Androgens, Anabolic Steroids

and Antiandrogens
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong
Introduction

• Normally, testes are responsible for male characters

• Testes Functions:
1. Production of Androgenic hormones
2. Spermatogenesis occurring within the seminiferous tubules
• Androgens are the substances which cause
development of secondary sex characters in the
castrated male.
 Classification - Androgens
• Natural Androgens:
– From Testes:
• Testosterone (5-12 mg daily)
• Dihydrotestosterone (more active) by 5 α-reductase
– From Adrenal cortex: (weak androgens)
• Dehydroepiandrosterone
• Androstenedione
{Females testosterone: 0.25 – 0.5 mg/day (ovary + adrenals)}
• Androsterone – metabolite of testosterone
• Synthetic androgens:
• Methyltestosterone, Fluoxymesterone – 17-alkyl substituted
derivatives
– Orally effective: Testosterone undecanoate and Mesterolone
– Lipid soluble esters: Propionate and enanthate salts
Testosterone
1 2 3

• Produced from cholesterol primarily by LEYDIG CELLS in testes

• Secreted at adult levels during 1st trimester1, during neonatal life2,
continually after puberty3
• Converted by 5 α-reductase to the more potent, 5α-dihydrotestosterone
(DHT), which is responsible for many of the responses to testosterone in the
urogenital tract (e.g. prostate gland hyperplasia)
• Binds to and activates a single androgen receptor (AR)
• Androgen receptors are present in many tissues including reproductive
tissue, skeletal muscle, brain, kidney etc.
 Cholesterol ACTH

Oestriol
Pregnenolone 17-α- Hydroxy Dehydro-epi
pregnenolone androsterone

Progesterone 17- Hydroxy Andro-

progesterone stenedione Oestrone

11-Desoxy- 21,β hydroxylas e

corticosterone
11- Desoxy-
cortisol
Corticosterone
11,β hydroxylase
18-Hydroxy-
corticosterone

ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL

 Regulation of Secretion

•Testosterone secretion -
Leydig`s cell of testes
•Pulsatile LH – Pituitary
•FSH – only Spermatogenesis
•High testosterone – inhibits LH
(atrophy)
•Oestrogen – feedback inhibition
•Inhibin – FSH inhibition

•Plasma level of Testosterone:

0.3 to 1 mcg/dl (male)
20 to 60 ng/dl (female)
 Pharmacological Actions -
Testosterone
Androgenic Effects:
• In the foetus, testosterone promotes development of male reproductive tract
– internal genitalia, vas deferens, epididymis and external genitalia (sex
differentiation)
• During puberty, testosterone promotes development of :
– primary sexual characteristics (e.g. enlargement of penis, scrotum and
testes)
– secondary sexual characteristics (e.g. male body shape, axillary/pubic
hair, deeper pitch of voice, thickening of skin – greasy, loss of
subcutaneous fat)
– Adulthood: Baldness, BHP, Prostatic cancer
Testes: Promotion of spermatogenesis and maturation of sperm
• Moderately high dose causes testicular atrophy by inhibiting Gn
secretion
• Higher doses: direct sustaining effect and less marked atrophy
 Testosterone – anabolic effects
• Pubertal spurt of growth at puberty
– both boy and girl
• Bone growth – thickness and
length
• Oestrogen from testosterone –
fuse of bones and mineralization
• Muscle building – if aided by
exercise
• Positive nitrogen, minerals and
water balance – increase in weight
• Increase in appetite
• Acceleration of erythropoiesis
Androgens – Targets of Action
 Mechanism of Action
Androgen receptor:
• Both, testosterone and DH testosterone – act via Androgen
receptors (AR) – nuclear receptor super family
• Ligand binding and DNA binding domains
• Mutations in AR: Incomplete sexual development
– Kennedy`s disease: in spinal and
bulbar muscle atrophy
Estrogen Receptor:
•Teststerone converts to
estrogen by CYP19
•Deficiency of CYP19
and estrogen receptor –
failure to fuse long bones,
osteoporosis etc.
 cytoplasm Nucleus

T- R T- R

10%

90%
T DHT DHT- R

R
5- 
reductase
 Androgen - Pharmacokinetics
• Absorption: undergoes high first pass
metabolism. Therefore IM injections or synthetic
preparations are used

• Transport: highly protein bound in plasma to

albumin & sex hormone binding globulin (SHBG)
(98%, SHBG, albumin)
• Metabolism:
– by liver enzymes : androsterone & etiocholanolone
– excretion by urine after conjugation
– small quantity of oestrogen also produced from
testosterone, but not from fluoxymesterone and
Dihydrotestosterone
 Therapeutic Uses of Androgens
• Androgen replacement therapy (ART)
•
1. Androgen deficiency: clinical diagnosis confirmed by hormone assays
The aim is to restore tissue androgen exposure by using the natural androgen testosterone

is usually caused by
• underlying testicular disorders (high LH, but low testosterone levels)
• hypothalamic-pituitary disorders (low LH and low testosterone
levels)
• Goal: Mimic the normal testosterone concentration as closely as possible
(serum concentration monitoring)
• If untreated, does not shorten life expectancy, but is associated with
significant morbidity (ambiguous genitalia, delayed puberty & infertility)
•
 Uses – contd.
2. Hypopituitarism
– Monitoring at anticipated time of puberty
2. AIDS related muscle wasting
3. Hereditary angioneurotic edema (methyltestosterone)
4. Ageing
Misuse: involves prescription with no acceptable medical
indication
• Examples of misuse include:
– male infertility
– male sexual dysfunction or impotence
– “male menopause” (andropause)
no convincing evidence that androgen therapy is either
effective treatment or safe for older men unless there
is frank androgen deficiency
Androgens –
Adverse Effects
• Virilization:
– may occur in women receiving relatively high doses
for prolonged periods, such as for estrogen-dependent
mammary carcinoma
• Cholestatic Jaundice
– may be produced by steroids possessing a 17-alkyl substituted
group
• Priapism (sustained erection)
• Oligospermia
• Oedema--via promotion of salt and water retention
• Precocious puberty and short stature
• Acne
• Hepatic carcinoma`````
• Gynaecomastia