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Key evidence-based Recommendations1
Definition of testosterone deficiency
- Testosterone deficiency (TD) is a clinical and biochemical syndrome, frequently associated with age and comorbidities, and characterized by a deficiency in T and relevant symptoms (grade B evidence)
- TD may affect the function of multiple organ systems and result in significant detriment to quality of life, including alterations in sexual function (grade B)
Clinical diagnosis
- The clinical manifestations of TD are variable:
- Sexual dysfunction (particularly hypoactive sexual desire (HSD) [grade A], erectile dysfunction (ED) [grade B] and delayed ejaculation [grade C]) is prominent and often provides the presenting symptoms
- Visceral obesity is often associated with TD, and muscle mass and (very likely) bone mineral density are diminished (grade A)
- Diminished strength, alterations in spatial cognition and mood may be associated with TD (grade C)
TD and metabolic diseases: screening
- Patients with clinical conditions associated with insulin resistance (obesity, type 2 diabetes, metabolic syndrome [MetS]) should be screened for TD, since it is often comorbid (grade B)
- In these clinical conditions, it is important to measure sex hormone binding globulin (SHBG) to estimate calculated free T (cFT), which is very well correlated to the value of FT measured by the reference assay, equilibrium dialysis (grade B)
TD and metabolic diseases: possible benefits of treatment
- Visceral obesity should be appropriately managed because it is signi?cantly associated with subsequent vascular events (grade A)
- Visceral obesity seems to be both the cause and the consequence of TD (grade A)
- In subjects with TD, T treatment improves body composition by moderately decreasing fat mass and increasing lean body mass (grade A)
- Preliminary data indicates a positive effect on glycaemic control
T and cardiovascular diseases
- Cardiovascular disease (CVD) is often associated with low T. All men with TD should have their CV risk factors assessed and addressed (grade C)
- Routine T measurement is not advised in men with CVD without symptoms of TD like HSD, ED, visceral obesity, or diabetes, until randomized controlled trials of T therapy have con?rmed its utility (grade C)
Questionnaires to screen for TD
- Many questionnaires developed to aid in diagnosing TD are sensitive but not specific. Structured interviews such as Androtest demonstrate sufficient sensitivity and specificity in subjects with sexual dysfunction to raise the suspicion of TD (grade B)
- However, the diagnosis of TD should not be based exclusively on questionnaires or structured interviews (grade B)
Biochemical diagnosis
- In patients with ED, and/or HSD, and/or retarded ejaculation, these investigations are recommended:
- Serum sample for total T (TT) determination (grade C)
- In case of a low level, we recommend: 1. repeating the TT determination; 2. together with determining SHBG level (for calculation of FT); and 3. measuring serum luteinizing hormone and prolactin levels (grade C)
Threshold levels for the biochemical diagnosis of TD
- There are no generally accepted lower limits of normal TT. There is, however, general agreement that:
- TT >12 nmol/L (3.5 ng/mL or 350 ng/dL) does not usually require supplementation (grade C)
- Based on the data of young hypogonadal men, men with TT <8 nmol/L (2.3 ng/mL or 230 ng/dL) usually bene?t from T treatment (grade C)
- Between these levels:
- Measuring FT by equilibrium dialysis or calculating it from TT and SHBG levels may be helpful. A lower limit of 225 pmol/L (65 pg/mL) is accepted by many (grade C)
- A T treatment trial may be envisaged for 3–6 months. Beyond that time, T therapy would be continued only in case of substantial bene?t (grade C)
- Clinical judgment should be exercised for men who have symptoms and are above these T levels
Indication for T treatment
- A clear indication is necessary: A clinical picture together with biochemical evidence of hypoandrogenism should exist prior to initiation of androgen therapy (grade C)
Age and T treatment
- In the absence of definite contraindications, age is not a limiting factor to initiate T treatment in men with TD (grade C)
Indications for T treatment in men with sexual dysfunction
- Men with TD and HSD (grade A), erectile dysfunction (ED) (grade B) or retarded ejaculation (grade C) are candidates for T treatment
- Absence of an appropriate response after adequate T treatment for 3–6 months (grade C) calls for further investigations to rule out associated comorbidities (grade A)
Combination therapy with T and phosphodiesterase type 5 inhibitors
- Evidence is emerging suggesting a therapeutic synergy with the combined use of T and PDE5-Is in men with ED and low T. These observations are preliminary and need additional studies (grade B)
- However, combination therapy can be considered in TD men who have not improved with T alone (grade B)
- In addition, it is recommended to measure T in case of PDE5-I failure if not previously done (grade B)
Commercial T formulations
- Current commercially available preparations of T (with the exception of the 17α-alkylated ones) are safe and effective (grade A)
- The treating physician should have sufficient knowledge and adequate understanding of the advantages and drawbacks of each preparation
- The patient should be given the opportunity to actively participate in the choice of T formulation (grade C)
Serum T levels to be achieved with T treatment
- The purpose of T treatment is to return and maintain serum T levels within the physiological range. Supraphysiological levels are to be avoided (grade C)
- No evidence exists for the need to maintain a circadian rhythm of serum T (grade C)
Prostate safety
- Historically, androgen administration has been absolutely contraindicated in men suspected of, or with a history of prostate cancer. This is an area of ongoing research and reevaluation
- There is no compelling evidence that T treatment causes prostate cancer or prostate cancer progression in the noncastrated man (grade C)
- T treatment is contra-indicated in men with clinical evidence of prostate cancer until more evidence on safety is available (grade C)
- Men with TD >45 years old should be informed before treatment of the benefits of T therapy, the limits of knowledge concerning prostate safety, and the fact that current data are reassuring
T treatment after treatment for prostate cancer
- Men successfully treated for prostate cancer and suffering from con?rmed, symptomatic TD are candidates for testosterone replacement therapy, after a prudent interval, if there is no evidence of residual cancer (grade C)
- The risks and bene?ts must be clearly understood by the patient and the follow-up must be particularly careful
- Safety data are limited, but early reports are reassuring. However, the clinician must exercise caution together with adequate knowledge of the advantages and drawbacks of androgen therapy in this situation
Breast cancer
- T treatment is contraindicated in men with breast cancer (grade A)
Cautions in the use of T therapy
- Men with signi?cant erythrosis/polycythaemia (haematocrit > 52%) or severe symptoms of bladder outlet obstruction should not be started on T treatment without prior improvement of the co-morbid condition (grade C)
Monitoring
- Specific guidelines for patient monitoring during T treatment are provided. These include liver function, lipids and glycaemia, prostate health, haematocrit, mood and wellbeing, and monitoring in men with severe obstructive sleep apnea, severe congestive heart failure, significant erythrosis/polycythaemia, severe symptoms of bladder outlet obstruction (grades A–C)
T therapy and CV health
- T treatment is not associated with markedly increased CV risk until 36 months of use (clinical trials data beyond 36 months are lacking), and replacement can be advocated on conventional established clinical grounds. However, the possibility of T therapy induced polycythaemia should be considered (grade B)
- Preliminary evidence suggests the possibility of bene?cial effects of T treatment on CV function. (grade B) The body of evidence supports the need for long-term placebo controlled randomised trials of T replacement in hypogonadal men with regard to morbidity and mortality.
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