HOW TO TREAT 25 before presentation , although this had unfortunately not been investigated at the time . He also reports a history of infertility .
Hypogonadism : a diagnostic approach
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HOW TO TREAT 25 before presentation , although this had unfortunately not been investigated at the time . He also reports a history of infertility .
Testosterone replacement is initiated , with noticeable improvements in energy levels , libido and muscle strength . Given his established osteoporosis and the lack of fracture data with testosterone treatment , antiresorptive treatment with a bisphosphonate is also started .
Klinefelter syndrome is the most common cause of organic hypogonadism in men , with an estimated prevalence of one in 450 live-born Australian males . 2 Affected men present with uniformly elevated gonadotropins , while testosterone concentrations are either frankly low or , especially in younger men , normal to low-normal . Therefore , pubertal androgenisation can occur , and men may not appear to be obviously hypogonadal . However , more than 95 % of affected men have very small ( prepubertal-sized ) 3-4mL testes that are firm to palpation . 2 Infertility is typical , although in some men sperm can be retrieved by testicular sperm extraction . Given that genital examination is not routine in men , the Klinefelter diagnosis can be missed . Registry data suggest that only onethird of men with Klinefelter syndrome are diagnosed in their lifetime , with a median age at diagnosis of 27 , around the time affected men present with infertility . 2 Missed or delayed diagnosis and the ensuing untreated hypogonadism is associated with a reduced quality of life and increased morbidity , including osteoporosis and a risk of obesity , diabetes , sarcopenia and cardiovascular disease .
Case study two
James , a 32-year-old man , seeks evaluation for infertility . He attends the appointment with his wife Betty , aged 34 , who leads the discussion . They have been married for three years and have regular sexual intercourse . She is healthy and reports regular menses . He describes normal puberty , has no significant medical history , and reports no regular medication use . James does not smoke cigarettes or drink alcohol .
On physical examination , he is muscular and has pustular acne ( see figure 9 ) on his upper back and midline chest . Phallus is normal , and testicular volume is 5mL bilaterally , without masses . Laboratory test results ( drawn in the morning , in the fasting state ) show a total testosterone of 1.7nmol / L ( reference range : 10.4-31.2nmol / L ), SHBG 7.1nmol / L ( 10-60nmol / L ), LH 0.2 IU / L ( 1.0-9.0 IU / L ), FSH 0.3 IU / L ( 1.0-13.0 IU / L ), and haemoglobin 183g / L ( 138- 172g / L ). Prolactin is normal . Semen analysis reveals azoospermia ( see figure 10 ).
James presents with typical features of anabolic steroid abuse , which is often not readily disclosed by patients . Even close partners may not be aware of this . Therefore , taking a careful drug history that includes direct questioning in a non-judgemental manner , and , if appropriate , in the absence of the patient ’ s partner , is an important part of the evaluation . While precise epidemiologic data are difficult to establish , the lifetime prevalence of anabolic steroid use among men in the general population is about 1-5 %. 23 Men who abuse anabolic steroids often pursue a muscular physique to improve body image , and may have underlying psychiatric comorbidities , including muscle dysmorphia . They are typically in their
Androgen deficiency-like symptoms^ and end organ deficits *
^eg , fatigue , low mood , erectile dysfunction * eg , osteoporosis , sarcopenia , insulin resistance
20s or 30s , appear muscular , and , with long-term use , have small , atrophic testes because of the suppressive effect of exogenous anabolic steroids on spermatogenesis . They may have azoospermia when evaluated for infertility . Acne involving the upper back and midline chest is virtually pathognomonic . Other adverse effects include painful gynaecomastia ( often mitigated by concomitant use of antioestrogens , such as aromatase inhibitors ), male pattern hair loss , and tendon injuries , especially upper-extremity tendon ruptures . If synthetic non-testosterone anabolic steroids ( such as nandrolone , danazol ) are abused , typical biochemical abnormalities include suppressed
Obesity Chronic disease
?
gonadotropins and serum testosterone ; this is because these synthetic anabolic steroids are not detected by standard testosterone assays . If exogenous testosterone is abused , measured serum
testosterone will be high ( unless a testosterone formulation with a short half-life has been stopped before the venesection ) and gonadotropins will be suppressed . Because of the erythropoietic actions of anabolic steroids , other
Hypothalamic-pituitary-testicular axis suppression ‘ Eugonadal sick syndrome ’
Lowered testosterone
maladaptive ? adaptive ? neutral ?
Figure 5 . Obesity and any chronic disease can lead to suppression of the hypothalamic-pituitary-testicular axis causing on the one hand , a lowered serum testosterone and on the other hand , non-specific androgen deficiency-like symptoms and end organ deficits . Whether the lowered testosterone contributes to these remains uncertain . In the context of this so-called ‘ eugonadal sick syndrome ’ the lowered testosterone could be maladaptive ( harmful ) adaptative ( beneficial ) or simply neutral ( that is , of no health consequence ).
Figure 6 . Gynaecomastia .
Hypogonadism : a diagnostic approach
Clinical suspicion
Biochemical confirmation *
Disease localisation
* Clinically stable patient ( Intercurrent illness lowers testosterone )
Figure 7 . A diagnostic approach to hypogonadism .
Symptoms and signs of androgen deficiency
Repeatedly low testosterone
Morning , fasted
LH / FSH if low / normal Pituitary assessment
Evaluate for potentially reversible factors ( illness , drugs ) that could
• lower testosterone and / or
• confound clinical picture
Management of men who use anabolic steroids but are willing to stop is complex and controversial .
typical biochemical features include polycythaemia and a low SHBG level because anabolic steroids suppress SHBG production .
Management of men who use anabolic steroids but are willing to stop is complex and controversial . A supportive approach is best , providing education and reassurance that reactivation of the endogenous gonadal axis should occur eventually ( within 12-18 months in most men ), with regular biochemical monitoring , rather than prescribing hormonal treatment . 24
Case study three
Robert , a 32-year-old man , presents with a 12-month history of increasing fatigue , reduced libido , and reduced exercise tolerance , which he attributes to declining muscle strength . He is an avid weekend hiker but feels less motivated to maintain his hiking activities and has gained 2kg over the past six months . Robert has had no headaches or vision disturbances . He reports no history of head trauma or significant medical or family history and does not take any prescribed or illicit drugs . He has a normal sense of smell , and he underwent normal puberty .
On physical examination , his visual fields are full to confrontation and he has a full range of eye movements . Body hair is mildly reduced . There is no muscle wasting , gynaecomastia , facial plethora or purple striae . His testes are 20mL bilaterally . Laboratory results show an 8am fasting total testosterone of 5.2nmol / L ( reference range 10.4-31.2nmol / L ), with a repeated measurement of 4.9nmol / L . LH is 2.0 IU / L ( 1.0-9.0 IU / L ), FSH is 2.5 IU / L ( 1.0- 13.0 IU / L ), haemoglobin is 128g / L ( 138- 172g / L , with the remainder of the FBC normal . Thyroid function is normal .
Robert presents with symptoms and signs of hypogonadism , and the clinical diagnosis is confirmed by unequivocally and consistently reduced fasting 8am total testosterone concentrations . Once the diagnosis of hypogonadism is established , the next step is to measure gonadotropins to distinguish primary ( increased gonadotropins ) from secondary hypogonadism ( gonadotropins low to low-normal ). In Robert , the inappropriately low-normal gonadotropins indicate secondary hypogonadism . Hyperprolactinaemia is one of the most common causes of secondary hypogonadism in men . Prolactin excess induces hypogonadism by inhibiting the pulsatile secretion of gonadotropin-releasing hormone and , consequently , gonadotropin secretion . In cases of a pituitary macroadenoma , secondary hypogonadism can also be due to a mass effect . Measurement of serum prolactin and iron saturation to exclude iron overload syndromes , are first-line investigation in the assessment of secondary hypogonadism . Robert ’ s prolactin is 8700mU / L ( 150-500mU / L ), and a subsequent pituitary-directed MRI reveals an 8mm pituitary microadenoma ( see figure 11 ) not abutting the optic chiasm , thus explaining the absence of visual disturbance .
Following education about the rare side effect of impulse control disorders ( manifesting as pathological gambling , excessive spending , or hypersexuality ) Robert is started on a dopamine agonist , with normalisation of his prolactin and serum testosterone and resolution of his hypogonadal symptoms .
SUMMARY
TESTOSTERONE , the principal circulating androgen in men , has essential reproductive functions in establishing and maintaining the male phenotype . It also plays important anabolic roles in somatic tissue , such as muscle and bone . Organic hypogonadism is an important diagnosis to make , and an important differential diagnosis to consider in the man presenting with , for example , otherwise unexplained weakness , anaemia PAGE 27