Testosterone is the primary male hormone and is responsible for sexual development, which includes testicular descent, spermatogenesis, enlargement of the penis and testes, and libido.2

Testosterone treatment is the standard of care for reversing the consequences of hypogonadism

According to Hudson et al, the consequences of hypogonadism include diminished secondary sexual characteristics, sexual dysfunction, muscle wasting and weakness, osteoporosis, and reduced quality of life.1

Testosterone treatment is the standard of care for reversing the consequences of hypogonadism, but in recent years, a number of studies have reported conflicting results with some concluding that it may increase the risk of CV diseases (CVD) in men with hypogonadism, while others showed the opposite, note Hudson et al.1

As a result of conflicting results,  the American Food and Drug Administration (FDA) issued a black box warning of potential CV risks for all testosterone products. Furthermore, the FDA restricted testosterone use to men with hypogonadism caused by documented pituitary or testicular disease, excluding age-related hypogonadism.1

However, the European Medicines Agency found that there is ‘currently no consistent evidence that testosterone therapy causes increased CV risk in patients with properly diagnosed and managed hypogonadism’.1

The authors of the 2022 British Society for Endocrinology (BSE) guidelines for the testosterone replacement therapy in male hypogonadism concur, stating: ‘Available randomised control studies and observational data fail to reveal any consistent association between testosterone treatment and CV and cerebrovascular events’.3

The conflicting results of studies and recommendations by some health regulatory bodies and medical societies regarding an increased risk of CVD in patients with hypogonadism treated with testosterone, led to uncertainty about its use among clinicians. As a result, men with hypogonadism who might otherwise have benefitted from testosterone treatment were left out in the cold.1

Prevalence of male hypogonadism

The estimated prevalence of hypogonadism varies widely (between 2.1% and 38.7%) in middle-aged and older men. It increases to about 50% among men living with diabetes or obesity.4,5

Low total testosterone levels have been associated with a considerably increased risk of type 2 diabetes (with odds ratios from 1.6 with <15nmol/L with <7.9nmol/L),  while total testosterone <8.6nmol/L has been associated with significantly increased weight circumference and risk of CVD-related mortality.6,7

How is male hypogonadism diagnosed and managed?

Hypogonadism can be acquired (eg bilateral gonadectomy, trauma, chemo- and radiotherapy, smoking, ageing and age-associated comorbidities, HIV, chronic alcohol-use) or congenital (eg Klinefelter syndrome, uncorrected bilateral cryptorchidism, or testicular regression).3

The BSE guidelines state that a diagnosis of male hypogonadism is based on a combination of characteristic clinical features or risk factors and laboratory findings. The authors do concede that diagnosis may be challenging because some clinical features may be non-specific.3

Clinical features may include:3

  • Sexual (reduced libido and sexual activity, erectile dysfunction and reduced spontaneous erection)
  • Skeletal (loss of height, low trauma fractures and low bone density)
  • Reproductive (cryptorchidism, infertility, or low sperm count)
  • Vasomotor (hot flushes and sweats)
  • Haematological (reduced haemoglobin or haematocrit in the absence of other identifiable cause)
  • Tender glandular gynaecomastia.

The normal range for early morning testosterone in a male is between 10.4nmol/L to 34.7nmol/L. Hypogonadism is diagnosed when the morning serum testosterone level is <10.4nmol/L.10

However, clinical judgment can be exercised in the diagnosis of hypogonadism for patients with persistent symptoms of testosterone deficiency despite having testosterone levels are in the normal range.10

Of note, total testosterone less than 14.09nmol/L is below the fifth percentile. Elderly males should aim for testosterone levels between 17.35nmol/L and 27.7nmol/L while young adults should aim for testosterone levels between 20.8nmol/L and 31.2nmol/L.10

When testing patients with suspected hypogonadism it is important to differentiate between:3,8,9

  1. Primary hypogonadism: Defined as testicular failure that is characterised by low testosterone and elevated gonadotropins. It is associated with advanced age and may also be associated with independently occurring comorbidities that further exacerbate hypogonadism, and
  2. Secondary hypogonadism: Defined as pituitary–hypothalamic failure that is characterised by low testosterone and low or normal gonadotropins. It has been strongly associated with obesity and comorbid conditions associated with ageing.

According to the BSE guidelines, the objective of testosterone therapy is to reverse or prevent symptoms and long-term effects of male hypogonadism and to maintain general well-being. Optimised testosterone treatment can:

  1. Induce or complete secondary sexual development
  2. Improve sex drive, libido, and sexual function
  3. Improve mood and well-being
  4. Improve muscle mass and strength
  5. Restore or maintain masculine characteristics, such as facial and body hair
  6. Maintain bone strength and prevent osteoporosis
  7. Maintain red cell production and prevent anaemia.

The BSE guidelines recommend testosterone transdermal gel and intramuscular injections. However, the authors caution that intramuscular injection, which must either given by their healthcare practitioner, can often cause lifestyle restrictions.3

Furthermore, intramuscular injections provide high levels of testosterone (peaks) shortly after the injection, which tend to drop below the reference range towards the end of the injection interval, resulting in some patients experiencing symptoms such as mood swings, differences in energy levels and sexual drive.3

Transdermal gel is applied once a day (preferably in the morning) on dry, clean, and unbroken skin.3 It is recommended that the gel be applied on the upper arms, and shoulders and abdomen (areas normally covered by a short-sleeve T-shirt). The gel should not be applied to any other parts of the body, such as the penis, scrotum, chest, armpits (axillae) or knees.11

The gel is absorbed rapidly through the skin within five to 10 minutes, elevating testosterone levels to the reference range within two to four hours after application.3

The authors of the BSE guidelines do warn that patients should be warned about the potential risk of skin-to-skin transfer of testosterone.3

What did the new study show?

Hudson et al conducted a systematic review and meta-analysis of all CV events observed during testosterone treatment involving 3431 patients. The following inclusion criteria were applied: men aged 18 years and older with a screening testosterone concentration of ≤12nmol/L, the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of three months, a comparator of placebo treatment and studies assessing the pre-specified primary or secondary outcomes of interest.1

Five key findings from the study showed that testosterone therapy:1

  1. Is not associated with an increased risk of various subtypes of CV events (arrhythmia, coronary heart disease, heart failure, cerebrovascular events, and myocardial infarction) compared with placebo in the short- to medium-term
  2. Do not have adverse effects on blood pressure or glycaemic markers compared with placebo
  3. Do not increase thrombotic events despite increased haematocrit
  4. Is associated with a modest lowering of total and high-density lipoprotein cholesterol and triglyceride concentrations compared with placebo
  5. Is associated with a lower risk of CV events with testosterone treatment when calculated free testosterone was 180pmol/L–220pmol/L. Furthermore, the authors found that there was no association between CV events and either free or total serum testosterone at baseline or during testosterone treatment.

 

Conclusion

Hudson et al concluded that the findings of their study indicate that testosterone treatment did not increase risks of any subtype of CV events in men with hypogonadism. Neither did they identify any patient characteristics that were associated with a significantly increased risk of CV events during testosterone treatment. Furthermore, we observed a similar mortality rate during testosterone treatment when compared with placebo, which was reassuring.1

An ongoing trial is investigating the longer-term safety of testosterone, however, the current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism.1

References

  1. Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events, and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity, 2022.
  2. Nassar GN, Leslie SW. Physiology, Testosterone. [Updated 2022 Jan 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526128/
  3. Jayasena CN, Anderson RA, Llahana S, et al. Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism. Clinical Endocrinology, 2022.
  4. Zarotsky V.Systematic literature review of the epidemiology of nongenetic forms of hypogonadism in adult males. J Hormones. 2014.
  5. Mulligan T, Frick MF, Zuraw QC, et al.Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 2006.
  6. Schipf S, Haring R, Friedrich N, et al.Low total testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP). Aging Male, 2011.
  7. Haring R, Volzke H, Steveling A, et al.Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79. Eur Heart J, 2010.
  8. Bhasin S, Brito JP, Cunningham GR, et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2018.
  9. Tajar A, Forti G, O’Neill TW, et al.Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010.
  10. Sizar O, Schwartz J. [Updated 2021 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532933/
  11. How to apply AndroGel 1.62%. https://www.androgel.com/how-to-apply-androgel-1-62-percent