Clinical guidelines for treatment of hypogonadism with testosterone therapy

Several international medical societies have issued recommendations on the diagnosis, treatment and monitoring of men with hypogonadism, also known as testosterone deficiency:

The British Society for Sexual Medicine (BSSM) 20171
https://www.jsm.jsexmed.org/article/S1743-6095(17)31538-2/pdf

The European Association of Urology (EAU) 20202
https://uroweb.org/guideline/sexual-and-reproductive-health

International Consultation for Sexual Medicine (ICSM) 20153 & 20194

American Urological Association (AUA) 20185
https://www.auajournals.org/doi/pdf/10.1016/j.juro.2018.03.115

The Endocrine Society (ES) 20186
https://academic.oup.com/jcem/article/103/5/1715/4939465

The International Society of Sexual Medicine (ISSM) 20157
https://professionals.issm.info/resources/clinical-guidelines

Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline8
(Canadian Men’s Health Foundation Multidisciplinary Guidelines Task Force on Testosterone Deficiency)
http://www.cmaj.ca/content/cmaj/187/18/1369.full.pdf
http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf

 

(Links are given to full-text pdf for guidelines that are published with open access)

The main points from the guidelines for the clinician to consider are summarised below.

 

Diagnosis of hypogonadism

Guidelines mandate that the diagnosis of hypogonadism is made based on typical symptoms and/or signs combined with a low testosterone level. While there is no universal diagnostic threshold for what should be counted as a low testosterone level, several guidelines recommend <12.1 nmol/L (<350 ng/dL) as a landmark.

Contraindications to testosterone therapy

Please refer to the SmPC for a full list of contraindications and precautions for use.

 

Testosterone therapy should not be given to men with:1,2

  • Androgen-dependent carcinoma of the prostate or of the male mammary gland
  • Male breast cancer
  • Haematocrit higher than and including 54%
  • Severe chronic heart failure (New York Heart Association class IV)
  • An active desire to have children

Some historical contraindications have been re-evaluated in light of recent evidence. Use of testosterone therapy may be acceptable in men with a PSA higher than 4.0 ng/mL as long as the patient has undergone adequate evaluation to exclude the presence of prostate cancer, which will usually require prostate biopsy examination.3 Numerous studies have shown no increased prostate cancer progression or recurrence in men after radical prostatectomy, external beam radiation therapy or brachytherapy, and even in small groups of men on active surveillance.9

Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude a risk of pre-existing prostatic cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum PSA) in patients receiving testosterone therapy at least once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial factors). Local guidelines for safety monitoring under testosterone replacement therapy should be taken into consideration.

 

Regarding LUTS (lower urinary tract symptoms), increasing testosterone levels may cause prostate growth and thus worsen obstructive voiding symptoms, recent evidence has shown that there may be an improvement in LUTS with testosterone therapy.10,11 More information about safety profile of testosterone therapy

Renal and urinary disorders (urine flow decreased, urinary retention, urinary tract disorder, nocturia, dysuria) are uncommon adverse reactions associated with nebido therapy.

The goal of testosterone therapy

The aim of testosterone therapy is to restore testosterone levels to a point that results in resolution of symptoms; hence, symptom resolution is a critical indicator of testosterone therapy efficacy.4,12-14

While there is no single optimal target serum testosterone level, the BSSM guidelines recommend a therapeutic target in the mid to upper part of the reference range. However, the Nebido SmPC states that serum levels should be within the lower third of the normal range.1 The absolute values corresponding to the mid to upper part of the reference range vary among assays and laboratories1

Failure to improve clinical symptoms within a reasonable period of time should result in re-evaluation of testosterone therapy with regard to dosage, compliance and achieved testosterone level.13 For more information, see “Testosterone Therapy Practical Advice

On-treatment monitoring of patients who receive testosterone therapy

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For men with hypogonadism who do not have any contraindications, after initiation of testosterone therapy it is recommended to evaluate patients at 3, 6 and 12 months, and then annually thereafter.

The injection interval should be within the recommended range of 10 to 14 weeks. Careful monitoring of serum testosterone levels is required during maintenance of treatment. It is advisable to measure testosterone serum levels regularly. Measurements should be performed at the end of an injection interval and clinical symptoms considered.

Proper follow-up of men receiving testosterone therapy should include:

  • Monitoring of testosterone levels.
  • Confirmation of symptomatic improvement.
  • Checking for any changes in haematocrit, PSA and digital rectal examination.15

Monitoring of serum testosterone levels

Measure testosterone levels at 3, 6 and 12 months and then annually after starting testosterone therapy. The dose of testosterone therapy should be adjusted to achieve a serum level within the lower third of the normal range. This commonly corresponds to testosterone levels in the range of 15-30 nmol/L.1 However, it should be noted that exact values can vary greatly between testosterone lab assays.

Due to inter-individual differences in androgen receptor sensitivity, some men may need to reach higher physiological testosterone levels in order achieve symptomatic relief.

Monitoring of symptomatic improvement

The primary aim of testosterone therapy is to alleviate symptoms of low testosterone. It is recommended that clinical assessment of symptoms is done by the use of validated questionnaires, such as the Ageing Male Symptoms Scale . The AMS provides a quantitative assessment of the severity of baseline symptoms, and the progressive symptomatic response to testosterone therapy.

It is critical to keep in mind that potential maximal benefits of testosterone therapy may be seen after 12 months.1 For instance, AMS scores may continue to progressively improve for 2 years and erectile function may continue to progressively improve for up to 9 years with uninterrupted testosterone treatment for a long period of time.16 Potential maximal improvements in obesity parameters (BMI and waist circumference), glycemic control, lipid profile and bone mineral density also take many years of uninterrupted testosterone therapy to be achieved.16-19

While symptomatic relief is the primary aim of testosterone therapy, treatment may provide other secondary benefits, such as increased muscle mass and bone mineral density, reduced body fat mass and improved glucose control and lipid profile.16-20 Monitoring and seeing improvements in these objective outcomes during testosterone therapy can help motivate patients to adhere to treatment.

Monitoring of hematocrit

Measure haematocrit levels at 3, 6 and 12 months and then annually after starting testosterone therapy.

Elevated haematocrit, defined as 54% or higher by most guidelines, is the most common side-effect of testosterone therapy and is caused by testosterone-induced erythrocytosis.

The clinical significance of a high haematocrit is unclear, but theoretically it may be associated with increased blood viscosity and thrombosis, although this has not been proven.21 The effect of testosterone therapy on erythropoiesis and haematocrit may become evident after 3 months and reaches a plateau at 9-12 months after start of testosterone therapy.22

Regular therapeutic phlebotomy may help keep haematocrit below 54%. If not, reduced dose frequency of testosterone therapy is recommended. If haematocrit remains 54%, temporary withholding of testosterone therapy may be necessary until haematocrit returns to below 54%.23 Testosterone therapy may then be reintroduced at a decreased dose, or a change of testosterone preparation may be advisable.

Monitoring of PSA and DRE (digital rectal examination)

Assess prostate health by checking PSA level and performing a digital rectal examination before the start of testosterone replacement therapy.

PSA should be measured at 3-6 months, 12 months and then annually thereafter. Men at high risk for prostate cancer may need more in-depth prostate monitoring by a urologist.

For patients who have an elevated PSA at baseline, a second confirmatory PSA measurement is recommended to rule out a spurious elevation. In patients who have two baseline PSA tests that raise suspicion for the presence of prostate cancer, referral to a urologist for a more in-depth prostate examination (which may include reflex testing and/or prostate biopsy) is recommended before initiating testosterone therapy.

Men with very low testosterone levels before start of testosterone therapy are more likely to experience elevation in PSA, albeit within the normal range. When PSA increases, it commonly does so over the first 6-12 months, then no further increases are usually seen with continued testosterone therapy.21

PSA increases greater than 1.4 ng/mL during any 1-year period after initiation of testosterone therapy or a PSA velocity greater than 0.4 ng/mL per year during sequential PSA measurements over more than 2 years warrant a urologic evaluation and more intensive surveillance for prostate cancer thereafter.1

Men with BPH can be prescribed testosterone therapy; these men may experience alleviation of LUTS with long-term testosterone therapy. However, BPH is a known common side effect of testosterone therapy and renal/urinary disorders are a known uncommon side effect.3,4,24

Monitoring of body weight, waist circumference, lipids and glycemic control

Monitoring of body weight, waist circumference, lipids and glycemia is not required for safety follow-up, but is useful for monitoring the efficacy of testosterone treatment.1,2 Several long-term “real life” studies in men with overweight and obesity have shown that testosterone therapy signfiicantly (P<0.0001) reduces body weight, waist circumference and HbA1c, and improves the lipid profile vs untreated group.17,25-29 Seeing improvement in these parameters can be a motivating factor for patients to adhere to testosterone therapy.

Monitoring of bone mineral density

In men with low bone mineral density or osteoporosis before initiation of testosterone therapy, it is recommended to repeatedly measure bone mineral density with DEXA (dual energy x-ray absorptiometry) every 1–2 years after start of testosterone therapy.1,2

References

  • 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
  • Salonia A, Bettocchi C, Carvalho J. EAU Guidelines on Sexual and Reproductive Health. 2020. 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
  • Morgentaler A, Traish A, Hackett G, Jones TH, Ramasamy R. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev. 2019;7(4):636-649. Return to content
  • Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200(2):423-432. Return to content
  • Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. 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. CMAJ. 2015;187(18):1369-1377. Return to content
  • Morgentaler A, Caliber M. Safety of testosterone therapy in men with prostate cancer. Expert opinion on drug safety. 2019;18(11):1065-1076. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Hypogonadal men with moderate-to-severe lower urinary tract symptoms have a more severe cardiometabolic risk profile and benefit more from testosterone therapy than men with mild lower urinary tract symptoms. Investig Clin Urol. 2018;59(6):399-409. Return to content
  • Traish AM, Johansen V. Impact of Testosterone Deficiency and Testosterone Therapy on Lower Urinary Tract Symptoms in Men with Metabolic Syndrome. The world journal of men's health. 2018;36(3):199-222. 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
  • Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. The ageing male : the official journal of the International Society for the Study of the Ageing Male. 2015;18(1):5-15. Return to content
  • Hackett GI. Controversies in the diagnosis and management of testosterone deficiency syndrome. CMAJ. 2015;187(18):1342-1344. Return to content
  • http://www.bssm.org.uk/wp-content/uploads/2018/09/guidelines-on-adulttestosterone-deficiency-with-statements-for-uk-practice.pdf 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 ageing male : the official journal of the International Society for the Study of the Ageing Male. 2020;23(1):81-92. 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
  • 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
  • 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
  • Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. 2016;174(3):R99-116. Return to content
  • König CS, Balabani S, Hackett GI, Strange RC, Ramachandran S. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sex Med Rev. 2019;7(4):650-660. Return to content
  • 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
  • Andrea Cervi et al. CMAJ 2017;189:E1286-8 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, 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 ageing male : the official journal of the International Society for the Study of the Ageing Male. 2019:1-12. Return to content
  • Traish AM, Haider A, Haider KS, 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. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433. 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
  • 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;48(7):793-799. 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

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