madman
Super Moderator
The role of testosterone in male sexual function (2022)
Giovanni Corona · Mario Maggi
Abstract
Sexual function, and testosterone (T) levels, progressively decline in aging men. Associated morbidities and metabolic disorders can accelerate the phenomenon. The specific contribution of low T to sexual function impairment in aging men has still not been completely clarified. Similarly, the role of T replacement therapy (TRT), as well as the combination of TRT with phosphodiesterase type 5 inhibitors (PDE5i) for patients with erectile dysfunction (ED), is still conflicting. Here we aim to summarize and critically discuss all available data supporting the contribution of low T to sexual impairment observed with aging as well as the possible role of TRT. Available data on men with sexual dysfunction show that reduced sexual desire is the most important correlate of male hypogonadism. Conversely, aging and associated morbidities substantially attenuate the relationship between ED and T. TRT is effective in improving sexual function in middle-aged and older subjects but its role is small and extremely variable. Lifestyle interventions can result in similar outcomes to those of TRT. In conclusion, it is our opinion that PDE5i along with lifestyle measures should be considered the first approach for treating ED even in subjects with milder T deficiency. When these interventions fail or are difficult to apply, TRT should be considered.
1 Introduction
Successful aging has been considered one of the main aspects of all societies since the Roman Empire. In the “Cato Maior de senectute”, Marcus Tullius Cicero, when he was 62 years old, concluded that the cornerstone for successful aging should be based on a combination of both adequate physical and mental lifestyle behaviors “…to adopt a regimen of health, to practice moderate exercise, to take just enough food and drink, to restore our strength and not to overburden it. Nor, indeed are we to give our attention solely to the body Much greater care is due to the mind and soul”. In line with Cicero’s thoughts, the progressive improvement of economic, social, cultural, and medical conditions, which have occurred particularly during the last two centuries, has allowed a tremendous global rise in life expectancy at birth from less than 30 years, at the beginning of last century, to over 72 years in 2019 (Life Expectancy). The progressive increase in the proportion of older people represents also a source of new challenges for all healthcare professionals, policy advisers, and decision-making organizations in order to guarantee social and medical support to permit an active and adequate quality of life for this aging population [1].
According to the World Health Organization, sexual health is fundamental to the overall health and well-being of individuals, couples, and families, and to the social and economic development of communities and countries (https:// www.who.int/health-topics/sexual-health#tab=tab_1). Several population-based studies have documented that, despite an age-dependent decline in sexual function, a large proportion of older adults are still interested in sexual activities, with men being more frequently sexually active compared to women [2–6]. The same studies have clearly demonstrated that, according to psychological, organic, and couple relationship modifications, occurring with advanced age, coital intercourse is not an essential prerequisite to remaining sexually active [7, 8]. In line with the latter finding, erectile dysfunction (ED) concern declines with aging [4, 5, 7, 9].
Despite this evidence, plenty of data has recognized that ED should be considered an early marker of forthcoming cardiovascular (CV) mortality and morbidity [10]. Accordingly, ED shares several traditional risk factors with CV diseases (CVD) [10, 11]. Hence, available data clearly indicate that sexual health should be considered a mirror of general health, which, in turn, is a prerequisite to remaining sexually active. In line with these considerations, the concept “sexually active life expectancy” defined as “the average number of years remaining spent as sexually active” has been introduced [12]. According to epidemiological data, men present a potentially longer sexually active life expectancy when compared to women; however, the real period of a sexually active life is reduced due to poorer general health [12].
Human sexuality is the result of a complex interaction between the endocrine milieu, general health, psychological well-being, and couple health [13–19]. The perturbation of any domain in one of the partners has detrimental effects on the couple, eventually leading to an overall marital and sexual health impairment [20–22]. Interestingly, we previously reported that among subjects seeking medical care for ED, not only organic but also relational and intrapsychic factors can contribute to the stratification of CV risk [23]. In older people, lifestyle changes occurring with advancing age – including the death of their partner, worsening of social status, deterioration of support networks, and health and finance-related family problems—might contribute to sexual difficulties. This change, by inducing and contributing to the development of depressive and anxiety symptoms as well as a couple of health perturbations, can, in turn, worsen and aggravate the CV risk profile [23].
Testosterone (T) is a well-recognized crucial factor in regulating male sexual response acting either at a central or peripheral level [17, 18, 24]. Several studies performed on community-dwelling men have documented that aging is associated with the progressive decline of T circulating levels [25–31]. Late-onset hypogonadism (LOH) is the most frequently used term to describe the latter phenomenon [32]. Although the specific mechanisms underlying LOH have not been completely clarified, mounting evidence has pointed out that associated morbidities, and in particular metabolic disorders, can play a critical role [33, 34]. However, it is important to recognize that LOH per se has been associated with worse metabolic and CV profiles [35, 36] although data derived from interventional studies are still conflicting [37, 38]. The European Male Aging Study (EMAS), a population-based survey performed on more than 3400 men recruited from eight European centers, clearly showed that sexual symptoms—particularly ED, decreased frequency of morning erections, and sexual thoughts—are the most sensitive and specific symptoms in identifying patients with LOH [39]. Similar results were recently reported by our group in a large cohort (n=4890) of subjects consulting for ED [40]. In contrast, psychological and physical symptoms were less informative [39].
*The aim of the present study is to summarize and critically discuss all available data supporting the role of T in the regulation of erectile function in aging men. Other aspects of sexual function including libido and ejaculation will also be analyzed. In addition, the possible contribution of T replacement therapy (TRT) to sexual outcomes as well as the role of the combined therapy with other ED drugs such as phosphodiesterase type 5 inhibitors (PDE5i) will also be addressed.
3 Aspect of male sexual function most closely related to androgen activation
4 Relationships between erectile dysfunction and T deficiency
5 Effect of testosterone replacement therapy in men with erectile dysfunction
6 Proportion of men presenting with ED and T deficiency and possible determinants
7 Screening men with sexual dysfunction for T deficiency
8 Testosterone added on to PDE5i
9 Conclusions
Sexual dysfunctions, such as ED and MHSDD, are associated with low T levels. This point is well accepted by all the major guidelines on the topic [24, 81–83]. Considering that loss of libido is less affected by age-associated comorbidities, it represents the most genuine symptom of T deficiency in adulthood. In contrast, other predictors, such as age and comorbidities, more often determine ED. The negative contribution of low T to impaired penile blood flow is more apparent in older than in younger subjects. The most important correlates of low T in subjects with sexual dysfunction are metabolic disturbances, including obesity, MetS, and T2DM, most probably because they are associated with metafammation of hypothalamic centers known to regulate GnRH production and release. Accordingly, secondary hypogonadism is by far the most prevalent form of T deficiency in adulthood. Gaining weight, and in particular abdominal obesity, is an important predictor of forthcoming secondary hypogonadism [104]. Weight reduction by lifestyle measures is associated with an increase in circulating gonadotropins and T levels, along with an improvement in erectile function. Meta-analyses have shown here and elsewhere [59, 61] indicate that TRT has a marginal effect (less than 10%) in restoring sexual life in otherwise hypogonadal subjects. Such an effect appears even lower than that obtained with lifestyle measures, such as physical activity, although the number of RCTs available is scanty [11, 77]. In addition, the positive effect of TRT on ED is less apparent in subjects with established metabolic disturbances, such as T2DM [70]. PDE5i are three times more effective in treating ED than TRT [62]. Although PDE5i, such as tadalafil, might be less effective in men with low T (<10.4 nmol/L), one trial still indicated an increase of 6 points IIEF-EFD [105]. Available data published so far cannot clarify the real significance of the combined therapy of T and PDE5i, although preliminary results suggest a possible role in more complicated patients. Larger placebo-controlled RCTs are advisable to better clarify this topic. Hence, a PDE5i along with lifestyle measures—such as moderate physical activity, smoking cessation, and dieting—is the most appropriate intervention for treating ED even in subjects with T deficiency. It should be considered that these lifestyle measures not only improve sexual life but also treat underlying metabolic conditions, often present in these subjects. When these interventions fail or are not applicable, TRT should be considered. TRT shows the advantage of improving body composition [70], including muscle mass, and, possibly, ameliorating glucose control [80], even in subjects with metabolic conditions. In addition, it can have a positive effect on sexual desire, whereas all the PDE5i are almost ineffective and no other specific treatment is available.
Giovanni Corona · Mario Maggi
Abstract
Sexual function, and testosterone (T) levels, progressively decline in aging men. Associated morbidities and metabolic disorders can accelerate the phenomenon. The specific contribution of low T to sexual function impairment in aging men has still not been completely clarified. Similarly, the role of T replacement therapy (TRT), as well as the combination of TRT with phosphodiesterase type 5 inhibitors (PDE5i) for patients with erectile dysfunction (ED), is still conflicting. Here we aim to summarize and critically discuss all available data supporting the contribution of low T to sexual impairment observed with aging as well as the possible role of TRT. Available data on men with sexual dysfunction show that reduced sexual desire is the most important correlate of male hypogonadism. Conversely, aging and associated morbidities substantially attenuate the relationship between ED and T. TRT is effective in improving sexual function in middle-aged and older subjects but its role is small and extremely variable. Lifestyle interventions can result in similar outcomes to those of TRT. In conclusion, it is our opinion that PDE5i along with lifestyle measures should be considered the first approach for treating ED even in subjects with milder T deficiency. When these interventions fail or are difficult to apply, TRT should be considered.
1 Introduction
Successful aging has been considered one of the main aspects of all societies since the Roman Empire. In the “Cato Maior de senectute”, Marcus Tullius Cicero, when he was 62 years old, concluded that the cornerstone for successful aging should be based on a combination of both adequate physical and mental lifestyle behaviors “…to adopt a regimen of health, to practice moderate exercise, to take just enough food and drink, to restore our strength and not to overburden it. Nor, indeed are we to give our attention solely to the body Much greater care is due to the mind and soul”. In line with Cicero’s thoughts, the progressive improvement of economic, social, cultural, and medical conditions, which have occurred particularly during the last two centuries, has allowed a tremendous global rise in life expectancy at birth from less than 30 years, at the beginning of last century, to over 72 years in 2019 (Life Expectancy). The progressive increase in the proportion of older people represents also a source of new challenges for all healthcare professionals, policy advisers, and decision-making organizations in order to guarantee social and medical support to permit an active and adequate quality of life for this aging population [1].
According to the World Health Organization, sexual health is fundamental to the overall health and well-being of individuals, couples, and families, and to the social and economic development of communities and countries (https:// www.who.int/health-topics/sexual-health#tab=tab_1). Several population-based studies have documented that, despite an age-dependent decline in sexual function, a large proportion of older adults are still interested in sexual activities, with men being more frequently sexually active compared to women [2–6]. The same studies have clearly demonstrated that, according to psychological, organic, and couple relationship modifications, occurring with advanced age, coital intercourse is not an essential prerequisite to remaining sexually active [7, 8]. In line with the latter finding, erectile dysfunction (ED) concern declines with aging [4, 5, 7, 9].
Despite this evidence, plenty of data has recognized that ED should be considered an early marker of forthcoming cardiovascular (CV) mortality and morbidity [10]. Accordingly, ED shares several traditional risk factors with CV diseases (CVD) [10, 11]. Hence, available data clearly indicate that sexual health should be considered a mirror of general health, which, in turn, is a prerequisite to remaining sexually active. In line with these considerations, the concept “sexually active life expectancy” defined as “the average number of years remaining spent as sexually active” has been introduced [12]. According to epidemiological data, men present a potentially longer sexually active life expectancy when compared to women; however, the real period of a sexually active life is reduced due to poorer general health [12].
Human sexuality is the result of a complex interaction between the endocrine milieu, general health, psychological well-being, and couple health [13–19]. The perturbation of any domain in one of the partners has detrimental effects on the couple, eventually leading to an overall marital and sexual health impairment [20–22]. Interestingly, we previously reported that among subjects seeking medical care for ED, not only organic but also relational and intrapsychic factors can contribute to the stratification of CV risk [23]. In older people, lifestyle changes occurring with advancing age – including the death of their partner, worsening of social status, deterioration of support networks, and health and finance-related family problems—might contribute to sexual difficulties. This change, by inducing and contributing to the development of depressive and anxiety symptoms as well as a couple of health perturbations, can, in turn, worsen and aggravate the CV risk profile [23].
Testosterone (T) is a well-recognized crucial factor in regulating male sexual response acting either at a central or peripheral level [17, 18, 24]. Several studies performed on community-dwelling men have documented that aging is associated with the progressive decline of T circulating levels [25–31]. Late-onset hypogonadism (LOH) is the most frequently used term to describe the latter phenomenon [32]. Although the specific mechanisms underlying LOH have not been completely clarified, mounting evidence has pointed out that associated morbidities, and in particular metabolic disorders, can play a critical role [33, 34]. However, it is important to recognize that LOH per se has been associated with worse metabolic and CV profiles [35, 36] although data derived from interventional studies are still conflicting [37, 38]. The European Male Aging Study (EMAS), a population-based survey performed on more than 3400 men recruited from eight European centers, clearly showed that sexual symptoms—particularly ED, decreased frequency of morning erections, and sexual thoughts—are the most sensitive and specific symptoms in identifying patients with LOH [39]. Similar results were recently reported by our group in a large cohort (n=4890) of subjects consulting for ED [40]. In contrast, psychological and physical symptoms were less informative [39].
*The aim of the present study is to summarize and critically discuss all available data supporting the role of T in the regulation of erectile function in aging men. Other aspects of sexual function including libido and ejaculation will also be analyzed. In addition, the possible contribution of T replacement therapy (TRT) to sexual outcomes as well as the role of the combined therapy with other ED drugs such as phosphodiesterase type 5 inhibitors (PDE5i) will also be addressed.
3 Aspect of male sexual function most closely related to androgen activation
4 Relationships between erectile dysfunction and T deficiency
5 Effect of testosterone replacement therapy in men with erectile dysfunction
6 Proportion of men presenting with ED and T deficiency and possible determinants
7 Screening men with sexual dysfunction for T deficiency
8 Testosterone added on to PDE5i
9 Conclusions
Sexual dysfunctions, such as ED and MHSDD, are associated with low T levels. This point is well accepted by all the major guidelines on the topic [24, 81–83]. Considering that loss of libido is less affected by age-associated comorbidities, it represents the most genuine symptom of T deficiency in adulthood. In contrast, other predictors, such as age and comorbidities, more often determine ED. The negative contribution of low T to impaired penile blood flow is more apparent in older than in younger subjects. The most important correlates of low T in subjects with sexual dysfunction are metabolic disturbances, including obesity, MetS, and T2DM, most probably because they are associated with metafammation of hypothalamic centers known to regulate GnRH production and release. Accordingly, secondary hypogonadism is by far the most prevalent form of T deficiency in adulthood. Gaining weight, and in particular abdominal obesity, is an important predictor of forthcoming secondary hypogonadism [104]. Weight reduction by lifestyle measures is associated with an increase in circulating gonadotropins and T levels, along with an improvement in erectile function. Meta-analyses have shown here and elsewhere [59, 61] indicate that TRT has a marginal effect (less than 10%) in restoring sexual life in otherwise hypogonadal subjects. Such an effect appears even lower than that obtained with lifestyle measures, such as physical activity, although the number of RCTs available is scanty [11, 77]. In addition, the positive effect of TRT on ED is less apparent in subjects with established metabolic disturbances, such as T2DM [70]. PDE5i are three times more effective in treating ED than TRT [62]. Although PDE5i, such as tadalafil, might be less effective in men with low T (<10.4 nmol/L), one trial still indicated an increase of 6 points IIEF-EFD [105]. Available data published so far cannot clarify the real significance of the combined therapy of T and PDE5i, although preliminary results suggest a possible role in more complicated patients. Larger placebo-controlled RCTs are advisable to better clarify this topic. Hence, a PDE5i along with lifestyle measures—such as moderate physical activity, smoking cessation, and dieting—is the most appropriate intervention for treating ED even in subjects with T deficiency. It should be considered that these lifestyle measures not only improve sexual life but also treat underlying metabolic conditions, often present in these subjects. When these interventions fail or are not applicable, TRT should be considered. TRT shows the advantage of improving body composition [70], including muscle mass, and, possibly, ameliorating glucose control [80], even in subjects with metabolic conditions. In addition, it can have a positive effect on sexual desire, whereas all the PDE5i are almost ineffective and no other specific treatment is available.
