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15 November 2016

Testosterone Therapy in Men with Prostate Cancer – new research

Testosterone Therapy in Men with Prostate Cancer – new research

Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. J Urol. 2016;196(4):1082-1089.

Historically, prostate cancer – both active and treated - has been an absolute contraindication to testosterone therapy and – from a regulatory perspective – still is. The incidence of prostate cancer is higher in older men, in whom prostate cancer accounts for one in five new cancer diagnoses. Thanks to improvement in early detection and treatment of prostate cancer, prostate cancer mortality has decreased 50% during the past two decades, and more men are living with a history of prostate cancer.

The aging of the male population and the increasing number of prostate cancer survivors have resulted in a significant increase in the number of men presenting with hypogonadism and treated prostate cancer. Therefore, it is important to consider the growing number of recent studies which have challenged the long-standing belief that prostate cancer is an absolute contraindication to testosterone therapy. Here we summarise the results of a notable study which investigated the effects of testosterone therapy in men with treated and untreated prostate cancer, and conclude with the latest recommendations on managing testosterone deficiency in men with history of prostate cancer.

Key Points

  • An initial increase in PSA when starting testosterone therapy is normal and is not synonymous with prostate disease progression.
  • Emerging research shows that testosterone therapy in men after radical prostatectomy or radiation, and in men on active surveillance, in most cases does not cause prostate cancer recurrence or worsening.
  • The risk of prostate cancer recurrence appears to be lower after radical prostatectomy than after radiation.

15 October 2016

Dispelling the myth of testosterone treatment and prostate cancer

Dispelling the myth of testosterone treatment and prostate cancer

Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. Debruyne FM, Behre HM, Roehrborn CG, et al. BJU Int. 2016.

Fear of prostate cancer remains one of the major concerns with testosterone therapy among doctors, and reason to deny suffering hypogonadal men testosterone treatment. This fear persists despite mounting research over the past decade that has clearly refuted the belief that testosterone therapy increased risk of prostate cancer among men in the general population. Aside prostate cancer, benign prostatic hyperplasia (BPH) with its associated lower urinary tract symptoms (LUTS) are also common concerns with testosterone therapy.

In this editorial we summarize and comment on the results of the Registry of Hypogonadism in Men (RHYME) study; a large, multi-national prospective registry of men with testosterone deficiency, which was designed and powered specifically to assess prostate cancer outcomes in hypogonadal men receiving testosterone therapy compared with untreated hypogonadal men or general population estimates.

Key Points

  • BPH, LUTS and prostate cancer have long been considered major risks associated with testosterone therapy, but accumulating research shows these fears are unfounded.
  • The RHYME study showed that testosterone therapy does not increase prostate cancer incidence or BPH/LUTS progression compared to matched untreated men.
  • There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score in testosterone treated men compared to untreated men.
  • Testosterone therapy may improve voiding symptoms.
  • Testosterone therapy has no clinically significant adverse impact on prostate cancer incidence among men regardless of administration method.

15 September 2016

Waist-to-height ratio as screening tool for testosterone deficiency and health risk

Waist-to-height ratio as screening tool for testosterone deficiency and health risk

A common belief is that testosterone deficiency is an “old man’s issue”. This is very wrong. Actually, an excess amount of body fat can cause a man’s testosterone levels to drop as much as 10 years of aging. Several studies have demonstrated that too much body fat is associated with reduced testosterone levels independent of aging.

Excess intra-abdominal fat (also known as visceral fat) – a hallmark of the metabolic syndrome - is particularly detrimental, and low levels of both total testosterone and free testosterone are consistent features of men with metabolic syndrome. Therefore, it has been suggested that low testosterone levels should be included in the definition of the metabolic syndrome.

Blood testing of testosterone levels is not part of routine clinical practice. Therefore, it is important that physicians are aware of conditions which indicate that a male patient may have testosterone deficiency and warrant blood testing of testosterone levels.

Key Points

  • Abdominal obesity is a strong risk factor for cardiovascular disease independent of BMI (a proxy for obesity).
  • An enlarged belly is an especially strong indicator of metabolic risk in men and is associated with markedly reduced testosterone levels, regardless of age.
  • Adjusting waist for height – known as the waist-to-height ratio - is a more accurate indicator of cardiometabolic risk and life expectancy than is waist alone or BMI.
  • The waist-to-height ratio improves prediction of both total and free testosterone levels, compared with either waist alone or BMI, even after adjustment for age.
  • A waist-to-height ratio below 0.5 is considered ideal. This translates into the health message “keep your waist circumference to less than half your height.”
  • Use out waist-to-height ratio tool to calculate your waist-to-height ratio: http://www.nebido.com/en/hcp/your-patients/waist-to-height-ratio/index.php
  • In men with a waist-to-height ratio of >0.5, symptoms that are indicative of testosterone deficiency should be assessed. It is recommended that this is done with the Aging Male Symptoms (AMS) questionnaire http://www.nebido.com/en/hcp/your-patients/ams-questionnaire-tool/index.php
  • Testosterone therapy reduces belly size and the waist-to-height ratio.

15 August 2016

Testosterone Deficiency and Treatment - International Expert Consensus Resolutions

Testosterone Deficiency and Treatment - International Expert Consensus Resolutions

Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Morgentaler A, Zitzmann M, Traish AM, et al. Mayo Clin. Proc. 2016;91(7):881-896.

Testosterone deficiency and treatment is a very misunderstood and controversial topic among scientists, regulatory agencies (such as the FDA and EMA) and doctors, as well as the popular media.

On October 1, 2015, an international expert consensus conference about testosterone deficiency and its treatment was held in Prague, sponsored by King’s College London and the International Society for the Study of the Aging Male (ISSAM). The impetus for this meeting was to address the widespread misinformation and confusion about testosterone deficiency and testosterone therapy.

The ultimate goal of this consensus conference was to document what is true or untrue about testosterone deficiency and testosterone therapy, to the best degree possible based on existing scientific and clinical evidence.

There were 18 experts from 11 countries on 4 continents. Specialties included urology, endocrinology, internal medicine, diabetology, and basic science research. Experts were invited on the basis of extensive clinical experience with testosterone deficiency and its treatment and/or research experience.

Key Points

  • Testosterone deficiency is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.
  • Symptoms and signs of testosterone deficiency occur as a result of low levels of testosterone and may benefit from treatment regardless of whether there is an identified underlying cause.
  • Symptoms and signs of testosterone deficiency should get more attention because of the limitations of measuring and interpreting testosterone levels in men.
  • Testosterone deficiency is a global public health concern.
  • Testosterone therapy for men with testosterone deficiency is effective, rational, and evidence based.
  • There is no scientific basis for any age-specific recommendations against the use of testosterone therapy in men.
  • The evidence does not support increased risks of either cardiovascular events or prostate cancer with testosterone therapy.
  • Evidence supports a major research initiative to explore possible benefits of testosterone therapy for cardiometabolic disease, including diabetes.

15 July 2016

Real-life data - men with testosterone deficiency and a history of cardiovascular disease benefit from long-term testosterone therapy

Real-life data - men with testosterone deficiency and a history of cardiovascular disease benefit from long-term testosterone therapy

Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. 2016;12:251-261.

The topic of testosterone and cardiovascular disease has been receiving a lot of attention over the past years. Despite the common belief that testosterone may increase the incidence of coronary artery disease, the scientific evidence shows the opposite; testosterone deficiency is associated with increased prevalence and severity of coronary atherosclerosis and testosterone therapy is associated with beneficial cardiovascular outcomes.

To date, no long-term studies have assessed the effects of testosterone therapy in men with a history of cardiovascular disease. Here we summarise the results of an observational study that investigated the effects of long-term testosterone therapy - up to 8 years - in hypogonadal men with a history of cardiovascular disease.

Key Points

  • In men with testosterone deficiency and a history of cardiovascular disease, who received testosterone therapy for up to 8 years, a significant weight loss (from 114 kg to 91 kg) and a decrease in waist circumference (112 cm to 99 cm) was observed. BMI decreased from 37 to 29.
  • Cardio-metabolic parameters such as lipid profile, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably.
  • No patient suffered a major adverse cardiovascular event during the full observation time.
  • In men with testosterone deficiency, testosterone therapy appears to be effective in achieving sustained improvements in all cardiometabolic risk factors, and may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.

15 June 2016

AUA Congress Report– new studies on long-term testosterone therapy

The American Urological Association (AUA) is a premier urologic association, which provides the global urology community opportunities to present, learn and share news of discovery and advancement. In this editorial we summarize four key presentations from the AUA 2016 annual congress in San Diego, May 6-10, 2016.



Key Points

  • Long-term testosterone therapy in hypogonadal men with prediabetes results in sustained weight loss, and improves glycaemic control. Testosterone therapy may prevent progression from prediabetes to diabetes in men with testosterone deficiency.
  • Long-term treatment with testosterone undecanoate in hypogonadal men may reduce incidence of PCa and protect against high-grade PCa.
  • Long-term testosterone therapy (up to 10 years) in hypogonadal men significantly improves and preserves erectile function, as well as reduces body weight and waist circumference, all of which deteriorate in untreated hypogonadal men.
  • Long-term testosterone therapy in symptomatic hypogonadal men improves urinary function, while untreated controls experience a worsening.
  • Long-term testosterone undecanoate is well tolerated, and excellent adherence suggests a high level of patient satisfaction in a real-life urology practice.

15 May 2016

Survival and cardiovascular events in men treated with testosterone

Survival and cardiovascular events in men treated with testosterone

Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Wallis CJD, Lo K, Lee Y, et al. The Lancet Diabetes & Endocrinology. 2016;May 7

On the surface, testosterone therapy is a controversial treatment because previous studies investigating the effects of testosterone therapy have been conflicting, with some studies showing supposed harm and others showing significant benefit.

Here we present the results of a new study published in The Lancet Diabetes & Endocrinology on May 7 2016, which addressed some shortcomings in previous studies by analyzing effects based on duration of testosterone treatment.



Key Points

  • After a follow-up for over 5 years, men treated with testosterone had 12% lower mortality than non-testosterone treated men.
  • Compared to non-testosterone treated men, men with the shortest duration of testosterone treatment had 11% increased risk of mortality and 26% increased risk cardiovascular events. In contrast, those with the longest duration of testosterone treatment had 33% decreased risk of mortality and 16% decreased risk of cardiovascular events.
  • Risk of prostate cancer diagnosis was decreased by 40% in men with the longest duration of testosterone treatment, compared to non-testosterone treated men. No effect on prostate cancer risk was seen among men with shortest duration of testosterone treatment.
  • It is speculated that the increased risk of cardiovascular events and mortality for men with the shortest duration of testosterone treatment could be driven by the consequences of underlying testosterone deficiency and inadequate treatment, rather than the testosterone treatment.

15 April 2016

Effects of Testosterone Therapy for up to 10 years on Obesity and Metabolic Parameters

Effects of continuous long-term testosterone therapy on anthropometric, endocrine and metabolic parameters for up to 10 years

Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.
Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Andrologia 2016:Jan 14 [Epub ahead of print]

While it is well documented that testosterone levels decline in aging men, recent studies show that obesity and impaired general health can be more influential causes of testosterone deficiency than chronological age per se.

Here we present real-life results from a registry study which investigated the effects of continuous long-term testosterone therapy on anthropometric, endocrine and metabolic parameters in obese hypogonadal men, for up to 10 years.

Key Points

  • In this prospective registry study, 115 hypogonadal men, mean age 59 years, received injections with testosterone undecanoate in 12-week intervals for up to 10 years.
  • Body weight and waist circumference decreased from 97.3 to 84.6 kg and from 107 to 92 cm, respectively. BMI decreased from 31 to 27.
  • Fasting glucose, HbA1c, and the triglyceride:HDL ratio, a surrogate marker of insulin resistance, declined.
  • Lipid profile significantly improved, with an increase in HDL levels, decrease in total cholesterol:HDL ratio, and marked reduction in non-HDL cholesterol and remnant cholesterol.
  • Reductions in systolic and diastolic blood pressure, and inflammation (measured by C-reactive protein) were also seen.
  • No major adverse cardiovascular events were observed throughout the study.

15 March 2016

Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins.
Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Int. J. Clin. Pract. 2016;70(3):244-253.

The prevalence of testosterone deficiency is higher in men with type 2 diabetes than among non-diabetic men, and testosterone deficiency is associated with increased mortality.

Type 2 diabetic men often have dyslipidemia and erectile dysfunction, and hence concomitant medications are widely used in these patients.

Here we present the results of a study by Hackett et al. which investigated the impact of testosterone levels and testosterone therapy on mortality, and assessed if this was affected by concomitant statin and PDE5I use.

Key Points

  • Mortality is higher in men who are not on testosterone therapy or PDE5I.
  • Men who are eugonadal or on testosterone therapy have a 38% and 62% reduced risk of mortality, compared to hypogonadal men not receiving testosterone therapy.
  • Use of PDE5I reduces mortality rates to a greater degree in eugonadal men and hypogonadal men not on testosterone therapy, than in testosterone treated men.
  • Statin use is not significantly associated with mortality.
  • Mortality rates in the Low testosterone untreated, Normal testosterone and Low testosterone treated groups were 19.74%, 13.31% and 3.64%, respectively.

15 February 2016

Effects of testosterone treatment in older men

Effects of testosterone treatment in older men

Effects of Testosterone Treatment in Older Men.
Snyder PJ, Bhasin S, Cunningham GR, et al. N. Engl. J. Med. 2016;374(7):611-624.

The double-blind randomized controlled trial (RCT) is accepted by medicine as the gold standard objective scientific methodology, and provides the highest strength of evidence for the effectiveness of a treatment. An accumulating body of evidence shows that treating hypogonadal men with testosterone therapy provides a number of wide-ranging benefits beyond mere relief of symptoms, including improvements in muscle mass, insulin sensitivity, fat mass (both total body fat and visceral fat), endothelial function, blood pressure, lipid profile and bone mineral density.

Recent clinical practice guidelines state that testosterone therapy is safe if treatment and monitoring are appropriately executed, and the totality of available evidence to date does not support alleged concerns regarding risk of cardiovascular disease and prostate cancer. Despite this, opponents state that the clinical benefits and potential long-term risks of testosterone therapy have not been adequately assessed in large RCTs, and that therefore a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified.

To address the lack of large RCTs on testosterone therapy, the US National Institute of Health has funded The Testosterone Trials, which is a coordinated set of 7 large double-blind RCTs. Here we report the first results from The Testosterone Trials.

Key Points

  • Testosterone treatment for 1 year in men aged 65 years and older improves:

    • Sexual desire, erectile function, and sexual activity.
    • Basic activities of daily living and walking speed.
    • Mood and depressive symptoms.
  • A greater increase in testosterone levels during treatment is associated with a greater increase in sexual activity and a greater reduction in fatigue.
  • Men in the testosterone group were more likely than those in the placebo group to report that their sexual desire, perception of walking ability and energy had improved.
  • The rates of adverse events were similar in the testosterone and placebo groups. During the follow-up year, there were 8 myocardial infarctions in the placebo group compared to 1 in the testosterone group.

15 January 2016

Testosterone Therapy Reduces Insulin Resistance and Inflammation in Men with Type 2 Diabetes

Testosterone Therapy Reduces Insulin Resistance and Inflammation in Men with Type 2 Diabetes

Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes.
Dhindsa S, Ghanim H, Batra M, et al. Diabetes Care. 2016;39(1):82-91.

Testosterone deficiency – defined as low levels of total testosterone in the presence of symptoms - is common among men with obesity and type 2 diabetes, with a reported prevalence of 58% and 45%, respectively. However, even after adjusting for age and BMI, the prevalence of subnormal free testosterone levels (<5 ng/dL or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).

Here we summarize the results of a well conducted randomized, parallel, placebo controlled, double-blind, prospective trial that specifically selected men with type 2 diabetes based on low free testosterone levels (calculated free testosterone of <6.5 ng/dL on two occasions).

The aims of the study were to investigate:

1) The impact of testosterone deficiency (hypogonadotropic hypogonadism) on insulin resistance, inflammation, and body composition in men with type 2 diabetes.

2) The effects of intramuscular testosterone replacement on insulin sensitivity, inflammation, and body composition.

Key Points

  • Men with testosterone deficiency and type 2 diabetes had higher subcutaneous and visceral fat mass, and more severe insulin resistance, than eugonadal men.
  • Testosterone treatment for 6 months in hypogonadal men reduced insulin resistance and subcutaneous fat mass (approx. 3 kg) and increased lean mass (approx. 3 kg), without changing body weight.
  • The expression of insulin signaling genes (IR-beta, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in hypogonadal men and was upregulated after testosterone treatment.
  • Testosterone treatment also caused a significant fall in inflammatory mediators and circulating concentrations of free fatty acids, C-reactive protein, interleukin-1beta, tumor necrosis factor-alpha, and leptin.
  • Testosterone treatment additionally improved parameters of sexual function.
  • In this study PSA levels did not change, and no subject developed hemoglobin >18 g/dL, hematocrit >55%, supranormal PSA concentrations (>4 ng/mL), or a prostate nodule during the trial.

15 December 2015

Testosterone Replacement Therapy and Mortality in Older Men

Testosterone Replacement Therapy and Mortality in Older Men

Testosterone Replacement Therapy and Mortality in Older Men.
Hackett GI. Drug Saf. 2015 Oct 19.

Despite a large prevalence of hypogonadism and increased testosterone prescribing over the past decade, population-based (BACH, Boston Area Community Health) and clinical-based studies (HIM, Health In Men) report that only 10-12% of hypogonadal patients (comprising 40-45% of studied populations) are receiving treatment.

One important reason for the under-treatment of men with testosterone deficiency is the widespread misperception about testosterone therapy on risk of cardiovascular disease. In this editorial we summarize a review paper by Hackett, which addresses the effects of testosterone therapy on cardiovascular risk factors, as well as mortality.

Key Points

  • There is a high level of evidence that hypogonadism is associated with increased all-cause mortality and reduced quality of life.
  • A large body of evidence shows that testosterone replacement therapy according to expert guidelines is safe and effective for men suffering from testosterone deficiency.
  • Emerging evidence shows that testosterone replacement therapy in hypogonadal men may reduce all-cause mortality.
  • Recent studies suggesting that testosterone replacement therapy may increase cardiovascular risk are severely flawed and do not exclude the possibility that the increased risk is related to hypogonadism and not the testosterone treatment.

15 November 2015

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.
Basaria S, Harman SM, Travison TG, et al. JAMA. 2015;314(6):570-581.

Currently there are only a few high quality studies investigating the effects of testosterone therapy for a duration of 3 years and medical societies have long been urging for more long-term studies evaluating the safety and efficacy of testosterone therapy.

On August 11th 2015 a notable 3-year long RCT was published in JAMA (Journal of the American Medical Association), which attracted a lot of Attention. While interpreted by many as showing that testosterone therapy does not confer any benefits on atherosclerosis, sexual function and quality of life, a closer look at the data actually does show two important findings…

15 October 2015

Critical Update of the 2010 Endocrine Society Guidelines for Hypogonadism

Critical Update of the 2010 Endocrine Society Guidelines for Hypogonadism

Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Seftel AD, Kathrins M, Niederberger C. Mayo Clin Proc. 2015; 90(8): 1104-1115.

In 2010, the Endocrine Society published a Clinical Practice Guideline “Testosterone Therapy in Adult Men With Androgen Deficiency Syndromes”, which addressed important issues regarding the diagnosis and treatment of male hypogonadism.

Since publication of this Guideline, several high-quality trials have been conducted, warranting an update of the 2010 recommendations in several areas, especially that of testosterone therapy in men with the metabolic syndrome, type 2 diabetes, sexual dysfunction, and frailty. In addition, many of the previously stated contraindications to testosterone therapy – including severe lower urinary tract symptoms (LUTS) and untreated obstructive sleep apnea (OSA) - have been reexamined in recent trials.

Here we summarize the results of a systematic analysis of the latest high-quality studies, which call for some important updates of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism.

Key Points

  • Men with metabolic syndrome, who were previously not addressed by the 2010 Endocrine Society Clinical Practice Guidelines, may benefit from testosterone replacement therapy based on improvements in biometrics and insulin sensitivity. Effects of testosterone replacement therapy on similar end points in men with type 2 diabetes remain inconclusive.
  • Several recent clinical trials have studied the effects of testosterone replacement therapy in men with frailty, who were previously unrepresented in the 2010 Endocrine Society Clinical Practice Guidelines. Improvements in muscle strength and bone health were noted.
  • Untreated sleep apnea and severe lower urinary tract symptoms may not be absolute contraindications to testosterone replacement therapy.

15 September 2015

Normalization of testosterone level is associated with reduced incidence of heart attack, stroke and mortality in men

Normalization of testosterone level is associated with reduced incidence of heart attack, stroke and mortality in men

Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.
Sharma R, Oni OA, Gupta K, et al. Eur. Heart J. 2015:Aug 6 [Epub ahead of print]

The effect of testosterone replacement therapy on cardiovascular outcomes such as myocardial infarction (MI) and stroke are controversial and have been generating heated discussions among clinicians as well as researchers. This, coupled with biased media sensationalism blowing up the supposed “dangers” of testosterone therapy has created great confusion among suffering men, who could gain tremendous health benefits from testosterone therapy.

In this editorial we report the results of a new study that examined the relationship between normalization of total testosterone levels with testosterone therapy and cardiovascular events as well as all-cause mortality, in patients without a previous history of MI and stroke. This notable study was published in the European Heart Journal on August 6th, 2015.

Key Points

  • In men who have low total testosterone levels but no previous MI or stroke, testosterone therapy is associated with decreased risks of MI, stroke, and all-cause mortality during a long-term follow-up of up to 14 years.
  • Compared to non-treated men, testosterone treated men who achieved normalization of their testosterone levels had a major and significant reduction in MI, stroke and all-cause mortality by 24%, 36% and 56%, respectively.
  • Compared to non-treated men, testosterone treated men who failed to achieve normalization of their testosterone levels did not have a reduction in heart attack or stroke, and had significantly less benefit on mortality risk.
  • Testosterone therapy should aim for doses resulting in normalization of total testosterone level, as this is a prerequisite to achieve a reduction in MI and stroke.

15 August 2015

Effects of long-term testosterone treatment on weight and waist size in men with obesity - observational data from two registry studies

Effects of long-term testosterone treatment on weight and waist size in men with obesity - observational data from two registry studies

Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity Classes I-III: Observational data from two registry studies.
Saad F, Yassin A, Doros G, Haider A. Int J Obes (Lond). 2015;Jul 29

Testosterone, historically believed to be important only for male reproduction and sexuality, has over the past decades transformed from niche hormone to multi-system player. A rapidly accumulating body of research is showing that testosterone is an important metabolic hormone with marked effects on energy metabolism and body composition.

In the USA, 36% of the adult population are obese (BMI >30), (affecting a similar proportion of men and women), and obesity prevalence is escalating worldwide. According to the McKinsey Global Institute (MGI) report “Overcoming obesity: An initial economic analysis”, obesity is “one of the top three preventable social burdens (along with smoking and violence/war/terrorism) generated by human beings” imposing an estimated annual global direct economic burden amounting to 2 trillion USD.

Obesity treatments with comprehensive lifestyle modification and/or drugs are notorious for their poor long-term efficacy and inability to achieve long-term weight loss maintenance. Even with continued lifestyle treatment, significant weight regain occurs. And obesity drugs have side effects which limit their long-term and widespread use. Therefore, new interventions are urgently needed to combat this alarming preventable threat to society.

In this editorial we present a recent study by Saad et al., which investigated the effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III.

Key Points

  • Testosterone therapy for up to 8 years results in progressive, continuous and sustained reduction in body weight, waist circumference and BMI, regardless of obesity grade and age.
  • Improvements in obesity parameters are accompanied by significant improvements in glycemic control (fasting glucose and HbA1c), lipids (total cholesterol, LDL, HDL, triglycerides and total cholesterol:HDL ratio), liver transaminases, inflammation, blood pressure (both systolic and diastolic) and quality of life, regardless of obesity grade and age.
  • Treating obese hypogonadal men with testosterone for 8 years is safe. Elevations in PSA and hematocrit stayed within normal ranges, and the incidence of prostate cancer is lower than expected from the prostate cancer incidence reported in the general population of men not treated with testosterone.
  • Using testosterone therapy as a mode of obesity treatment may result in greater beneficial effects on body composition than diet and/or drug induced weight loss.

28 July 2015

Long-term testosterone treatment with different testosterone preparations

Long-term testosterone treatment with different testosterone preparations

- provocative results on diagnosis and adherence

Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes. Carruthers M, Cathcart P, Feneley MR. The aging male : the official journal of the International Society for the Study of the Aging Male. Published online July 28, 2015.

Due to lack of consistent clear-cut guidelines for diagnosis and treatment of testosterone deficiency, there is a lot of confusion among both health professionals and suffering men. The multiple different testosterone preparations available further add to the complexity of testosterone treatment.

This editorial presents the intriguing results from a notable study that analyzed effects of testosterone therapy with seven different testosterone preparations, in symptomatic men who had previously been denied treatment because of "normal" baseline testosterone levels. The results are quite provocative and highlight several important practical issues relating to diagnosis and treatment of hypogonadism…

Key Points

  • Symptoms indicative of testosterone deficiency do not correlate with either total or free testosterone levels a baseline. Symptomatic patients with testosterone levels in the “normal range” benefit as much as do those with very low testosterone levels.
  • Symptomatic relief may require longer than 1 year to achieve – this underscores the critical importance of long-term adherence to testosterone therapy.
  • None of the commonly available testosterone preparations cause any adverse effects on prostate or cardiovascular related parameters.

20 July 2015

Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy

Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy

Baillargeon, J., et al., Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy.
Mayo Clin Proc, 2015. July 15 [Epub ahead of print].

Venous thromboembolism has been suggested to be one main risk with testosterone replacement therapy. In 2014, both the US Food and Drug Administration (FDA) and Health Canada implemented a requirement for manufacturers to add a warning about the potential risks of venous thromboembolism and deep vein thrombosis to the label of all testosterone products.

However, to date no comparative studies examining an association between testosterone replacement therapy and venous thromboembolism have been reported. In this editorial we report the results of a recent case-control study by Baillargeon et al., which specifically examined the risk of venous thromboembolism associated with testosterone therapy in middle-aged and older men.

Key Points

  • In June 2014 FDA mandated a requirement for manufacturers to add a warning about potential risks of venous thromboembolism and deep vein thrombosis to the label of all testosterone products.
  • The FDA warning was based on spontaneous reporting in post-marketing surveillance.
  • Testosterone may have both prothrombotic and protective endothelial effects.
  • Endogenous testosterone levels are not associated with venous thromboembolism.
  • A comparative study that specifically evaluated a possible link between testosterone therapy and venous thromboembolism in the general population shows no increased risk.

1 June 2015

Testosterone Therapy and Cardiovascular Risk

Testosterone Therapy and Cardiovascular Risk

- Advances and Controversies

Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM.
Testosterone therapy and cardiovascular risk: advances and controversies.
Mayo Clin. Proc. 2015;90(2):224-251.

One of the most debated issues related to testosterone therapy is its effects on cardiovascular risk and related clinical outcomes. This editorial summarizes key conclusions from a special review article written by the Androgen Study Group and published in Mayo Clinic Proceedings.

Key Points

  • Low levels of total, bioavailable, and free testosterone are associated with increased risk of development of cardiovascular risk factors, atherosclerosis and mortality.
  • Testosterone therapy has beneficial effects on a wide range of risk factors and risk biomarkers related to these clinical conditions.

15 May 2015

Associations between Testosterone and Estradiol and Development of Metabolic Syndrome

Associations between Testosterone and Estradiol and Development of Metabolic Syndrome

Associations between Sex Steroids and the Development of Metabolic Syndrome: a Longitudinal Study in European Men.
Antonio L, Wu FC, O'Neill TW, Pye SR, Carter EL, Finn JD, Rutter MK, Laurent MR, Huhtaniemi IT, Han TS, Lean ME, Keevil BG, Pendleton N, Rastrelli G, Forti G, Bartfai G, Casanueva FF, Kula K, Punab M, Giwercman A, Claessens F, Decallonne B, Vanderschueren D. J Clin Endocrinol Metab. 2015 Jan 30

It is well established that both low total testosterone and low sex hormone binding globulin (SHBG) levels are associated with an increased risk of existing and incident metabolic syndrome in men.

However, it is still debated whether testosterone and SHBG are independently associated with incident development of the metabolic syndrome. In addition, the potential role of estradiol in this association is unknown. A recently published study specifically investigated these issues, using data from the European Male Aging Study (EMAS), a prospective study of aging in European men.

Key Points

  • Both low total testosterone and low SHBG levels are associated with an increased risk of both existing and incident metabolic syndrome in men. However, it is still debated whether testosterone and SHBG are independently associated with incident development of the metabolic syndrome.
  • Men with lower baseline total testosterone levels are at 1.7-fold higher risk for developing metabolic syndrome, even after adjustment for SHBG, BMI, body fat (measured by DEXA) and insulin resistance.
  • Estradiol is not associated with development of metabolic syndrome. However, a lower estradiol/testosterone ratio, reflecting less aromatisation of testosterone into estradiol, is associated with a 62% reduced risk of incident metabolic syndrome. This association was also independent of SHBG, insulin resistance and BMI, but not of body fat (measured by DEXA).
  • Lower baseline levels of total and free testosterone, and SHBG, are associated with higher triglyceride and glucose levels and lower HDL levels at follow-up.
  • A lower estradiol/testosterone ratio is associated with lower triglyceride and glucose levels and higher HDL levels. Total estradiol is only associated with a higher triglyceride level.

1 May 2015

Testosterone, Mortality and Longevity

Testosterone, Mortality and Longevity

Testosterone and mortality. Muraleedharan V, Jones TH. Clin. Endocrinol. (Oxf). 2014;81(4):477-487.

Observational studies demonstrate that men with low or low-normal endogenous testosterone are at an increased risk of mortality compared to those with higher levels, and that cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone.

This editorial summarises a review paper which addressed the following two questions:

  1. Is testosterone deficiency directly involved in the pathogenesis of these conditions or is it merely a biomarker of ill health and the severity of underlying disease processes?
  2. Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival?

Key Points

  • Testosterone deficiency is an independent risk factor for future development of obesity, the metabolic syndrome and type 2 diabetes, which are major risk factors for cardiovascular disease, which is the leading cause of death worldwide.
  • Testosterone deficiency is an indicator of general poor health and the severity of underlying disease processes.
  • Experimental data suggest that testosterone deficiency may be directly involved in the pathogenesis of atherogenesis and development of cardiovascular disease.
  • Men with testosterone deficiency have an up to 2-fold increased mortality risk primarily from cardiovascular disease.
  • Survival and longevity are the ultimate goals of interventions in medicine. Two notable studies show that testosterone therapy increases longevity in hypogonadal men 2-fold.

15 April 2015

Health Consequences of Subclinical Hypogonadism

Health Consequences of Subclinical Hypogonadism

Characteristics of compensated hypogonadism in patients with sexual dysfunction. Corona G, Maseroli E, Rastrelli G, et al. The journal of sexual medicine. 2014;11(7):1823-1834.

In discussions about diagnosis and health consequences of hypogonadism, the prime focus is given to testosterone levels and signs/symptoms. However, emerging research has identified a less clinically evident gonadal dysfunction called “subclinical” hypogonadism (or “compensated” hypogonadism).

Subclinical hypogonadism is characterized by normal testosterone levels in the presence of elevated LH level. As testosterone levels are not markedly reduced in subclinical hypogonadism, intuitively one may think it does not confer negative health consequences. However, a recent study by Corona et al., which specifically was conducted to investigate the potential health ramifications of subclinical hypogonadism, shows that it should not be neglected.

Key Points

  • There are three types of hypogonadism:

    • Primary:
      • low testosterone with elevated LH (due primarily to insufficient testicular function);
    • Secondary:
      • low testosterone with low-normal LH (due primarily to insufficient hypothalamic-pituitary function);
    • Subclinical (also called compensated hypogonadism):
      • normal testosterone levels with elevated LH levels.
  • Men with subclinical hypogonadism have more hypogonadal symptoms (primarily psychological) than eugonadal men, and have an equally elevated cardiovascular risk as do men with overt hypogonadism.
  • Subclinical hypogonadism is associated with an almost 10-fold increased risk of cardiovascular mortality, comparable to that for overt hypogonadism.
  • Elevated LH in the context of apparently eugonadal total testosterone levels may be an indicator of a general poor health status, and should be followed up with a more comprehensive medical examination.

1 April 2015

Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years

Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years

One of the major concerns among doctors and patients with testosterone therapy is its allegedly negative effect on the prostate. However, according to the current ISA, ISSAM, EAU, EAA, ASA clinical guidelines, there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia. The guidelines also state that there is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer.

Despite this, many men are being denied testosterone therapy because of undue fears that it would cause harm to the prostate. In this editorial we summarize the results from a study that investigated incidence of prostate cancer with testosterone therapy for up to 17 years.

Key Points

  • New study shows that prostate cancer incidence (1.08%) after up to 17 years of testosterone therapy with Nebido® is much lower than that reported in the general population of men who are not on testosterone therapy (7.35 to 9.6%).
  • This supports previously presented new insights on the testosterone - prostate relationship, and the saturation limit of androgen-dependent prostate growth.
  • Testosterone therapy has no clinically significant adverse impact on prostate cancer incidence among men regardless of administration method.

15 March 2015

Cardiovascular Risk and Elevation of Blood DHT Levels Vary by Testosterone Preparation

Cardiovascular Risk and Elevation of Blood DHT Levels Vary by Testosterone Preparation

Cardiovascular risks and elevation of blood DHT vary by route of testosterone administration: a systematic review and meta-analysis.
Borst SE, Shuster JJ, Zou B, et al. BMC medicine. 2014;12(1):211.

The cardiovascular effects of endogenous testosterone and testosterone replacement therapy are subject to intense investigation in medical research and have recently generated heated discussions among healthcare professionals.

While the main focus has been on testosterone per se, it is important to remember that testosterone is both a hormone in its own right, and a pro-hormone that gets converted to both estradiol and DHT (dihydrotestosterone), which exert effects themselves that are different from testosterone.

Therefore, when analyzing the effects of testosterone, especially exogenous testosterone administered as testosterone replacement therapy, it is critical to take into consideration how it affects downstream testosterone metabolites.

A recent systematic review and meta-analysis specifically investigated how different routes of testosterone replacement administration (i.e. different testosterone preparations) affect blood testosterone and DHT levels, and how this in turn relates to cardiovascular adverse events.

Key Points

  • Meta-analysis of 35 RCTs and more than 3,700 patients receiving testosterone replacement therapy shows no cardiovascular risk among studies of various testosterone replacement therapy administration routes.
  • When properly dosed, there is no significant difference in the elevation of blood testosterone between intramuscular or transdermal testosterone preparations.
  • Transdermal testosterone preparations elevate blood DHT to a greater magnitude than intramuscular testosterone preparations, 5.46-fold and 2.20-fold, respectively.
  • Too high blood DHT levels have been shown to be associated with cardiovascular risk in observational studies. The optimal range of DHT seems to be around 45-70 ng/dL.

1 March 2015

Testosterone Deficiency - Prevalence and Treatment Rates

Testosterone Deficiency - Prevalence and Treatment Rates

Systematic Literature Review of the Epidemiology of Non-Genetic Forms of Hypogonadism in Adult Males. Victoria Zarotsky, Ming-Yi Huang, Wendy Carman, Abraham Morgentaler, Puneet Singhal, Donna Coffin, and T. H. Jones, Journal of Hormones 2014

Testosterone deficiency, also known as hypogonadism, is gaining recognition among both clinicians and the general population. This article summarizes the findings from a review on the prevalence of testosterone deficiency, as well as the proportion of hypogonadal men who are receiving testosterone treatment. While testosterone prescribing has increased lately, as you will find out here, the prevalence of testosterone deficiency far exceeds the prescribing rate; i.e. majority of men with low-T are still not being treated with testosterone therapy.

Key Points

Abbreviations: TT = total testosterone, FT = free testosterone

  • In population-based studies, the prevalence of hypogonadism in men aged 47-60 years ranges from 2.1% to 12.8%. The operational definition of hypogonadism used across studies varies considerably:

    • the Study of Health in Pomerania (SHIP, 1997–2001) (Germany)5 used the most liberal definition of hypogonadism (TT < 300 ng/dL, no symptom criteria) and reported the highest prevalence at 12.8%;
    • the European Male Aging Study (EMAS, 2003–2005) used the most stringent definition of symptomatic hypogonadism (TT < 317 ng/dL plus 3 specific symptoms of decreased frequency of morning erections, sexual thoughts, and erectile dysfunction) and reported the lowest prevalence at 2.1%.
    • the Massachusetts Male Aging Study (MMAS,1987–1989) defined hypogonadism as TT 200–400 ng/dL plus FT <8.91 ng/dL plus ≥3 symptoms, and reported a prevalence of 6% at baseline and 12% after a 10 year follow-up.
  • In community-based studies, cut-offs of TT ranging from <200 to <400 ng/dL, with and without low FT, and with and without symptoms, the prevalence of hypogonadism in men aged 54-76 years ranges from 9.5% to 31.2%.
  • In primary care/screening-based studies, the prevalence of hypogonadism in men aged 53-62 years ranges from 12% to 38.7%:

    • Using a cut-off for TT <300 ng/dL, prevalence was 19.3%, 19.8%, 24.1%, 24.2%, and 38.7%.
    • Adding symptoms as a criterion, the prevalence decreased from 24.1% to 12% and from 24.2% to 20.4%.
  • Clinical condition-based studies assessed prevalence of hypogonadism among patients with specific medical conditions. The prevalence of hypogonadism in men aged 53-62 years with morbidities ranges up to 78.8% and varies considerably by medical condition.

    • Hypogonadism occurs commonly among patients with obesity, type 2 diabetes, and/or the metabolic syndrome.
    • The prevalence of hypogonadism in obese patients was found to be 57.7% and 35.6%, using the cut-offs TT <317 ng/dL and FT <78 pg/ml, respectively. Another study using the cut-offs TT < 300 ng/dl or FT < 65 pg/ml found the prevalence in obese patients to be 78.8% and 51.5%, respectively.
    • The prevalence of hypogonadism in patients with type 2 diabetes ranges from 24.5% to 43% using the cut-off TT <10.4mmol/L (300 ng/dL). With the cut-off TT <12nmol/L (346 ng/dL), the prevalence is 45%.
    • Even after adjusting for age and BMI, the prevalence of subnormal FT levels (<50 pg/ml or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).
    • The prevalence of hypogonadism in patients with the metabolic syndrome ranges from 30 to 35%.
    • The prevalence of hypogonadism in patients with type 2 diabetes who are also obese or have the metabolic syndrome is 51% and 47%, respectively.
  • The prevalence of hypogonadism in men with erectile dysfunction is 7%, 23%, 33%, and 47% for testosterone levels of less than 200, less than 300, less than 346, and less than 400 ng/dL, respectively.
  • Prevalence of hypogonadism increases with age.
    An abrupt increase in hypogonadism prevalence occurred in men aged 45 to 50 yr.
    Using the cut-off < 300 ng/dL, hypogonadism prevalence in primary care patients has been reported to be 34% in men aged 45–54 yr, 40.2% in men aged 55–64 yr, 39.9% in men aged 65–74 yr, 45.5% in men aged 75–84 yr, and 50% in men aged 85 yr and older. Every 10-year increase in age confers a 17% increase in risk of hypogonadism.
  • Population-based (BACH, Boston Area Community Health) and clinical-based (HIM, Health In Men) studies report that only 10% to 12% of hypogonadal patients were receiving treatment for hypogonadism.

15 February 2015

Testosterone and Weight Loss - the Evidence

Testosterone and Weight Loss - the Evidence

Lowered testosterone in male obesity: mechanisms, morbidity and management. Ng Tang Fui M, Dupuis P, Grossmann M. Asian journal of andrology. 2014;16(2):223-231.

Testosterone and weight loss: the evidence. Traish AM. Current opinion in endocrinology, diabetes, and obesity. 2014;21(5):313-322.

Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F, Aversa A, Isidori AM, Gooren LJ. Current diabetes reviews. 2012;8(2):131-143.

The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. Saad F, Gooren LJ. Journal of obesity. 2011

It is well documented that obesity may cause hypogonadism, and that hypogonadism may cause obesity.1-4 This has generated debate about what condition comes first; obesity or hypogonadism? And what should be the first point of intervention?

In this editorial we summarize data from several reviews on the association of obesity and hypogonadism1-4, and make the case that obesity and hypogonadism create a self-perpetuating vicious circle. Once a vicious circle has been established, it doesn’t matter where one intervenes; one can either treat the obese condition or treat hypogonadism first. The critical issue is to break the vicious circle as soon as possible before irreversible health damage arises.

Nevertheless, as we will explain here, treating hypogonadism first may prove more effective in that it to a large extent “automatically” takes care of the excess body fat and metabolic derangements, and also confers psychological benefits that will help obese men become more physically active. Thereby, restoring testosterone levels in hypogonadal obese men will relatively quickly break the self-perpetuating vicious circle, and transform it into a “health promoting circle.”

Key Points

  • Non-obese men who become obese experience a decline of testosterone levels comparable to that of 10 years of aging.
  • Testosterone deficiency and obesity each contribute independently to a self-perpetuating vicious cycle. Long-term testosterone replacement therapy in men with hypogonadism improves body composition, metabolic syndrome components and quality of life, and thereby can help break the vicious cycle.
  • Treatment of hypogonadism with long-term testosterone replacement therapy, with or without lifestyle modifications, effectively treats obesity by correcting testosterone deficiency; one physiological root cause of obesity.
  • In contrast to the U-shaped curve for weight loss seen with traditional obesity treatments, which are characterized by weight loss and weight regain, treatment with testosterone replacement therapy results in a continuous reduction in obesity parameters (waist circumference, weight and BMI) for >5 years, or until metabolic abnormalities return to healthy ranges.
  • The significant effectiveness of testosterone replacement therapy in combating obesity in hypogonadal men remains largely unknown to doctors. Educational efforts are therefore critical to bring research findings into clinical practice in order to improve patient care and health outcomes.

1 February 2015

Adherence to testosterone therapy

Adherence to testosterone therapy

- short term treatment is not sufficient for achievement of maximal benefits

Long-term treatment patterns of testosterone replacement medications.
Donatucci C, Cui Z, Fang Y, Muram D. The journal of sexual medicine. Aug 2014;11(8):2092-2099.

Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis.
Schoenfeld MJ, Shortridge E, Cui Z, Muram D. The journal of sexual medicine. May 2013;10(5):1401-1409.

Testosterone therapy confers a wide range of health benefits for hypogonadal men, including improvements in body composition (reduction in body fat, increase in muscle mass, weight loss), lipid profile, cardiovascular function, insulin sensitivity/glucose metabolism, bone mineral density, inflammatory parameters, quality of life and potentially longevity.

Despite this, there is a high discontinuation rate with testosterone therapy. This editorial presents findings from two studies which have investigated adherence to testosterone therapy and treatment patterns.

Key Points

  • 66% of patients discontinued testosterone therapy with a topical gel after 2 months, and only 31% and 14% of patients remained on therapy for 6 months and 1 year, respectively.
  • The rates of testosterone therapy discontinuation are similar between men using topical testosterone formulations and short-acting testosterone injections.
  • A large proportion of patients stop and restart therapy every 2 to 3 months.
  • Majority of patients who begin testosterone therapy discontinue its use within 3 years.
  • Because continuous therapy over a longer period (years, if not indefinitely) is necessary to derive all the benefits of testosterone therapy, these low adherence rates mean that the majority of men who start testosterone therapy will not achieve maximum benefits from it.

15 January 2015

Testosterone thresholds and hypogonadal symptoms in young, middle-aged and elderly men

Testosterone thresholds and hypogonadal symptoms in young, middle-aged and elderly men

Hypogonadal symptoms are associated with different serum testosterone thresholds in middle-aged and elderly men. Ramasamy R, Wilken N, Scovell J, Kovac J, Lipshultz L. Urology 2014;84:1378–82.

Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. Scovell J, Ramasamy R, Wilken N, Kovac J, Lipshultz L. BJU Int 2014;doi:10.1111/bju.12970.

There are a number of symptoms associated with hypogonadism, categorised as sexual, psychological and physical symptoms. Two retrospective analyses of men who presented to the same outpatient men’s health clinic with a complaint of low testosterone (T) are summarised below. Both studies involved retrospective analysis of the charts of consecutive, T supplementation (TS) naïve men; aged 40–90 years (n=360), and those aged <40 years (n=352). All men had their T levels measured and completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire which assessed 10 hypogonadal symptoms.

Key Points

  • A retrospective analysis from a single US centre (between May 2013 and March 2014) involving TS naïve men presenting with symptoms of low T, aged 40–90 years (n=360; mean age 57.1±11.4 years; mean total T level 337.8±147.2 ng/dL) and <40 years (n=352; mean age 33.2±4.2 years; mean total T level 308±170 ng/dL)
  • In men aged 40–90 years, decreased libido, lack of energy, decrease in strength or endurance, falling asleep after dinner, and deterioration in the ability to play sports all exhibited significant differences (p<0.05) between men with serum T levels <300 ng/dL and >300 ng/dL
  • In men aged <40 years, the occurrence of feeling sad, lack of energy, decreased strength and endurance, deterioration in work performance, and a deterioration in the ability to play sports were significantly different (p<0.05) between men with serum T levels of <400 ng/dL and >400 ng/dL
  • In men aged 40–90 years there are unique T thresholds based on symptoms which are a better predictor of hypogonadism than a solitary predefined T level
  • Men aged 40–90 years exhibited an inverse relationship between symptom expression and serum T levels
  • For men aged <40 years, hypogonadal symptoms appear to be associated with a total serum T level of <400 ng/dL
  • In men of all ages, a lack of energy appears to be the most effective predictor of a total T level <400 ng/dL
  • Rather than a single predefined total serum T, different thresholds of T levels based on symptomatology are recommended

1 January 2015

Testosterone-boosting Medications and Cardiovascular Risk

Testosterone-boosting Medications and Cardiovascular Risk

- a systematic review and meta-analysis

Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Corona G, Maseroli E, Rastrelli G, et al. Expert opinion on drug safety. Oct 2014;13(10):1327-1351.

Accumulating evidence shows beneficial effects of testosterone therapy on a wide range of health outcomes, including inflammation, insulin sensitivity, muscle mass, body fat mass, lipid profiles, endothelial function, bone mineral density, energy and vitality, mood, sexual function and overall quality of life. Despite this, concerns have been raised that testosterone therapy could have detrimental effects on cardiovascular disease.

This editorial summarizes results from a comprehensive systematic review and meta-analysis, the largest to date, of all placebo-controlled randomized clinical trials (RCTs) on the effect of testosterone therapy on cardiovascular-related problems.

Key Points

  • Meta-analysis of the largest number of studies collected so far, concludes that testosterone therapy is not related to any increase in cardiovascular risk, and that data do not support a causal role between testosterone therapy and cardiovascular events.
  • Testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.
  • The principal outcome of this analysis was the effect of testosterone therapy, as compared with placebo, on the incidence of new major adverse cardiovascular events (MACE). This was done to comply with requirements for drug safety assessment, as required by regulatory agencies.
  • In studies performed in subjects with metabolic derangements a protective effect of testosterone therapy on cardiovascular risk was observed.
  • No sponsorship bias was detected, because no difference in MACE risk was found when the analysis was performed according to the presence or absence of drug company financing.

15 December 2014

Late onset hypogonadism of men is not equivalent to menopause

Late onset hypogonadism of men is not equivalent to menopause
Late onset hypogonadism of men is not equivalent to menopause
Saad F, Gooren LJ. Maturitas. 2014 Sep;79(1):52-7.

In their review paper, Saad and Gooren elegantly contrast the differences between late onset hypogonadism, also known as testosterone deficiency, and menopause. Many men who reach middle-age start to experience symptoms that resemble those of menopause; reduced libido, lack of energy, weight gain, fatigue, depression and osteoporosis, to name a few.

Therefore these conditions are frequently seen as being equivalent, and late onset hypogonadism has therefore been called "andropause", "male climacteric", "male menopause" or "MANopause. However, as Saad and Gooren correctly point out, this is very misleading.

Key Points

For several reasons, hypogonadism in men and menopause cannot be equated:

  • Menopause is universal and obvious and develops relatively rapidly.

    • Hypogonadism does not affect every man, and when it does, it develops slowly over a long time period.
  • The hormones involved are different.

    • Estrogen and testosterone have contrasting effects on most physiological functions.
  • Treatment vs. non-treatment has vastly different consequences.

    • Reduced levels of testosterone in men contribute to the development of cardiovascular disease, and may, despite long-held beliefs to the opposite, have a negative impact on the prostate. It is also well documented that hypogonadism increases mortality and that testosterone therapy may reduce mortality and may even increase longevity.
    • The consequences of reduced levels of estrogen in postmenopausal women are less well-documented, and treatment with estrogen (hormone replacement therapy, HRT) likely confers a different risk-benefit ratio than treatment of hypogonadism with testosterone therapy.

3 December 2014

Testosterone therapy in male sexual function

Testosterone therapy in male sexual function
Testosterone Therapy and Sexual Function: A Meta-Analysis Study
Corona G, Isidori A, Buvat J, et al. J Sex Med 2014;11:1577–92.


Male sexual dysfunction is a common occurrence in clinical practice, especially in hypogonadal patients, however it is often untreated or undiagnosed. This summary is based on a meta-analysis of 41 studies that compared testosterone therapy with placebo or as add-on therapy to phosphodiesterase type 5 inhibitors (PDE5i), and aimed to evaluate the role of testosterone therapy in male sexual function where previous meta-analyses have produced conflicting results. Based on an extensive search of the Medline, Embase, and Cochrane databases, 1,702 studies were identified and 41 met the criteria for this analysis.

Key Points

  • This meta-analysis (which included the largest number of studies so far) was performed to more clearly understand the effects of testosterone therapy on male sexual dysfunction, as prior meta-analyses have yielded conflicting results
  • 41 studies were included that compared the effects of testosterone therapy with placebo (29 studies), or testosterone therapy as add-on to PDE5i (12 studies) on male sexual function
  • Mean follow-up for studies analysing TS with placebo was 27 weeks. 5 trials evaluated testosterone therapy in eugonadal patients, 5 in a mixed population of hypogonadal/eugonadal patients, and 19 in hypogonadal patients
  • Compared with placebo, testosterone therapy significantly improved overall erectile function (EF) and improved other aspects of male sexual response
  • Testosterone therapy was not associated with any increase in cardiovascular diseases compared with placebo; whilst hematocrit levels increased, there was no increase in the risk of pathological hematocrit levels compared with placebo
  • Overall, the lower testosterone levels at baseline, the more pronounced the beneficial effect of testosterone therapy
  • In 894 patients who were treated with testosterone therapy as add-on to PDE5i (mean follow-up of 12 weeks), a positive effect of T was found in non-placebo-controlled trials (effect size 2.96 [95% CI, 1.28–4.64]) but not in placebo-controlled trials
  • Well-designed studies with large study populations (many of which are industry sponsored) are most likely to produce robust clinical data and are more likely to be published than smaller independent studies

29 November 2014

Testosterone and Cardiovascular Risk in Men

Testosterone and Cardiovascular Risk in Men
Kelly D.M., Jones T.H. In: Granata R, Isgaard J (eds): Cardiovascular Issues in Endocrinology. Front Horm Res. Basel, Karger, 2014, vol 43, pp 1–20

Hypogonadism, also known as testosterone deficiency, is increasing in prevalence worldwide. While a rapidly expanding body of research is documenting the detrimental health consequences of hypogonadism, at the same time there is a prevailing concern and misunderstanding about the effects of testosterone therapy on cardiovascular risk.

This editorial presents a summary of a recently published comprehensive review on the association of hypogonadism and cardiovascular risk factors, and the effect of testosterone therapy on those risk factors.

27 October 2014

Efficacy and safety of injectable TU for the treatment of hypogonadism

Nebido products

Drug Evaluation: Injectable testosterone undecanoate for the treatment of hypogonadism Corona G, Maseroli E, Maggi M; Expert Opin. Pharmacother 2014;15(13):1903-1926

Since its approval in 2004, many clinical studies have been conducted with testosterone undecanoate, the first long-acting injectable form of testosterone. Testosterone undecanoate has been proven to have an excellent safety profile and need only be administered four times annually to produce stable testosterone levels. Long-term studies have validated the clinical efficacy of testosterone undecanoate in maintaining stable therapeutic levels of testosterone and safely conferring the desired benefits of androgen replacement.

Here we summarize the results from a comprehensive meta-analysis of all uncontrolled and placebo-controlled randomized clinical trials (RCTs) demonstrating the effect of injectable testosterone undecanoate on multiple clinical outcomes.



Key Points

  • Injectable testosterone undecanoate is a long-acting testosterone formulation that has been available in EU for the treatment of male hypogonadism since 2003.
  • A meta-analysis of 33 intervention studies, of which 11 were randomized controlled trials (RCTs), using injectable testosterone undecanoate for treatment of hypogonadism, found the following main significant effects after a mean study duration of 34.1 months (2.8 years) in men with a mean age of 56.8 years:

    • reduction of BMI and body weight (mean weight loss; 5.88 kg, range 2.64-9.11 kg)
    • reduction of waist circumference (mean waist loss; -7.11 cm, range -4.64 to -9.59 cm)
    • reduction in fat mass; mean fat loss of -4.56% (range 3.36% to -5.76%)
    • reduction of fasting glucose (mean -0.51 mmol/L, range -0.27 to 0.75)
    • reduction of HbA1c levels (mean -0.68%, range -0.32% to -1,04%), and improvement of insulin resistance (measured by HOMA index)
    • reduction of total cholesterol (mean -0.89 mmol/L, range -0.60 to -1.19 mmol/L)
    • reduction of triglyceride levels (mean -0.44 mmol/L, range -0.24 to -0.63 mmol/L)
    • increase in HDL levels (mean +0.15 mmol/L, range +0.08 to +0.23 mmol/L)
    • reductions in systolic and diastolic blood pressure of 10 mmHg and 7 mmHg, respectively.
    • improvement in sexual function, International Prostate Symptom Score (IPSS), bone mineral density and depressive symptoms.
  • Testosterone undecanoate treatment is well tolerated and no increased risk of prostate cancer or cardiovascular disease was observed, and has a more favorable pharmacokinetic and safety profile than older short-acting testosterone formulations.
  • Figure 1 provides a summary of the main effects of testosterone undecanoate treatment:

27 October 2014

Treatment with testosterone improves cardiovascular risk factors in obese hypogonadal men, with or without type 2 diabetes mellitus

Treatment with testosterone improves cardiovascular risk factors in obese hypogonadal men

Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study
Haider A, Saad F, Doros G, and Gooren L. Obesity Research & Clinical Practice 2014;8:e339–49

Obesity is a well-known risk factor for the development of cardiovascular disorders. Globally, obese patients have a higher risk of morbidity and mortality; risk of type 2 diabetes, cardiovascular mortality, and premature death is increased by ~30% in obese patients. In addition, obesity leads to a decrease in serum testosterone and vice versa. This summary discusses the effects of normalising testosterone levels in obese hypogonadal men, with and without type 2 diabetes mellitus (T2DM). Based on a registry of 255 hypogonadal men this was a long-term observational analysis of a subgroup of obese men (n=181).

Key Points

  • In a prospective, observational, long-term study, 181 obese (BMI ≥30kg/m2) hypogonadal men, with and without type 2 diabetes mellitus (T2DM), were treated with testosterone undecanoate (TU) over 5 years. 40% (72 patients) also had T2DM
  • After 5 years treatment with TU, there were significant anthropometric improvements with all patients having lost weight (mean reduction 18.86±0.36 kg), mean waist circumference decreased by 8.87% and BMI reduced by 16.44%

    • There were similar reductions in anthropometric parameters in the diabetic subgroup. Mean body weight and BMI decreased by 15.97%, waist circumference decreased by 10.31 cm
  • In the total study population there was an improvement in all cardiovascular risk factors and metabolic state. Significant improvements were seen in lipid profile, blood pressure, fasting glucose, HbA1c and liver function

    • In the diabetic subgroup there were significant improvements in fasting glucose and HbA1c with comparatively greater decreases seen in the diabetic subgroup than in the general population. Fasting glucose decreased by 1.35 mmol/L and HbA1c decreased by 2.01%
  • Treatment with TU was well tolerated. Increases in both haemoglobin (3.37%) and haematocrit (5.32%) remained within the normal range. Both parameters reached a plateau after 3 years of treatment with minor fluctuations thereafter
  • Prostate volume increased slightly (<10%) over three years then stabilised, and mean prostate specific antigen increased over the 5 years by 0.18 ng/dL

5 September 2014

Effects of testosterone replacement therapy in men with hypogonadism

Alleged concerns regarding risk of cardiovascular disease with testosterone replacement therapy have been promulgated recently. However, a large and growing number of intervention studies show to the contrary that testosterone therapy reduces cardiovascular risk factors and confers multiple beneficial health effects. Thus, fears promoted by some recent flawed studies need to be critically re-evaluated.

This summary gives an overview of a comprehensive review of studies that have investigated health effects and safety of testosterone therapy. As outlined here, the position that hypogonadism (also known as testosterone deficiency) should be regarded as a risk factor for cardiovascular disease is supported by a rapidly expanding body of evidence.



Key Points

  • Testosterone therapy has beneficial effects on body composition:

    • Increased muscle mass
    • Reduced visceral fat mass
    • Reduced total body fat mass
  • Testosterone therapy has beneficial effects on lipid profile:

    • Reduced Total cholesterol (TC)
    • Reduced LDL cholesterol
    • Reduced triglycerides (TGs)
    • Increased HDL levels
  • Testosterone therapy has beneficial effects on cardiovascular function:

    • Reduced arterial stiffness
    • Reduced CIMT (carotid intima media thickness)
    • Reduced blood pressure
  • Testosterone therapy has beneficial effects on glucose metabolism, which reduce risk of diabetes:

    • Increased insulin sensitivity
    • Reduced glucose levels
    • Reduced HbA1c levels
  • Testosterone therapy has beneficial effects on inflammatory parameters:

    • Decreased levels of liver enzymes
    • Decreased CRP levels
    • Reduction in inflammatory cytokines
  • Testosterone therapy has beneficial effects on longevity:

    • Reduced risk of mortality and improved survival
  • Testosterone therapy has beneficial effects on sexual function:

    • Increased libido, improved erectile function and ejaculatory function
  • Testosterone therapy has beneficial effects on quality of life:

    • Less fatigue and improvement in energy, mood, vitality
  • This review in addition highlights results from multiple long-term registry studies which demonstrate the following key results:

    • Testosterone therapy effectively restores physiological testosterone levels within the first 12 months and these restored testosterone levels are maintained with testosterone therapy throughout the entire study period, which at this point is up to 6 years.
    • Long-term testosterone therapy results in a marked and sustained reduction in body weight and waist circumference (figure 1), BMI, CRP, HbA1c and improves the lipid profile by reducing total cholesterol, LDL and triglycerides while increasing HDL.
    • It is especially notable that the long-term reductions in body weight, waist circumference and HbA1c keep progressing throughout 5 years, and further improve after each year of testosterone therapy.
  • Safety of TRT

    • The most common side effects of testosterone therapy are increases in hematocrit and PSA. However, these elevations occur within the first 12 months, and thereafter remain stable with continued testosterone therapy for up to 5 years. This corroborates findings from a previous 3 year-long study which demonstrated that elevations (within the reference range) of hemacocrit and PSA plateau at 12 months and 6 months respectively, after initiation of testosterone therapy.
    • 5 years of testosterone therapy also does not change the International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate, post-void residual (PVR) volume, or prostate size.Thus, long-term testosterone therapy does not impact negatively on lower urinary tract symptoms (LUTS) and prostate volume.

5 September 2014

Long-term testosterone therapy is associated with a reduction in obesity parameters, improved metabolic syndrome and health-related quality of life in men with hypogonadism

Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Yassin AA, Doros G. Clinical Obesity 2013;3:73–83.

Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. Yassin DJ, Doros G, Hammerer PG, et al. J Sex Med 2014;11:1567–76.

This editorial summarises two papers based on the same observational study of 261 hypogonadal men: the first focused specifically on obesity and assessed the long-term effects of normalising testosterone (T) levels on obesity parameters. The second paper focused on parameters associated with the metabolic syndrome (MetS) as well as obesity measures.

Hypogonadism is associated with several clinical symptoms, including increased adiposity, reduced muscle mass, reduced bone density, obesity, diabetes, and erectile dysfunction (ED). Diabetes and obesity are of particular concern as they are well known risk factors for cardiovascular disorders. Although, several studies have found that treatment with T can ameliorate these symptoms, it is not known if these improvements can be sustained in the long-term. The studies summarised in this editorial investigated the long-term effects of testosterone undecanoate (TU) on a number of these symptoms.

Both papers analysed the same registry of 261 hypogonadal men (aged 59.5 ± 8.4 years), all of whom had sought treatment for ED at a single urologist’s office. Patients received parenteral TU 1000 mg at baseline, week 6 and every 12 weeks thereafter for up to 5 years. All 261 patients were followed for ≥1 year, 260 patients for 2 years, 237 for 3 years, 195 for 4 years and 163 for 5 years. Adherence to treatment was excellent and the decline in patient numbers each year represented duration of treatment rather than drop-out rates.

The first paper measured anthropometric parameters. Patient height, body weight, body mass index (BMI) and waist circumference (WC) were measured at baseline, and weight, BMI and WC were measured at least once a year. Blood samples were taken prior to the next TU injection, consequently this meant that T levels measured were trough levels.

The second paper also measured (at baseline and at every visit) body weight, WC and BMI as well as parameters associated with the MetS; total cholesterol, LDL, HDL, triglycerides, glucose, HbA1c (glycated hemoglobin), blood pressure (BP) and total T concentrations.



Key Points

  • In an unselected cohort of hypogonadal men presenting with ED to a single urologist’s office, only 4% were of normal weight, 34% were overweight, and 62% were obese

    • Only 3% had a normal WC (≤94 cm), 28% had an increased waist size (94–101.9 cm), and 69% had a substantially increased waist size (≥102 cm)
  • At the end of the observation period (maximum 5 years) 96% of men had lost weight (mean loss 11.1 kg)

    • 98% of men showed a reduction in WC with a mean decrease of 9.4 cm
  • In the obese subgroup (n=162), mean weight loss was 12.8 kg and mean reduction in WC was 10.5 cm
  • MetS parameters were measured in the same overall cohort:

    • Lipid pattern improved with substantial and sustained reductions in total cholesterol, LDL and triglycerides, and an increase in HDL
    • The total cholesterol to HDL ratio, a cardiovascular risk marker, declined from 6.84 to 4.09 over the course of the study
    • Fasting glucose and HbA1c decreased suggesting improved glycemic control
    • Both systolic and diastolic BP decreased significantly
  • Long-term health-related quality of life was improved by TU treatment resulting from contributions of sustained improvements in erectile function (p<0.0001) and muscle and joint pain
  • No increased risk of prostate cancer was observed; prostate cancer was seen in only 2.3% of TU treated hypogonadal men

19 August 2014

Testosterone Treatment and Heart Attack Risk

Testosterone Treatment and Heart Attack Risk

- New study shows testosterone treatment can even be beneficial

Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Baillargeon, J., et al., Ann Pharmacother 1060028014539918, first published on July 2, 2014 as doi:10.1177/1060028014539918, 2014

Testosterone therapy has been in use for more than 70 years for the treatment of hypogonadism, also called testosterone deficiency. In the past 30 years there has been a growing body of scientific research demonstrating that testosterone deficiency is associated with increased body weight/adiposity/waist circumference, insulin resistance, type 2 diabetes, hypertension, inflammation, atherosclerosis and cardiovascular disease, erectile dysfunction (ED) and increased risk of mortality. In line with the detrimental health outcomes seen with testosterone deficiency, testosterone therapy has been shown to confer beneficial effects on multiple risk factors and risk biomarkers related to these clinical conditions.

Despite these well-documented health benefits, testosterone therapy is still controversial, in large part due to a few flawed studies about potential elevated myocardial infarction (MI) risk with testosterone therapy. On July 2, 2014, a study was published which demonstrated that testosterone therapy is not associated with an increased risk of MI, and may actually confer protection against MI.



Key Points

  • Testosterone deficiency is associated with increased body weight/adiposity/waist circumference, insulin resistance, type 2 diabetes, hypertension, inflammation, atherosclerosis and cardiovascular disease, erectile dysfunction (ED) and increased risk of mortality.
  • Testosterone therapy beneficially impacts multiple risk factors and risk biomarkers related to highly prevalent clinical conditions that are associated with testosterone deficiency.
  • The most recent study reported in this editorial demonstrates that testosterone therapy does not increase risk of MI, and that it actually may protect against MI in high-risk population. This is in line with a large body of research showing beneficial effects of testosterone therapy in hypogonadal men.
  • Three large meta-analyses specifically focusing on identifying potential adverse effects of testosterone treatment report no significant increases in cardiovascular risk.
  • A review of all testosterone trials up to 2012 found that testosterone therapy in patients with preexisting cardiovascular conditions, the effect on disease markers has typically been either neutral or beneficial, and does not increase the incidence of cardiovascular events.

19 August 2014

Adverse health effects of testosterone deficiency in men

Adverse health effects of testosterone deficiency in men

Adverse health effects of testosterone deficiency (TD) in men.
Traish AM. Steroids. 2014 Jun 2. pii: S0039-128X(14)00122-6. doi: 10.1016/j.steroids.2014.05.010. [Epub ahead of print]

Testosterone deficiency, also known as hypogonadism, is a state with sub-optimal circulating levels of testosterone concomitant with clinical signs and symptoms attributed to low physiological testosterone levels.

Sexual dysfunction is the most commonly recognized symptom of testosterone deficiency. However, testosterone also plays a broader role in men's health. A growing body of evidence has established associations between low testosterone levels and multiple risk factors and diseases including the metabolic syndrome, obesity, type 2 diabetes, sarcopenia, frailty, mobility limitations, osteoporosis, cognitive impairment, depression, cardiovascular disease, and reduced longevity.

This summary gives an overview of a comprehensive review of studies that have investigated the detrimental impact of testosterone deficiency on a wide range of health outcomes.

14 July 2014

Testosterone treatment in men with osteoporosis and subnormal serum testosterone levels

Testosterone treatment in men with osteoporosis and subnormal serum testosterone levels

Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. Haider A, Meergans U, Traish A, et al. Int J Endocrinol 2014; Article ID: 496948

Testosterone treatment can have a beneficial effect on bone loss resulting from testosterone deficiency. This summary discusses the key findings from a long-term, observational, open-label, prospective, cumulative, registry study that investigated the use of parenteral testosterone undecanoate (TU) 1,000 mg/12 weeks in hypogonadal men with osteoporosis. Bone mineral density (BMD), expressed as a T-score in 45 men (mean age 53 ± 7 years) was measured over the six year period of TU treatment.



Key Points

  • This is the first long-term (6-year follow-up) study of men with osteoporosis treated with testosterone undecanoate (TU) 1,000 mg
  • In total, 45 men with osteoporosis and diagnosed with testosterone deficiency, aged between 40–68 years, were investigated
  • Most patients had been referred by an orthopedic clinic where serum testosterone levels were routinely monitored in patients with osteoporosis, especially in relatively young men
  • Many of the patients in this study were subsequently diagnosed with Klinefelter’s syndrome which had previously been undiagnosed
  • Other underlying causes of osteoporosis in patients included in this study were other forms of primary hypogonadism, alcohol abuse and Crohn’s disease
  • TU significantly and progressively improved bone mineral density (BMD) over 6 years
  • BMD, expressed as T-score measurements of the spine (L2–4) and femoral neck, significantly improved over 6 years compared with baseline and each year compared with the previous year (p<0.0001)
  • At the end of the observation time, patients were reclassified as having osteopenia rather than osteoporosis
  • Measures of blood pressure, metabolic parameters and levels of inflammatory biomarkers were significantly improved after 6 years

14 July 2014

Effects of testosterone deficiency on body composition, strength and sexual function in men, and the tolerability of long-acting testosterone undecanoate in daily clinical practice

Effects of testosterone deficiency on body composition, strength and sexual function in men, and the tolerability of long-acting testosterone undecanoate in daily clinical practice

Gonadal steroids and body composition, strength, and sexual function in men. Finkelstein JS, Lee H, Burnett-Bowie S-A, et al. N Engl J Med 2013;369:1011−22.

IPASS: A study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Zitzmann M, Mattern A, Hanisch J, et al. J Sex Med 2013;10:579−88.

This editorial includes summaries of two studies: the first is an experimental study in men looking at the effects of testosterone deficiency on body composition, strength and sexual function; the second is a post-observational surveillance study (IPASS) investigating the tolerability of long-acting testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting.

The classification of low testosterone levels – at least 2 standard deviations below the mean value for healthy young adults – does not take into account the physiological consequences of various testosterone levels. In particular the implications of the concomitant decline in serum levels of estradiol, a metabolite of testosterone, are generally not considered. This summary describes the results from an experimental study in two cohorts of healthy men, both of whom received goserelin acetate to suppress endogenous testosterone and estradiol (Cohort 1; n=198; Cohort 2; n=202). Participants were randomly assigned to receive placebo, 1.25 g, 2.5 g, 5 g or 10 g of testosterone gel daily for 16 weeks. In order to differentiate between the effects of testosterone and estradiol, participants in Cohort 2 also received anastrozole 1 mg daily, an aromatase inhibitor, to block the conversion of testosterone to estradiol. The primary outcome variables were changes in percentage of body fat and total-body lean mass. Changes in subcutaneous- and intraabdominal-fat areas, thigh-muscle area and leg-press strength, and sexual function were also assessed.

The prospective, observational IPASS was conducted in 23 countries in Europe, Asia, Latin America, and Australia and investigated the safety and efficacy of intramuscular injections of TU in men with hypogonadism in a “real-life setting”.
A total of 1493 men (age 49.2 ± 13.9 years; 72.5% Caucasian) with hypogonadism were enrolled into the study to receive up to five injections of TU over an observation period of 9–12 months. The first and second injections were given at intervals of 6–10 weeks, and subsequent injections at intervals of 12 ± 2 weeks. Patients subjectively assessed the intensity of hypogonadism-related symptoms at each study visit, and at the end of the treatment period gave a rating of overall tolerability. Laboratory measurements, including prostate-specific antigen (PSA), hemoglobin, hematocrit, and lipid profiles, as well as digital rectal examination were also assessed at each study visit. At baseline and the time of the fifth injection a total of 1438 and 1140 men were evaluable, respectively. At baseline, body weight was 86.8 ± 17.6 kg, waist circumference 99.5 ± 15.25 cm and serum testosterone 9.6 ± 7.5 nmol/L.The summary of this study reports the results for the safety, anthropometric and sexual function measurements.



Key Points

  • The randomized controlled study showed that there is considerable variation in the dose of testosterone required to prevent adverse changes in body composition, strength and sexual function

    • Only the highest dose of testosterone (10 g) achieved levels sufficient to reduce body fat
  • In this experimental study, administration of an aromatase inhibitor allowed the effects of testosterone and estrogen to be distinguished

    • Decreases in total-body lean mass, thigh-muscle area and leg-press strength were attributed to testosterone deficiency
    • Estrogen deficiency played a role in the increases in body fat
  • Both testosterone and estradiol are needed for maintenance of normal sexual function
  • Interpretation and treatment of hypogonadism in men should be individualized
  • In IPASS, TU was well tolerated in men with hypogonadism, and ADRs were rare (5.8%)
  • Increases in hematocrit and PSA, and injection site pain were the most common ADRs occurring in <1% of patients
  • Treatment-related ADRs lead to discontinuation in 31 men
  • Marked improvements in overall levels of sexual desire/libido were observed with TU
  • At the fifth injection of TU there was a significant decrease in waist circumference (p≤0.003), and a slight decrease in body weight

27 June 2014

Testosterone and Prostate Cancer - a paradigm shift

Testosterone and Prostate Cancer - a paradigm shift

"Bye-bye Androgen Hypothesis, Welcome Saturation Model"

A new era of testosterone and prostate cancer: from physiology to clinical implications. Khera M, Crawford D, Morales A, et al., Eur Urol 2014; 65(1): 115-23.

A long-held belief is that testosterone stimulates development of prostate cancer (PCa) and/or accelerates its growth. This summary gives an overview of an in-depth review of current literature regarding the relationship of serum testosterone and PCa and the effect of testosterone replacement therapy (TRT) on PCa progression and recurrence. Key studies which have refuted the old belief that testosterone has harmful effects on the prostate are presented, along the new testosterone-prostate paradigm known as the saturation model.



Key Points

  • The longstanding concerns regarding putative detrimental effects of testosterone and TRT on PCa, known as the \"androgen hypothesis\", stem from several observations;

    • dependence of the prostate on androgens for normal development and function;
    • beneficial response to androgen-deprivation therapy (ADT) in men with advanced or metastatic PCa;
    • historical reports of rapid PCa progression in men who received testosterone administration;
    • dramatic prostate specific antigen (PSA) declines in men with PCa who undergo ADT;
    • reduction in PSA and prostate volume in men with benign prostatic hyperplasia treated with 5alpha-reductase (5-AR) inhibitors;
    • parallel rise in PSA and serum testosterone upon cessation of luteinizing hormone-releasing hormone (LH-RH) agonists (medications that lower the endogenous production of testosterone).
  • The androgen hypothesis arose from two small studies in the 1940s in which men with metastatic PCa demonstrated clinical and biochemical improvement with androgen deprivation via castration, and rapid PCa progression with testosterone administration. However, these observations were made in a special population (castrated men) and are therefore not relevant to TRT in hypogonadal men.
  • The \"saturation model\" explains the paradoxical observations that prostate tissue is exquisitely sensitive to changes in serum testosterone at low concentrations but becomes indifferent to changes at higher testosterone concentrations.
  • A threshold effect occurs in which increasing androgen concentrations reach a limit (the saturation point) beyond which there is no further ability to induce androgen-driven changes in prostate tissue growth.
  • A mechanism contributing to the saturation model is the finite ability of androgens to bind to the androgen receptor (AR).

    Maximal androgen–AR binding (i.e., saturation) occurs at fairly low androgen levels. It has been established in clinical practice that the saturation point appears to be around 8 nmol/L (230 ng/dL), subject to inter-individual variation.
  • The saturation model explains the following important clinical observations:

    • A comprehensive analysis of pooled worldwide epidemiologic data from 18 prospective studies, comprising a study population of 3886 men with PCa and 6438 age-matched controls, found no relationship between PCa risk and serum concentrations of testosterone, calculated free testosterone or DHT.
    • Two meta-analyses of TRT intervention studies, which specifically focused on analyzing potential adverse effects of testosterone therapy, did not find any significant differences in prostate outcomes between TRT vs. placebo treated men.
    • In the UK Androgen Study, 1365 men 28–87 yr of age (mean 55) received testosterone therapy for up to 20 yr, with PSA and digital rectal examination (DRE) performed every 6month. 14 new cases of PCa, all localized, were detected after 1–12 years (mean 6.3 years). However, this PCa is the same as in a general population which has never been treated with testosterone. Initiating testosterone treatment had no statistically significant effect on total PSA, free PSA or free/total PSA ratio, and any initial PSA change had no predictive relationship to subsequent diagnosis of cancer.
    • In a study on transdermal testosterone patch use for up to 6 years, PSA increased at 3 months from 0.47 to 0.60 ng/ml, followed by negligible change in PSA (0.03 ng/ml per year) over the remaining 5 yr. No PCa was identified in this trial.
  • The current ISA, ISSAM, EAU, EAA, ASA guidelines state:

    • There is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia.
    • There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer.
  • Provocative new research evidence suggests that it is not high serum T that is problematic for PCa, but to the contrary that it is low serum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, positive biopsy, and increased risk of biochemical recurrence after surgery. Patients with PCa and lower testosterone levels have undesirable prognosis factors and higher tumor burden before treatment onset. These findings reinforce the idea that low testosterone levels pretreatment are related to a poor prognosis in PCa.
  • New experimental research has uncovered mechanisms that explain why low serum T may be detrimental for prostate health, and support the view that TRT actually may have beneficial effects with regard to PCa. Specifically, androgens promote less aggressive PCa phenotypes and inhibit dedifferentiation (i.e. metastasis) in some PCa cell lines.

6 May 2014

Testosterone replacement therapy and its withdrawal in hypogonadal men with severe obesity

Big guy sweating on the bike

Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. Francomano D, Bruzziches R, Barbaro G, et al. J Endocrinol Invest 2014; [Epub ahead of print]

Obesity is a chronic, worldwide health problem that has serious economic and social consequences. This summary discusses the results of an observational, open-label, parallel-arm study that investigated the cardiometabolic effects of diet and physical exercise (DPE) with or without testosterone undecanoate (TU) 1,000 mg/12 weeks for 54 weeks in 24 hypogonadal men with severe obesity (mean age, 54 ± 8 years; total testosterone level, <12 nmol/L; mean BMI, 42 kg/m2). A 24-week extension period of DPE alone investigated the effects of withdrawal of TU from treatment. The DPE program consisted of a personalized hypocaloric diet and requirement to complete ≥150 min/week of aerobic exercise of moderate intensity and/or ≥90 min/week of vigorous exercise.



Key Points

  • Testosterone undecanoate (TU) + diet and physical exercise (DPE) improved hormonal and cardiometabolic parameters at 54 weeks in hypogonadal men with severe obesity, but improvements were not maintained following withdrawal of TU for 24 weeks
  • This is the second study to demonstrate the added benefit of testosterone treatment to DPE
  • This is the second study to show that testosterone + DPE resulted in significant and persistent improvements in body composition, weight loss, and reductions in all metabolic syndrome parameters at 54 weeks

    • Lean mass (p<0.0001) and fat mass (p<0.01) were improved only in the DPE + TU group, but were lost after withdrawal of TU for lean mass only
    • DPE + TU improved glycemia, basal and peak insulin serum levels, total and LDL cholesterol, and both systolic and diastolic blood pressure, and significance was maintained after withdrawal of TU (all p<0.01)
  • Epicardial fat, a measure of cardiovascular performance, was significantly reduced in the DPE + TU group (p<0.01) but not in the group without TU treatment; however, improvements were not maintained following withdrawal of TU
  • This is the first study to show that DPE + TU improved surrogate markers of endothelial function, measured using the Endopat2000 device; however, such improvements were lost following TU withdrawal

    • Significant improvements in T/B ratio and CIMT were achieved only in the DPE + TU group (both p<0.01) at 54 weeks
    • Only patients treated with DPE + TU showed a significant reduction of overall cardiovascular risk (p<0.01)

9 April 2014

The role of testosterone in cardiovascular health

Capsules and medical form

Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Mesbah Oskui P, French W, Herring M, et al. J Am Heart Assoc 2013; 2: e000272

This summary gives an overview of a comprehensive review of studies that have examined the association between testosterone levels and cardiovascular health. The review focuses on the role of testosterone in cardiovascular diseases, including the incidence of coronary artery disease (CAD), congestive heart failure (CHF), and heart-rate-corrected QT (QTc) length prolongation. The role of testosterone on risk factors for atherosclerosis, including type 2 diabetes mellitus (T2DM), obesity, and inflammation, are also reviewed. Findings from studies that investigated the use of testosterone replacement therapy (TRT) on cardiovascular diseases in men with testosterone deficiency (TD) are summarized and possible mechanisms of action (MoA) for testosterone with respect to these outcomes are discussed.



Key Points

  • Testosterone levels are inversely associated with severity of CAD and CHF

    • TRT improved several components of CAD, including myocardial ischemia, vasodilation, and coronary artery blood flow, possibly through interaction with potassium and calcium channels, or modulation of nitric oxide release
    • TRT improved predictors of exercise capacity (6-minute walk test, isometric walk test, peak VO2), a fundamental feature of CHF
  • The risk of developing T2DM, a major risk factor for atherosclerosis, significantly decreases with higher endogenous total testosterone levels

    • Measures of T2DM, such as HbA1c, HOMA-IR and fasting plasma glucose, are improved following TRT in hypogonadal men with diabetes
  • Total testosterone levels are inversely related to BMI, a risk factor for atherosclerosis

    • TRT has been shown to improve obesity, with significant reductions in BMI (–1.3 kg/m2 at 30 weeks) and fat mass (–2.19%)
    • This may be achieved through increased lipolysis and decreased fat accumulation in visceral adipose tissue
  • Testosterone may exert protective effects against cardiovascular events such as atherosclerosis by suppressing the systemic inflammatory response and leukocyte activation in the vasculature

    • In-vitro studies suggest that the mechanism of action of testosterone may be via androgen or estrogen receptors, or via a mechanism that is independent of these receptors
  • Testosterone levels are significantly negatively associated with QTc length, a marker of CAD

    • TRT may reduce QTc length and regulate ventricular polarization by interacting with potassium and L-type calcium channels

7 March 2014

Testosterone treatment in obese hypogonadal men with type 2 diabetes

Testosterone treatment in obese hypogonadal men with type 2 diabetes

Effects of long-term testosterone therapy on patients with “diabesity”: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Haider A, Yassin A, Doros G, et al. Int J Endocrinol 2014; [Epub ahead of print]

Obesity is a chronic disease of increasing concern in developing and developed countries. It is associated with many comorbidities, including insulin resistance, type 2 diabetes mellitus (T2DM), and hypogonadism (testosterone deficiency [TD]). Patients who present with obesity and T2DM, termed “diabesity”, have an increased risk of cardiovascular disease (CVD). This summary discusses the key findings from a report using pooled data from two long-term, observational, prospective, cumulative registry studies to investigate the use of parenteral testosterone undecanoate (TU) 1,000 mg in obese hypogonadal men with T2DM.



Key Points

  • Treatment with testosterone undecanoate (TU) 1,000 mg was followed for up to 6 years, the longest follow-up period to date.
  • In total, 156 obese (BMI ≥30 kg/m2) hypogonadal men with T2DM and dyslipidemia, aged between 41–73 years, were investigated
  • TU significantly and progressively improved anthropometric parameters of obesity over 6 years

    • Waist circumference (p<0.0001), actual body weight (p=0.001), percentage body weight change (p<0.0001), and BMI (p<0.0001) were improved over 6 years compared with baseline and each year compared to previous year
  • TU progressively and significantly decreased levels of HbA1c by a mean of 1.93 ± 0.06% over 6 years (p<0.0001) and each year compared to previous year
  • Measures of BP, lipid profiles, liver enzymes, and levels of inflammatory biomarkers were significantly improved after 6 years

    • Mean improvements in systolic (23.15 ± 0.83 mmHg) and diastolic (15.07 ± 0.8 mmHg) BP reached a level of statistical significance (p<0.0001) at 3 years, and were sustained for 6 years
    • Improvements in HDL-C (+35.03 ± 5.11%), total cholesterol (–32.12 ± 1.41%), LDL-C (–25.93 ± 1.63%), triglycerides (–29.91 ± 2%), liver enzymes aspartate transaminase (12.01 ± 1.33 U/L) and alanine transaminase (12.46 ± 1.83 U/L), and the inflammatory marker C-reactive protein (2.88 ± 0.28 U/L) were gradual and significant (all p<0.0001)

21 February 2014

Testosterone replacement therapy can improve metabolic and sexual parameters in men with type 2 diabetes

Image: Older man giving himself injection

The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Hackett G, Cole N, Bhartia M, et al. Int J Clin Pract 2013; [epub ahead of print]

Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study. Hackett G, Cole N, Bhartia M, et al. J Sex Med 2013; [epub ahead of print]

Testosterone deficiency syndrome (TDS) is an increasingly common problem and healthcare burden. Low serum levels of testosterone have been shown to be more common in men with type 2 diabetes mellitus (T2DM) than in the general population, with 40−50% of men with T2DM having testosterone levels

Key Points

  • Men in the BLAST study were divided into MILD (testosterone 8.1−12 nmol/L) or SEVERE (testosterone <8.0 nmol/L) groups according to baseline testosterone levels
  • Increases in testosterone levels after 30 weeks were greater in the SEVERE group than the MILD group (2.20 vs. 1.47 nmol/L, measured as trough levels prior to the next injection)
  • After 30 weeks’ treatment with testosterone undecanoate (TU) 1,000 mg, only the SEVERE group showed significant improvements in sexual function (erectile function, p=0.029; intercourse satisfaction, p=0.020; sexual desire, p<0.001)
  • Only the MILD group showed improvements in metabolic and psychological parameters (weight, p=0.003; BMI, p=0.002; waist circumference, p<0.001; Hospital Anxiety and Depression Score [HADS], p=0.007)
  • The presence of baseline depression (HADS ≥11) reduced the response of metabolic parameters to TU
  • TU significantly reduced HbA1c in men with T2DM, particularly in men with poorly controlled diabetes

    • HbA1c was significantly reduced by 6 weeks and maintained at 18 weeks (both p=0.007)
    • In men with baseline HbA1c ≥7.5%, TU reduced HbA1c by 0.41% at 6 weeks, and this level was maintained at 30 weeks
  • TU significantly improved subjective measurements of general health at30 weeks (p<0.001)
  • Testosterone level thresholds may exist, with improvement of sexual and metabolic parameters dependent on achieving certain levels of testosterone, and all symptoms improving at trough levels ≥12 nmol/L
  • Target testosterone trough levels of 15 nmol/L and improvements in symptoms were only achieved after 12 months’ treatment, suggesting that a period of 3−6 months recommended by current guidelines is insufficient and 12−18 months’ treatment are required to attain target therapeutic levels

20 December 2013

Testosterone replacement therapy can improve components of metabolic syndrome

Testosterone replacement therapy can improve components of metabolic syndrome

Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry.Traish AM, Haider A, Doros G, et al. Int J Clin Pract 2013; doi: 10.1111/ijcp.12319.Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Francomano D, Ilacqua A, Bruzziches R, et al. Urology 2013; doi: 10.1016/j.urology.2013.08.019.

Recent evidence suggests that a relationship exists between testosterone deficiency (TD) and metabolic syndrome (MetS) and, indeed, TD could itself be considered an additional clinical feature of MetS. However, this relationship has yet to be explored in long-term studies, and only limited, short-term data in small populations exist for testosterone replacement therapy (TRT) in males with TD and MetS. Furthermore, there is a lack of data investigating the potential side effects of long-term TRT on both the prostate and bladder in this patient population. In addressing this gap, two recently-published studies investigated the use of TRT in men with TD and MetS over a 5-year period.



Key Points

  • Long-term testosterone replacement therapy (TRT) significantly increased levels of total testosterone by ~9 nmol/L in men with testosterone deficiency (TD) and metabolic syndrome (MetS; p<0.0001)
  • In hypogonadal men with MetS, long-term TRT improved anthropometric parameters associated with MetS, including weight, BMI, and waist circumference (all p<0.0001)
  • TRT in hypogonadal men demonstrated gradual and consistent long-term improvements in lipid profiles, a key component of MetS

    • Treatment with testosterone undecanoate (TU) 1,000 mg resulted in significant reductions in levels of total cholesterol (TC), LDL cholesterol, and triglycerides (TG), which were maintained over 5 years of treatment
    • TU 1,000 mg slightly, but significantly, increased levels of HDL cholesterol at 12 months (p<0.0001 vs. baseline), which remained elevated for 5 years of treatment
  • Studies have shown that TRT was associated with rapid improvements in cardiovascular risk factors, such as diastolic and systolic blood pressure, and levels of fibrinogen (p<0.0001), which were sustained over 5 years of treatment
  • TRT in men with TD and MetS improved insulin resistance over 5 years, including fasting blood glucose, HbA1c, and homeostatic measurement assessment-insulin resistance
  • Inflammatory response, as measured by C-reactive protein, was reduced by TRT in men with MetS and TD (p<0.0001)
  • TRT reduced levels of liver function enzymes (aspartate transaminase and alanine transaminase; both p<0.0001), which reached a plateau at 24 and 36 months, respectively
  • TRT may have a role in improving components of MetS, whilst the reduction in inflammatory response may contribute to maintenance of unaltered urinary function and protection of the prostate gland in men with TD

11 November 2013

Testosterone undecanoate can improve sexual function and quality of life in males with type 2 diabetes

Image: Blood meter

Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. Hackett G, Cole N, Bhartia M, et al. J Sex Med 2013; 10(6):1612-1617.

This editorial discusses the key findings and implications of a study published in 2013 by Hackett et al. (The BLAST study) that investigated the effect of testosterone replacement therapy on sexual function and quality of life parameters versus placebo in males with type 2 diabetes (T2D). The study was separated into two phases. The first phase was a 30-week, prospective, randomized, double-blind, placebo-controlled multicenter study conducted between September 2008 and June 2011 at eight UK Midland centers. A total of 190 males (age >18 years) with T2D received long-acting Testosterone Undecanoate (TU) 1000 mg or placebo for 30 weeks (at weeks 0, 6, and 18). The second phase was a 52-week follow-on with open-label TU therapy in 96 patients proceeding from the first phase. The primary outcome of the study was a statistically significant change from baseline in the 15-item International Index of Erectile Function (IIEF) domains. Notable secondary outcomes included health-related quality-of-life symptoms, as measured by the 17-item Ageing Male Symptom Scale (AMS) questionnaire.



Key Points

  • The 82-week BLAST study, which included 190 males age >18 years with T2D, is the largest and longest study to date that investigates the effects of TU therapy in males with T2D
  • In contrast with comparative studies, the study was performed by general practitioners in the primary care setting, rather than specialist diabetes centers
  • TU significantly improved all IIEF domains versus placebo at 30 weeks, with significant improvements also seen at 18 weeks

    • At 30 weeks, improvement with TU versus placebo included erectile function, p=0.005; intercourse satisfaction, p=0.015; sexual desire, p=0.001; orgasm, p=0.004
    • For erectile function, there were significant improvements at 18 and 30 weeks for TU versus placebo in males aged ≥60 years
  • Improvements in sexual function scores were seen as early as 6 weeks with TU versus placebo
  • Sexual function scores continued to improve in the open-label extension to the end of study (weeks 30 to 82)

    • An improvement from baseline in erectile function was observed for the active group continuing on TU therapy and the placebo group proceeding to TU therapy (4.31 and 2.97, respectively)
  • Health-related quality-of-life measures were significantly improved at 30 weeks for TU versus placebo in males without depression (p=0.02), but not in males with baseline depression
  • In a subgroup of males taking phosphodiesterase type 5 inhibitors, there was improvement in erectile function in the open-label phase only

23 September 2013

Updated guidance on the diagnosis and treatment of hypogonadism: Focus on the European Association of Urology (EAU) Guidelines 2012

Updated guidance on the diagnosis and treatment of hypogonadism: Focus on the European Association of Urology (EAU) Guidelines 2012

Guidelines on male hypogonadism. Dohle GR, Arver S, Bettocchi C, et al. European Association of Urology 2012. Feb:1–28.

ISA, ISSAM, EAU, EAA and ASA recommendations: Investigation, treatment and monitoring of late-onset hypogonadism in males. The Aging Male 2009;12:5–12.

Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. Bahsin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab 2010;95:2536–2559.

This editorial focuses on the conclusions and recommendations of the Guidelines on Male Hypogonadism recently published by the European Association of Urology (EAU) in 2012. Conclusions and recommendations in these guidelines are compared to those presented in earlier guidelines published by the International Society for the Study of the Aging Male (ISSAM, 2009) and Endocrine Society (2010).



Key Points

  • Late-onset hypogonadism (LOH) is defined as hypogonadism in a person who has had normal pubertal development that resulted in the development of normal male secondary sex characteristics

    • Levels of testosterone are below the reference range for young, healthy adult males (aged 20–30 years)
  • Clinical symptoms and signs suggestive for androgen deficiency and hypogonadism now include visceral obesity, metabolic syndrome, insulin resistance

    • Testosterone assessment is explicitly recommended in men with type 2 diabetes
  • The lower (normal) level of total serum testosterone that distinguishes between normal levels and levels possibly associated with deficiency is 12.1 nmol/L

    • Levels of serum testosterone below this new limit are associated with a greater likelihood of presenting symptoms
  • Testosterone treatment provides several benefits in metabolic control, waist size and body composition
  • Testosterone therapy is not related to the development of de novo cardiovascular events

    • However, caution is advised when using testosterone treatment in males with existing cardiovascular diseases
  • In patients undergoing surgery for localized prostate cancer, testosterone therapy for treatment of hypogonadism should not be initiated before 1 year of follow-up without prostate-specific antigen (PSA) recurrence

20 August 2013

Obesity is strongly linked to hypogonadism in males regardless of age

Obesity is strongly linked to hypogonadism in males regardless of age

Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Camacho EM, Huhtaniemi IT, O’Neill TW, et al. Eur J Endocrinol 2013;168(3):445-455.

Determinants of testosterone recovery after bariatric surgery: is it only a matter of reduction of body mass index? Luconi M, Samavat J, Seghieri G, et al. Fertil Steril 2013;99(7):1872-1879.

Testosterone concentrations in young pubertal and post-pubertal obese males. Mogri M, Dhindsa S, Quattrin T, et al. Clin Endocrinol (Oxf) 2013;78(4):593-599.

The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Saboor Aftab SA, Kumar S, Barber TM. Clin Endocrinol (Oxf) 2013;78(3):330-337.

This summary presents an overview of four published papers that describe the relationship between obesity and decreased testosterone levels (hypogonadism): one review focusing on the association between obesity, type 2 diabetes mellitus (T2DM) and secondary hypogonadism and three clinical studies. The three clinical studies included a cross-sectional survey assessing the correlation between body mass index (BMI) and sex steroid hormone levels in a general population of 161 males, as well as a longitudinal study investigating the effects of weight loss on sex hormone levels in 24 morbidly obese (BMI >40 kg/m2) males undergoing bariatric surgery; a cross-sectional observational study evaluating the impact of obesity on pubertal and post-pubertal males (n=50) aged 14-20 years; and a community-based longitudinal survey of 2736 men (baseline age 40-79 years) recruited from eight centers across Europe which aimed to assess the relationship between health and lifestyle factors and reproductive hormone levels in aging men.



Key Points

  • Obesity is a major cause of hypogonadism
  • In the general male population, the prevalence of hypogonadism increases with BMI

    • The prevalence of hypogonadism in men with a normal BMI (<30 kg/m2) and men considered obese (≥30 kg/m2) was 7% and 32%, respectively
    • Hypogonadism is found in 75% of men with a BMI >40 kg/m2
  • The association of obesity with hypogonadism is found in men at all ages, even adolescents aged 14-20 years

    • In young men aged 14-20 years, those considered obese had significantly lower total and calculated free testosterone versus those considered non-obese (10.5 vs. 21.44 nmol/L and 0.26 vs 0.44 nmol/L; p<0.001 for all)
  • Weight loss in obese patients is associated with an increase in testosterone levels

    • Following bariatric surgery, patients with a baseline BMI >40 kg/m2 had a median weight loss of 24.6% and 27.0% at 6 and 12 months post-surgery, respectively
    • This weight loss was associated with significantly increased total testosterone levels versus baseline at both time points (14.80 and 13.90 vs. 8.75 nmol/L, respectively; p<0.001 for both)
  • The common decrease in testosterone is not due to age, but rather to increasing body weight, and weight loss or gain can result in significant changes in testosterone Levels

    • Age-related testosterone decreases can, at least partially, be reversed with weight loss

22 July 2013

Weight loss following testosterone treatment in hypogonadal men

Weight loss following testosterone treatment in hypogonadal men

Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Saad F, Haider A, Doros G, et al. Obesity 2013; [epub ahead of print]

Obesity is a global public health problem reaching epidemic levels and has a huge impact on overall health, reduced quality of life and premature death. Testosterone (T) plays an important role in modulating adipogenesis and metabolism of carbohydrates and fats, and reduced plasma T levels have been associated with obesity and type 2 diabetes. However, treatment of obese subjects with T has resulted in marked decreases in fat mass, increases in lean body mass and improved sensitivity to insulin. Furthermore, T treatment in hypogonadal men has resulted in improvements in various cardiovascular parameters including serum LDL-cholesterol, blood pressure and heart rate.

The effect of T treatment on anthropometric parameters was investigated in 255 men being treated with testosterone replacement therapy (TRT). This study was not designed to treat obesity or induce weight loss but rather examined measures of obesity recorded in hypogonadal men receiving T treatment for various medical conditions. The men were between 33 and 69 years of age, however, they were predominantly elderly (mean age, 58 years). Data were collected from patients treated in a single urologist’s office and all received treatment with parenteral testosterone undecanoate (TU) 1,000 mg. The study reported changes in body weight, body mass index (BMI) and waist circumference following long-term T treatment for up to 5 years. This study has the longest duration to date of any study using testosterone in hypogonadal men.



Key Points

  • Low T has been associated with the development of obesity and related conditions such as type 2 diabetes
  • Lifestyle changes (diet and exercise) are typically recommended by physicians to combat obesity but weight loss is often modest and not sustainable over long periods of time
  • The effect of TRT on weight and waist circumference was assessed in hypogonadal men receiving treatment for various medical conditions over a period of up to 5 years. The study reported substantial reductions in body weight, BMI and waist circumference following long-term treatment with T, and these reductions were consistent year after year over the 5-year observation period. Significant and marked weight loss occurred in almost all patients (95%). No significant weight gain was observed in obese or overweight men
  • The potential benefit and contribution of T treatment in combating obesity in hypogonadal men is new and unexpected, as such profound effects of T treatment on weight had not previously been reported
  • T treatment may be a useful tool for facilitating weight loss in hypogonadal men

9 June 2013

Testosterone treatment and cardiometabolic health

Testosterone treatment and cardiometabolic health

Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Eur J Endocrinol 2012;167:531-541.

Impaired aortic elastic properties in patients with adult-onset hypogonadism.
Canpolat U, Tokgözoğlu L, Aydin K, Dural M, Gϋrses KM, Yorgun H, et al. Blood Press 2013;22:114-119.

Reduced plasma testosterone levels can affect vascular function, as shown by the strong association with several conditions including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, diabetes, vascular disease, insulin resistance and arterial stiffness. Studies have shown that testosterone therapy may improve cardiometabolic risk in some at-risk male populations. However, this effect of testosterone therapy has not been systematically studied in obese men with obstructive sleep apnoea (OSA) who are at greater cardiometabolic risk and who have some degree of relative androgen deficiency.

The effect of reduced plasma testosterone levels on aortic elasticity (measured by transthoracic echocardiography) was investigated in 22 men with hypogonadism and 25 matched eugonadal healthy subjects. In a separate randomized, placebo-controlled study, the effect of testosterone therapy on cardiometabolic health parameters was evaluated in obese men with severe OSA (the effects of testosterone therapy on sleep and breathing in this study have recently been published). Eligible subjects were enrolled into an 18-week weight loss program and randomized to receive three intramuscular injections of either testosterone undecanoate 1,000 mg or placebo. Assessments included precise measures of cardiometabolic risk including radiographically determined liver fat and tonometry determined arterial stiffness. Additional outcomes included changes in anthropometry, abdominal visceral fat, total body fat and lean muscle, basal metabolic rate, insulin sensitivity, blood lipids and metabolic syndrome status.



Key Points

  • Sex steroid hormones play an important role in modulating vascular function in men, given that reduced levels of plasma testosterone are linked with several conditions including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, diabetes, vascular disease, insulin resistance and arterial stiffness
  • Aortic stiffness has been shown to be associated with a variety of hormonal disturbances including hypogonadism. This was confirmed in a study of patients with hypogonadism which showed they had increased arterial stiffness, as measured by β index, aortic strain (AoS) and aortic distensibility (AoD)
  • The effect of testosterone therapy on cardiometabolic risk was also studied in obese men with OSA, a population which is at increased cardiometabolic risk and which has some degree of relative androgen deficiency. Eighteen weeks of testosterone therapy in obese men with OSA improved several important cardiometabolic parameters, including arterial stiffness, but did not differentially reduce overall weight or the metabolic syndrome.

2 May 2013

Testosterone treatment and sleep disorders

Testosterone treatment and sleep disorders
Testosterone therapy and obstructive sleep apnea: is there a real connection?
Hanafy HM. J Sex Med 2007;4(5):1241-1246.


Millions of men have received testosterone therapy over the past several decades, but only a few studies have addressed the possible link between testosterone treatment and obstructive sleep apnea (OSA). Despite the small number of patients studied, publications have generally cautioned clinicians about the possible cause or aggravation of OSA by testosterone therapy. A review of the literature by Hanafy in 2007 evaluated the scientific data behind these cautionary statements and found a lack of consistent findings from case studies and different patient groups and that the link between testosterone and OSA was weak. Further well designed studies in this area were recommended from this review.

Key Points

  • Cautionary statements about testosterone therapy have appeared in the scientific literature despite a lack of convincing evidence that testosterone causes and/or aggravates obstructive sleep apnea (OSA)
  • A conclusion from a review from 2007 indicated that the link between testosterone therapy and OSA was weak (due to methodological issues in many studies often involving low patient numbers) and that further studies in this area were needed
  • OSA may affect up to 25% of middle-aged men, many of whom are obese. Men with both OSA and obesity are likely to be at greatest risk for androgen deficiency
  • A randomized study was designed to assess sleep and breathing effects of testosterone treatment (1,000 mg testosterone undecanoate or placebo at 0, 6 and 12 weeks) as an adjunct to weight loss in obese men with severe OSA (n=67)
  • The results showed that testosterone therapy in obese men with OSA mildly worsened sleep disordered breathing (oxygen desaturation index [ODI] was worsened by 10.3 events/h, p=0.03; nocturnal hypoxemia worsened by 6.1%, p=0.01) after 7 weeks (but not 18 weeks) irrespective of initial testosterone concentrations
  • Although statistically significant, these acute changes in sleep measures were small in magnitude and did not result in a worsening in subjective sleepiness
  • Obese patients with OSA requiring testosterone therapy should continue to be cautiously monitored and assessed on an individual basis
  • Lifestyle modification to achieve weight loss should remain the first-line therapy for all obese men with OSA

22 April 2013

Testosterone may be beneficial for metabolic syndrome-associated prostate inflammation

The Correlation Between Metabolic Syndrome and Prostatic Diseases. De Nunzio C, Aronson W, Freedland SJ, Giovannucci E. Eur Urology 2012;61:560-570.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. Vignozzi L, Morelli A, Sarchielli S, et al. J Endocrinology 2012;212:71-84.



Key Points

  • There is evidence of a strong and independent association between obesity/metabolic syndrome and BPH/LUTS; one of their common denominators is hypogonadism
  • As the prevalence of this condition increases the management of metabolic syndrome is considered a major challenge to global public health. An effective way to combat metabolic syndrome and its related consequences is through primary prevention. However, examination of metabolic syndrome molecular pathways and prostatic diseases may offer new therapeutic perspectives for these conditions
  • In a rabbit model of metabolic syndrome overt hypogonadism was induced and characterized by low testosterone along with prostate, seminal vesicle, and testis hypotrophy when compared with controls. In this model, prostatic mRNA levels of several inflammatory markers (e.g., IL-8, IL-1β, TNF-α and IL-6) were upregulated as was the expression of fibrotic and myofibroblast activation markers (including TGFβ1, αSMA, RhoA, ROCK1 and ROCK2)
  • Testosterone prevented (and did not induce) prostatic diseases and normalized markers of metabolic syndrome in HFD-treated rabbits. In addition, oral treatment with INT-747 also significantly (p<0.05) normalized fasting glucose, glucose tolerance, and decreased visceral fat in HFD-treated rabbits
  • Whereas testosterone treatment normalized prostate fibrosis and levels of HFD-upregulated mRNA of all the prostatic inflammatory markers plus expression of fibrotic and myofibroblast activation markers, INT-747 treatment had no effect on these parameters suggesting that the positive effect of testosterone on the prostate gland is not via a metabolic syndrome component
  • It is evident that testosterone protects rabbit prostate from metabolic syndrome-induced prostatic hypoxia, fibrosis and inflammation, thus providing new insights and perspectives for prevention and intervention in BPH/LUTS

27 March 2013

Testosterone for the treatment of obesity in hypogonadal men

Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F, Aversa A, Isidori AM, et al. Curr Diabetes Rev 2012;8(2):131-143.

A recent review of the PubMed literature evaluated studies reporting data on the role of testosterone in counteracting obesity and its associated complications in men with testosterone deficiency (hypogonadism).1 The role of testosterone in this regard was summarized from three perspectives: i) evidence from epidemiological and observational studies; ii) evidence from androgen deprivation therapy (ADT), mainly in men undergoing treatment for prostate cancer (PCa); and iii) evidence from testosterone treatment of men with testosterone deficiency.



Key Points

  • T is an important factor in the etiology of obesity, MetS, T2DM and CVD, with sub-normal T levels increasing the accumulation of fat deposits, particularly abdominal (visceral) fat
  • Lifestyle changes (diet and exercise) are typically recommended by physicians to combat obesity but the often transient effects are only marginally successful and of limited clinical benefit
  • T treatment in hypogonadal men reverses fat accumulation with a significant improvement in lean body mass, insulin sensitivity and markers of cardiovascular risk
  • Medical professionals are largely unaware of the potential benefit and contribution of T in combating obesity and managing MetS in hypogonadal men, with many physicians fearing an increased risk of PCa and CVD (despite the lack of supportive evidence)
  • Combined with lifestyle changes, T may be a useful tool for the treatment of obesity in hypogonadal men; it also improves mood levels and vitality, while reducing fatigue, and may motivate men to adhere to diet and exercise regimens designed to combat obesity

19 November 2012

Changes in the worldwide diagnosis and treatment of testosterone deficiency between 2006 and 2010

Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010. Gooren LJ, Behre HM. The Aging Male 2012;15(1):22-27.

This physician-based survey investigated the diagnosis and treatment of testosterone deficiency (hypogonadism) in various parts of the world in 2010. The study, conducted in Germany, Spain, the United Kingdom, Brazil and Saudi Arabia between April and May 2010, involved 353 physicians (229 urologists, 84 endocrinologists and 40 primary care physicians) who were interviewed to address the following issues (1) the reasons to use/not use testosterone in patients who have testosterone deficiency (2) the role of safety and other concerns in the decision to not provide testosterone treatment and (3) to evaluate the actual use of testosterone preparations for the treatment of erectile dysfunction. The results of this survey were compared with a previous survey conducted in Germany, Spain, the United Kingdom, Brazil and South Korea by the same investigators in 2006 to determine if any significant changes in clinical practice have occurred over the last 4 years.

Key Points

  • The majority of physicians surveyed (82%) would regularly use laboratory measurements of total testosterone to diagnose testosterone deficiency
  • Physicians consider the main symptoms of testosterone deficiency to be erectile dysfunction, lack of libido, fatigue, loss of power, depression, weight gain and loss of hair/reduced body hair

    • There was an increased awareness among physicians of depression and weight gain as clinical symptoms of low testosterone
  • For 70% of the physicians surveyed, the severity of the symptoms experienced was considered a more significant reason to start testosterone treatment than the laboratory value of testosterone
  • In 2010, significantly more physicians expressed concern about the adverse effects of testosterone treatment compared with 2006 (78% vs 54%)

    • Eleven percent of patients eligible for testosterone therapy did not receive treatment due to these concerns
  • The proportion of patients diagnosed with erectile dysfunction who have testosterone deficiency ranged from 41% to 63% depending on the country

    • These patients were more likely in 2010 to be treated with phosphodiesterase type 5 (PDE5) inhibitor monotherapy or testosterone plus PDE5 inhibitors than in 2006.

26 October 2012

Efficacy and safety of long-acting testosterone undecanoate in men with hypogonadism in daily clinical practice

IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Zitzmann M, Mattern A, Hanisch J, et al. J Sex Med 2012 [Epub ahead of print].

This prospective, observational, post-authorization surveillance study investigated the safety and efficacy of intramuscular injections of testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting. The study, conducted in 23 countries throughout Europe, Asia, Latin America and Australia, enrolled 1493 men (mean age 49.2 ± 13.9 years) with a diagnosis of primary or secondary testosterone deficiency syndrome (serum total testosterone 8–12 nmol/L for newly diagnosed treatment-naïve patients). The men received up to five injections of TU during an observation period of 9–12 months. Between the first and second injections of the agent there was an interval of 6–10 weeks, and subsequent injections were given at intervals of 12 ± 2 weeks.

The study aimed to assess treatment outcomes of male patients with testosterone deficiency syndrome who received TU under ‘real-life’ conditions, and to assess the treatment continuation rate in such patients and further confirm the safety profile of TU. Parameters of erectile function, libido, vigor/vitality, mood and ability to concentrate were assessed by physician interview using items and five-point Likert scales. Certain physical and circulatory parameters, as well as other laboratory parameters, were also measured at each injection visit.

Of the 1493 men enrolled, 72.5% were Caucasian, followed by 19.7% and 7.5% of Asian and Latin American descent, respectively. A total of 1438 and 1140 men were evaluable at baseline and at the time of the fifth injection, respectively. At baseline, mean body weight was 86.8 kg, and 54% of those enrolled had previously received androgen therapy. Mean serum testosterone (T) was 9.6 ± 7.5 nmol/L, and comorbidities included erectile dysfunction (ED), hypertension and dyslipidemia.

Key Points

  • Mean trough serum total T increased from 9.6 nmol/L at baseline to 17.3 nmol/L before the fifth injection (p<0.0001)
  • The proportion of patients with a high/very high libido increased from 10% at baseline to 61% at injection 5 (overall p<0.0001)
  • Significant improvements over each injection interval were seen in the overall levels of vigor/vitality, mood and ability to concentrate (p<0.0001 for each)
  • The proportion of patients reporting moderate, severe or extremely severe ED was significantly decreased from baseline at the time of the fifth TU injection, from 65% to 19% (p<0.0001)
  • Statistically significant reduction in waist circumference (Figure 1)
  • Adverse drug reactions related to TU therapy were rare (5.8%).

5 October 2012

Effects of long-acting testosterone undecanoate on quality of life in Asian men with testosterone deficiency syndrome

Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Tong SF, Ng CJ, Lee BC, et al. Asian J Androl 2012;14(4):604-611.

This 12-month double blind, randomized controlled study investigated the effects of intramuscular injections of testosterone undecanoate on overall quality of life (QoL) in men with testosterone deficiency syndrome (hypogonadism). The study, conducted in Malaysia, enrolled 120 men aged ≥40 years with a diagnosis of testosterone deficiency syndrome (serum total testosterone <12 nmol/L (346 ng/dL) and total Aging Males’ Symptoms (AMS) scores ≥27). Men received placebo or 1000 mg testosterone undecanoate by intramuscular injection at weeks 0, 6, 18, 30 and 42.

The primary analysis of the study, treatment effects using the AMS scale, has been published previously and was reported in the Research News on this website on 25 July 2012. This paper reported the secondary analysis of QoL changes, measured by the Medical Outcomes Study Short-Form-12 (SF-12) scale at baseline, week 30 and week 48. SF-12 is a self-administered validated tool designed to measure general health-related QoL. It measures 8 domains of QoL and has 2 composite scores for physical and mental health.

A total of 114 men (58 in the placebo group and 56 in the testosterone group) completed the study. Participants had low serum total testosterone levels and AMS subscale scores in the moderate-to-severe categories. Baseline characteristics were comparable for both groups, except for metabolic parameters (lower body mass index, waist circumference and diastolic blood pressure in the placebo group) and AMS scores (higher total and psychological subscale scores in the testosterone treatment group).

Key Points

  • Serum total testosterone increased from 8.9 nmol/L (256.5 ng/dL) at baseline to 23.7 nmol/L (683.0 ng/dL) at week 48 in the testosterone group (p<0.001) and from 9.1 nmol/L (262.3 ng/dL) to 11.2 nmol/L (322.8) ng/dL in the placebo group (p<0.001; between group difference p<0.001)
  • At week 48 unadjusted quality of life scores of men in the testosterone treatment group improved significantly in five out of the eight domains on the Short-Form-12 survey

    • Physical health composite scores improved 4.0 points in the treatment group compared to 0.8 points in the placebo group (F=3.652, p=0.027)
    • Mental health composite scores improved 4.4 points in the treatment group compared to 1.0 point in the placebo group (F=4.514, p=0.018)
  • After adjusting for baseline differences, significant improvement was observed in vitality and social functioning domains and mental health composite scores, but not in physical health composite scores
  • No significant adverse events were observed.

10 September 2012

Effects of long-term long-acting testosterone undecanoate on bone mineral density in men with late-onset hypogonadism and metabolic syndrome

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aversa A, Bruzziches R, Francomano D, et al. Aging Male 2011;15(2):96-102.

This study evaluated the long-term effects of testosterone replacement therapy (TRT) on the bone mineral density (BMD) of obese patients with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM) and late-onset hypogonadism. Sixty Caucasian men aged 45–65 (mean 57) years with low serum testosterone (>11 nmol/L [320 ng/dL]) or calculated free testosterone >74 pg/mL (255 pmol/L) were enrolled. Treatment consisted of intramuscular testosterone undecanoate 4 times/year for 36 months (20 men). Twenty age-matched hypogonadal men with MetS in whom TRT was contraindicated were used as controls.

The remaining 20 men in the TRT group did not complete the study (and were not included in the analysis) because of mild and transient erythrocytosis (4 patients), increased prostate-specific antigen levels (1), personal reasons (6) or dropped out before completing the 36 months of observation (9). At baseline, mean lumbar BMD was 0.891±0.097 g/cm2, femoral BMD was 0.847±0.117 g/cm2, lumbar T-score was –1.6±0.9 and femoral neck T-score was 0.9±0.8, indicating that patients had mild osteopenia.

Key Points

  • Bone mineral density (BMD) improved significantly (by approximately 5% per year) in men treated with testosterone undecanoate for 36 months, but there was no improvement in BMD in the control group
  • At 36 months:
    • Lumbar BMD was 1.053±0.145 g/cm2 in the testosterone replacement therapy (TRT) group versus 0.866±0.109 g/cm2 in controls (p <0.002 vs testosterone undecanoate)
    • Femoral BMD was 0.989±0.109 g/cm2 versus 0.823±0.126 g/cm2 in controls (p <0.003 vs testosterone undecanoate)
  • There was a direct correlation between change in total testosterone levels and change in BMD at the lumbar site (r2 = 0.66, p<0.0001) and femoral site (r2 = 0.52, p <0.0001)
  • There was a significant reduction in high-sensitivity C-reactive protein (hs-CRP) levels in the TRT, but not the untreated control, group after 12, 24 and 36 months
  • No relationship between improvement in BMD and estradiol levels was observed

21 August 2012

Retrospective observational study finds hypogonadism prevalent in men with sexual dysfunction and related to a range of chronic illnesses

Image: Senior person getting blood pressure examination by a cardiologist

Hypogonadism in men with erectile dysfunction may be related to a host of chronic illnesses. Guay A, Seftel AD, Traish A. Int J Impot Res 2010; 22(1):9-19 [Erratum in: Int J Impot Res 2010; 22(3):210].

This retrospective, observational study evaluated the prevalence of hypogonadism among men with sexual dysfunction, and examined its association with medical and psychological factors. The study involved 990 men (90% Caucasian) who attended an endocrinology specialist centre for sexual function as a new consultation between July 1995 and July 1997. To identify medical and psychological conditions, patients underwent a detailed clinical evaluation and their medical history was examined. A diagnosis of hypogonadism was made based on a total testosterone level of <300 ng/dL (<10.4 nmol/L) accompanied by three or more signs/symptoms of hypogonadism. Primary hypogonadism was identified when low testosterone levels were accompanied by normal levels of luteinizing hormone (≥9 IU/L). Associations between conditions (medical and psychological) and hypogonadism were examined using the Mantel−Haenszel-test.

The mean age of the men was 57.4 years and all had sexual dysfunction. Overall, 359 men (36.3%) had hypogonadism, most of whom were diagnosed with secondary hypogonadism (301 men). The men in this study had a high prevalence of chronic medical and/or psychological conditions, including; diabetes mellitus (23.1%), hypertension (35.8%), atherosclerotic coronary artery disease (19.9%), work-related stress (27.5%) and anxiety/depression (21.0%), and 28.2% of men were on multiple medications.

Key Points

  • The prevalence of hypogonadism among men with sexual dysfunction and common medical causes of ED ranged from 30.8−64.3%
  • Hypogonadism was prevalent among men who used alcohol excessively or who smoked
  • The prevalence of hypogonadism was also substantial among men receiving medication for anxiety or depression and in men with work-related stress
  • The highest prevalence of hypogonadism was observed in men in their 50’s and 60’s
  • A significant association between the medical or psychiatric causes of ED and hypogonadism was limited to hypertension, tobacco abuse, sleep apnea and work stress
  • Sleep apnea and work stress in particular were positively associated with hypogonadism.

8 August 2012

In a retrospective observational cohort study testosterone therapy was associated with decreased mortality in men with low testosterone levels compared with no testosterone treatment

Testosterone Treatment and Mortality in Men with Low Testosterone Levels. Shores MM, Smith NL, Forsberg CW, et al. Testosterone. J Clin Endocrinol Metab 2012; Published ahead of print April 11, 2012; doi:10.1210/jc.2011-2591.

This observational, retrospective cohort study based on a clinical database that included seven Veteran Affairs medical centres in the US was the first to examine the association between testosterone treatment and mortality in men with low testosterone levels. Mortality was compared in testosterone-treated compared with untreated hypogonadal men, using appropriate statistical models adjusted for age, diabetes and coronary heart disease. Testosterone formulations included intramuscular injections (88.6%), patch (9.1%) or gel (2.3%). The cohort included 1031 men aged >40 (mean 62) years with low total testosterone levels ≤8.7 nmol/L (250 ng/dL) at study entry, no history of prostate cancer, who were assessed in 2001–2002 and followed-up until the end of 2005 (mean follow-up time 40.5 months).

Mean body mass index (BMI) was 32.0 kg/m2, and mean total testosterone level was 6.3 nmol/L (181 ng/dL). There was a high degree of medical comorbidity in the cohort; a mean of 6.7 pharmacologically-treated medical conditions, including diabetes (38%), sexual dysfunction (36%) and coronary heart disease (21%). There was an association between lower testosterone levels and higher medical comorbidity (p=0.037).

Key Points

  • Testosterone (T) replacement therapy was started in 39% of 1031 men with low testosterone levels [≤8.7 nmol/L (250 ng/dL)] during routine clinical care at 7 Veteran Affairs medical centres in the US
  • After a mean follow-up of 40.5 months, overall mortality in T-treated men was 10.3%, compared with 20.7% for untreated men (p<0.001)
  • The mortality rate was 3.4 deaths/100 person-years in T-treated men, compared with 5.7/100 person years in untreated men
  • T-treated men had longer a survival time than untreated men (p=0.029)
  • There was a 39% reduction in mortality risk for T-treated compared with untreated men when data were adjusted for age, treatment site, BMI, baseline testosterone level, overall medical morbidity, hospitalisation, and for the presence of coronary heart disease and diabetes mellitus
  • T treatment appeared to be associated with greater mortality reduction in younger men (age <60 years), diabetic men and men without coronary heart disease
  • During the retrospective observational study, 1.6% of T-treated men and 2.0% of untreated men were diagnosed with incident prostate cancer (p=0.68).

21 May 2012

Examining the role of testosterone in the etiology and treatment of obesity, the metabolic syndrome and diabetes in hypogonadal men

Image: overweighted man

The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. Saad F, Gooren LJ. J Obes 2011:pii:471584.

This Research News article reviews an open-access article available in full from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931403/. The original article may be referred to for additional detail and supporting references for the statements summarised in this article, which are too numerous to cite in full.

The review looks beyond the role of testosterone in the male reproductive system and sexual functioning to consider its significance in the development and treatment of obesity, a condition that is acknowledged to be reaching global epidemic proportions.1 The role of testosterone in glucose homeostasis, lipid metabolism and cardiovascular (CV) pathology is examined, and the implications of low testosterone levels on morbidity and mortality are discussed. The article outlines evidence for the effects of normalizing testosterone levels on insulin sensitivity, visceral adiposity and lipid profiles, and addresses the safety of testosterone, particularly in elderly men.

Key Points

Testosterone plays a significant role in obesity, glucose homeostasis, and lipid metabolism:

  • Although androgens appear to be involved in the deposition of visceral fat in males, continued androgen stimulation is not required once fat is stored, and low testosterone adversely affects fat storage and metabolism
  • There is a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels increase the risk of type 2 diabetes mellitus
  • Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome (MetS)
  • Testosterone replacement therapy (TRT) reverses part of the unfavourable risk profile for the development of diabetes and atherosclerosis in hypogonadal men

There is a growing evidence and acceptance that testosterone is a pivotal hormone for many aspects of men’s health and the administration of TRT to elderly men with hypogonadism is a responsible strategy provided that accepted treatment guidelines are followed.

2 May 2012

Rational approach to categorizing testosterone levels using community-based reference ranges

Image: Testosterone levels

Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. Bhasin S, Pencina M, Jasuja GK, et al. J Clin Endocrinol Metab 2011;96(8):2430-2439.

This study generated reference limits for total and free testosterone levels in a community-based sample of nonobese healthy young (19-40 years) men enrolled in the Framingham Heart Study third generation cohort. These reference limits were then applied to three geographically distinct cohorts of community dwelling men drawn from the Framingham Heart Study (FHS) generations 2 and 3, the European Male Aging Study (EMAS) and the Osteoporotic Fractures in Men Study (MrOS). A ‘gold standard’ assay method, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used throughout to determine total testosterone levels; free testosterone levels were calculated using a published law-of-mass-action equation.
Researchers then investigated whether men deemed to have low total and free testosterone levels by the proposed reference limits had a higher prevalence of physical dysfunction, sexual symptoms, and diabetes mellitus, the three categories of conditions most consistently associated with low testosterone levels. Physical function measures (including low walking speed, difficulty climbing stairs, self-reported mobility limitation and frailty) and diabetes were investigated in all three cohorts; sexual symptoms (including decreased morning erections, erectile dysfunction and decreased frequency of sexual thoughts) were available only in EMAS.

Key Points

Reference ranges of total and free testosterone (TT and FT)

  • TT was measured using gold standard liquid chromatography tandem mass spectrometry in nonobese healthy men aged 19-40 years old enrolled in the third generation (G3) of the Framingham Heart Study; FT was calculated
  • Values below the 2.5th percentile of reference sample (348.3 ng/dL [12.1 nmol/L] for TT and 70.0 pg/mL [243 pmol/L] for FT) were classified as low
Association of low T with sexual, physical and metabolic conditions

  • Men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs or frailty, and diabetes than those with normal level
  • Men with low TT and FT were more likely to report sexual symptoms than men with normal levels and were more likely to have at least one of the following:


    • Sexual symptoms
    • Physical dysfunction, or
    • Diabetes

Conclusions

  • These reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal
  • Men with low TT or FT had a higher prevalence of physical dysfunction, sexual dysfunction, and diabetes

6 April 2012

Time-course of biological effects of testosterone replacement therapy

Picture: Wheel

Onset of effects of testosterone treatment and time span until maximum effects are achieved. Saad F, Aversa A, Isidori AM, et al. Eur J Endocrinol 2011;165(5):675-685.

This article reviewed the published literature of studies analyzing the effects of testosterone administration in hypogonadal men to estimate the onset or time-dependency effects of testosterone. The analysis consisted of studies performed with testosterone (including testosterone esters and dihydrotestosterone preparations, independent of delivery method) where:

  • the use of an active treatment group was compared with a matched placebo or control group
  • a description of the time course of the effect of active treatment was included, and
  • randomization, adherence to protocol and single/double-blind study design was reported.

Key Points

Time-course of effects of testosterone replacement therapy in hypogonadal men as shown in clinical studies:

  • Effects on sexual interest appear after 3 weeks and plateau at 6 weeks
  • Changes in erections/ejaculations occur within 6 months
  • Effects on quality of life evident within 3–4 weeks and continue thereafter
  • Effects on depressive mood noted after 3–6 weeks and reach a maximum after 18–30 weeks
  • Effects on glycaemic control become evident after 3–12 months, although insulin sensitivity may improve within a few days
  • Changes in body composition and muscle strength occur within 12–16 weeks and stabilize at 6–12 months
  • Effects on bone mineral density are detectable after 6 months and continue for at least 3 years
  • Beneficial effects on lipids appear after 4 weeks and reach a maximum after 6–12 months
  • Prostate-specific antigen and prostate volume marginally rise, plateauing at 12 months.

2 April 2012

Current knowledge on testosterone deficiency with practical recommendations for diagnosis and treatment

Image: compass

Testosterone deficiency. Traish AM, Miner MM, Morgentaler A, et al. Am J Med 2011;124(7):578-587.

This article aimed to provide practical recommendations for the diagnosis of testosterone deficiency (TD) and information on the benefits and risks of testosterone replacement in middle-aged and older men through a comprehensive review of epidemiological and clinical studies. The review addressed the potential role of testosterone in general men’s health concerns, including the sexual realm, metabolic effects, body composition and mortality, and included an analysis of treatment modalities and examination of current areas of concern and uncertainty.

Key Points

  • Testosterone (T) deficiency (TD; hypogonadism) is a common and under-diagnosed condition associated with aging and with common medical comorbidities
  • Significantly increased risk of TD associated with obesity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and hypertension
  • Significant associations exist between T levels and all-cause and cardiovascular death in men ≥40 years
  • There is rigorous evidence supporting T replacement therapy (TRT) in reducing fat mass, a key component in treating individuals with MetS or T2DM
  • TRT reduces fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and increases high-density lipoprotein cholesterol in patients with TD and MetS
  • Consistent support for the benefits of TRT in improving sexual desire, erectile function and performance
  • Current commercial formulations for TRT include short-acting IM injections, topical gels or patches, subcutaneous T pellets and long-acting intramuscular T undecanoate
  • Current treatment modalities appear relatively safe, and adverse events definitively associated with treatment are reversible on withdrawal of treatment
  • Lack of a clearly-defined serum threshold for distinguishing T deficiency –published consensus guidelines recommend arbitrary thresholds, generally ranging from 200 to 350 ng/dL
  • Physicians managing patients with TD should use their clinical judgment and experience in determining which patients require diagnosis and treatment, based on low T and the presence of symptoms.

8 March 2012

Data strongly suggests a relationship between testosterone deficiency and frailty in elderly men

Image: Senior patient and doctor

The relationship between testosterone deficiency and frailty in elderly men. Saad F. Horm Mol Biol Clin Invest 2010;4(1):529-538.

This review aimed to discuss the relationship between low testosterone level and frailty in elderly men and to evaluate the data which show that treatment of frail hypgonadal men with testosterone replacement therapy (TRT) improves physical functioning and reduces some common risk factors for cardiovascular disease.

Key Points

In elderly men:

  • Testosterone (T) is important as a regulator of body composition and for maintaining bone mineral density

    • Low T is associated with frailty
  • Low T is associated with higher mortality

    • Increased risk of type 2 diabetes, depression, cardiovascular disease, chronic obstructive pulmonary disease, metabolic syndrome, chronic renal disease, and a higher incidence of mortality
  • Low T is common in men with heart failure

    • Low T and dehydroepiandrosterone level appear to be independent predictors of death in men with heart failure

T replacement therapy has been shown to be beneficial in elderly frail men, including those with cardiac dysfunction and/or heart failure

  • Improves lean body mass and reduces fat mass
  • Ameliorates a number of cardiovascular risk factors
  • Improves strength, physical and metabolic function

1 December 2011

Long-acting testosterone undecanoate (TU) injection, but not oral TU, improves metabolic parameters in hypogonadal men

Image: medical pills and syringe

Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. Aversa A, Bruzziches R, Francomano D, et al. J Endocrinol Invest 2010;33(11):776-783.

This randomized, double-blind, double-dummy study was the first clinical trial to compare the efficacy and safety of long-term testosterone replacement therapy using two different preparations of testosterone undecanoate (TU), in hypogonadal men with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM). Patients were randomized to one of three parallel treatment arms; oral TU (80 mg twice daily), intramuscular (IM) TU (1000 mg initially, then repeated every 12 weeks from week 6) or transdermal placebo gel (3–4 g/day). After 6 months, the oral testosterone group was crossed over to receive IM TU for 6 months; the other groups continued with their initial treatment for a further 6 months.

Fifty-two Caucasian men (mean age 57 years) with mean total T

Key Points

After 6 and 12 months, IM testosterone undecanoate (TU) significantly:

  • Improved metabolic parameters by reducing homeostasis model assessment index of insulin resistance (HOMA-IR) (p<0.001), decreasing waist circumference (p<0.0001), decreasing fat mass (p<0.001) and increasing fat-free mass (p<0.001)
  • Improved International Index of Erectile Function (IIEF-5) and Aging Males’ Symptoms (AMS) scores

In contrast 6 months of oral TU did not significantly improve any parameters studied

In patients who crossed over from oral TU, 6 months of IM TU:

  • Increased TT and FT (p<0.0001)
  • Improved metabolic parameters (p<0.001)
  • Improved IIEF-5 and AMS scores (p<0.01)

Haemoglobin and haematocrit values increased with oral and IM TU, but remained stable and within the normal range during treatment.

1 September 2011

Endocrine aspects of the diagnosis and treatment of male sexual dysfunction: new ISSM Guidelines

Image: Endocrine aspects of the diagnosis and treatment of male sexual dysfunction

Endocrine aspects of male sexual dysfunctions. Buvat J, Maggi M, Gooren L, et al. J Sex Med 2010;7(4 Pt 2):1627-1656.

This article is a summary of the report by the Endocrine Aspects of Male Sexual Dysfunctions international experts Committee aimed to provide guidelines based on best evidence for the diagnosis and treatment of endocrine-related male sexual dysfunction. It was prepared in collaboration with the Standards Committee of the International Society of Sexual Medicine (ISSM) and presented at the Third International Consultation of Sexual Medicine (ICSM) in Paris in July 2009. The report was finalized following detailed review of the medical literature, extensive discussion over two years, and public presentation and discussion with other experts, and provides a standardized process for the diagnosis and treatment of endocrine-related male sexual dysfunction. A total of 30 evidence-based recommendations were made and the supporting evidence detailed, including updated knowledge on the prostate and cardiovascular safety of testosterone; key recommendations are presented in this article.

Key Points

Key evidence-based recommendations included:

  • Clinical and biochemical diagnosis
  • Testosterone (T) deficiency (TD) and metabolic diseases
  • T and cardiovascular (CV) diseases
  • T therapy and CV health
  • Questionnaires to screen for TD
  • Indications for T treatment
  • Age and T treatment
  • Indications for T treatment in men with sexual dysfunction
  • Combination therapy with T and phosphodiesterase type 5 inhibitors
  • Commercial T formulations
  • Serum T levels to be achieved with T treatment
  • Prostate safety
  • Cautions in the use of T therapy
  • Monitoring

28 June 2011

Testosterone undecanoate injection normalizes testosterone levels and improves sexual function in Korean men with hypogonadism and ED

Image: Senior couple

The efficacy and safety of testosterone undecanoate (Nebido®) in testosterone deficiency syndrome in Korean: a multicenter prospective study. Moon DG, Park MG, Lee SW, et al. J Sex Med 2010;7(6):2253-2260.

This prospective, multicentre study assessed the efficacy and safety of testosterone replacement therapy (TRT) with a long-acting intramuscular injection of testosterone undecanoate (Nebido®) in an Asian population.1 A total of 133 Korean patients (mean age 54, range 42–75 years) with erectile dysfunction (ED) and testosterone deficiency syndrome (serum testosterone <3.5 ng/mL [12 nmol/L]) were treated with testosterone undecanoate 1000 mg at baseline and again at 6 and 18 weeks. The primary efficacy endpoints were the changes in International Index of Erectile Function (IIEF) score from the initial visit to the final visit (24 weeks) and from the initial visit to each visit. Changes in the Aging Males' Symptoms (AMS) Scale and the Global Efficacy Question (GEQ) for improvement of erectile function were also evaluated.

Key Points

 

  • Testosterone replacement therapy (TRT) significantly increased serum total T and free T by week 12 in Korean men with ED and hypogonadism
  • TRT also significantly improved:

    • total IIEF score and all 5 domain scores
    • total AMS scale and all three domain scores of AMS
  • 77% of men reported improved erectile function
  • Improvements in lipid profile and some metabolic components were seen
  • Serum glucose levels tended to improve with treatment, reaching statistical significance in men with elevated initial glucose levels
  • TRT was effective, safe and well tolerated in hypogonadal Asian men.

 

8 June 2011

Evidence-based criteria identifying late-onset hypogonadism defined

Image: Sleeping man

Identification of late-onset hypogonadism in middle-aged and elderly men. Wu FC, Tajar A, Beynon JM, et al. N Engl J Med 2010;363(2):123-135.

This was a systematic investigation of a random population sample of 3369 middle-aged and elderly men (aged 40–79 years) to establish evidence-based criteria for identifying late-onset hypogonadism in the general population on the basis of an association between symptoms and a low testosterone level. The men surveyed were participating in the European Male Aging Study (EMAS) at eight European centers. Data were collected on the men’s general, sexual, physical, and psychological health, and total testosterone levels were measured in morning blood samples and free testosterone levels were calculated. Data were randomly split into separate training and validation sets for confirmatory analyses.

A total of 32 items were considered as possible candidates for symptoms of androgen deficiency on the basis of previous recommendations and studies; all items were then screened statistically and those that were significantly associated with total or free testosterone levels were selected for independent validation and further divided into symptomatic and asymptomatic categories. The findings were published in the New England Journal of Medicine.

Key Points

Nine symptoms were confirmed to be significantly related to total or freetestosterone (T) level

  • Three sexual symptoms
  • Three physical symptoms
  • Three psychological symptoms
  • The probability of symptoms increased with decreased levels of T and the presence of the three sexual symptoms correlated most closely with low T
  • Total T <317 ng/dL (11 nmol/L) + free T levels <64 pg/mL (220 pmol/L) + all 3 sexual symptoms were diagnostic of late-onset hypogonadism.

5 May 2011

Meta-analysis supports association between metabolic syndrome and hypogonadism; testosterone replacement therapy may improve metabolic control and reduce central obesity

Image: analyzing blood glucose

Testosterone and metabolic syndrome: a meta-analysis study. Corona G, Monami M, Rastrelli G, et al. J Sex Med 2011;8(1):272-283.

A systematic review and meta-analysis of available prospective and cross-sectional studies comparing androgen levels in men with or without metabolic syndrome (MetS) was performed to analyse the relationship between androgen levels and MetS. Additionally, a separate meta-analysis of available randomized controlled trials reporting the metabolic effects of testosterone replacement therapy was performed. Overall, 21 quality studies were included; 13 cross-sectional, 3 longitudinal and 4 randomized controlled published trials, and 1 unpublished randomized controlled trial. Data for 2,254 men with and 6,407 men without MetS were included.

Key Points

  • Men with MetS had significantly lower levels of total plasma testosterone compared with healthy subjects
  • This was also true when men with or without erectile dysfunction were analysed separately and when different definitions of MetS were used
  • The presence of type 2 diabetes mellitus (T2DM) further enhanced the MetS-related decline in testosterone levels
  • Adjusted for age and body mass index, both T2DM and MetS independently predicted low testosterone (p<0.001 and p<0.05, respectively)
  • Data from longitudinal studies showed that baseline testosterone was significantly lower among patients with MetS than in controls (mean -2.17 nmol/L; p<0.0001)
  • Testosterone replacement therapy significantly reduced metabolic risk factors, including fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and increased HDL-cholesterol.

25 April 2011

Testosterone deficiency – data available from RHYME study in 2013

The natural history of testosterone deficiency in men and outcomes associated with testosterone therapy: a multi-national patient registry. RC Rosen, AB Araujo, AB O'Donnell, JB McKinlay. New England Research Institutes, Watertown, MA, USA.

Despite testosterone (T) therapy being used to treat testosterone deficiency for approximately 70 years, no large scale, long term study has fully addressed the natural history of testosterone deficiency or the long term safety of testosterone treatment.

In May 2009 it was announced that a Registry of HYpogonadism in MEn (RHYME) would be established to maintain a multi-national (European) data-set of around 1,000 patients (aged 18 and over), drawn from some 20 clinical sites, diagnosed with late-onset hypogonadism (HG), hypogonadism secondary to medical illness, and classical hypogonadism (eg, Klinefelter's syndrome).1,2 Men registered on RHYME are not required to undergo T treatment for diagnosed HG.

The primary goal of RHYME is to examine the association between testosterone therapy and prostate health (eg, rate of positive prostate biopsies (primary endpoint), incidence of prostate cancer and Benign Prostatic Hyperplasia) of men with HG that some believe is put at risk by testosterone therapy. Other goals include the assessment of HG symptoms and general health outcomes in men with HG treated with T, as well as their clinical course compared to those men with HG who are not treated.

The Registry will draw on observational studies at baseline, three months, and then yearly intervals (for a minimum of two years). Data collected will include a full medical history, a physical examination, blood sampling, and patient questionnaires.

21 April 2011

Testosterone replacement therapy improves body composition, insulin resistance and markers of atherosclerosis in men with low testosterone and metabolic syndrome

Image: Overweight men check up

Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. Aversa A, Bruzziches R, Francomano D, et al. J Sex Med 2010;7(10):3495-3503.

The aim of this study was to evaluate whether long-term testosterone replacement therapy could modify cardiovascular risk factors and atherosclerosis progression in a population of hypogonadal men with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM). The randomized, double-blind, double-dummy, placebo-controlled, parallel group study enrolled 50 men (mean age 57 years) to receive intramuscular (IM) testosterone undecanoate (TU) 1000 mg every 12 weeks (n=40) or placebo transdermal gel (3-6 g daily; n=10) for 24 months. Hypogonadism was defined as total testosterone ≤11 nmol/L or free testosterone ≤250 pmol/L; MetS and T2DM were defined according to National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria.

Key Points

  • After 12 months, there was a significant difference in homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT) and high-sensitivity C-reactive protein (hsCRP) between the TU and placebo groups (p<0.01)
  • No modification of metabolic factors occurred during treatment with placebo
  • Consequently, all patients received TU for the remaining 12 months of the study
  • TU markedly improved insulin sensitivity from baseline to 12 months (p<0.0001), and maintained the improvement after 24 months
  • HOMA-IR significantly improved in patients shifted from placebo to testosterone undecanoate (p<0.001) due to a reduction in fasting glucose and fasting insulin levels
  • TU also significantly reduced hsCRP levels (p<0.0001) and CIMT values (p<0.001)
  • Overall at 24 months, only 35% and 58% of patients still met NCEP-ATPIII and IDF criteria, respectively, for a diagnosis of MetS
  • The main determinants of improvement in MetS were reduction in waist circumference (p<0.0001), visceral fat mass (p<0.0001) and improvement in HOMA-IR (Figure 1).

1 April 2011

Men with erectile dysfunction and low testosterone levels have an increased risk of dying from cardiovascular disease

Image: Human heart

Citation: Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. Corona G, Monami M, Boddi V, et al. J Sex Med 2010;7(4 Pt 1):1557-1564.

A consecutive series of 1687 patients attending an andrology clinic for erectile dysfunction (ED) was followed for a mean of 4.3 ± 2.6 years to investigate whether low testosterone levels predict incident fatal or nonfatal major adverse cardiovascular events (MACE) in men with ED. Patients in this prospective cohort study were interviewed using the structured interview on erectile dysfunction (SIEDY) and the ANDROTEST structured interview to measure aspects of ED and hypogonadal-related symptoms. Total testosterone was evaluated at baseline and information on MACE was obtained from registry database records.

Key Points

The nested case-control study showed:

  • At baseline, over 20% of men were hypogonadal, according to a widely accepted lower limit for normal total testosterone levels
  • Hypogonadism ranged from 5.2% to 13.8% and 22.4% depending on the threshold used (total testosterone less than 8, 10.4 and 12 nmol/L, respectively
  • During follow-up, 139 of the patients had a major cardiac event, such as ischaemic heart disease, cerebrovascular events (stroke or transient ischaemic attack) or peripheral artery disease
  • MACE were fatal in 15 men
  • Although low testosterone in itself was not associated with MACE, those patients with total testosterone levels below 10.4 nmol/L who had a major cardiac event were significantly more likely to die than those with higher testosterone levels
  • When adjusted for Chronic Diseases Score (an index of comorbidities) the risk of death was increased by a factor of seven (hazard ratio [HR] 7.1) in men with testosterone below 8 nmol/L
  • Of interest, fatal MACE were associated with a higher ANDROTEST score measuring hypogonadal-related symptoms and signs (HR = 1.2 for each ANDROTEST score increment; P = 0.05).

11 March 2011

Low testosterone is common in men with coronary heart disease and negatively impacts survival

Man clutching his chest

Low serum testosterone and increased mortality in men with coronary heart disease. Malkin CJ, Pugh PJ, Morris PD, et al. Heart 2010;96(22):1821-1825.

A total of 930 men (mean age 61 years) were followed in a prospective cohort study for a mean of 6.9 years to determine the prevalence of testosterone deficiency and to investigate the effect of serum testosterone levels on survival in men with confirmed coronary disease.1 The cohort was a consecutive series of men referred to a tertiary cardiothoracic centre for diagnostic coronary angiography between June 2000 and June 2002. Significant coronary artery disease was defined as 70% or greater stenosis in any epicardial coronary artery or 50% or greater stenosis of the main stem of the left coronary artery.

Key Points

  • 20.9% of men had biochemical testosterone deficiency defined as bioavailable testosterone <2.6 nmol/L, 16.91% using testosterone <8.1 nmol/L and 24% using either
  • There was excess mortality in testosterone-deficient men; 21% versus 12% in those with testosterone levels in the normal range (>2.6 nmol/L), p=0.002 (Figure 1)
  • Low serum testosterone was one of only four variables found to influence the time to all-cause mortality in multivariate analysis (hazard ratio [HR] 2.27)
  • The other variables significantly influencing time to all-cause mortality were presence of left ventricular dysfunction (HR 3.85), aspirin therapy (HR 0.63) and β-blocker therapy (HR 0.45)
  • Low bioavailable testosterone more than doubled adjusted all-cause and vascular mortality (HR 2.2, p<0.0001 for all-cause mortality and HR 2.2, p=0.007 for vascular mortality) compared with those with normal levels of testosterone
  • Overall, serum total testosterone was inversely associated with mortality (HR 0.96), with a baseline level of <15.1 nmol/L associated with an all-cause HR of 1.86 and vascular mortality with a HR of 2.5.

22 February 2011

Study shows testosterone (T) improves body composition and hip bone mineral density in elderly men with low T

Image: Pelvic x-ray image

Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. J Svartberg, I Agledahl, Y Figenschau, T Sildnes, K Waterloo and R Jorde. International Journal of Impotence Research. 2008:20;378–387.

Researchers examined whether lower than normal T levels in elderly men were associated with a reduced quality of life (QoL), as well as physical and mental health, and whether T treatment could improve these conditions.

Unlike earlier testosterone treatment studies that recruited by advertising or direct mailing, researchers contacted elderly men (aged 60–80 years old) surveyed as part of the fifth (2001) Tromsø survey that measured T in 3,447 men. Sixty-nine elderly men with low T (defined as ≤11.0 nmol/l) and 104 men with normal T (>11.0 nmol/l) (control group) took part in a nested case-control study. Of the 69 men with low T, 31were excluded from participation in the one year intervention study due mainly to PSA levels above the reference range (>4.0µg/l) (no.18) or the use of warfarin (no.6). As a result 19 men were included in each of the T and placebo treatment groups (randomized in a double-blind fashion) – one man later withdrew from each group and one man from the T group died from cardiac arrhythmia not considered to be related to T therapy. Treatment was by an intramuscular injection of testosterone undecanoate 1000mg (Nebido®) or an identical looking placebo administered by a nurse (ensuring 100 per cent compliance) at baseline and again at six, 16, 28, and 40 weeks. After 52 weeks the initial examinations and tests were repeated.

Key Points

The nested case-control study showed:

  • No difference in Fat Free Mass (FFM) beween the two groups (low and normal T), but Fat Mass (FM) percentage was significantly higher in the low T group (32.2% vs 25.9%; P<0.001) compared with controls – this group also had higher weight, waist circumference, and total abdominal adipose tissue (TAT)
  • Muscle strength was similar between the groups, but the control group performed significantly better in two of the three functional tests. Bone Mineral Density (BMD) measured in both the lumbar spine and hip showed no significant difference between the groups
  • At the Oral Glucose Tolerance Test men with low T had significantly higher fasting and two hour glucose levels compared with the control group. Likewise, the HbA1c, insulin, C-peptide and triglycerides levels and insulin resistance (HOMA) values were significantly higher in men with subnormal testosterone levels
  • Men in the control group reported better overall and somatic Quality of Life (QoL) scores (AMS) although the scores in the sexual domain were not significantly different. In the Beck Depression Inventory the control group reported a significantly better total and second subscale score
  • There were no differences between groups in the General Health Questionnaire or World Health Organisation quality of life old score (WHOQOL-OLD)

The intervention study showed that:

  • Total and free T increased significantly in the T group. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) decreased in the T group and at the end of the study were significantly lower in the T group compared with placebo
  • FFM increased and FM reduced significantly during T treatment compared to the placebo group at the end of the study (FFM: +4.2 kg in T group, +0.4 kg in placebo; FM: -5.3kg in T group, -0.6 kg in placebo) while weight, BMI and waist circumference did not change significantly
  • BMD in the hip increased significantly in the T group and there was a significant difference between the groups at the end of the study
  • T did not increase strength in knee extension or handgrip strength, but in the placebo group handgrip strength was reduced in both the dominant and non-dominant hand such that at the end of the study there were significant differences between the groups
  • There was no significant difference in QoL, cognitive function or emotional function between the groups at the end of the study
  • Serum PSA, hematocrit and hemoglobin increased in the T group and by the end of the study were significantly higher than in the placebo group; two men in the T group (and one in the placebo group) had PSA levels >4.0µg/l by the end of the study

19 January 2011

Testosterone with diet and exercise reverses Metabolic Syndrome and improves glycemic control in hypogonadal men with newly diagnosed Type 2 Diabetes

Picture: Overweight men

Fifty-two week treatment with diet and exercise plus transdermal testosterone reverses the Metabolic Syndrome (MetS) and improves glycemic control in men with newly diagnosed Type 2 Diabetes and subnormal plasma testosterone. AE Heufelder, F Saad, M Bunck, and L Gooren. November/December 2009. Journal of Andrology;30:(6);726-733.


Key Points

  • Serum testosterone, glycosylated haemoglobin (HbA1c), fasting plasma glucose, high-density lipoprotein cholesterol, triglyceride concentrations, and waist circumference improved in both groups after 52 weeks of treatment
  • The addition of testosterone significantly further improved these measures compared with D&E alone
  • All D&E and testosterone treated patients reached the HbA1c glycemic control goal of less than 7.0%, and 87.5% achieved HbA1c of less than 6.5%. In comparison, only 40.4% of the D&E alone participants reached HbA1c less than 7.0%, and none reached less than 6.5%
  • Based on Adult Treatment Panel III criteria, 81.3% of the D&E with testosterone patients no longer met the criteria of MetS compared with 31.3% of those receiving D&E alone
  • Testosterone treatment improved insulin sensitivity (HOMA model), adiponectin, and high-sensitivity C-reactive protein
  • Serum PSA concentrations did not differ between the two treatment groups indicating that 52 weeks of testosterone replacement does not appear to increase risks of prostate problems.

8 December 2010

Largest international trial indicates that testosterone replacement therapy is an effective and well tolerated treatment for male hypogonadism

IPASS: Final data from the worldwide largest study of the tolerability and effectiveness of injectable testosterone undecanoate (TU) for the treatment of male hypogonadism involving 1493 patients. M Zitzmann, JU Hanisch, A Mattern, M Maggi. A presentation to the Men’s Health World Congress, 2010.

Key Points

  • Restoring plasma testosterone levels to normal alleviated the symptoms of testosterone deficiency
  • The percentage of patients who reported “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10% after four TU injection intervals
  • At baseline, 67% of patients had moderate, severe or extremely severe erectile dysfunction (ED), this decreased to 19% after TU therapy. 61% of patients with some degree of ED reported a decrease in severity
  • TU therapy markedly improved patients ability to concentrate and their reported mood
  • 89% of patients were “satisfied” or “very satisfied” with TU therapy
  • The mean waist circumference in patients decreased from 100 cm to 96 cm
  • Intramuscular TU was well tolerated and safe for treatment of male hypogonadism in daily clinical practice, irrespective of ethnic background: adverse events and adverse drug reactions were recorded for 12% and 6% of patients respectively. These were mostly mild to moderate in severity
  • The most commonly reported ADRs were increase in hematocrit, increase in PSA and injection site pain (all <1%)
  • No case of prostate cancer was observed

24 November 2010

Exercise performance in men with stable angina improved by testosterone over 12 month period

Long term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Mathur A, Malkin C, Saeed B et al. European Journal of Endocrinology. 2009;161;443 –449.

Key Points

  • This is the longest term study investigating testosterone in patients with stable chronic angina.
    (Angina is severe chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries)
  • In the testosterone group, 'time to ST depression' is significantly prolonged, ie the time during exercise when severe chest pain occurs as a result of ischemia (which also becomes visible on the electrocardiogram). This reflects an increase in exercise capacity
  • Peak metabolic equivalents (METS) also increased significantly in the testosterone treated patients indicating an improved exercise capability
  • BMI and triglycerides were numerically, though significantly reduced in the treatment group
  • There was a non-significant reduction in waist-to-hip ratio (a measure of visceral obesity) in the Nebido® group
  • Carotid intima-media thickness (CIMT), a measure of atherosclerosis, improved in the Nebido group and did not change in the placebo group. However, the comparison between groups did not reach statistical significance.

15 October 2010

Testosterone improves depression and quality of life scores in hypogonadal men

Picture: Senior man contemplating

Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome.Giltay EJ, Tishova YA, Mskhalaya GJ, et al. J Sex Med. 2010 Jul;7(7):2572-82.





Key Points

  • This is the first publication from The Moscow Study, a placebo-controlled study in men with metabolic syndrome with a total duration of three years. The first 30 weeks are placebo-controlled, then all men are switched to Nebido®
  • All three questionnaires, the Beck Depression Inventory (BDI-IA), the Aging Males' Symptoms (AMS) scale, and the International Index of Erectile Function 5-item (IIEF-5) scale improved significantly in the testosterone group
  • These improvements persisted after correcting for smoking habits, BMI, and the presence or absence of type 2 diabetes
  • These improvements correlated with improvements in BMI. This means that patients felt better and functioned better when they lost weight, and the more weight they lost, the more they improved

17 August 2010

Testosterone improves functional performance in elderly men with chronic heart failure

Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure. Caminiti G, Volterrani M, Iellamo F, et al. J Am Coll Cardiol 2009; 54(10): 919-927.

Key Points

  • Long-acting testosterone treatment (Nebido) for 3 months in frail elderly patients was well tolerated
  • Nebido significantly improved skeletal muscle function, cardiorespiratory parameters and metabolic parameters, including insulin resistance
  • Patients with lower testosterone at baseline achieved the greatest improvements, but eugonadal patients also benefited

4 August 2010

Testosterone reduces visceral fat and increases muscle mass in non-obese men aged ≥ 55 years

Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. Allan CA, Strauss BJG, Burger HG, Forbes EA, McLachlan RI. J Clin Endocrinol Metab 2008;93(1):139-146.

Key Points

  • Testosterone treatment consistently reduces fat mass and increases muscle mass. This study confirms these findings in a healthy (non-obese and without hypogonadism) cohort
  • Changes in visceral fat were more pronounced than changes in subcutaneous fat
Last updated: 2016
G.GM.MH.04.2015.0334