Testosterone Deficiency: Treat Men Who Have Bothersome Symptoms

Professor Geoff Hackett and Professor Mike Kirby Discuss the Latest Recommendations from BSSM on the Diagnosis, Assessment, and Treatment of Testosterone Deficiency in Men

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signs and symptoms that suggest testosterone deficiency diagnosing testosterone deficiency, including which tests to use and when testosterone therapy treatment thresholds.  Key Points and Implementation Actions for STPs and ICSs are at the bottom of this article.

Testosterone is the most important sex hormone in men and is essential for the development and maintenance of secondary male characteristics.¹ When testosterone levels drop, men can experience adverse physical and psychological effects, and a consequent reduction in quality of life.

Diagnosing testosterone deficiency (TD) within primary care is important as it helps with the identification of those patients who may benefit from testosterone therapy (T therapy). However, identification can be challenging, as many of the signs and symptoms are non-specific, multifactorial in origin, and may be associated with various lifestyle and psychological factors, as well as with normal ageing.^2,3 Primary care practitioners may also be unsure about the best way to manage TD once it has been diagnosed.

The British Society for Sexual Medicine (BSSM) has produced a guideline to help UK practitioners effectively diagnose and manage primary and age-related TD in adult men.⁴ The guideline includes statements for UK practice, together with levels of evidence and grades of recommendation, based on a critical review of the available literature. The guideline can be downloaded from: www.bssm.org.uk/resources/

Testosterone Deficiency

Testosterone deficiency is a clinical and biochemical syndrome associated with advancing age and co-morbidities, and characterised by a deficiency in serum testosterone levels and specific signs and symptoms.^5,6

The European Male Ageing Study (EMAS)^7,8 evaluated the biochemistry and symptoms of a random population sample of 3369 men aged 40–79 years from eight European centres. Testosterone deficiency was defined as three or more sexual symptoms associated with a total testosterone (TT) less than 11 nmol/l and a free testosterone (FT) less than 0.22 nmol/l).⁷ Overall, TD prevalence was 2.1% and levels increased with age (0.1% in men aged 40–49 years, 0.6% in men aged 50–59 years, 3.2% in men aged 60–69 years, 5.1% in men aged 70–79 years). However, three-quarters of men maintained normal testosterone levels into old age, suggesting that TD is not solely due to ageing.^4,8 In the same study, the prevalence of secondary TD was 11.8%, primary TD was 2%, and compensated (subclinical) TD was 9.5%.⁸

Primary, Secondary, and Combined Tesosterone Deficiency

Testosterone deficiency occurs when the body is unable to produce enough testosterone for normal function, caused by disruption of one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis (see Figure 1):^4,5

• the testes (primary TD)
• the hypothalamus and pituitary gland (secondary TD)
• the testes, hypothalamus, and pituitary gland (combined/mixed TD)

Compensated Testosterone Deficiency

Compensated (subclinical) TD is characterised by normal testosterone levels and high luteinising hormone (LH) levels in older men. Men with compensated TD should be monitored as it may eventually progress to overt primary TD.⁸

Functional Testosterone Deficiency

The term ‘functional TD’ (also known as late-onset, age-related, adult-onset, or secondary TD) has been used to describe low testosterone levels and androgen-deficiency-like features in men over 50 years, who have conditions such as obesity, type 2 diabetes, or metabolic syndrome, without intrinsic structural HPG axis pathology or specific pathological conditions suppressing the HPG axis (e.g. microprolactinoma or endogenous Cushing syndrome).⁹ It is important that the patient’s co-morbid conditions are also treated.

Testosterone deficiency may also stem from impaired testosterone action, resulting from decreased bioavailability of the hormone (due to variations in sex hormone binding globulin [SHBG])⁵ or changes in the androgen receptor affecting androgen activity.^5,10

When considering potential causes of TD, it is important to remember that testosterone levels can be suppressed by some medications, including oral glucocorticoids, opioids, and antipsychotics.^10–14

Signs and Symptoms

The signs and symptoms suggestive of TD are summarised in Figure 2. Many of these symptoms are also experienced by men with normal testosterone levels and may have other causes.² The three most common symptoms of TD are erectile dysfunction (ED), loss of early morning erections, and low sexual desire. In primary care, men often present with sexual dysfunction and a desire for treatment. Testosterone deficiency is more common in patients with:^15,16

• a large waist circumference
• obesity
• metabolic syndrome
• poor overall health
• hypertension
• hyperlipidaemia
• asthma or chronic obstructive pulmonary disease
• prostate disease.

Testosterone deficiency is a risk factor for chronic anaemia and osteoporosis.^4,16

Screening for Testosterone Deficiency

Primary care practitioners may help identify patients who should be screened for TD by routinely asking about any sexual concerns, particularly those who are at high risk, including those with cardiovascular disease, diabetes, sexual dysfunction, osteoporosis/fragility fractures, or depression, and those on long-term oral glucocorticoid, opiate or antipsychotic medications (see Box 1).⁴

Diagnosis

For a diagnosis of symptomatic TD, the man should have characteristic signs and symptoms, as well as reduced serum concentrations of total testosterone (TT) or free testosterone (FT).¹¹

Clinical History

The clinical history should be used to establish the patient’s:²

• signs and symptoms indicative of TD
• pharmacologic treatment (including previous treatment with, or use of, testosterone)
• recreational drug use
• alcohol intake.

It is also important to assess and exclude systemic illness, acute disease, malabsorption, and malnutrition.²

Clinical assessment can be supported by validated questionnaires (e.g. the Ageing Males’ Symptoms [AMS] rating scale, available at: www.issam.ch/ams.html), which provide a quantitative assessment of baseline symptoms and help evaluate the response to treatment. Information on interpreting the scores can be found at: www.issam.ch/AMS_English_Evaluation.pdf and zeg-berlin.de/wp-content/uploads/2017/01/norm.pdf

Physical Examination

Physical examination should include assessment of the degree and distribution of body hair (including facial and pubic),¹¹ and examination for the presence and degree of any breast enlargement, and abnormalities of the penis, testicles,^2,11 and scrotum.¹¹ The prostate should be checked via digital rectal examination (DRE).² The patient’s height, weight, and waist circumference should be measured, and their body mass index (BMI) calculated.¹¹

Blood Tests

Blood tests should include serum testosterone, prostate specific antigen (PSA), haematocrit, as well as appropriate tests based on the physical assessment of the patient, and to determine cardiovascular risk.

Serum testosterone testing

Total testosterone (TT) should be measured in the morning between 7.00 and 11.00,^2,11 using a reliable method, on at least two occasions,² ideally 4 weeks apart and not during acute illness. Fasting levels are preferable where possible,² as these may be up to 30% higher than non-fasting levels.^17,18

Free testosterone (FT) should be measured when TT is close to the lower normal range (8–12 nmol/l) or there are suspected or known abnormal SHBG levels.⁴ The Primary Care Testosterone Advisory Group (PCTAG) provides an online Free and Bioavailable Testosterone Calculator plus a downloadable app at: www.pctag.uk/testosterone-calculator/

If TT is low/borderline, serum LH should be measured to differentiate between primary and secondary TD.² Follicle-stimulating hormone (FSH) should be measured if fertility is an issue.

Prolactin levels should be assessed when TT is less than 5.2 nmol/l and LH and FSH levels are low. Men with TT levels less than 5.2 nmol/l alongside low LH and FSH or increased prolactin levels, should receive an endocrinology referral or pituitary magnetic resonance imaging (MRI) to exclude a pituitary adenoma.¹⁹

Treatment

Treatment thresholds for men with symptomatic TD are shown in Table 1.

Table 1: Treatment Thresholds for Testosterone Deficiency in Symptomatic Men^15,20–23

Initiating Testosterone Therapy

Testosterone therapy (T therapy) should only be initiated in men with bothersome symptoms, often after referral to a specialist or by a suitably trained primary care clinician. It is usually prescribed in conjunction with erectogenic therapy, especially in men with associated co-morbidities. Many individuals with TD are obese or have other metabolic conditions so treatment should be combined with weight-loss advice, lifestyle modification, and optimal management of co-morbidities as appropriate.⁴

Before starting treatment, prostate (via DRE and/or PSA test), breast, and haematological assessments should be performed. Cardiovascular risk factors should also be assessed, and secondary prevention optimised in men with established cardiovascular disease.

In patients with sexual dysfunction, a desire to achieve a satisfactory sexual response is a motive for T therapy, either alone or in combination with erectogenic therapy. Testosterone therapy has been shown to improve sexual desire, morning erections, and erectile function, especially in cases where:^2,4,20,24

• TT levels are less than 8 nmol/l
• calculated FT is less than 0.225 nmol/l
• ED treatment with oral medication has failed (especially when TT levels are less than 10.4 nmol/l).

Appropriate intervention with T therapy also reduces the need for more invasive and expensive second- and third-line ED treatments.²⁵ Men starting T therapy can be co-prescribed a phosphodiesterase type 5 inhibitor (PDE5-i), as long as there are no contraindications, as it can take many months for T therapy to correct ED.

Testosterone therapy can be prescribed to men with symptomatic TD who have successfully treated, localised, low-risk prostate cancer (e.g. treated with radical prostatectomy and radiotherapy, Gleason score less than 8, stages 1–2, preoperative PSA level less than 10 ng/ml, and not starting before 1 year of follow up), as long as there is no evidence of active disease (based on PSA level and/or DRE result, and presence/absence of metastatic disease).⁴

Treatment Choice

In the UK, the choice of testosterone preparation usually lies between transdermal gels and long-acting undecanoate injections. When considering side-effects and drug withdrawal times, practitioners should bear in mind the pharmacokinetic and pharmacodynamic properties of the different formulations. The features of each method should be discussed with the patient, to facilitate a joint decision on treatment choice.

Contraindications to Testosterone Therapy

The main contraindications to T therapy are shown in Box 2. Men with an unevaluated prostate nodule or induration, or raised PSA, should have this fully investigated prior to starting treatment with testosterone. While untreated sleep apnoea and severe lower urinary tract symptoms (LUTS) have previously been considered contraindications to T therapy, this may no longer be the case.²⁶ These conditions however, should be fully investigated and optimally managed prior to starting treatment with testosterone.

If a man wants to father a child in the near future, T therapy should be avoided if possible, as it may reduce spermatogenesis. Possible alternatives include human chorionic gonadotropin (HCG), selective oestrogen receptive modulators (SERMS, e.g. clomifene), and aromatase inhibitors (AIs); however, these drugs should not be used if pituitary function is compromised. It is also worth noting that SERMs and AIs are not currently (April 2018) licensed for TD; the prescriber should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices²⁷ for further information.

Monitoring and Follow-up

After starting T therapy, patients should be evaluated at 3, 6, 12 months, and annually thereafter, to assess serum testosterone levels (therapeutic target mid–upper range: 15–30 nmol/l), confirm symptomatic improvement, and check for any changes in haematocrit and PSA levels. Patients who experience a suboptimal response to treatment or safety issues may require follow up every 3 months.⁵

Haematocrit Levels

Haematocrit levels should remain below 54%. Dose adjustments, or switching preparation, may be necessary to keep haematocrit levels within range.^2,11 If haematocrit levels remain high, consider stopping T therapy and then reintroducing it at a lower dose.

Prostate Specific Antigen

Patients should be referred for urological evaluation and receive more intensive surveillance for prostate cancer if PSA (measured 6 months after commencing therapy, taken as baseline):²⁰

• levels increase more than 1.4 ng/ml during any 1-year period following initiation of T therapy, or
• velocity increases more than 0.4 ng/ml/year during sequential measurement over more than 2 years.

Serum Lipids and Glycaemia

Monitoring of serum lipids and glycaemia is not necessary for safety during T therapy, but may be required to assess the efficacy of other aspects of treatment.⁵ In patients with cardiovascular disease, cardiovascular risk factors should be monitored throughout therapy.⁴

Bone Mineral Density

Bone mineral density need only be monitored in men with abnormal dual energy X-ray absorptiometry (DEXA) results prior to starting T therapy.^2,5 These individuals should receive repeat DEXA after 1–2 years of treatment.^4,5

Treatment Outcome

The assessment of treatment outcome, and the decision about continuation of T therapy, should be based on the degree of improvement of TD signs and symptoms. If patients fail to benefit within a reasonable time frame (defined as 6 months for libido, sexual function, muscle function, and improved body fat), T therapy should be discontinued and other causes of their symptoms investigated.²⁰

Conclusion

Testosterone deficiency is an increasingly common problem, that can adversely affect multiple organ systems and significantly reduce quality of life. Improved diagnosis and management of this condition within primary care should provide physical and psychological benefits for affected patients, and related improvements in quality of life.

Professor Geoff Hackett

Consultant in Urology, University Hospital Birmingham NHS Foundation Trust

Visiting Professor in Human Sciences, Aston University Birmingham

Professor Mike Kirby

Visiting Professor, Centre for Research in Primary and Community Care, University of Hertfordshire and The Prostate Centre, London

On behalf of The British Society for Sexual Medicine guidelines on adult testosterone deficiency, with statements for UK practice 2017