Around 1 in 200 men have abnormally low levels of circulating testosterone that result in hypogonadism.1 Most of these men should be offered testosterone replacement therapy. Here we outline the rationale for such treatment and the different preparations available. We do not discuss the use of testosterone to induce pubertal development in prepubertal males with hypogonadism.
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Relevant BNF section: 6.4.2
Influences on androgen levels
Gonadotrophin-releasing hormone (GnRH) is secreted in pulses from the hypothalamus into the pituitary gland. This causes pituitary gonadotrophs to release pulses of luteinising hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates testicular Leydig cells to produce the androgens testosterone and dihydrotestosterone, and a small amount of the oestrogen oestradiol. FSH (with testosterone) stimulates testicular Sertoli cells to release the hormone inhibin and induces sperm production. Both testosterone and inhibin reduce GnRH (and thereby gonadotrophin) secretion by negative feedback.
Testosterone secretion follows a circadian rhythm, with a peak at 7-9a.m. and a trough in the late afternoon, a pattern that diminishes with age.2 In certain tissues, the enzyme 5α-reductase converts testosterone into its more potent metabolite dihydrotestosterone. Some testosterone is converted into oestradiol in adipose tissue, the liver and the CNS.3 Testosterone is also converted to mainly inactive metabolites in the liver, kidney, muscle and adipose tissue. Conjugation of such metabolites to glucuronides in the liver allows renal excretion.
About 60-70% of plasma testosterone is bound to sex hormone binding globulin (SHBG), while most of the rest is loosely bound to albumin, α1 acid glycoprotein and transcortin.3 About 2% of testosterone is not protein-bound3 and is free to enter cells and bind to intracellular androgen receptors. Exogenous androgens, obesity or abnormally high growth hormone levels lower SHBG levels and so reduce total testosterone concentrations. By contrast, thyrotoxicosis, oestrogens and liver failure raise SHBG levels and, therefore, total testosterone concentrations. Despite such effects, free testosterone levels usually remain within the normal range because of feedback adjustment of gonadotrophin secretion. The SHBG binding capacity increases with age.
Causes of hypogonadism
Hypogonadism may be due to testicular (i.e. primary gonadal) failure. In these circumstances, the resulting lack of negative feedback on the hypothalamo-pituitary axis results in increased secretion of LH and FSH (hence the alternative name for the condition - hypergonadotrophic hypogonadism). Alternatively, hypogonadism may be due to hypothalamic or pituitary disease that causes reduced gonadotrophin secretion (known as secondary or hypogonadotrophic hypogonadism). More rarely, hypogonadism results from enzyme defects (e.g. 5α-reductase deficiency) or germ cell cancers.
Primary hypogonadism can be congenital (as in Klinefelter's syndrome or anorchia) or acquired (e.g. after orchidectomy). Secondary hypogonadism may also be congenital (as in Kallmann's syndrome) or acquired (e.g. with pituitary tumours). Reversible secondary hypogonadism can also be caused by systemic illness (such as end-stage renal or respiratory disease),4 obesity, poor nutritional status, long-term excessive exercise, hyperprolactinaemia or supraphysiological doses of corticosteroids and drugs (such as ketoconazole, spironolactone or marijuana).
The characteristic clinical features of postpubertal hypogonadism are diminished sex drive and erection, loss of ejaculation, regression of spermatogenesis, muscle atrophy and low stamina, decreased secondary sexual hair and less frequent shaving. No changes occur in the voice or the proportions of the body or the penis.5 Primary hypogonadism is suggested by a history of orchitis, testicular trauma, surgery or torsion, irradiation or chemotherapy. Underlying hypothalamic-pituitary tumours are suggested by headaches, impairment of visual fields, polyuria and polydipsia, or evidence of pituitary hormone excess such as Cushing's disease, acromegaly or hyperprolactinaemia.5
A single measurement of morning basal total testosterone, LH, FSH and prolactin levels is usually sufficient to confirm the diagnosis of male hypogonadism. Those with primary hypogonadism have elevated gonadotrophin levels with low plasma testosterone.5 Patients with secondary hypogonadism have low to normal gonadotrophin and low testosterone levels.5 When diagnostic difficulties arise (e.g. low-normal testosterone with normal gonadotrophin levels), it may be necessary to make serial testosterone measurements, estimate free testosterone by measuring SHBG levels or carry out an intravenous GnRH test.
Principles of androgen therapy
The aim of testosterone replacement therapy in adults with hypogonadism is to provide near-physiological blood testosterone levels while avoiding over-treatment. Testosterone should restore (or develop) secondary sexual characteristics, maintain bone mass (partially reversing osteoporosis in secondary hypogonadism),6 increase muscle mass7 and libido,8 and improve wellbeing.9 Testosterone can be given orally (as capsules of testosterone undecanoate), as intramuscular injections (testosterone enanthate or a mixture of testosterone esters), as implants or as patches (both containing testosterone itself). These preparations differ in their ease and frequency of administration and unwanted effects. The individual needs of the patient are crucial in choosing which preparation to use. In practice, intramuscular injections or subdermal implants tend to be the treatment of choice for most patients.
The increase in SHBG binding capacity in ageing men is not fully matched by a rise in LH,10 resulting in a reduction of free testosterone levels. However, most ageing men still have free testosterone levels in the normal range and do not therefore need treatment. Furthermore, although testosterone therapy can increase skeletal muscle strength and protein synthesis11 in ageing men, the long-term outcome of such treatment is unknown.
Are gonadotrophins needed?
In patients with secondary hypogonadism, testosterone replacement alone neither causes testicular growth nor maintains (or restores) testicular volume and spermatogenesis. If the cause of the hypogonadism is pituitary disease, the patient will also need FSH and human chorionic gonadotrophin (HCG) therapy to induce high concentrations of testosterone within the testes. (HCG has LH-like actions and a long biological half-life.) FSH is usually given as human menopausal gonadotrophin (HMG), which is a mixture of FSH and LH. More expensive purified urinary FSH and recombinant human FSH (not licensed for hypogonadism) are also available. If the cause of hypogonadism is hypothalamic disease, GnRH is required; this can be given subcutaneously for up to 6 months by means of a pulsatile pump. These treatments are complex, costly and inconvenient for the patient, so should be reserved for those who are attempting to achieve or regain fertility.9 Infertility associated with Klinefelter's syndrome is irreversible.9
Restandol capsules (Organon) contain 40mg of testosterone undecanoate which is converted to testosterone after hydrolysis in the body. The adult dose recommended by the manufacturer is 120-160mg daily for the first 2-3 weeks, followed by a maintenance dose of 40-120mg daily in two divided doses after meals. A short-lived plasma testosterone peak occurs about 5 hours after ingestion of testosterone undecanoate.12 This peak serum level is subject to marked variation in individual patients and from patient to patient.12 Such unpredictability makes testosterone undecanoate inconvenient to use. 12
Sustanon (Organon) is available as Sustanon 100 and 250. Sustanon 100 contains testosterone propionate (20mg), testosterone phenylpropionate (40mg) and testosterone isocaproate (40mg). It requires intramuscular injection every 2 weeks and is rarely used. Sustanon 250 is a mixture of short- and long-acting testosterone esters (testosterone propionate 30mg, testosterone phenylpropionate 60mg, testosterone isocaproate 60mg and testosterone decanoate 100mg). Sustanon 250 is usually given once every 3 weeks. Although this preparation was designed to produce a more physiological testosterone profile, in reality, the mixture of short- and long-acting esters actually heightens initial undesirable testosterone peak shortly after injection.12 Some patients may need to have their treatment regimen altered to avoid this.
Testosterone enanthate (Cambridge) is licensed for intramuscular injection at a dose of 250mg every 2-3 weeks for the initial treatment of deficiency symptoms, followed by a maintenance dose of 250mg every 3-6 weeks.
About 7% of patients find the intramuscular injection of testosterone preparations causes local pain and about 15% experience bruising and bleeding.3 Prominent fluctuations in mood and libido can also occur.13 Supraphysiological testosterone levels may lead to polycythaemia (especially in older men) and, potentially, raise circulating lipid levels, although this is an infrequent problem clinically. Uncommon effects include coughing fits or fainting (possibly due to oil microembolisation),3 or an allergic reaction (probably due to the injection vehicle).9
Subdermal testosterone implants
Testosterone implants (Organon) used in the UK consist of pellets (containing 100mg or 200mg of testosterone) which are 6mm or 12mm long and 4.5mm in diameter. They are inserted under local anaesthetic (using a small scalpel incision, and a trocar and cannula) usually in the lower abdomen or buttock. The dosage recommended by the manufacturer is 100-600mg depending on individual requirements. About 1.5mg of testosterone is absorbed daily from a 200mg pellet.14 Plasma testosterone levels peak at 1 month and are maintained at physiological levels for 4-5 months (600mg dose) or 6 months (1200mg dose) after a single implantation procedure.14 Extrusion and/or infection occur at the site of insertion in around 5-14% of patients.14,15 Bleeding, haematoma, scarring and fibrosis can occur but are rare.14 The disadvantages of a minor surgical procedure and its attendant risks have to be weighed against the advantages of a therapy given once every 4-6 months that provides steady testosterone levels. Patients usually find this treatment quite acceptable15 although the Joint Formulary Committee of the British National Formulary consider testosterone implants to be less suitable for prescribing than the other available preparations.16
▼Andropatch (SmithKline Beecham) is the only transdermal testosterone preparation available in the UK. Patches contain either 12.2mg or 24.3mg of testosterone in an alcohol base, delivering an average of 2.5mg or 5mg testosterone, respectively, over a 24-hour period. The manufacturer suggests that most patients should apply one 5mg patch or two 2.5mg patches at around 10pm each night to intact, clean dry skin on the back, abdomen, upper arms or thighs (but not over bony prominences, pressure sites or the scrotum), using a different site every 24 hours. Patients weighing more than 130kg may require 7.5mg per day. Around 10% of patients develop unacceptable local skin reactions (probably due to the adhesive or the alcohol base).17 Reported skin reactions range from simple erythema to more severe allergic responses or blistering eruptions that heal with scarring. Although the 24-hour testosterone profile produced by the patches may be closer to that of normal men than is achieved with intramuscular testosterone injections,17 the clinical benefits of this effect are unclear. Many patients find the rustling sound of the patch irritating and worry that the patch is conspicuous. Experience with this form of treatment is limited in the UK.
Potential unwanted effects
Supraphysiological levels of testosterone can aggravate latent or overt cardiac failure, stimulate appetite, cause weight gain, water and sodium retention, priapism (and other signs of excessive sexual stimulation), oligospermia and decreased ejaculatory volume. Testosterone replacement may induce or worsen obstructive sleep apnoea. Its use is contraindicated in prostatic carcinoma or male breast cancer.9
It is not clear how best to monitor patients on androgen replacement therapy. Ideally, the dosage and/or frequency of intramuscular administration should be adjusted to ensure that testosterone levels remain in the mid-normal range 1 week after an injection and within the normal range until the next injection,9 avoiding unphysiological peaks and troughs. For patches, testosterone levels should be measured 24-48 hours after patch application. For subdermal implants, testosterone levels should be measured 3-4 weeks after insertion and just before the next implantation. Once physiological steady-state testosterone levels have been achieved, patients should be reassessed every 6 months. If patients report undue tiredness or depression, their trough testosterone levels should be measured before the next dose. It is worth screening for prostatic cancer and checking haematocrit and serum lipids at least yearly.
Hypogonadism in men may be due to primary testicular failure (hypergonadotrophic hypogonadism) or be secondary to hypothalamic or pituitary disease (hypogonadotrophic hypogonadism). Both types require testosterone replacement to restore secondary sexual characteristics and maintain muscle and bone mass. Clinical assessment plus a single measurement of morning basal testosterone, luteinising hormone, follicle-stimulating hormone and prolactin levels are usually sufficient for diagnosis of hypogonadism. Testosterone can be given orally (three times daily), by intramuscular injection (at intervals of around 3 weeks), by subdermal implants (which last 4-6 months) or by transdermal patches (replaced every 24 hours). Patient preference is essential in choosing the preparation to be given. Intramuscular preparations require frequent and potentially painful injections and can give rise to severe fluctuations in mood and libido. Transdermal patches often cause local skin reactions and may feel conspicuous. Although testosterone implants need minor surgery for insertion and can result in local infection, they have the advantage of only needing to be given every 4-6 months.
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