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

2. 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.

3. 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

4. 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

5. REGULATION OF SECRETION

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

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

8. 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

9. Androgens A. Androgens Testosterone Testosterone undecanoate
Nandrolone phenylpropionate

11. 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

12. 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.

13. 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 ↑

14. 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.

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

16. 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).

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

18. 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

19. 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

20. 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

21. × ×

23. 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

24. 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

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

26. 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.

27. 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

28. Receptor inhibitors Cyproterone Cyproterone acetate Flutamide
Bicalutamide
Nilutamide
Spironolactone

29. 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

30. 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.

31. 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

32. 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: mg/d

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

34. C. Drugs used to treat erectile dysfunction

35. 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.

36. C. Drugs used to treat erectile dysfunction

37. 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.

38. 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

39. 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)

40. SAR
5 α ANDROSTANE

41. 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

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

43. ESTERIFICATION AT C-17 WITH A NO OF ACID RESULT IN LONG DURATION OF ACTION WHEN USED PARENTERALLY
R = COCH2CH propionate
= CO(CH2)5CH enanthate
= COCH2CH2(C5H9) cypionate

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

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

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

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

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

49. 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

50. Structure Activity Relationships in Androgens
Anabolic Androgenic
Testosterone
(injectable)
Testosterone
esters (injectable)
R = COCH2CH propionate
= CO(CH2)5CH enanthate
= COCH2CH2(C5H9) cypionate

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

52. Structure Activity Relationships in Androgens
Anabolic Androgenic
Nandrolone
(injectable)
Oxymetholone
(oral)

53. Structure Activity Relationships in Androgens
Anabolic Androgenic
Stanozolol
(oral)
Dromostanolone
(oral)