Androgens and Antiandrogens

Dr. Chen

three main endogenous androgen

testosterone, DHT, androstenedione

main function of endogenous androgens

Stimulates or controls the development and maintenance of male characteristics
in vertebrates by binding to androgen receptors

androgen Structure elements required for bioactivity

C19 steroid scaffold with O in both 3- and 17-positions

Testosterone:

Most common naturally occurring androgen found in the blood

DHT:

Reduced from testosterone by 5-reductase, more potent than testosterone

starting material of biosynthesis

cholesterol

common precursor for biosynthesis

pregnenolone

key enzyme for biosynthesis

CYP17A (P450 enzyme 17R-hydroxylase-17,20-lyase

key metobolite for estrogen metabolism

more potent DHT

key enzyme for estrogen metabolism

5alpha-reductase

key reaction for estrogen metabolism

Reduction reaction at C4-C5 double bond to 5-OH

structure modification of esters of testosterone

(propionate, enanthate, cypionate) from 17-OH group. Prodrugs

purpose of esters of testosterone

overcome rapid first-pass effect

17alpha-methyltestosterone MOA

17alpha-methyl group addition to testosterone, blocking the metabolism of the 17β-OH; oral bioavailable, long DOA, adding 4-OH can improve activity.

Fluoxymesterone

9α-F and 17alpha-methyl group additions to testosterone, 20x the anabolic activity
and 10x the androgenic activity; sodium and water retention activities (mineralocorticoid activity

testosterone anabolic effect

stimulate muscle growth

anabolic agents

Used therapeutically to stimulate muscle growth and appetite, induce male puberty and treat chronic wasting conditions, such as cancer and AIDS. Abuse potential

antiandrogens

androgen antagonists or testosterone blockers, prevent androgens (testosterone and
DHT) from mediating their biological effects in the body

antiandrogens MOA

Block the AR or inhibit or suppress androgen production.

antiandrogen therapuetic applications

androgen-dependent conditions like prostate cancer, enlarged prostate,
scalp hair loss, acne etc

antiandrogen classes

androgen receptor antagonist

androgen synthesis inhibitors

5-alpha- reductase inhibitors

antigonadotropins

Androgen receptor antagonists:

bind directly to and block the AR

Androgen synthesis inhibitors:

inhibit the androgen biosynthesis

5alpha-reductase inhibitors:

inhibit synthesis of DHT from testosterone

Antigonadotropins:

suppress the GnRH-induced release of gonadotropins and consequent activation of gonadal androgen production

treatment of AR+ prostate cancer

hormone therapy, androgens, lowering androgen lvls, drugs

AR+ prostate cancer hormone therapy

or androgen suppression therapy, to reduce androgen levels in the body

AR+ prostate cancer androgens

necessary for prostate cancers to grow

AR+ prostate cancer

owering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does NOT cure prostate cancer

AR+ prostate cancer DRugs

GnRH agonists, GnRH antagonists, CYP17A inhibitors, and AR antagonists

AR antagonist 1st gen

competitively bind to the ligand-binding domain on androgen receptors

AR antagonist 1st gen Drugs

Flutamide, Nilutamide, and Bicalutamide

Ar antagonist 2nd gen

competitively suppress androgen-AR binding; inhibit the AR translocation from cytoplasm to nucleus, the coactivator recruitment, and the AR-DNA binding

AR antagonist Drugs

Enzalutamide, Apalutamide, Darolutamide

CYP17A inhibitors as androgen biosynthesis inhibitors

P450 enzyme 17R-hydroxylase-17,20-lyase (CYP17A1), converts progesterone to 17alpha-OH progesterone (17alpha-hydroxylase), and 17alpha-OH progesterone to androstenedione (17,20-lyase)

CYP17A inhibitors as androgen biosynthesis inhibitors drugs

abiraterone and ketoconazole

abiraterone

decreases circulating levels of androgens; for mCRPC and mCSPC

ketoconaxole

antifungal drug, 2nd line treatment for certain type of PC

5alpha-Reductase inhibitors (DHT blockers) MOA

inhibit 5alpha-Reductase, block the synthesis of more potent DHT from testosterone

5alpha-Reductase inhibitors applications

primarily in the treatment of enlarged prostate and scalp hair loss

5- alpha- reductase inhibitor drugs

finasteride and dutasteride

antigonadotropin MOA

Suppress the activity and/or downstream effects of FSH and LH. Decrease the levels of sex steroids in the body

antigonadotropin application

hormonal birth control, treatment of hormonally sensitive cancers

GnRH agonists:

Synthetically modeled after the natural GnRH decapeptide with specific modifications, usually double and single substitutions and typically in position 6 (amino acid substitution), 9 (alkylation) and 10 (deletion). These substitutions inhibit rapid degradation.

GnRH antagonists:

Antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and the action of gonadotropin-releasing hormone (GnRH). Used in the treatment of prostate cancer and other indications.

1) Peptide molecules:

similar in structure to natural GnRH.

2) Small molecules:

non-peptide, no GnRH similarity.

3) Differences from agonists:

GnRH agonists cause an initial stimulation of the hypothalamic–
pituitary–gonadal axis (HPG axis) that leads to a surge in testosterone or estrogen levels

GnRH antagonists have an immediate onset of action and rapidly reduce sex hormone levels without an initial surge.