Benefits of Testosterone Therapy in Men with Testosterone Deficiency

Benefits of Testosterone Therapy in Men with Testosterone Deficiency

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 reason that prompts men to seek medical help.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 number of medical research studies 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 “belly” fat mass).
  • Testosterone therapy improves insulin sensitivity and blood glucose metabolism, 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 Large population studies report strong associations of lower testosterone levels with worse health outcomes in men, including reduced sexual activity, obesity, insulin resistance, inflammation, cholesterol abnormalities, metabolic syndrome, atherosclerosis, heart complications 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 atherosclerosis, heart disease incidence and death are increased in men with low 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 doctors 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 have their cardiovascular disease risk factors checked.33

In the general population, up to 39% of men aged 53-62 have testosterone deficiency.34 Among men with the metabolic syndrome or diabetes, around 45% have testosterone deficiency.35 Similarly, 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 muscle.43

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

Long-term real-life studies have shown that testosterone therapy for up to 10 years ameliorates components of metabolic syndrome and improves the cholesterol profile, blood sugar levels, insulin sensitivity, inflammation, as well as blood pressure.48-61

Testosterone therapy improves sexual function

Considering that testosterone plays a key role in male sexual function, it is not surprising that a large number of medical research studies show that testosterone therapy results in significant improvements in most - if not all - domains of sexual function in men with testosterone deficiency.4,5,51,61-66 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 of 14 studies of men with a mean age of 60 years showed that testosterone treatment significantly improved erectile function compared with placebo.3 Men 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 life67, and that testosterone treatment improves quality of life and mood parameters4,5,65,68,69 Mood parameters and sexual function improve relatively rapidly and improvements are maintained throughout the testosterone treatment period.4,5,70 Testosterone treatment also has been found to improve global cognition71 and reduce fatigue.72

Testosterone therapy improves bone mineral density (BMD)

Another well documented effect of testosterone treatment is improvement in BMD, which is important because men with testosterone deficiency often have a low BMD and osteoporosis.51,73-77

Long-term testosterone treatment for 3 years in obese patients with metabolic syndrome resulted in a significant improvement in BMD in the spine and legs, with a 5%/year increase.77 A direct relationship between testosterone level and BMD increments was found.77 Treatment with testosterone for 6 years in men with osteoporosis resulted in a progressive improvement of BMD throughout the treatment period.76 After 6 years, 40 of 45 treated men (89%) no longer fulfilled criteria for osteoporosis at the last measurement.76 In a third long-term study, treatment with testosterone for 8 years significantly increased BMD in the back and legs.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 the link connecting lower urinary tract symptoms and the metabolic syndrome in men.78 One study reported that lower testosterone levels were associated with greater severity of LUTS and higher testosterone levels with less severe LUTS78, and it has been suggested that testosterone deficiency is an important risk factor for LUTS/BPH.79

Contrary to old beliefs, numerous observational and small, randomized trials have pointed to a possible improvement in male LUTS in patients treated with testosterone.80 Interestingly, testosterone therapy results in simultaneous improvement of the metabolic syndrome and LUTS as testosterone levels increase during treatment of testosterone deficient elderly men.81

In an impressive real-life study, treatment with testosterone 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.82

Testosterone therapy ameliorates anemia, including unexplained anemia

In one-third of older adults with anemia no known cause can be found.83-86 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.87,88 and testosterone treatment of men with low testosterone increases hemoglobin levels65,70,89-91, 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.92 In line with the consequences of anemia in elderly - such as fatigue, weakness, reduced muscular strength and physical performance, impaired cognitive function, dementia, and depression93 - 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.92 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

Many population studies have investigated the relation between mortality and testosterone levels.94-116 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.117

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 heart attack, stroke, blood clots, or overall mortality.118 Two notable studies showed that testosterone therapy reduced mortality by half in Veterans114 and in men with type 2 diabetes110, compared with men with testosterone deficiency from each population who remained untreated.

An especially notable real-life long-term study showed that testosterone treatment 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.119 The testosterone-group had an estimated reduction in death between 66% and 92% compared to non-treated men.119 Another long-term real-life study showed that testosterone treatment of testosterone deficient men with a history of heart disease for up to 8 years resulted in sustained improvements in several cardiometabolic risk factors; including weight loss, reduced waist circumference and improved cholesterol profile, blood sugar metabolism and blood pressure.120 No patient had any heart problems.120 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.

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

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 heart attacks in the placebo group compared to 1 in the testosterone group.65,121 This is the most rigorous scientific 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 population 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.122 On a global scale, this amounts to an enormous public health and financial burden.

References

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Morales A. Androgens are fundamental in the maintenance of male sexual health. Current urology reports. 2011;12(6):453-460.
8. Saad F. The emancipation of testosterone from niche hormone to multi-system player. Asian journal of andrology. 2015;17(1):58-60.
9. Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev. 2018;6(1):86-105.
10. 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.
11. 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.
12. 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.
13. Khera M, Broderick GA, Carson CC, 3rd, et al. Adult-Onset Hypogonadism. Mayo Clin Proc. 2016;91(7):908-926.
14. 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).
15. 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.
16. 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.
17. Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male ageing? Crit Rev Clin Lab Sci. 2012;49(5-6):168-182.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. Fahed AC, Gholmieh JM, Azar ST. Connecting the Lines between Hypogonadism and Atherosclerosis. International Journal of Endocrinology. 2012;2012.
29. 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.
30. Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian journal of andrology. 2018;20(2):120-130.
31. 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.
32. 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.
33. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018.
34. 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.
35. 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.
36. Kohler TS, Kim J, Feia K, et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology. 2008;71(4):693-697.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. Bhasin S. Regulation of body composition by androgens. J Endocrinol Invest. 2003;26(9):814-822.
45. 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.
46. 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.
47. 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.
48. 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.
49. Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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).
55. 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.
56. 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.
57. 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.auanet.org/University/abstract_detail.cfm?id=MP47-07&meetingID=16SAN (accessed June 17, 2016).
58. Yassin A, Nettleship JE, Talib RA, Almehmadi Y, Doros G. Effects of testosterone replacement 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.
59. 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].
60. 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.
61. 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.
62. Haider A, Haider K, Doros G, Traish A. Effects of long-term testosterone undecanoate injections (TU) on urinary and sexual function in hypogonadal men: real-life data from a controlled registry study. Presented at AUA 2016. Available at https://www.auanet.org/University/abstract_detail.cfm?id=PD50-02&meetingID=16SAN (accessed June, 17, 2016).
63. 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.
64. 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.
65. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624.
66. 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.
67. Khera M. Male hormones and men's quality of life. Current opinion in urology. 2016;26(2):152-157.
68. Nian Y, Ding M, Hu S, et al. Testosterone replacement therapy improves health-related quality of life for patients with late-onset hypogonadism: a meta-analysis of randomized controlled trials. Andrologia. 2017;49(4).
69. 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.
70. 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.
71. 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.
72. 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.
73. 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.
74. 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.
75. 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.
76. 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.
77. 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.
78. 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.
79. Baas W, Kohler TS. Testosterone Replacement Therapy and BPH/LUTS. What is the Evidence? Current urology reports. 2016;17(6):46.
80. Jarvis TR, Chughtai B, Kaplan SA. Testosterone and benign prostatic hyperplasia. Asian journal of andrology. 2015;17(2):212-216.
81. 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.
82. 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.
83. 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.
84. 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.
85. 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.
86. 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.
87. 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.
88. 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.
89. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670-2677.
90. 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.
91. Zhang LT, Shin YS, Kim JY, Park JK. Could Testosterone Replacement 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.
92. 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.
93. Halawi R, Moukhadder H, Taher A. Anemia in the elderly: a consequence of aging? Expert review of hematology. 2017;10(4):327-335.
94. 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.
95. 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.
96. 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.
97. 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.
98. 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.
99. 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.
100. 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.
101. 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.
102. 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.
103. 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.
104. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75.
105. Lehtonen A, Huupponen R, Tuomilehto J, et al. Serum testosterone but not leptin predicts mortality in elderly men. Age Ageing. 2008;37(4):461-464.
106. 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.
107. 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.
108. 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.
109. 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.
110. 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.
111. 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.
112. 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.
113. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166(15):1660-1665.
114. 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.
115. 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.
116. 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.
117. 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.
118. Shores MM. Testosterone treatment and cardiovascular events in prescription database studies. Asian journal of andrology. 2018;20(2):138-144.
119. 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.
120. 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.
121. Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the Testosterone Trials. Endocr Rev. 2018.
122. 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.
G.COM.GM.MH.04.2018.0514

Last updated: 2018
G.MKT.GM.MH.02.2018.0506