madman
Super Moderator
Abstract: Testosterone is the most important hormone in male health. Aging is characterized by testosterone deficiency due to decreasing testosterone levels associated with low testicular production, genetic factors, adiposity, and illness. Low testosterone levels in men are associated with sexual dysfunction (low sexual desire, erectile dysfunction), reduced skeletal muscle mass and strength, decreased bone mineral density, increased cardiovascular risk, and alterations of the glycometabolic profile. Testosterone replacement therapy (TRT) shows several therapeutic effects while maintaining a good safety profile in hypogonadal men. TRT restores normal levels of serum testosterone in men, increasing libido and energy level and producing beneficial effects on bone density, strength, and muscle as well as yielding cardioprotective effects. Nevertheless, TRT could be contraindicated in men with untreated prostate cancer, although poor findings are reported in the literature. In addition, different potential side effects, such as polycythemia, cardiac events, and obstructive sleep apnea, should be monitored. The aim of our review is to provide an updated background regarding the pros and cons of TRT, evaluating its role and its clinical applicability in different domains.
1. Introduction
The passage from adulthood to advanced age represents for men a pivotal point, producing a multitude of physiological, psychological, and social changes. One of the most important, and often silent, modifications are related to the change in testosterone values, which could drastically decrease with increasing age. In particular, 25–30% of men > 60 years show low levels of serum testosterone (defined as total testosterone < 350 ng/dL and free testosterone < 225 pmol/L) [1]. Testosterone deficiency is very common in elderly men and is linked to different signs and symptoms (such as reduced libido, reduced sexual functioning, decreases in mobility and energy) that could heavily affect the aging process and the quality of life [2–4]. Testosterone effects are mediated via the androgen receptor (AR). Depending on its sensitivity, a significant amount of variations of endogenous and exogenous androgens effects are reported [5]. In particular, CAG repeat polymorphism of AR gene could influence the transcriptional activity of testosterone target genes, consequently providing a multitude of effects on bone density, body composition, behavioral aspects, and even prostate cancer [6,7] (Figure 1).
As result, the use of testosterone replacement therapy (TRT) in clinical practice has been an appealing perspective. However, the issue related to the potential adverse effects of TRT, and in particular its impact on cardiovascular events and mortality, have represented a controversial topic of discussion. Despite those concerns, recent studies have reported non-consistent results regarding the relationship between TRT and increased risk of diabetes, obesity, and metabolic syndrome. Contrarily, an adequate replacement therapy appears to improve sexual and physical function, increase bone density, and, most importantly, not influence the risk of prostate cancer [8]. In addition, different studies have shown how low endogenous testosterone levels may be associated with reduced cognitive ability and how TRT could help in avoiding cognitive dysfunction associated with hypogonadism [9,10]. Considering the potential benefits of TRT, and, bearing in mind as well, the wide variability of testosterone values and comorbidities in the elderly, TRT should be individualized. The aim of our review is to provide an updated background regarding the pros and cons of TRT.
2. Clinical Findings
2.1. Late-Onset Hypogonadism: The Aging Male
2.2. Testosterone and Body Composition—Fat and Lean Mass
2.3. Testosterone and Bone Density
2.4. Testosterone and Sexual Activity
2.5. Testosterone and Glycometabolic Profile—The Effects on Insulin Sensitivity
2.6. Testosterone and Cardiovascular Disease
2.7. Testosterone and Mental Activity
2.8. Testosterone and Quality of Life
2.9. Testosterone and Prostate Cancer
3. Safety of TRT
Despite the beneficial effects of TRT being widely reported and publicized in literature, a paucity of findings on TRT side effects are currently reported. If it is true that the effects of TRT on prostate enlargement, prostate cancer, and lower urinary tract symptoms are controversial, it has been reported that there is a significant increase in hemoglobin of 5–7%, secondary to testosterone-induced polycythemia [175–177]. As a result, it has been supposed that there is an increased risk of vascular events related to this condition, which, however, has not been demonstrated in men on TRT [52,178]. Additionally, although it has been reported an increased risk of obstructive sleep apnea in patients on TRT, its etiology is not fully understood, and findings are inconsistent [179,180]. As result, TRT has been considered, overall, a safe therapy, albeit a proper follow-up should be required to check hematocrit [181] (Table 1)
4. Future Perspectives and Conclusions
Testosterone plays a pivotal role in the integrity and maintenance of systems and organs of the aging male. Aging is, indeed, characterized by a wide variety of declines in testosterone production, which could heavily affect health and quality of life (Table 2). The use of TRT in older patients, to normalize testosterone levels, is a tempting perspective that could provide several important benefits in terms of sexual life, mental activity, metabolism, and bone/musculature integrity. Many factors could modulate androgen production and its effects on the elderly. However, a lack of reliable and practical markers limits the possibility to assess the real action of exogenous testosterone in tissue and organs. In our opinion, an effort should be directed towards the identification of patients who could obtain more benefits from TRT. This objective could be further and ideally assisted by the identifications of AR polymorphisms. In this regard, different ongoing clinical trials are exploring the role of TRT in the aging male (as NCT02873559, NCT04743466, and NCT04584918). In addition, the development of several testosterone preparations has increased the personalization and compliance of TRT [182]. Future research should, therefore, focus on a tailored and multidisciplinary approach, in order to balance the benefits and risks of TRT.
1. Introduction
The passage from adulthood to advanced age represents for men a pivotal point, producing a multitude of physiological, psychological, and social changes. One of the most important, and often silent, modifications are related to the change in testosterone values, which could drastically decrease with increasing age. In particular, 25–30% of men > 60 years show low levels of serum testosterone (defined as total testosterone < 350 ng/dL and free testosterone < 225 pmol/L) [1]. Testosterone deficiency is very common in elderly men and is linked to different signs and symptoms (such as reduced libido, reduced sexual functioning, decreases in mobility and energy) that could heavily affect the aging process and the quality of life [2–4]. Testosterone effects are mediated via the androgen receptor (AR). Depending on its sensitivity, a significant amount of variations of endogenous and exogenous androgens effects are reported [5]. In particular, CAG repeat polymorphism of AR gene could influence the transcriptional activity of testosterone target genes, consequently providing a multitude of effects on bone density, body composition, behavioral aspects, and even prostate cancer [6,7] (Figure 1).
As result, the use of testosterone replacement therapy (TRT) in clinical practice has been an appealing perspective. However, the issue related to the potential adverse effects of TRT, and in particular its impact on cardiovascular events and mortality, have represented a controversial topic of discussion. Despite those concerns, recent studies have reported non-consistent results regarding the relationship between TRT and increased risk of diabetes, obesity, and metabolic syndrome. Contrarily, an adequate replacement therapy appears to improve sexual and physical function, increase bone density, and, most importantly, not influence the risk of prostate cancer [8]. In addition, different studies have shown how low endogenous testosterone levels may be associated with reduced cognitive ability and how TRT could help in avoiding cognitive dysfunction associated with hypogonadism [9,10]. Considering the potential benefits of TRT, and, bearing in mind as well, the wide variability of testosterone values and comorbidities in the elderly, TRT should be individualized. The aim of our review is to provide an updated background regarding the pros and cons of TRT.
2. Clinical Findings
2.1. Late-Onset Hypogonadism: The Aging Male
2.2. Testosterone and Body Composition—Fat and Lean Mass
2.3. Testosterone and Bone Density
2.4. Testosterone and Sexual Activity
2.5. Testosterone and Glycometabolic Profile—The Effects on Insulin Sensitivity
2.6. Testosterone and Cardiovascular Disease
2.7. Testosterone and Mental Activity
2.8. Testosterone and Quality of Life
2.9. Testosterone and Prostate Cancer
3. Safety of TRT
Despite the beneficial effects of TRT being widely reported and publicized in literature, a paucity of findings on TRT side effects are currently reported. If it is true that the effects of TRT on prostate enlargement, prostate cancer, and lower urinary tract symptoms are controversial, it has been reported that there is a significant increase in hemoglobin of 5–7%, secondary to testosterone-induced polycythemia [175–177]. As a result, it has been supposed that there is an increased risk of vascular events related to this condition, which, however, has not been demonstrated in men on TRT [52,178]. Additionally, although it has been reported an increased risk of obstructive sleep apnea in patients on TRT, its etiology is not fully understood, and findings are inconsistent [179,180]. As result, TRT has been considered, overall, a safe therapy, albeit a proper follow-up should be required to check hematocrit [181] (Table 1)
4. Future Perspectives and Conclusions
Testosterone plays a pivotal role in the integrity and maintenance of systems and organs of the aging male. Aging is, indeed, characterized by a wide variety of declines in testosterone production, which could heavily affect health and quality of life (Table 2). The use of TRT in older patients, to normalize testosterone levels, is a tempting perspective that could provide several important benefits in terms of sexual life, mental activity, metabolism, and bone/musculature integrity. Many factors could modulate androgen production and its effects on the elderly. However, a lack of reliable and practical markers limits the possibility to assess the real action of exogenous testosterone in tissue and organs. In our opinion, an effort should be directed towards the identification of patients who could obtain more benefits from TRT. This objective could be further and ideally assisted by the identifications of AR polymorphisms. In this regard, different ongoing clinical trials are exploring the role of TRT in the aging male (as NCT02873559, NCT04743466, and NCT04584918). In addition, the development of several testosterone preparations has increased the personalization and compliance of TRT [182]. Future research should, therefore, focus on a tailored and multidisciplinary approach, in order to balance the benefits and risks of TRT.
