22 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
22 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
9 AUGUST 2024 ausdoc . com . au
Figure 2 . Hypothalamic-pituitary-gonadal axis .
PAGE 20 see table 1 . On clinical assessment , be vigilant for clues of an underlying organic aetiology , such as signs of pituitary dysfunction or mass effect ( for example , bitemporal hemianopia or unexplained new-onset headache ), or Cushing syndrome . Many features such as fatigue , low libido , and reduced muscle bulk are non-specific and can be caused by almost any chronic disease .
The initial assessment also includes identification of comorbidities that may confound the clinical picture or represent potentially reversible causes ( such as obesity , depression or uncontrolled sleep apnoea ), or medications that can suppress the HPT axis ( such as opioids or glucocorticoids ), see figure 7 . In addition , a history of radiation to the pelvis , chemotherapy , testicular trauma , or mumps orchitis may raise the suspicion of primary hypogonadism .
Of note , androgen deprivation therapy given to men with prostate cancer is the most common contemporary cause of severe hypogonadism in older men and requires dedicated assessment and management ( see box 3 ). 12
LABORATORY TESTING Confirm the clinical impression of androgen deficiency by measuring a morning fasting serum total testosterone using a validated assay . There is no role for testosterone measurement in asymptomatic men . In contrast to , for example bone density , where age-dependent reference ranges are quite well defined , there is no general agreement on the acceptable normal range of testosterone , especially in older men . This is because there have been relatively few large population-based studies of healthy older men .
Testosterone assays are poorly standardised , and reference ranges vary between laboratories . The accuracy of currently used immunoassays is variable , especially in the lower range . One Australian study comparing seven commonly used immunoassays has shown that compared with a liquid chromatography – mass spectrometry-based assay , the current gold standard , testosterone levels at the lower limit of the male reference range differed by as much as 30 % between the different immunoassays . 14 Given that liquid chromatography – mass spectrometry technology is not widely available in Australia , clinicians are advised to become familiar with their local assay and its reference range .
Any acute illness can temporarily reduce serum testosterone , therefore it should not be measured in men
Table 1 . Clinical features of testosterone deficiency^ in men
Specific Very small testes ( combined volume 8mL or less ) Pubertal delay * Eunuchoid body proportions * Deficient male pattern body hair +
Suggestive
Non-specific
Decreased or low libido Loss of early morning erections Vasomotor symptoms ( hot flushes ) New-onset or increasing gynaecomastia ( see figure 6 ) with breast tenderness Reduced testicular volume ( a volume of 6-12mL for each testis ) Unexplained anaemia Poor semen quality and / or sperm concentration less than 15 million / mL Unexplained osteoporosis or osteopenia
Fatigue Low mood Erectile dysfunction Reduced lean-to-fat mass
^ Some effects PAGE 20 of testosterone deficiency ( such as reduced bone density , increased fat mass , vasomotor symptoms ) might be predominantly mediated by a concomitant deficiency of oestradiol , a testosterone metabolite ). * Seen only in men with prepubertal onset of hypogonadism ; uncommon in older men without a diagnosis of classical hypogonadism .
+
Only in men with very longstanding , untreated hypogonadism .
Source : Grossmann M et al 2023 9
who are unwell until they have recovered from their acute illness . Given the circadian rhythmicity of testosterone , request an early morning testosterone level . This allows for a fasting sample ; this is important because
Artoria2e5 / CC BY 3.0 / bit . ly / 3TcqTCB overnight fasting increases serum testosterone by 9-16 %, and reduces the variability in serum testosterone . 7 However , this assessment is complicated in shift workers , and specialist input may be required .
A low total testosterone level needs confirmation because a falsely low level from intercurrent illness or assay imprecision in the lower range is more likely than a falsely normal level . Multiple factors , including a poor night ’ s sleep , may temporarily reduce the serum testosterone concentration . A diagnosis of androgen deficiency should not be made based on a single low testosterone level . Up to 35 % of men with a low testosterone level will have a normal result on repeat testing . 15 Therefore , at least two low fasting morning total testosterone levels are required to provide biochemical evidence of androgen deficiency .
In contrast , a fasting early morning total testosterone level of greater than 12nmol / L , measured by a reliable assay , is generally consistent with eugonadism , and does not require confirmation , with exceptions noted below .
Depending on the assay , serum testosterone concentrations between 6-10nmol / L can be considered borderline ; however , interpretation of the serum testosterone depends on patient characteristics .
For example , in a young , otherwise healthy man who presents with specific features of hypogonadism , a serum testosterone level below the assay reference range generally confirms a diagnosis of hypogonadism , whereas in older men with obesity and multiple comorbidities , a serum testosterone level as low as 5-6nmol / L may be due to eugonadal sick syndrome . For example , in an Australian study of consecutive men without a history of organic hypogonadism presenting to a diabetes outpatient clinic , the mean serum testosterone was 2nmol / L below the lower limit of the assay range , and only 43 % of men had a serum testosterone level above the lower limit of the reference range . 16
The clinical utility of quantifying free testosterone is controversial but may be helpful when total testosterone is borderline and abnormalities in sex hormone binding globulin ( SHBG ) are suspected ( see table 2 ). Although equilibrium dialysis is the gold standard , in practice , free testosterone is usually calculated using empirical formulae .
Free testosterone may be helpful in excluding hypogonadism where low total testosterone is caused by low SHBG because of insulin resistance in obesity or diabetes , but the free testosterone is normal ( a scenario also called pseudo-hypogonadism ). In this context , a normal free testosterone will reassure the patient that their non-specific symptoms are not due to androgen deficiency . 17 Note that neither equations to calculate free testosterone , nor reference ranges in older men are well validated . 18
Because of the age-related increase in SHBG and resultant steeper decline of age-related free testosterone compared with total testosterone , a low free testosterone level should be used with caution to confirm hypogonadism in older men . The risk of overdiagnosis is substantial given reference ranges are usually based on young men . Even in young men , reported reference ranges for free testosterone vary widely from 170-310pmol / L in different assays .
Much less commonly , men can be androgen deficient despite a normal total testosterone level . This PAGE 24