20 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
20 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
9 AUGUST 2024 ausdoc . com . au examinations are not routinely performed , men with Klinefelter syndrome may be diagnosed late in life , sometimes when they present with complications of longstanding untreated hypogonadism .
Organic hypogonadism is generally irreversible ; however , reversal of congenital hypogonadotropic hypogonadism ( that is , Kallmann syndrome or normo-osmotic congenital hypogonadotropic hypogonadism ) has been reported in rare cases and is usually heralded by increasing testicular size despite testosterone therapy . Apart from these rare exceptions , men with organic hypogonadism usually require lifelong testosterone replacement .
In men with organic hypogonadism , testosterone replacement rectifies the clinical features of androgen deficiency , but does not restore fertility , and may even reduce fertility . 3 This is because exogenous testosterone replacement suppresses FSH that is required for spermatogenesis . Spermatogenesis also requires high intratesticular testosterone concentrations that is not achieved by exogenous testosterone replacement . While testosterone replacement for men with organic hypogonadism is undisputed , the evidence for its benefit is from uncontrolled case series and clinical experience . 3 This is because , for ethical reasons , men with organic hypogonadism have been excluded from randomised controlled clinical trials . Men with hypogonadotropic hypogonadism ( from hypothalamic or pituitary pathology ) can achieve spermatogenesis and successful paternity with gonadotropin therapy . 4 In contrast , gonadotropin therapy is not helpful in achieving fertility in men with primary organic hypogonadism ( where gonadotropins are already elevated ). Men with Klinefelter syndrome , despite usually having azoospermia on sperm analysis , may have sperm that can be retrieved by sperm harvesting , for example by testicular sperm extraction . Specialist referral is indicated in men with organic hypogonadism who seek fertility . In general , and given the PBS eligibility criteria for testosterone treatment ( see box 2 ), men with organic hypogonadism are managed in conjunction with a specialist .
Functional hypogonadism
Functional hypogonadism is a somewhat controversial entity . It refers to the coexistence of androgen deficiency-like symptoms and low serum testosterone in the absence of identifiable pathology affecting the HPT axis . If this occurs in older men ( usually 50 or older ) functional hypogonadism is also referred to as ‘ late-onset hypogonadism ’. Of note , the coexistence of non-specific features consistent with androgen deficiency ( such as fatigue , low mood and erectile dysfunction ) and a low serum testosterone does not necessarily indicate that the lowered serum testosterone is causing the clinical presentation . For example , a European study has shown that of 39 symptoms commonly attributed to androgen deficiency , only three ( reduced sexual thoughts , reduced morning erections and low libido ) were clustered with a low testosterone level , and the prevalence of late-onset hypogonadism according to this definition was only 2.1 %. 5 It is important to note that in contrast to women who experience a sudden drop of oestradiol around the time of cessation of menses , the age-related drop in testosterone
Box 1 . Classification of male hypogonadism
• Primary hypogonadism — Organic :
• Congenital :
• Klinefelter syndrome .
• Y-chromosome microdeletions .
• Cryptorchidism , anorchia .
• Mutations in androgen biosynthesis enzymes .
• LH / FSH receptor mutations .
• Myotonic dystrophy .
• Acquired testicular damage :
• Irradiation , chemotherapy .
• Castration , trauma , torsion .
• Orchitis .
• Autoimmune .
— Functional :
• Ketoconazole .
• Spironolactone .
• Chronic illness .*
• Secondary hypogonadism — Organic :
• Congenital :
• Gonadotropin-releasing hormone deficiency ( Kallmann syndrome , normo-osmotic varieties ).
• LH / FSH beta subunit mutations .
• Prader-Willi syndrome ( see figure 1 ).
• Acquired hypothalamic / pituitary damage :
• Pituitary / hypothalamic tumour .
• Surgery / radiation .
• Stalk section or disease .
• Hypopituitarism .
• Infiltrative ( iron overload / histiocytosis / sarcoid ).
• Apoplexy / haemorrhage .
— Functional :
• Opioids .
• Glucocorticoids .*
• Hyperprolactinaemia .
• Chronic illness *, wasting .
• Organ failure .
• Malnutrition , obesity , type 2 diabetes .
• Excess exercise .
• Androgens , progestogens , oestrogens , gonadotropin-releasing hormone agonists .
• Older age ( with comorbidities ).*
Organic hypogonadism typically presents with specific clinical features such as low libido , small testes , or gynaecomastia and serum testosterone concentrations are consistently and severely low . In contrast , functional hypogonadism usually presents with non-specific features such as erectile dysfunction , low energy or low mood , and serum testosterone concentrations are borderline and fluctuate around the lower limit of the assay reference range . * Combined primary and secondary hypogonadism . Source : Grossmann M et al 2017 1
in men is more gradual , about 0.5- 2.0 % per year from early adulthood onwards . 6 In contrast to women , there is no inflection point or clinical correlate equivalent to cessation of menses and thus no evidence for the existence of andropause ( see figure 4 ). Most older men have testosterone levels in the normal range . 7 In men with a high comorbid burden , reverse causality is a possibility ; for example , non-specific symptoms such as low libido and fatigue / low mood may be due to undiagnosed depression or sleep apnoea , and erectile dysfunction may be caused by neurovascular disease or psychogenic causes . Simultaneously , these comorbidities cause non-specific suppression of the HPT axis leading to a lowered serum testosterone , which is incidental to the clinical symptoms . Almost any acute or chronic disease can suppress the HPT axis , causing a so-called ‘ eugonadal sick syndrome ’ ( see figure 5 ), akin to the euthyroid sick syndrome .
Conditions such as type 2 diabetes , obesity , depression , obstructive sleep apnoea , chronic kidney disease or anorexia nervosa are associated with decreases in testosterone levels of between 2-10nmol / L , depending on their severity . 8 In addition , medications to treat chronic illness , particularly glucocorticoids or opioids , can further reduce testosterone levels . Consistent with this , there is good evidence that age-related accumulation of chronic disease and especially obesity — rather than ageing itself — largely explains , or at least accelerates this age-related decline in testosterone levels . 8 Australian data suggest that healthy ageing by itself may not be associated with marked decreases in testosterone levels . 7 Overall , the evidence suggests that low testosterone is a sensitive biomarker of poor health , rather than a causal factor .
Functional hypogonadism is a diagnosis of exclusion and requires a tailored workup to exclude organic hypogonadism . Clinically , middle-aged and older men with functional hypogonadism usually present with non-specific androgen deficiency-like symptoms ( see table 1 ) and modest reductions in serum testosterone fluctuating around the lower limit of the assay range .
Functional hypogonadism generally presents as secondary hypogonadism ( low or low-normal gonadotropins ). In the European study mentioned earlier , functional / late-onset hypogonadism had an estimated population frequency of 2.1 %, increasing from
Figure 1 . Prader-Willi syndrome .
Box 2 . Eligibility criteria for PBS-subsidised testosterone treatment in adults
• Men over 40 who do not have an established pituitary or testicular disorder must have a circulating testosterone level of less than 6nmol / L , confirmed by at least two morning testosterone measurements .
• Total testosterone levels between 6.0-15.0nmol / L provided the LH level is greater than 1.5 times the upper limit of the eugonadal reference range , or greater than 14 IU / L .
• There are no restrictions for testosterone replacement in men with organic hypogonadism from an established pituitary or testicular disorder .
• PBS-subsidised testosterone therapy can only by prescribed in conjunction with a specialist endocrinologist , urologist or registered member of the Australasian Chapter of Sexual Health Medicine .
Source : Yeap BB et al 2016 4
0.6 % in 50-59-year-old men to 5.1 % in 70-79-year-old men . 5 Less frequently , functional hypogonadism can occur in young men , for example in the setting of energy deficit ( such as anorexia nervosa , excessive exercise ), or from undisclosed use of anabolic steroids . 10
In principle , functional hypogonadism is considered reversible by optimisation of comorbidities , as there is no intrinsic structural pathology of the HPT axis . For example , functional hypogonadism associated with unhealthy weight ( obesity , anorexia nervosa ) can be reversible with restoration of a healthy body weight , although achieving and maintaining a healthy body weight can be difficult
10 , 11 in practice . Of note , there are currently no long-term randomised controlled trials of testosterone therapy in men with so-called functional hypogonadism that inform regarding the health outcomes that are important to these men .
ASSESSMENT
AS with any endocrine condition , the diagnosis of male hypogonadism follows a three-step process , starting with clinical suspicion , followed by biochemical confirmation and then localisation of the disease ( that is , confirming the underlying aetiology , see figure 7 ). This process is usually straightforward with frank hypogonadism , for example in a young otherwise healthy man who presents with low libido , gynaecomastia , reduced male pattern body hair , small testes with an unequivocally low serum testosterone and elevated gonadotropin concentrations . However , the assessment is more complex in an older man with obesity and multiple comorbidities who presents with fatigue , low mood and erectile dysfunction , and who has a borderline serum testosterone and gonadotropin concentrations in the normal range .
Clinical evaluation
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HISTORY AND EXAMINATION Hypogonadism is primarily a clinical diagnosis supported by consistent biochemical findings . Therefore , men who present with features suggestive of androgen deficiency require a thorough history and physical examination to determine the degree of clinically significant androgen deficiency .
Clinical assessment focusses on eliciting the more specific features of androgen deficiency , such as reduced testicular volume ( see figure 8 ) and gynaecomastia ( palpable breast tissue and not merely lipomastia ), PAGE 22