madman
Super Moderator
Controversial aspects of testosterone in the regulation of sexual function in late-onset hypogonadism
Abstract
Background: Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive, and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection, and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions - such as type 2 diabetes mellitus and obesity - that often associated with low T. In particular, this is the case of ED, but not of HSD, which, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late-onset hypogonadism, LOH).
Objectives: The aim of this review is to scrutinize evidence from our and other studies on the sexual effects of T replacement therapy (TRT) in LOH.
Materials and methods: We will use preclinical and clinical data coming from our and other laboratories and meta-analyses. Results: Intervention studies in clinical trials involving subjects with LOH, and their meta-analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection, and ED. However, the relative improvement of ED by TRT is marginal [2-3 points of International Index of Erectile Function-erectile function domain (IIEF-EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta-analyses.
Discussion and conclusions: Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity.
1 | INTRODUCTION
The Roman poet Marcus Valerius Martialis (c. 38 and 41 AD-c. 102 and 104 AD) wrote in one of his epigrams “Cur tantum eunuchos habeat tua Caelia, quaeris, Pannyche? Volt futui Caelia, nec parere" (Martial Epigrams 6 67). The American poet William Procter Matthews III translated this epigram into English: “Your Celia keeps company with eunuchs:/Pannychus, do you find this odd?/It's the child she hopes to be spared, Pannychus, not the rod” (https://brief poems.wordpress.com/2016/06/11/bedside-lamps-brief-poems -by-martial/). This is tantamount to say that in subjects without testes, as in eunuchs, fertility is impossible but sexuality could be preserved. The topic of eunuch sexuality, from a historical perspective, has been extensively covered in a review by Aucoin & Wassersung.1 The authors conclude that eunuchs, from different cultural backgrounds, were both sexually active and objects of men's and women's active sexual desire. For instance, this was the case for concubines in a harem, at least in pre-modern polygamous societies.1 Modern research has substantiated the notion that severe testosterone (T) deficiency is associated with a preserved erection. In a double-blind, placebo-controlled study, explicit erotic movies stimulated full erections in severely hypogonadal patients.2 Interestingly, these erections were longer lasting than in control individuals.2 However, spontaneous erections, as objectively measured by nocturnal penile tumescence, were quantitatively reduced in hypogonadal subjects and restored by T replacement therapy (TRT).2 Do these findings indicate that T is not essential for male sexuality?
3 TESTOSTERONE AND MALE SEXUALITY
4 TESTOSTERONE AND ERECTION IN LOH
4.1 Preclinical data
4.2 Clinical data
4.3 Meta-analyses of randomized controlled trials
5 TESTOSTERONE AND OTHER ASPECTS OF MALE SEXUALITY IN LOH
5.1 Testosterone and sexual desire in LOH
5.2 Testosterone and orgasmic function in LOH
6 FINAL CONCLUSIONS
T exerts an important role in shaping the male phenotype. However, its role decreases, in an exponential manner, as a function of male age, as it is essential in fetal life, extremely relevant during the pubertal transition and ancillary later on. In fact, the LOH cross-sectional, longitudinal, and intervention studies discussed above substantiate a statistically significant relevance of T in supporting adult male sexual life, whereas other potential roles of T in adulthood—such as in improving bone turnover, body composition, and metabolism, erythropoiesis, wellbeing, and mood—are still under debate and are not the topic of this review. Concerning the effects of T in adult male sexual life, the evidence summarized here indicates that hypogonadism decreases and TRT increases, in a statistically significant way, spontaneous and sexual-related erections as well as sexual desire, as also stated before in previous recommendations of the International Consultation of Sexual Medicine.48 Saying that these effects are statistically significant does not automatically mean that they are clinically meaningful. As an example, TRT ameliorates erectile dysfunction by 2-3 points of IIEF-EFD that is at least one-half of the effect of any PDE5i. In other words, TRT per se is effective in treating only a mild ED, but ineffective in more severe forms of the same disorder. This small effect is even attenuated in subjects with metabolic derangements, as in obesity and T2DM, most probably because the cardiovascular and neurological problems associated with these conditions bury the positive effect of TRT. Interestingly, subjects with obesity or T2DM represent the large majority of those with LOH. These observations are in line with the aforementioned paradox of preserved erectile function in castrated individuals.
Effects of TRT on sexual desire are, in our opinion, more clinically meaningful for several reasons. First, more than 20% of subjects consulting for sexual dysfunction in our andrology service have low T (<12 nmol/L). Of those, nearly one-half has reduced sexual desire. Considering that there are no specific treatments for reduced sexual desire, apart from removing the underlying condition, TRT is a clinically meaningful option in hypogonadal subjects for improving libido. The more severe the T deficiency, the more evident the effect of TRT. In contrast, the effect is almost null in eugonadal individuals. Positive effects of TRT could be envisaged also for improving orgasmic function, although the latter point is still a matter of debate. The clinical implication of these findings in LOH (that is often associated with other comorbidities) could be that T alone might restore sexual desire in LOH individuals without a clinically meaningful effect on erection. Hence, the associations with other medications, such as PDE5i is an important caveat. Otherwise, a T2DM patient with hypogonadism treated only with T might experience an increase in sexual drive without the possibility to do it, which might result even frustrating. On the other side, treating these patients with PDE5i only might restore the possibility to have erections, but without the necessary desire to use them.
In conclusion, TRT is a reasonable treatment for restoring sexual drive-in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm.
Abstract
Background: Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive, and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection, and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions - such as type 2 diabetes mellitus and obesity - that often associated with low T. In particular, this is the case of ED, but not of HSD, which, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late-onset hypogonadism, LOH).
Objectives: The aim of this review is to scrutinize evidence from our and other studies on the sexual effects of T replacement therapy (TRT) in LOH.
Materials and methods: We will use preclinical and clinical data coming from our and other laboratories and meta-analyses. Results: Intervention studies in clinical trials involving subjects with LOH, and their meta-analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection, and ED. However, the relative improvement of ED by TRT is marginal [2-3 points of International Index of Erectile Function-erectile function domain (IIEF-EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta-analyses.
Discussion and conclusions: Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity.
1 | INTRODUCTION
The Roman poet Marcus Valerius Martialis (c. 38 and 41 AD-c. 102 and 104 AD) wrote in one of his epigrams “Cur tantum eunuchos habeat tua Caelia, quaeris, Pannyche? Volt futui Caelia, nec parere" (Martial Epigrams 6 67). The American poet William Procter Matthews III translated this epigram into English: “Your Celia keeps company with eunuchs:/Pannychus, do you find this odd?/It's the child she hopes to be spared, Pannychus, not the rod” (https://brief poems.wordpress.com/2016/06/11/bedside-lamps-brief-poems -by-martial/). This is tantamount to say that in subjects without testes, as in eunuchs, fertility is impossible but sexuality could be preserved. The topic of eunuch sexuality, from a historical perspective, has been extensively covered in a review by Aucoin & Wassersung.1 The authors conclude that eunuchs, from different cultural backgrounds, were both sexually active and objects of men's and women's active sexual desire. For instance, this was the case for concubines in a harem, at least in pre-modern polygamous societies.1 Modern research has substantiated the notion that severe testosterone (T) deficiency is associated with a preserved erection. In a double-blind, placebo-controlled study, explicit erotic movies stimulated full erections in severely hypogonadal patients.2 Interestingly, these erections were longer lasting than in control individuals.2 However, spontaneous erections, as objectively measured by nocturnal penile tumescence, were quantitatively reduced in hypogonadal subjects and restored by T replacement therapy (TRT).2 Do these findings indicate that T is not essential for male sexuality?
3 TESTOSTERONE AND MALE SEXUALITY
4 TESTOSTERONE AND ERECTION IN LOH
4.1 Preclinical data
4.2 Clinical data
4.3 Meta-analyses of randomized controlled trials
5 TESTOSTERONE AND OTHER ASPECTS OF MALE SEXUALITY IN LOH
5.1 Testosterone and sexual desire in LOH
5.2 Testosterone and orgasmic function in LOH
6 FINAL CONCLUSIONS
T exerts an important role in shaping the male phenotype. However, its role decreases, in an exponential manner, as a function of male age, as it is essential in fetal life, extremely relevant during the pubertal transition and ancillary later on. In fact, the LOH cross-sectional, longitudinal, and intervention studies discussed above substantiate a statistically significant relevance of T in supporting adult male sexual life, whereas other potential roles of T in adulthood—such as in improving bone turnover, body composition, and metabolism, erythropoiesis, wellbeing, and mood—are still under debate and are not the topic of this review. Concerning the effects of T in adult male sexual life, the evidence summarized here indicates that hypogonadism decreases and TRT increases, in a statistically significant way, spontaneous and sexual-related erections as well as sexual desire, as also stated before in previous recommendations of the International Consultation of Sexual Medicine.48 Saying that these effects are statistically significant does not automatically mean that they are clinically meaningful. As an example, TRT ameliorates erectile dysfunction by 2-3 points of IIEF-EFD that is at least one-half of the effect of any PDE5i. In other words, TRT per se is effective in treating only a mild ED, but ineffective in more severe forms of the same disorder. This small effect is even attenuated in subjects with metabolic derangements, as in obesity and T2DM, most probably because the cardiovascular and neurological problems associated with these conditions bury the positive effect of TRT. Interestingly, subjects with obesity or T2DM represent the large majority of those with LOH. These observations are in line with the aforementioned paradox of preserved erectile function in castrated individuals.
Effects of TRT on sexual desire are, in our opinion, more clinically meaningful for several reasons. First, more than 20% of subjects consulting for sexual dysfunction in our andrology service have low T (<12 nmol/L). Of those, nearly one-half has reduced sexual desire. Considering that there are no specific treatments for reduced sexual desire, apart from removing the underlying condition, TRT is a clinically meaningful option in hypogonadal subjects for improving libido. The more severe the T deficiency, the more evident the effect of TRT. In contrast, the effect is almost null in eugonadal individuals. Positive effects of TRT could be envisaged also for improving orgasmic function, although the latter point is still a matter of debate. The clinical implication of these findings in LOH (that is often associated with other comorbidities) could be that T alone might restore sexual desire in LOH individuals without a clinically meaningful effect on erection. Hence, the associations with other medications, such as PDE5i is an important caveat. Otherwise, a T2DM patient with hypogonadism treated only with T might experience an increase in sexual drive without the possibility to do it, which might result even frustrating. On the other side, treating these patients with PDE5i only might restore the possibility to have erections, but without the necessary desire to use them.
In conclusion, TRT is a reasonable treatment for restoring sexual drive-in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm.
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