MALE GONADAL HORMONES (Androgens & Anabolic steroids) & INHIBITORS (Antiandrogens)

Androgens Also called androgenic hormone or testoid generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors includes the activity of the accessory male sex organs and development of male secondary sex characteristics The primary and most well-known androgen is testosterone.

Androgens SYNTHESIS Testis - primary site of androgen synthesis in males … Leydig (95%) both gametogenic & endocrine functions Adrenals (5%) Control of secretion in males ICSH (interstitial cell stimulating hormone) and FSH Biosynthesis

Androgens Androgens in Females   Sites of synthesis--ovaries, adrenals, placenta Physiological significance - apparently not necessary for normal menstrual cycling, but may be involved in pubertal growth libido

REGULATION OF SECRETION

Cholesterol Oestriol 17-α- Hydroxy pregnenolone Pregnenolone Dehydro-epi androsterone Progesterone 17- Hydroxy progesterone Andro-stenedione Oestrone TESTOSTERONE OESTRADIOL

Regulation of secretion Oestrogen – similar to Testosterone Inhibin inhibits FSH secretion at A.P level

Drugs affecting male reproductive system Classification A. Androgens 　1. testosterone 　2. methyltestosterone orally effective 3. testosterone propionate ( most commonly used 　4. mesterolone 5.fluoxymesterone 6.testosterone phenyl-acetate 7.tristeronum compositum testosterone propionate 25mg estradiol benzoate(1.25mg progesterone 12.5mg，i.m B. Antiandrogens cyproterone C. Drugs used to treat erectile dysfunction sidenafil

Androgens A. Androgens Testosterone Testosterone undecanoate Nandrolone phenylpropionate

A. Androgens Pharmacological effects (1) Development of the male sexual apparatus and secondary sex characteristics (2) Necessary for normal spermatogenesis (3) Increasing protein anabolism (4) Promoting growth of blood cells in bone marrow, especially for red blood cells (5)Other effects: immune regulation, antiinflammation effects,CVS effects

A. Androgens Clinical uses (1) Replacement therapy in men: hypogonadism (2)Female disorders: dysfunctional uterine bleeding, endometriosis , advanced breast and ovarian cancers (3) Anemia: aplastic or other anemia (largely replaced by recombinant erythropoietin ) (4) Infirmity : anabolic steroids ( (5) Others: male contraception, osteoporosis(either alone or in conjunction with estrogens. Replaced by bisphosphonates) etc.

A. Androgens Adverse effects - due largely to their masculinizing actions and are most noticeable in women and prepubertal children. (1) Sex dysfunction: virilisation in female(hirsutism, acne, amenorrhea, clitoral enlargement, and deepening of the voice, testosterone> 200–300 mg of per month) increased libido in male (2) Hepatic toxicity occurs early in the course of treatment, the degree is proportionate to the dose. bilirubin levels ↑

A. Androgens Contraindications 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.

A. Androgens Classic anabolic hormones Growth hormone IGF1 and other insulin-like growth factors Insulin Testosterone and analogs Estradiol

Anabolic-androgen steroids (AAS) A. Androgens Anabolic-androgen steroids (AAS) Drugs which mimic the effects of the male sex hormones testosterone and dihydrotestosterone. They increase protein synthesis within cells, which results in the buildup of cellular tissue (anabolism), especially in muscles. Anabolic steroids also have androgenic and virilizing properties, including the development and maintenance of masculine characteristics such as the growth of the vocal cords, testicles, and body hair (secondary sexual characteristics).

Antiandrogens Steroid synthesis inhibitors: Ketoconazole Conversion of steroid precursors to androgens Abiraterone Finasteride Dutasteride Receptor inhibitors Cyproterone Cyproterone acetate Flutamide Bicalutamide Nilutamide Spironolactone

Cyproterone B.Antiandrogens Antigonizing androgen receptor; inhibiting hypothalamus-pituitary axis: LH↓, FSH↓, testosterone↓ Used for treatment of prostatic cancer, severe acne and hersulism, and contraception

Adverse effects 1. Antiandrogenic action gynecomastia (breast growth), galactorrhea (milk outflow), and erectile dysfunction. 2.Liver toxicity high dose (200–300 mg/day). 3. Increased risk of DVT ( in combination with ethinylestradiol ) 4. Other reactions Depressive mood changes Suppression of adrenal function and reduced response to ACTH Osteoporosis- suppresses production of estrogen due to its antigonadotrophic effect

Other antiandrogens 1.Other receptor Inhibitors Flutamide( Bicalutamide& nilutamide Spironolactone 2. Steroid synthesis inhibitors- Ketoconazole 3. Conversion of Steroid Precursors to Androgens Abiraterone (nhibitor of 17-hydroxylase Finasteride( inhibitor of 5 -reductase Dutasteride similar to but much longer t1/2 than finasteride

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Steroid synthesis inhibitors: Ketoconazole Primarily an anti-fungal agent Inhibitor of adrenal & gonadal steroid synthesis Displaces estradiol & dihydrotestosterone from SHBP & increases estradiol: testosterone ratio in plasma. Men treated develop gynecomastia Not useful in woman due to toxicity

Conversion of steroid precursors to androgens Abiraterone Finasteride Dutasteride Inhibit 17-hydroxylation of progesterone or pregnenolone preventing the action of the side chain-splitting enzymes and the further transformation of these steroid precursors to active androgens

Abiraterone Newer 17-hydroxylase inhibitor May prove to be clinically useful

Finasteride: 5  reductase inhibitors Orally active Decreases DHT levels in 8 hrs & lasts 24 hrs T1/2 : 8 hrs 40-50% metabolism More than half excreted in feces Benign prostatic hyperplasia – reduces size Treatment of hirsuitism in women Also used for baldness in males Dose: 5mg/day Side effects: Loss of libido & impotence in 5 % pts.

Dutasteride : 5  reductase inhibitors A similar orally active steroid Slow OOA & longer DOA Dose 0.5mg/d Both not approved for use in women or children

Receptor inhibitors Cyproterone Cyproterone acetate Flutamide Bicalutamide Nilutamide Spironolactone

Cyproterone & Cyproterone acetate Block androgen receptors secretion of gonadotropins Uses: Acne Male pattern of baldness Hirusitism CA of prostate Virilizing syndrome Precocious puberty Inappropriate behaviour

Flutamide Non-steroidal anti-inflammatory Antagonise androgens: Accessory sex organs Pituitary Uses: Cancer of prostate along with GnRH agonist Female hirusitism Dose: 250 mg tds.

Bicalutamide & Nilutamide Orally active antiandrogens OD dose Metastatic carcinoma of prostate Bicalutamide recommended for use in combination with GnRH analog & have fewer Aes than Flutamide

Spironolactone A competitive inhibitor of aldosterone Also competes with DHT for androgen receptors in target tissues Also reduces 17 hydroxylase activity, lowering plasma levels of testosterone & androstenedione Treatment of hirsuitism in women As effective as other finasteride, Cyproterone & Flutamide Dose: 50-200mg/d

C. Drugs used to treat erectile dysfunction Phosphodiesterase type 5 isoenzyme inhibitors (PDE5I) Sidenafil Vardenafil Tadalafil

C. Drugs used to treat erectile dysfunction

C. Drugs used to treat erectile dysfunction Sildenafil citrate(Viagra) Acts by inhibiting cGMP-specific PDE5, an enzyme that delay degradation of cGMP, which regulates blood flow in the penis The prime treatment for erectile dysfunction in all settings, including diabetes.

C. Drugs used to treat erectile dysfunction

C. Drugs used to treat erectile dysfunction Clinical uses (1) Sexual dysfunction (2) Pulmonary arterial hypertension (PAH) relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure→workload of the right ventricle ↓, symptoms of right-sided heart failure↑ acts selectively in the lungs and penis without inducing vasodilation in other areas of the body →PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis (3) Altitude sickness prevention and treatment of high-altitude pulmonary edema associated with altitude sickness -such as that suffered by mountain climbers.

C. Drugs used to treat erectile dysfunction Adverse effects 1.Headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred (lead to vision impairment in rare cases) - the most common adverse effects 2. Priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss -rare but serious

C. Drugs used to treat erectile dysfunction Contraindications Administration of nitric oxide donors Recent stroke or heart attack, or in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors Hypotension (low blood pressure) Severe hepatic/ renal function impairment Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

SAR 5 α ANDROSTANE

RING EXPANSION OR RING CONTRACTION AND CHANGE IN CONFIGURATION REDUCE OR DESTROY THE ANDROGENIC AND ANABOLIC ACTIVITY TESTOSTERONE IS NOT GIVEN ORALLY BECAUSE METABOLIC CHANGES OCCURS AT 17 β OXYGEN WHICH IS REQUIRED FOR ATTACHMENT TO THE RECEPTOR

ALKYL GROUP IS ATTACHED AT 17 ALPHA TO THESE METABOLIC CHANGES AND TO RENDER COMPOUND ORALLY ACTIVE INCREASE THE ALKYL CHAIN REDUCES THE ACTIVITY

ESTERIFICATION AT C-17 WITH A NO OF ACID RESULT IN LONG DURATION OF ACTION WHEN USED PARENTERALLY R = COCH2CH3 propionate = CO(CH2)5CH3 enanthate = COCH2CH2(C5H9) cypionate

A HYDROXYL GROUP AT 17-α POSITION DOES NOT INCREASE OR DECREASE ANDROGENIC OR ANBOLIC ACTIVITY

INTRODUCTION OF AN SP2 HYBRIDISEED CARBON INTO THE RING MORE PLANAR RESULTING IN GREATER ANABOLIC ACTIVITY OXYMETHOLONE

HALOGEN DERIVATIVE OF TESTSTERONE PRODUCE COMPOUNDS WITH DECREASED ACTIVITY EXCEPT WHEN INSERTED INTO POSITION 4 AND 9 4-CHLOROTESTSTERONE FLUOXYMESTERONE

INTRODUCTION OF α-METHYL GROUP AT C-2 ATOM BY OXYGEN RESULTS IN POTENT ANABOLIC REAGENT DROMASTOLONE

HETEROCYCLIC RINGS ARE ALSO INCORPORATED TO RING A YIELD ANABOLIC AGENT STANAZOLOL

TESTOLACTONE THE ONLY COMPOUND WITH PURE ANABOLIC BUT MINIMUM ANDROGENIC ACTIVITY.IT IS 20 TIMES MORE ANABOLIC AND 9.5 TIMES MORE ANDROGENIC ACTIVITY THAN 17-α-METHYLTESTSTERONE TESTOLACTONE

Structure Activity Relationships in Androgens Anabolic Androgenic Testosterone 1 1 (injectable) Testosterone 1 1 esters (injectable) R = COCH2CH3 propionate = CO(CH2)5CH3 enanthate = COCH2CH2(C5H9) cypionate

Structure Activity Relationships in Androgens Anabolic Androgenic 17a-methyl Testosterone 1 1 (oral) Fluoxymesterone 1 1 (oral)

Structure Activity Relationships in Androgens Anabolic Androgenic Nandrolone 2.5 1 (injectable) Oxymetholone 2.5 1 (oral)

Structure Activity Relationships in Androgens Anabolic Androgenic Stanozolol 3 1 (oral) Dromostanolone 4 1 (oral)