24 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
24 HOW TO TREAT : EVALUATION OF LOW TESTOSTERONE IN MEN
92 AUGUST 2024 ausdoc . com . au
PAGE 22 usually occurs if SHBG is markedly elevated , most commonly in the setting of antiepileptic treatment or chronic liver disease . These men usually have elevated gonadotropin levels and a clearly low free testosterone .
Once the low testosterone value has been confirmed on repeated morning measurements in men with consistent symptoms and signs , next measure the gonadotropins , LH and FSH to distinguish between primary and secondary hypogonadism . Elevated gonadotropin values denote primary hypogonadism ( testicular failure ). If the testes are small , a karyotype is indicated to evaluate for Klinefelter syndrome . If fertility is desired , a semen analysis should be requested .
In men with functional / late-onset hypogonadism , gonadotropins are usually low to low-normal because of hypothalamic-pituitary suppression . 19 In older men , elevated LH levels may denote an intact pituitary response to testicular failure as well as identify men with primary hypogonadism , who may have a higher likelihood of response to testosterone treatment .
Exclusion of organic hypothalamic-pituitarytesticular axis pathology
As discussed earlier , if the serum testosterone is repeatedly low and serum gonadotropins are elevated ( denoting primary hypogonadism ), exclude Klinefelter syndrome with a karyotype . If serum testosterone is low and gonadotropins are low or low-normal , it is important to identify hypothalamic-pituitary pathology causing secondary hypogonadism .
Most older men with obesity and lowered testosterone will have low-normal gonadotropin concentrations because of hypothalamic-pituitary inhibition from obesity and chronic disease rather than from organic pathology . 19 Evaluation for underlying organic HPT axis pathology in these men is commonly of low yield , and should be individualised . In men with low serum testosterone and non-elevated gonadotropins , the probability of organic hypothalamic-pituitary pathology is inversely related to BMI , age , number of comorbidities and testosterone concentration . 9
In the absence of clinical suspicion of pituitary disease , biochemical workup can be limited to measuring prolactin . In addition , in men younger than 65 , perform iron studies to exclude haemochromatosis , which can present as isolated hypogonadotropic hypogonadism . The testosterone cut-off level below which pituitary imaging is indicated is not well defined . The published literature is limited to 313 middle-aged men with predominantly sexual symptoms and a mean total testosterone level of 6.6nmol / L . 20 The overall prevalence of pituitary microadenoma was 6.5 %, similar to that expected in the general population . Six patients ( 1.9 %) had a macroadenoma , all of whom had total testosterone levels of 3.6nmol / L or less . The Endocrine Society guidelines recommend restricting pituitary imaging , in the absence of clinical suspicion , to men with a total testosterone level of 5.2nmol / L or less . 21 Of note , if prolactin is not elevated , a pituitary lesion has to be relatively large to cause hypogonadotropic hypogonadism , and therefore
Figure 3 . Kallmann syndrome .
Figure 4 . Sex hormone production by age .
a pituitary CT , if indicated , has sufficient sensitivity . Compared with MRI , a CT , although involving radiation exposure , is less likely to detect an incidental pituitary microadenoma .
CASE STUDIES
Case study one
PETER , a 58-year-old man , presents with spontaneous onset back pain . Spine X-ray reveals a midthoracic compression fracture . Dual energy X-ray absorptiometry shows T-scores of -2.8 at the lumbar spine , and -2.5 at the femoral neck . Investigations for secondary osteoporosis are notable for a serum testosterone of 1.7nmol / L ( reference range : 10.4-31.2nmol / L ), with a repeat one week later of 2.4nmol / L . LH is 39.2 IU / L ( 1.0-9.0 IU / L ) and FSH 66.6 IU / L
Table 2 . Causes of high and low circulating sex hormone binding globulin
Decreased sex hormone binding globulin ( SHBG )
Increased SHBG
Obesity Diabetes mellitus with poor glycaemic control Androgens , glucocorticoids and some progestogens SHBG gene polymorphisms Hypothyroidism ( untreated ) Acromegaly ( untreated ) End-stage liver cirrhosis with severe synthetic dysfunction Nephrotic syndrome
Ageing SHBG gene polymorphisms Chronic high alcohol consumption Some anticonvulsants ( eg , phenobarbital ) Oestrogens Untreated or undertreated HIV infection ( a direct hepatic effect ) Liver disease ( other than end-stage cirrhosis ) Hyperthyroidism ( untreated ) Severe energy deficit ( reduced caloric intake and / or excessive exercise )
Source : Grossmann M et al 2023 9
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Box 3 . Hypogonadism from androgen deprivation therapy for prostate cancer
• The lifetime incidence of prostate cancer in men is one in six , and more than 50 % of men with prostate cancer will receive androgen deprivation therapy ( ADT ) during the course of their illness , often for several years . 12
• ADT reduces sex steroids to castration levels and is therefore one of the most common contemporary causes of severe hypogonadism .
• The overall prognosis of prostate cancer is favourable ( 10-year disease-specific mortality is less than 90 %), and most men die with , rather than from prostate cancer .
• ADT-associated toxicities are a consequence of the severe hypogonadism and include fatigue , reduced sexual function , anaemia , accelerated bone loss with increased risk of fragility fractures , muscle loss , and visceral obesity leading to insulin resistance and increased risk of diabetes , and , although this is still controversial , of cardiovascular events . — It is therefore important that ADT is only prescribed in situations where there is high-level evidence for benefit , for example adjuvant to radiotherapy in men with high-risk prostate cancer .
— To optimise the risk – benefit ratio of ADT , men receiving this therapy require monitoring for ADT-associated toxicities . This includes baseline and regular follow-up assessment for bone and cardiometabolic health according to a standardised , evidence-based management plan . 12
• While specific biomarkers of testosterone deficiency are lacking , otherwise unexplained anaemia , reduced bone density , or a low PSA can be supportive of clinically relevant androgen deficiency . 13
( 1.0-13.0 IU / L ). Physical examination findings include gynaecomastia and reduced muscle bulk . Testicular volume is 3mL bilaterally and testes feel firm to palpation .
Secondary causes are found in up to 60 % of men with osteoporosis , with the most common causes including hypogonadism , glucocorticoid exposure and excess alcohol consumption . 22 Recommended initial laboratory testing in men with osteoporosis includes serum testosterone measurement . In this patient , serum testosterone is low , prompting the measurement of gonadotropins , which are elevated . These findings are indicative of primary hypogonadism . On examination , he has features consistent with hypogonadism ( that is , gynaecomastia and loss of muscle bulk ) and his testes are small and firm to palpation , consistent with a clinical diagnosis of Klinefelter syndrome . This is later confirmed by karyotype . On further questioning , he reports a history of a left wrist fracture after a fall from standing height two years