Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men

September 2021

With the growing population of older men, testosterone deficiency (also known as hypogonadism) and its treatment are an active area of clinical research. Medical societies publish clinical guidelines with recommendations for best practices regarding the diagnosis, treatment and monitoring of testosterone deficiency. As clinical research with new findings regarding testosterone deficiency and its treatment accumulate at a rapid pace, clinical guidelines are evolving with ongoing re-evaluation of recommendations as new evidence gets published.

The International Society for the Study of the Aging Male (ISSAM) was established with the objective of promoting research, study and education on all matters related to men's health. The ISSAM Hypogonadism panel consists of a multidisciplinary group of experts, including urologists, endocrinologists, andrologists and internists with various subspecialties. Previous ISSAM guidelines were published in 20051 , 20092 , 20133 and 2015.4 Here we summarise the updated 2021 ISSAM recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men.5

KEY POINTS

  • Testosterone deficiency in men is a clinical and biochemical syndrome associated with a low level of testosterone, which may adversely affect multiple organ functions and quality of life.
  • Men with symptoms and signs of testosterone deficiency should have their testosterone level checked.
  • Medical examination of men with symptoms and signs of testosterone deficiency should include checking for existing diseases and medication use that may cause impaired testosterone production.
  • Improvement in hypogonadism signs and symptoms occur at various time points after start of testosterone therapy. Hence, achievement of maximal benefits of testosterone therapy requires long-term uninterrupted treatment.
  • Evidence shows that testosterone therapy:
    1. reduces fat mass, waist size, BMI, fasting plasma glucose, post-prandial glucose levels, HbA1c, insulin and C-reactive protein levels and depressive symptoms.
    2. increases lean (muscle) mass and bone density (vertebral and hip).
    3. improves libido and erectile function.
  • There is no evidence that testosterone treatment increases risk of BPH (BPH) and prostate cancer, or contributes to worsening of lower urinary tract symptoms (LUTS).
  • Totality of evidence shows no increased risk of heart attack, stroke or death with testosterone therapy.

Recommendation 1: Definition

Testosterone deficiency in adult men is a clinical and biochemical syndrome associated with a low level of testosterone, which may adversely affect multiple organ functions and quality of life.

Although the clinical significance of testosterone deficiency in men is becoming increasingly recognized, a large number of men with testosterone deficiency who would be expected to benefit from testosterone treatment remain undiagnosed and untreated, due to deficient medical training and lack of basic knowledge how to diagnose and treat men with hypogonadism.6, 7

Recommendation 2: Clinical diagnosis

Check for testosterone deficiency in men with symptoms and signs of testosterone deficiency

The diagnosis of testosterone deficiency requires the presence of characteristic symptoms and signs in combination with decreased testosterone level. The presence of symptoms alone does not constitute testosterone deficiency. Symptoms must be accompanied by decreased levels of total testosterone or free testosterone to support a diagnosis of testosterone deficiency.

The greater the number of symptoms in a man, the greater the probability that he truly has testosterone deficiency.8 However, the presence of even one symptom may raise suspicion of symptomatic testosterone deficiency.

The prevalence of symptomatic testosterone deficiency is particularly high in men with obesity and type 2 diabetes,9 benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).10, 11

Recommendation 3: Causes

Check for existing diseases and medication use that may cause impaired testosterone production

Several medical conditions, listed in table 1, are associated with testosterone deficiency. The ISSAM guidelines recommend measurement of testosterone levels in men with these conditions.

While testosterone deficiency caused by decreased Leydig cell function (also known as primary hypogonadism) is most common in older men, testosterone deficiency caused by suppressed hypothalamic–pituitary function (also known as secondary hypogonadism) is most common in men with comorbidities listed in table 1, especially obesity, metabolic syndrome and type 2 diabetes, regardless of age. With the rising prevalence of obesity and type 2 diabetes among all age groups, testosterone deficiency is becoming more and more common even in younger men. Commonly used medications can also cause low testosterone levels or decreased testosterone bioactivity (table 2).

Table 1: Disorders and conditions most frequently associated with testosterone deficiency.5

Sexual disorders Low libido*
Poor morning erections*
Erectile dysfunction*
Difficulty in achieving orgasm or reduced intensity of orgasm
Metabolic and physical conditions: Insulin resistance
Obesity, abdominal obesity*
Anemia
Metabolic syndrome*
Arterial hypertension
Dyslipidemia
Type 2 diabetes*
Sarcopenia (decreased muscle mass and strength)*
Decreased bone mineral density and osteoporosis
Chronic pain
Sleep apnea
Psychological disorders Depressed mood
Fatigue *
Decreased vitality *
Cognitive impairment

* Most frequently associated with testosterone deficiency.

Table 2: Medications that may cause low testosterone levels or decreased testosterone bioactivity.

Opioids
Statins
Glucocorticoids
Antipsychotics
Alkylating agents
Testosterone synthesis inhibitors
Estrogens
Progestogens (including cyproterone acetate)
Ketoconazole
Aminogutethimide
Mitotane
Metyrapon GnRH agonist or antagonist
Prolactin increasing agents
Drug-induced aromatase activity blockade
  • Letrozole
  • Anastrazole
  • Exemestane

Drug-induced 5-aplha reductase activity blockade
  • Finasteride
  • Dutasteride
  • Drug-induced ER blockade
  • Clomiphene
  • Tamoxifen
  • Raloxifene

Drug-induced AR blockage / Steroidal antiandrogen
  • Cyproterone acetate
  • Spironolactone

Non-steroidal antiandrogen
  • Flutamide
  • Bicalutamide
  • Nilutamide

Recommendation 4: Laboratory diagnosis

In patients at risk or suspected of testosterone deficiency, a thorough biochemical and physical work-up is recommended.

The ISSAM recommends measurement of testosterone levels and physical examination in men with the conditions listed in table 1. Measuring serum testosterone is mandatory to make the diagnosis of testosterone deficiency. Either total testosterone or free testosterone can be used. In symptomatic men with borderline low testosterone levels, a low level of free testosterone (either calculated or measured) can confirm the diagnosis.

Total testosterone measurement is more readily available and less expensive than measurement of free testosterone, and hence the main laboratory test used in making the diagnosis of testosterone deficiency. Assessment of free testosterone, which may have better correlation with symptoms of testosterone deficiency,12 is recommended in men with symptoms and borderline or low-normal testosterone levels.

Recommendation 5: Assessment of treatment outcome and decisions on continued therapy

Improvement in hypogonadal signs and symptoms occur at various times points after start of testosterone therapy.

The time it takes for improvement in signs and symptoms of testosterone deficiency is different for each outcome.13 For more information, see “How soon can effects from testosterone therapy be expected?” A wide range of benefits have been documented in men who receive testosterone treatment, summarized in table 2.

If symptoms do not improve after 6-12 months of testosterone treatment and lab results during monitoring show that serum testosterone levels are still below mid-range of lab specific reference range, the most likely reasons are poor patient adherence and/or inadequate dose of testosterone preparation.

If lab results during monitoring show that serum testosterone levels have been in the mid-to-high end of the reference range, further investigation is needed to determine other causes of the symptoms.

Table 2: Benefits of testosterone treatment, supported by available evidence.5

OutcomeBenefit with testosterone treatment
Body composition and mobilityReduction in fat mass
Consistent increase in lean mass
Bone density and fracturesIncreased vertebral and hip bone density
Sexual functionImproves libido and erectile function
Obesity, metabolic syndrome and type 2 diabetesReduced waist size, BMI, fasting plasma glucose, HbA1c, insulin and C-reactive protein levels

Improvement of post-prandial glucose levels
Cardiovascular disease and all-cause mortalityThere is no evidence showing increased cardiovascular mortality or morbidity with testosterone therapy
Depression and cognitive functionTestosterone therapy is associated with a mild reduction of depressive symptoms
benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)There is no evidence that testosterone therapy either increases the risk of BPH or contributes to worsening of LUTS
Prostate cancerThere is no evidence of increased prostate cancer risk in men receiving testosterone therapy
Treatment and delivery systemsTestosterone preparations should be prescribed according to patient preference

 

Details regarding evidence for the benefits of testosterone treatment listed in table 2 can be found in the ISSAM guidelines publication,5 available at: https://www.tandfonline.com/doi/full/10.1080/13685538.2021.1962840 (accessed September 6th, 2021)

Commentary

The ISSAM recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men underscore that guideline recommendations can never replace clinical expertise. Also, treatment decisions, selection of treatment protocols or choice of products for individual patients must take into account individual patients’ needs and preferences.

A natural physiological response to testosterone treatment is a slight elevation in hematocrit14 and PSA.15 In the vast majority of men, these elevations stay within the normal reference range, and stabilize at a new steady-state level approximately 1 year after start of testosterone treatment. Only a minority of men experience elevation in hematocrit and PSA that go above the upper limit of the normal range. Excessive elevations in hematocrit and PSA are two legitimate side effects of testosterone treatment. As a safety precaution, all clinical guidelines state that it is mandatory to regularly monitor levels of testosterone, hematocrit and PSA during testosterone treatment, although the recommendation on frequency of doing follow-up blood testing varies slightly between guidelines.

High hematocrit is a contributing cause to increased blood viscosity.16, 17 Patients with markedly elevated hematocrit due to polycythemia vera are at increased risk of arterial thrombosis and venous thromboembolism, and this risk has been attributed in part to increased blood viscosity due to elevated hematocrit.18 Therefore, some regulatory institutions such as the FDA have issued a warning that testosterone therapy could possibly increase the risk of thromboembolism.

Although the erythrogenic effect of testosterone that leads to elevated levels of hemoglobin and hematocrit is well documented,14 the presumed association between testosterone-induced hematocrit elevation and subsequent risk of venous thromboembolism remains unproven, as there is no direct evidence for this.19 On the contrary, one study showed that higher testosterone levels in both older men and women were associated with reduced platelet activation and reactivity, compared to lower testosterone level.20 Meta-analyses of randomized controlled trials show that despite higher incidence of elevated hemoglobin and hematocrit in men receiving testosterone therapy compared to placebo, there were no significant adverse effects on cardiovascular outcomes or mortality.21, 22 A meta-analysis that specifically aimed to examine the association between testosterone therapy in men and venous thromboembolism concluded, based on data from 6 RCTs (n=2236) and 5 observational studies (n=1,249,640), that evidence does not support an association between testosterone therapy and venous thromboembolism in men.23

The question has been raised whether high hematocrit is a risk factor for venous thrombosis or just an innocent bystander? 24 In the general population (excluding patients with polycythemia vera), an alternative explanation for the association between increased levels of hematocrit and the risk of venous thrombosis could be presence of conditions that co-exist with elevated hematocrit and that increase the risk of venous thrombosis, such as obesity, smoking, lung disease or heart disease.24

A report from the Emerging Risk Factors Collaboration and the UK Biobank study investigated associations of several established cardiovascular risk factors with the incidence of venous thromboembolism outcomes, analyzing data from more than 1.1 million participants in 76 prospective studies.25 It was found that obesity, older age and smoking were consistently associated with higher venous thromboembolism risk.25 Obesity was also associated with pulmonary embolism. It was concluded that tackling obesity would yield important benefits for venous thromboembolism prevention.25

In terms of cardiovascular risk, prospective, randomized, controlled trials have failed to show a direct relationship between testosterone-induced hematocrit elevation and subsequent risk for cardiovascular events (including stroke and deep vein thrombosis).26 The lack of increase in cardiovascular events in the majority of men with elevated hematocrit due to testosterone therapy may be due to the fact that testosterone acts as a vasodilator and has anti-atherosclerotic effects.27 For example, testosterone has been shown to inhibit platelet aggregation by stimulation of endothelial nitric oxide synthase and vascular endothelial cell growth.28 Furthermore, real-life evidence studies have shown that long-term treatment with testosterone undecanoate injections significantly reduces obesity markers (BMI and waist size),29, 30 which presumably would reduce the obesity-related venous thromboembolism risk.

Nevertheless, as a safety precaution, clinical guidelines recommend that during testosterone therapy, if hematocrit increases to ≥54%, measures need to be taken to lower hematocrit back to below 54%,31-34 such as switching from a short-acting testosterone injection preparation (testosterone cypionate or enanthate) to the long-acting testosterone injection preparation, testosterone undecanoate, which has the lowest risk of causing hematocrit elevation to ≥54%.35-37 Doing regular therapeutic phlebotomy (venesection, 500 mL) to lower hematocrit is also effective in managing testosterone treatment–induced hematocrit elevation.31, 33

The ISSAM guidelines recommend that hematocrit is measured before start of testosterone therapy, at month 3-4 and 12 during the first year of treatment, and annually thereafter. It should be pointed out that isolated hematocrit elevation can be the result of insufficient fluid intake on a hot day. Only repeated measures of hematocrit >54% should be followed by intervention such as therapeutic phlebotomy and/or switch to a long-acting testosterone preparation such as testosterone undecanoate injection.

The ISSAM guidelines point out that while two meta-analyses showed no increased risk of prostate cancer development or progression in men receiving testosterone therapy compared to placebo,38, 39 as a safety precaution, before starting testosterone therapy risk of prostate cancer must be assessed by, at a minimum, measurement of PSA and consideration of common risk predictors of prostate cancer; family history of prostate cancer, age and ethnicity/race. If there is suspicion of prostate cancer, a prostate biopsy is warranted, and if negative, testosterone therapy may be initiated in these men.

Men with a baseline PSA level of >4.0 ng/mL, which is a contraindication for testosterone therapy, should be referred to a urologist for further medical examination and clearance to start testosterone therapy. After start of testosterone therapy, PSA levels should be measured at 3-6 months, 12 months and annually thereafter. An initial small increase in PSA level and prostate volume is commonly seen during the first 6 months, after which a new steady-state level is reached.13 This should then be used as the new baseline and reference point for monitoring with continued testosterone therapy.

During testosterone therapy, if a patient has a worrisome rise in PSA – defined as a PSA level increase of 1.0 ng/mL over baseline PSA or a PSA increase velocity greater than 0.35 ng/mL per year40 - or develops a palpable prostate abnormality on digital rectal exam, referral to a urologist for prostate evaluation and possible biopsy is needed.40

It is essential that patients are informed that achievement of maximal benefits requires long-term uninterrupted testosterone therapy13

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