A power point presentation on “Adrogens and anti androgenic drugs” suitable for undergraduate level MBBS students

1. Androgens, Anabolic Steroids
and Antiandrogens
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. 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

3. 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: Submaximal andrgenic and Cholestatic
jaundice
– Methyltestosterone, Fluoxymesterone – 17-alkyl substituted
derivatives
– Orally effective: Testosterone undecanoate and Mesterolone
– Lipid soluble esters: Propionate and enanthate salts

4. Testosterone
• 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.
1 2 3

5. Testosterone
17-alkyl substitution Methyltestosterone
Fluoxymesterone
• All androgens contain a Testosterone structures
• Testosterone has 19-carbons and in general its a steroidal
structure

6. Cholesterol
Pregnenolone
Progesterone
Corticosterone
11-Desoxy-
corticosterone
18-Hydroxy-
corticosterone
ALDOSTERONE
17-α- Hydroxy
pregnenolone
11- Desoxy-
cortisol
17- Hydroxy
progesterone
21,β hydroxylase
CORTISOL
11,β hydroxylase
Dehydro-epi
androsterone
Andro-
stenedione
Oestrone
Oestriol
TESTOSTERONE OESTRADIOL
ACTH

7. 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)

8. 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

9. 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

10. Androgens – Targets of Action

11. 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.

12. T DHT DHT- R
T- R
R
R
T- R
Nucleus
90%
10%
5- α
reductase
cytoplasm

13. 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

14. Therapeutic Uses of Androgens
• Androgen replacement therapy (ART)
• ART uses derivatives of testosterone, rather than synthetic
Androgens, because they are safe, effective and easy to monitor
1. Androgen deficiency: clinical diagnosis confirmed by hormone assays
– 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)
• Treated by androgen replacement therapy (ART), usually for the remainder
of life. The aim is to restore tissue androgen exposure by using the natural
androgen testosterone

15. 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

16. 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

17. Anabolic Steroids
• Synthetic androgens – higher anabolic but lower
androgenic activity (1: 3 ratio) – decreased
virilizing effect
• Similar anabolic effect, same receptors and
same androgenic effects
• Examples:
– Nandrolone propionate 10-25 mg/ml (10 – 50 mg
IM/week) – inj. Durabolin
– Nandrolone decanoate 25-100 mg/ml (25-
100mg/week) – inj. Decadurabolin
– Stanazolol (2 mg tablets (2-6 mg/day)

18. Anabolic Steroids – Therapeutic
uses
1. Catabolic states: Acute illness, severe trauma, major
surgery
2. Renal insufficiency
3. Osteoporosis
4. Suboptimal growth in boys
5. Anaemia: haemolytic and malignancy associated
6. Performance enhancement

19. Anti-androgens
• Danazol
• Cyproterone acetate
• Flutamide
• Finasteride, Bicalutamide

20. Danazol
• Ethisterone derivative effective orally
• Weak androgenic, anabolic, progestational & glucocorticoid action
• Also Labeled as impeded/attenuated androgen:
– Induces some androgen specific mRNA production
• Prominent effect –
– suppression of Gn (FSH and LH) secretion from Pituitary - FSH & LH
release in both sexes decrease – inhibition of testicular/ovarian function
directly
– Directly by inhibition of steroidogenic enzymes
– Results in endometrial atrophy and ammenorrhoea
• Half life – 12-18Hrs
• Preparations:
– 50. 100 and 200 mg. tablets
– Dose is 200 – 600 mg/day

21. Danazol – contd.
• Uses:
– Endometriosis : 3-6
months course
– Menorrhagia
– Fibrocystic breast
disease
– Hereditary
angioneurotic oedema
– Gynecomastia
– Infertility
• Side effects: Dose
related
• Amenorrhea (High
doses)
• Androgenic effects -
Decreased breast
size, hirsutism, weight
gain etc.
• Hot flashes, night
sweating, cramps
• Loss of libido in men

22. Cyproterone acetate
• Direct antiantiandrogenic action
• Progesterone like activity – inhibits LH causing
antiandrogenic action
• Competes with dihydroteststerone for intracellular
receptor
Uses:
• Precocious puberty in Boys
• Inappropriate sexual behaviour in men
• Virilization in women
• Limited use

23. Flutamide
• Non-steroidal and no hormonal activity but specific
antiandrogenic action
• Active metabolite “2-hydroxyflutamide” causes
competitive block Androgen action – Accessory sex
organs and Pituitary
• Increased LH secretion by blocking feedback inhibition
• Plasma testosterone level may increase – to overcome
direct antiandrogenic effect
• Uses:
– Cancer of prostate along with GnRH agonist
– Female hirusitism
• ADRs: Gynaecomastia and breast tenderness and also
liver damage
• Dose: 250 mg tds.

24. Finasteride
• MOA: Competitive inhibitor of 5 α-reductase
– Selective of 5 α-reductase type-2 isoenzyme
– Mainly acts on urogenital tract (prostate) – DHT level lowered
but not plasma Testosterone level
• Uses:
1. Benign prostatic hypertrophy – decrease in prostate volume,
improved urinary flow, reversion of disease progression
– Withdrawal results in regrowth – prolonged therapy
1. Male pattern baldness
– Kinetics: effective orally, metabolized in liver (t1/2 – 4-6
hrs)
– Side effects: loss of libido, impotence, decreased
ejaculation
– Doses: 5 mg OD (BHP) or 1 mg OD in baldness

25. Erectile Dysfunction Drugs
PDE-5 Inhibitors: Sidenafil, tadalafil
– Nitric oxide (NO) pathway

26. Sidenafil
• Absorbed orally and half-life is 4 Hrs
• Inhibits PDE5 in the corpus cavernosa of the penis
• 50 mg 1 h before sexual activity
• Potentiate nitrate’s hypotension activity
• Ketoconazole, erythromycin, Verapamil increases its level – due to
CYP3A4 inhibition
• renal & hepatic disease increases its level
• Side effects:
– headache, flushing, dyspepsia, myalgia, loose motion
– Colour vision impairement (PDE6)
– NAION
– Fall in BP and precipitation of MI
– Patient with Nitrates for angina
• Other Uses: Pulmonary hypertension

27. Summary
1. Testosterone – Pharmacological action,
MOA, Pharmacokinetics, Uses and its
preparations
2. Anabolic steroids and uses
3. Antiandrogens – details of Danazol and
Flutamide
4. PDE – 5 inhibitors, MOA and Adverse
effects

28. Thank you