The Society for Endocrinology’s position statement on male hypogonadism and ageing has recently been updated. The authors of the 2018 update, Richard Quinton and Jeremy Tomlinson, tell us more.

HOW IS MALE HYPOGONADISM DEFINED?

Male hypogonadism is a clinical syndrome comprising symptoms and signs AND laboratory evidence of testosterone deficiency. Although the diagnosis conventionally requires sexual symptoms,^1–3 testosterone is as important for general health in men as it is for sexual health.

Clinical features can be reproductive (infertility and sexual dysfunction) or non-reproductive (fatigue, reduced physical strength and endurance, loss of motivation or concentration, irritability, low or labile mood, anaemia, and osteoporosis or fracture).

The absence of a ubiquitous male andropause indicates that men with a well-founded diagnosis of hypogonadism should generally receive testosterone therapy. Therefore, contentious issues in older men generally relate to issues of diagnosis rather than treatment decisions.

MORE GUIDANCE, OH WHAT JOY!

Hypogonadism is misdiagnosed, over-diagnosed and undiagnosed in equal measures. There is a worldwide explosion in testosterone prescriptions that by no means target the men with the greatest need or potential to derive clinical benefit.

A plethora of updated diagnostic guidelines have recently appeared that are notable for major differences of emphasis.^4–9 Some of these rather inflexibly champion diagnostic purity,^5,6 but others^4,7,8 are startlingly ‘permissive’ in terms of diagnostics, treatment and monitoring. By ‘permissive’ we mean the ‘routine diagnosis’ of men with borderline-low testosterone and low-normal luteinising hormone (LH) as having secondary hypogonadism (SH) – rather than potentially exhibiting physiological non-gonadal illness (NGI) – and tolerating androgen-induced polycythaemia up to an unphysiological 54% haematocrit.

Accordingly, the Society for Endocrinology’s Clinical Committee directed us to update its 2012 position statement, which has broader applicability across all ages and, as we were gratified to discover, has largely stood the test of time. The revised version is now freely available on the Society’s website.¹⁰

WHAT IS LATE-ONSET HYPOGONADISM?

Late-onset hypogonadism (LoH) was originally characterised as a clinical and biochemical syndrome associated with ageing-related co-morbidities (especially obesity), symptoms of testosterone deficiency and consistently low testosterone, after exclusion of classical causes of hypogonadism (e.g. Klinefelter’s syndrome, or pituitary tumours).¹¹

The number of men with LoH by this original definition is small, with the European Male Ageing Study (EMAS) reporting only 2.1% of men aged greater than 40 years.¹ EMAS also found the decline in serum testosterone to reside overwhelmingly in accumulating NGI (particularly obesity), with only a very limited impact of ageing per se.^1–3 EMAS did, however, identify a small subset of men with genuine age-related primary hypogonadism (PH) and raised LH levels from Leydig cell dysfunction, so the term LoH may be better reserved for older men with otherwise unexplained PH. Although the incidence of PH in men is low (0.2% per year), it increases with both age and illness.^2,3

SECONDARY HYPOGONADISM OR NON-GONADAL ILLNESS?

Due to physiological suppression of the reproductive axis, older men with common medical conditions (e.g. obesity, metabolic syndrome, type 2 diabetes mellitus, chronic obstructive pulmonary disease, ischaemic heart disease, HIV, inflammatory disease, cardiac, renal and liver impairment) have a higher prevalence of borderline-low serum testosterone levels with low-normal LH.¹² Testosterone levels normalise when these conditions remit (e.g. through lifestyle change) and it is thus not yet established whether these men have genuine SH or NGI instead. The ‘Testosterone Trials’ identified relatively limited benefits of testosterone treatment on sexual and motor function in older men with SH (or obesity-related NGI?), with ‘anaemia’ and ‘bone density’ study arms being the only ones to show major effects.^13,14

We therefore emphasise the primacy of lifestyle interventions over testosterone treatment in men with borderline-low serum testosterone levels and low-normal LH, unless there are other compelling reasons, such as osteoporosis, anaemia, small testes or sexual dysfunction refractory to first line treatment. Importantly, a diagnosis of hypogonadism, at any age, is more secure when framed in the context of a recognised clinical syndrome (e.g. primary hypogonadism resulting from past orchitis, or SH due to opiate analgesia).

LABORATORY DIAGNOSIS

As LH-stimulated testosterone levels exhibit a circadian rhythm and are acutely lowered by oral carbohydrate intake, the biochemical fingerprint of true SH (low testosterone, with low or inappropriately normal LH level) can be artefactually reproduced by postprandial or afternoon venepuncture. Therefore, serum total testosterone levels should always be measured fasted before 11.00, preferably after a good night’s sleep and not during intercurrent illness. Readings below the reference range on at least two different occasions support a diagnosis of hypogonadism, as do raised LH level (signalling PH), low bone density or anaemia.^5,9

When LH levels are not raised, additional investigations including measurement of prolactin and (when total testosterone is borderline) sex hormone-binding globulin (SHBG) levels, allowing estimation of free testosterone (e.g. www.issam.ch), are indicated. Although the validity of free testosterone calculations is not universally accepted,⁵ we believe they can usefully improve diagnostic specificity in men with extreme (high or low) SHBG levels, e.g. reassuring obese men with low-normal testosterone and low SHBG levels arising from insulin resistance. They can instead be directed to lifestyle modification.

TREATMENT AND MONITORING

Testosterone treatment of men with a well-founded diagnosis of hypogonadism is effective and safe, and should not be withheld on the basis of age or disability.¹⁵ Modern testosterone preparations achieve more stable, physiological, serum testosterone levels. Treatment aims to achieve serum testosterone levels within the mid-reference range, whilst ensuring a normal haemoglobin and haematocrit. Testosterone treatment should be avoided in men who are actively seeking biological parenthood.

Whilst testosterone treatment in older men with low testosterone and low-normal LH levels that are often underpinned by obesity may confer short term benefits, longer term studies of sufficient power to document clinical outcomes are notably lacking. Therefore, whereas testosterone replacement has been used for many years, effectively and without major adverse effects, in men of all ages with classical hypogonadism, this experience and the risk–benefit balance cannot be extrapolated to older men whose low testosterone levels predominantly reflect frailty or other NGI.⁶ Occult prostate cancer is common in elderly men and, in the absence of long term studies, it is unclear whether testosterone therapy can promote tumour growth. Therefore, before commencing testosterone treatment in men over 40 years, a history of prostatic symptoms should be taken and prostrate-specific antigen (PSA) should be measured. Surveillance with annual PSA measurement on testosterone treatment is recommended, with referral to urology if abnormal. However, the overriding concern underpinning treatment is the avoidance of androgen-induced secondary polycythaemia, so haematocrit should be assessed before and annually after therapy, and the replacement dose adjusted accordingly. The long term effects of testosterone treatment on cardiovascular disease susceptibility are currently unknown⁷ and it should therefore be used cautiously in men with symptomatic cardiovascular disease.

Richard Quinton, Consultant Physician (Endocrinologist), The Newcastle upon Tyne Hospitals NHS Foundation Trust

Jeremy Tomlinson, Consultant Endocrinologist, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford

REFERENCES

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8. Hackett G et al. 2017 Journal of Sexual Medicine 14 1504–1523.
9. Bhasin S et al. 2018 Journal of Clinical Endocrinology & Metabolism 103 1715–1744.
10. Quinton R & Tomlinson J 2018 Society for Endocrinology Position Statement on Male Hypogonadism and Ageing www.endocrinology.org/media/2710/male-hypogonadism-and-ageing-2018.pdf.
11. Wang C et al. 2008 European Journal of Endocrinology 159 507–514.
12. Turner HE & Wass JAH 1997 Clinical Endocrinology 47 379–403.
13. Roy CN et al. 2017 JAMA Internal Medicine 177 480–490.
14. Snyder PJ et al. 2017 JAMA Internal Medicine 177 471–479.
15. Fernandez-Balsells MM et al. 2010 Journal of Clinical Endocrinology & Metabolism 95 2560–2575.