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Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

Published:January 26, 2015DOI:https://doi.org/10.1016/j.mayocp.2014.10.011

      Abstract

      Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

      Abbreviations and Acronyms:

      CAD (coronary artery disease), CHF (congestive heart failure), CV (cardiovascular), FDA (Food and Drug Administration), HbA1c (hemoglobin A1c), HDL (high-density lipoprotein), HR (hazard ratio), MACE (major adverse cardiac events), MI (myocardial infarction), PDE5i (phosphodiesterase type 5 inhibitor), RCT (randomized controlled trial), SHBG (sex hormone–binding globulin), T (testosterone), TD (T deficiency), TT (total T)
      In November 2013 and January 2014, 2 studies were published reporting increased cardiovascular (CV) risks in men who received testosterone (T) prescriptions.
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      These articles gained wide media attention. Media coverage of these studies was frequently combined with data indicating rapidly increased sales of T products,
      • Baillargeon J.
      • Urban R.J.
      • Ottenbacher K.J.
      • Pierson K.S.
      • Goodwin J.S.
      Trends in androgen prescribing in the United States, 2001 to 2011.
      • Handelsman D.J.
      Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse.
      raising concerns that the pharmaceutical industry was promoting a treatment associated with important risks. This view was captured best by a New York Times editorial entitled “Overselling Testosterone, Dangerously.”

      Overselling testosterone, dangerously [editorial]. New York Times website. http://www.nytimes.com/2014/02/05/opinion/overselling-testosterone-dangerously.html?_r=0. Published February 4, 2014. Accessed August 31, 2014.

      The impact of these studies on patient management and the ensuing public attention has been substantial. Men discontinued treatment, occasionally criticizing their physicians for putting their health at risk; some physicians stopped prescribing T products, and others warned against treatment of T deficiency (TD) (also called hypogonadism or, more casually, low T). The Endocrine Society issued a statement cautioning against the use of T therapy in older men and in men with a history of coronary artery disease (CAD).

      Endocrine Society. Endocrine Society calls for large-scale studies to evaluate testosterone therapy risks [press release]. Endocrine Society website. https://www.endocrine.org/news-room/current-press-releases/endocrine-society-calls-for-large-scale-studies-to-evaluate-testosterone-therapy-risks. Accessed August 31, 2014.

      The US Food and Drug Administration (FDA) announced plans to review the CV safety of T products 2 days after publication of the second article.

      US Food and Drug Administration. Testosterone products: drug safety communication - FDA investigating risk of cardiovascular events. US Food and Drug Administration website. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm384225.htm. Published January 31, 2014. Accessed August 31, 2014.

      Plaintiff attorneys began a nationwide campaign seeking cases of myocardial infarctions (MIs) and strokes in men who had used T products for a class action lawsuit. These concerns thrust T therapy into the news, where the reported CV risks anchored a variety of unrelated concerns regarding other aspects of T therapy, such as overuse and abuse, false claims by antiaging medicine, profiteering by low-T clinics, and the failure of men to accept the rigors of natural aging.
      It is beyond the scope of this article to address these various issues. Instead, we wish to address the key scientific question, namely, whether T therapy is associated with increased CV risks. This review encompasses an analysis of the literature previously submitted by us to the FDA and to the European Medicines Agency to assist with their own investigations of this topic. This article provides in-depth analysis of studies suggesting increased CV risks with T therapy, a historical perspective, and a systematic literature review. Because of the large number of studies reviewed, much of the information is presented in tables, with text limited to summaries of data.
      There are no large, long-term, placebo-controlled randomized clinical trials in the field of T therapy to provide definitive conclusions about CV risk. Nonetheless, there exists a rich literature spanning many decades that provides valuable information. As described in more detail subsequently, the 2 recent articles contradict this literature, and on careful review, neither provides credible evidence of increased CV risks. Only 2 additional studies are generally cited as support for that view. In contrast, many dozens of studies, including a modest number of randomized controlled trials (RCTs), indicate that low serum T concentrations are associated with increased CV risk and mortality and that T therapy may have clinically relevant CV benefits. This last point will be new to many readers. A recently published meta-analysis of 75 placebo-controlled studies, the largest to date, found no evidence of increased CV risk with T therapy and clear evidence of improved metabolic profiles.
      • Corona G.
      • Maseroli E.
      • Rastrelli G.
      • et al.
      Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.
      Given the personal suffering of men with TD as well as the public health burden of TD, the recent controversy regarding T and CV disease presents an important opportunity to understand the science underlying this critical medical issue.

      Background

      Testosterone deficiency is a clinical syndrome characterized by a set of signs and symptoms in combination with low serum T concentrations.
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • et al.
      Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA)
      Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
      Symptoms include decreased libido, erectile dysfunction, difficulty achieving orgasm, reduced intensity of orgasm, fatigue, decreased energy, depressed mood, irritability, and decreased sense of well-being. Objective signs include anemia, decreased bone density, reduced muscle strength and mass, increased body fat mass (both visceral and total), and weight gain.
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • et al.
      Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA)
      Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
      Androgen deprivation therapy, used in the treatment of advanced prostate cancer, causes profound TD and is associated with negative changes in body composition as well as increased risk of incident diabetes mellitus.
      • Keating N.L.
      • O'Malley A.J.
      • Smith M.R.
      Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.
      The goal of T therapy is to alleviate symptoms and signs by restoring T concentrations to optimal levels within the physiologic range.
      Established benefits of T therapy in hypogonadal men include improved sexual desire and function,
      • Boloña E.R.
      • Uraga M.V.
      • Haddad R.M.
      • et al.
      Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials.
      • Corona G.
      • Isidori A.M.
      • Buvat J.
      • et al.
      Testosterone supplementation and sexual function: a meta-analysis study.
      • Wang C.
      • Swerdloff R.S.
      • Iranmanesh A.
      • et al.
      Testosterone Gel Study Group
      Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      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.
      improved energy, mood, and vitality,
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      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.
      • Tong S.F.
      • Ng C.J.
      • Lee B.C.
      • et al.
      Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
      • Pexman-Fieth C.
      • Behre H.M.
      • Morales A.
      • Kan-Dobrosky N.
      • Miller M.G.
      A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel.
      • Yassin D.J.
      • Doros G.
      • Hammerer P.G.
      • Yassin A.A.
      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.
      • Srinivas-Shankar U.
      • Roberts S.A.
      • Connolly M.J.
      • et al.
      Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
      increased lean mass,
      • Wang C.
      • Swerdloff R.S.
      • Iranmanesh A.
      • et al.
      Testosterone Gel Study Group
      Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.
      • Srinivas-Shankar U.
      • Roberts S.A.
      • Connolly M.J.
      • et al.
      Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
      • Finkelstein J.S.
      • Lee H.
      • Burnett-Bowie S.A.
      • et al.
      Gonadal steroids and body composition, strength, and sexual function in men.
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      • Bhasin S.
      • Travison T.G.
      • Storer T.W.
      • et al.
      Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.
      decreased waist circumference,
      • Haider A.
      • Yassin A.
      • Doros G.
      • Saad F.
      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.
      • Saad F.
      • Haider A.
      • Doros G.
      • Traish A.
      Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss.
      • Traish A.M.
      • Haider A.
      • Doros G.
      • Saad F.
      Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study.
      • Yassin A.
      • Doros G.
      Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss.
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      BLAST Study Group
      Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.
      reduced total body fat mass,
      • Srinivas-Shankar U.
      • Roberts S.A.
      • Connolly M.J.
      • et al.
      Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
      • Finkelstein J.S.
      • Lee H.
      • Burnett-Bowie S.A.
      • et al.
      Gonadal steroids and body composition, strength, and sexual function in men.
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      • Bhasin S.
      • Travison T.G.
      • Storer T.W.
      • et al.
      Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.
      and increased bone mineral density.
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      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.
      • Wang C.
      • Cunningham G.
      • Dobs A.
      • et al.
      Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men.
      • Wang C.
      • Swerdloff R.S.
      • Iranmanesh A.
      • et al.
      Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men.
      Promising new data reveal that T therapy improves insulin sensitivity
      • Jones T.H.
      • Arver S.
      • Behre H.M.
      • et al.
      TIMES2 Investigators
      Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      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.
      • Heufelder A.E.
      • Saad F.
      • Bunck M.C.
      • Gooren L.
      Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
      and reduces blood glucose
      • Haider A.
      • Yassin A.
      • Doros G.
      • Saad F.
      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.
      • Traish A.M.
      • Haider A.
      • Doros G.
      • Saad F.
      Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study.
      • Haider A.
      • Saad F.
      • Doros G.
      • Gooren L.
      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.
      and hemoglobin A1c (HbA1c)
      • Haider A.
      • Yassin A.
      • Doros G.
      • Saad F.
      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.
      • Traish A.M.
      • Haider A.
      • Doros G.
      • Saad F.
      Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study.
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      BLAST Study Group
      Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.
      • Haider A.
      • Saad F.
      • Doros G.
      • Gooren L.
      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.
      levels in men with type 2 diabetes or obesity.
      Biochemical confirmation of TD has traditionally been made on the basis of low serum concentrations of total T (TT). Although no specific value reliably distinguishes men who will respond to treatment from those who will not, recommended thresholds for low TT range from 300 ng/dL (10.4 nmol/L)
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • et al.
      Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      to 400 ng/dL (13.9 nmol/L).
      • Morgentaler A.
      • Khera M.
      • Maggi M.
      • Zitzmann M.
      Commentary: who is a candidate for testosterone therapy? a synthesis of international expert opinions.
      Because a majority of circulating T is rendered biologically unavailable due to tight binding to sex hormone–binding globulin (SHBG), the unbound fraction called free T and/or the portion of T weakly bound to albumin may be more indicative of a man’s true androgen status.
      • Buvat J.
      • Maggi M.
      • Guay A.
      • Torres L.O.
      Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment.
      • Halmenschlager G.
      • Rhoden E.L.
      • Riedner C.E.
      Calculated free testosterone and radioimmunoassay free testosterone as a predictor of subnormal levels of total testosterone.
      These 2 fractions together represent bioavailable T. Men with high-normal or elevated SHBG concentrations may have TT concentrations within the normal range yet may still have TD due to reduced free T concentrations. This issue may be particularly relevant for older men because SHBG levels increase with age.
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • et al.
      EMAS Group
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      Levels below 65 to 100 pg/mL (<174-288 pmol/L) for calculated free T and 0.8 to 1.5 ng/dL (27-52 pmol/L) for directly measured free T have been used clinically to identify men who are candidates for treatment.
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA)
      Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • et al.
      EMAS Group
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      • Morgentaler A.
      Commentary: guideline for male testosterone therapy; a clinician's perspective.
      However, laboratory-provided reference ranges are problematic because they are not clinically based and vary widely between assays, and even among laboratories using the same assays.
      • Lazarou S.
      • Reyes-Vallejo L.
      • Morgentaler A.
      Wide variability in laboratory reference values for serum testosterone.
      The prevalence of symptomatic TD ranges from 2.1% to 12.8% in middle-aged to older men, with an incidence of 12 new cases per 1000 person-years in the United States and Europe.
      • Zarotsky V.
      • Huang M.-Y.
      • Carman W.
      • et al.
      Systematic literature review of the epidemiology of nongenetic forms of hypogonadism in adult males.
      Populations at high risk for low serum T levels include men with type 2 diabetes, obesity, chronic obstructive pulmonary disease, infection with human immunodeficiency virus, and chronic opioid use, all with prevalence rates greater than 30%.
      • Zarotsky V.
      • Huang M.-Y.
      • Carman W.
      • et al.
      Systematic literature review of the epidemiology of nongenetic forms of hypogonadism in adult males.
      Prescription rates for T products have increased substantially over the past decade.
      • Baillargeon J.
      • Urban R.J.
      • Ottenbacher K.J.
      • Pierson K.S.
      • Goodwin J.S.
      Trends in androgen prescribing in the United States, 2001 to 2011.
      • Gan E.H.
      • Pattman S.
      • Pearce S.H.S.
      • Quinton R.
      A UK epidemic of testosterone prescribing, 2001-2010.
      • Layton J.B.
      • Li D.
      • Meier C.R.
      • et al.
      Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011.
      This increase has led to concerns that T products are overprescribed because of aggressive marketing. However, as recently as 2007, the FDA indicated that as few as 5% of the hypogonadal population was treated,

      US Food and Drug Administration. http://www.fda.gov/fdac/departs/196_upd.html. Accessed March 6, 2007.

      with other studies reporting similarly low treatment rates.
      • Hall S.A.
      • Araujo A.B.
      • Esche G.R.
      • et al.
      Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey.
      The increase in T prescriptions seems to have resulted from increased awareness of TD and the benefits of T therapy among both physicians and patients, coupled with reduced concern regarding prostate cancer risk.
      • Khera M.
      • Crawford D.
      • Morales A.
      • Salonia A.
      • Morgentaler A.
      A new era of testosterone and prostate cancer: from physiology to clinical implications.
      Although it has been asserted that direct-to-consumer marketing is responsible for this growth, the evidence would suggest otherwise, as 2010 industry data failed to include any T products within the 25 most-marketed drugs in the United States.
      • Snyder Bulik B.
      Ad spending: 15 years of DTC.
      Whereas it was once believed that TD only occurred in association with several rare disorders, such as pituitary tumors, Klinefelter syndrome, or mumps orchitis, it is now understood that TD is common and often idiopathic. Symptoms and signs result directly from reduced serum concentrations of T, regardless of etiology, and can be induced experimentally in healthy volunteers of all ages simply by reducing serum T concentrations.
      • Finkelstein J.S.
      • Lee H.
      • Burnett-Bowie S.A.
      • et al.
      Gonadal steroids and body composition, strength, and sexual function in men.
      The relatively high prevalence of TD in middle-aged and older men has given rise to the concept of male menopause, or andropause. Although these terms have some conceptual appeal, TD differs importantly from menopause in that most men are unaffected, and the onset is gradual over an extended time course.
      • Saad F.
      • Gooren L.J.
      Late onset hypogonadism of men is not equivalent to the menopause.
      In addition, the age-related decline in serum T is relatively small,
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • et al.
      EMAS Group
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      and much of the decline can be attributed to comorbid conditions such as obesity.
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • et al.
      EMAS Group
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      • Travison T.G.
      • Araujo A.B.
      • Kupelian V.
      • O'Donnell A.B.
      • McKinlay J.B.
      The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men.
      • Fui M.N.
      • Dupuis P.
      • Grossmann M.
      Lowered testosterone in male obesity: mechanisms, morbidity and management.
      At this time, there are insufficient data to support T therapy for disease prevention or antiaging.
      Testosterone therapy has been in use for more than 70 years for the treatment of TD,
      • Nieschlag E.
      • Nieschlag S.
      Testosterone deficiency: a historical perspective.
      and several of the earliest reports documented benefits specifically for CV disease. From the late 1930s into the 1950s, several studies reported marked benefits of T therapy in patients with peripheral vascular disease
      • Beaser S.B.
      • Massell T.B.
      Therapeutic evaluation of testosterone in peripheral vascular disease.
      • Edwards E.A.
      • Hamilton J.B.
      • Duntley S.Q.
      Testosterone propionate as therapeutic agent in patients with organic disease of the peripheral vessels—preliminary report.
      and angina pectoris.
      • Uricchio J.F.
      • Calenda D.G.
      Treatment of angina pectoris.
      • Lesser M.A.
      The treatment of angina pectoris with testosterone propionate—preliminary report.
      • Lesser M.A.
      The treatment of angina pectoris with testosterone propionate—further observations.
      • Levine S.A.
      • Likoff W.B.
      The therapeutic value of testosterone propionate in angina pectoris.
      • Lesser M.A.
      Testosterone propionate therapy in one hundred cases of angina pectoris.
      Lesser
      • Lesser M.A.
      Testosterone propionate therapy in one hundred cases of angina pectoris.
      described 100 consecutive patients (92 men and 8 women) ranging from 34 to 77 years of age with angina pectoris who received T therapy with follow-up ranging from a few months to 5 years. Improvement was noted in 91%, with no appreciable improvement in patients treated with placebo.
      • Lesser M.A.
      Testosterone propionate therapy in one hundred cases of angina pectoris.
      A wealth of modern data accumulated over the past 2 decades has generally revealed that a low serum T level is associated with increased risks of atherosclerosis, CV risk factors, and mortality and that T therapy has beneficial effects on multiple risk factors and risk biomarkers related to these clinical conditions. Notably, TD has been projected to be involved in the development of approximately 1.3 million new cases of CV disease, 1.1 million new cases of diabetes, and over 600,000 osteoporosis-related fractures.
      • Moskovic D.J.
      • Araujo A.B.
      • Lipshultz L.I.
      • Khera M.
      The 20-year public health impact and direct cost of testosterone deficiency in U.S. men.
      Over a 20-year period, TD has been estimated to be directly responsible for approximately $190 to $525 billion in inflation-adjusted US health care expenditures.
      • Moskovic D.J.
      • Araujo A.B.
      • Lipshultz L.I.
      • Khera M.
      The 20-year public health impact and direct cost of testosterone deficiency in U.S. men.
      In addition, longitudinal models predict increased outpatient visits and costs related to low baseline serum T levels independent of socioeconomic and lifestyle factors; even when controlling for age, men aged 20 to 79 years at baseline with low serum T levels had 29% more outpatient visits and 38% higher outpatient costs at 5-year follow-up.
      • Haring R.
      • Baumeister S.E.
      • Völzke H.
      • et al.
      Prospective association of low serum total testosterone levels with health care utilization and costs in a population-based cohort of men.
      Numerous intervention studies have consistently found improvements in CV risk factors such as fat mass, obesity, waist circumference, blood pressure, and glycemic control. These important findings provide a reasonable biological mechanism to explain the frequently observed outcome of increased mortality among men with the lowest quartiles or quintiles of serum T or with frank TD.
      • Khaw K.T.
      • Dowsett M.
      • Folkerd E.
      • et al.
      Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
      • Laughlin G.A.
      • Barrett-Connor E.
      • Bergstrom J.
      Low serum testosterone and mortality in older men.
      • Corona G.
      • Rastrelli G.
      • Monami M.
      • et al.
      Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study.
      • Haring R.
      • Völzke H.
      • Steveling A.
      • et al.
      Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79.
      • Menke A.
      • Guallar E.
      • Rohrmann S.
      • et al.
      Sex steroid hormone concentrations and risk of death in US men.
      • Tivesten A.
      • Vandenput L.
      • Labrie F.
      • et al.
      Low serum testosterone and estradiol predict mortality in elderly men.
      • Yeap B.B.
      • Alfonso H.
      • Chubb S.A.
      • et al.
      In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality.
      Importantly, TD in older men is associated with increased risk of death during the 20 years after diagnosis, independent of multiple traditional risk factors and several preexisting health conditions.
      • Laughlin G.A.
      • Barrett-Connor E.
      • Bergstrom J.
      Low serum testosterone and mortality in older men.
      • Haring R.
      • Völzke H.
      • Steveling A.
      • et al.
      Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79.
      Small randomized, placebo-controlled T trials have documented reduction in carotid intima-media thickness with T therapy, raising the possibility that normalizing serum T may actually cause reversal of atherosclerosis in critical vascular beds. Moreover, 2 studies published within the past 2 years, one in a Veterans Administration population
      • Shores M.M.
      • Smith N.L.
      • Forsberg C.W.
      • Anawalt B.D.
      • Matsumoto A.M.
      Testosterone treatment and mortality in men with low testosterone levels.
      and the other in diabetic men,
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      found mortality reduced by half in men with TD who received T prescriptions compared with similar men who did not, It was therefore surprising that publication of 2 retrospective studies reporting increased risks of CV adverse events would cause such great concern. In one of these studies, Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      reported increased rates of MIs, strokes, and deaths in men who received T prescriptions compared with untreated men; this study used unvalidated statistical methodology that reversed the raw data, which actually revealed that the percentage of adverse events in T-treated men was lower by half compared with untreated men.
      • Morgentaler A.
      • Kacker R.
      Andrology: testosterone and cardiovascular risk—deciphering the statistics.
      Large data errors revealed postpublication led to a call for retraction by no less than 29 medical societies.
      • Morgentaler A.
      • Lunenfeld B.
      Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation.
      The second study by Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      reported an increased rate of nonfatal MI up to 90 days after receipt of a T prescription compared with the previous 12 months. However, MI rates postprescription were low, there was no control group, and methodological issues again rendered the study results highly questionable.
      • Morgentaler A.
      Testosterone, cardiovascular risk, and hormonophobia.
      In response to the publication of these 2 studies and their attendant publicity, the FDA

      US Food and Drug Administration. Testosterone products: drug safety communication - FDA investigating risk of cardiovascular events. US Food and Drug Administration website. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm384225.htm. Published January 31, 2014. Accessed August 31, 2014.

      announced its intention to review CV risks with T products 2 days after publication of the study by Finkle et al.
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      Although an advisory committee meeting was scheduled for September 17, 2014, the FDA had already made public its own analysis of the literature in its denial of a petition by the group Public Citizen to add black box warnings and other restrictions to T products.

      US Food and Drug Administration. Citizen petition denial response from FDA CDER to Public Citizen. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003. Published July 16, 2014. Accessed August 31, 2014.

      The FDA’s comments are included where appropriate in the analysis that follows.

      Methods

      A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. Additional studies were sought by examining publications with their own literature reviews. Tables were created with results provided by abstracts or from the full text of the article, depending on the adequacy of abstracted information.
      A review of the literature was performed for 9 specific topics related to T and CV risks: mortality; incident CAD; severity of CAD; ischemic stroke; carotid intima-media thickness; obesity/fat mass; lipid profiles; glycemic control; and inflammatory markers. A summary statement was made regarding the interpretation of relevant studies in those areas, and level of evidence supporting that conclusion was adjudicated by 2 authors (M.M., A.T.).

      Analysis

      In contrast to many dozens of studies documenting the beneficial CV effects of T therapy in humans, there appear to be only 4 articles that suggest increased CV risk. These 4 articles were also identified by the FDA analysis. These articles are the 2 retrospective large dataset analyses of Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      and Finkle et al,
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      a meta-analysis by Xu et al,
      • Xu L.
      • Freeman G.
      • Cowling B.J.
      • Schooling C.M.
      Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
      and a report of incidental CV adverse events in a placebo-controlled T gel study designed to assess muscular and functional benefits in elderly, frail men with mobility limitations by Basaria et al.
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      Although few in number, these studies have garnered considerable attention in the medical literature and lay press, and therefore merit individual analysis here.

      Vigen et al, JAMA 2013

      Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      conducted a retrospective analysis of men who had undergone coronary angiography within the Veterans Administration health care system. The authors reported that the overall rate of MI, stroke, and death in men with serum T levels less than 300 ng/dL (to convert to nmol/L, multiply by 0.0347) was higher in men who received a T prescription compared with untreated men. Although no statistically significant differences were noted at years 1, 2, or 3, the overall rate of events over the course of the study was reported to be significantly higher (29%) in T-treated men.
      Strangely, the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk, 10.1%) as in the untreated group (1587 events in 7486 men, 21.2%) (Figure).
      • Traish A.M.
      • Guay A.T.
      • Morgentaler A.
      Death by testosterone? we think not!.
      The authors failed to acknowledge this fact and came to an opposite interpretation of the data based on complex statistics that included adjustment for more than 50 variables. The methodology in this study, ie, stabilized inverse propensity treatment weighting applied to Kaplan-Meier curves with time as a covariate, was described in an article by senior author Michael P. Ho just a year earlier (2012) as follows: “Clearly, assessing and confirming adequate covariate balance in IPTW time-varying models is challenging and needs further study… Further work with simulations and contrasts to other methods and other study applications would help elucidate the advantages and disadvantages of this approach.”
      • Xu S.
      • Shetterly S.
      • Powers D.
      • et al.
      Extension of Kaplan-Meier methods in observational studies with time-varying treatment.
      The authors fail to provide any citations or other evidence in their 2013 article by Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      that these major methodological concerns have been resolved and that the methodology itself is accurate or accepted by other investigators.
      Figure thumbnail gr1
      FigureActual percentage of individuals who experienced an adverse cardiovascular event in the testosterone (T)-treated and untreated groups in the study by Vigen et al.
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      The authors reported a higher rate of adverse events in the T-treated group using inverse stabilized propensity weighting in which an event was counted as more than 1 event in the T-treated group and less than 1 event in the untreated group. MI = myocardial infarction.
      From J Sex Med,
      • Traish A.M.
      • Guay A.T.
      • Morgentaler A.
      Death by testosterone? we think not!.
      with permission. ©2014 International Society for Sexual Medicine.
      This article has already undergone 2 official corrections. The first, published January 15, 2014, was for misreporting of primary results as “absolute risk,” a term that suggests the results were based on raw data.
      Correction: Incorrect language.
      In response to criticism following publication, the article was corrected to replace the term absolute risk with Kaplan-Meier estimated cumulative percentages with events, a term that more accurately reflects the highly statistical nature of the results. On March 5, 2014, JAMA published a second correction.
      Correction: Incorrect number of excluded patients reported in the text and figure.
      In response to a letter challenging the exclusion of 1132 men who had suffered adverse events in the non-T group, the authors revealed they had made a series of errors. The number of men in this excluded group was changed from 1132 to 128 men, a difference of greater than 1000 men. The value for a second group was found to be incorrect by more than 900 men. Most astonishingly, the all-male study group was found to include nearly 10% women. In response to these errors, 29 international medical societies and more than 160 physician-scientists from 32 countries petitioned JAMA to retract this article, citing “gross data mismanagement and contamination” that rendered the study “no longer credible.”
      • Morgentaler A.
      • Lunenfeld B.
      Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation.
      The medical societies urging retraction are listed in Table 1.
      Table 1Professional Societies Calling for Retraction of Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      Current list can be found at http://www.androgenstudygroup.org/co-signers/list-of-co-signersmedical-organizations.
      American Society for Men’s Health (ASMH)
      Brazilian Society of Endocrinology and Metabolism
      Canadian Men's Sexual Health Council
      Canadian Society for the Study of Men’s Health (CSSAM)
      European Society for the Study of the Aging Male (ESSAM)
      European Society for Sexual Medicine (ESSM)
      German Society for Men and Health
      Indonesian Andrologist Association
      International Society of Men’s Health (ISMH)
      International Society for Sexual Medicine (ISSM)
      International Society for the Study of the Aging Male (ISSAM)
      Irish Association of Sexual Medicine
      Italian Society of Andrology
      Italian Society of Andrology and Sexual Medicine
      Japan ASEAN Council for Men’s Health and Aging
      Japanese Society for Men’s Health
      Korean Society for Sexual Medicine and Andrology
      Malaysian Men’s Health Initiative
      Malaysian Society of Andrology and the Study of the Aging Male
      Men’s Health Initiative of British Columbia (Canada)
      Mexican Association of Bone and Mineral Metabolism
      Middle East Society for Sexual Medicine
      Russian Society for Men’s Health
      South Asian Society for Sexual Medicine
      Sexual Medicine Society of North America
      Sociedade Latinoamericana de Medicina Sexual (Latin American Society for Sexual Medicine)
      Society for Men's Health, Singapore
      Society for the Study of Androgen Deficiency
      Society for the Study of Andrology and Sexology, Singapore (SSASS)
      In summary, this study used an unvalidated methodology to reverse the results of raw data, which revealed a lower percentage of adverse events in the T-treated group compared with untreated men. Putting aside the multiple disturbing data errors that undermine the integrity of the study, this lower percentage of adverse CV events in the T-treated group is consistent with the results of 2 prior studies that reported mortality reduced by half in T-treated men compared with untreated men.
      • Shores M.M.
      • Smith N.L.
      • Forsberg C.W.
      • Anawalt B.D.
      • Matsumoto A.M.
      Testosterone treatment and mortality in men with low testosterone levels.
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      Those studies are reviewed in further detail in the “Testosterone Prescriptions and CV Outcomes” section.
      The FDA’s concluding comment regarding Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      was as follows: “Given the described limitations of the study by Vigen et al it is difficult to attribute the reported findings to testosterone treatment.”

      US Food and Drug Administration. Citizen petition denial response from FDA CDER to Public Citizen. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003. Published July 16, 2014. Accessed August 31, 2014.

      Finkle et al, PLoS One 2014

      The study by Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      was a retrospective study of a health insurance database that reported rates of nonfatal MI in the period up to 90 days after a T prescription and compared these rates to MI rates in the previous 12 months. The postprescription period was the time to first prescription refill, which for an unspecified number of men would have been 30 days rather than 90 days. The authors reported the rate ratio of MI postprescription to preprescription was 1.36, and the rate in men older than 65 years was 2.19. In comparison, no increase in MI rate was noted for men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i).
      Because the source was an insurance claims database, available information was limited to diagnosis codes, procedure codes, and prescriptions. There was no information available regarding several standard CV risk factors, such as diabetes, hypertension, hyperlipidemia, smoking history, or obesity, and no information concerning any blood test results, including serum T, or lipid profiles. The weakness of the dataset as an investigative tool for assessment of CV risk is underscored by the fact that the end point in the study, nonfatal MI, was determined solely by the use of an insurance diagnosis code without verification that MI occurred and without measures to increase the likelihood of capturing a true event, such as limiting events to the primary diagnosis code at hospital discharge.
      • Petersen L.A.
      • Wright S.
      • Normand S.L.
      • Daley J.
      Positive predictive value of the diagnosis of acute myocardial infarction in an administrative database.
      An error rate as high as 12% has been reported when such measures are not followed.
      • Fisher E.S.
      • Whaley F.S.
      • Krushat W.M.
      • et al.
      The accuracy of Medicare's hospital claims data: progress has been made, but problems remain.
      Methodologically, it was inappropriate to compare posttreatment rates of MI to pretreatment rates because these rates measure different things.
      • Morgentaler A.
      Testosterone, cardiovascular risk, and hormonophobia.
      The post–T prescription MI rate reasonably reflects the naturally occurring MI rate in this population, albeit with the aforementioned caveats regarding the accuracy of this type of database investigation. However, because men were included in the study on the basis of real-world receipt of a T prescription, the pre–T prescription MI reflected how often health care providers were willing to prescribe T to men with a recent (within 12 months) MI. Any reluctance to prescribe T to men with recent MI would result in a reduced preprescription MI rate. The rates of MI in the preprescription and postprescription periods thus measure different things, and the comparison is therefore meaningless.
      Moreover, the reported MI rates post–T prescription were all low, overall and for all subgroups. For example, the overall postprescription MI rate reported by Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      was 4.75 events per 1000 person-years. This result compares with a rate of 13 expected MIs per 1000 person-years using the National Institutes of Health heart attack risk calculator, inputting age 54 years (the mean age of the study participants) and favorable risk parameters (nonsmoker; total cholesterol, 230 mg/dL [to convert to mmol/L, multiply by 0.0259]; high-density lipoprotein [HDL] cholesterol, 40 mg/dL [to convert to mmol/L, multiply by 0.0259]; systolic blood pressure, 140 mm Hg).

      National Institutes of Health, National Heart, Lung, and Blood Institute. Risk assessment tool for estimating your 10-year risk of having a heart attack. National Heart, Lung, and Blood Institute website. http://cvdrisk.nhlbi.nih.gov/calculator.asp. Updated May, 2013. Accessed April 21, 2014.

      The observed MI rate among men who received a T prescription was thus approximately one-third the expected rate. In the absence of a control group of men who were untreated, it is impossible to determine whether these reported MI rates were higher, lower, or unchanged in association with a T prescription.
      Finally, the comparison with men who received a PDE5i prescription is uninterpretable. These were 2 dissimilar groups treated with dissimilar medications for dissimilar indications. Phosphodiesterase type 5 inhibitors are known to have vasodilatory properties, and one medication in this class, sildenafil, is approved for treatment of pulmonary hypertension, confounding any comparison because of the possibility that PDE5i’s may have beneficial effects on CV risk. This is a classic case of comparing apples and oranges.
      A key concept not addressed by Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      is that TD itself has been identified as a risk factor for CV events (reviewed in the “Testosterone and Mortality section). Given the short T exposure time of 30 to 90 days, one unexplored possibility is that any observed increased risk of MI was due to the underlying condition rather than from the treatment. For this reason, we agree with the FDA analysis, which concluded that “it is difficult to attribute the increased risk for non-fatal MI seen in the Finkle study to testosterone alone and not consider that the study participants might have remained hypogonadic and thus at higher risk for non-fatal MI.”

      US Food and Drug Administration. Citizen petition denial response from FDA CDER to Public Citizen. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003. Published July 16, 2014. Accessed August 31, 2014.

      Basaria et al, New England Journal of Medicine 2010

      Basaria et al
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      conducted a prospective randomized trial designed to investigate whether T gel provided greater muscular and functional benefits than placebo in a population of frail elderly men treated for 6 months. The study did indeed find a benefit of T treatment over placebo for muscular and functional responses but was terminated early because of the observation of increased adverse events categorized as “cardiovascular” in the treatment arm. There were 23 of these events in the T arm and 5 in the placebo arm.
      However, this study was not designed to investigate CV events, and none of these events were primary or secondary end points. Most of the reported “events” were incidentally noted, subjective, or of questionable clinical importance, such as palpitations, pedal edema, and premature ventricular contractions. None of these adverse events were defined before study enrollment, and there was no attempt to systematically investigate all participants for the presence of any of these events. The most frequently reported adverse event was pedal edema, with 5 cases in the T group and none in the placebo group. Given that the placebo group was composed of more than 100 frail elderly men with multiple comorbidities, it seems unlikely that none of them had any degree of pedal edema. This flaw underscores concerns about the interpretation of these data by Basaria et al
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      as indicative of true CV risk rates because it violated foundational concepts in clinical trials, ie, defined end points and systematic data acquisition.
      Four major adverse cardiac events (MACE) occurred: 1 death, 2 MIs, and 1 stroke, all of which occurred in the T group. Although troubling, this asymmetry is not uncommon with rare events in clinical trials. In a similar study in frail elderly men performed in the United Kingdom, there were 2 MACE (1 death, 1 MI), both occurring in the placebo group.
      • Srinivas-Shankar U.
      • Roberts S.A.
      • Connolly M.J.
      • et al.
      Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
      As Basaria et al
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      concluded, “The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.” A subsequent analysis suggested that events were associated with higher serum concentrations of T achieved with treatment using higher than approved doses of T, contrary to the recommendations of the Endocrine Society guidelines.
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • et al.
      Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      It is impossible to conclude from this study that T prescriptions confer an increased risk of CV events. The FDA concluded, “The Basaria study does appear to show an empirical dose-dependent association between testosterone and cardiovascular risk, but it was non-conclusive because of the small sample size and small number of events reported in the study, as well as the limitations with respect to confirming the events. The authors of this study have explicitly indicated that the differences between the groups in cardiovascular adverse events might have been due to chance alone.”

      US Food and Drug Administration. Citizen petition denial response from FDA CDER to Public Citizen. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003. Published July 16, 2014. Accessed August 31, 2014.

      Xu et al, BMC Medicine 2013

      In a meta-analysis of CV events in 27 placebo-controlled T studies of 12 weeks’ duration or longer, Xu et al
      • Xu L.
      • Freeman G.
      • Cowling B.J.
      • Schooling C.M.
      Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
      reported that more CV events occurred in men who received T compared with those who received placebo. This study is the only one of several meta-analyses and systematic reviews to suggest any increased risk with T therapy. As with all meta-analyses, results are greatly influenced by the definitions of end points of interest and the selection of studies. In this case, the authors specifically included only studies in which one or more CV events were reported, meaning that studies without any CV events were excluded. This selection process exaggerates the apparent rate of events and distorts absolute differences in event rates between groups. In addition, just 2 of the 27 studies contributed 35% of all CV events in the T arm.
      The disproportionate influence of these 2 studies on the outcome of the meta-analysis merits closer scrutiny. One is the study by Basaria et al
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      discussed previously, in which 18 of 23 events (incorrectly reported as 25 events by Xu et al
      • Xu L.
      • Freeman G.
      • Cowling B.J.
      • Schooling C.M.
      Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
      ) would not normally qualify as CV events. The other was the 1986 Copenhagen study
      Copenhagen Study Group for Liver Diseases
      Testosterone treatment of men with alcoholic cirrhosis: a double-blind study.
      in which a nonapproved oral formulation of micronized T was administered at a remarkably high dose of 600 mg/d to men with cirrhosis of the liver, resulting in serum T concentrations exceeding 4000 ng/dL (approximately 140 nmol/L) in a quarter of the T group and levels as high as 21,000 ng/dL (745 nmol/L), a value approximately 20 times the upper limit of the normal range. Because these oral forms of T are known to cause liver toxicity via a first-pass effect, it should be no surprise that markedly supraphysiologic T doses in a hepatically compromised population would prove harmful. Moreover, the authors appear to have categorized any bleeding event as “cardiovascular,” including the most frequently observed cause of death in this study, bleeding from esophageal varices. The authors listed 21 events as CV, yet only 1 (MI) could reasonably be considered as CV. This trial has little relevance to the question as to whether the clinical use of T therapy increases CV risks. Its inclusion and misreporting led to distorted results.
      Without the contributions of the Copenhagen study
      Copenhagen Study Group for Liver Diseases
      Testosterone treatment of men with alcoholic cirrhosis: a double-blind study.
      and the non-MACE in the study by Basaria et al,
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      the rates of adverse CV events in the T and placebo groups were similar, with a slightly lower rate in the T group (78 events in 1599 men [4.88%] vs 60 events in 1174 men [5.1%], respectively). It should be underscored that this is the only one of several previously published meta-analyses and systematic reviews to report increased risk with T treatment.
      • Calof O.M.
      • Singh A.B.
      • Lee M.L.
      • et al.
      Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.
      • Fernández-Balsells M.M.
      • Murad M.H.
      • Lane M.
      • et al.
      Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.
      • Haddad R.M.
      • Kennedy C.C.
      • Caples S.M.
      • et al.
      Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.
      Recently, Corona et al
      • Corona G.
      • Maseroli E.
      • Rastrelli G.
      • et al.
      Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.
      reported a meta-analysis of 75 studies, compared with the 27 analyzed by Xu et al.
      • Xu L.
      • Freeman G.
      • Cowling B.J.
      • Schooling C.M.
      Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
      The meta-analysis by Corona et al
      • Corona G.
      • Maseroli E.
      • Rastrelli G.
      • et al.
      Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.
      included 3016 men treated with T and 2446 treated with placebo for a mean treatment duration of 34 weeks. They found no significant association between T therapy and CV events, either as single events or as combined CV end points. Studies in men with metabolic derangements revealed a protective effect of T treatment.
      • Corona G.
      • Maseroli E.
      • Rastrelli G.
      • et al.
      Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.

      Summary

      None of the 4 studies cited as evidence supporting an increased CV risk with T administration provide compelling evidence of increased risk. Indeed, the articles by Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      and Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      could each arguably be described as documenting protective effects of T therapy on CV risk because the percentage of events was lower by half in the former and overall MI rates were only a fraction of expected rates in the latter. Events reported by Basaria et al
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      were not systematically investigated in all individuals, and most events were of questionable clinical importance. Finally, the results of Xu et al
      • Xu L.
      • Freeman G.
      • Cowling B.J.
      • Schooling C.M.
      Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
      appear to be due to the inclusion of questionable events and studies, and their conclusions are contradicted by several other meta-analyses.

      Review of Existing Literature

      Any objective assessment of the literature regarding T and CV effects must recognize a broad, rich literature in which numerous studies reveal increased CV concerns with TD and improvement in a variety of CV risk factors and some CV outcomes with T therapy. That literature has been summarized and tabulated and is included here in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9. Summary statements and levels of supporting evidence are provided in Table 10.
      Table 2Observational Studies of Serum Testosterone Concentrations and Mortality
      ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BT = bioavailable testosterone; CAD = coronary artery disease; CHD = coronary heart disease; CVD = cardiovascular disease; DHT = dihydrotestosterone; ESRD = end-stage renal disease; FT = free testosterone; HD = hemodialysis; HR = hazard ratio; LH = luteinizing hormone; MACE = major adverse cardiovascular events; MI = myocardial infarction; 25(OH)D = 25-hydroxyvitamin D; OR = odds ratio; PWV = pulse wave velocity; SHBG = sex hormone–binding globulin; TRT = testosterone replacement therapy; TT = total testosterone.
      Modified from J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, year (study)Subfraction of testosterone used for analysisSample sizeAge range/mean age (y)Mean follow-up (y)PopulationMajor findingRemarks
      Studies documenting a negative (inverse) association between endogenous testosterone and mortality
       Pye et al,
      • Pye S.R.
      • Huhtaniemi I.T.
      • Finn J.D.
      • et al.
      EMAS Study Group
      Late-onset hypogonadism and mortality in aging men.
      2014 (European Male Aging Study)
      TT, FT259940-794.3Community-based, EuropeTestosterone deficiency is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of testosterone and the presence of sexual symptoms contribute independentlyHR of low TT <8 nmol/L (irrespective of symptoms) for all-cause mortality, 2.3 (95% CI, 1.2-4.2)

      HR of low TT <8 nmol/L and FT <220 pmol/L for all-cause mortality, 5.5 (95% CI, 2.7-11.4)

      HR with 3 sexual symptoms (irrespective of serum testosterone level; compared with asymptomatic men), 3.2 (95% CI, 1.8-5.8)

      Similar risks observed for cardiovascular mortality
       Haring et al,
      • Haring R.
      • Teng Z.
      • Xanthakis V.
      • et al.
      Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.
      2013 (Framingham Heart Study)
      TT25475.55 and 10Community-based, United StatesHigher baseline TT concentrations were associated with lower mortality risk at 5 y

      Correction for multiple statistical testing (P<.005) rendered this association statistically nonsignificant

      Repeated analyses at 10-y follow-up revealed no significant association between sex steroids, gonadotropins or their trajectories and mortality
      HR (per quartile increment) of high FT for all-cause mortality, 0.74 (95% CI, 0.56-0.98)
       Muraleedharan et al,
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      2013
      5815.8Type 2 diabetesLow testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetesMortality increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=.003) when controlled for covariates

      In Cox regression model, multivariate-adjusted HR for decreased survival was 2.02 (95% CI, 1.2-3.4; P=.009).

      TRT (mean duration, 41.6±20.7 mo; n=64) associated with a reduced mortality of 8.4% compared with 19.2% (P=.002) in the untreated group (n=174)

      Multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI, 1.3-3.9; P=.004)
       Hyde et al,
      • Hyde Z.
      • Norman P.E.
      • Flicker L.
      • et al.
      Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study.
      2012 (Health in Men Study)
      TT, FT424970-88/775.1Population-based, AustraliaLower free testosterone (and higher SHBG and LH levels) were associated with all-cause mortality

      In cause-specific analyses, lower free testosterone (and higher LH) predicted CVD mortality, while higher SHBG predicted non-CVD mortality
      HR of low FT for all-cause mortality, 1.62 (95% CI, 1.20-2.19) for 100 vs 280 pmol/L

      HR of low FT for CVD mortality, 1.71 (95% CI, 1.12-2.62) for 100 vs 280 pmol/L
       Lerchbaum et al,
      • Lerchbaum E.
      • Pilz S.
      • Boehm B.O.
      • Grammer T.B.
      • Obermayer-Pietsch B.
      • März W.
      Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.
      2012
      TT, FT20697.7Coronary angiographyA combined deficiency of FT and 25(OH)D is significantly associated with fatal events in a large cohort of men referred for coronary angiographyMultivariate-adjusted HR for all-cause mortality, 2.11 (95% CI, 1.60-2.79)

      Multivariate-adjusted HR for CVD mortality, 1.77 (95% CI, 1.23-2.55)

      Multivariate-adjusted HR for non-CVD mortality, 2.33 (95% CI, 1.45-3.47)
       Haring et al,
      • Haring R.
      • Nauck M.
      • Völzke H.
      • et al.
      Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy.
      2011
      TT9.9Kidney dysfunctionMeasured TT levels may help detect high-risk individuals for potential therapeutic interventions and improve mortality risk assessment and outcomeHR for all-cause mortality in men with kidney dysfunction, 1.4 (95% CI, 1.02-1.92)

      HR for all-cause mortality in men with kidney dysfunction and low TT, 2.52 (95% CI, 1.08-5.85)
       Kyriazis et al,
      • Kyriazis J.
      • Tzanakis I.
      • Stylianou K.
      • et al.
      Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients.
      2011
      TT11127 moHD patientsTestosterone deficiency in male HD patients is associated with increased CVD and all-cause mortality

      Increased arterial stiffness may be a possible mechanism explaining this association
      Patients with testosterone deficiency had increased CVD and all-cause mortality, even after adjustment for age, body mass index, serum albumin and C-reactive protein levels, prevalent CVD, and HD duration

      Testosterone levels were inversely related to PWV (r=−0.441; P<.001)

      The association of testosterone with CVD mortality, but not with all-cause mortality, was lost after adjusting for PWV, an index of arterial stiffness
       Carrero et al,
      • Carrero J.J.
      • Qureshi A.R.
      • Nakashima A.
      • et al.
      Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease.
      2011
      TT26048-67/593ESRD, SwedenTestosterone deficiency is independently associated with cardiovascular comorbidity and death in logistic regression analyses

      Testosterone deficiency is a common finding among male patients with ESRD, and it is independently associated with inflammation, cardiovascular comorbidity and outcome
      OR of low TT for cardiovascular comorbidity was 2.51 (95% CI, 1.32-4.76) and for death was 2.0 (95% CI, 1.01-3.97)
       Haring et al,
      • Haring R.
      • Völzke H.
      • Steveling A.
      • et al.
      Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79.
      2010 (Study of Health in Pomerania)
      TT195420-79/58.77.2Population-based, GermanyLow TT is associated with increased risk of mortality from all causes and CV diseaseHR of low TT for all-cause mortality, 1.92 (95% CI, 1.18-3.14; P<.001)

      HR of low TT for CV mortality, 2.56 (95% CI, 1.15-6.52; P<.05)
       Malkin et al,
      • Malkin C.J.
      • Pugh P.J.
      • Morris P.D.
      • Asif S.
      • Jones T.H.
      • Channer K.S.
      Low serum testosterone and increased mortality in men with coronary heart disease.
      2010
      TT, BT930Not reported6.9CHD (positive angiographic findings)Low BT is inversely associated with time to all-cause and vascular mortalityHR of low BT for all-cause mortality, 2.2 (95% CI, 1.4-3.6; P<.0001)

      HR of low BT for vascular mortality, 2.2 (95% CI, 1.2-3.9; P=.007)
       Menke et al,
      • Menke A.
      • Guallar E.
      • Rohrmann S.
      • et al.
      Sex steroid hormone concentrations and risk of death in US men.
      2010 (Third National Health and Nutrition Examination Survey)
      TT, BT, FT1114≥20/4016Population-based, United StatesDecrease in FT and BT from 90th to 10th percentile is associated with increased risk of all-cause and CV mortality during the first 9 y of follow-upHR of FT decrease for all-cause mortality, 1.43 (95% CI, 1.09-1.87)

      HR of BT decrease for all-cause mortality, 1.52 (95% CI, 1.15-2.02)

      HR of FT decrease for CV mortality, 1.53 (95% CI, 1.05-2.23)

      HR of BT decrease for CV mortality, 1.63 (95% CI, 1.12-2.37)
       Corona et al,
      • Corona G.
      • Monami M.
      • Boddi V.
      • et al.
      Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction.
      2010
      16874.3Erectile dysfunctionTestosterone levels are associated with a higher mortality of MACE

      Identification of low testosterone levels identifies patients with an increased cardiovascular risk
      Proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds

      After adjustment for age and Chronic Disease Score in a Cox regression model, only the association between incident fatal MACE and testosterone <8 nmol/L (230 ng/dL) was confirmed (HR, 7.1 [95% CI, 1.8-28.6]; P<.001)
       Ponikowska et al,
      • Ponikowska B.
      • Jankowska E.A.
      • Maj J.
      • et al.
      Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease.
      2010
      TT, FT15365±919 moType 2 diabetes with CHDIn diabetic men with stable CAD, testosterone deficiency is common and related to high cardiovascular mortalityHR for CVD mortality per 1-SD increment in TT and FT: TT, 0.58 (95% CI, 0.39-0.87); FT, 0.65 (95% CI, 0.52-0.81)
       Militaru et al,
      • Militaru C.
      • Donoiu I.
      • Dracea O.
      • Ionescu D.D.
      Serum testosterone and short-term mortality in men with acute myocardial infarction.
      2010
      TT12630 dAcute MIA low level of testosterone was independently related to total short-term mortalityOR for TT quartiles 2,3, and 4 vs 1: 0.82 (95% CI, 0.67-1.03), 0.67 (95% CI, 0.52-0.86), and 0.70 (95% CI, 0.56-0.89), respectively (P trend, <.01)

      The mean level of TT = 4.1±2.9 ng/mL

      All nonsurvivors had TT ≤3 ng/mL
       Vikan et al,
      • Vikan T.
      • Schirmer H.
      • Njølstad I.
      • Svartberg J.
      Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study.
      2009 (Tromsø Study)
      TT, FT1568Not reported/ 59.611.2Population-based, Norway24% Higher risk of all-cause mortality for men with low FT levelsHR of low FT for all-cause mortality, 1.24 (95% CI, 1.01-1.54)
       Tivesten et al,
      • Tivesten A.
      • Vandenput L.
      • Labrie F.
      • et al.
      Low serum testosterone and estradiol predict mortality in elderly men.
      2009 (Osteoporotic Fractures in Men Study [MrOS])
      TT, FT2639 with TT,

      2618 with FT
      69-80/75.44.5Population-based, SwedenIncreasing levels of TT and FT are associated with decreasing risk of all-cause mortalityHR of high TT for all-cause mortality, 0.59 (P<.001)

      HR of high FT for all-cause mortality, 0.50 (P<.001)
       Carrero et al,
      • Carrero J.J.
      • Qureshi A.R.
      • Parini P.
      • et al.
      Low serum testosterone increases mortality risk among male dialysis patients.
      2009
      12641 moHemodialysisIn men undergoing hemodialysis, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney diseaseHR for TT in the lowest tertile for all-cause mortality, 2.03 (95% CI, 1.24-3.31)

      HR for TT in the lowest tertile for CVD mortality, 3.19 (95% CI, 1.49-6.83)

      Increased risk with low TT persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers but was lost after adjustment for creatinine
       Lehtonen et al,
      • Lehtonen A.
      • Huupponen R.
      • Tuomilehto J.
      • et al.
      Serum testosterone but not leptin predicts mortality in elderly men.
      2008
      TT18771-7210Population-based, FinlandSerum TT in elderly men is inversely associated with mortality

      Higher endogenous testosterone levels have a favorable effect on survival in elderly men
      OR of low TT for all-cause mortality, 0.93 (95% CI, 0.87-0.99)

      Mean baseline serum testosterone concentration was ∼14% higher (P<.024) in men who were alive at the end of the follow-up period compared with the deceased men
       Laughlin et al,
      • Laughlin G.A.
      • Barrett-Connor E.
      • Bergstrom J.
      Low serum testosterone and mortality in older men.
      2008 (Rancho Bernardo Study)
      TT, FT79463-78.9/71.211.8Population-based, United StatesLow TT and BT are associated with higher risk of all-cause and CV mortalityHR of low TT for all-cause mortality, 1.44 (P<.002)

      HR of low BT for all-cause mortality, 1.50 (P<.001)

      HR of low TT for CV mortality, 1.38 (95% CI, 1.02-1.85)

      HR of low BT for CV mortality, 1.36 (95% CI, 1.04-1.79)
       Khaw et al,
      • Khaw K.T.
      • Dowsett M.
      • Folkerd E.
      • et al.
      Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
      2007 (European Prospective Investigation Into Cancer in Norfolk)
      TT11,60640-79/67.37Population-based, EuropeLow TT is associated with higher risk of all-cause and CV mortality. Same trend was noted for CHD mortality, but statistical significance was not achievedOR of low TT for all-cause mortality, 0.59 (P<.001)

      OR of low TT for CV mortality, 0.53 (P<.01)
       Araujo et al,
      • Araujo A.B.
      • Kupelian V.
      • Page S.T.
      • Handelsman D.J.
      • Bremner W.J.
      • McKinlay J.B.
      Sex steroids and all-cause and cause-specific mortality in men.
      2007 (Massachusetts Male Aging Study)
      TT, FT168640-8015.3Population-based, United StatesHigh FT and low DHT levels are associated with ischemic heart diseaseTT and SHBG levels are not associated with all-cause mortality
       Shores et al,
      • Shores M.M.
      • Matsumoto A.M.
      • Sloan K.L.
      • Kivlahan D.R.
      Low serum testosterone and mortality in male veterans.
      2006
      TT858≥40/61.44.3Population-based, United StatesLow TT is associated with higher risk of all-cause mortalityHR of low TT for all-cause mortality, 1.88 (P<.001)
      Studies documenting no association between endogenous testosterone and mortality
       Shores et at,
      • Shores M.M.
      • Biggs M.L.
      • Arnold A.M.
      • et al.
      Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the Cardiovascular Health Study.
      2014 (Cardiovascular Health Study)
      TT, FT, DHT103266-97/769Community-based, United StatesIn a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortalityIn models adjusted for cardiovascular risk factors, TT and FT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P<.002 and P=.04, respectively) and all-cause mortality (P<.001 for both)
      Studies documenting a positive association between endogenous testosterone and mortality
       None identified
      a ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BT = bioavailable testosterone; CAD = coronary artery disease; CHD = coronary heart disease; CVD = cardiovascular disease; DHT = dihydrotestosterone; ESRD = end-stage renal disease; FT = free testosterone; HD = hemodialysis; HR = hazard ratio; LH = luteinizing hormone; MACE = major adverse cardiovascular events; MI = myocardial infarction; 25(OH)D = 25-hydroxyvitamin D; OR = odds ratio; PWV = pulse wave velocity; SHBG = sex hormone–binding globulin; TRT = testosterone replacement therapy; TT = total testosterone.
      Table 3Association Between Testosterone Level and Incident Coronary Artery Disease
      BT = bioavailable testosterone; CAD = coronary artery disease; CCS = case-control study; CHD = coronary heart disease; CS = cohort study; ECG = electrocardiography; FAI = free androgen index; FT = free testosterone; H&P = history and physical examination; HR = hazard ratio; IAD = ischemic arterial disease; PCS = prospective cohort study; SHBG = sex hormone–binding globulin; TT = total testosterone.
      Modified from J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, year (type of study, No. of patients)Subfraction of testosterone used for analysisPrimary end point measured (method)Main finding of studyPotential confounding factors
      Studies documenting an association between low testosterone levels and incident CAD
       Zhao & Lil,
      • Zhao S.P.
      • Li X.P.
      The association of low plasma testosterone level with coronary artery disease in Chinese men.
      1998 (CCS, 201)
      TTCAD (H&P, ECG, cardiac catheterization in 27 patients)Men with CAD have lower levels of TTBT not used for analysis

      Limited number of patients underwent catheterization

      Small sample size
       English et al,
      • English K.M.
      • Mandour O.
      • Steeds R.P.
      • Diver M.J.
      • Jones T.H.
      • Channer K.S.
      Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms.
      2000 (CCS, 90)
      TT, FT, BT, FAICAD (cardiac catheterization)Men with catheterization-proven CAD have lower levels of FT, BT, and FAISmall sample size
       Dobrzycki et al,
      • Dobrzycki S.
      • Serwatka W.
      • Nadlewski S.
      • et al.
      An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
      2003 (CCS, 96)
      TT, FT, FAICAD (cardiac catheterization)Men with catheterization-proven CAD have lower levels of TT, FT, and FAIBT not used for analysis

      Small sample size
       Akishita et al,
      • Akishita M.
      • Hashimoto M.
      • Ohike Y.
      • et al.
      Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors.
      2010 (CS, 171)
      TTCardiovascular events
      Cardiovascular events included stroke, CAD, sudden cardiac death, and peripheral arterial disease.
      (H&P, physician and hospital records)
      Men with lower levels of endogenous TT are more likely to have cardiovascular eventsBT not used for analysis

      Small sample size

      End points other than CAD were pulled in the analysis

      Patients did not undergo cardiac catheterization
       Rosano et al,
      • Rosano G.M.
      • Sheiban I.
      • Massaro R.
      • et al.
      Low testosterone levels are associated with coronary artery disease in male patients with angina.
      2007 (CCS, 129)
      TT, FT, BTCAD (cardiac catheterization)Men with catheterization-proven CAD have lower levels of TT and BTSmall sample size
       Hu et al,
      • Hu X.
      • Rui L.
      • Zhu T.
      • et al.
      Low testosterone level in middle-aged male patients with coronary artery disease.
      2011 (CCS, 87)
      TTCAD (cardiac catheterization)Men with catheterization-proven CAD have lower levels of TTBT not used for analysis

      Small sample size
      Studies documenting a complex association between serum testosterone concentrations and incident CAD
       Soisson et al,
      • Soisson V.
      • Brailly-Tabard S.
      • Helmer C.
      • et al.
      A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study.
      2013 (PCS [French 3C], 3650 men aged >65 y)
      TT, BTCHD and strokeAfter adjustment for cardiovascular risk factors, a J-shaped association between plasma TT and IAD risk was found (P<.01)

      The HRs associated with the lowest and the highest TT quintiles relative to the second quintile were 2.23 (95% CI, 1.02-4.88) and 3.61 (95% CI, 1.55-8.45), respectively
      Additional analysis for CHD had similar results (HR, 3.11 [95% CI, 1.27-7.63] and 4.75 [95% CI, 1.75-12.92], respectively)

      Similar J-shaped association was observed between BT and IAD risk (P=.01)

      No significant association of estradiol and SHBG with IAD was found
      Studies documenting no association between testosterone levels and incident CAD
       Cauley et al,
      • Cauley J.A.
      • Gutai J.P.
      • Kuller L.H.
      • Dai W.S.
      Usefulness of sex steroid hormone levels in predicting coronary artery disease in men.
      1987 (CCS, 163)
      TT, FTAcute, nonfatal myocardial infarction, death from cardiovascular disease (ECG, hospital records)No difference in TT or FT levels between cases and controlsBT not used for analysis

      Small sample size

      Patients did not undergo cardiac catheterization
       Barrett-Connor & Khaw,
      • Barrett-Connor E.
      • Khaw K.T.
      Endogenous sex hormones and cardiovascular disease in men: a prospective population-based study.
      1988 (CS, 1009)
      TTCardiovascular disease or mortality, ischemic heart disease morbidity or mortality (death certificates, hospital records)No statistically significant association between levels of TT and primary end pointsBT not used for analysis

      Patients did not undergo cardiac catheterization
       Kabakci et al,
      • Kabakci G.
      • Yildirir A.
      • Can I.
      • Unsal I.
      • Erbas B.
      Relationship between endogenous sex hormone levels, lipoproteins and coronary atherosclerosis in men undergoing coronary angiography.
      1999 (CCS, 337)
      TT, FTCAD (cardiac catheterization)No statistically significant difference in FT or TT levels between cases and controlsBT not used in analysis

      Small sample size

      Suboptimal method used for measurement of FT
       Arnlöv et al,
      • Arnlöv J.
      • Pencina M.J.
      • Amin S.
      • et al.
      Endogenous sex hormones and cardiovascular disease incidence in men.
      2006 (PCS, 2084)
      TTCardiovascular disease
      Cardiovascular disease included CAD, myocardial infarction, angina pectoris, coronary insufficiency, death from CAD, stroke, transient ischemic attack, congestive heart failure, and peripheral vascular disease.
      (physician and hospital records)
      No significant association between levels of endogenous TT and incidence of CADBT not used for analysis

      End points other than CAD were pooled in the analysis

      Patients did not undergo cardiac catheterization
      Studies documenting an association between high serum concentrations of testosterone and incident CAD
       None identified
      a BT = bioavailable testosterone; CAD = coronary artery disease; CCS = case-control study; CHD = coronary heart disease; CS = cohort study; ECG = electrocardiography; FAI = free androgen index; FT = free testosterone; H&P = history and physical examination; HR = hazard ratio; IAD = ischemic arterial disease; PCS = prospective cohort study; SHBG = sex hormone–binding globulin; TT = total testosterone.
      b Cardiovascular events included stroke, CAD, sudden cardiac death, and peripheral arterial disease.
      c Cardiovascular disease included CAD, myocardial infarction, angina pectoris, coronary insufficiency, death from CAD, stroke, transient ischemic attack, congestive heart failure, and peripheral vascular disease.
      Table 4Association Between Serum Testosterone Concentrations and Severity of Coronary Artery Disease
      CAD = coronary artery disease; CCS = case-control study; FAI = free androgen index; FT = free testosterone; TT = total testosterone.
      From J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, year (type of study, No. of patients)Subfraction of testosterone used for analysisMethod of measuring CAD severityMain finding of studyComment
      Negative (inverse) correlation
       Dobrzycki et al,
      • Dobrzycki S.
      • Serwatka W.
      • Nadlewski S.
      • et al.
      An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
      2003 (CCS, 96)
      TT, FT, FAIDuke index
      Duke prognostic coronary artery index: a prognostic tool involving the extent and severity of atherosclerotic lesions in coronary arteries.
      Inverse correlation between FT and CAD severityr=−0.69, P=.048
       Li et al,
      • Li L.
      • Guo C.Y.
      • Jia E.Z.
      • et al.
      Testosterone is negatively associated with the severity of coronary atherosclerosis in men.
      2012 (CCS, 803)
      TTGensini score
      Genisi score: Calculation based on location and number of stenotic coronary artery segments and degree of luminal narrowing.
      Inverse correlation between TT and CAD severityr=−0.188, P<.001
       Phillips et al,
      • Phillips G.B.
      • Pinkernell B.H.
      • Jing T.Y.
      The association of hypotestosteronemia with coronary artery disease in men.
      1994 (CCS, 55)
      TT, FTVisual estimation of coronary artery occlusion and calculation of mean percent occlusion
      Authors visually estimated the maximum percent reduction in luminal diameter of the left main, left anterior descending, left circumflex, and right coronary arteries. The mean of these 4 values was used to estimate CAD severity.
      Inverse correlation between TT and FT levels and CAD severityTT: r=−0.43, P<.02;

      FT: r=−0.62, P<.001
       Rosano et al,
      • Rosano G.M.
      • Sheiban I.
      • Massaro R.
      • et al.
      Low testosterone levels are associated with coronary artery disease in male patients with angina.
      2007 (CCS, 129)
      TTCoronary artery score
      Coronary artery score: authors multiplied the degree of coronary artery obstruction by the number of stenoses.
      Inverse correlation between TT and CAD severityr=−0.52, P<.01
      Positive correlation
       None identified
      a CAD = coronary artery disease; CCS = case-control study; FAI = free androgen index; FT = free testosterone; TT = total testosterone.
      b Duke prognostic coronary artery index: a prognostic tool involving the extent and severity of atherosclerotic lesions in coronary arteries.
      c Genisi score: Calculation based on location and number of stenotic coronary artery segments and degree of luminal narrowing.
      d Authors visually estimated the maximum percent reduction in luminal diameter of the left main, left anterior descending, left circumflex, and right coronary arteries. The mean of these 4 values was used to estimate CAD severity.
      e Coronary artery score: authors multiplied the degree of coronary artery obstruction by the number of stenoses.
      Table 5Association Between Endogenous Testosterone Level and Carotid Intima-Media Thickness
      BMI = body mass index; CCS = case-control study; CS = cross-sectional study; FT = free testosterone; IMT = intima-media thickness; SHBG = sex hormone–binding globulin; TT = total testosterone.
      Reference, year (type of study)Sample sizeAge range/mean age (y)Main findings
      Negative (inverse) correlation
       De Pergola et al,
      • De Pergola G.
      • Pannacciulli N.
      • Ciccone M.
      • Tartagni M.
      • Rizzon P.
      • Giorgino R.
      Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men.
      2003 (CS)
      127 Overweight or obese men18-45/34After adjustment for age, total body fat, central obesity, and fasting glucose concentration, carotid artery IMT was inversely associated with FT
       Fu et al,
      • Fu L.
      • Gao Q.P.
      • Shen J.X.
      Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients.
      2008 (CCS)
      106 Men50-70/64FT was independently inversely associated with carotid artery IMT
       Fukui et al,
      • Fukui M.
      • Kitagawa Y.
      • Nakamura N.
      • et al.
      Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes.
      2003 (CS)
      154 Diabetic men62FT was inversely associated with carotid artery IMT

      Free testosterone was inversely associated with carotid artery plaque score

      Carotid artery IMT and plaque score were significantly higher in patients with lower levels of FT
       Mäkinen et al,
      • Mäkinen J.
      • Järvisalo M.J.
      • Pöllänen P.
      • et al.
      Increased carotid atherosclerosis in andropausal middle-aged men.
      2005 (CCS)
      96 Nondiabetic men40-70/57After adjustment for age, BMI, blood pressure, smoking, and total cholesterol, TT was inversely associated with carotid artery IMT
       Muller et al,
      • Muller M.
      • van den Beld A.W.
      • Bots M.L.
      • Grobbee D.E.
      • Lamberts S.W.
      • van der Schouw Y.T.
      Endogenous sex hormones and progression of carotid atherosclerosis in elderly men.
      2004 (CS)
      195 Men73-91/77FT was inversely associated with mean progression of carotid artery IMT independent of age

      FT was inversely associated with mean progression of carotid artery IMT after adjustment for cardiovascular risk factors
      Cardiovascular risk factors included body mass index, waist-to-hip ratio, hypertension, diabetes, smoking, and serum cholesterol levels.
       Soisson et al,
      • Soisson V.
      • Brailly-Tabard S.
      • Empana J.P.
      • et al.
      Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men.
      2012 (CS)
      354 Men≥65Analyses with and without adjustment for cardiovascular risk factors revealed that carotid IMT was inversely and significantly correlated with TT and bioavailable testosterone levels but not with SHBG and estradiol levels
       Svartberg et al,
      • Svartberg J.
      • von Mühlen D.
      • Mathiesen E.
      • Joakimsen O.
      • Bønaa K.H.
      • Stensland-Bugge E.
      Low testosterone levels are associated with carotid atherosclerosis in men.
      2006 (CS)
      1482 Men25-84/60After adjustment for age, smoking, physical activity, blood pressure, and lipid levels, TT was inversely associated with carotid artery IMT

      The association between TT and carotid artery IMT was not independent of BMI

      There was no association between FT and carotid artery IMT
       Tsujimura et al,
      • Tsujimura A.
      • Yamamoto R.
      • Okuda H.
      • et al.
      Low serum free testosterone level is associated with carotid intima-media thickness in middle-aged Japanese men.
      2012 (CS)
      176 Men≥40A multivariate model adjusted for age, BMI, mean arterial pressure, and treatment for hypertension revealed a significant association between FT and carotid artery IMT

      Even after adjustment for other clinically relevant factors, the significant association between FT and carotid artery IMT was not attenuated

      After adjustment for all other clinically relevant factors, both univariate and multivariate models ascertained the stepwise association that an FT level of ≤10.0 pg/mL was significantly associated with carotid artery IMT
       van den Beld et al,
      • van den Beld A.W.
      • Bots M.L.
      • Janssen J.A.
      • Pols H.A.
      • Lamberts S.W.
      • Grobbee D.E.
      Endogenous hormones and carotid atherosclerosis in elderly men.
      2003 (CS)
      403 Men73-94/77.8After adjustment for age, serum TT was inversely related to carotid artery IMT
       Vikan et al,
      • Vikan T.
      • Johnsen S.H.
      • Schirmer H.
      • Njølstad I.
      • Svartberg J.
      Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromsø study.
      2009 (CS)
      2290 Men55-74/66After adjustment for age, systolic blood pressure, smoking, and use of lipid-lowering medications, TT was inversely associated with total carotid plaque area

      SHBG was not associated with changes in carotid artery IMT or plaque area
      Positive correlation
       None identified
      a BMI = body mass index; CCS = case-control study; CS = cross-sectional study; FT = free testosterone; IMT = intima-media thickness; SHBG = sex hormone–binding globulin; TT = total testosterone.
      b Cardiovascular risk factors included body mass index, waist-to-hip ratio, hypertension, diabetes, smoking, and serum cholesterol levels.
      Table 6Changes in Parameters of Obesity With Testosterone Treatment vs Placebo
      From Curr Diabetes Rev,
      • Saad F.
      • Aversa A.
      • Isidori A.M.
      • Gooren L.J.
      Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review.
      with permission from Eureka Science LTD. ©2014 Bentham Science Publishers.
      Reference, yearTestosterone preparationTreatment durationChange T groupChange P groupNet change T over P
      Total fat mass (kg)
       Mårin et al,
      • Mårin P.
      • Holmäng S.
      • Gustafsson C.
      • et al.
      Androgen treatment of abdominally obese men.
      1993
      Gel9 mo−1.80.6−2.4
       Snyder et al,
      • Snyder P.J.
      • Peachey H.
      • Hannoush P.
      • et al.
      Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age.
      1999
      Patch36 mo−3.3−1.3−2.0
       Kennyet al,
      • Kenny A.M.
      • Prestwood K.M.
      • Gruman C.A.
      • Marcello K.M.
      • Raisz L.G.
      Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels.
      2001
      Patch12 mo−1.70.3−2.0
       Ferrando et al,
      • Ferrando A.A.
      • Sheffield-Moore M.
      • Yeckel C.W.
      • et al.
      Testosterone administration to older men improves muscle function: molecular and physiological mechanisms.
      2002
      TE6 mo−3.60.3−3.9
       Boyanov et al,
      • Boyanov M.A.
      • Boneva Z.
      • Christov V.G.
      Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
      2003
      Oral TU3 mo−1.65−0.25−1.4
       Crawford et al,
      • Crawford B.A.
      • Liu P.Y.
      • Kean M.T.
      • Bleasel J.F.
      • Handelsman D.J.
      Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment.
      2003
      Mixed esters12 mo−2.30.7−3.0
       Steidle et al,
      • Steidle C.
      • Schwartz S.
      • Jacoby K.
      • Sebree T.
      • Smith T.
      • Bachand R.
      North American AA2500 T Gel Study Group
      AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.
      2003
      Gel3 mo−0.8−0.1−0.7
      Patch3 mo−0.4−0.1−0.3
       Wittert et al,
      • Wittert G.A.
      • Chapman I.M.
      • Haren M.T.
      • Mackintosh S.
      • Coates P.
      • Morley J.E.
      Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status.
      2003
      Oral TU12 mo−0.20.85−1.05
       Casaburi et al,
      • Casaburi R.
      • Bhasin S.
      • Cosentino L.
      • et al.
      Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease.
      2004
      No trainingTE10 wk−1.01−0.08−0.93
      TrainingTE10 wk−1.41−0.13−1.28
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−5.4−0.6−4.8
       Allan et al,
      • Allan C.A.
      • Strauss B.J.
      • Burger H.G.
      • Forbes E.A.
      • McLachlan R.I.
      Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.
      2008
      Patch12 mo−0.50.1−0.6
       Emmelot-Vonk et al,
      • Emmelot-Vonk M.H.
      • Verhaar H.J.
      • Nakhai Pour H.R.
      • et al.
      Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.
      2008
      Oral TU6 mo−1.0−0.1−0.9
       Srinivas-Shankar et al,
      • Srinivas-Shankar U.
      • Roberts S.A.
      • Connolly M.J.
      • et al.
      Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
      2010
      Gel6 mo−0.8−0.3−0.5
      Visceral adipose tissue (kg)
       Mårin et al,
      • Mårin P.
      • Holmäng S.
      • Gustafsson C.
      • et al.
      Androgen treatment of abdominally obese men.
      1993
      Gel9 mo−0.60.2−0.8
       Allan et al,
      • Allan C.A.
      • Strauss B.J.
      • Burger H.G.
      • Forbes E.A.
      • McLachlan R.I.
      Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.
      2008
      Patch12 mo−0.20.5−0.7
      Trunk fat (kg)
       Casaburi et al,
      • Casaburi R.
      • Bhasin S.
      • Cosentino L.
      • et al.
      Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease.
      2004
      No trainingTE10 wk−0.550.34−0.89
      TrainingTE10 wk−0.670.11−0.78
       Page et al,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      2005
      TE36 mo−1.9−0.4−1.5
       Allan et al,
      • Allan C.A.
      • Strauss B.J.
      • Burger H.G.
      • Forbes E.A.
      • McLachlan R.I.
      Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.
      2008
      Patch12 mo0.10.00.1
      Visceral adipose tissue (cm3)
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−38−11−27
      Subcutaneous adipose tissue (kg)
       Mårin et al,
      • Mårin P.
      • Holmäng S.
      • Gustafsson C.
      • et al.
      Androgen treatment of abdominally obese men.
      1993
      Gel9 mo−1.20.5−1.7
       Allan et al,
      • Allan C.A.
      • Strauss B.J.
      • Burger H.G.
      • Forbes E.A.
      • McLachlan R.I.
      Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.
      2008
      Patch12 mo−0.10.0−0.1
      Subcutaneous adipose tissue (cm3)
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−49−10−39
      Total adipose tissue (cm3)
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−86−27−59
      Right leg fat (kg)
       Page et al,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      2005
      TE36 mo−0.90.1−1.0
      Percentage total body fat (%)
       Sih et al,
      • Sih R.
      • Morley J.E.
      • Kaiser F.E.
      • Perry III, H.M.
      • Patrick P.
      • Ross C.
      Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial.
      1997
      TC12 mo−1.919.3−21.2
       Boyanov et al,
      • Boyanov M.A.
      • Boneva Z.
      • Christov V.G.
      Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
      2003
      Oral TU3 mo−3−0.1−2.9
       Crawford et al,
      • Crawford B.A.
      • Liu P.Y.
      • Kean M.T.
      • Bleasel J.F.
      • Handelsman D.J.
      Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment.
      2003
      Mixed esters12 mo−10.93.4−14.3
       Steidle et al,
      • Steidle C.
      • Schwartz S.
      • Jacoby K.
      • Sebree T.
      • Smith T.
      • Bachand R.
      North American AA2500 T Gel Study Group
      AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.
      2003
      Gel3 mo−1.2−0.2−1.0
      Patch3 mo−0.5−0.2−0.3
       Casaburi et al,
      • Casaburi R.
      • Bhasin S.
      • Cosentino L.
      • et al.
      Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease.
      2004
      No trainingTE10 wk−6−0.1−5.9
      TrainingTE10 wk−9.4−2.2−7.2
       Page et al,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      2005
      TE36 mo−17.01.0−18.0
       Kapoor et al,
      • Kapoor D.
      • Clarke S.
      • Stanworth R.
      • Channer K.S.
      • Jones T.H.
      The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.
      2007
      Mixed esters3 mo−3.7−1.5−2.2
       Kapoor et al,
      • Kapoor D.
      • Goodwin E.
      • Channer K.S.
      • Jones T.H.
      Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
      2006
      Mixed esters3 mo−3.0−1.8−1.2
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−18.9−1.9−17.0
       Allan et al,
      • Allan C.A.
      • Strauss B.J.
      • Burger H.G.
      • Forbes E.A.
      • McLachlan R.I.
      Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.
      2008
      Patch12 mo−2.90.4−3.3
       Emmelot-Vonk et al,
      • Emmelot-Vonk M.H.
      • Verhaar H.J.
      • Nakhai Pour H.R.
      • et al.
      Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.
      2008
      Oral TU6 mo−4.70.0−4.7
       Aversa et al,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      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.
      2010
      Inj TU24 mo−18.50.5−19
       Aversa et al,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • Spera G.
      • Lenzi A.
      Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome.
      2010
      Inj TU12 mo−18.40.6−19.0
      Waist circumference (cm)
       Mårin et al,
      • Mårin P.
      • Holmäng S.
      • Gustafsson C.
      • et al.
      Androgen treatment of abdominally obese men.
      1993
      Gel9 mo−2.5−0.6−1.9
       Kapoor et al,
      • Kapoor D.
      • Clarke S.
      • Stanworth R.
      • Channer K.S.
      • Jones T.H.
      The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.
      2007
      Mixed esters3 mo−2.00.1−2.1
       Kapoor et al,
      • Kapoor D.
      • Goodwin E.
      • Channer K.S.
      • Jones T.H.
      Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
      2006
      Mixed esters3 mo−1.6NANA
       Svartberg et al,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      2008
      Inj TU12 mo−3.0−1.0−2.0
       Heufelder et al,
      • Heufelder A.E.
      • Saad F.
      • Bunck M.C.
      • Gooren L.
      Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
      2009
      Gel12 mo−14.6−6.7−7.9
       Aversa et al,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      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.
      2010
      Inj TU24 mo−8.5−0.5−8.0
       Kalinchenko et al,
      • Kalinchenko S.Y.
      • Tishova Y.A.
      • Mskhalaya G.J.
      • Gooren L.J.
      • Giltay E.J.
      • Saad F.
      Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
      2010
      Inj TU30 wk−5.8−1.5−4.3
       Aversa et al,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • Spera G.
      • Lenzi A.
      Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome.
      2010
      Inj TU12 mo−8.71.1−9.7
      Inj TU = parenteral testosterone undecanoate; Mixed esters = mixed parenteral testosterone esters; NA = not available; TC = parenteral testosterone cypionate; TE = parenteral testosterone enanthate; TU = testosterone undecanoate.
      Table 7Meta-analyses Regarding the Effects of Testosterone Administration on Lipid Concentrations
      From J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, yearMain findings
      Haddad et al,
      • Haddad R.M.
      • Kennedy C.C.
      • Caples S.M.
      • et al.
      Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.
      2007
      In patients with low levels of baseline testosterone, exogenous testosterone did not affect any of the lipid subfractions

      In patients with normal levels of baseline testosterone, exogenous testosterone resulted in a significant decrease in total cholesterol levels

      In patients with normal levels of baseline testosterone, exogenous testosterone did not affect the levels of LDL, HDL, or triglyceride levels

      In patients with chronic disease or in those on glucocorticoid therapy, exogenous testosterone resulted in a small decrease in levels of HDL

      In patients with chronic disease or in those on glucocorticoid therapy, exogenous testosterone did not affect the levels of total cholesterol, LDL, or triglycerides
      Isidori et al,
      • Isidori A.M.
      • Giannetta E.
      • Greco E.A.
      • et al.
      Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis.
      2005
      Exogenous testosterone resulted in reduced levels of total cholesterol

      The improvement in total cholesterol was more significant for patients with reduced levels of baseline testosterone

      No significant change in total cholesterol in patients with baseline testosterone of >10 nmol/L

      Exogenous testosterone did not affect levels of LDL or HDL

      The effect of testosterone replacement therapy on triglyceride levels was not examined in this meta-analysis
      Whitsel et al,
      • Whitsel E.A.
      • Boyko E.J.
      • Matsumoto A.M.
      • Anawalt B.D.
      • Siscovick D.S.
      Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis.
      2001
      Exogenous testosterone resulted in small but significant reduction in the levels of total cholesterol, LDL, and HDL

      Exogenous testosterone did not affect triglyceride levels
      HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol.
      Table 8Effects of Testosterone Therapy on Indices of Glycemic Control
      BMI = body mass index; CHF = congestive heart failure; DBPCC = double-blind placebo-controlled crossover study; DBRCT = double-blind randomized controlled trial; HgA1c = hemoglobin A1c; HOMA-IR = homeostatic model of insulin resistance; IM = intramuscular; MetS = metabolic syndrome; SBPCC = single-blind placebo-controlled crossover study; SBRCT = single-blind randomized controlled trial; T2DM = type 2 diabetes mellitus; T = transdermal; TG = triglycerides; TRT = testosterone replacement therapy; WC = waist circumference.
      From J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, year (study type)Testosterone formulation usedSample sizeEnd points measuredMain findings
      Studies documenting a beneficial effect of testosterone therapy on indices of glycemic control
       Corona et al,
      • Corona G.
      • Monami M.
      • Rastrelli G.
      • et al.
      Type 2 diabetes mellitus and testosterone: a meta-analysis study.
      2011 (meta-analysis, 37 studies)
      Various formulations (meta-analysis)1822 Diabetic men and 10,009 nondiabetic men (meta-analysis)HbA1c, fasting plasma glucose, triglyceridesHgA1c decreased by 0.76% with TRT

      Fasting plasma glucose decreased by 1.18 mmol/L with TRT

      TG decreased by 0.67 with TRT
       Heufelder et al,
      • Heufelder A.E.
      • Saad F.
      • Bunck M.C.
      • Gooren L.
      Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
      2009 (SBRCT)
      TD
      Heufelder et al34 administered testosterone gel, 50 mg TD, for 52 wk.
      16 Hypogonadal men with T2DMHOMA-IR, HbA1c, fasting plasma glucoseHOMA-IR decreased by 4.2 in TRT group (P<.001)

      HbA1c decreased by about 1% after 13 wk in TRT group (P<.001)

      HbA1c decreased by about 1.5% after 52 wk in TRT group (P<.001)

      Fasting plasma glucose decreased by 1.9 mmol/L in TRT group (P=.062)
       Jones et al,
      • Jones T.H.
      • Arver S.
      • Behre H.M.
      • et al.
      TIMES2 Investigators
      Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
      2011 (DBRCT)
      TD
      Jones et al32 administered testosterone 2% gel, 3-g metered dose (60 mg testosterone), for 12 mo.
      220 Hypogonadal men with T2DM and/or MetSHOMA-IR, HbA1c, body compositionHOMA-IR decreased by 15.2% after 6 mo with TRT (P=.018)

      HOMA-IR decreased by 16.4% after 12 mo with TRT (P=.006)

      HbA1c decreased by 0.44% after 9 mo with TRT (P=.035)
       Kalinchenko et al,
      • Kalinchenko S.Y.
      • Tishova Y.A.
      • Mskhalaya G.J.
      • Gooren L.J.
      • Giltay E.J.
      • Saad F.
      Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
      2011 (DBRCT)
      IM
      Kalinchenko et al145 administered testosterone undecanoate, 1000 mg IM, given at baseline and after 6 and 18 wk.
      113 Hypogonadal men with MetSHOMA-IR, fasting plasma glucose, BMI, WC, waist-to-hip ratioHOMA-IR decreased by 1.49 in TRT group (overall P=.04)

      No significant change in fasting plasma glucose in TRT group

      Significant reduction in BMI, weight, waist-to-hip ratio, hip circumference, and WC in TRT group (P<.001 for all except for waist-to-hip ratio; P=.04 for waist-to-hip ratio)
       Kapoor et al,
      • Kapoor D.
      • Goodwin E.
      • Channer K.S.
      • Jones T.H.
      Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
      2006 (DBPCC)
      IM
      Kapoor et al143 administered testosterone, 200 mg IM once every 2 wk for 3 mo.
      24 Hypogonadal men with T2DMHOMA-IR, HgA1c, fasting plasma glucoseHOMA-IR decreased by 1.73 in TRT group (P=.02)

      HgA1c decreased by 0.37% in TRT group (P=.03)

      Fasting plasma glucose decreased by 1.58 mmol/L in TRT group (P=.03)
       Malkin et al,
      • Malkin C.J.
      • Jones T.H.
      • Channer K.S.
      The effect of testosterone on insulin sensitivity in men with heart failure.
      2007 (SBPCC)
      IM
      Malkin et al150 administered Sustanon 250 (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/mL) IM injection. Two IM injections were given 2 wk apart.
      13 Men with CHF and no T2DMHOMA-IR, fasting plasma glucose, glucose tolerance, body compositionHOMA-IR decreased by 1.9 in TRT (P=.03)

      Fasting plasma glucose decreased by 0.61 mmol/L in TRT (P=.03)

      Total body mass increased by 1.5 kg in TRT (P=.008)

      Percent body fat decreased by 0.8% in TRT (P=.02)
      Studies documenting a detrimental effect of testosterone therapy on indices of glycemic control
       None identified
      a BMI = body mass index; CHF = congestive heart failure; DBPCC = double-blind placebo-controlled crossover study; DBRCT = double-blind randomized controlled trial; HgA1c = hemoglobin A1c; HOMA-IR = homeostatic model of insulin resistance; IM = intramuscular; MetS = metabolic syndrome; SBPCC = single-blind placebo-controlled crossover study; SBRCT = single-blind randomized controlled trial; T2DM = type 2 diabetes mellitus; T = transdermal; TG = triglycerides; TRT = testosterone replacement therapy; WC = waist circumference.
      b Heufelder et al
      • Heufelder A.E.
      • Saad F.
      • Bunck M.C.
      • Gooren L.
      Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
      administered testosterone gel, 50 mg TD, for 52 wk.
      c Jones et al
      • Jones T.H.
      • Arver S.
      • Behre H.M.
      • et al.
      TIMES2 Investigators
      Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
      administered testosterone 2% gel, 3-g metered dose (60 mg testosterone), for 12 mo.
      d Kalinchenko et al
      • Kalinchenko S.Y.
      • Tishova Y.A.
      • Mskhalaya G.J.
      • Gooren L.J.
      • Giltay E.J.
      • Saad F.
      Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
      administered testosterone undecanoate, 1000 mg IM, given at baseline and after 6 and 18 wk.
      e Kapoor et al
      • Kapoor D.
      • Goodwin E.
      • Channer K.S.
      • Jones T.H.
      Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
      administered testosterone, 200 mg IM once every 2 wk for 3 mo.
      f Malkin et al
      • Malkin C.J.
      • Jones T.H.
      • Channer K.S.
      The effect of testosterone on insulin sensitivity in men with heart failure.
      administered Sustanon 250 (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/mL) IM injection. Two IM injections were given 2 wk apart.
      Table 9Effects of Testosterone Therapy on Markers of Inflammation
      CCS = case-control study; CIMT = carotid artery intima-media thickness; CRP = C-reactive protein; DBPCC = double-blind placebo-controlled crossover study; DBRCT = double-blind randomized controlled trial; HDL = high-density lipoprotein cholesterol; HOMA-IR = homeostatic model of insulin resistance; hsCRP = high-sensitivity CRP; IL = interleukin; IM = intramuscular; LDL = low-density lipoprotein cholesterol; PO = by mouth; SBRCT = single-blind randomized controlled study; sICAM-1 = soluble intracellular adhesion molecule 1; sIL = soluble IL; sVCAM-1 = soluble vascular cell adhesion molecule 1; TD = transdermal; TG = triglycerides; TNF-α = tumor necrosis factor α; TRT = testosterone replacement therapy; TTh = testosterone therapy; VLDL = very low-density lipoprotein cholesterol.
      From J Am Heart Assoc,
      • Mesbah Oskui P.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      with permission.
      Reference, year (type of study)Sample sizeTestosterone formulation usedDuration of TThMain outcomes measuredMajor findings
      Studies documenting beneficial effect of testosterone therapy on markers of inflammation
       Aversa et al,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      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.
      2010 (DBRCT)
      50 Men (40 received TRT and 10 received placebo)Testosterone undecanoate, 1000 mg IM once every 12 wk24 mohsCRP, HOMA-IR, CIMTSignificant reduction in hsCRP with TTh

      Significant reduction in HOMA-IR with TTh

      Significant reduction in CIMT with TTh
       Guler et al,
      • Guler N.
      • Batyraliev T.
      • Dulger H.
      • et al.
      The effects of short term (3 weeks) testosterone treatment on serum inflammatory markers in men undergoing coronary artery stenting.
      2006 (CCS)
      41 Men (25 received TRT and 16 received placebo)Sustanon 250 IM once weekly
      Sustanon 250 contains 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate, and 100 mg testosterone decanoate.
      3 wkhsCRP, IL-6, TNF-αSignificant reduction in hsCRP with TTh

      Significant reduction in IL-6 with TTh

      Significant increase in TNF-α in both groups
       Kalinchenko et al,
      • Kalinchenko S.Y.
      • Tishova Y.A.
      • Mskhalaya G.J.
      • Gooren L.J.
      • Giltay E.J.
      • Saad F.
      Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
      2010 (DBRCT)
      171 Men (105 received TRT and 65 received placebo)Testosterone undecanoate, 1000 mg IMGiven at baseline and after 6 and 18 wkCRP, IL-1β, IL-6, IL-10, TNF-αSignificant reduction in CRP with TTh

      Significant reduction in TNF-α with TTh

      Significant reduction in IL-1β with TTh
       Kapoor et al,
      • Kapoor D.
      • Clarke S.
      • Stanworth R.
      • Channer K.S.
      • Jones T.H.
      The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.
      2007 (DBPCC)
      20 MenSustanon 200 IM once every 2 wk
      Sustanon 200 contains 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate, and 100 mg testosterone decanoate.
      3 moCRP, IL-6, TNF-α, leptin, adiponectin, resistinNo significant change in levels of CRP with TTh

      No significant change in levels of TNF-α with TTh

      No significant change in levels of IL-6 with TTh
       Malkin et al,
      • Malkin C.J.
      • Pugh P.J.
      • Jones R.D.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men.
      2004 (SBRCT)
      27 MenSustanon 100 IM once every 2 wk
      Sustanon 100 contains 20 mg testosterone propionate, 40 mg testosterone phenylpropionate, and 40 mg testosterone isocaproate.
      1 moTNF-α, IL-1β, IL-10Significant reduction in TNF-α with TTh

      Significant reduction in IL-1β with TTh

      Significant increase in IL-10 with TTh
      Studies documenting no effect of testosterone therapy on markers of inflammation
       Nakhai-Pour et al,
      • Nakhai-Pour H.R.
      • Grobbee D.E.
      • Emmelot-Vonk M.H.
      • Bots M.L.
      • Verhaar H.J.
      • van der Schouw Y.T.
      Oral testosterone supplementation and chronic low-grade inflammation in elderly men: a 26-week randomized, placebo-controlled trial.
      2007(DBRCT)
      237 MenTestosterone undecanoate, 160 mg PO daily26 wkhsCRPNo significant change in levels of hsCRP with TTh
       Ng et al,
      • Ng M.K.
      • Liu P.Y.
      • Williams A.J.
      • et al.
      Prospective study of effect of androgens on serum inflammatory markers in men.
      2002 (CCS)
      33 Men (16 received TTh and 17 were controls)Dihydrotestosterone, 70 mg TD daily3 mohsCRP, sIL-6, sICAM-1, sVCAM-1No significant change in levels of hsCRP with TTh

      No significant change in sICAM-1 with TTh

      No significant change in sVCAM-1 with TTh
       Singh et al,
      • Singh A.B.
      • Hsia S.
      • Alaupovic P.
      • et al.
      The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.
      2002 (DBRCT)
      61 MenPatients randomized to 1 of 5 treatment groups, each group receiving varying doses of testosterone enanthate
      Singh et al155 study: group 1 (n=12) received testosterone enanthate, 25 mg IM weekly; group 2 (n=12) received testosterone enanthate, 50 mg IM weekly; group 3 (n=12) received testosterone enanthate, 125 mg IM weekly; group 4 (n=11) received testosterone enanthate, 300 mg IM weekly; and group 5 (n=14) received testosterone enanthate, 600 mg IM weekly.
      20 wkTotal cholesterol, LDL, HDL, VLDL, TG, CRP, apolipoprotein B, apolipoprotein C-IIINo significant correlation between endogenous testosterone levels and levels of CRP

      No change in CRP levels with T therapy, regardless of the testosterone dose
      Studies documenting negative effect of testosterone therapy on markers of inflammation
       None identified
      a CCS = case-control study; CIMT = carotid artery intima-media thickness; CRP = C-reactive protein; DBPCC = double-blind placebo-controlled crossover study; DBRCT = double-blind randomized controlled trial; HDL = high-density lipoprotein cholesterol; HOMA-IR = homeostatic model of insulin resistance; hsCRP = high-sensitivity CRP; IL = interleukin; IM = intramuscular; LDL = low-density lipoprotein cholesterol; PO = by mouth; SBRCT = single-blind randomized controlled study; sICAM-1 = soluble intracellular adhesion molecule 1; sIL = soluble IL; sVCAM-1 = soluble vascular cell adhesion molecule 1; TD = transdermal; TG = triglycerides; TNF-α = tumor necrosis factor α; TRT = testosterone replacement therapy; TTh = testosterone therapy; VLDL = very low-density lipoprotein cholesterol.
      b Sustanon 250 contains 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate, and 100 mg testosterone decanoate.
      c Sustanon 200 contains 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate, and 100 mg testosterone decanoate.
      d Sustanon 100 contains 20 mg testosterone propionate, 40 mg testosterone phenylpropionate, and 40 mg testosterone isocaproate.
      e Singh et al
      • Singh A.B.
      • Hsia S.
      • Alaupovic P.
      • et al.
      The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.
      study: group 1 (n=12) received testosterone enanthate, 25 mg IM weekly; group 2 (n=12) received testosterone enanthate, 50 mg IM weekly; group 3 (n=12) received testosterone enanthate, 125 mg IM weekly; group 4 (n=11) received testosterone enanthate, 300 mg IM weekly; and group 5 (n=14) received testosterone enanthate, 600 mg IM weekly.
      Table 10Summary Statements
      Testosterone and cardiovascular risk summary assessmentsEvidence level
      Low levels of total, bioavailable, and free testosterone are associated with increased risk of mortality from all causes and CV diseaseIIa
      Incident CAD is associated with lower levels of total, bioavailable, or free testosteroneIIa
      Severity of CAD is inversely correlated with serum concentrations of total, bioavailable, or free testosteroneIIa
      The available evidence is insufficient to conclude whether there exists a relationship between ischemic stroke and serum androgensNA
      Carotid intima-media thickness and/or carotid plaque volume are inversely correlated with serum concentrations of total, bioavailable, or free testosteroneIIa
      Testosterone therapy is associated with a significant reduction in obesity and fat massIb
      Testosterone therapy is associated with small decreases in serum concentrations of total cholesterol, HDL, and LDL. No clear effect on triglycerides has been documentedIIa
      Testosterone therapy is associated with a decrease in serum glucose concentrations, HbA1c, and insulin resistance in diabetic and prediabetic menIa
      Testosterone therapy is associated with an inconsistent reduction in serum concentrations of inflammatory markersIb
      Testosterone therapy improves time to onset of symptomatic angina with exerciseIb
      Testosterone therapy improves exercise capacity and peak oxygen consumption in men with symptomatic congestive heart failure as defined by NYHA functional class IIIa
      CAD = coronary artery disease; CV = cardiovascular; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; NA = not available; NYHA = New York Heart Association.

      Testosterone Prescriptions and CV Outcomes

      Three additional studies beyond those of Vigen et al
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      and Finkle et al
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      have investigated mortality or MI rates in association with T therapy.
      • Shores M.M.
      • Smith N.L.
      • Forsberg C.W.
      • Anawalt B.D.
      • Matsumoto A.M.
      Testosterone treatment and mortality in men with low testosterone levels.
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      • Baillargeon J.
      • Urban R.J.
      • Kuo Y.-F.
      • et al.
      Risk of myocardial infarction in older men receiving testosterone therapy.
      Shores et al
      • Shores M.M.
      • Smith N.L.
      • Forsberg C.W.
      • Anawalt B.D.
      • Matsumoto A.M.
      Testosterone treatment and mortality in men with low testosterone levels.
      studied 1031 men in the Veterans Administration health care system with serum T levels of less than 250 ng/dL. The mean age was 62 years, and mean follow-up was 40.5 months. Mortality in T-treated men was reduced by half in treated men compared with untreated men, at 10.3% vs 20.7%, respectively (P=.0001). Multivariate adjustment for age, body mass index, T level, medical morbidity, diabetes, and coronary heart disease yielded a hazard ratio (HR) of 0.61 (95% CI, 0.42-0.88; P=.008), indicating significant reduction in mortality with T therapy.
      Muraleedharan et al
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      investigated a group of 581 diabetic men followed for a mean of 5.8 years. Men with low levels of serum T, defined as a serum T level of less than 10.4 nmol/L (300 ng/dL), had increased mortality compared with men with T values above this threshold. Adjusted mortality in the low T group was 17.2% compared with 9.0% in the normal T group (P=.003). In these populations, the multivariate-adjusted HR for decreased survival was 2.02 (95% CI, 1.2-3.4; P=.009). Untreated men with low T concentrations had mortality of 19.2%, compared with treated men, in whom mortality was again reduced by approximately half, at 8.4%. Notably, this value approximated the mortality in men with normal serum T concentrations. After multivariate adjustment, the HR for decreased survival in the untreated group was 2.3 (95% CI, 1.3-3.9; P=.004).
      After publication of the study by Finkle et al,
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      Baillargeon et al
      • Baillargeon J.
      • Urban R.J.
      • Kuo Y.-F.
      • et al.
      Risk of myocardial infarction in older men receiving testosterone therapy.
      studied 25,420 US Medicare recipients aged 65 years and older. In this study, a cohort of 6355 men treated with at least 1 injection of T between January 1, 1997, and December 31, 2005, were matched to 19,065 T nonusers at a 1:3 ratio based on a composite MI prognostic score. A significant trend toward reduced MI rates with T administration was noted with increasing quartiles of risk.
      • Baillargeon J.
      • Urban R.J.
      • Kuo Y.-F.
      • et al.
      Risk of myocardial infarction in older men receiving testosterone therapy.
      For men in the highest prognostic MI risk quartile, treatment with T therapy was associated with significantly reduced risk (HR, 0.69; 95% CI, 0.53-0.92). Eisenberg et al

      Eisenberg ML, Li S, Herder D, Lamb DJ, Lipshultz LI. Testosterone therapy and mortality risk [published online ahead of print July 31, 2014]. Int J Impot Res. http://dx.doi.org/10.1038/ijir.2014.29.

      found no difference in 10-year mortality between T users and nonusers using an andrology database from Baylor College of Medicine.

      Testosterone and Mortality

      A substantial number of observational studies have investigated mortality as a function of serum T concentrations (Table 2).
      • Khaw K.T.
      • Dowsett M.
      • Folkerd E.
      • et al.
      Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
      • Laughlin G.A.
      • Barrett-Connor E.
      • Bergstrom J.
      Low serum testosterone and mortality in older men.
      • Haring R.
      • Völzke H.
      • Steveling A.
      • et al.
      Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79.
      • Menke A.
      • Guallar E.
      • Rohrmann S.
      • et al.
      Sex steroid hormone concentrations and risk of death in US men.
      • Tivesten A.
      • Vandenput L.
      • Labrie F.
      • et al.
      Low serum testosterone and estradiol predict mortality in elderly men.
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      • Pye S.R.
      • Huhtaniemi I.T.
      • Finn J.D.
      • et al.
      EMAS Study Group
      Late-onset hypogonadism and mortality in aging men.
      • Haring R.
      • Teng Z.
      • Xanthakis V.
      • et al.
      Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.
      • Hyde Z.
      • Norman P.E.
      • Flicker L.
      • et al.
      Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study.
      • Lerchbaum E.
      • Pilz S.
      • Boehm B.O.
      • Grammer T.B.
      • Obermayer-Pietsch B.
      • März W.
      Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.
      • Haring R.
      • Nauck M.
      • Völzke H.
      • et al.
      Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy.
      • Kyriazis J.
      • Tzanakis I.
      • Stylianou K.
      • et al.
      Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients.
      • Carrero J.J.
      • Qureshi A.R.
      • Nakashima A.
      • et al.
      Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease.
      • Malkin C.J.
      • Pugh P.J.
      • Morris P.D.
      • Asif S.
      • Jones T.H.
      • Channer K.S.
      Low serum testosterone and increased mortality in men with coronary heart disease.
      • Corona G.
      • Monami M.
      • Boddi V.
      • et al.
      Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction.
      • Ponikowska B.
      • Jankowska E.A.
      • Maj J.
      • et al.
      Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease.
      • Militaru C.
      • Donoiu I.
      • Dracea O.
      • Ionescu D.D.
      Serum testosterone and short-term mortality in men with acute myocardial infarction.
      • Vikan T.
      • Schirmer H.
      • Njølstad I.
      • Svartberg J.
      Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study.
      • Carrero J.J.
      • Qureshi A.R.
      • Parini P.
      • et al.
      Low serum testosterone increases mortality risk among male dialysis patients.
      • Lehtonen A.
      • Huupponen R.
      • Tuomilehto J.
      • et al.
      Serum testosterone but not leptin predicts mortality in elderly men.
      • Araujo A.B.
      • Kupelian V.
      • Page S.T.
      • Handelsman D.J.
      • Bremner W.J.
      • McKinlay J.B.
      Sex steroids and all-cause and cause-specific mortality in men.
      • Shores M.M.
      • Matsumoto A.M.
      • Sloan K.L.
      • Kivlahan D.R.
      Low serum testosterone and mortality in male veterans.
      • Shores M.M.
      • Biggs M.L.
      • Arnold A.M.
      • et al.
      Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the Cardiovascular Health Study.
      The majority have reported a significant association of low T with mortality in community cohorts as well as in populations with medical conditions, including renal disease, diabetes, erectile dysfunction, and prostate cancer treated with androgen deprivation. A meta-analysis by Araujo et al,
      • Araujo A.B.
      • Dixon J.M.
      • Suarez E.A.
      • Murad M.H.
      • Guey L.T.
      • Wittert G.A.
      Endogenous testosterone and mortality in men: a systematic review and meta-analysis.
      which investigated 16,184 community-based participants with a mean follow-up of 9.7 years, found that low T levels were associated with an increased risk of CV-related mortality with an HR of 1.35 (95% CI, 1.13-1.62; P<.001). Androgen deprivation therapy has also been associated with increased CV events and mortality.
      • Zhao J.
      • Zhu S.
      • Sun L.
      • et al.
      Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies.
      Although no study has documented a direct association between high serum T and mortality, Yeap et al
      • Yeap B.B.
      • Alfonso H.
      • Chubb S.A.
      • et al.
      In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality.
      reported that the third quartile for serum T was associated with the lowest mortality and higher mortality occurred in men in the lowest 2 quartiles as well as the highest quartile.

      Summary Statement

      Low levels of TT, bioavailable T, and free T are associated with increased risk of mortality from all causes and CV disease.

      Level of Evidence

      IIa

      Testosterone and Incident CAD

      Eleven studies have reported on the association of serum T concentrations and incident CAD (Table 3).
      • Zhao S.P.
      • Li X.P.
      The association of low plasma testosterone level with coronary artery disease in Chinese men.
      • English K.M.
      • Mandour O.
      • Steeds R.P.
      • Diver M.J.
      • Jones T.H.
      • Channer K.S.
      Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms.
      • Dobrzycki S.
      • Serwatka W.
      • Nadlewski S.
      • et al.
      An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
      • Akishita M.
      • Hashimoto M.
      • Ohike Y.
      • et al.
      Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors.
      • Rosano G.M.
      • Sheiban I.
      • Massaro R.
      • et al.
      Low testosterone levels are associated with coronary artery disease in male patients with angina.
      • Hu X.
      • Rui L.
      • Zhu T.
      • et al.
      Low testosterone level in middle-aged male patients with coronary artery disease.