Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

GnRH-gonadotropin release hormoneLH-ICSH-Interstitial cell stimulating hormoneFSH-inhibin- supresses FSH

activin- stimulates FSH synthesisFSH in males-spermatogensis, sertoli cellsLH in males-androgen and testosterone in leydig cells

SERTOLI cells-gonadal peptides- Inhibin- b and activinFSH germ cell proliferation and maturation in semniferous tubules

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

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)

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

- Estrogens: Diethylstilbesterol; mestranol...- Progestins: Cyproterone acetate- GnRH superagonists (Leuprolide acetate); GnRH

antagonists (Ganirelix)

- Flutamide; Bicalutamide and Nilutamide- 5α- reductase inhibitors: Finasteride- Ketoconazole- Spironolactone- Gossypol

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

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

NH

O

O

NH

CH3

CH3

CH3

H

Danazol(endometriosis)

Finesteride(baldness)

Bicalutamide(prostate cancer)

Flutamide(prostate cancer)

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

HOH

OH

Cholesterol Pregnenolone Testosterone

Androstendione5a-DHTOther metabolites

1. 3.

2.

hormonal families of the anterior lobe:

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

Transport & MOA of androgens: SHBG

5α-reductaseTestosterone 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…)

- Virilizing=masculinizing effect1° & 2° sexual characteristics

- ↑ Spermatogenesis- ↑ Erythropoiesis- Anabolic or growth promoting effect (bone; skeletal

muscles) Pharmacokinetics-Testosterone metabolism:

AndrosteroneHepatic → 17-ketosteroids

Etiocholanolone

OCH

3

CH3

O

O

H

HH

Testolactone - Teslac®

TESTOLACTONEIndications: palliative therapy in advanced disseminated breast cancer MOA: irreversible inhibitor of the enzyme steroid aromatase that is responsible for the synthesis of estrone from androstenedioneHepatic metabolismMost commonly used androgen for breast cancer. Few or no androgenic side effects - hirsutismAdrenal estrogen depletion – post menopausal women

Contraindicated in male breast cancer

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 monthsrebound fertility Used in hemophiliaproco-agulant factor VIII increased S/E-hot flushes, muscle cramps, teratogenic

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-danazol6. Endometriosis and fibrocystic disease of breast-

Danazol

1. Virilization (masculinization)2. Hirsutism; acne; menstrual disorders 3. Precocious puberty & hirsutism in children4. Salt & water retention5. Jaundice; gall bladder stones (methyltestosterone)6. Enlargement of prostate7. Liver cancer

ANTIANDROGENS

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 animuscle of male rats)

- 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

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

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

NH

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)

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 edemaCaution: 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.

Oral therapy-Phoshodiesterase-5 inhibitors-Sildenafil, Tadalafil,

VardenafilIntracavernosal injection therapy-AlprostidilTranscutaneous application therapy-GlycerlylTrinitrate, Papaverine, Minoxidil, AlprostidilTriple therapy-Alprostidil + Papaverine +

PhentolamineHerbal agents-Ginseng, Kava, Ginko biloba

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%

Metabolite-N-desmethyl sildenafil is about 50% potent Elimination –biliaryAdverse effects- headache, nasal congesiton, decrease in

BP, disturbance in colour visionDrug interaction-concurrent organic nitrates (angina, MI,

hypertension)CYP inhibitors such as ketoconazole,

itraconazole, cimetidine and erythromycin increase plasma levels of drugCarbamazepine and rifampicin decrease levels of drugContra-indication- Retinitis Pigmentosa

Physiology 0f penile erection

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- suppositoryS/E- low incidence of priapism and fibrosis

Triple therapy ( Alprostidil + Papavarine + Phentolamine)- less side effects

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