Age related changes, beginning in the middle age, heralds the reduction of growth and sex hormones. By the fifth to seventh decade, there are noticeable age related clinical changes, including reduction in lean muscle mass, energy, exercise ability and sexual function. But isn’t this just normal ageing? In 1944, Helers and Myers first associated decreased testosterone levels and deterioration of the general and sexual conditioning in older males. They are credited with the term ‘male menopause’ or ‘andropause’. The analogy between menopause and andropause remains controversial. There is gradual decline in male testosterone by an average of one percent per year, and not a distinct event as seen in women. Hence there is a move away from the term ‘andropause’ to adult testosterone deficiency (TD) or late onset hypogonadism.
TD results from defects at various levels of the hypothalamic-pituitary-testis axis: it can be primary, secondary or mixed. TD also can result from an impairment of the T action because of decreased bioavailability of the hormone (owing to SHBG variations) or because of androgen receptor alterations.
Even though low testosterone levels are associated with symptoms, many men with low testosterone levels are asymptomatic. In a famous study of 1475 men in Boston, 47.6 percent of men older than 50 years, who had low T levels, had no symptom of TD and only 5.6 percent of men with low testosterone had clinical criteria of testosterone deficiency. Other large cohorts have supported these results. Hence the importance of recognising TD as a defined clinical AND biochemical syndrome is highlighted in order to prevent over diagnosis and this is heavily supported by guidelines.
Signs and symptoms
The clinical manifestations of TD are variable. The various aspects of the clinical syndrome is summarised in Table 1. Sexual symptoms are prominent and often the presenting symptoms. Low sexual desire (libido) and decreased nocturnal and morning erections are highly associated, whereas erectile dysfunction during sexual activity is less evident.
Signs of low T in adult males could results in loss of secondary sexual characteristic such as loss of pubic and facial hair, decreased muscle mass and visceral obesity. Height loss and low trauma fractures could be signs of osteoporosis and mineral loss.
Different questionnaires have been proposed to help with screening or diagnosing TD. Most are sensitive, but not adequately specific and hence questionnaires are not recommended as a screening tool for TD.
Low T and medical comorbidities
T is often low in men with chronic diseases, such as obesity, T2DM, metabolic syndrome, chronic steroid and opioid use. It is important to avoid routinely screening for low T in the absence of signs or symptoms of TD. Screening for low T should occur only in those conditions for which discovering a low T level could have important consequences for the management of the patients.
Offering a morning serum T is justified when facing issues discussed under symptoms and signs in Table 1 and considering other comorbidities. Unfortunately, there is no universally agreed threshold for ‘normal’ serum T levels; however, some thresholds are used.
It is recommended that blood samples for diagnosing TD should be obtained in the morning, usually from 8 to 11am, because of the diurnal rhythm of serum T in which values are highest in the early morning. Measurement of T before 11am is even more important for men younger than 40 years.
• Step 1 – morning determination of Total T.
• Step 2 – in case of a low level (defined as Total T < 12 nmol/L or 350 ng/dL), repeating the Total T measurement, measuring with serum LH and prolactin measurements. • Step 3 – if Total T is low to normal or borderline, SHBG levels should be assessed, especially in obese or older men.In a study of 3000 men, the authors found that late-onset hypogonadism could be clinically defined by the presence of the three preceding sexual symptoms (morning erections, erection sufficient for intercourse and desire for sex) associated with a Total T level lower than 320 ng/dL (11 nmol/L) and an Free T level lower than 6.4 ng/dL (6.4 pg/mL, 220 pmol/L). These three sexual symptoms were the only symptoms that had a syndromic relation with decreased T levels.Replacement
Total T levels below 200 ng/dL (7 nmol/L) are in most cases associated with impairment of sexual function and nocturnal erections, and the effect of T replacement seems to reach its maximum benefit from levels of at least 350 to 400 ng/dL (12-16 nmol/L). There seems to be a grey zone, from 200 to 400 ng/dL.
A trial of T replacement in symptomatic men with Total T higher than 12 nmol/L or 350 ng/dL can be considered based on clinical presentation. There are many commercially available T compounds for use in T replacement. They differ in their formulations, route of administration, dose and interval.
Two common concerns have been prostate and cardiovascular safety. In males with an unevaluated prostate nodule or elevated PSA, severe lower urinary tract symptoms associated with BPH, uncontrolled CHF, haematocrit greater than 50 percent and male breast cancer, specialist assessment is warranted prior to any replacement.
Special recommendation – prostate cancer
Men older than 45 years with TD should be informed before treatment that safety data regarding T replacement and prostate safety are limited, but current data are reassuring. There is no compelling evidence that T treatment increases the risk of developing PCa or that its use is associated with PCa progression. In those successfully treated for PCa with confirmed, symptomatic TD are candidates for T replacement after a prudent interval (depending on the type of cancer treatment), if there is no evidence of residual cancer.
The AUA guidelines have been updated recently and provide an excellent summary, along with publications from all other major societies.
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