The three most common symptoms suggestive of TD are: Erectile dysfunction (ED), loss of early morning erections, and low sexual desire including decreased spontaneous erections.³  

Non-specific symptoms include fatigue, sleep disturbance, loss of physical strength, reduced energy and motivation, depressed mood, visceral obesity, reductions in muscle mass and bone mineral density (BMD), hot flushes, and changes in cognition and memory.³  

Who is at risk? 

About 40% of men >45-years and 50% of men in their 80s are affected by TD. Testosterone levels decrease by an estimated 3.74nmol/l every 10 years or an average rate of 1%–2 % per year in men >30.² 

Clinicians should keep in mind that although TD is more common in older men because the ageing testes lose the ability to produce adequate levels of testosterone, it can affect men of all ages.²  

In younger men, TD may be caused by an underlying genetic condition, a primary defect in the HPGA, environmental factors, or past infection or injury to the testis. In some younger patients, TD is transient, and may resolve once the underlying disease/condition is successfully treated or show improvement.² 

How is testosterone deficiency diagnosed? 

According to Hackett et al, it is important to ask patients about the loss of early morning erections, even in men not in a sexual relationship when taking a history. The absence of early morning erections is an important sign of TD and a predictor of future cardiovascular (CV) events.³ 

Measuring serum testosterone between 7am and 11am, using a reliable method, on at least two occasions, preferably four weeks apart, is recommended to diagnose TD. Furthermore, testing of luteinising (LH) and follicle-stimulating hormones are required to distinguish between primary and secondary hypogonadism.³ 

The normal range for early morning testosterone in men is between 10nmol/l to 34nmol/l. Hypogonadism is diagnosed when the morning serum testosterone level is <10nmol/l. However, in younger men, a level of <13.8 nmol/l may be indicative of TD.^1,2  

Hackett et al stress that clinical judgment also plays a role in the diagnosis of TD – especially in patients who present with persistent symptoms, yet normal testosterone levels.³ 

Clinical features suggestive of TD, include reduced body hair, decreased testicular size, gynaecomastia (man boobs), fine wrinkling of the skin, especially around the mouth, increased waist circumference, obesity, and impaired health status.³ 

Who should be screened? 

Screening is recommended in all men:³ 

• With consistent and multiple signs/symptoms of TD 
• Presenting with ED, loss of spontaneous erections, or reduced sexual desire (even without a sexual partner) 
• With type 2 diabetes (T2DM), chronic kidney disease, and a body mass index (BMI) >30m2 and/or waist circumference >102cm 
• On long-term opiate, antipsychotic or anticonvulsant medication. 

When is testosterone therapy recommended?  

The 2023 British Society for Sexual Medicine (BSSM) Guidelines on Male Adult TD do not support the recommendation for lifestyle intervention alone as first-line therapy to treat TD.⁴ 

Patients with low testosterone (supported by evidence of low biochemical levels [see thresholds below]), who present with distressing symptoms, with no contraindications (see below), and who want to, should receive testosterone therapy (TTh).⁴ 

The BSSM and the International Society for Sexual Medicine guidelines recommend the following thresholds for treatment intervention in symptomatic men:⁴ 

• Total testosterone level of <12nmol/l or free testosterone <0.225nmol/l (based on two separate 8am to 11am levels) usually requires TTh 
• Total testosterone level of >12nmol/l, or >0.225nmol/l, does not require TTh 
• Levels between 8nmol/l to 12nmol/L may require a trial of TTh for a minimum of six months, based on symptom severity. 

The BSSM also recommends:⁴ 

• Evidence supports the treatment of men with total testosterone levels <14nmol/l who experience symptoms of prediabetes to prevent progression to  T2DM 
• A free testosterone level of <0.225 nmol/l provides supportive evidence for TTh in the presence of appropriate symptoms.  

Additional recommendations include:⁴ 

• Raised LH levels and testosterone below normal or in the lower quartile range, indicates testicular failure, so TTh should be considered based on symptom severity 
• Raised LH levels in men with normal testosterone levels but symptoms of TD, should be considered as TD  
• Data from the European Male Ageing Study found that clinical symptoms and all-cause mortality were more closely related to calculated free testosterone. 

TTh has been shown to:⁴  

• Improve insulin sensitivity (most markedly in poorly controlled patients)  
• Promote weight loss  
• Reduce waist circumference and BMI 
• Reduce total and low-density lipoprotein cholesterol and triglycerides  
• Increase high-density lipoprotein cholesterol 
• Reduce systolic and diastolic blood pressure and blood glucose 
• Modestly improve the six-minute walking test 
• Improve mood and depression 
• Increase volumetric BMD and estimated bone strength (greater in trabecular than peripheral bone, and in the spine than the hip) 
• Reduce progression (by 40%) to T2DM in patients with testosterone levels of <14nmol/l treated for two years, with additional benefits in BMI waist circumference, and grip strength 
• Increase haemoglobin levels in men with anaemia from unexplained or known causes 
• Significantly improve sexual desire and erectile function (particularly in men below with testosterone levels of <8nmol/l), and increases sexual activity, satisfaction, and orgasm. 

Does testosterone therapy increase the risks of CV and prostate cancer? 

According to Hackett et al, there is no evidence that TTh is associated with increased risks of prostate cancer or CV. In fact, state the authors, current evidence suggests a likely benefit in CV outcomes, especially in men with chronic kidney disease and atrial fibrillation, and after a previous myocardial infarction.³ 

Which formulation is best? 

Various formulations are available worldwide including gel, creams, patches, and intramuscular injections (IMIs). However, Hackett et al only included gel and IMIs in their practical guide for the assessment and management of TD in adult men. Both formulations have advantages and disadvantages, state the authors.³ In South Africa, only gel and IMIs are registered for use in patients with TD.   

Transdermal gel 

Available as 1% gel for daily application. The advantages of testosterone transdermal gel include:   

• Rapid onset of action with no variability in effectiveness, reaching a steady state on day two 
• Uniform and normal serum levels during a 24-hour cycle 
• Convenience and flexible dosing 
• Short duration of action (72-96 hours from the final dose), which allows for effective drug withdrawal in the event of side-effects.⁵  

Testosterone levels are maintained within the physiological range with a daily application. Daily changes in testosterone concentrations are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The gel has also been shown to significantly improve overall health-related quality of life in men with TD. 

Disadvantages include possible skin irritation at the application site,  potential for interpersonal transfer, and adherence may be an issue long term.³ 

According to the product manufacturer, skin irritations have only been reported in 3%-5% of patients. Interpersonal transfer can be avoided with appropriate precautions (eg covering the application area with clothing once the gel is dry). Areas of application include the shoulders, upper arms, and/or abdomen. The gel should not be applied to the genitals (penis and scrotum) or to damaged skin.⁵ 

Intramuscular injections 

Intramuscular preparations approved in South Africa are long-acting (testosterone undecanoate) or short-acting (testosterone enanthate and testosterone cypionate). Testosterone undecanoate IMI needs to be administered every 12 weeks. Its advantages include: Infrequent dosing due to its longer action and adherence due to the reduced frequency of administration. Disadvantages include: Possible injection site pain, long duration of action delays drug withdrawal in the event of adverse side-effects.³ 

Testosterone enanthate and cypionate IMI are administered every two to three weeks. They are usually inexpensive and provide reliable absorption. Disadvantages include fluctuating testosterone levels (from high to low) among the short-acting formulations, but not the longer-acting undecanoate, and  greater risk of erythrocytosis than transdermal formulations.⁶  

The main contraindications to TTh are:³

• Prostate cancer (locally advanced or metastatic) 
• Male breast cancer 
• An active desire to have children, currently or possibly in the future 
• Haematocrit >54% 
• Severe chronic heart failure (New York Heart Association class IV). 

Conclusion 

There is no scientific basis for withholding TTh from men with TD based on age. Physicians should identify individuals who should be screened for TD, particularly those at high risk. These include men with diabetes, osteoporosis or fragility fractures, CVD, ED, depression, and those on long-term opiate or oral glucocorticoid therapy.⁴ 

TTh is evidence-based, effective, and safe, and evidence suggests that treatment-related sustained normalisation of serum testosterone levels is associated with reduced morbidity and mortality.⁴  

The choice of which formulation to use should be made in consultation with the patient following discussions of the advantages and disadvantages and ensuring maximal adherence to treatment.⁴  

References 

1. Sizar O, Schwartz J. Hypogonadism. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532933/ 
2. Cohen J, Nassau DE, Patel P and Ramasamy R. Low Testosterone in Adolescents & Young Adults. Front Endocrinol, 2020. 
3. Hackett G, Kirby M,  on behalf of the British Society for Sexual Medicine (BSSM). A practical guide to the assessment and management of testosterone deficiency in adult men. Trends in Urology and Men’s Health, 2023. 
4. Hackett G, Kirby M, Rees R, et al. The British Society for Sexual Medicine guidelines on male adult testosterone deficiency, with statements for practice. World J Mens Health, 2023. 
5. Androgel. Professional Information published Oct 2010. Available from Medi Challenge.  
6. Morgentaler A, Traish A, Hackett G, Jones TH, Ramasamy R. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev, 2019