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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. 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.
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.
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.
Medical research can be of varying quality. 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. Growing research evidence shows that treating testosterone deficient 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 most of the available evidence 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 (a surrogate measure for obesity), the prevalence of subnormal free testosterone levels in men with type 2 diabetes is higher than in men without.
Insulin resistance occurs when the body’s cells become insensitive to the insulin, which is a hormone that is necessary for transport of blood sugar (glucose) into cells. To compensate for the resistance to insulin, the pancreas increases insulin production up to the point until the pancreas’ capability to produce insulin is exhausted.
Here we summarize the results of a study conducted by a research team at the Division of Endocrinology, Diabetes and Metabolism, State University of New York. This study specifically selected men with type 2 diabetes based on low free testosterone levels. The aims of the study were to investigate:
1) The impact of testosterone deficiency 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, large studies 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 published in the medical journal Drug Safety, 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.
The effects of testosterone replacement therapy on cardiovascular outcomes such as heart attack 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 heart attack and stroke. This notable study was published in the European Heart Journal on August 6th, 2015.
- provocative results on diagnosis and adherence
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…
Venous thromboembolism is a blood clot that forms in a vein deep inside a part of the body; it mainly affects the large veins in the lower leg and thigh.
Blood clot formation (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. Here we report the results of a recent case-control study – published July 20, 2015 - that specifically examined the risk of venous thromboembolism associated with testosterone therapy in middle-aged and older men.
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, such as heart attack and stroke. 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
Sex hormone binding globulin (SHBG) is a “hormone carrier” that binds and transports testosterone in the blood. It is well established that both low total testosterone and low 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 (the main estrogen) 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 Therapy and Cardiovascular Risk: Advances and Controversies. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Mayo Clin. Proc. 2015;90(2):224-251.
Testosterone and mortality. Muraleedharan V, Jones TH. Clin. Endocrinol. (Oxf). 2014;81(4):477-487.
One of the most debated issues related to testosterone replacement therapy is its effects on cardiovascular risk and clinical events, like for example heart attack. A few flawed studies over the past years made it appear that testosterone replacement therapy increases cardiovascular risk and incidence of heart attacks. However, less known is the vast and rapidly accumulating body of evidence showing the contrary; that higher testosterone levels and testosterone replacement therapy actually may reduce mortality and increase longevity.
This editorial summarises key conclusions from a special medical review article on testosterone and cardiovascular risk, written by the Androgen Study Group, as provides answers to 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 which specifically was conducted to investigate the potential health ramifications of subclinical hypogonadism, shows that it should not be neglected.
A rapidly growing body of medical research is showing that testosterone deficiency (aka hypogonadism and low-T) is strongly associated with a wide range of detrimental health outcomes, and that testosterone replacement therapy improves those health parameters that are negatively affected by testosterone deficiency. Therefore, leading testosterone scientists now view testosterone deficiency as a cardiovascular risk factor that contributes to the development of cardiovascular disease.
As general practitioners and cardiologists primarily care for these patients with cardiovascular disease, a survey study was conducted to assess their knowledge, beliefs and clinical practice with respect to testosterone deficiency and cardiovascular health.
A questionnaire was distributed to 20 cardiologists and 128 family practitioners in British Columbia, Canada. Of the 13 questions, 10 assessed knowledge and beliefs on testosterone deficiency and 3 assessed current practice patterns.
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 editorial 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.
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;2011.
It is well documented that obesity may cause hypogonadism, and that hypogonadism may cause obesity. 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 hypogonadism, 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.”
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.
- 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 (blood vessel) 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.
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, this is very misleading. Here we will contrast the differences between late onset hypogonadism, also known as testosterone deficiency, and menopause, and explain why these condition should not be regarded as being equivalent.
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.
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 (loss of muscle mass), 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.
- 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 heart attack 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 heart attack, and may actually confer protection against heart attack.
"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.
This study, published in the New England Journal of Medicine, identified the most important symptoms linked to late-onset hypogonadism (low testosterone levels in aging men) in a large group of men representative of the general population. When testosterone levels were also taken into consideration, having these three symptoms and low testosterone levels was a specific diagnosis of late-onset hypogonadism.
There is increasing evidence that erectile dysfunction may be a warning sign of a number of disease conditions, such as high blood pressure, metabolic syndrome, diabetes mellitus, depression and coronary heart disease.
Nearly 1700 men attending an andrology clinic for erectile dysfunction were monitored for an average of 4.3 years to find out whether those with low testosterone levels were more likely to suffer a major cardiovascular disease event, such as a heart attack or stroke.