Research news

Benefits of testosterone therapy in men with testosterone deficiency

April 2018

STUDY: Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev. 2018;6(1):86-105.

Testosterone is well known to be essential for male sexual function and reproduction. Because testosterone regulates all steps of the male sexual response (including sexual desire, arousal, and to a lesser degree orgasm and ejaculation), sexual dysfunction is a prominent symptom of testosterone deficiency and often the presenting symptom.^1-⁷ Poor morning erection, low sexual desire and erectile dysfunction are considered hallmark symptoms of testosterone deficiency.¹

However, accumulating research over the past decades transformed our knowledge of testosterone from niche hormone to multi-system player.⁸ There is increasing recognition of the wide spectrum of beneficial health effects of testosterone and the deleterious consequences of testosterone deficiency. In addition, a growing body of data support the safety of testosterone treatment. Here we summarize the results of a comprehensive review on the health benefits of testosterone treatment in men with testosterone deficiency, published in the Journal of Sexual Medicine Reviews.⁹

KEY POINTS

Testosterone therapy improves body composition by increasing lean body (muscle) mass and decreasing fat mass (both total body fat and visceral fat mass).
Testosterone therapy increases insulin sensitivity, ameliorates components of the metabolic syndrome and reduces risk of type 2 diabetes.
Testosterone therapy improves sexual function.
Testosterone therapy improves mood and depressive symptoms, energy, and quality of life.
Testosterone therapy improves bone mineral density (BMD).
Testosterone therapy attenuates lower urinary tract symptoms (LUTS).
Testosterone therapy ameliorates anemia, regardless whether the anemia is caused by established causes (such as iron and/or vitamin B12 deficiencies, chronic inflammation) or unexplained.
An overwhelming body of research on testosterone therapy has refuted the widespread claims of cardiovascular disease risk.
Testosterone therapy reduces all-cause and cardiovascular mortality.

What is known about testosterone deficiency

Testosterone deficiency is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.^10-¹⁶ Observational studies report strong associations of lower testosterone levels with worse health outcomes in men, including reduced sexual activity, obesity, insulin resistance, inflammation, dyslipidemia, metabolic syndrome, atherosclerosis, cardiovascular events and mortality, as well as depressed mood, reduced motivation, fatigue, frailty, anemia, bone loss and decreased quality of life.^17-²⁷

Testosterone deficiency is associated with an adverse cardiovascular risk profile and increased atherosclerotic burden.^28-³⁰ A substantial body of evidence indicates that coronary artery disease incidence and severity, carotid intima-media thickness, atherosclerosis, and mortality are inversely correlated with testosterone levels.³¹ Consistent with this, men with low testosterone levels have an increased number and severity of multiple cardiovascular risk markers.³² Hence, there is a need for greater awareness of the impact of testosterone deficiency on general health and particularly on cardiovascular risk. The 2018 American Urological Association (AUA) guideline urges clinicians to inform patients who have testosterone deficiency that low testosterone is a risk factor for cardiovascular disease, and recommends that all testosterone deficient patients should be evaluated for cardiovascular disease risk factors.³³

In primary care/screening-based studies, the prevalence of testosterone deficiency in men aged 53-62 years is up to 39%³⁴. Among men with the metabolic syndrome or diabetes, around 45% have testosterone deficiency.³⁵ Similarly, up to half of men with erectile dysfunction are testosterone deficient.³⁶ In men over 40 years of age with abdominal obesity and erectile dysfunction, 68% have low testosterone levels.³⁷ In obese men, up to 78% have testosterone deficiency.^38,³⁹ Among men with a waist circumference of >120 cm, 87% have low testosterone levels.⁴⁰ Considering that the prevalence of obesity is close to 40% in the general male population⁴¹, testosterone deficiency has become a global public health concern.¹⁰

What this review adds about the effects of testosterone therapy

Testosterone therapy improves body composition by increasing lean body (muscle) mass and decreasing fat mass

It is well documented that testosterone treatment dose-dependently increases lean body (muscle) mass and decreases body fat mass.^42-⁴⁷ Notably, older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle.⁴³

Testosterone therapy increases insulin sensitivity, ameliorates components of the metabolic syndrome and reduces risk of type 2 diabetes

Long-term observational real-life studies have shown that testosterone therapy for up to 10 years ameliorates components of metabolic syndrome and improves the lipid profile, blood glucose and HbA_1c, insulin sensitivity, inflammation, as well as systolic and diastolic blood pressure.^48-⁶¹

Meta-analyses show that testosterone therapy reduces fasting plasma glucose, HbA_1c, fat mass, insulin resistance (HOMA-IR), waist circumference and triglycerides in men with the metabolic syndrome or type 2 diabetes.^62,⁶³ In men with the metabolic syndrome, an increase in HDL levels has also been observed.⁶³

A randomized controlled trial showed that treatment with testosterone undecanoate injections for 24 months reduced insulin resistance (HOMA-IR), carotid intima media thickness (CIMT) and high-sensitivity C-reactive protein (hsCRP) levels.⁶⁴

Testosterone therapy improves sexual function

Considering that testosterone plays a key role in male sexual function, it is not surprising that both observational^4,^5,^51,^61,⁶⁵ and placebo-controlled randomized clinical trials^66-⁶⁹ show that testosterone therapy results in significant improvements in most - if not all - domains of sexual function in men with testosterone deficiency. An 8-year long study showed that testosterone therapy significantly improved 5-item and 15-item International Index of Erectile Function (IIEF) scores.⁵¹

A meta-analysis included 14 placebo-controlled randomized clinical trials with a total of 2298 men with a mean age of 60 year.³ The mean testosterone treatment duration was 40 weeks and the IIEF-erectile function domain (IIEF-EFD) was used as outcome measure. Results showed that testosterone treatment significantly improved erectile function compared with placebo. Patients with more severe hypogonadism (total testosterone level <8 nmol/L) reported greater changes in final IIEF-EF score when compared with those with a milder testosterone deficiency (total testosterone levels <12 nmol/L). The magnitude of the effect was lower in the presence of metabolic derangements, such as obesity and diabetes. Other aspects of sexual function (as evaluated by IIEF subdomains) were also improved, including libido, intercourse satisfaction, orgasm, and overall sexual satisfaction.³ The meta-analysis argued that sexual dysfunction should be considered a hallmark manifestation of testosterone deficiency, since those symptoms can be significantly improved with normalization of testosterone levels with testosterone treatment.³

Testosterone therapy improves mood and depressive symptoms, energy, and quality of life

It is well documented that testosterone deficiency significantly impairs quality of life⁷⁰, and that testosterone treatment improves quality of life and mood parameters in both clinical trials^68,^71,⁷²and observational studies.^4,⁵ Mood parameters and sexual function improve relatively rapidly and improvements are maintained throughout the testosterone treatment period.^4,^5,⁷³ Testosterone treatment also has been found to improve global cognition⁷⁴ and reduce fatigue.⁷⁵

Testosterone therapy improves bone mineral density (BMD)

Several clinical trials^76-⁷⁸ and observational studies^51,^79,⁸⁰ have demonstrated that testosterone treatment improves BMD. A significant increase in structural and mechanical properties of trabecular bone in response to testosterone treatment was reported in the Testosterone Trials.⁷⁸Increases in vertebral and hip BMD over 36 months was seen both when testosterone was administered alone and when combined with finasteride.⁸¹ This suggests that dihydrotestosterone is not essential for the beneficial effects of testosterone on BMD.⁸¹

Long-term testosterone treatment with testosterone undecanoate injections for 3 years in hypogonadal obese patients with metabolic syndrome resulted in a significant improvement in lumbar BMD and femoral BMD, with a 5%/year increase.⁸⁰ A direct relationship between testosterone level and BMD increments was found.⁸⁰ Treatment with testosterone undecanoate injections for 6 years in hypogonadal men with osteoporosis resulted in a progressive improvement of BMD throughout the treatment period.⁷⁹ After 6 years, 40 of 45 treated men (89%) no longer fulfilled criteria for osteoporosis at the last measurement.⁷⁹ In a third long-term study, treatment with testosterone undecanoate injections for 8 years significantly increased T scores of vertebral and femoral BMD.⁵¹

Testosterone therapy attenuates Lower Urinary Tract Symptoms (LUTS)

It has been suggested that testosterone has a beneficial effect on lower urinary tract function and that testosterone deficiency may be a pathophysiological mechanism connecting lower urinary tract symptoms and the metabolic syndrome in men.⁸² One study reported that endogenous T levels correlate negatively with severity of LUTS (in other words; lower testosterone levels were associated with greater severity of LUTS and higher testosterone levels with less severe LUTS).⁸²Another study found no consistent associations were seen for circulating testosterone, free testosterone, or SHBG. However, circulating androstanediol glucuronide, a metabolite of dihydrotestosterone, and estradiol were associated with an increased risk of LUTS.⁸³ Nevertheless, it has been suggested that testosterone deficiency is an important risk factor for LUTS/BPH.⁸⁴

The data on the effect of testosterone therapy on LUTS is more consistent than the associations of endogenous testosterone levels and LUTS. Contrary to old beliefs, numerous observational and small, randomized trials have pointed to a possible improvement in male LUTS in patients treated with testosterone.⁸⁵ The exact mechanism of this improvement is still debated but may have a close relationship to metabolic syndrome.⁸⁵ Support for this comes from a study showing concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of testosterone levels in hypogonadal elderly men.⁸⁶

Evidence for lack of worsening of LUTS during long-term testosterone treatment comes from a “real life” registry study in which men were treated with testosterone undecanoate injections for 5 years.⁸⁷ A meta-analysis of 14 clinical trials provides further evidence that testosterone therapy does not worsen lower urinary tract symptoms.⁸⁸ Even more impressively, in another registry study, treatment with testosterone undecanoate injections for up to 10 years resulted in significant improvements in urinary and sexual function, and quality of life. Notably, in untreated hypogonadal men, voiding and erectile function deteriorated over time.⁵ Improvements in voiding symptoms and lower IPSS irritative sub-scale scores were also reported in testosterone treated men compared to untreated men in the RHYME study.⁸⁹

Testosterone therapy ameliorates anemia, including unexplained anemia

In one-third of older adults with anemia no known cause can be found.^90-⁹³ Currently there is no established treatment for this unexplained anemia. One possible cause of unexplained anemia in older men is testosterone deficiency, because low testosterone levels are significantly associated with unexplained anemia.^94,⁹⁵ and testosterone treatment of men with low testosterone increases hemoglobin levels^68,^73,96-⁹⁸, and thereby resolves unexplained anemia.

The Anemia Trial of the Testosterone Trials showed that testosterone treatment for 12 months significantly increased hemoglobin levels and reduced the prevalence of both unexplained anemia and anemia of known cause.⁹⁹ In line with the consequences of anemia in elderly - such as fatigue, weakness, reduced muscular strength and physical performance, impaired cognitive function, dementia, and depression¹⁰⁰ - increases in hemoglobin levels with testosterone treatment were associated with improvement in walking and vitality, as well as with men’s impression of change in overall health and energy.⁹⁹ This, combined with large magnitude of the changes and the correction of anemia in most men suggests that the amelioration of anemia with testosterone treatment is clinically meaningful.

Testosterone therapy reduces all-cause and cardiovascular mortality

A large number of observational studies have investigated the relation between mortality and testosterone levels.^101-¹²³ The majority reported a significant association of low testosterone with increased mortality among men in the general population, as well as in clinical populations of men with diabetes, erectile dysfunction and renal disease. A large meta-analysis, which investigated 16,184 subjects from the general population with a mean follow-up of 9.7 years, found that low testosterone levels were associated with a significant 35% increased risk of cardiovascular related mortality (hazard ratio = 1.35).¹²⁴

Contrary to widespread concern about testosterone therapy and cardiovascular risk, an overwhelming body of evidence is showing that testosterone therapy does not increase risk of myocardial infarction, stroke, deep venous thrombosis events or overall mortality.¹²⁵ Two notable studies showed that testosterone therapy reduced mortality by half in Veterans¹²¹ and in men with type 2 diabetes¹¹⁷, compared with men with testosterone deficiency from each population who remained untreated.

The largest systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCT) showed that testosterone therapy is not related to any increase in cardiovascular risk.¹²⁶ In RCTs performed in subjects with metabolic derangements testosterone therapy reduced cardiovascular risk.¹²⁶

An especially notable real-life long-term study showed that treatment with testosterone undecanoate for up to 10 years in obese men with testosterone deficiency reduced deaths and non-fatal heart attacks and strokes, compared to men not receiving testosterone therapy.¹²⁷ The testosterone-group had an estimated reduction in mortality between 66% and 92% compared to non-treated men.¹²⁷ Another long-term real-life study showed that testosterone undecanoate treatment of testosterone deficient men with a history of cardiovascular disease for up to 8 years resulted in sustained improvements in numerous cardiometabolic risk factors; weight loss, reduced waist circumference and improved lipid profile, glycemic control, blood pressure, heart rate and pulse pressure).¹²⁸ No patient suffered a major adverse cardiovascular event during the full observation time.¹²⁸ It was suggested that testosterone therapy may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.¹²⁸ These two long-term studies provide excellent evidence for the safety of testosterone treatment in a real-life scenario of men seeking treatment for urological complaints.

Commentary

The research summarized here clearly provide evidence that that testosterone is not a “niche” hormone confined to reproduction or sexual functions, but a multi‑system hormone with wide range of physiological effects, as summarized in the figure.⁸

Figure: Wide range of health benefits of testosterone therapy in men with testosterone deficiency.

A large body of evidence from randomized clinical trials, observational and registry studies, and meta-analyses support a therapeutic role of testosterone therapy in hypogonadal men. The Testosterone Trials showed that the number of adverse events were similar in the testosterone and placebo groups during the testosterone treatment year. During the follow-up year, there were 8 myocardial infarctions in the placebo group compared to 1 in the testosterone group.^68,¹²⁹ This is the most rigorous RCT evidence to date of the safety of testosterone therapy. Considering the well documented cardiovascular risks of testosterone deficiency, improvements in numerous cardiovascular risk factors with testosterone therapy, and suggestive data from observational studies in which mortality was reduced with testosterone therapy, concern that testosterone therapy would increase risk of cardiovascular events is unjustified.

Withholding suffering hypogonadal men testosterone treatment can do more harm than good. One US study estimated that over a 20-year period, testosterone deficiency would be directly responsible for approximately $190 to $525 billion in inflation-adjusted US health care expenditures, particularly in regard to its effect on obesity.¹³⁰ On a global scale, this amounts to an enormous public health and financial burden.

Recommendations

Long term therapy with Nebido^®

Resources

Related topics

Hypogonadism Therapy Product Information

References

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(2):123-135. Return to content
Hackett G, Kirby M, Wylie K, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017. The journal of sexual medicine. 2018. Return to content
Corona G, Rastrelli G, Morgentaler A, Sforza A, Mannucci E, Maggi M. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. Eur Urol. 2017;72(6):1000-1011. Return to content
Rosen RC, Wu F, Behre HM, et al. Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). The journal of sexual medicine. 2017;14(9):1104-1115. Return to content
Haider KS, Haider A, Doros G, Traish A. Long-Term Testosterone Therapy Improves Urinary and Sexual Function, and Quality of Life in Men with Hypogonadism: Results from a Propensity Matched Subgroup of a Controlled Registry Study. J Urol. 2018;199(1):257-265. Return to content
Isidori AM, Buvat J, Corona G, et al. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review. Eur Urol. 2014;65(1):99-112. Return to content
Morales A. Androgens are fundamental in the maintenance of male sexual health. Current urology reports. 2011;12(6):453-460. Return to content
Saad F. The emancipation of testosterone from niche hormone to multi-system player. Asian journal of andrology. 2015;17(1):58-60. Return to content
Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev. 2018;6(1):86-105. Return to content
Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016;91(7):881-896. Return to content
Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. 2017;14(12):1504-1523. Return to content
Khera M, Adaikan G, Buvat J, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). The journal of sexual medicine. 2016;13(12):1787-1804. Return to content
Khera M, Broderick GA, Carson CC, 3rd, et al. Adult-Onset Hypogonadism. Mayo Clin Proc. 2016;91(7):908-926. Return to content
Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S. 2017 EAU Guidelines on Male Hypogonadism. Available at http://uroweb.org/wp-content/uploads/18-Male-Hypogonadism_2017_web.pdf (accessed April 1st, 2018). Return to content
Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686. Return to content
Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016). CMAJ. 2015;187(18):1369-1377. Return to content
Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male aging? Crit Rev Clin Lab Sci. 2012;49(5-6):168-182. Return to content
Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036-1041. Return to content
Antonio L, Wu FC, O'Neill TW, et al. Associations between Sex Steroids and the Development of Metabolic Syndrome: a Longitudinal Study in European Men. J Clin Endocrinol Metab. 2015:jc20144184. Return to content
Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011;58(16):1674-1681. Return to content
Lasaite L, Ceponis J, Preiksa RT, Zilaitiene B. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia. 2014;46(10):1107-1112. Return to content
Almeida OP, Yeap BB, Hankey GJ, Jamrozik K, Flicker L. Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men. Arch Gen Psychiatry. 2008;65(3):283-289. Return to content
Kische H, Gross S, Wallaschofski H, et al. Associations of androgens with depressive symptoms and cognitive status in the general population. PloS one. 2017;12(5):e0177272. Return to content
Kelly DM, Jones TH. Testosterone and obesity. Obesity reviews: an official journal of the International Association for the Study of Obesity. 2015;16(7):581-606. Return to content
Ng Tang Fui M, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian journal of andrology. 2014;16(2):223-231. Return to content
Gaffney CD, Pagano MJ, Kuker AP, Stember DS, Stahl PJ. Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome. Sex Med Rev. 2015;3(4):298-315. Return to content
Golds G, Houdek D, Arnason T. Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. International journal of endocrinology. 2017;2017:4602129. Return to content
Fahed AC, Gholmieh JM, Azar ST. Connecting the Lines between Hypogonadism and Atherosclerosis. International Journal of Endocrinology. 2012;2012. Return to content
Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis. 2009;207(2):318-327. Return to content
Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian journal of andrology. 2018;20(2):120-130. Return to content
Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2015;90(2):224-251. Return to content
Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The journal of sexual medicine. 2017;14(9):1095−1103. Return to content
Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018. Return to content
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769. Return to content
Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin Endocrinol (Oxf). 2012;76(5):665-673. Return to content
Kohler TS, Kim J, Feia K, et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology. 2008;71(4):693-697. Return to content
Fillo J, Breza J, Levcikova M, et al. Occurrence of erectile dysfunction, testosterone deficiency syndrome and metabolic syndrome in patients with abdominal obesity. Where is a sufficient level of testosterone? Int Urol Nephrol. 2012;44(4):1113-1120. Return to content
Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Me. 2008;66(3):103-109. Return to content
Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835-1842. Return to content
Fillo J, Levcikova M, Ondrusova M, Breza J, Labas P. Importance of Different Grades of Abdominal Obesity on Testosterone Level, Erectile Dysfunction, and Clinical Coincidence. American journal of men's health. 2017;11(2):240-245. Return to content
Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in us youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA. 2018. Return to content
Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172-1181. Return to content
Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90(2):678-688. Return to content
Bhasin S. Regulation of body composition by androgens. J Endocrinol Invest. 2003;26(9):814-822. Return to content
Srinivas-Shankar U, Roberts SA, Connolly MJ, 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. J Clin Endocrinol Metab. 2010;95(2):639-650. Return to content
O'Connell MD, Roberts SA, Srinivas-Shankar U, et al. Do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist six months after treatment in intermediate-frail and frail elderly men? J Clin Endocrinol Metab. 2011;96(2):454-458. Return to content
Corona G, Giagulli VA, Maseroli E, et al. THERAPY OF ENDOCRINE DISEASE: Testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. 2016;174(3):R99-116. Return to content
Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J Endocrinol Invest. 2014;37(4):401-411. Return to content
Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in aging men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470. Return to content
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. International journal of endocrinology. 2014;2014:683515. Return to content
Permpongkosol S, Khupulsup K, Leelaphiwat S, Pavavattananusorn S, Thongpradit S, Petchthong T. Effects of 8-Year Treatment of Long-Acting Testosterone Undecanoate on Metabolic Parameters, Urinary Symptoms, Bone Mineral Density, and Sexual Function in Men With Late-Onset Hypogonadism. The journal of sexual medicine. 2016;13(8):1199-1211. Return to content
Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring). 2013;21(10):1975−1981. Return to content
Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes (Lond). 2016;40(1):162-170. Return to content
Saad F, Yassin D, Dorsos G, Yassin A. Most hypogonadal men with type 2 diabetes mellitus (T2DM) achieve HbA1c targets when treated with testosterone undecanoate injections (TU) for up to 12 years. Diabetes. 2017;66(Suppl.1):A305 (abstract). Return to content
Traish AM, 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. Int J Clin Pract. 2014;68(3):314-329. Return to content
Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clinical obesity. 2013;3(3-4):73-83. Return to content
Yassin A, Haider A, Haider H, Doros G, Traish A, Saad F. Prediabetes, hypogonadism & erectile dysfunction: glycaemic control in 109 hypogonadal men treated with testosterone undecanoate injections (TU) for up to 8 years: real-life data from registry studies. Presented at AUA 2016. https://www.auajournals.org/doi/full/10.1016/j.juro.2016.02.326 (accessed June 17, 2016). Return to content
Yassin A, Nettleship JE, Talib RA, Almehmadi Y, Doros G. Effects of testosterone therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity, voiding function and prostate safety parameters. The aging male: the official journal of the International Society for the Study of the Aging Male. 2016;19(1):64-69. Return to content
Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016:Jan 14. doi: 10.1111/and.12514. [Epub ahead of print]. Return to content
Yassin DJ, Doros G, Hammerer PG, Yassin AA. 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. The journal of sexual medicine. 2014;11(6):1567-1576. Return to content
Saad F, Yassin A, Haider A, Doros G, Gooren L. Elderly men over 65 years of age with late-onset hypogonadism benefit as much from testosterone treatment as do younger men. Korean journal of urology. 2015;56(4):310-317. Return to content
Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl. 2011;34(6 Pt 1):528-540. Return to content
Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. The journal of sexual medicine. 2011;8(1):272-283. Return to content
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. The journal of sexual medicine. 2010;7(10):3495- 3503. Return to content
Haider KS, Haider A, Doros G, Traish A. Long-Term Testosterone Therapy Improves Urinary and Sexual Function, and Quality of Life in Men with Hypogonadism: Results from a Propensity Matched Subgroup of a Controlled Registry Study. J Urol. 2018;199(1):257-265. Return to content
Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab. 2016;101(8):3096- 3104. Return to content
Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011-1022. Return to content
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. Return to content
Canguven O, Talib RA, El-Ansari W, Shamsoddini A, Salman M, Al-Ansari A. RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries, penile length and girth, erectile function, and nocturnal penile tumescence and duration. The aging male: the official journal of the International Society for the Study of the Aging Male. 2016;19(4):215-220. Return to content
Khera M. Male hormones and mens quality of life. Current opinion in urology. 2016;26(2):152-157. Return to content
Nian Y, Ding M, Hu S, et al. Testosterone therapy improves health-related quality of life for patients with late-onset hypogonadism: a meta-analysis of randomized controlled trials. Andrologia. 2017;49(4). Return to content
Amanatkar HR, Chibnall JT, Seo BW, Manepalli JN, Grossberg GT. Impact of exogenous testosterone on mood: a systematic review and meta-analysis of randomized placebo-controlled trials. Ann Clin Psychiatry. 2014;26(1):19-32. Return to content
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. J Clin Endocrinol Metab. 2004;89(5):2085-2098. Return to content
Wahjoepramono EJ, Asih PR, Aniwiyanti V, et al. The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men. CNS & neurological disorders drug targets. 2016;15(3):337-343. Return to content
Pexman-Fieth C, Behre HM, Morales A, Kan-Dobrosky N, Miller MG. A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. The aging male: the official journal of the International Society for the Study of the Aging Male. 2014;17(1):1-11. Return to content
Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-293. Return to content
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. Int J Impot Res. 2008;20(4):378-387. Return to content
Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA internal medicine. 2017;177(4):471-479. Return to content
Haider A, Meergans U, Traish A, et al. Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. International journal of endocrinology. 2014;2014:496948. Return to content
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. The aging male: the official journal of the International Society for the Study of the Aging Male. 2012;15(2):96-102. Return to content
Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004;89(2):503-510. Return to content
Chang IH, Oh SY, Kim SC. A possible relationship between testosterone and lower urinary tract symptoms in men. J Urol. 2009;182(1):215-220. Return to content
Rohrmann S, Nelson WG, Rifai N, et al. Serum sex steroid hormones and lower urinary tract symptoms in Third National Health and Nutrition Examination Survey (NHANES III). Urology. 2007;69(4):708-713. Return to content
Baas W, Kohler TS. Testosterone Therapy and BPH/LUTS. What is the Evidence? Current urology reports. 2016;17(6):46. Return to content
Jarvis TR, Chughtai B, Kaplan SA. Testosterone and benign prostatic hyperplasia. Asian journal of andrology. 2015;17(2):212-216. Return to content
Haider A, Gooren LJ, Padungtod P, Saad F. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia. 2009;41(1):7-13. Return to content
Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014;83(1):167-173. Return to content
Kohn TP, Mata DA, Ramasamy R, Lipshultz LI. Effects of Testosterone Therapy on Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis. Eur Urol. 2016;69(6):1083-1090. Return to content
Debruyne FM, Behre HM, Roehrborn CG, et al. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int. 2017;119(2):216-224. Return to content
Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104(8):2263- 2268. Return to content
Ferrucci L, Guralnik JM, Bandinelli S, et al. Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol. 2007;136(6):849-855. Return to content
Tettamanti M, Lucca U, Gandini F, et al. Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study. Haematologica. 2010;95(11):1849-1856. Return to content
Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. J Gerontol A Biol Sci Med Sci. 2011;66(8):925-932. Return to content
Waalen J, von Lohneysen K, Lee P, Xu X, Friedman JS. Erythropoietin, GDF15, IL6, hepcidin and testosterone levels in a large cohort of elderly individuals with anaemia of known and unknown cause. Eur J Haematol. 2011;87(2):107-116. Return to content
Ferrucci L, Maggio M, Bandinelli S, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med. 2006;166(13):1380-1388. Return to content
Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670- 2677. Return to content
Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2839- 2853. Return to content
Zhang LT, Shin YS, Kim JY, Park JK. Could Testosterone Therapy in Hypogonadal Men Ameliorate Anemia, a Cardiovascular Risk Factor? An Observational, 54-Week Cumulative Registry Study. J Urol. 2016;195(4 Pt 1):1057-1064. Return to content
Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA internal medicine. 2017;177(4):480-490. Return to content
Halawi R, Moukhadder H, Taher A. Anemia in the elderly: a consequence of aging? Expert review of hematology. 2017;10(4):327-335. Return to content
Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007;167(12):1252-1260. Return to content
Carrero JJ, Qureshi AR, Nakashima A, et al. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transplant. 2011;26(1):184-190. Return to content
Carrero JJ, Qureshi AR, Parini P, et al. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol. 2009;20(3):613-620. Return to content
Corona G, Monami M, Boddi V, et al. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. The journal of sexual medicine. 2010;7(4 Pt 1):1557-1564. Return to content
Haring R, Nauck M, Volzke H, et al. Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy. Am J Nephrol. 2011;33(3):209-217. Return to content
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. Clin Endocrinol (Oxf). 2013;78(4):629-634. Return to content
Haring R, Volzke 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. Eur Heart J. 2010;31(12):1494-1501. Return to content
Hyde Z, Norman PE, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012;97(1):179-189. Return to content
Khaw KT, 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. Circulation. 2007;116(23):2694 - 2701. Return to content
Kyriazis J, Tzanakis I, Stylianou K, et al. Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients. Nephrol Dial Transplant. 2011;26(9):2971-2977. Return to content
Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75. Return to content
Lehtonen A, Huupponen R, Tuomilehto J, et al. Serum testosterone but not leptin predicts mortality in elderly men. Age Aging. 2008;37(4):461-464. Return to content
Lerchbaum E, Pilz S, Boehm BO, Grammer TB, Obermayer-Pietsch B, Marz W. Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography. Clin Endocrinol (Oxf). 2012;77(3):475-483. Return to content
Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010;96(22):1821-1825. Return to content
Menke A, Guallar E, Rohrmann S, et al. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010;171(5):583-592. Return to content
Militaru C, Donoiu I, Dracea O, Ionescu DD. Serum testosterone and short-term mortality in men with acute myocardial infarction. Cardiology journal. 2010;17(3):249-253. Return to content
Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725-733. Return to content
Ponikowska B, Jankowska EA, 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. Int J Cardiol. 2010;143(3):343-348. Return to content
Pye SR, Huhtaniemi IT, Finn JD, et al. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014;99(4):1357-1366. Return to content
Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166(15):1660-1665. Return to content
Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058. Return to content
Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94(7):2482- 2488. Return to content
Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol. 2009;161(3):435-442. Return to content
Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007- 3019. Return to content
Shores MM. Testosterone treatment and cardiovascular events in prescription database studies. Asian journal of andrology. 2018;20(2):138-144. Return to content
Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert opinion on drug safety. 2014;13(10):1327-1351. Return to content
Traish A, Haider A, Haider K, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. Journal of cardiovascular pharmacology and therapeutics. 2017;epub. Return to content
Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. 2016;12:251-261. Return to content
Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the Testosterone Trials. Endocr Rev. 2018. Return to content
Moskovic DJ, Araujo AB, Lipshultz LI, Khera M. The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. The journal of sexual medicine. 2013;10(2):562-569. Return to content