64. Androgens, anabolic steroids, antiandrogens

From greek.doctor

Androgens

The main endogenous androgen is testosterone. Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione are all weaker androgens. The weak androgens can be converted into testosterone.

Endogenous biosynthesis

In men the Leydig cells of the testes are the main producer of androgens, while the adrenal cortex doesn’t contribute too much to overall androgen production. In women the adrenal cortex is the main producer, but the ovaries also synthesize small amounts.

Regulation of androgen production

GnRH produced by the hypothalamus stimulates the anterior pituitary to produce FSH and LH. LH stimulates androgen synthesis in the testis. FSH, together with androgens, stimulate spermatogenesis.

Testosterone exerts negative feedback effects on the anterior pituitary and the hypothalamus.

Actions of androgens

  • Development of male primary and secondary sex characteristics
  • Stimulation of prostate and seminal vesicle
  • Maintenance of libido
  • Stimulation of spermatogenesis (with FSH)
  • Increased protein synthesis
  • Stimulation of longitudinal growth
  • Closure of epiphyseal plates
  • Stimulation of sebaceous glands, induction of acne
  • Stimulation of EPO
  • Increased LDL
  • Decreased HDL
  • Alopecia (hair loss)
  • Prostate hyperplasia in elderly

Mechanism of action

As all steroid hormones androgens have intracellular receptors called the androgen receptors (AR). There are two isoforms, AR-A and AR-B. When androgens bind to this receptor, they modulate gene expression, but, like oestrogens and progestins they also have faster, non-genomic effects on the cells.

In most target cells testosterone is convert by the enzyme 5α-reductase to dihydrotestosterone (DHT), which has higher affinity to the androgen receptor. This occurs in cells like the prostate, liver, hair follicles and skin.

Certain molecular effects of androgens are actually mediated by estradiol. In these tissues androgens are converted into estradiol by aromatase, and this estradiol binds to the oestrogen receptor, mediating the effects. This is the case for the negative feedback of androgens in the pituitary and for the closure of epiphyseal plates.

Androgens in therapy

Many androgens can be used therapeutically. Testosterone itself can be used but also esters of testosterone like testosterone enanthate and testosterone undecanoate. 17α-alkylated androgens like methyltestosterone and danazol are also used.

Indications

Hypogonadism – testosterone is the drug of choice

Endometriosis, hereditary angioedema, haemophilia A, immune thrombocytopenic purpura – danazol is the drug of choice

They may be effective in improving muscle mass and quality of life in elderly with androgen deficiency, but androgens are not approved for this use.

Less important uses of androgens include osteoporosis and refractory anaemia.

Mechanisms of action

17α-alkylated testosterone derivatives like danazol increase the synthesis of the protein “C1q inhibitor”, which is deficient in hereditary angioedema. Danazol also enhances the synthesis of factor VIII, which makes it effective in haemophilia A, where factor VIII is deficient.

Danazol has both progestin and androgen activity, so it can bind to progesterone and androgen receptors on the pituitary, which inhibits the production of gonadotropins. This inhibition is not strong enough to inhibit the basal secretion of FSH and LH, but it is enough to inhibit their mid-cycle peak secretion, thereby inhibiting ovulation. This gives positive effects in endometriosis, menorrhagia and fibrocystic breast disease.

Most androgens (except dihydrotestosterone and nandrolone) are converted into oestrogen in tissues and therefore can cause feminizing effects.

Pharmacokinetics

Testosterone is well absorbed but undergoes marked first-pass metabolism and therefore cannot be used orally.

Almost all testosterone in the plasma is bound to sex hormone-binding globulin.

Testosterone is metabolized in the liver to weaker androgens like androsterone, that are then conjugated with glucuronate and sulphate and excreted in urine. It has a short half-life of just 30 minutes.

Testosterone esters are longer acting and can be used as depot preparations.

17α-alkylated testosterone derivatives have good oral bioavailability and can be taken orally.

Dosing

Testosterone can be given as a transdermal patch or gel, as a buccal system or as a nasal gel.

Testosterone esters can be given as intramuscular depot injections.

17α alkylated testosterones can be given orally.

Adverse effects

Androgens cause many unwanted effects. Some effects are gender-specific and some occur in both genders.

In women:

  • Menstruation disorders
  • Transformation into male secondary sex characteristics/virilization
    • Hirsutism
    • Clitoris enlargement (irreversible)
    • Masculinization of voice

In men:

  • Reduced spermatogenesis (due to inhibition of FSH secretion in men)
  • Smaller testicles
  • Prostate hyperplasia
  • Gynecomastia

In prepubertal boys:

  • Premature puberty
  • Premature closure of epiphyseal plates

In foetus:

  • Dysgenesis of external genital organs

In all ages and genders:

  • Acne
  • Sodium and water retention
  • Alopecia
  • Hepatotoxicity – only with 17α-alkylated derivatives
  • Polycythaemia
  • Musculoskeletal effects
    • Increased muscle strength
    • Myalgia
    • Tendon rupture
  • Cardiovascular effects
    • Increased LDL
    • Decreased HDL
  • Mental changes
    • Increased aggressiveness
    • Depression
    • Psychosis

Anabolic steroids

Androgens in high doses are abused by people to increase muscle mass and physical performance.

Many androgens, both marketed for medical use and not, are abused as anabolic steroids:

  • Testosterone
  • Dihydrotestosterone
  • 17α-alkylated testosterone derivatives
    • Nandrolone
    • Oxandrolone
    • Trenbolone
  • Tetrahydrogestrinone

and many more.

They are often used in high doses which makes the side effects mentioned above even worse than when used in therapeutic doses.

Antiandrogens

Antiandrogens is a term used to describe all drugs who have antiandrogen activity. Some use it to just refer to the androgen receptor antagonists.

  • Weak progestins
    • Cyproterone (acetate)
    • Chlormadinone (acetate)
  • Androgen receptor antagonists
    • Flutamide
    • Nilutamide
    • (Spironolactone)
  • 5α-reductase inhibitors
    • Finasteride
    • Dutasteride
  • Long-acting GnRH agonists, antagonists
    • Leuprolide
    • Degarelix
    • See topic 60
  • Abiraterone

Indications

  • Hirsutism
  • Acne
  • Alopecia
  • Prostate hyperplasia
    • 5α-reductase
  • Prostate cancer
    • GnRH agonists or antagonists
    • Androgen receptor antagonists
  • Premature puberty in boys

GnRH agonists or antagonists can be used to induce medical castration.

Mechanism of action

Cyproterone (acetate) and chlormadinone (acetate) are weak progestins. Due to their progestin action they inhibit gonadotropin secretion, which decreases the synthesis of testosterone.

Flutamide and nilutamide are nonsteroidal androgen receptor antagonists. However, this inhibits the negative-feedback effect of testosterone on the hypothalamus and pituitary, which indirectly increases testosterone synthesis. For this reason, they’re often combined with GnRH agonists or antagonists.

You’d think that GnRH agonists would just stimulate further testosterone disease. However, since they’re present continuously and not in a pulsatile manner (like physiological GnRH) they actually inhibit the pituitary gland. They do cause an initial surge in testosterone, however.

5α-reductase converts testosterone to the more potent dihydrotestosterone in target tissues. By blocking these enzymes finasteride and dutasteride elicit an antiandrogen effect.

Abiraterone inhibits the enzyme CYP17A1 which has two activities, 17α-hydroxylase and 17,20-lyase. These enzymes are involved in the synthesis of androgens but also cortisol and oestrogens.

Spironolactone block androgen receptors in addition to blocking mineralocorticoid receptors. It also inhibits 17α-hydroxylase.

Side effects

Gynecomastia, tiredness, reduced libido, impotence, increased hair growth, etc.

Abiraterone indirectly increases the production of aldosterone by re-routing the substrates of steroid hormones to aldosterone instead of androgens, cortisol and oestrogens. This causes sodium and water retention, hypertension and hypokalaemia.