Androgens, anti-androgens and anabolic steroids

sexual differentiation in the fetus,

sexual development of the male testis, penis, epididymis, seminal vesicles and prostate at puberty, and maintenance of these tissues in adults,

spermatogenesis in adults,

stimulation and maintenance of sexual function and behaviour,

metabolic actions. Testosterone is a powerful anabolic agent producing a positive nitrogen balance with an increase in the bulk of tissues such as muscle and bone. In the skin, sebum production is increased, which can provoke acne. Growth of axillary, pubic, facial and chest hair is stimulated. In the liver, testosterone increases the synthesis of several proteins, including clotting factors, but decreases high-density lipoprotein (HDL) synthesis (Ch. 48). Testosterone also induces several liver enzymes, including steroid hydroxylases,

haematological actions. Testosterone stimulates the production of erythropoietin by the kidneys, leading to higher haemoglobin concentrations in men than in women.

Pharmacokinetics

Oral preparations. Testosterone is well absorbed from the gut but is almost completely degraded by first-pass metabolism in the gut wall and liver. Oral absorption can be enhanced by esterification of testosterone to create hydrophobic compounds, such as testosterone undecanoate, which are absorbed via lacteals into the lymphatic system, thus avoiding hepatic metabolism. Mesterolone is a synthetic testosterone derivative that has a greater oral bioavailability than testosterone, but less androgenic activity.

Depot injection. The most popular form of therapy for hypogonadism in men is an intramuscular injection of a testosterone ester, usually in oily solution, given at intervals from 2–3 weeks up to 10–14 weeks depending on the formulation. Testosterone is absorbed gradually after ester hydrolysis at the site of injection. Examples are testosterone enantate, propionate and undecanoate.

Transdermal delivery. A transdermal delivery patch containing testosterone can be applied to the back, abdomen, upper arm or thigh, rotating the site daily to avoid skin irritation. Testosterone gel is an alternative way to deliver the drug transdermally.

Buccal delivery. Testosterone can be delivered via a buccal tablet which softens to a gel and adheres to the mucosa. This provides sustained release of testosterone, and avoids hepatic first-pass metabolism.

Subcutaneous implant. A pellet of pure crystalline testosterone provides a reservoir for gradual absorption into the systemic circulation for 4–5 months. A minor surgical procedure is necessary, and therefore this method of delivery is rarely used.

Testosterone is metabolised in the liver to androstenedione, and then to inactive compounds. Some testosterone undergoes conversion in specific organs to dihydrotestosterone, and a small amount undergoes aromatisation to oestradiol (see above). Mesterolone is not metabolised to oestrogenic compounds.

Unwanted effects

Prostate cancer.

In hypogonadal adolescents, initial nitrogen retention and a spurt in linear growth is followed by premature epiphyseal closure and short stature. A short course of testosterone can be used for the treatment of delayed puberty without inducing epiphyseal closure.

Headache.

Anxiety, depression.

Nausea, vomiting, gastrointestinal bleeding.

Sodium retention with oedema and hypertension.

Hirsutism, male-pattern baldness, acne. Virilisation occurs in women given testosterone.

Conversion to oestrogens by aromatase can produce gynaecomastia (see Fig. 44.2). This is less likely to occur with mesterolone.

Suppression of gonadotropin release with diminished testicular size and reduced spermatogenesis. Hypogonadal men will not regain fertility while taking androgens.

Cholestatic jaundice. Liver tumours are a rare complication.

Local irritation from topical formulations.

Clinical uses of testosterone

The main clinical use is as hormone-replacement therapy for primary hypogonadism in adult males. Late-onset hypogonadism may present with erectile dysfunction, fatigue, depression, hot flushes, muscle weakness and reduced body hair. Testosterone replacement can improve quality of life in this situation.

It can be used briefly in constitutionally delayed puberty, even in the absence of hypogonadism.

Androgens are occasionally beneficial for promoting erythropoiesis in some forms of aplastic anaemia.

Danazol

Mechanism of action

Danazol is an androgen derivative described as an ‘impeded’ androgen, which is weakly androgenic on peripheral tissues. It has no oestrogenic activity as, unlike testosterone, it is not converted into an oestrogen by aromatases. Its main action is feedback inhibition of gonadotropin and gonadotropin-releasing hormone (GnRH) secretion. It therefore has anti-oestrogenic and anti-progestogenic actions.