madman
Super Moderator
Introduction
Late-onset hypogonadism is the clinical entity characterized by low testosterone concentrations associated with clinical symptoms in the absence of organic disease in aging men. It has been associated with metabolic syndrome, reduced bone mineral density, and increased cardiovascular morbidity and mortality risk. Although testosterone replacement therapy (TRT) reverses most of these conditions in young hypogonadal men, the risk/benefit ratio of TRT in older men is debatable.
Aim
To update the 2015 EMAS statement on TRT in older men with new research on late-onset hypogonadism and TRT.
Materials and methods
Literature review and consensus of expert opinion.
Summary recommendations
TRT should be offered only to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment. TRT may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire and erectile, and orgasmic function. It should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus. TRT may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition. TRT is contraindicated in hypogonadal men actively seeking fertility treatment. Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline. TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer all men who have had myocardial infarction or stroke within the last four months, and those with severe order compensated heart failure. The quality of evidence regarding patients with previous prostate cancer or cardiovascular disease is too low to draw definitive conclusions. Any limits on the duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis. Withdrawal should be considered when hypogonadism is reversed after the resolution of the underlying disorder. Short-acting transdermal preparations should be preferred for TRT initiation in older men, but injectable forms may be considered subsequently. Older men on TRT should be monitored at 3, 6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated. Evaluation should include assessment of the clinical response, and measurement of total testosterone, hematocrit, and prostate-specific antigen (PSA) concentrations. Bone density and/or quality should also be assessed. Obese and overweight patients should be encouraged to undergo lifestyle modifications, including exercise and weight loss, to increase endogenous testosterone.
1. Introduction
People worldwide are living longer. The population aged over 60 years now surpasses 1 billion and is expected to double by 2050 [1]. Several population-based studies have documented an age-dependent, modest reduction of serum testosterone (T) concentrations in men after the fourth decade, with a decrease of about 1 % per year [2], and the T concentrations of some men will eventually drop below 8 nmol/L (250 ng/dL), the threshold agreed by most scientific societies to correspond to clinically meaningful testosterone deficiency (TD). Late-onset hypogonadism (LOH) is the clinical entity in which TD in older men is associated with clinical symptoms in the absence of organic diseases that permanently disrupt the hypothalamic-pituitary-testis (HPT) axis. Its reported prevalence varies from 2.1 % to 12.3 % [3,4]. LOH is associated with symptoms that may negatively impact the quality of life of older men, such as sexual dysfunction, and decreased energy and mobility. Has also been associated with metabolic syndrome, reduced bone mineral density, and an increased risk of cardiovascular (CV) morbidity and mortality [5,6] (Fig. 1). T replacement therapy (TRT) has been demonstrated to reverse most of these conditions in hypogonadal men of all ages, but while the risk/benefit ratio of TRT is clear for younger men, for aging men it is uncertain [7,8].
In 2015 EMAS published a position statement on TRT in the aging [9]. This 2023 document takes into account new research, new T-formulations, and recently published clinical guidance [10–14]. It discusses the evidence on TRT in aging men regarding the diagnosis of hypogonadism, the indications and contraindications of therapy, and the application and monitoring of TRT. There is a specific focus on controversial areas, especially safety.
2.1. Diagnosis of hypogonadism
2.1.1. When the diagnosis is established
Summary recommendation
The diagnosis of hypogonadism in aging men should be based on low T concentrations when accompanied by relevant symptoms, especially sexual ones (low sexual desire, reduced spontaneous erections, and erectile dysfunction). Universal screening of aging men for low T concentrations is not justified. The use of clinical questionnaires for diagnosing hypogonadism is not recommended.
2.2. Biochemical diagnosis and T measurement
Summary recommendation
Biochemical diagnosis of hypogonadism should rely on standardized T assays with morning (7.00–11.00 am) fasting samples. Samplings should be avoided in the presence of acute stressors, and abnormal results should be confirmed on a different day. Hypogonadism is highly probable when tT concentrations are below 8 nmol/L (231 ng/dL), whereas tT concentrations above 12 nmol/L (345 ng/dL) typically exclude the diagnosis. For values between 8 and 12 nmol/L, the assessment of fT should be employed (either using EqD or calculated fT). Free T should also be used for patients with conditions that disrupt SHBG secretion.
2.3. Differential diagnosis of hypogonadism
Summary recommendation
The assessment of LH should follow the diagnosis of hypogonadism to differentiate between primary and secondary hypogonadism. In primary hypogonadism, karyotyping to exclude Klinefelter syndrome may be considered. In secondary hypogonadism, particularly in the presence of very low tT concentrations (<6 nmol/L, <175 ng/dL) and concomitant signs and symptoms of a sellar mass and/or other pituitary hormone deficiencies, the investigation should be completed with an MRI of the sellar region. If an organic disorder is not established, the conditions should be diagnosed and managed as functional hypogonadism. An overview is given in Fig. 2.
2.4. Testosterone replacement therapy
2.4.1. When to treat – indications
Summary recommendation
TRT in older men should be offered after setting realistic goals depending on the presenting symptoms, after a thorough evaluation of the patient's comorbidities, and after explaining the uncertain long-term safety of this approach.
2.4.2. Sexual function
Summary recommendation
TRT should be offered to older men with sexual complaints to improve sexual desire and orgasmic function. TRT is expected to improve erectile dysfunction in men with severe hypogonadism (tT <8 nmol/L) and mild erectile dysfunction (IEEF ED score≥22). In men with mild hypogonadism (tT 8–12 nmol/L) and/or severe erectile dysfunction (IEEF ED score <22), established treatment options for erectile dysfunction, such as PDE5-inhibitors, should be tried before TRT.
2.4.3. Obesity, metabolic syndrome, and testosterone treatment
Summary recommendation
Data suggest favorable effects of TRT on insulin resistance and body composition in patients with T2DM and obesity, but the discrepancies regarding its efficacy on HbA1c do not support its widespread use as monotherapy for diabetes treatment. TRT should be considered in those patients with hypogonadism (T < 12nmol/L) and severe insulin resistance or T2DM, alongside a concomitant lifestyle program and standard medical care.
2.4.4. Bone health
Summary recommendation
Men with hypogonadism should be screened for osteoporosis. TRT is recommended to prevent bone loss and help maintain peak bone mass as it can improve BMD and bone structure. This effect is more prominent in the lumbar spine, in men with lower pre-treatment T concentrations, and, notably, in the presence of osteopenia/osteoporosis at baseline. However, available evidence does not support the beneficial effect of TRT in decreasing the incidence of fractures; therefore, in patients with hypogonadism and high fracture risk, TRT should be adjunctive to standard anti-osteoporotic medical care.
2.4.5. Quality of life - mood
Summary recommendation
TRT may be offered as monotherapy to hypogonadal men with persistent mild depressive symptoms and/or low self-perceived QoL; however, when a major depressive disorder is diagnosed, TRT should be used only as adjunctive treatment to antidepressants
2.5. When not to treat – lack of efficacy
2.5.1. Physical function
2.5.2. Cognitive function
Summary recommendation
Due to a lack of robust data supporting its efficacy, TRT should not be routinely used in older hypogonadal men to improve exercise capacity/physical function or cognitive function or to prevent cognitive decline.
2.6. When not to treat – contraindications
Diseases known, or believed to be, aggravated by TRT, such as breast cancer (BrCa), prostate cancer (CaP) or severe lower urinary tract symptoms, and recent CV disease (including stroke), raise concern and preclude affected men from participating in trials evaluating TRT. Moreover, most RCTs lack adequate statistical power and duration to determine whether TRT has a causative role in the development of these conditions; therefore, the long-term safety of TRT in this context is unknown [102].
2.6.1. Hormone-sensitive cancers
2.6.2. Elevated hematocrit, cardiovascular disease, and thrombosis
2.6.3. Fertility
Summary recommendation
TRT should not be attempted in older men with BrCa and untreated CaP and should be preceded by digital rectal examination (DRE) and PSA measurement to identify pre-existing CaP. Those with abnormal DRE and PSA >4 ng/mL should undergo further neurological evaluation. Men with a recent history (<4 months) of myocardial infarction or stroke and severe (NYHA Class III or IV) or decompensated heart failure should also be precluded from TRT. Haematocrit should be measured before initiating TRT, and if it exceeds the normal range therapy has to be postponed until it has normalised. A personal history of VTE is a contraindication for TRT; for men with a family history of VTE, inherited thrombophilia should be excluded before the initiation of TRT. TRT is contraindicated in hypogonadal men actively seeking fertility.
2.7. Areas of uncertainty
2.7.1. Cardiovascular risk and testosterone treatment
Summary recommendation
The quality of evidence regarding the cardiovascular safety of TRT in LOH has been low. However, the most recent data have shown that testosterone treatment in older men with hypogonadism and at increased cardiovascular risk is safe, at least in terms of major adverse cardiac events. Nevertheless, a thorough evaluation of the patient's CV risk prior to TRT is mandatory, as is strict compliance with prescription guidelines regarding dose and treatment monitoring. CV risk must be re-evaluated during TRT, and patients should be informed about the lack of definitive studies on TRT's long-term effects (>3 years). TRT must not be offered as a cardio prevention therapy to frail older men until better outcome data are available.
2.8. Prostate health and testosterone treatment
Summary recommendation
TRT may be considered in hypogonadal men with a history of previous low-risk, localized CaP (Gleason score <7, pT1–2, preoperative PSA <10 ng/mL) who have constantly undetectable PSA concentrations after a radical prostatectomy; however, close monitoring is mandatory.TRT should not be avoided in men with hypogonadism and benign prostate hyperplasia/LUTS; however, caution should be paid to those with severe LUTS (IPSS >19).
2.9. How to treat
Summary recommendation
There is no clear maximum duration for TRT. Short-acting transdermal preparations should be the preferred method of administration for older men, due to the avoidance of liver metabolism, a lower complication rate, in particular regarding polycythemia, and the possibility of prompt withdrawal if required. Injectable forms of T may be considered if transdermal TRT has proven beneficial and safe in a given patient. In cases suggestive of functional hypogonadism, withdrawal or substitution of detrimental factors should be advised when possible, and in overweight or obese patients, weight loss by any means combined with exercise should be the first-line recommendation, possibly supported with TRT to augment the effects and reinforce the patient's commitment to lifestyle modifications.
2.10. Monitoring schedule
Summary recommendation
Older men on TRT should be monitored at 3, 6, and 12 months after initiation and yearly after that. Evaluation should include the assessment of clinical response, and measurement of tT concentrations, hematocrit, and PSA. BMD should be assessed using DXA and follow-up may be at one year or up to 5 years according to the patient's fracture risk. The monitoring schedule is summarised in Fig. 3.
3. Conclusions
The identification of clear, evidence-based indications for treating LOH remains an unmet need. An individualized, tailored approach is strongly recommended when considering hormone replacement therapy. TRT has shown the potential to reduce age-related comorbidities and improve quality of life. However, there are multiple areas of uncertainty and a need for large-scale, prospective, adequately powered RCTs specifically designed to examine the efficacy of TRT and its safety particularly in relation to metabolic and bone health, and prostate disease.
Late-onset hypogonadism is the clinical entity characterized by low testosterone concentrations associated with clinical symptoms in the absence of organic disease in aging men. It has been associated with metabolic syndrome, reduced bone mineral density, and increased cardiovascular morbidity and mortality risk. Although testosterone replacement therapy (TRT) reverses most of these conditions in young hypogonadal men, the risk/benefit ratio of TRT in older men is debatable.
Aim
To update the 2015 EMAS statement on TRT in older men with new research on late-onset hypogonadism and TRT.
Materials and methods
Literature review and consensus of expert opinion.
Summary recommendations
TRT should be offered only to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment. TRT may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire and erectile, and orgasmic function. It should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus. TRT may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition. TRT is contraindicated in hypogonadal men actively seeking fertility treatment. Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline. TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer all men who have had myocardial infarction or stroke within the last four months, and those with severe order compensated heart failure. The quality of evidence regarding patients with previous prostate cancer or cardiovascular disease is too low to draw definitive conclusions. Any limits on the duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis. Withdrawal should be considered when hypogonadism is reversed after the resolution of the underlying disorder. Short-acting transdermal preparations should be preferred for TRT initiation in older men, but injectable forms may be considered subsequently. Older men on TRT should be monitored at 3, 6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated. Evaluation should include assessment of the clinical response, and measurement of total testosterone, hematocrit, and prostate-specific antigen (PSA) concentrations. Bone density and/or quality should also be assessed. Obese and overweight patients should be encouraged to undergo lifestyle modifications, including exercise and weight loss, to increase endogenous testosterone.
1. Introduction
People worldwide are living longer. The population aged over 60 years now surpasses 1 billion and is expected to double by 2050 [1]. Several population-based studies have documented an age-dependent, modest reduction of serum testosterone (T) concentrations in men after the fourth decade, with a decrease of about 1 % per year [2], and the T concentrations of some men will eventually drop below 8 nmol/L (250 ng/dL), the threshold agreed by most scientific societies to correspond to clinically meaningful testosterone deficiency (TD). Late-onset hypogonadism (LOH) is the clinical entity in which TD in older men is associated with clinical symptoms in the absence of organic diseases that permanently disrupt the hypothalamic-pituitary-testis (HPT) axis. Its reported prevalence varies from 2.1 % to 12.3 % [3,4]. LOH is associated with symptoms that may negatively impact the quality of life of older men, such as sexual dysfunction, and decreased energy and mobility. Has also been associated with metabolic syndrome, reduced bone mineral density, and an increased risk of cardiovascular (CV) morbidity and mortality [5,6] (Fig. 1). T replacement therapy (TRT) has been demonstrated to reverse most of these conditions in hypogonadal men of all ages, but while the risk/benefit ratio of TRT is clear for younger men, for aging men it is uncertain [7,8].
In 2015 EMAS published a position statement on TRT in the aging [9]. This 2023 document takes into account new research, new T-formulations, and recently published clinical guidance [10–14]. It discusses the evidence on TRT in aging men regarding the diagnosis of hypogonadism, the indications and contraindications of therapy, and the application and monitoring of TRT. There is a specific focus on controversial areas, especially safety.
2.1. Diagnosis of hypogonadism
2.1.1. When the diagnosis is established
Summary recommendation
The diagnosis of hypogonadism in aging men should be based on low T concentrations when accompanied by relevant symptoms, especially sexual ones (low sexual desire, reduced spontaneous erections, and erectile dysfunction). Universal screening of aging men for low T concentrations is not justified. The use of clinical questionnaires for diagnosing hypogonadism is not recommended.
2.2. Biochemical diagnosis and T measurement
Summary recommendation
Biochemical diagnosis of hypogonadism should rely on standardized T assays with morning (7.00–11.00 am) fasting samples. Samplings should be avoided in the presence of acute stressors, and abnormal results should be confirmed on a different day. Hypogonadism is highly probable when tT concentrations are below 8 nmol/L (231 ng/dL), whereas tT concentrations above 12 nmol/L (345 ng/dL) typically exclude the diagnosis. For values between 8 and 12 nmol/L, the assessment of fT should be employed (either using EqD or calculated fT). Free T should also be used for patients with conditions that disrupt SHBG secretion.
2.3. Differential diagnosis of hypogonadism
Summary recommendation
The assessment of LH should follow the diagnosis of hypogonadism to differentiate between primary and secondary hypogonadism. In primary hypogonadism, karyotyping to exclude Klinefelter syndrome may be considered. In secondary hypogonadism, particularly in the presence of very low tT concentrations (<6 nmol/L, <175 ng/dL) and concomitant signs and symptoms of a sellar mass and/or other pituitary hormone deficiencies, the investigation should be completed with an MRI of the sellar region. If an organic disorder is not established, the conditions should be diagnosed and managed as functional hypogonadism. An overview is given in Fig. 2.
2.4. Testosterone replacement therapy
2.4.1. When to treat – indications
Summary recommendation
TRT in older men should be offered after setting realistic goals depending on the presenting symptoms, after a thorough evaluation of the patient's comorbidities, and after explaining the uncertain long-term safety of this approach.
2.4.2. Sexual function
Summary recommendation
TRT should be offered to older men with sexual complaints to improve sexual desire and orgasmic function. TRT is expected to improve erectile dysfunction in men with severe hypogonadism (tT <8 nmol/L) and mild erectile dysfunction (IEEF ED score≥22). In men with mild hypogonadism (tT 8–12 nmol/L) and/or severe erectile dysfunction (IEEF ED score <22), established treatment options for erectile dysfunction, such as PDE5-inhibitors, should be tried before TRT.
2.4.3. Obesity, metabolic syndrome, and testosterone treatment
Summary recommendation
Data suggest favorable effects of TRT on insulin resistance and body composition in patients with T2DM and obesity, but the discrepancies regarding its efficacy on HbA1c do not support its widespread use as monotherapy for diabetes treatment. TRT should be considered in those patients with hypogonadism (T < 12nmol/L) and severe insulin resistance or T2DM, alongside a concomitant lifestyle program and standard medical care.
2.4.4. Bone health
Summary recommendation
Men with hypogonadism should be screened for osteoporosis. TRT is recommended to prevent bone loss and help maintain peak bone mass as it can improve BMD and bone structure. This effect is more prominent in the lumbar spine, in men with lower pre-treatment T concentrations, and, notably, in the presence of osteopenia/osteoporosis at baseline. However, available evidence does not support the beneficial effect of TRT in decreasing the incidence of fractures; therefore, in patients with hypogonadism and high fracture risk, TRT should be adjunctive to standard anti-osteoporotic medical care.
2.4.5. Quality of life - mood
Summary recommendation
TRT may be offered as monotherapy to hypogonadal men with persistent mild depressive symptoms and/or low self-perceived QoL; however, when a major depressive disorder is diagnosed, TRT should be used only as adjunctive treatment to antidepressants
2.5. When not to treat – lack of efficacy
2.5.1. Physical function
2.5.2. Cognitive function
Summary recommendation
Due to a lack of robust data supporting its efficacy, TRT should not be routinely used in older hypogonadal men to improve exercise capacity/physical function or cognitive function or to prevent cognitive decline.
2.6. When not to treat – contraindications
Diseases known, or believed to be, aggravated by TRT, such as breast cancer (BrCa), prostate cancer (CaP) or severe lower urinary tract symptoms, and recent CV disease (including stroke), raise concern and preclude affected men from participating in trials evaluating TRT. Moreover, most RCTs lack adequate statistical power and duration to determine whether TRT has a causative role in the development of these conditions; therefore, the long-term safety of TRT in this context is unknown [102].
2.6.1. Hormone-sensitive cancers
2.6.2. Elevated hematocrit, cardiovascular disease, and thrombosis
2.6.3. Fertility
Summary recommendation
TRT should not be attempted in older men with BrCa and untreated CaP and should be preceded by digital rectal examination (DRE) and PSA measurement to identify pre-existing CaP. Those with abnormal DRE and PSA >4 ng/mL should undergo further neurological evaluation. Men with a recent history (<4 months) of myocardial infarction or stroke and severe (NYHA Class III or IV) or decompensated heart failure should also be precluded from TRT. Haematocrit should be measured before initiating TRT, and if it exceeds the normal range therapy has to be postponed until it has normalised. A personal history of VTE is a contraindication for TRT; for men with a family history of VTE, inherited thrombophilia should be excluded before the initiation of TRT. TRT is contraindicated in hypogonadal men actively seeking fertility.
2.7. Areas of uncertainty
2.7.1. Cardiovascular risk and testosterone treatment
Summary recommendation
The quality of evidence regarding the cardiovascular safety of TRT in LOH has been low. However, the most recent data have shown that testosterone treatment in older men with hypogonadism and at increased cardiovascular risk is safe, at least in terms of major adverse cardiac events. Nevertheless, a thorough evaluation of the patient's CV risk prior to TRT is mandatory, as is strict compliance with prescription guidelines regarding dose and treatment monitoring. CV risk must be re-evaluated during TRT, and patients should be informed about the lack of definitive studies on TRT's long-term effects (>3 years). TRT must not be offered as a cardio prevention therapy to frail older men until better outcome data are available.
2.8. Prostate health and testosterone treatment
Summary recommendation
TRT may be considered in hypogonadal men with a history of previous low-risk, localized CaP (Gleason score <7, pT1–2, preoperative PSA <10 ng/mL) who have constantly undetectable PSA concentrations after a radical prostatectomy; however, close monitoring is mandatory.TRT should not be avoided in men with hypogonadism and benign prostate hyperplasia/LUTS; however, caution should be paid to those with severe LUTS (IPSS >19).
2.9. How to treat
Summary recommendation
There is no clear maximum duration for TRT. Short-acting transdermal preparations should be the preferred method of administration for older men, due to the avoidance of liver metabolism, a lower complication rate, in particular regarding polycythemia, and the possibility of prompt withdrawal if required. Injectable forms of T may be considered if transdermal TRT has proven beneficial and safe in a given patient. In cases suggestive of functional hypogonadism, withdrawal or substitution of detrimental factors should be advised when possible, and in overweight or obese patients, weight loss by any means combined with exercise should be the first-line recommendation, possibly supported with TRT to augment the effects and reinforce the patient's commitment to lifestyle modifications.
2.10. Monitoring schedule
Summary recommendation
Older men on TRT should be monitored at 3, 6, and 12 months after initiation and yearly after that. Evaluation should include the assessment of clinical response, and measurement of tT concentrations, hematocrit, and PSA. BMD should be assessed using DXA and follow-up may be at one year or up to 5 years according to the patient's fracture risk. The monitoring schedule is summarised in Fig. 3.
3. Conclusions
The identification of clear, evidence-based indications for treating LOH remains an unmet need. An individualized, tailored approach is strongly recommended when considering hormone replacement therapy. TRT has shown the potential to reduce age-related comorbidities and improve quality of life. However, there are multiple areas of uncertainty and a need for large-scale, prospective, adequately powered RCTs specifically designed to examine the efficacy of TRT and its safety particularly in relation to metabolic and bone health, and prostate disease.
