Androgens and Drugs for Erectile Dysfunction

Dr. Vishaal BhatAssociate ProfessorMMMC, Manipal

FeMale

WoMan

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Androgens:

2o sex characteristics

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• Transport & MOA of androgens: SHBG

5α-reductaseTestosterone 5α-dihydrotestosterone (sex organs)

(skeletal muscles)

cytosloic; 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 apparatus (prostate; seminal vesicle, epididymis…)

MOA:

Testosterone to DHT in target organ

DHT + cytoplasmic receptor (AR) complex formation

This complex moves towards DNA and binds with

androgen response elements of target gene

Specific mRNA transcription is enhanced

Protein synthesis

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1.Androgenic action

2. Anabolic action – skeleton and muscle building, wt.↑

3.Erythropoiesis - ↑erythropoietin & haeme production

4.Feed back - large dose inhibits Gn secretion from pituitary,

causes testicular atrophy

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Testosterone

Aromatase Estradiol

5-α-reductase Dehydrotestosterone

Testosterone Dihydrotestosterone Estrogen

Internal genitalia growth in fetus(epididymis, vasdeference, seminal vesicle)

External genitalia growthin fetus (scrotum, penis, urethra). Maturation in adult

Libido

Testis -spermatogenesis

Prostate growth, male behavior, hair growth in puberty, hair loss in adult

Erythropoiesis

Feed back - LH inhibition in pituitary

↑ bone & muscle mass and strength ↑ bone growth, epiphyseal closure 8

Synthetic androgens:

1. Methyltestosterone

2. Testosterone undecanoate

3. Fluoxymesterone

4. Mesterolone

Natural androgens:

1. Testosterone

2. Dihydrotestosterone

3. Dehydroepiandrosterone

4. Androstenedione

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1. Testicular failure:

Primary – delayed puberty in children.

Secondary - loss of libido, impotence in adult.

Parenteral and transdermal preperations

2. Hypopituitarism:

Lead to hypogonadism. Androgens added during puberty.

3. Ageing – testosterone is declined in old age, osteoporosis.

↑ muscle mass & bone mineral density

Therapeutic uses of androgens:

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4. AIDS related muscle wasting:

Improve weakness, muscle wasting

5.Carcinoma of breast:

Tumor contains estrogen receptor (ER).

Testosterone is the physiological antagonist to estrogen

6. Osteoporosis in elder male due to prolonged

immobilization. BPNs preferred

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6. Hereditary angioneurotic edema:

Deficiency of C1Inh (complement esterase inhibitor)

Swelling - skin, mucous membrane, intestinal organs

Chronic use - ↑ synthesis of complement esterase inhibitor. 12

Adverse effects of androgens:

Acne – in male and female

Precocious puberty and closure of epiphysis

Reversible cholestatic jaundice with synthetic drugs

oral route, not in parenteral

Hepatic carcinoma

Gynaecomastia – children with liver disease.

Peripheral conversion of testosterone to estrogen13

Lowering of HDL level with synthetic androgens

Painful erection in males

Oligozoospermia – due to feedback inhibition

Edema – due to salt and water retention.

Seen in heart and kidney diseases

Female – Virilization (masculinization).

Excess body hair, menstrual irregularity, voice change,

breast atrophy 14

C/I of androgens:

Carcinoma of prostrate

Kidney, liver diseases – edema develops

Pregnancy - masculinization of female fetus

Androgenic + Anabolic = Androgen

Androgen – Androgenic activity = ???

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Danazol

1. Gonadotropin inhibitor with antiestrogen,

progestational and androgenic properties

2. Synthetic version of the male hormone testosterone

3. Inhibits the release of FSH and LH by the pituitary

gland

4. Decreases estrogen levels similar to menopause, stops

ovulation

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Danazol

Indications:

1. Endometriosis

2. Mammary dysplasia (fibrocystic breast

nodularity)

3. Menorrhagia

4. Infertility in women

5. Gynaecomastia.

Danazol

Side effects

• androgenic effects (deepening of the voice, abnormal hair growth, reduced breast size, water retention, acne, weight gain ;nearly all gain weight between 8-10 lbs.)

• hypoestrogenic reactions (flushing, sweating, vaginal dryness, irritation)

• amenorrhea

• irregular vaginal bleeding, muscle cramps

Anabolic steroids

1. Nandrolone

2. Oxymetholone

3. Methandienone

4. Stanzolol

Drugs with higher anabolic and lesser androgenic activity

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Therapeutic uses of anabolic steroids:

1. Catabolic states:

Negative nitrogen balance – acute illness, major surgery.

Under-nurished, during convalescence

Improve appetite, sense of well being, protein anabolism

2. Renal insufficiency: (R. failure)

Reduce urea production, dialysis frequency ↓

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4. Suboptimal growth in boys:

Linear growth is accelerated.

Premature closure of epiphysis may seen in long use

5. Severe anemia associated wit hypoplastic,

hemolytic and malignancy.

↑RBC count, ↑Hb%. Erythropoietin is preferred.

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6. To enhance physical ability in athletes

↑ strength of exercised muscles.

Drugs of abuse, dope test before competitive games.

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Adverse effects of anabolic steroids:

Produce jaundice

Worsen lipid profile

Similar to androgen

(retained minimal androgenic activity)

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Antiandrogens

1.GnRH Analogues – leuprolide, goserelin, nafarelin

2.Androgen synthesis inhibitor – ketoconazole, spironolactone

3.5-alpha-reducatase inhibitors – Finasteride, Dutasteride

4.Androgen Receptor antagonists – Flutamide, Bicalutamide

5.Cyproterone acetate

Anti Androgens

Androgen Receptor Blockers

• Block the activity of androgen hormones at target tissue (prostate) receptors

• flutamide

• nilutamide

• bicalutamide

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Flutamide and bicalutamide are nonsteroidal antiandrogens (androgen receptor blockers) for use in conjunction with the GnRH analogues (e.g. goserelin, leuprolide) in the treatment of prostatic cancer.

5-Alpha-Reductase Inhibitors

• Finasteride and dutasteride

• Block the effects of endogenous androgens

• Used to treat benign prostatic hyperplasia (BPH)

• Results in alleviation of symptoms of BPH– Easier passage of urine

• May also be used for treatment of

male-pattern baldness (minoxidil)

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Adverse effects of 5-alpha-reductase inhibitors• Impotence• Reduced libido• Gynecomastia• Dizziness• Heart failure• Angioedema• Allergic skin reactions• Male breast cancer

Drugs for Erectile Dysfunction

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Penile erection :

Physiological phenomenon where the penis becomes

enlarged and firm - enables sexual intercourse

Complex interaction of psychological, neural, vascular

and endocrine factors

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Sexual stimulation → parasympathetic stimulation

Ach → releases NO from endothelial cells of penile arteries

Arteriodilation, fill blood (cavernosal sinusoids) in corpora

cavernosa muscle

Venonstriction limits blood drainage - enlarge penis

Erection subsides when parasympathetic stimulation is

discontinued

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Erectile dysfunction: (impotence)

Inability to attain and maintain an erect penis

to allow sexual intercourse.

Psychology, hormone, neurogenic, vascular, autonomic

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Drugs used for erectile dysfunction:

1. Androgens – if androgen deficiency is seen

2. Prostaglandin E1 (PDE1) - Alprostadil

3. Papaverine / Phentolamine induced penile erection therapy

4. Phosphodiesterase-5 (PDE-5) inhibitors

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Drugs used to treat erectile dysfunction

PDE-5 Inhibitors

PDE-5 inhibitors:SildenafilTadalafilVardenafil

Introduced for pulmonary H.T – reduce pul. Pressure

50mg orally taken 1 hr. before intercourse

No erection in the absence of sexual activity

Useful in diabetic neuropathy ED

Ineffective – lost libido, spinal injury

Do not causes priapism (Painful condition, in which the

erect penis/clitoris do not return to its flaccid state)

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A/E:

Vasodilation

Headache, nasal congestion, fall in BP

Impairment of color vision, sudden vision loss

Potentiate dilatory action of nitrates

- worsen coronary cardiac disease

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