UK policy statements on testosterone deficiency

October 2017

Hackett G, Kirby M, Edwards D, Jones TH, Rees J, Muneer A. UK policy statements on testosterone deficiency. Int J Clin Pract. 2017;71(3-4).

Testosterone deficiency (also known as hypogonadism) and its treatment is a medical issue that has long been neglected, despite causing significant physiological and psychological health complications among affected men. Longstanding dogmatic fears about prostate cancer and more recent misleading studies alluding to heart attack and stroke risk, has made testosterone treatment a controversial topic.

Here we summarize the newly published UK policy statements on testosterone deficiency, which are based on an International expert consensus conference on testosterone deficiency and its treatment.¹ These statements, developed by the British Society for Sexual Medicine, address widespread media and scientific concerns over the appropriate treatment of testosterone deficiency with testosterone therapy.¹

KEY POINTS

British Society for Sexual Medicine (BSSM) policy statements on testosterone deficiency:

Testosterone deficiency is a well-established, significant medical condition.
Testosterone deficiency has well-established symptoms.
Testosterone therapy for men with testosterone deficiency is effective, rational and evidence based.
There is no scientific basis for withholding testosterone therapy from men on the basis of age.
Testosterone deficiency is associated with increased cardiovascular and all-cause mortality.
The evidence does not support an increased cardiovascular risk associated with testosterone therapy.
There is no evidence that supports any increase in the risk of prostate cancer with testosterone therapy.
A major research initiative to explore the benefits of testosterone therapy in cardiometabolic disease is overdue.

What caused recent concerns about testosterone therapy?

Testosterone has been used in medicine since the 1940s.^2,3 With the growing recognition of health consequences of testosterone deficiency and the beneficial effects of proper testosterone treatment (the words treatment and therapy are commonly used interchangeably),^4-7 it has attracted interest both in the scientific community and the media.

Recent media coverage of two high profile but flawed studies confused the situation concerning the safety of testosterone therapy.^8,9 This prompted the US Food and Drug Administration to demand a label change on testosterone products to inform of possible increased risk of heart attack and stroke.¹⁰ No such concerns were expressed by the European Medicine Agency.¹¹

What these policy statements add

1) Testosterone deficiency is a well-established, significant medical condition

All major clinical guidelines define hypogonadism – also known as testosterone deficiency – as follows:

“A biochemical syndrome associated with advancing age and characterised by a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens. It may result in significant alterations in the quality of life and adversely affect the function of multiple organ systems.”^5,7,12,13.

To make the diagnosis of hypogonadism, signs/symptoms indicative of testosterone deficiency need to occur in the presence of low testosterone levels. There is no universal agreement about what counts as low testosterone levels. The European Association of Urology, International Society for Sexual Medicine and BSSM guidelines suggest that a level of:

Total testosterone of <8 nmol/L or free testosterone of <180 pmol/L (based on two separate 8-11 morning blood samples) requires testosterone therapy.
Total testosterone of >12 nmol/L or free testosterone of >225 pmol/L does not require testosterone therapy.

Between these levels, a trial of testosterone therapy for a minimum of 6 months should be considered based on symptoms.⁵

It is recommended that total testosterone levels are measured in men with a disease in which testosterone deficiency is common and/or who are taking medications that reduce testosterone levels.¹²

This includes men with sexual dysfunction, metabolic syndrome, obesity, type 2 diabetes and those who are treated with opiates or corticosteroids.

2) Testosterone deficiency has well-established symptoms

The most common symptoms of hypogonadism are reduced sexual desire and sexual activity, erectile dysfunction, loss of morning erections and hot flushes.^5,7,12,13 Other factors found associated with low testosterone include increased waist circumference, obesity, metabolic syndrome and impaired health status. Other less-specific symptoms are loss of physical strength and muscle mass, fatigue, changes in mood, anger, sleep disturbance and cognitive impairment. Classical signs are breast tissue development (gynaecomastia), decreased testicular volume and less body hair.

3) Testosterone therapy for men with testosterone deficiency is effective, rational and evidence based

Several meta-analyses of randomized controlled trials – the gold standard scientific research method - have found numerous beneficial effects of testosterone therapy in hypogonadal men:¹⁴

Improved sexual desire, erectile function (especially in men with testosterone levels below 8 nmol/L), sexual activity, satisfaction and orgasm.¹⁴
Reduced body fat mass, and increased lean (muscle) mass and bone mineral density.^15,16
Reduction in waist circumference, BMI, blood pressure, and improved cholesterol profile.¹⁷

Notably, all these studies confirmed the safety of testosterone treatment. Long-term efficacy and safety has also been confirmed in real-life registry studies, where men from urology offices were treated with testosterone undecanoate for over 10 years; these studies showed progressive weight loss, decreased waist circumference and improvement in metabolic parameters.^18-24

Cessation of testosterone therapy results in relapse and reversal of benefits within 6 months^25,26. A study that specifically investigated the effects of intermission and resumption of long-term testosterone therapy on body weight and metabolic parameters confirmed that withdrawal of testosterone treatment reverses beneficial effects, which appear again when treatment is resumed.²⁷ Therefore, hypogonadism may require lifelong testosterone treatment.¹

It is important to note that the response to testosterone treatment is unrelated to the underlying cause of the testosterone deficiency⁴, as all the previously mentioned meta-analyses and the two milestone RCTs showed benefits in men without “classical hypogonadism” (hypogonadism caused by Klinefelter’s syndrome, pituitary injury, or testicular damage).

4) There is no scientific basis for withholding testosterone therapy from men on the basis of age

While testosterone levels, especially the free testosterone fraction, decline with age, lifestyle factors (sedentariness, stress, unhealthy food habits), obesity, metabolic syndrome, diabetes and other chronic diseases also greatly contribute to the declining testosterone levels (in some cases more so than aging per se).²⁸

The beneficial effects of testosterone therapy are seen in both younger and older men.^29-31 Some benefits, such as muscle mass and strength, may be of greater clinical and economic significance in older men, as reduced muscle mass and lower limb strength are related to frailty and increased rate of falls.³² As shown in figure 1, men over 75 who receive testosterone therapy (gray bar) have the greatest reduction in all-cause mortality when compared to age-matched hypogonadal men who do not receive testosterone therapy (blue bar).³³

Effect of testosterone therapy in hypogonadal men on reduction in mortality, compared to non-treated hypogonadal and men without testosterone deficiency, in various age groups

Figure 1: Effect of testosterone therapy in hypogonadal men on reduction in mortality, compared to non-treated hypogonadal and men without testosterone deficiency, in various age groups.

5) Testosterone deficiency is associated with increased cardiovascular and all-cause mortality

Several long-term studies show that hypogonadism is associated with increased cardiovascular and all-cause mortality.^34-36 Importantly, even after adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low testosterone levels continued to be significantly associated with a 2-fold increased risk of mortality.³⁵

6) The evidence does not support an increased cardiovascular risk associated with testosterone therapy

The fear of increased risk of heart attack and stroke was mainly caused by two high profile but flawed studies.^8,9 Since the publication of these studies, many new studies have refuted the alleged cardiovascular risks.^37-50

7) There is no evidence that supports any increase in the risk of prostate cancer with testosterone therapy.

Historically, fear of prostate cancer was the major reason men were denied testosterone therapy. All major medical guidelines conclude that there is no evidence that testosterone therapy is associated with increased risk of prostate cancer.^5,7,12,51

The 2017 European Association of Urology guidelines make the following statement:¹²

“Testosterone therapy results in a marginal increase in PSA and prostate volume, plateauing at twelve months.⁵² Previous fears that testosterone treatment might increase the risk of prostate cancer have been contradicted by large meta-analyses.”^53,54

However, prostate monitoring is required during testosterone therapy. Patients with a substantial or continuous increase in PSA level (taking the level 6 months after treatment initiation as baseline) need to be investigated further to exclude prostate cancer.¹²

8) A major research initiative to explore the benefits of T Therapy in cardio-metabolic disease is overdue

A common theme in medical research on testosterone is a call for more research and longer-term RCTs. The Testosterone for the prevention of Diabetes Mellitus (T4DM) – www.t4dm.org.au - study in Australia is conducted in obese men with glucose intolerance and testosterone levels of 14 nmol/L or lower, randomised to treatment with testosterone or placebo.⁵⁵

Commentary

Many physicians are unsure how to make the diagnosis of hypogonadism. Several factors are contributing to the diagnostic dilemma; uncertainty about what testosterone levels should be considered low, wide variation in laboratory reference ranges for different testosterone assays, weak correlations between signs, symptoms and testosterone levels.⁵⁶

The UK policy statements on testosterone deficiency are helpful by recommending that a trial of testosterone therapy for a minimum of 6 months should be considered in symptomatic men. It was suggested already 10 years ago that a therapeutic trial should be an integral part of a trio of diagnostic criteria; assessment of symptoms and signs, laboratory results and efficacy of a therapeutic trial.^57,58

Several guidelines recommend a trial of treatment as a component of the diagnostic process, particularly in patients with borderline testosterone levels. What is at issue is the length of the trial.⁵⁹ Both the Canadian 7 and Endocrine Society guidelines recommend a 3 month trial of testosterone treatment. In line with the policy statements presented here from the British Society for Sexual Medicine, the International Society for Sexual Medicine Guideline 5 recommend a minimum period of 6 months when assessing response to a trial of testosterone treatment.

In a randomized controlled trial of testosterone undecanoate in men with type 2 diabetes, it was shown that improvement continued until six months, and even extended to 12 months in some patients.⁶⁰ Contributing factors to long response times in testosterone therapy include compliance issues with topical treatment. In addition, for patients receiving testosterone undecanoate treatment, a three-month trial period would include only two long-acting injections, with peak levels not necessarily being reached.⁵⁹ Because men are likely to get a trial of testosterone therapy only once, it is vital that it is done properly; exposing patients to sustained levels of testosterone for an adequate period to achieve at least some benefits in order to warrant continued treatment and ultimately achieve maximal benefits.⁵⁹

Recommendations

Do you have symptoms of low testosterone?

Testosterone deficiency FAQs

References

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