Endo 13: Androgen And Male Pharmacology

Front 1

What are the natural androgen?

Back 1

- Testosterone
- Dehydroepiandrosterone
- Androstenedione
- Dihydrotestosterone (DHT)

Front 2

What are the non-natural androgens?

Back 2

- Testosterone esters (Cypionate)
- 17-Alkylated Androgen (Stanozolol)

Front 3

What are the Anti-Androgens?

Back 3

- Flutamide
- Finasteride

Front 4

What are the drugs used for impotence?

Back 4

- Alprostadil
- Sildenafil
- Vardenafil
- Tadalafil

Front 5

How does Testosterone mediate its effects directly and indirectly?

Back 5

- Direct: binds androgen receptor
- Indirect: conversion to DHT and then binding to the androgen receptor

Front 6

What can Testosterone be converted to?

Back 6

- 5α-Reductase: T → DHT
- Aromatase: T → Estradiol

Front 7

What are the types of 5α-Reductase? Location?

Back 7

- Type 1: non-genital skin, liver, and bone
- Type 2: urogenital skin in men and genital skin in men and women

Front 8

What is the other name for the androgen receptor? What kind of receptor is it?

Back 8

- NR3A = Androgen Receptor
- Member of the Steroid Nuclear Receptor family

Front 9

What happens to the Androgen Receptor when there is no ligand?

Back 9

- Androgen receptor is located in the cytoplasm
- Associated with Heat Shock Protein complex

Front 10

What happens to the Androgen Receptor when there is ligand (T or DHT)?

Back 10

- T or DHT binds to the ligand-binding domain
- Androgen receptor dissociates from the Heat Shock Protein complex
- Receptor dimerizes and translocates to the nucleus
- Dimer then binds via the DNA-binding domain to androgen response elements on certain responsive genes
- Ligand-receptor complex recruits coactivators and acts as a transcription factor complex, stimulating or repressing gene expression

Front 11

What accounts for the varying action of androgens in different tissues?

Back 11

- Higher affinity with which DHT binds to and activates the androgen receptor compared to T
- Tissue-specific transcription factors (both activators and repressors)

Front 12

What percent of the circulating estradiol in men is from testosterone conversion via Aromatase?

Back 12

85% of circulating estradiol is converted from T

Front 13

What happens in men that do not express Aromatase?

Back 13

- Epiphyses do not fuse and long-bone growth continues indefinitely
- Osteoporosis

Front 14

How does an aromatase deficiency compare to an estrogen receptor defect?

Back 14

- Both cause bone abnormalities (eg, epiphyses don't fuse, long bone growth continues indefinitely, and osteoporosis)
- Only aromatase deficiency can be corrected with administration of estradiol
- Estrogen-receptor defect will not be corrected by administration of estradiol

Front 15

What is important for the regulation of epiphyseal growth plate closure?

Back 15

Testosterone conversion to estradiol

Front 16

What happens when you take Testosterone orally? Why?

Back 16

- Testosterone can not be taken in sufficient amounts orally to maintain normal serum T concentrations in hypogonadal men
- This is because T has a high first pass effect

Front 17

What pharmacologic preps are there for Testosterone?

Back 17

- Testosterone patches, gels, and buccal tablets
- Testosterone esters (Cypionate)
- 17α-Alkylated compounds (Stanozolol)

Front 18

What drug is a Testosterone ester? How is it administered? How is it different from regular T?

Back 18

Cypionate
- Injected IM
- Esterify a fatty acid to the 17-hydroxyl group of T making it more lipophilic than T

Front 19

How is Cypionate different from Testosterone? Effect?

Back 19

- Testosterone esterified with a fatty acid to the 17 hydroxyl group
- This makes the compound more lipophilic
- Ester hydrolyzes in vivo and results in serum testosterone concentrations that range from higher than normal in the first few days after the injection to low normal just before the next injection

Front 20

Which drug has an ester that is hydrolyzed resulting in slow testosterone release?

Back 20

Cypionate

Front 21

What drug is a 17α Alkylated compound?

Back 21

Stanozolol

Front 22

How is Stanozolol administered? How is it modified from Testosterone?

Back 22

- Oral
- Add an alkyl group to the 17 position of testosterone

Front 23

What is the effect of the 17α-alkyl group on Testosterone (Stanozolol)?

Back 23

Slows hepatic catabolism, less androgenic than testosterone itself

Front 24

What is the side effect of Stanozolol?

Back 24

Hepatotoxicity

Front 25

What are the therapeutic uses of androgens?

Back 25

- Male hypogonadism
- Testosterone deficiency

Front 26

What is the most important aspect of monitoring the efficacy testosterone treatment?

Back 26

Measuring serum testosterone concentration

Front 27

What is the goal of testosterone therapy?

Back 27

Mimic as closely as possible the normal serum testosterone concentration

Front 28

What are the undesirable effects of testosterone therapy?

Back 28

- Acne
- Gynecomastia
- More aggressive sexual behavior

Front 29

When administering testosterone to testosterone deficient boys at the type of puberty, what do you need to consider?

Back 29

- Consider the epiphyseal closure and permanent cessation of linear growth
- Height and growth hormone status of the patient must be considered
- Boys who are short because of GH deficiency should be treated w/ GH before their hypogonadism is treated with T

Front 30

What are some other (non-FDA approved) uses of testosterone?

Back 30

- Male senescence
- Women with low serum T
- Muscle wasting d/t AIDS
- Blood dyscrasias
- Angioedema
- Improve athletic performance

Front 31

What is male senescence? Why would you treat with T?

Back 31

- Men whose serum levels of T are decreased due to age
- Use T to increase bone mineral density and lean mass and decrease fat mass

Front 32

When would you use T in women?

Back 32

- Women with low serum T
- Possibly increase bone mineral density, fat-free mass, and sexual function

Front 33

Why would you use T in AIDS patients?

Back 33

To treat muscle wasting associated with AIDS, which is often accompanied by hypogonadism

Front 34

What blood dyscrasias would you use T to treat? When?

Back 34

- Hemolytic anemia and idiopathic thrombocytopenic purpura
- Use androgens (such as danazol) as adjunctive treatment when they are refractory to first-line agents

Front 35

What causes Angioedema? How would you treat?

Back 35

- Caused by hereditary impairment of C1-esterase inhibitor or acquired development of antibodies against it
- 17-alkylated androgens like Stanozolol, stimulates hepatic synthesis of the esterase inhibitor

Front 36

What forms of testosterone are abused by athletes?

Back 36

Testosterone precursors:
- Androstenedione
- Dehydroepiandrosterone (DHEA)

Front 37

What are the most commonly detected anabolic-androgenic steroids in competitive athletes?

Back 37

- Tesosterone
- Stanozolol
- Androstenedione
- Dehydroepiandorsterone (DHEA)

Front 38

How effective are anabolic steroids in athletes?

Back 38

- Men who receive testosterone increased muscle strength compared to those who took placebo
- Men who exercised simultaneously experienced even greater increase in muscle strength

Front 39

What are the effects of anabolic steroid abuse?

Back 39

- Suppress gonadotropin secretion, suppressing endogenous testicular function
- Decreases endogenous testosterone and sperm production, decreasing fertility
- Diminishes testicular size
- Decreases HDL and increases LDL

Front 40

What are the side effects of anabolic steroid abuse?

Back 40

- Decreased fertility
- Erythrocytosis
- Diminished testicular size
- Gynecomastia (except DHT)
- Hepatotoxicity (17-alkylated androgens)
- Decreased HDL and increased LDL
- Psychological disorders
- Sudden death d/t cardiac disease
- Stunting of linear growth (in those who have not yet close their growth plates)
- Women get virilization: facial and body hirsutism, male pattern hair loss, and acne
- Phallic enlargement in boys and clitoral enlargement in girls

Front 41

Does fertility return after stopping anabolic steroid abuse?

Back 41

Testosterone and sperm production usually returns to normal within a few months of discontinuation, but may take longer

Front 42

Which form of T does not cause gynecomastia when taken in excess? Why?

Back 42

Dihydrotestosterone (DHT) - has a modification so that it can't be aromatized

Front 43

What are the inhibitors of testosterone secretion?

Back 43

Leuprolide = GnRH analog

Front 44

What is the action of Leuprolide?

Back 44

- GnRH analog that inhibits Testosterone secretion by inhibiting LH secretion
- Transient stimulation of gonadotropin secretion, which then down-regulates GnRH receptor and inhibits gonadotropin secretion

Front 45

What is Leuprolide used for?

Back 45

- Treatment of advanced prostate cancer
- Management of endometriosis
- Treatment of anemia caused by uterine fibroids
- Central precocious puberty

Front 46

What are the side effects of long acting GnRH analogs (Leuprolide)

Back 46

- Suppression of gonadal steroidogenesis including hot flashes and decreased bone density
- Vaginal dryness and atrophy in women
- Erectile dysfunction in men

Front 47

What is the androgen receptor antagonist?

Back 47

Flutamide

Front 48

What is the effect of Flutamide?

Back 48

- Androgen receptor antagonist
- When used alone, increases LH secretion, which stimulates higher serum T concentration

Front 49

With what should Flutamide be used? Function?

Back 49

In conjunction with a GnRH analog (Leuprolide) for:
- Metastatic Prostate Cancer

Front 50

What are the uses of Flutamide?

Back 50

- Metastatic prostate cancer with a GnRH analog (Flutamide)
- Hirsutism in women (off label)

Front 51

What are the side effects of Flutamide?

Back 51

- Galactorrhea (9-42%)
- Breast tenderness
- Gynecomastia
- Hot flashes
- Impotence
- Decreased libido
- Tumor flare
* Black box warning of HEPATIC FAILURE

Front 52

What is the 5α-reductase inhibitor drug?

Back 52

Finasteride

Front 53

What is the action of Finasteride?

Back 53

5α-Reductase Antagonist, especially Type II
- Blocks the conversion of T to DHT, especially in male external genitalia

Front 54

What are the uses of Finasteride? Side effects?

Back 54

Uses
- Benign Prostate Hyperplasia
- Male Pattern Baldness

Side Effects
- Impotence
- Decreased libido

Front 55

What drugs are used for impotence?

Back 55

- Alprostadil
- Sildenafil
- Vardenafil
- Tadalafil

Front 56

How is Alprostadil administered? Use?

Back 56

- Intracavernous injection or urethral suppository
- Used for treatment of impotence
- Erection will last 1-3 hours and is sufficient for sexual intercourse

Front 57

What are the side effects of Alprostadil?

Back 57

- Penile pain
- Urethral burning

Front 58

What is the mechanism of Sildenafil, Vardenafil, and Tadalafil?

Back 58

Phosphodiesterase 5 (PDE5) inhibitors:
- Nerves and vascular endothelial cells in the corpus cavernosum produce NO during sexual arousal
- NO stimulates formation of cyclic GMP, which relaxes smooth muscle of the corpus cavernosum and penile arteries
- Causes corpus cavernosum engorgement and erection
- Cyclic GMP accumulation is enhanced by inhibiting the cGMP specific PDE5

Front 59

What is the use of Sildenafil, Vardenafil, and Tadalafil?

Back 59

Improves erectile function (penile engorgement) in patients with erectile dysfunction

Front 60

What is the time to onset of action and duration of the PDE5 inhibitors?

Back 60

Tadalafil has a longer time to onset of action and duration (36 hours) than other PDE5 inhibitors (2-4 hours)

Front 61

What happens in men taking anti-anginal therapy AND PDE5 inhibitors for erectile dysfunction?

Back 61

Combination of Sildenafil and other PDE5 inhibitors with organic nitrate vasodilators can cause extreme hypotension

Front 62

What are the side effects of Sildenafil, Vardenafil, and Tadalafil?

Back 62

- Extreme hypotension in patients also taking nitrate vasodilators
- Headache
- Flushing
- Rhinitis
- Dyspepsia

- Sildenafil and Vardenafil can cause visual disturbances

Front 63

How can Sildenafil and Vardenafil cause visual disturbances?

Back 63

They can also weakly inhibit PDE6, the enzyme involved in photoreceptor signal transduction causing visual disturbances (changes in the perception of color hue or brightness)

Front 64

How are PDE5 inhibitors (Sildenafil, Vardenafil, and Tadalafil) metabolized? Implications?

Back 64

CYP3A4 - toxicity may be enhanced in patients who receive other substrates of this enzyme (including macrolide and imidazole antibiotics, some statins, and antiretroviral agents)

Front 65

When are PDE5 inhibitors contraindicated?

Back 65

In patients taking organic nitrate vasodilators and should be used in caution in patients taking adrenergic receptor antagonists

Front 66

What hormone is responsible for male pattern balding? What drug can treat this?

Back 66

- DHT is responsible for it
- Finasteride can treat it

Front 67

What hormone is responsible for prostate hyperplasia?

Back 67

DHT