Androgens, Anabolic Steroids, Antiandrogens

Question 1

Androgens

Biosynthesis

Answer 1

Cholesterol–> pregnenolone–>progesterone
Progesterone–>weak androgens–>Estriol, estrone and
estradiol

Estrogens are produced by androgenic precursors.

Question 2

Regulation of Male Sexual Hormone Production

Answer 2

Hypothalamus–> GnRH–> Ant Pituitary
Ant. Pituitary–> LH and FSH–> Testes

LH: Leydig Cells to produce Testosterone
FSH: Sertoli Cells to–> spermatogenesis

Testosterone has negative feedback on both the Ant Pituitary (via estrogenic R as testosterone–>estradiol) and the Hypothalamus

Question 3

Factors req for normal Spermatogenesis

Answer 3

FSH

Androgen (Testosterone)

Question 4

Classification of Androgens

Answer 4

Endogenous
Therapeutically used:
testosterone esters
17 alkylating derivative

Question 5

Characteristics of Endogenous Testosterone

Answer 5

Produced in: testes, ovaries, adrenal cortex

Testosterone: 2 possible conversions

• dihydrotestosterone by 5a reductase
• estradiol by aromatase

Weak androgens can be converted–> testosterone

Question 6

Characteristics of Therapeutically Used Androgens

Answer 6

Testosterone Esters (ester bond with OH group)
Testosterone cypionate
Testosterone underccanoate

17 alkylating derivative
Methyltestosterone
Stanozolol
Nandrolone

Question 7

Main Actions of Androgens

Answer 7

Dev. of male 1ary and 2are sexual characteristics
Stimulation of prostate and seminal vesicle function
Libido maintenance
Stimulation of spermatogenesis (with FSH!)
Stimulation of longitudinal growth
(epiphyseal closure done by estradiol)
Anabolic effects: Positive N balance
Stimulation of Sebaceous Glands
Stimulation of EPO production
Decrease HDL, increase LDL, clotting factors
((Decreases (!) transport proteins: opposite of estrogen))
Alopecia in those genetically susceptible
Prostate Hyperplasia in Elderly

Question 8

Molecular Mode of Action

Answer 8

Cytoplasmic R has 2 isoforms (ARa and ARb) due to
alternative splicing (one gene)
DHT is more active compound and better oral bioavailability

Genomic direct, genomic indirect, non genomic actions

Question 9

Androgens

Pharmacokinetics

Answer 9

Good oral absorption, marked first pass metabolism
Alkylated androgens have good oral bioavailability and
are resistant to 1st pass metabolism
Binds to SHBG in plasma
Metabolised in liver –> 17 ketosteroid
then conjugated with glucuronate and sulfate and
excreted renally

Conversions possible:
DHT
Estradiol

Question 10

Androgens

Medical Uses and CIs

Answer 10

Medical Uses:
Hypogonadism (hypothalamic and pituitary)
testosterone drug of choice due to conversion
Improve muscle mass and quality of life in elderly
Hereditary amgioneurotic edema (due to lack of
complement inhibitor)
Only 17 alkylated derivatives efficacious

CIs:
Pregnancy (malformation of genitalia in both cases)
Prostate Hyperplasia and cancer
Congestive HF: CI due to possible increase blood visco.

Question 11

Androgens

Side Effects

Answer 11

Virilising SE
female: menstruation disorders, male sex characteristic
puberty male: puberty praecox, epiphyseal closure
male: reduced spermatogenesis (inhibition FSH secret)
–> infertility. Prostate hyperplasia, possibly cancer

Feminising SE due to conversion to estradiol
male: gynecomastia

Others:
   Acne
   Water and salt retention
   Increased LDL, decreases HDL
   Intrahepatic cholestasis
   Alkylated derivatives: Increased plasma bilirubin, GOT

Question 12

Androgens

Endogenous Testosterone
Names and Characteristics

Answer 12

Testosterone, DHT

Transdermal patch

Question 13

Androgens

Testosterone Esters
Names and Characteristics

Answer 13

Testosterone cypionate, Testosterone undeccanoate

long acting esters–> prodrugs releasing free
testosterone
IM depot injections–> active for 1-4 weeks

Testosterone Undeccanoate
Effective orally as mainly absorbed via lymphatics

Question 14

Androgens

17 Alkylating Derivatives
Names and Characteristics

Answer 14

EFFECTIVE ORALLY
Methyltestosterone, Stanozolol, Danazol

Uses: hereditary angioneurotic edema by increasing C1q inhibitor synthesis

Special SE: Liver damage
Intrahepatic cholestasis
Elevation of bilirubin plasma level
Hepatic adenoma and carcinoma (rare)

Danazol is also used in endometriosis, hemophilia A (mild cases, increase synthesis of factor VII)

Question 15

Anabolic Steroids

General
Abuse
Side Effects

Answer 15

General: Used for + N balance–> protein synthesis
Th dosis: increases muscle mass and performance in
women, kiddies, hypogonodal men
Extreme high dosis: same also in healthy men when
combo with training and increased protein intake

Abuse
Weight lifters, body builders, athletes

Side Effects
Virilising SE
female: menstruation disorders, male sex characteristic
puberty male: puberty praecox, epiphyseal closure
male: reduced spermatogenesis (inhibition FSH secret)
–> infertility. Prostate hyperplasia, possibly cancer

Feminising SE due to conversion to estradiol
male: gynecomastia

Others:
Acne
Water and salt retention
Increased LDL, decreases HDL

Question 16

Anabolic Steroids

Drug Names

Answer 16

Endogenous Testosterone: Testosterone and DHT

17 alkylating derivatives: Stanozolol, Nandrolone
classical anabolic steroids used illegaly

Question 17

Anti Androgens or SARMs

Medical Use

Answer 17

Hirsutism in females
Acne/Seborrhea
Androgen dep. Alopecia
Prostate Hyperplasia (often overexpression) and cancer
Pubertas Praecox
Some countries: th of sexual offenders

Question 18

Anti Androgens

Drug Names

Answer 18

Dienogest, Cyproterone acetate
Progestin activity–> - feedback; androgen antagonists

Flutamide
No Progestin activity
Inhibits - feedback effect of testosterone–> increases
testosterone therefore req high doses

Finasteride
5 a reductase (testosterone–>DHT) inhibitor
Teratogenic

Spironolactone
Aldosterone antagonist, androgen antagonist to some
extent

Ametidine
H2 antagonist and some androgen antagonism

Question 19

Uses of SARMs in Females with Breast Cancer

Answer 19

Some cases:

tumor cells don’t express estrogen, progesterone Rs or HER2–> but may express androgen Rs.