session 14

Two Endogenous Androgens

estosterone

• 3- to 5-Fold less potent than DHT

• Primary circulating androgen

• Primary androgen in bone, muscle and brain

5a-Dihydrotestosterone (DHT)

• Most potent endogenous androgen

• 6 - 8% of testosterone is converted to DHT in target tissue

• Primarily androgen in gonadal tissue and prostate

Uses of Androgens and Anti-Androgens

• Androgens: Androgen Insufficiency

– Male Hypogonadism/Andropause

– Erectile Dysfunction

• Androgens: Anabolic Steroids

– Performance Enhancement

– Building Muscle Mass, Bone Density

• Anti-Androgens: Treatment of Androgen-Sensitive

Hyperplasias

– Prostate Cancer

– Benign Prostatic Hyperplasia (BPH)

What About Using Testosterone & DHT as Drugs?

• Testosterone – Available in US

– Buccal Mucosal

- Intramuscular Injection

- Transdermal Gel

- Transdermal Patch

- Sublingual: Available Through Compounding but Rarely Used

Anabolic Steroids: Steroids “On Steroids”

• Testosterone and DHT Have Both Androgenic & Anabolic Activities

• Anabolic Steroid Drug Discovery Has Pursued Two Goals

- Greater Potency

- Greater Selectivity for Anabolic Processes over Androgenic Processes

Androgenic Steroids Target Reproductive Pathways of Androgen Physiology

Anabolic Steroids Target Metabolic Pathways of Androgen Physiology

What is the Down Side of Taking Anabolics

Most Anabolics (including SARMS) Retain Some Degree of Androgenic Activity

• Some Drug Reaches the Hypothalamus/Pituitary Where it Acts as an Androgen

• Decreases Natural Production of Testosterone Through the Negative Feedback Loop

• This Results in Low Levels of DHT in Gonadal Tissue & Prostate

• Anabolics Can Actually Have Side Effects Similar to Androgen Antagonists in Those Tissues

Anti-Androgens

Three Classes of Anti-Androgens

Steroidal Androgen Receptor Antagonists

• Bind to AR

• Prevent Testosterone/DHT from Binding

Non-Steroidal Androgen Receptor Antagonists

• Bind to AR

• Prevent Testosterone/DHT From Binding

Biosynthesis Inhibitors

• Inhibit the Enzymes that Produce Androgens

Used Primarily to Treat Androgen-Sensitive Prostate Cancer

Androgen Biosynthesis Inhibitors

• Two Forms of 5a-Reductase

- Type 1: In skin, muscle, bone

- Type 2: In prostate, other reproductive tissues

• Used to Treat Benign Prostatic Hyperplasia (Enlarged Prostate)

- BPH caused by too much DHT in prostate

- 5a-reductase inhibitors prevent conversion of testosterone to DHT

• Dutasteride inhibits Type 1 and Type 2 5a-reductase; finasteride is Type 2 selective

• Both lower DHT, dutasteride more completely because it blocks both isoenzymes

• Finasteride is also used to treat male pattern baldness

SARMs: Selective Androgen Receptor Modulators

• Interest in SARMS based on Success of SERMs

• Ideal SARM:

- Androgen Agonist in Testosterone-Utilizing Tissues

- Little or no Effect in DHT-Utilizing Tissues

- Unlike Drugs Used Today (Testosterone Esters), SARMS Would be Orally Bioavailable (Non-Steroidal)

• Valid Therapeutic Indications:

- Men: Andropause, Osteoporosis, Age-Related Loss of Muscle Mass

- Women: Osteoporosis, Low Libido (Without Risk of Viralization)

• Risk: Abused as Performance Enhancing Drugs Most SARMs are Non-Steroidal Anabolics

Testosterone is used as an anabolic agent, but it can be detected and requires a prescription to obtained

• Testosterone Use Detected by Assessing the Ratio of Testosterone (17b-OH) to Epitestosterone (17a-OH)

Measuring Anabolic/Androgenic Ratio

hershberger assay

• Muscle is a Tissue that Responds to Anabolic Activity

• Prostate is a Tissue that Responds to Androgenic Activity

• When a Rat is Castrated, Muscle Mass Declines Significantly

• Treatment With an Anabolic Steroid Increases Muscle Mass

Significantly but Has Little Effect on Prostate Mass

1. Castrate Rat

2. Treat with Testosterone or Anabolic Steroid in Question

3. Measure Muscle Mass and Prostate Mass

The Higher the Ratio of Compared to Testosterone,

The Higher Degree of Anabolic Activity the Steroid Has