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Diagnosing and treating low testosterone (hypogonadism) in men

Diagnosing and treating low testosterone (hypogonadism) in men

Key learning points:

– The key symptoms and signs of low testosterone (hypogonadism)

– The common causes of hypogonadism

– How to treat hypogonadism, an update from Nursing in Practice issue 83, pages 56-58

In men, androgens are produced by the testes (approximately 95%) and adrenal glands (approximately 5%). The primary androgen produced is testosterone, which is present at concentrations several hundred fold higher in the testis than elsewhere in the body. The concentration of testosterone in other tissues is naturally lower due to the diluting effect of circulation, however local expression of the enzyme 5-alpha reductase converts testosterone to its more potent metabolite dihydrotestosterone (DHT), in essence, increasing the effective concentration of testosterone in peripheral tissues. The production of testosterone is controlled by Luteinising hormone (LH), a peptide hormone secreted by the anterior pituitary. Conversely, testosterone signals back to the brain to negatively regulate LH production, together forming a homeostatic feedback loop (see Figure 1 section A).

Low levels of testosterone during development can lead to congenital abnormalities in male reproductive tissues. Androgens are also essential for the development of secondary sexual characteristics, fertility, body composition, bone health and also influence behaviour.1 Testosterone levels decrease slightly as men get older, which is considered a normal part of the ageing process. However significantly low testosterone in adulthood is associated with sexual dysfunction, reduced fertility, decreased muscle mass and bone mineralisation, and also with poor health status for example, obesity and chronic diseases like diabetes and cardiovascular disease. However, many men with low testosterone might not have any symptoms at all.

Hypogonadism is a clinical syndrome primarily defined by low circulating testosterone concentrations, which can manifest with a number of symptoms.2 Hypogonadism can either be caused by insufficient testosterone production by the testes (primary hypogonadism), or due to failure of the hypothalamic-pituitary-gonadal axis (HPG) resulting in loss of the LH cue to the testes to produce testosterone (secondary hypogonadism or hypogonadotrophic hypogonadism) (see Figure 1). Hypogonadism may be congenital, which may present with impaired development of male sexual organs, undescended testes, or a failure to proceed through puberty, or acquired, presenting later in life with the signs and symptoms discussed below.3,4


Low testosterone can be associated with a myriad of symptoms. The symptoms most predictive of hypogonadism are erectile dysfunction, reduced sexual thoughts and lack of early morning erections.5,6 However, presentation or severity of any one symptom can vary depending on the age of onset, duration and severity of testosterone deficiency. It is important to note that many of these symptoms are also found in men with normal testosterone levels and thus while they may be indicative, they are not diagnostic of androgen deficiency. The European Male Aging Study found the prevalence of true hypogonadism, defined as at least three sexual symptoms (decreased frequency of morning erections and sexual thoughts and erectile dysfunction) a testosterone of less than 11nmol/l and free testosterone less than 220pmol/l to be 2.1% in 40-79 year olds.7

Diagnosing low testosterone in men

Hypogonadism can be diagnosed by measuring serum testosterone concentrations. As levels of testosterone change during the day and are highest in the morning, the best time to diagnose low testosterone is by taking a blood sample in the morning before 11am. If low, the blood test should be repeated after four weeks to confirm the finding.2,3 If hypogonadism is confirmed then the patient should be referred to and further investigated by an endocrinologist.

Diagnosing primary or secondary, congenital or acquired hypogonadism

Primary and secondary hypogonadism can be differentiated by measuring the pituitary hormone LH. A high LH concentration suggests primary hypogonadism as the pituitary gland has increased LH production in an attempt to stimulate the testes, which are failing to respond. A low (or normal) LH suggests secondary hypogonadism (a problem at the level of the hypothalamus or pituitary), as the HPG-axis is not responding adequately to the low testosterone cue (Figure 1 section B and C).

History and examination of the patient can also give clues as to the cause of the hypogonadism:

·      Has he gone through puberty?

·      Has he developed pubic hair?

·      Can he get an erection and ejaculate?

·      How frequently does he need to shave?

·      Can he have children?

·      Does the patient experience sexual dysfunction?

·      Are they obese?

·      Do they report loss of vigour?

In addition to collating a history, the patient should also undergo assessment of body mass index (BMI), waist-hip ratio, body hair, enlargement of breast tissue (gynaecomastia), and measurement of testis size, along with digital rectal examination of the prostate. Other aspects to consider include if he has normal sense of smell (lack of the ability to smell, anosmia, is associated with Kallmann syndrome), and if he has any problems with his vision, headaches, or history of head injury, which might suggest a cause in the pituitary gland or hypothalamus.

A diagnosis of male hypogonadism is based on signs and symptoms of androgen deficiency together with consistently low serum testosterone measurements.

Causes of hypogonadism

One of the most common causes of low testosterone is illness, measurement should therefore be avoided while a man is acutely unwell. Medications may also lower testosterone levels, for example opiates and glucocorticoids. Testosterone levels may also be lower in men abusing anabolic steroids, cannabis, cocaine and amphetamines.

Further tests might help to diagnose the cause of the hypogonadism. For example, checking for genetic causes of primary hypogonadism (by checking karyotype for Klinefelter syndrome) or secondary hypogonadism (checking for mutations causing Kallmann syndrome if suspected). Iron studies (serum ferritin and transferrin) can be helpful to rule out haemochromatosis. In the case of secondary hypogonadism, the rest of pituitary function should be checked; prolactin, IGF-1 (insulin like growth factor 1), a short Synacthe test, thyroid function and follicle stimulating hormone tests will identify if the rest of the pituitary is working properly. An MRI scan of the pituitary and hypothalamus might be carried out to check for a structural cause and a dual-energy x-ray absorptiometry scan can also be useful to check for osteoporosis. A raised prolactin (hyperprolactinaemia) can result in secondary hypogonadism. Hyperprolactinaemia can occur due to a problem with the pituitary gland (either a prolactinoma or disruption of the pituitary stalk), or can be a side effect of medications including antipsychotics, anti-depressants and antiemetics. 

Treatment options

Weight reduction and lifestyle modification can provide significant improvement in testosterone levels. Treatment with testosterone can improve sexual function and bone mineral density and is normally initiated and monitored by an endocrinologist.

As oral testosterone can be toxic to the liver, the patient will normally be offered topical testosterone therapy, in the form of a gel or a depot injection, which is usually administered either every four or 12-14 weeks depending on the preparation.

Patients using testosterone gel should be advised to apply the gel after washing, when the skin has dried and cooled down, to apply it to unbroken skin, allow the gel to dry prior to dressing, and to avoid close skin contact with others (of the area to which the gel has been applied). Short acting preparations (such as the gel) are normally preferred when starting therapy as they are easier to stop if there are any unwanted side-effects.

As testosterone replacement can increase the growth of breast and prostate cancers, these are a contraindication to treatment. Patients should also have a prostate specific antigen (PSA) blood test prior to initiation, and then at three, six, 12 months and there after annually. Testosterone replacement can also increase the red blood cell count (polycythaemia), so a full blood count (FBC) should also be obtained prior to initiation of treatment and checked alongside the PSA. Other contraindications to initiating testosterone replacement include untreated obstructive sleep apnoea and uncontrolled congestive heart failure.3

Once treatment has been initiated, the adequacy of testosterone replacement should be checked by testing the serum testosterone, with the aim to get levels into the mid-normal range. The patient’s symptoms should also be monitored to check for a response, for example has erectile function and libido improved? Improvements would normally occur within six months. Bone mineral density might take longer to show improvements. If no improvement to symptoms have occurred despite adequate testosterone replacement then it might be discontinued, and alternative treatment strategies discussed.

Hypogonadism might not always be treated; there is some evidence that replacement can result in an increase in cardiovascular risk, particularly in older men and early following initiation of treatment8,9 although a more recent meta-analysis of trials did not find the risk changed.10

Properly powered trials are required to determine if testosterone replacement does increase cardiovascular risk, and if so in which population(s) of men. Thus, in older men, the pros and cons of treatment will be discussed with the patient by an endocrinologist. The patient might be offered a trial of testosterone replacement therapy to see if it improves symptoms, and if not it should be discontinued.4

Testosterone replacement therapy will inhibit endogenous testosterone production by the testes, and may lead to a reduction in sperm production. Thus, although testosterone levels should normalise, normal fertility may not. If fertility is required then an alternative treatment should be considered.


To summarise, the recognition of hypogonadism in men has increased over the past two decades. Healthcare professionals should be aware of the symptoms and signs of hypogonadism and feel at ease bringing them up with patients. The benefits and risks of treatment should be discussed with patients. Future research should help us to decide who is likely to benefit the most from replacement, and in which patients it is best avoided.


1. Smith LB, Mitchell RT and McEwan IJ. (2013) Testosterone: From Basic Research To Clinical Applications. Springer Briefs in Reproductive Biology, Springer Press.

2. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2010 Jun 1;95(6):2536–59.

3. Basaria S. Male hypogonadism. The Lancet. 2014 April 11;383(9924):1250–63.

4. Hugh Jones T. ‘What should I do with a 60-year old man with a slightly low serum total testosterone concentration and normal levels of serum gonadotrophins? Clinical Endocrinology (Oxford). 2010 May 1;72(5):584–8.

5. Dohle, Arver, Bettocchi, Jones, Kliesch, Punab. Male Hypogonadism [Internet]. Uroweb. 2015. (accessed 15 June)

6. Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of late-onset hypogonadism in middle-aged and
elderly men. The New England Journal of Medicine. 2010 July; 8;363(2):123–35.

7. Tajar A1, Huhtaniemi IT, O'Neill TW, Finn JD, Pye SR, Lee DM, Bartfai G, Boonen S, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Labrie F, Lean ME, Pendleton N, Punab M, Vanderschueren D, Wu FC; EMAS Group. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). The Journal of Clinical Endocrinology & Metabolism. 2012;97(5):1508-16.

8. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. The New England Journal of Medicine. 2010 July;8;363(2):109–22.

9. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. Biomed Central Medicine. 2013;11:108.

10. Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opinion on Drug Safety. 2014 October;13(10):1327–51.

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