Recent findings from testosterone studies
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Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. Journal of cardiovascular pharmacology and therapeutics. 2017:epub. Traish A, Haider A, Haider K, Doros G, Saad F.
Most men with testosterone deficiency need testosterone therapy for the rest of their life in order to achieve and maintain best possible health outcomes. Therefore, studies that investigate the effects of testosterone therapy in real-life are needed, to shed light on adherence and health outcomes in routine clinical practice. While randomized controlled trials (RCTs) are gold standard in medical research, RCTs are conducted in highly controlled environments and therefore their results may not carry over to the uncontrolled setting of real-life. It is increasingly recognized that conclusions drawn from RCTs are not always a useful aid for decision-making because evaluating the value of a drug or technology requires an understanding of its impact on current clinical practice and management of patients in a real-life setting.
A series of “real-life studies” have been conducted, all showing numerous health benefits of testosterone therapy in hypogonadal men and confirming its safety, with an observation period of up to 17 years. Here we summarize the results from the most recent real-life study, published in the Journal of Cardiovascular Pharmacology and Therapeutics, which investigated the long-term effects and safety of testosterone therapy for up to 8 years in hypogonadal men attending a urological office. Differences in cardiovascular risk factors and mortality with testosterone therapy were compared to those seen in hypogonadal men not receiving testosterone therapy but attending the same urological office.
American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Garvey WT, Mechanick JI, Brett EM, et al. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016;22 Suppl 3:1-203.
The combined prevalence of overweight and obesity is 71% in adults, and up to 50 - 80% of obese men have testosterone deficiency (also known as hypogonadism). The most common comorbidity among the growing obese population is type 2 diabetes; about half of all men with type 2 diabetes have hypogonadism.
Recent clinical guidelines on hypogonadism state that increased visceral body fat and obesity are signs of hypogonadism, and that testosterone should be assessed in men with obesity, metabolic syndrome and diabetes. However, due to the epidemic prevalence of overweight/obesity and related metabolic diseases, the large majority of hypogonadal men will see a primary care physician and/or a diabetologist or cardiologist, who is likely not aware of the clinical guidelines on hypogonadism.
It is therefore laudable that The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) Clinical Practice Guidelines for Comprehensive Medical Care of Patients with Obesity in their 2016 revision dedicated two comprehensive sections on testosterone deficiency and treatment. Here we summarize these AACE / ACE recommendations.
Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Maggi M, Wu FC, Jones TH, et al. Int J Clin Pract. 2016;70(10):843-852.
It is well-documented that testosterone therapy effectively restores testosterone levels in hypogonadal men and improves many health outcomes, such as quality of life, libido, metabolic parameters and body composition.
However, a few conflicting studies raised concerns about the cardiovascular safety of testosterone therapy which in 2015 prompted the FDA to issue warnings to physicians and patients about potential cardiovascular risks of testosterone therapy. In contrast, the European Medicines Agency (EMA) acknowledged the flaws of the conflicting studies and concluded that there is no consistent evidence of harm associated with testosterone therapy, regardless of mode of delivery.
Here we present the cardiovascular results of the notable RHYME (The Registry of Hypogonadism in Men) study, which contrary to prior clinical trials, enrolled patients with a wide range of comorbid illnesses and cardiovascular risk factors. The aim was to evaluate the safety of testosterone therapy in a sufficiently diverse population to reflect real-world, clinical experience.
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.
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. 2017;119(2):216-224.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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…
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.
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.
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.
- 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…
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.
- 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.
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.
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:
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.
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.
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.
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.
Abbreviations: TT = total testosterone, FT = free testosterone
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.”
- 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.
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.
- 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.
For several reasons, hypogonadism in men and menopause cannot be equated:
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.
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).
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.
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.
- 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.
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.
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.
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.
"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.
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.
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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.
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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.
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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
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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.
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.
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.
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).
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.
Testosterone plays a significant role in obesity, glucose homeostasis, and lipid metabolism:
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.
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 PointsReference ranges of total and free testosterone (TT and FT)
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:
Time-course of effects of testosterone replacement therapy in hypogonadal men as shown in clinical studies:
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.
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.
In elderly men:
T replacement therapy has been shown to be beneficial in elderly frail men, including those with cardiac dysfunction and/or heart failure
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
After 6 and 12 months, IM testosterone undecanoate (TU) significantly:
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:
Haemoglobin and haematocrit values increased with oral and IM TU, but remained stable and within the normal range during treatment.
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 evidence-based recommendations included:
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.
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.
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.
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.
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.
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.
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.
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.
The intervention study showed that:
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.
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.
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.
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.
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.
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.