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Hypogonadism relates to a failure of the testes to produce sufficient testosterone. It can be divided into primary or secondary hypogonadism according to whether the gonadotrophins are elevated or not in the presence of a low 09.00 testosterone level, respectively (Figure 28.1). Patients present with failure to progress through puberty, infertility, erectile dysfunction and/or reduced libido. The clinical presentation depends on the severity, age of onset and duration of disease (Figure 28.2).


Primary hypogonadism
This occurs as a result of testicular failure. Causes include the following.
Klinefelter’s syndrome, affecting 1 in 500–1000 men. Most commonly caused by a 47XXY karyotype.
Other chromosomal disorders (e.g. XX males, mixed gonadal dysgenesis, XYY syndrome).
Cryptorchidism. Although undescended testes are common in male neonates, most will descend into the scrotum. Postpubertal cryptocrchidism occurs in <0.5%. There is an increased risk of testicular malignancy in addition to infertility.
Testicular torsion, trauma or castration.
Infection (e.g. mumps orchitis, HIV).
Chemotherapy and radiotherapy (e.g. for lymphoma). Alkylat-ing agents in particular are gonadotoxic.
Other causes including systemic illness such as renal failure, haemochromatosis (which can cause combined primary and secondary hypogonadism), liver cirrhosis, and drug or surgical treatment for prostate cancer.

Secondary hypogonadism
This occurs as a result of hypothalamic or pituitary disease. In addition to the causes of hypopituitarism listed in Chapter 5, specific causes of secondary hypogonadism include the following.
• Kallmann’s syndrome. A genetic disorder arising from disrupted migration of GnRH producing neurons into the hypothalamus. Leads to isolated gonadotrophin deficiency, often but not invari-ably with ansomia (from failure of olfactory lobe development).
Drugs. Anabolic steroids and opiates. Potentially reversible with drug cessation but recovery can take a long time.
Systemic illness of any kind.
Type 2 diabetes and metabolic syndrome. Total testosterone levels are lower in men with these conditions related to central obesity and insulin resistance. Routine treatment with testoster-one is not currently indicated in the absence of symptoms.

Late onset hypogonadism
Testosterone levels decline with age, at an average of 1–2% per year, because of both testicular and hypothalamic pituitary dysfunction. As a result, a significant number of older men have testosterone levels below the lower end of the reference range for healthy young men. There is currently much uncertainty about the risks and benefits of testosterone replacement in this group, hence a decision to treat should be undertaken on an individual basis. This should be considered only in men with confirmed hypogonadism on more than one occasion and with definite symptoms of androgen deficiency.

Because testosterone levels show a circadian variation, blood samples for testosterone should be taken in the morning when concentrations are at their highest. If the initial result is in the mildly hypogonadal range, a repeat sample is recommended because up to 30% of men have a normal result on repeat testing. LH and FSH should be measured to distinguish primary from secondary hypogonadism. In men with secondary hypogonadism, further evaluation for hypothalamic and/or pituitary disease is needed with measurement of prolactin, ferritin (to screen for haemochromatosis) and pituitary function in addition to MRI (Chapter 2). In men with primary hypogonadism where the aetiology is unclear, a karyotype should be requested to test for Klinefelter’s syndrome.

Androgen replacement can improve libido, erectile function, mood, muscle mass and strength, reduce fat mass and improve bone mineral density. Treatment is given as a testosterone gel or injection (monthly or 3-monthly depot preparations) and should be considered in symptomatic patients with biochemically confirmed hypogonadism provided the patient does not have prostate or breast cancer. Caution is needed in patients with benign prostate hyperplasia, polycythaemia or sleep apnoea. Assessment of response to treatment and a screen for adverse effects should be undertaken at 6-12 month intervals via symptomatic enquiry, rectal examination of the prostate and measurement of prostate-specific antigen (PSA), haematocrit and testosterone levels. Dosage should be adjusted according to symptomatic and biochemical response, aiming for a testosterone level in the mid-normal range.
Fertility is not improved with androgen replacement therapy. In men with secondary hypogonadism, substitution of testosterone replacement with gonadotrophin therapy can help initiate and maintain spermatogenesis. Men with primary hypogonadism will not respond to gonadotrophin therapy, and may require assisted conception via testicular sperm extraction and intra-cytoplasmic sperm injection (ICSI).