Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism have recently been published in Clinical Endocrinology.¹ Here, guideline working group members Channa N Jayasena and Richard Quinton discuss some of the topical issues that they addressed in developing the guidelines.

Many of us find male hypogonadism (MH) a difficult condition to diagnose and manage. Unfortunate trends in over-diagnosis and over-prescribing, which originated in North America, but which resonate worldwide, have put clinicians ‘on guard’ about the safety of testosterone treatment. The lack of unified clinical and biochemical thresholds for treatment, and the considerable heterogeneity among existing (largely monospecialty) guidelines has created huge variation in how men presenting with possible MH are managed.

For this reason, the Clinical Committee of the Society for Endocrinology commissioned us to develop new guidance for the UK, which we felt was best achieved through a multidisciplinary approach, comprising expertise from endocrinology (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices, and a patient expert. Using a narrative approach, we aimed to address head-on those particular issues that clinicians feel most uncomfortable about with regard to MH management, aiming to offer pragmatic advice based on consensus opinion. We also aspired to create something that clinicians might actually enjoy reading. Here is a selection of some key issues upon which we have provided guidance.

NON-GONADAL ILLNESS

Not all cases of MH are equal. It is easy to diagnose primary hypogonadism (low testosterone level and raised gonadotrophins), but hypogonadotrophic or central MH may be difficult to distinguish from non-gonadal illness (NGI), and thus careful clinical correlation is required.

The big problem in treating NGI with testosterone is that there is poor evidence for its efficacy to relieve symptoms. This makes sense when considering that symptoms such as low libido and tiredness will be caused by many (non-testosterone-related) reasons, due to systemic ill-health in NGI. Thus, solving a patient’s low testosterone will neither magically address these symptoms, nor make them healthier overall.

So, it should not surprise us that, following an initial appearance of benefit, the effects of testosterone treatment in NGI might be disappointing for both patients and clinicians in the long term.

Obesity is a great example of NGI. Weight loss is a highly effective way of increasing testosterone levels in men with obesity, just like testosterone treatment. However, weight loss substantially reduces cardio-metabolic risk (unlike testosterone treatment, which is probably neutral; see below). For this reason, lifestyle intervention and addressing other root causes of NGI should be the first-line treatment for hypogonadal symptoms, over testosterone treatment, as these have the best chance of alleviating symptoms and improving overall health.

DIAGNOSING MH

We all get preoccupied with the testosterone threshold for ‘how low levels need to be for testosterone treatment’, but spotting the clinical features of MH is equally important. The most specific features of MH are sexual (low libido, erectile dysfunction, loss of morning erections), non-sexual (low bone density, vasomotor flushing, normocytic anaemia and gynaecomastia) and testicular (cryptorchidism, infertility). By contrast, altered mood, sleep or concentration, are much less specific to MH, and correspondingly less likely to improve with testosterone treatment.

Many criteria have been proposed for the diagnosis of MH, as discussed in two recent reviews comparing current guidelines.

In 9,000 healthy young men without obesity from Europe and North America, 95% had serum testosterone levels between 9.2 and 31.8nmol/l. Several double-blinded randomised controlled trials have shown that testosterone treatment improves sexual symptoms in men with serum testosterone <8nmol/l unrelated to NGI; so, there is little doubt of treatment effectiveness for these men. However, there are hardly any data demonstrating that testosterone treatment improves features of MH in men when the serum total testosterone is >12nmol/l. Clinicians would also benefit from better standardisation of local testosterone assays and assay-specific reference ranges across the UK.

FREE TESTOSTERONE

When sex hormone-binding globulin (SHBG) is abnormal, total testosterone measurement may not accurately assess the true biological effects of testosterone, or ‘androgenicity’. In particular, men with obesity may have slightly low total testosterone levels, but with very low SHBG levels due to hyperinsulinaemia, androgenicity is usually preserved.

Free testosterone is notoriously difficult to measure; calculated free testosterone is an accepted estimate, which has been shown in the European Male Ageing Study (EMAS) to correlate with sexual symptoms associated with MH. Unfortunately, substantial assay variation affects the key components needed to calculate free testosterone (total testosterone and especially SHBG), and the mass action equation itself is not fully perfected. It is therefore a sobering reality that the accuracy and clinical utility of free testosterone quantification in optimising the diagnosis of MH will remain limited until these issues have been fully addressed.

CARDIOVASCULAR SAFETY

It seems a paradox that MH is associated with increased cardiovascular risk, yet testosterone treatment has been mired in controversy regarding the risk of provoking cardiovascular events cited by the US Food and Drug Administration, although not by the European Medicines Agency or the UK Medicines and Healthcare Products Regulatory Agency.

Although testosterone treatment increases the risk of erythrocytosis, the available randomised controlled trials and observational data have failed to reveal any consistent association (positive or negative) between testosterone treatment and cardiovascular or cerebrovascular events. This year, the National Institute for Health Research testosterone safety and efficacy consortium study will report results from the most robust analysis of testosterone safety to date. Meanwhile, clinicians are advised

to consider cardiovascular risk in men before initiating testosterone treatment. In men with high cardiovascular risk, we recommend counselling them that the cardiovascular safety of testosterone therapy remains uncertain.

PROSTATE SAFETY

We enlisted a prostate onco-urologist to review this contentious issue. It is broadly accepted that testosterone treatment does not increase the risk of developing new prostate cancer. But we also know that there is a physiological restoration of prostate size after starting testosterone treatment for MH which may unmask incidental problems. We strongly advise that you ask men with MH about new urinary symptoms within the first few months following testosterone treatment initiation and refer for urological assessment appropriately.

Theoretically, prostate screening might exclude a pre-existing tumour during testosterone treatment, but endocrinologists have little experience recognising prostate cancer during digital rectal examination (DRE), which therefore risks harm. In contrast, increased age, black ethnicity and family history of prostate cancer unquestionably increase the risk of prostate cancer, which have triggered some countries to roll out national screening for high risk individuals. However, testosterone therapy does not have sufficient evidence of prostate cancer risk to recommend mandatory screening.

AGE AND DISABILITY

With the overwhelming majority of males retaining Leydig cell sensitivity to luteinising hormone stimulation into old age, we can envisage no compelling circumstances wherein testosterone treatment should be withheld from patients with MH on the basis of chronological age per se. Indeed, treatment would be anticipated to improve clinical parameters that are even more important to older men, such as anaemia, frailty, sarcopenia and osteopenia. Similarly, we cannot envisage compelling circumstances wherein testosterone treatment should be withheld from patients with MH who have physical or mental disabilities.

We hope this guidance provides a sensible and rational framework for diagnosing and managing MH, which chimes with the views of members of the Society for Endocrinology and helps us all to treat men effectively.

If you found this information interesting, please do read the full version published in Clinical Endocrinology.¹ Finally, we wish to acknowledge the useful input we received from members of the Society’s Clinical Committee and the Irish Endocrine Society.

Channa N Jayasena
Hammersmith Hospital, Imperial College London

Richard Quinton
Royal Victoria Infirmary, Newcastle-upon-Tyne

REFERENCE

Jayasena CN et al. 2022 Clinical Endocrinology 96 200−219.