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 (EAU), International Society for Sexual Medicine (ISSM) 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.
-- Type 2 diabetes.
-- Metabolic syndrome.
-- Treatment with medications that cause suppression of testosterone levels - e.g. corticosteroids and opiates.
-- Moderate to severe chronic obstructive lung disease.
-- Osteoporosis or low-trauma fractures.
-- HIV infection with sarcopenia.
-- Pituitary mass, following radiation involving the sellar region and other diseases in the hypothalamic and sellar region.
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 gynaecomastia, decreased testicular volume and less body hair.
Signs and symptoms of androgen deficiency vary depending on age of onset, duration and the severity of the deficiency.5,7,12,13 Hypogonadism-related loss of libido or vigor increases below T concentrations of 15 nmol/L, increased visceral fat is observed below concentrations of 12 nmol/L, and depression and type 2 diabetes become more prevalent below 10 nmol/L. Erectile dysfunction becomes more common at more severe testosterone deficiency with testosterone levels below 8 nmol/L.14,15
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: 16
Improved sexual desire, erectile function (especially in men with testosterone levels below 8 nmol/L), sexual activity, satisfaction and orgasm.16
Reduced body fat mass, and increased lean (muscle) mass and bone mineral density.17,18
Reduction in waist circumference, BMI, blood pressure, and improved lipid profile.19
In the largest double-blind placebo-controlled study to date, 790 men over 65 years were treated with testosterone therapy for 12 months.20 Results showed significant improvements in sexual function and modest improvement in 6-minute walking test, functional performance, mood, depression and fatigue.20 The composite benefits of these improvements are likely to translate into major quality of life and health-related economic benefit.1
In the longest-duration double-blind placebo-controlled study, 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL) were treated with testosterone therapy for 3 years. It was found that in men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group.21
Notably, all these meta-analyses and RCTs 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.22-28
Cessation of testosterone therapy results in relapse and reversal of benefits within 6 months 29,30. A study that specifically investigated the effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters confirmed that withdrawal of testosterone treatment reverses beneficial effects, which appear again when treatment is resumed.31 Therefore, hypogonadism may require lifelong testosterone treatment.1
It is important to note that the clinical response to testosterone treatment is unrelated to the underlying cause of hypogonadism 4, 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).32
The beneficial effects of testosterone therapy are seen in both younger and older men.33-35 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.36 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).37