Androgens, Anabolic Steroids, Antiandrogens and Drugs for Erectile Dysfunction

What are the types of natural androgens?

testosterone, and 5α-dihydrotestosterone (DHT)

What is the role of natural androgens?

responsible for development of sex organs and pubertal secondary sexual characters in males

What is the role of Pulsatile GnRH?

stimulates FSH/LH release

What is the role of constant GnRH?

initially stimulates then inhibits FSH/LH

How is testosterone synthesized?

Secreted by leydig cells (90%) and adrenal cortex (10%) the converted to DHT by 5α-reductase and estradiol (E2) in liver/fat by aromatase

What is the target tissue action of testosterone?

- LH inhibition at pituitary

- Erythropoiesis

- increased bone/skeletal muscle mass and strength

What is the target tissue action of Dihydrotestosterone?

Prostate growth in elderly and balding in adults

What is the mechanism of action of androgen agonists?

Androgens binds to intracellular AR leading to DNA response elements later translated to specific proteins

What are the reproductive effects of androgens?

- male sexual differentiation in fetus

- growth of prostate and seminal vesicles

- maintenance of sexual function

- pubertal penile and scrotal growth

What are the anabolic actions of androgens?

- ↑ protein synthesis ↓ breakdown

- Na+ and water retention

- ↑ in muscle mass and erythropoiesis

- ↑ skeletal growth

- ↑ BMD but osteoporosis in old age when levels decline

What are the metabolic actions of androgens?

↑ hepatic synthesis of clotting factors,

What are the effects of androgens in females?

hirsutism, deepening of voice, frontal baldness, acne, clitoromegaly, prominent musculature, suppression of ovulation and irregular menstruation

What is the clinical use of AR agonists?

- Androgen replacement in primary and secondary male hypogonadism

- gender-affirming masculinizing therapy

- catabolic states (cachexia and protein anabolism)

What are the adverse effects of AR agonists?

Oligospermia, testicle atrophy, infertility, gynecomastia, low libido, growth of prostatic neoplasm, virilization of female fetus

What are the precautions and contraindications of AR agonsits?

pregnancy, lactation, breast/prostate carcinoma, HTN, elderly, liver and kidney dysfunction, nephrotic syndrome, CHF

What are the types of anabolic steroids?

Oxymetholone, Oxandrolone, Nandrolon decanoate

What is the increased action of anabolic steroids?

3x more anabolic activity than androgenic activity

How much of the therapeutic dose is increased in anabolic steroid abuse?

25-30x the therapeutic dose

What is the mechanism of action of antiandrogens?

- gonadotropin suppression

- inhibition of testosterone synthesis

- inhibition of testosterone to DHT conversion

- androgen receptor blockade

What are the clinical uses of antiandrogens?

precocious puberty, hirsutism, acne, and testicular/prostate cancer

What are the types of GnRH agonists?

leuprolide, goserelin, histrelin, triptorelin

What is the mechanism of action for GnRH agonists?

suppress the release of FSH and LH when given continuously that later decreases testosterone production through desensitization

What are the adverse effects of GnRH agonists?

hypogonadism, ￬ libido, erectile dysfunction

What are the clinical uses of GnRH agonists?

Precocious puberty, BPH, Androgen-sensitive prostate cancer (palliative)

What are the types of GnRH antagonists?

degarelix, relugolix

What is the mechanism of action of GnRH antagonists?

Blocks GnRH action on anterior pituitary gonadotrophs, inhibiting LH secretion immediately

What is the clinical use of GnRH antagonists?

androgen-sensitive prostate cancer (palliative)

What are the types of AR antagonists?

flutamide, bicalutamide, apalutamide, enzalutamide, darolutamide

What is the mechanism of action of AR antagonists?

non-steroidal competitive antagonists at androgen receptors that block target tissue action

What are the adverse effects of AR antagonists?

decreased libido, gynecomastia, decreased muscle strength, osteoporosis, hot flashes

What is the clinical use of AR antagonists?

Used in combination with GnRH agonists for Rx of prostatic cancer

What is an advantage of Enzalutamide?

a "pure" antagonist with no partial agonistic effect that is useful for “castration-resistant” prostate cancer

What are the types of 5-𝛼 Reductase Inhibitors?

finasteride: only inhibits type-2 5α reductase

dutasteride: inhibits both types-1 & 2 of 5α reductase

What is the mechanism of action of 5-𝛼 Reductase Inhibitors?

Blocks tissue conversion of T to DHT enhancing hair growth and 𝛼1A adrenoceptor and assisting in urinary flow

What are the adverse effects of 5-𝛼 Reductase Inhibitors?

Gynecomastia and sexual dysfunction

How are 5-𝛼 Reductase Inhibitors inhibited?

in combination with tamsulosin

What are the types of 17 𝛼 hydroxylase and 17,20-lyase inhibitors?

abiraterone

What is the mechanism of action of abiraterone?

halts the synthesis of androgens in testis, adrenal, prostate tumor cells, cortisol and its precursors

How is abiraterone administered?

must be given with corticosteroid supplementation

What is the use of abiraterone?

castration-resistant advanced prostate cancer

What is the adverse effect of abiraterone?

Adrenal insufficiency

What is the physiology of an erection?

NO release stimulating parasympathetic neurons to release Ach for vasodilation

What are the types of PED-5 Inhibitors?

Sildenafil, Vardenafil, Tadalafil, Avanafil

What is the mechanism of action of PED-5 Inhibitors?

Increases t1/2 of cGMP leading to vasodilation only in the presence of sexual stimulation

What is the comparable onset of action to duration for each type of PED-5 Inhibitors?

Sildenafil: 30-60min / 12 hrs

Vardenafil: 30-60min / 10 hrs

Tadalafil: 30-120mins / 36 hrs

Avanafil: 15-30mins / 6 hrs

What are the adverse effects of PDE-5 inhibitors?

HA, flushing, bluish discoloration of vision (sildenafil, vardenafil)

What are the DDIs of PDE-5 inhibitors?

Hypotension when used with organic nitrates (nitroglycerin) or with α blockers (prazosin, doxazosin etc.)

What are the clinical uses of PDE-5 inhibitors?

Erectile dysfunction, BPH (Tadalafil), Pulmonary hypertension