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Tricky ten minutes - ‘I think I’m going through the male menopause. I’d like some testosterone’

Professor Mike Kirby, GP and visiting professor at The Prostate Centre, discusses this consultation from a man requesting testosterone

The term ‘male menopause’ is incorrect. Unlike women, men do not have an abrupt cessation in the production of hormones, although the blood testosterone levels do diminish by about 1% per year from the age of 50. A more accurate term is ‘late-onset hypogonadism (LOH)’, also referred to as age-associated testosterone deficiency syndrome (TDS). This is a clinical and biochemical syndrome associated with advancing age, characterised by a serum testosterone level below that of the young healthy adult male reference range. Because of the media interest in testosterone, GPs will see more patients enquiring if they have low testosterone in the next few years.

Testosterone deficiency can be primary or secondary. If the defect is at the level of the testes, this is a primary problem and the gonadotropins may be elevated (luteinising hormone [LH] and follicle stimulating hormone [FSH]). In secondary hypogonadism, there is hypothalamic-pituitary failure to stimulate testicular testosterone production and the gonadotropins may be low or normal, depending on the cause. Sometimes there can be a combination of both.

The actual prevalence of low-serum testosterone in ageing men is not known with certainty, but it is projected to be up to 25%. One study noted an overall prevalence of hypogonadism of 2.1%, finding an increase with age from 0.1% for 40- to 49-year-old men to 5.1% for 70- to 79-year-old men.1 The Massachusetts Male Aging study reported that the overall prevalence of symptomatic androgen deficiency was 5.6%, with an increased prevalence of 18.4% among 70-year-old men.2

Common symptoms include fatigue, reduced wellbeing, depression, loss of concentration, hot flushes and sweats, weakness, reduced muscle mass and reduced body hair. The sexual symptoms include low libido, erectile dysfunction (ED), ejaculatory dysfunction, loss of night-time erections and poor morning erections. The presence of these sexual symptoms and a low testosterone of less than 8nmol/l makes the diagnosis very likely. The recent publicity given to testosterone level may drive patients to consult about replacement therapy. The other non-sexual symptoms are very non-specific and other causes need to be excluded.

The main differential diagnoses of TDS include: depression; stress; anxiety; sexual dysfunction; muscle weakness; sleep apnoea; and increasing abdominal weight gain.

Associated conditions include: chronic obstructive lung disease; inflammatory arthritis; osteoporosis; and infertility. Obesity and the metabolic syndrome can predispose to hypogonadism, as can excessive alcohol consumption. Rare causes include prolactinoma and haemochromatosis. Men using chronic opiate therapy are also at risk.

History and investigations

A careful history is important because the diagnosis requires the presence of symptoms – particularly the five sexual symptoms – and signs suggesting testosterone deficiency combined with confirmatory blood tests. The initial assessment will include a thorough clinical examination to look for confirmatory signs, especially the presence of small, atrophied testes, loss of body hair, decreased muscle mass and increased central obesity.   

Investigations include a total testosterone assay. A level greater than 12nmol/l is normal and therefore does not require any replacement therapy. Patients with a serum total testosterone level below 8nmol/l will usually benefit from testosterone therapy. If the level is between 8-12nmol/l, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) and albumin will allow you to calculate free testosterone. A free testosterone level below 225nmol/l provides supportive evidence. The measurement of testosterone should take place ideally at 9am, without fasting.

Measurement of serum LH will help differentiate primary and secondary hypogonadism, and it is advisable to do a serum prolactin level if the serum testosterone is lower than 5.2nmol/l, or when secondary hypogonadism is suspected. Consider referral for pituitary MRI if the testosterone is less than 5.2nmol/l and the LH is low.

Total testosterone assay is widely available and inexpensive to perform. Although the ranges and methods vary, physicians can consult their local laboratories for the applicable values in their clinical practice. Total testosterone values, however, must be interpreted carefully in the ageing male because SHBG levels might be elevated. If the total testosterone level is normal in the ageing male with hypogonadism, the clinician can measure calculated free testosterone. Free testosterone can also be measured by equilibrium dialysis or ultrafiltration, which are difficult to perform and largely unavailable, but reliable. In contrast, the radioimmunoassay for free testosterone is widely available but unreliable. Because total testosterone and SHBG assays are readily available and cheap, calculating free testosterone might be a good compromise. Whichever method is chosen, if the early morning testosterone level is at or below the lower limit of normal for the individual laboratory, then a repeat measurement of the early morning testosterone level should be performed to confirm the result. As testosterone is secreted in a pulsatile fashion, it is important to obtain two early morning testosterone levels.

Patients with blood levels of 8-12nmol/l may benefit from treatment, but advice to lose weight and get fit is important, as this can raise the testosterone level.

Tests to be completed prior to initiation

• FBC.

• PSA.

• Digital rectal examination (DRE).

If there are significant lower urinary tract symptoms or a raised PSA, the patient should be referred to urology.

Prostate cancer risk must be assessed by DRE and PSA. If the PSA is greater than 4ng/ml, or  greater than 3ng/ml in individuals at high risk of prostate cancer, such as African-Caribbeans or those with a family history of the disease, a urological assessment is necessary.

Conditions that may be associated with hypogonadism

• Type 2 diabetes.

• Cancer.

• AIDS.

• Cirrhosis of the liver.

• Renal failure.

• Hyperthyroidism or hypothyroidism.

• Cushing syndrome.

• Protein-calorie malnutrition (and anorexia nervosa).

• Morbid obesity.

• Haemochromatosis or sickle-cell anaemia.

• Certain psychiatric disorders, including depression.

Management

The goal of therapy is to achieve a serum testosterone level in the middle of the normal range of the young adult (around 15nmol/l) and to improve symptoms. A six- to 12-month trial of treatment should be given. Treatment is stopped if symptoms do not improve.

The following testosterone preparations are available:

• Oral testosterone – this is rapidly degraded and not clinically recommended.

• Transdermal gels – require daily administration and levels can be checked two to four hours after administration.

• Injections – after a loading dose at zero and six weeks of long-acting testosterone undecanoate is given, treatment continues every 10-12 weeks. The short-acting testosterone injections are given every three weeks. These are less convenient and do not produce a stable blood level.

Monitoring is recommended every three to six months during the first year and at least annually thereafter (twice yearly in the elderly and in patients with risk factors). The recommended checks are DRE, where appropriate, and PSA, testosterone and haematocrit. Erythrocytosis can develop during testosterone treatment, especially in older men treated with injectable preparations. The aim is to keep the haematocrit below 52-55% by adjusting dose intervals.

There is increasing evidence that TDS is associated with increased cardiovascular and all-cause mortality. Many of these men will also have cardiovascular risk factors such as hypertension, dyslipidaemia and type 2 diabetes. ED is highly predictive for cardiovascular events within three to five years, and men presenting with ED or TDS provide an opportunity to address future cardiovascular risk.

Two recent retrospective studies have shown reduced mortality in patients on testosterone replacement therapy in a cohort of US veterans and in a UK population with type 2 diabetes.3, 4

There is considerable evidence of modest cardiac and metabolic benefits, as well as sexual, mood and quality of life improvements, associated with restoring testosterone levels to the normal range. However, these benefits may potentially be denied to patients because of fears over prostate and cardiac risk that are not currently supported by evidence.

Well-conducted long-term studies are required to evaluate the benefits or otherwise of testosterone therapy, but men correctly identified have much to gain from treatment.

Professor Mike Kirby is visiting professor at The Prostate Centre, London, and a former GP in Hertfordshire

References

  1. Wu FC, Tajar A, Beynon JM et al. Identification of late-onset hypogonadism in middle-aged and elderly men. NEJM 2010; 363:123-35
  2. Araujo AB, O’Donnell AB, Brambilla DJ et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89:5920-6
  3. Shores MM, Smith NL, Forsberg CW et al. Testosterone treatment and mortality in men with low testosterone. J Clin Endocrinol Metab 2012; 97:2050-8
  4. Muraleedharan V, Marsh H, Kapoor D et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169:725-33

Patient resources

NHS Choices provides patient information on the ‘male menopause’ (Accessed March 2014).

 

Readers' comments (1)

  • Have we really not learnt anything from the HRT fiasco?

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