this class is in brief for under graduate understanding and examination purpose

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

2. GnRH-gonadotropin release hormone
LH-ICSH-Interstitial cell stimulating hormone
FSH-inhibin- supresses FSH
activin- stimulates FSH synthesis
FSH in males-spermatogensis, sertoli cells
LH in males-androgen and testosterone in leydig cells
SERTOLI cells-gonadal peptides- Inhibin- b and activin
FSH germ cell proliferation and maturation in
semniferous tubules

3.  Naturally occurring androgenic hormones are:
1. Testosterone, the principal androgenic hormone
produced by the Leydig cells of testis.
2. Dehydroepiandrosterone (DHEA) (Adrenal cortex
produces DHEA)
3. Androstenedione
 The testis produce other hormones like 1) Small
quantities of Estradiol 2) Inhibin and 3) Activin

4.  Testosterone preparations:
Use for androgen replacement:
- Testosterone I.M; S.C
- Testosterone propionate I.M, S.L
- Testosterone cypionate I.M; depo I.M
- Methyltestosterone O; S.L
- Fluoxymestrone O
Use for breast cancer:
Testolactone (progesterone derivative and aromatase
inhibitor)

5. Use for anabolism (osteoporosis):
Androgen:anabolic ratio=1:2 or 1:3 (promote + ve
anabolism and muscular growth but little effect on
sex)
- Ethylestrenol O
- Stanozolol O
- Oxandrolone O
- Nandrolone decanoate I.M
- Methandienone O

6. - Estrogens: Diethylstilbesterol; mestranol...
- Progestins: Cyproterone acetate
- GnRH superagonists (Leuprolide acetate); GnRH
antagonists (Ganirelix)
- Flutamide; Bicalutamide and Nilutamide
- 5α- reductase inhibitors: Finasteride
- Ketoconazole
- Spironolactone
- Gossypol

7. Androgenic Steroids
CH3
OH
O
CH3
CH3
O
CH3
O
CH3
OH
O
CH3
H
Androstendione
(Andro)
5a-Dihydro-testosterone
Testosterone
Structure and Nomenclature
(17b-hydroxy-androst-4-en-3-one)
3D-structure
(androst-4-en-3,17-dione)
(17b-hydroxy-5b-androstan-3-one)
3D-structure

8. Androgens Antagonists
NH
CF3
S
F
CN
O O O
CH3OH
NH
CF3
O
CH3
NO2
CH3
O
CH3
CH3
OH
CH
N
CH3
CH3
N
H
O
O
N
H
CH3
CH3
CH3
H
Danazol
(endometriosis)
Finesteride
(baldness)
Bicalutamide
(prostate cancer)
Flutamide
(prostate cancer)

9. Biosynthesis and Metabolism of Testosterone
CH3
CH3
OH
CH3
CH3
CH3
O
OH
CH3
CH3
OH
O
CH3
O
CH3
O
CH3
OH
O
CH3
H
CH3
CH3
H
OH
OH
Cholesterol Pregnenolone Testosterone
Androstendione5a-DHTOther metabolites

10. 1. 3.
2.
hormonal families of the
anterior lobe:

11. Androgenic Steroids – Physiological Activities
Androgenic Activity
Growth and development of male sex organs
• Important for male sex drive and performance
• Development of secondary sexual characteristics
• Important role in spermatogenesis
Anabolic Activity
• Development of muscle mass
• Reverse catabolic or tissue-depleting processes

12.  Transport & MOA of androgens:
SHBG
5α-reductase
Testosterone 5α-dihydrotestosterone (sex
organs)
(skeletal muscles)
cytosolic; nuclear receptors
increase transcription of a specific protein
androgen effects
DHT is 10 times more potent than testosterone and
mediates effects of testosterone on skin and sexual
organs (prostate; seminal vesicle, epididymis…)

13. - Virilizing=masculinizing effect
1° & 2° sexual characteristics
- ↑ Spermatogenesis
- ↑ Erythropoiesis
- Anabolic or growth promoting effect (bone; skeletal
muscles)
 Pharmacokinetics-Testosterone metabolism:
Androsterone
Hepatic → 17-ketosteroids
Etiocholanolone

14. O
CH3
CH3
O
O
H
HH
Testolactone - Teslac®
TESTOLACTONE
Indications: palliative therapy in advanced disseminated
breast cancer
MOA: irreversible inhibitor of the enzyme steroid
aromatase that is responsible for the synthesis of
estrone from androstenedione
Hepatic metabolism
Most commonly used androgen for breast cancer.
Few or no androgenic side effects - hirsutism
Adrenal estrogen depletion – post menopausal women
Contraindicated in male breast cancer

15.  Mild androgenic, anabolic and progestational activity
 Treatment of endometriosis, fibrocystic disease of breast
and premenstrual tension syndrome
 Used to prevent the attacks of hereditary angioneurotic
oedema recurrent oedema of skin and larynx these
patients lack endogenous inhibitor of activated first
component of complement danazol increases serum
conc of C1
 Danazol withdrawl after 3-4 monthsrebound fertility
 Used in hemophiliaproco-agulant factor VIII increased
 S/E-hot flushes, muscle cramps, teratogenic

16. 1. Replacement therapy in men: hypogonadism,
impotency; ↓ libido; aging, infertility
2. Anemia: aplastic or other anemia, leukemia;
lymphoma (largely replaced by recombinant
erythropoietin)
3. Protein anabolic steroids-METHANDIENONE,
NANDROLONE, OXYMETHOLONE, STANOZOLOL
4. Osteoporosis(either alone or in conjunction with
estrogens. Replaced by bisphosphonates)
5. Angioneurotic edema-danazol
6. Endometriosis and fibrocystic disease of breast-
Danazol

17. 1. Virilization (masculinization)
2. Hirsutism; acne; menstrual disorders
3. Precocious puberty & hirsutism in children
4. Salt & water retention
5. Jaundice; gall bladder stones (methyltestosterone)
6. Enlargement of prostate
7. Liver cancer

19. ANTIANDROGENS

20. OSTARINE-
Customized response-selective anabolic effect on
bones and muscles except androgenic effect on
prostate and testis(10:1)
-females-increase bone mas and libido without causing
virilization, devoid of hepatotoxicity
HERSHBERGER ASSAY-for determining the androgen
and anabolic ratio(ventral prostate and levator ani
muscle of male rats)

21. - Carcinoma prostate
- Benign hyperplasia of the prostate (Finasteride)
- Severe acne and hirsutism (Spironolactone;
Cyproterone acetate)
- Precocious puberty
- Antifertility agents ( contraceptive) (Gossypol)
- baldness (Cyoctol=topical antiandrogen; Finasteride)
- Female disorders: dysfunctional uterine bleeding,
endometriosis advanced breast and ovarian cancers-
GnRH agonists and antoagonists
-
Antiandrogens side effects:
↓ libido; impotency; ↓ spermatogenesis; ↓ ejaculate

22. CH3
N
H
NO2
CF3
O
CH3
Flutamide - Eulexin®
FLUTAMIDE
Indications: metastatic carcinoma of the prostate
MOA: non-steroidal anti-androgen inhibits cellular
uptake of androgen steroids and inhibits nuclear
binding of androgens to their receptors – adrenal
hepatic metabolism with renal excretion, 96% protein
bound
Used with LHRH (GnRH) agonists
DEMERITS-photosensitivity,
Urine color changes

23.  NILUTAMIDE-Indications: For use in treatment
with surgical castration for metastatic carcinoma
of the prostate
 MOA: non-steroidal anti-androgen that inhibits
cellular uptake of testosterone and inhibits
nuclear binding to its receptor - adrenal
 Hepatic metabolism of methyl group produces
two enantiomers in which one is major active
compound
 Inhibits a variety of CYP enzymes

24. N
H
CF3
O
CH3
CN
OH
SO2
Bicalutamide - Casodex®
F
Indications: Advanced prostate cancer
MOA: a non-steroidal competitive inhibitor of the
cytosolic androgen receptors - adrenal
Prostatic carcinoma is androgen sensitive
Mixture of enantiomers - stereospecific metabolism
occurs; R-enantiomer of the drug is predominate
serum drug
Drug must be taken in combination with luteinizing-
hormone releasing hormone (LHRH)

25.  pregnant women, infants and young children
(somatotropin is more appropriate to produce a
growth spurt).
 male patients with carcinoma of the prostate or
breast.
 renal or cardiac disease predisposed to edema
Caution: Several cases of hepatocellular carcinoma
have been reported in patients with aplastic anemia
treated with androgen anabolic therapy.
Erythropoietin and colony-stimulating factors should
be used instead.

26. Oral therapy-
Phoshodiesterase-5 inhibitors-Sildenafil, Tadalafil,
Vardenafil
Intracavernosal injection therapy-Alprostidil
Transcutaneous application therapy-Glycerlyl
Trinitrate, Papaverine, Minoxidil, Alprostidil
Triple therapy-Alprostidil + Papaverine +
Phentolamine
Herbal agents-Ginseng, Kava, Ginko biloba

27.  NO activates guanylyl cyclase which forms cGMP from
GTP produces smooth muscle relaxation leading to
erection
 Sildenafil inhibits PD-5 enzyme increases cGMP levels
 Erectile dysfunction due to organic and psychogenic
causes
 25-50mg taken 1 hour prior to anticipated sexual activity
and beneficial effects lasts for 4hrs after administration
 P/K-oral bioavailability-40%
- Plasma protein binding-95%

28.  Metabolite-N-desmethyl sildenafil is about 50% potent
 Elimination –biliary
Adverse effects- headache, nasal congesiton, decrease in
BP, disturbance in colour vision
Drug interaction-concurrent organic nitrates (angina, MI,
hypertension)
CYP inhibitors such as ketoconazole,
itraconazole, cimetidine and erythromycin increase
plasma levels of drug
Carbamazepine and rifampicin decrease levels of drug
Contra-indication- Retinitis Pigmentosa

29. Physiology 0f penile erection

30.  Most useful method for ED before sildenafil
 Needs repeated self injection into penis- painful
Alprostadil-PGE1 analogue , can also be placed in
urethra as mini- suppository
S/E- low incidence of priapism and fibrosis
Triple therapy ( Alprostidil + Papavarine +
Phentolamine)- less side effects

31. THANKYOU
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