modification

38
Q

Type C ad B Modifications

Modification of A/B/C rings AND C17 a-alkylation

A

MOST POTENT

  • enhances the androgenic potency
  • usually found in combination with C17 a-methylation, thus increasing bioavailability
  • can increase affinity for receptor
    OR
  • can make not a substrate for aromatase, causing it to hang around longer
39
Q

Oxandrolone

A

C/B modification

- does not aromatize

40
Q

Stanozolol

A

B/C modification

- does not aromatize

41
Q

Fluoxymesterone

A

B/C modification

  • 5x potency of T
  • does not aromatize
42
Q

Danazol

A

B/C modification

- does not aromatize

43
Q

Anabolic Steroid Misnomer

A

there are no purely anabolic steroids

- initial studies done on animals

44
Q

Side Effects of Androgenic Drugs

A
  • prostate enlargement/malignancy
  • dyslipidemia
  • severe acne
  • thinning of hair on scalp/baldness
  • fluid retention/edema
  • high BP
  • liver damage (esp C17 a-alkylated derivatives)
  • erythrocytosis
45
Q

Anti-Androgens

2 Classes

A
  • drugs that block endogenous androgen production

- drugs that block the androgen receptor

46
Q

Therapeutic uses of Anti-Androgens

A
  • prostate cancer
  • benign prostate hyperplasia (BPH)
  • male-patter hair loss
  • hirsutism (females)
47
Q

Prostate Cancer

A
  • most commonly diagnosed malignancy

- initially dependent on androgens for growth and survival

48
Q

Huggins and Hodges Key Findings

A
  • reduction of testosterone levels by surgical orchiectomy (castration) or by injection of estrogens results in regression of prostate cancer
  • exogenous testosterone injections results in progression of prostate cancer
49
Q

Drugs that Block Endogenous Androgen Production

3 Classes

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling
2) Inhibitors of Androgen Biosynthesis
3) Inhibitors of DHT Biosynthesis

50
Q

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling

A
  • GnRH receptor agonists and antagonists

- estrogenic treatment

51
Q

Ketoconazole

A

2) Inhibitors of Androgen Biosynthesis
First Generator

  • prevents oxidation
  • – sterically occludes anything from getting into active site
  • potent NONSELECTIVE inhibitor
  • inhibits 3 out of 4 enzymes involved in testosterone biosynthesis
  • if female took it would also inhibit estrogen
  • also inhibits CYP3A4: could interfere with drug metabolism
52
Q

Finesteride

A

3) Inhibitors of DHT Biosynthesis
- 90% DHT reduction in prostate
- can act as androgen receptor antagonist

53
Q

Duasteride

A

3) Inhibitors of DHT Biosynthesis
- 99% DHT reduction in the prostate
- prevents most hairloss

54
Q

Abiraterone

A

2) Inhibitors of Androgen Biosynthesis
Second Generation
- SELECTIVE inhibitor
- does NOT inhibit CYP3A4

55
Q

Estradiol

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling

Estrogenic Treatment

56
Q

DES

Diethylsilbestrol

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling

Estrogenic Treatment

57
Q

Leuprolide

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling
GnRH receptor agonists

D Leu

58
Q

Goserelin

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling
GnRH receptor agonists

D Ser

59
Q

Degarelix

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling

GnRH receptor agonists and antagonists

60
Q

Relugolix

A

1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling

GnRH receptor agonists and antagonists

61
Q

Inhibitors of Hypothalamic-Pituitary-Testes Signaling

A

Ranking

1) GnRH Receptor Agonists or Antagonists: chemical castration
2) Orchiectomy: surgical castration
3) Estrogen Treatment
- will not bind AR & promote growth of tumor
- need v. high levels; nasty side effects

62
Q

Castration Level

63
Q

GnRH Receptor Agonists

A
  • reversible
  • used clinically for infertility

Mechanism of action:

  • distorts normal pulsatile signaling from hypothalamic GnRH thus desensitizing the pituitary to GnRH
  • – overwhelms pituitary and shuts down LH & FSH
  • painful with metastases
64
Q

GnRH Receptor Antagonists

A
  • reversible
  • bind GnRH receptor and block gonadotropic secretion

Mechanism of Action: competitively and reversibly inhibit GnRH receptors in pituitary gland which blocks FSH, LH, and T release

65
Q

Synthetic GnRH Agonists

A

> > t1/2 and binding affinity for GnRH receptor than GnRH

66
Q

Advantages of GnRH ANTagonists over GnRH agonists

A

1) RAPID suppression of FSH, LH, and T
2) no microsurges
3) prolonged suppression of FSH, LH, and T

67
Q

GnRH Antagonist Side Effects

A
  • injection site reaction
  • hot flashes
  • fatigue
  • weight gain
  • hepatotoxicity
68
Q

Abiraterone vs Ketoconazole at Adrenal Cortex

A

Ketoconazole: shuts down everything

  • side effects: blocks cortisol and aldosterone synthesis too
  • inhibits CYP3A4 actively in liver affecting drug metabolism
Abiraterone: inhibit in adrenal cortex
- CYP17
- DHEA
- Aldosterone
~ Cortisol
69
Q

Inhibitors of DHT Biosynthesis

A
  • inhibits 5-a-reductase
  • target tissue: prostate, scalp

Used to treat:

  • hair loss
  • benign prostate hyperplasia
  • prostate cancer
70
Q 
AR antagonists (aka Anti-androgens)
First Generation
A

Flutamide

Bicalutamide

71
Q 
AR antagonists (aka Anti-androgens)
Second Generation
A

Enzalutamide
Apalutamide
Darolutamide

72
Q

Enzalutamide

A

nonsteroidal AR antagonist

  • been around the longest
  • approved for all stages of prostate cancer
  • very expensive
73
Q

1st & 2nd Generation AR Antagonists

A
  • work by binding to AR and preventing binding of either
  • – DHT
  • – Testosterone
  • Drugs inhibit
  • – localization of AR to nucleus
  • – ability of receptor to bind to DNA
  • – ability to recruit co-activators
  • – ability to regulate gene expression
74
Q

1st vs 2nd AR Antagonists

AR Nuclear Import

A
  • 1st: inhibits nuclear import
  • 2nd: completely blocks AR transport into nucleus
  • – if AR can’t get into nucleus: ALL STOP
75
Q

1st vs 2nd AR Antagonists

AR Binding Dd

A
  • 1st: 160
  • 2nd: 25
  • DHT: 5
76
Q

Which 2nd Generation AR Antagonist has highest potency/shortest t1/2?

A

Darolutamide

77
Q

Which 2nd AR Antagonists can cross brain/blood barrier?

A

Enzalutamide & Apalutamide

- why such significant CNS side effects

78
Q

Prostate Cancer Treatment Paradigm

Advanced Castration Sensitive Prostate Cancer

A

Goal: lower serum testosterone to “castrate” levels (<50 ng/dL)

Treatment: Androgen Deprivation Therapy
#1: Chemical Castration (80%)
2) Surgical Castration (Orchiectomy)
3) Estrogen (last resort; nasty side effects)

79
Q

Castrate Levels

A

Serum testosterone <50 ng/dL

80
Q

Prostate Cancer Treatment Paradigm

Cancer Progression to Castrate Resistant Prostate Cancer

A
  • increasing PSA levels & metastases
  • introduce Secondary Hormonal Therapy
  • Chemotherapy
  • Immunotherapy
81
Q

Secondary Hormonal Therapies

A
  • 1st & 2nd Gen Anti-Androgen
  • Androgen Inhibitors
  • DHT Inhibitors
82
Q

Buserelin

A
  • inhibitor of hypothalamic-pituitary-testes signaling
  • GnRH Receptor Agonist (increases GnRH released from hypothalamus to pituitary)

D-Ser

83
Q

Testosterone Enanthate

A

Testosterone Ester

  • esterification of C17 hydroxyl group
  • Type A modification
  • Intramuscular injection; every 2-3 weeks
84
Q

Testosterone Cypionate

A
  • testosterone ester
  • esterification of C17 hydroxyl group
  • type A modification

Pharmacology Test 2 (8 decks)

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