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
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
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
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