Testosterone Found to Cause Heart Attacks in Obese Smokers With Heart Disease

by Jeffrey Dach MD

This article is Part One, For Part Two Click Here.

For part three click here.

How Not to Do a Testosterone Clinical Trial

A testosterone study by Bhasin published in the New England Journal was halted early because the testosterone treated group had more heart attacks.  The study participants were a very skewed population of immobilized, elderly, obese, men with underlying heart disease. Most were heavy smokers with advanced heart disease on Lipitor and blood pressure meds. These results are opposite to decades of research showing testosterone benefits the heart.  I would suggest that giving virtually anything to these men to get them moving around would cause the same increase in heart attack rate. (1)(2)(3)(4)

Above left image : photo of obese smoker courtesy of Huffington Post.

Sending Old Men Up the Hill

If we recruited a group of immobilized, obese, elderly frail men with heart disease, and then instructed them to run up a mountain hill, they would be unable to go more than a few steps, and no harm would come from it. However, if this same group used testosterone gel for a few weeks, the testosterone would give them the leg muscle strength to run up the hill and many would succumb to heart attacks. This is a nutshell is what happened in the New England Journal, Bhasin study.  Again, I would suiggest that virtually any drug stimulation would accomplish the same increase heart attack risk, simply by making the men more active.

Decades of Research Shows Health Benefits of Testosterone

Low Testosterone Is Associated with Increased Mortality

Three separate population studies have shown that low testosterone levels is associated with  40% increased cardiovascular mortality. (5)(6)(7)  A study by Malkin published in Heart followed 900 men over 8 years with known coronary artery disease. The men with low testosterone had 22% mortality compared to only 12 % for men with normal testosterone levels, almost double the mortality rate for the low testosterone group.

Testosterone Improves Time to Cardiac Ischemia on Treadmill Test

In addition, multiple studies over decades have shown testosterone is beneficial in men with coronary artery disease by prolonging time to cardiac ischemia.   An elegant study by English et al. showed the testosterone group showed longer times on the treadmill before reaching abnormal EKG changes or chest pain (angina).  This indicates improved blood flow in the coronary artery circulation, a benefit of testosterone. (8)(9)(10)(11)

Testosterone Benefits For Heart Failure Patients

Dr Malkin published a study showing testosterone improves cardiac function in men with heart failure.  Similarly, another study looked at heart failure in women, again finding testosterone beneficial.

Dr Morgentaler to the Rescue

A more reasonable approach for testosterone replacement is described by Morgentaler in his 2007 commentary, “Guidelines for Male Testosterone Therapy: A Clinician’s Perspective.”

Abraham Morgentaler is a Harvard trained Urologist, who says he was taught in medical school that low testosterone was rare and treatment ineffective.  Once he started clinical practice in 1988, he was surprised to find that many of his patients had low testosterone associated with erectile dysfunction (ED) which greatly improved with testosterone injections. Patients thanked him for finally “feeling normal again.”   Nowadays in 2010, testosterone is accepted treatment for diminished libido and erectile dysfunction (ED).  Dr Morgentaler actually prefers to start with transdermal gel testosterone before using the Viagra and Cialis type drugs, (the phosphodiesterase type-5 inhibitors PDE5i).

Left Image: Courtesy of Abraham Morgentaler MD.

Risks of Testosterone Treatment Reviewed by Morgentaler

Dr Morgentaler 2004 NEJM article is also useful, covering the “Risks of testosterone-replacement therapy and recommendations for monitoring”.  Dr Morgentaler says that  4 million men may be candidates for testosterone treatment, yet only 5 percent are actually treated.  Even though there are no large scale, long term clinical studies looking at risks and adverse effects, the number of testosterone prescriptions have increased 500 percent since 1993.

Previous Studies Contradict Bhasin

In his 2004 report, Dr Morgentaler says that previous studies of testosterone-replacement have not shown increased of heart disease such as heart attacks, myocardial infarction, stroke, or angina.  This is opposite to the findings of the Bhasin report.   Increased blood count (Polycythemia) is an adverse effect noted in about 3% of men after testosterone treatment. This is controlled by reducing dosage or donating blood.  Dr Morgentaler also discusses, prostate, PSA, sleep apnea, and other issues.  He finds that testosterone treatment is not associated with increased prostate cancer, although he recommends prostate surveillance.  Finally he discusses that a small percentage of men may note breast enlargement or tenderness from treatment.  For more, take a look at  Morgentaler’s 2009 book, Testosterone for Life: Recharge Your Vitality, Sex Drive, Muscle Mass, and Overall Health

Left Image: Book Cover courtesy of Abraham Morgentaler MD

Conclusion: Testosterone therapy for immobilized elderly men with underlying chronic conditions such as obesity, heart disease, hypertension, and cigarette smoking is not recommended.   However, for all other candidates for testosterone therapy, the health benefits clearly outweigh the risks and adverse effects which are quite manageable.

Articles With Related Content:

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Low Testosterone Diagnosis and Treatment

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Testosterone Benefits, PSA and Prostate Part One

Testosterone and PSA Part Two

Clomid for Men with Low Testosterone Part One

Low Testosterone From Pain Pills

Low Testosterone Associated with Increased Mortality

Testosterone Reduces Mortality

Testosterone Blockade Increases Mortality

Testosterone Found Beneficial For Diabetes

Links and References

(1)http://www.ncbi.nlm.nih.gov/pubmed/20592293
N Engl J Med. 2010 Jul 8;363(2):109-22. Epub 2010 Jun 30.
Adverse events associated with testosterone administration.
Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118, USA.

BACKGROUND: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.

METHODS: Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.

RESULTS: A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.

CONCLUSIONS: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.

(2) http://www.nytimes.com/2010/07/06/health/06hormone.html?_r=1&ref=health
Testosterone Gel Trial Ends After Heart Issue By RONI CARYN RABIN
Published: July 5, 2010

The New York Times (7/6, D7, Rabin – reports, “A federally financed study to see if testosterone gel helps frail elderly men build muscle and strength was abruptly halted late last year after participants taking it suffered a disproportionate number of heart attacks and other serious cardiac problems, and one died of what was apparently a heart attack.” The Times says that “researchers were taken aback by the high rate of adverse heart problems.” The FDA “has approved it for use only in men with hypogonadism, whose sex glands produce extremely low amounts of testosterone or none at all because of an underlying disorder,” yet, “off-label use has increased in recent years.”

(3) EDITORIAL: Bremner WJ. Testosterone Deficiency and Replacement in Older Men. N Engl J Med;363(2):189-91.

(4) http://www.businessweek.com/news/2010-06-30/auxilium-testosterone-gel-linked-to-heart-problems-in-older-men.html

Bloomberg News 07/21/2010 – More than one-fifth of patients using a testosterone gel sold by Auxilium Pharmaceuticals Inc. developed heart problems in a study of mobility-impaired men aged 65 and older.

The study found that 23 of 106, or 22 percent, of men getting the gel, Testim, had heart-related side effects such as chest pain, heart attack, stroke, or elevated blood pressure, according to a report published today in the New England Journal of Medicine. Of the 103 men who got a placebo, just five, or 5 percent, had similar adverse effects, the researchers at Boston University Medical Center found.

Testosterone supplements have been shown to boost muscle mass and strength in aging men, the report said. This trial was designed to see if Testim could improve physical function in men with limited mobility. While the testosterone group did show improvement in their ability to climb stairs and do leg presses, the study was halted early because of concern that the drug may be linked to cardiovascular problems.

“Physicians and patients, especially older men, should consider this study’s findings on adverse effects along with other information on the risks and benefits of testosterone therapy,” the study authors said in a statement. They urged further research “to clarify the safety issues raised by this trial.”

Testim had worldwide revenue of $160.5 million last year, 98 percent of the company’s total, according to a regulatory filing. Auxilium rose 65 cents, or 2.8 percent, to $23.50 in Nasdaq Stock Market composite trading at 4 p.m. New York time. The stock has declined 25 percent in the last 12 months.

Low Testosterone

Testim, a skin gel, was approved in October 2002 as a testosterone replacement therapy for men with hypogonadism, a condition in which the body doesn’t produce enough of the hormone. Hypogonadism can cause fatigue, infertility, decreased sex drive and loss of bone mass. Testim competes with Androgel, sold by Abbott Park, Illinois-based Abbott Laboratories.

The study, which was discontinued in December, was funded by a grant to Shalender Bhasin, the chief of endocrinology at Boston Medical Center, from the National Institute on Aging, part of the U.S. National Institutes of Health. Auxilium donated the product and wasn’t involved in the study design or execution, according to the report.

Twice as many men in the Testim group had complications requiring medical evaluations compared with the placebo group, according to the report. Ten men had full-blown cardiac events, including two confirmed heart attacks and one death.
Bhasin and his co-authors said aspects of this study make it difficult to draw conclusions about the safety of Testim. The main limitations they cited were the small size of the clinical trial and the nature of the population being studied.

Frail Men
Patients in the study were frail, had higher rates of chronic disease than the general population, and had an average age of 74, according to the study. In contrast, 95 percent of patients getting Testim in the real world are under 75, said Eboo Versi, vice president of drug safety and medical affairs of Malvern, Pennsylvania-based Auxilium.

Another factor that makes the findings not apply to other men is that some study participants were given 15 grams of Testim a day, while the medicine’s label recommends starting patients on 5 grams and going up to 10 grams only if needed. That dosing was “totally off label,” Versi said in a telephone interview today.
Overall in the study, 16 men received the highest dose or 15 grams of testosterone, while 61 received 10 grams and 29 received 5 grams, according to the journal report.

Earlier Research

Another study of testosterone gel in men over 65, published online Jan. 8 in the Journal of Clinical Endocrinology & Metabolism, found no significant difference in cardiac events between the treatment group and those who got a placebo gel. Auxilium analyzed its Testim registration studies and didn’t find any increased risk of cardiovascular events, Versi said.

Corona, G., Mannucci, E., Ricca, V., Lotti, F., Boddi, V., Bandini, E., Balercia, G., Forti, G., & Maggi, M. (2009). The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction International Journal of Andrology, 32 (6), 720-728 DOI: 10.1111/j.1365-2605.2009.00952.x

Spetz, A., Palmefors, L., Skobe, R., Strmstedt, M., Fredriksson, M., Theodorsson, E., & Hammar, M. (2007). Testosterone correlated to symptoms of partial androgen deficiency in aging men (PADAM) in an elderly Swedish population
Menopause, PAP DOI: 10.1097/gme.0b013e318057786b

Allan, C., Forbes, E., Strauss, B., & McLachlan, R. (2008). Testosterone therapy increases sexual desire in ageing men with low–normal testosterone levels and symptoms of androgen deficiency International Journal of Impotence Research, 20 (4), 396-401 DOI: 10.1038/ijir.2008.22

Reyes-Vallejo, L., Lazarou, S., & Morgentaler, A. (2007). Subjective Sexual Response to Testosterone Replacement Therapy Based on Initial Serum Levels of Total Testosterone The Journal of Sexual Medicine, 4 (6), 1757-1762 DOI: 10.1111/j.1743-6109.2006.00381.x

(4A) http://www.healther.net/2010/09/testosterone-gel-linked-to-heart-problems/
Testosterone gel linked to heart problems healther 2010/09/26/ 18:04

(4AA)   http://www.nih.gov/news/health/jun2010/nia-30.htm
Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men
Treatment Phase of Clinical Trial Halted

Increased Mortality and Low testosterone

(5) http://eurheartj.oxfordjournals.org/content/31/12/1494.abstract
Eur Heart J (2010) 31 (12): 1494-1501.
Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79,
Robin Haring1,2,*, Henry Völzke2, Antje Steveling3, Alexander Krebs1, Stephan B. Felix4, Christof Schöfl5, Marcus Dörr4, Matthias Nauck1 and Henri Wallaschofski1

Conclusion Low serum testosterone levels were associated with an increased risk of all-cause mortality independent of numerous risk factors. As serum testosterone levels are inversely related to mortality due to CVD and cancer, it may be used as a predictive marker.
Haring and colleagues add to the growing evidence of the importance of a link in a prospective population-based study (mean follow-up 7.2 years) showing in a sample of men aged 20–79 years that a testosterone level <8.7 nmol/L (250 ng/dL) doubled the risk of all-cause mortality independently of age, waist circumference, cigarette smoking, excess alcohol, and decreased physical activity.3

EPIC

(6) http://circ.ahajournals.org/cgi/content/abstract/116/23/2694

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 (Circulation. 2007;116:2694-2701.) 2007 American Heart Association, Inc. Conclusions— In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

(7) http://archinte.ama-assn.org/cgi/content/abstract/166/15/1660
Vol. 166 No. 15, Aug 14/28, 2006
Low Serum Testosterone and Mortality in Male Veterans
Molly M. Shores, MD; Alvin M. Matsumoto, MD; Kevin L. Sloan, MD; Daniel R. Kivlahan, PhD
Arch Intern Med. 2006;166:1660-1665.

Anti-Anginal Heart Study

(8) http://circ.ahajournals.org/cgi/content/full/102/16/1906
Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina A Randomized, Double-Blind, Placebo-Controlled Study
Katherine M. English, MBChB, MRCP; Richard P. Steeds, MBBS, MRCP;
T. Hugh Jones, MD, MRCP; Michael J. Diver, PhD; Kevin S. Channer, MD, FRCP

Conclusions—Low-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia. (Circulation. 2000;102:1906-1911.)

(9) http://circ.ahajournals.org/cgi/content/full/99/13/1666
Rosano GMC, Leonardo F, Pagnotta P, et al. Acute anti-ischemic effect
of testosterone in men with coronary artery disease. Circulation. 1999;
99:1666 –1670.   Conclusions—Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

(10) http://www.ncbi.nlm.nih.gov/pubmed/10072236
Webb CM, Adamson DL, de Zeigler D, et al. Effect of acute testosterone
on myocardial ischemia in men with coronary artery disease. Am J
Cardiol. 1999;83:437– 439.

(11) http://www.eje-online.org/cgi/content/abstract/161/3/443

CLINICAL STUDY Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men Atish Mathur, Christopher Malkin, Basil Saeed1, R Muthusamy2, T Hugh Jones3,4 and Kevin Channer

Introduction: In short-term studies, testosterone replacement therapy has been shown to protect male subjects from exercise-induced ischaemia and modify cardiovascular risk factors such as insulin resistance, fat mass and lipid profiles.

Conclusion: The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement. Previously noted potentially beneficial effects of testosterone on body composition were confirmed and there were no adverse effects.

Morgentaler Articles

(12) http://jcem.endojournals.org/cgi/content/full/92/2/416
Guideline for Male Testosterone Therapy: A Clinician’s Perspective
Abraham Morgentaler Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 416-417 2007

(13) http://www.ncbi.nlm.nih.gov/pubmed/%2014749457
N Engl J Med. 2004 Jan 29;350(5):482-92.
Risks of testosterone-replacement therapy and recommendations for monitoring.
Rhoden EL, Morgentaler A. Division of Urology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, USA.

(14) http://www.ncbi.nlm.nih.gov/pubmed/20104673
J Sex Med. 2010 Jan;7(1 Pt 1):277-83.
Symptomatic response rates to testosterone therapy and the likelihood of completing 12 months of therapy in clinical practice. Rhoden EL, Morgentaler A.
Men’s Health Boston, Division of Urology, Harvard Medical School, Boston, MA, USA.
INTRODUCTION: Despite increasing medical interest in testosterone therapy (TTh) for men with testosterone deficiency (TD) there is limited information regarding subjective response rates and acceptability of medium- to long-term TTh in routine clinical practice.
AIM: To evaluate results in a consecutive series of men in clinical practice treated with TTh.

MATERIAL AND METHODS: A chart review was performed for a consecutive series of men for whom TTh was initiated over 1 year for a clinical diagnosis of TD. A diagnosis of TD was based on the presence of symptoms and on laboratory evaluation indicating total testosterone (<300 ng/dL) or free testosterone (FT) (<1.5 ng/dL). Presenting symptoms were noted at baseline, and improvement was documented in domains of erectile function, libido, energy,and mood.

MAIN OUTCOME MEASURES: Percentage of men who completed 12 months of TTh, and symptomatic response rates.

RESULTS: There were 127 men included in the evaluation. The most common presenting symptoms were the combination of erectile dysfunction (ED) and reduced libido in 82 (64.6%), ED alone in 29 (22.8%), and reduced libido alone in 13 (10.2%). Initial mode of TTh was injections (testosterone enanthate or cypionate) in 70 (55.1%)and transdermal gel (Androgel, Solvay Pharmaceuticals, Marietta, GA, USA) in the remainder. Improvements in erections, libido, energy, and/or mood were reported by 70% of men by 3 months. Eighty men (63%) completed 12 months of TTh with subjective benefit (responders). Treatment was discontinued in 34 (26.8%) who reported no major benefit (non-responders), and 13 (10.2%) were lost to follow-up. Among men who discontinued TTh, 64.7%failed to report benefits by 3 months. Baseline FT was lower among responders than non-responders. One case(1.25%) of prostate cancer was identified after one year of TTh.

CONCLUSION: Approximately two-thirds of men with TD who begin TTh will experience symptomatic benefit and will complete at least 12 months of treatment. Benefit was noted in a majority by 3 months.

Heart Failure

http://eurheartj.oxfordjournals.org/content/27/1/57.abstract
Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial Chris J. Malkin1, Peter J. Pugh1, John N. West1, Edwin J.R. van Beek2, T. Hugh Jones4 and Kevin S. Channer1,3,*

Chronic heart failure is associated with maladaptive and prolonged neurohormonal and pro-inflammatory cytokine activation causing a metabolic shift favouring catabolism, vasodilator incapacity, and loss of skeletal muscle bulk and function. In men, androgens are important determinants of anabolic function and physical strength and also possess anti-inflammatory and vasodilatory properties.

Methods and results We conducted a randomized, double-blind, placebo-controlled parallel trial of testosterone replacement therapy (5 mg Androderm®) at physiological doses in 76 men (mean±SD, age 64±9.9) with heart failure (ejection fraction 32.5±11%) over a maximum follow-up period of 12 months. The primary endpoint was functional capacity as assessed by the incremental shuttle walk test (ISWT). At baseline, 18 (24%) had serum testosterone below the normal range and bioavailable testosterone correlated with distance walked on the initial ISWT (r=0.3, P=0.01). Exercise capacity significantly improved with testosterone therapy compared with placebo over the full study period (mean change +25±15 m) corresponding to a 15±11% improvement from baseline (P=0.006 ANOVA). Symptoms improved by at least one functional class on testosterone in 13 (35%) vs. 3 (8%) on placebo (P=0.01). No significant changes were found in handgrip strength, skeletal muscle bulk by cross-sectional computed tomography, or in tumour necrosis factor levels. Testosterone therapy was safe with no excess of adverse events although the patch preparation was not well tolerated by the study patients.

Conclusion Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.

http://content.onlinejacc.org/cgi/content/abstract/56/16/1310
CLINICAL RESEARCH: HEART FAILURE
Testosterone Therapy in Women With Chronic Heart Failure A Pilot Double-Blind, Randomized, Placebo-Controlled Study Ferdinando Iellamo, MD*,,*, Maurizio Volterrani, MD*, Giuseppe Caminiti, MD*, Roger Karam, MD, Rosalba Massaro, MD*, Massimo Fini, MD*, Peter Collins, MD, PhD*, and Giuseppe M.C. Rosano, MD*

Objectives: The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure (CHF).

Background: Patients with CHF show decreased exercise capacity and insulin sensitivity. Testosterone supplementation improves these variables in men with CHF. No study has evaluated the effects of testosterone supplementation on female patients with CHF.

Methods: Thirty-six elderly female patients with stable CHF, (ejection fraction 32.9 ± 6) were randomly assigned (2:1 ratio) to receive testosterone transdermal patch (T group, n = 24) or placebo (P group, n = 12), both on top of optimal medical therapy. At baseline and after 6 months, patients underwent 6-min walking test (6MWT), cardiopulmonary exercise test, echocardiogram, quadriceps maximal isometric voluntary contraction, dynamic quadriceps isokinetic strength (peak torque), and insulin resistance assessment by homeostasis model.

Results: Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group, whereas they were unchanged in the P group (p < 0.05 for all comparisons). The homeostasis model was significantly reduced in the T group in comparison with the P group (–16.5% vs. +5%, respectively; p < 0.05). Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group. Increase in distance walked at 6MWT was related to the increase in free testosterone levels (r = 0.593, p = 0.01). No significant changes in echocardiographic parameters were observed in either group. No side effects requiring discontinuation of T were detected.
Conclusions: Testosterone supplementation improves functional capacity, insulin resistance, and muscle strength in women with advanced CHF. Testosterone seems to be an effective and safe therapy for elderly women with CHF.

http://circ.ahajournals.org/cgi/content/full/114/17/1829
Circulation. 2006;114:1829-1837.) 2006 American Heart Association, Inc.
-Heart Failure Anabolic Deficiency in Men With Chronic Heart Failure
Prevalence and Detrimental Impact on Survival

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

Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with
testosterone administration. N Engl J Med 2010; 363: 109-122.

Liverman CT, Blazer DG, editors. Testosterone and aging: clinical
research directions. Washington, DC: Institute of Medicine, The National
Academies Press, 2004.

Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold
for androgen deficiency symptoms. J Clin Endocrinol Metab 2004; 89:
3813-3817.

Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and
metabolic risks with serum testosterone in older men. J Clin Endocrinol
Metab 2006; 91: 4335-4343.

Travison TG, Shackelton R, Araujo AB, et al. The natural history of
symptomatic androgen deficiency in men: onset, progression, and spontaneous
remission. J Am Geriatr Soc 2008; 56: 831-839.

Travison TG, Araujo AB, Hall SA, McKinlay JB. Temporal trends in
testosterone levels and treatment in older men. Curr Opin Endocrinol
Diabetes Obes 2009; 16: 211-217.

Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1:
adverse effects of testosterone therapy in adult men: a systematic review
and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560-2575.

Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with
moderate severity heart failure: a double-blind randomized placebo
controlled trial. Eur Heart J 2006; 27: 57-64.

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men
with androgen deficiency syndromes: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559.

Sikaris K, McLachlan RI, Kazlauskas R, et al. Reproductive hormone
reference intervals for healthy fertile young men: evaluation of automated
platform assays. J Clin Endocrinol Metab 2005; 90: 5928-5936.

Sartorius G, Ly LP, Sikaris K, et al. Predictive accuracy and sources of
variability in calculated free testosterone estimates. Ann Clin Biochem
2009; 46: 137-143.

European Male Ageing Study (EMAS).

http://www.ncbi.nlm.nih.gov/pubmed/19929914
J Sex Med. 2010 Apr;7(4 Pt 1):1362-80. Epub 2009 Nov 19.
Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa0911101
Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men
Frederick C.W. Wu, M.D., et al for the EMAS Group .
N Engl J Med 2010; 363:12 3-135 July 8, 2010

——————

http://www.primaryissues.org/testosterone/
Testosterone Deficiency and Men’s Health: A Crucial Connection André T. Guay, MD, and Martin Miner, MD

http://jcem.endojournals.org/cgi/content/abstract/jc.2010-0266v1
Why Is Androgen Replacement in Males Controversial? Glenn R. Cunningham* and Shivani M. Toma Baylor College of Medicine and St. Luke’s Episcopal Hospital, Houston, Texas 77030

http://www.slate.com/id/2269042/
The Mel Gibson Excuse Does male menopause actually exist? By Jessica Dweck
Posted Thursday, Sept. 30, 2010, at 10:23 AM ET

http://thestar.com.my/health/story.asp?file=/2010/10/3/health/7143684&sec=health
Sunday October 3, 2010 The hormonal male Art of Healing By DR AMIR FARID ISAHAK
The ins and outs of male sex hormones.

http://jcem.endojournals.org/cgi/content/abstract/95/6/2536
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM, & Task Force, Endocrine Society (2010). Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism, 95 (6), 2536-59 PMID: 20525905

http://jcem.endojournals.org/cgi/content/abstract/92/11/4241
Araujo, A., Esche, G., Kupelian, V., O’Donnell, A., Travison, T., Williams, R., Clark, R., & McKinlay, J. (2007). Prevalence of Symptomatic Androgen Deficiency in Men Journal of Clinical Endocrinology & Metabolism, 92 (11), 4241-4247 DOI: 10.1210/jc.2007-1245

http://www.myhousecallmd.com/archives/3993
Testosterone: The New Anti-Aging Wonder Drug? by Rebecca Shatsky, MD 2011 |

Endocrine Society Guidelines

http://media.pituitary.org/pdf/TestTherapyAndDef.pdf
Endocrine News June 2006 Article: TESTOSTERONE THERAPY FOR ANDROGEN DEFICIENT MEN New Clinical Guideline from the Endocrine Society By Cathy Kristiansen, Editor

Malkin

http://heart.bmj.com/content/early/2010/09/28/hrt.2010.195412
Heart doi:10.1136/hrt.2010.195412

Low serum testosterone and increased mortality in men with coronary heart disease by Chris J Malkin et al

Background: To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.9±2.1 years. Outcome: All-cause mortality and vascular mortality. Prevalence of testosterone deficiency. Results: The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%.

Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p=0.002). The only parameters found to influence time to all-cause and vascular mortality (HR ± 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), β-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6).

Conclusions In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.

 

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