Testosterone therapy practical advice

Testosterone therapy confers a wide range of health benefits for hypogonadal men, including improvements in libido, sexual function, body composition (reduction in body fat and waist size, and increase in muscle mass), lipid profile, cardiovascular function, insulin sensitivity/glucose metabolism, bone mineral density, inflammatory parameters, quality of life and increased longevity.1-3

Despite this, many men fail to achieve these treatment benefits simply because they do not adhere to testosterone therapy or take it intermittently. This can easily be prevented by informing patients about all benefits they have to gain if they adhere to their testosterone treatment, as well as how soon they can expect to notice the different health benefits.

Patient expectation about testosterone therapy

A survey found that nearly 40% of respondents had discontinued testosterone therapy because they felt it “failed to work”.4 In a chart review of men attending a men’s health practice, it was found that nearly 30% of men discontinued testosterone therapy within 12 months following initiation, primarily citing lack of symptomatic improvement as the reason for discontinuation.5

Testosterone therapy discontinuation due to perceptions of insufficient efficacy are likely caused by misguided expectations and/or sub-optimal dosing of testosterone therapy. Patients who have misguided expectations about testosterone therapy may discontinue treatment too soon before they can reasonably experience symptom relief. Therefore, it is critical to inform patients that improvement in hypogonadal signs and symptoms occur at different times points after the start of testosterone therapy, as summarized in table 1.

 

How soon can effects from testosterone therapy be expected?

While improvement in libido and quality of life can appear after 1 month of testosterone therapy,1 maximal improvements take longer time to manifest. For example, while a significant improvement in quality of life (as measured by reduction in AMS score) can occur after 3 months of testosterone therapy,6 long-term “real life” studies have shown that improvement in quality of life occurs progressively for up to 2-3 years during treatment with testosterone undecanoate injections.7-10 Similarly, while some improvement in erectile function can be noticed after 6 months of testosterone therapy,1 erectile function has been shown to continue to improve for up to 9 years with continued uninterrupted treatment with testosterone undecanoate injections.8

Table 1: When to expect health benefits with testosterone therapy.1,8,11,12

Testosterone therapy effect Time required to achieve effect

Sexual interest (libido)

3 weeks, plateauing at 6 weeks, with no further increments expected beyond.

Erections/ejaculations

Can be noticed after 6 months, but continued improvement is seen with ongoing testosterone therapy for 9 years.

Quality of life

3–4 weeks, but maximum improvement can take 2-3 years.

Depressive mood

3–6 weeks, with a maximum after 18–30 weeks.

Erythropoiesis

3 months, peaking at 9–12 months and then stabilizing.

PSA and prostate volume

Small increase within the normal range is a physiological response to testosterone therapy. This increase reaches a plateau at 12 months; any further increase is more likely related to aging rather than testosterone therapy.

Lipids
(primarily reduction in triglycerides and non-HDL cholesterol)

4 weeks, but improvements can continue with uninterrupted testosterone therapy for 11 years.

 

Insulin sensitivity

Improvements in glycemic control become evident only after 3–12 months. Further improvements can be seen with uninterrupted testosterone therapy for 11 years.

Reduction in waist circumference

Can be detectable after 6-12 months, but continued improvement is seen with ongoing testosterone therapy for 11 years.

Reduced fat mass / increased lean body mass and strength

6 months to several years.

Bone mineral density

Can be detectable after 6 months, but continued improvement is seen for at least 5 years with ongoing testosterone therapy.

Interactive testosterone tool

See a graphical visualization of when to expect onset of improvements as well as maximal improvements

The Aging Males’ Symptoms (AMS) questionnaire is commonly used to evaluate symptoms that may be related to low testosterone, and to monitor symptomatic improvement during testosterone therapy.13,14 When used to monitor efficacy of testosterone therapy, it is critical to know that improvement in AMS scores (symptom severity) can continue for up to 3 years.7-10 Hence, patients with hypogonadism who have been on testosterone therapy for 3-12 months but not experienced symptomatic improvement may do so if they stay on testosterone therapy without interruption for a longer time period.

Erectile dysfunction is one of the primary symptoms of hypogonadism.15 It was previously believed that maximal improvements in erectile function are achieved after 3-6 months of testosterone therapy.1 Based on this belief, several clinical guidelines recommend that men who present with symptoms such as erectile dysfunction but have borderline low testosterone levels should be given a therapeutic trial of testosterone therapy for 3 months16, 6 months17 or 12 months18, to see if it works. However, recent studies have shown that uninterrupted testosterone therapy can result in progressive improvement in erectile function for up to 9 years.8,19 This underscores the critical importance of long-term uninterrupted testosterone therapy for achievement of maximal symptomatic improvement, and that a therapeutic trial of testosterone therapy for even 1 year may not be enough to “see if it works”. It should also be pointed out that maximal improvements in non-symptomatic outcomes of testosterone therapy, such as body fat loss, waist circumference reduction, muscle gain and increase in bone mineral density take many years to achieve.

 

Importance of uninterrupted testosterone therapy

Achievement of maximal benefits from testosterone therapy requires uninterrupted treatment.20-23 If testosterone therapy is interrupted, achieved metabolic and symptomatic benefits will disappear.21-23 It is critical to inform patients about this, as many patients stop and restart therapy every 2 to 3 months.24 Although the beneficial effects may reappear when testosterone therapy is resumed,22,23 these patients will never experience the full benefits of testosterone therapy. Not surprisingly, majority of patients who begin testosterone therapy discontinue its use within 3 years,24 reporting that it failed to work.4,8 Therefore, patient education about the timelines for symptom improvement and need for long-term adherence to achieve the wide range of health benefits of testosterone therapy is essential for successful treatment of hypogonadism.

 

Importance of achieving effective testosterone levels

Besides treatment duration, a prerequisite for effective testosterone therapy is achievement of a large enough elevation in testosterone levels, that is sustained over time.25-28

There is no universal threshold level of testosterone that triggers response to testosterone therapy; due to differences in androgen receptor sensitivity and variations on sex hormone binding globulin (SHBG) (which can cause different levels of free testosterone for any given level of total testosterone), some men may need higher doses of testosterone therapy and higher on-treatment testosterone levels in order to respond. Therefore, what constitutes a large enough elevation in testosterone levels must be determined individually for each patient by regularly monitoring testosterone levels and symptomatic response during testosterone therapy, and if needed, adjusting the dose based on response.

While clinical guidelines recommend that testosterone therapy should aim to elevate testosterone levels into the middle tertile of the normal range29 (the exact values will vary between testosterone assays and laboratories), some men may need to get their testosterone level elevated into the upper end of the normal range before they experience relief of symptoms.

 

For how long should testosterone therapy be given?

A common question among HCPs and patients is how long testosterone therapy should be given. Several studies have demonstrated that the beneficial effects of testosterone therapy are not maintained after discontinuation of testosterone treatment.21-23,30-33 This applies to improvements in body composition, erectile function, HbA1c, total cholesterol, LDL, HDL, triglycerides, AMS, IPSS, IIEF-EF, residual voiding volume and bladder wall thickness, and quality of life, and likely most – if not all - other testosterone-related outcomes.22,23,30-32

An exception may be young men with extreme obesity. In a case-report of a 20-year old man with grade III obesity, testosterone therapy for 20 months reduced BMI from 44 kg/m2 to overweight 27 kg/m2.34 During a follow-up period of 19 months after discontinuation of testosterone therapy, improvements in testosterone levels, body weight, waist circumference, blood glucose, lipids remained. Nevertheless, in middle-age and older men, studies consistently show that the beneficial effects of testosterone therapy are not maintained after discontinuation of testosterone treatment.21-23,30-33

If testosterone therapy is discontinued, beneficial effects will appear again when testosterone therapy is resumed.22 As pointed out in the British Society for Sexual Medicine guidelines on Adult Testosterone Deficiency, discontinuation of testosterone therapy results in reappearance of symptoms and reversal of benefits within 6 months, so testosterone therapy is likely to be required lifelong for persistent symptom resolution and maintenance of health benefits.17

References

  • Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675-685. Return to content
  • Traish AM. Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids. 2014;88:117-126. 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
  • Shortridge EF, Polzer P, Donga P, et al. Experiences and treatment patterns of hypogonadal men in a U.S. health system. Int J Clin Pract. 2014;68(10):1257-1263. Return to content
  • Rhoden EL, Morgentaler A. Symptomatic response rates to testosterone therapy and the likelihood of completing 12 months of therapy in clinical practice. The journal of sexual medicine. 2010;7(1 Pt 1):277-283. Return to content
  • Almehmadi Y, Yassin AA, Nettleship JE, Saad F. Testosterone therapy improves the health-related quality of life of men diagnosed with late-onset hypogonadism. Arab J Urol. 2016;14(1):31-36. Return to content
  • Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. 2019;6(42):1104-1111. Return to content
  • Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. 2020;23(1):81-92. 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
  • 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, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes. 2020;44(6): 1264-1278. Return to content
  • 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. Return to content
  • Heinemann LA, Saad F, Zimmermann T, et al. The Aging Males' Symptoms (AMS) scale: update and compilation of international versions. Health and quality of life outcomes. 2003;1:15. Return to content
  • Heinemann LAJ, Zimmermann T, Vermeulen A, Thiel C. A New 'Aging Male's Symptoms' (AMS) Rating Scale. The Aging Male. 1999;2:105-114. Return to content
  • 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
  • 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 Sept 17, 2019). CMAJ. 2015;187(18):1369-1377. 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
  • 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
  • Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2018;36:e33. Return to content
  • Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2020;38(1):68-77. 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
  • Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin Endocrinol (Oxf). 2016;84(1):107-114. 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
  • Donatucci C, Cui Z, Fang Y, Muram D. Long-term treatment patterns of testosterone replacement medications. The journal of sexual medicine. 2014;11(8):2092-2099. Return to content
  • Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40): 2706-2715. Return to content
  • Sharma R, Oni OA, Gupta K, et al. Normalization of Testosterone Levels After Testosterone Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. Journal of the American Heart Association. 2017;6(5). Return to content
  • Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014;68(2):203-215. Return to content
  • Oni OA, Dehkordi SHH, Jazayeri MA, et al. Relation of Testosterone Normalization to Mortality and Myocardial Infarction in Men With Previous Myocardial Infarction. Am J Cardiol. 2019;124(8):1171-1178. Return to content
  • Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline (unabridged). J Urol. 2018;200(2):423-432. Return to content
  • Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2018. 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
  • Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The aging male : the official journal of the International Society for the Study of the Aging Male. 2018:1-10. Return to content
  • Ng Tang Fui M, Hoermann R, Zajac JD, Grossmann M. The effects of testosterone on body composition in obese men are not sustained after cessation of testosterone treatment. Clin Endocrinol (Oxf). 2017;87(4):336-343. Return to content
  • Mskhalaya G, Tishova Y, Alfaradzh A, Kalinchenko S. Remission of type 2 diabetes in a young, hypogonadal man under long-term testosterone therapy: A case report. Global Journal of Obesity, Diabetes and Metabolic Syndrome. 2020;7:23-27. Return to content