madman
Super Moderator
Morbidity and mortality in men: Role of androgens (2022)
Giuseppe Fallara, Edoardo Pozzi, Christian Corsini, Federico Belladelli, Luca Boeri, Paolo Capogrosso, Francesco Montorsi, Andrea Salonia
In this narrative review, we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity, and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigation, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with an increased risk of mortality.
As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce the risk of progression to diabetes, and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.
Introduction
Little is known on the true incidence and prevalence of male hypogonadism in the general population, due to the multiple difficulties in terms of recognized and unequivocal definitions, the so-called normality thresholds for circulating testosterone values, and the consequent lack of solid epidemiological studies [1,2]. In this context, it has been estimated that almost 500,000 men are diagnosed with hypogonadism [3-5]. Likewise, data from the cross-sectional survey European Male Ageing Study (EMAS) showed that in a large cohort of community-dwelling men aged 40-79 years in eight European centers the overall prevalence of hypogonadism (i.e., the secondary, primary, and compensated hypogonadism categories) was almost 23% [6]. Narrowing the focus, in an Italian tertiary-referral center for Sexual Medicine, 10% of primary infertile men presented with criteria solely suggestive of hypogonadism at first evaluation, with a slight increase throughout the last decade [7].
Although the definition of hypogonadism usually applied in the literature refers to an established testosterone deficiency and the concomitant presence of symptoms related to this deficiency (namely, late-onset hypogonadism (LOH) intended as a chronic condition) [8], the recent dramatic figures associated with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced disease (COVID-19) have clearly shown how potentially fragile the androgen synthesis system is in the male, what significant rebound in terms of overall health COVID-19 may have [9], and how a severe and sudden reduction of circulating testosterone levels may lead to a complex clinical picture, even associated with fatal outcomes [10].
Serum testosterone levels gradually decline with age in men, but the clinical significance of this decrease remains uncertain [11,12]. So far, evidence supports the hypothesis that low testosterone is an important biomarker for morbidity and mortality in men, even after accounting for age. Indeed, low levels of circulating testosterone have been frequently associated with long-term negative health consequences including earlier death from all-cause and cardiovascular disease, reduced bone health, as well as poorer quality of life, reduced libido and erectile function, and an increased risk of certain cancer, i.e. testicular and prostate cancer [13]. Indeed, low levels of testosterone have been associated with poor general health also in younger patients [14]. Literature has been profuse in the last decades on these issues, and the aim of the current narrative review is to summarize and critically discuss the impact of low testosterone and testosterone therapy (TTh) on main health conditions.
Androgens, testosterone therapy, and cardiovascular events
In conclusion, most data derived from available meta-analyses on RCTs and population-based or pharmaco-epidemiological observational studies showed that hypogonadism per se is associated with an increased risk of cardiovascular events, whilst TTh does not increase the risk of cardiovascular morbidity and mortality [22e24,32,37,38]. Numerous studies that oppose these findings are flawed by several limitations, but the general literature on this topic suffers from huge heterogeneity, and pooled evidence with definitive clear results is far from being produced.
A final answer to this long debate might be found thanks to an ongoing RCT, the Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE), which is the largest and longest-duration randomized study of TTh ever conducted and which is aimed at including more than 6000 men, aged 45-80 years, with serum testosterone concentration <3 ng/mL and hypogonadal symptoms, who have evidence of pre-existing CV disease or increased risk of CV disease followed up for 5 years [39].
Notwithstanding controversies, there are biological reasons for supporting the statistical association between cardiovascular risk and lower testosterone levels. Much evidence has documented that low testosterone could be involved in the regulation of inflammation at several tissues level both in animal models and in humans [40-43]. In this context, pro-inflammatory cytokines have been linked to atherosclerosis, metabolic syndrome (MetS), and cardiovascular morbidity in several studies [44]. Of note, whether or not LOH is a cause or a consequence of atherosclerosis/MetS has not been clearly determined; likewise, atherosclerosis is a chronic inflammatory disease that releases into the circulation proinflammatory cytokines which in turn - are known to suppress testosterone release from the hypothalamus-pituitary-gonadal axis [45].
Androgens, testosterone therapy, and diabetes mellitus type 2
In conclusion, despite controversies, it is possible that the benefit of testosterone supplementation goes beyond the “simple” correction of symptoms of hypogonadism in the specific subset of men with T2DM or with significantly impaired glucose control, thus including metabolic control, as it has been recently demonstrated Wittert et al. [73]. Of note, lifestyle and dietary changes and diabetes medications, when clinically indicated, are compulsory and key in this setting potentially along with TTh; therefore, so far, there is no evidence to support the recommendation that TTh alone is more beneficial in terms of glycemic control compared to diabetes medications.
Endogenous testosterone and prostate cancer
Finally, despite androgen receptor and endogenous androgen production blockage representing one of the mainstays of hormone sensible prostate cancer treatment, the available reports on TTh and risk of prostate cancer progression in prostate cancer survivors are not sufficient to draw a definitive conclusion [89]. Taken together, the literature does not support the hypothesis of an association between TTh and prostate cancer and even the association between endogenous testosterone levels and prostate cancer risk is far from being straightforward. As such, EAU Guidelines on Reproductive and Sexual Health still recommend TTh in case of symptomatic hypogonadal men, but precautiously excluding those with a high risk of prostate cancer recurrence and those with active locally advanced or metastatic prostate cancer [15].
Androgens, testosterone therapy, and overall mortality
As such, the association between reduced testosterone levels and mortality is not a surprise, given the reported associations of hypogonadism with several morbidities such as T2DM and MACE.
COVID-19 and serum testosterone levels in men: a call to action
As previously anticipated, the definition of hypogonadism over adulthood usually applied in the literature refers to an established testosterone deficiency (i.e., LOH), intended as a chronic condition [8]. Thereof, in theory, any acute although significant depletion in circulating testosterone levels should not be regarded as of clinical relevance in terms of mid- or long-term sequelae, thus including further development of comorbidities (e.g., cardiovascular events) or greater risk of mortality. Conversely, recent clinical findings in COVID-19 studies have outlined a possible dramatic impact of the specific viral infection also on testosterone production in men, along with its significant rebound in terms of COVID-19-related overall men's health, even with fatal outcomes [92].
Therefore, in line with the reported findings suggesting the clinical relevance of hypogonadism as a predictor of lower men's health, this manuscript provides a short summary of available evidence in terms of COVID-19-related male hypogonadism which emerged after the epidemiological observation that men had worse clinical outcomes compared to women so that the hypothesis of a possible biopathology link between male sex and COVID-19 severity was postulated [93-95]. Two main hypotheses have been formulated. First, according to the androgen-driven COVID-19 theory, testosterone might enhance SARS-CoV-2 infection by stimulating the transmembrane protease serine 2 (TMPRSS2) protein, a transmembrane protease receptor [96]. The activity of TMPRSS2 is thought to be critical for viral transmission and pathogenicity in infected hosts since it activates SARS-CoV-2 spike proteins and helps the cleavage of the viral receptor angiotensin-converting enzyme II (ACE2) in lung alveolar epithelial cells, thus resulting in an augmented viral entry [97-99]. Second, the cytokine hypothesis would suggest that lower testosterone levels may either cause or favor a progression of COVID-19 in men, due to an increase in proinflammatory cytokines, which can eventually lead to a cytokine storm. In fact, the clinical worsening of COVID-19 may be mediated by pro-inflammation cytokines; in this setting, a number of preclinical and clinical studies have shown that hypogonadism is linked to higher levels of pro-inflammatory cytokines, and TTh may lower IL-1, IL-6, and TNF-alpha circulating levels [100,101]. Whether a baseline hypogonadal status is a keystone in the entire pathway of pathological evolution of COVID-19 infection in males has not yet been adequately understood.
In clinical terms, published data showed that relevant rates of men admitted to intensive care units (ICU) for acute severe illness have a transitory suppression of testosterone and over the last months this data was further supported in patients with COVID-19 [102]. For instance, Rastrelli et al. [103] and Çayan et al. [104] independently observed that SARS-CoV-2 infected male individuals depicted low serum testosterone levels and that serum total testosterone levels at hospital admission were associated with an increased risk of ICU admission and death. This finding was further confirmed by a case-control study, showing that total testosterone levels were considerably lower in symptomatic SARS-CoV-2 infected men compared to healthy controls already at hospital admission, and testosterone levels were suggestive of hypogonadism in nearly 90% of men with COVID-19 [105]. Furthermore, total testosterone levels were related to COVID-19 clinical severity at the time of hospitalization, with testosterone levels considerably lower both in men who needed ICU admission and in those who eventually died [92]. Recently, Corona et al. developed a meta-analysis of studies investigating the relationship between baseline total testosterone levels and COVID-19 outcomes, thus including the probability of being admitted to ICU (any reason) and mortality risk (PROSPERO (CRD42021275185)) [106]. Overall, low testosterone levels resulted in up to four- and five-fold increased risk to be admitted to ICU (fully adjusted risk: RR 2.37 (1.30-4.31); p < 0.001) or to die (fully adjusted risk: RR 2.53 (1.27-5.03); p < 0.001), after adjusting for potential confounders, thus corroborating the clinical importance of hypogonadism status as a key player in terms of overall men's health [106].
On the contrary, a study from Montopoli et al. demonstrated that men with prostate cancer under androgen deprivation therapy (ADT) were at lower risk of being infected by SARS-CoV-2 and hospitalized because of COVID-19 compared to those without ADT [107]. However, the results of this study were based on 118 men with COVID-19 of whom only 4 were on ADT and 114 were not, and subsequent studies have failed to confirm these findings [108-110]. As such, the question of whether androgens have an impact on COVID-19 severity remains a matter of extensive debate [108-110].
Finally, alarming findings from prospective studies highlighted that circulating total testosterone recovered over time after several months from SARS-CoV-2 infection, but more than 50% of men who eventually recovered from COVID-19 still showed low circulating testosterone levels suggestive of hypogonadism at 7-mo follow-up [111]. Of clinical importance, the higher the burden of comorbid conditions at presentation, the lower the probability of testosterone levels recovery over time.
Conclusions
Male hypogonadism and major comorbidities such as T2DM, obesity, and cardiovascular disease, appear closely connected, fostering a vicious cycle that may lead to further hypogonadism. Hypogonadism has also been associated with an increased risk of mortality. As such, TTh has the potential to oppose this pattern and improve cardiovascular and metabolic health in hypogonadal men. There is instead no evidence of an increased risk of prostate cancer among TTh users. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.
Summary
In this narrative review, we discussed and summarized the main aspects related to hypogonadism and testosterone therapy and associated morbidity and mortality outcomes. Overall, men with hypogonadism are at risk of increased mortality when compared to eugonadal men. This increase in mortality might be due to increased cardiovascular risks, especially when considering major adverse cardiovascular events, and increased incidence of metabolic syndrome/type 2 diabetes mellitus. Testosterone therapy is not just aimed at normalizing testosterone levels, thus improving symptoms related to hypogonadism, but has been found also to likely reduce the risk of major cardiovascular events and improve glycemic control, waist circumference, and lipid profile. Despite quite strong evidence supporting these statements, the literature is still heterogeneous owing to different definitions of hypogonadism, different testosterone therapy modalities and therapeutic schemes, and diverse population characteristic in each study. There is instead no evidence of increased risk of prostate cancer among users of testosterone therapy. Of clinical relevance, hypogonadism has been associated with short- and long-term adverse outcomes also in COVID-19 patients.
Giuseppe Fallara, Edoardo Pozzi, Christian Corsini, Federico Belladelli, Luca Boeri, Paolo Capogrosso, Francesco Montorsi, Andrea Salonia
In this narrative review, we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity, and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigation, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with an increased risk of mortality.
As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce the risk of progression to diabetes, and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.
Introduction
Little is known on the true incidence and prevalence of male hypogonadism in the general population, due to the multiple difficulties in terms of recognized and unequivocal definitions, the so-called normality thresholds for circulating testosterone values, and the consequent lack of solid epidemiological studies [1,2]. In this context, it has been estimated that almost 500,000 men are diagnosed with hypogonadism [3-5]. Likewise, data from the cross-sectional survey European Male Ageing Study (EMAS) showed that in a large cohort of community-dwelling men aged 40-79 years in eight European centers the overall prevalence of hypogonadism (i.e., the secondary, primary, and compensated hypogonadism categories) was almost 23% [6]. Narrowing the focus, in an Italian tertiary-referral center for Sexual Medicine, 10% of primary infertile men presented with criteria solely suggestive of hypogonadism at first evaluation, with a slight increase throughout the last decade [7].
Although the definition of hypogonadism usually applied in the literature refers to an established testosterone deficiency and the concomitant presence of symptoms related to this deficiency (namely, late-onset hypogonadism (LOH) intended as a chronic condition) [8], the recent dramatic figures associated with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced disease (COVID-19) have clearly shown how potentially fragile the androgen synthesis system is in the male, what significant rebound in terms of overall health COVID-19 may have [9], and how a severe and sudden reduction of circulating testosterone levels may lead to a complex clinical picture, even associated with fatal outcomes [10].
Serum testosterone levels gradually decline with age in men, but the clinical significance of this decrease remains uncertain [11,12]. So far, evidence supports the hypothesis that low testosterone is an important biomarker for morbidity and mortality in men, even after accounting for age. Indeed, low levels of circulating testosterone have been frequently associated with long-term negative health consequences including earlier death from all-cause and cardiovascular disease, reduced bone health, as well as poorer quality of life, reduced libido and erectile function, and an increased risk of certain cancer, i.e. testicular and prostate cancer [13]. Indeed, low levels of testosterone have been associated with poor general health also in younger patients [14]. Literature has been profuse in the last decades on these issues, and the aim of the current narrative review is to summarize and critically discuss the impact of low testosterone and testosterone therapy (TTh) on main health conditions.
Androgens, testosterone therapy, and cardiovascular events
In conclusion, most data derived from available meta-analyses on RCTs and population-based or pharmaco-epidemiological observational studies showed that hypogonadism per se is associated with an increased risk of cardiovascular events, whilst TTh does not increase the risk of cardiovascular morbidity and mortality [22e24,32,37,38]. Numerous studies that oppose these findings are flawed by several limitations, but the general literature on this topic suffers from huge heterogeneity, and pooled evidence with definitive clear results is far from being produced.
A final answer to this long debate might be found thanks to an ongoing RCT, the Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE), which is the largest and longest-duration randomized study of TTh ever conducted and which is aimed at including more than 6000 men, aged 45-80 years, with serum testosterone concentration <3 ng/mL and hypogonadal symptoms, who have evidence of pre-existing CV disease or increased risk of CV disease followed up for 5 years [39].
Notwithstanding controversies, there are biological reasons for supporting the statistical association between cardiovascular risk and lower testosterone levels. Much evidence has documented that low testosterone could be involved in the regulation of inflammation at several tissues level both in animal models and in humans [40-43]. In this context, pro-inflammatory cytokines have been linked to atherosclerosis, metabolic syndrome (MetS), and cardiovascular morbidity in several studies [44]. Of note, whether or not LOH is a cause or a consequence of atherosclerosis/MetS has not been clearly determined; likewise, atherosclerosis is a chronic inflammatory disease that releases into the circulation proinflammatory cytokines which in turn - are known to suppress testosterone release from the hypothalamus-pituitary-gonadal axis [45].
Androgens, testosterone therapy, and diabetes mellitus type 2
In conclusion, despite controversies, it is possible that the benefit of testosterone supplementation goes beyond the “simple” correction of symptoms of hypogonadism in the specific subset of men with T2DM or with significantly impaired glucose control, thus including metabolic control, as it has been recently demonstrated Wittert et al. [73]. Of note, lifestyle and dietary changes and diabetes medications, when clinically indicated, are compulsory and key in this setting potentially along with TTh; therefore, so far, there is no evidence to support the recommendation that TTh alone is more beneficial in terms of glycemic control compared to diabetes medications.
Endogenous testosterone and prostate cancer
Finally, despite androgen receptor and endogenous androgen production blockage representing one of the mainstays of hormone sensible prostate cancer treatment, the available reports on TTh and risk of prostate cancer progression in prostate cancer survivors are not sufficient to draw a definitive conclusion [89]. Taken together, the literature does not support the hypothesis of an association between TTh and prostate cancer and even the association between endogenous testosterone levels and prostate cancer risk is far from being straightforward. As such, EAU Guidelines on Reproductive and Sexual Health still recommend TTh in case of symptomatic hypogonadal men, but precautiously excluding those with a high risk of prostate cancer recurrence and those with active locally advanced or metastatic prostate cancer [15].
Androgens, testosterone therapy, and overall mortality
As such, the association between reduced testosterone levels and mortality is not a surprise, given the reported associations of hypogonadism with several morbidities such as T2DM and MACE.
COVID-19 and serum testosterone levels in men: a call to action
As previously anticipated, the definition of hypogonadism over adulthood usually applied in the literature refers to an established testosterone deficiency (i.e., LOH), intended as a chronic condition [8]. Thereof, in theory, any acute although significant depletion in circulating testosterone levels should not be regarded as of clinical relevance in terms of mid- or long-term sequelae, thus including further development of comorbidities (e.g., cardiovascular events) or greater risk of mortality. Conversely, recent clinical findings in COVID-19 studies have outlined a possible dramatic impact of the specific viral infection also on testosterone production in men, along with its significant rebound in terms of COVID-19-related overall men's health, even with fatal outcomes [92].
Therefore, in line with the reported findings suggesting the clinical relevance of hypogonadism as a predictor of lower men's health, this manuscript provides a short summary of available evidence in terms of COVID-19-related male hypogonadism which emerged after the epidemiological observation that men had worse clinical outcomes compared to women so that the hypothesis of a possible biopathology link between male sex and COVID-19 severity was postulated [93-95]. Two main hypotheses have been formulated. First, according to the androgen-driven COVID-19 theory, testosterone might enhance SARS-CoV-2 infection by stimulating the transmembrane protease serine 2 (TMPRSS2) protein, a transmembrane protease receptor [96]. The activity of TMPRSS2 is thought to be critical for viral transmission and pathogenicity in infected hosts since it activates SARS-CoV-2 spike proteins and helps the cleavage of the viral receptor angiotensin-converting enzyme II (ACE2) in lung alveolar epithelial cells, thus resulting in an augmented viral entry [97-99]. Second, the cytokine hypothesis would suggest that lower testosterone levels may either cause or favor a progression of COVID-19 in men, due to an increase in proinflammatory cytokines, which can eventually lead to a cytokine storm. In fact, the clinical worsening of COVID-19 may be mediated by pro-inflammation cytokines; in this setting, a number of preclinical and clinical studies have shown that hypogonadism is linked to higher levels of pro-inflammatory cytokines, and TTh may lower IL-1, IL-6, and TNF-alpha circulating levels [100,101]. Whether a baseline hypogonadal status is a keystone in the entire pathway of pathological evolution of COVID-19 infection in males has not yet been adequately understood.
In clinical terms, published data showed that relevant rates of men admitted to intensive care units (ICU) for acute severe illness have a transitory suppression of testosterone and over the last months this data was further supported in patients with COVID-19 [102]. For instance, Rastrelli et al. [103] and Çayan et al. [104] independently observed that SARS-CoV-2 infected male individuals depicted low serum testosterone levels and that serum total testosterone levels at hospital admission were associated with an increased risk of ICU admission and death. This finding was further confirmed by a case-control study, showing that total testosterone levels were considerably lower in symptomatic SARS-CoV-2 infected men compared to healthy controls already at hospital admission, and testosterone levels were suggestive of hypogonadism in nearly 90% of men with COVID-19 [105]. Furthermore, total testosterone levels were related to COVID-19 clinical severity at the time of hospitalization, with testosterone levels considerably lower both in men who needed ICU admission and in those who eventually died [92]. Recently, Corona et al. developed a meta-analysis of studies investigating the relationship between baseline total testosterone levels and COVID-19 outcomes, thus including the probability of being admitted to ICU (any reason) and mortality risk (PROSPERO (CRD42021275185)) [106]. Overall, low testosterone levels resulted in up to four- and five-fold increased risk to be admitted to ICU (fully adjusted risk: RR 2.37 (1.30-4.31); p < 0.001) or to die (fully adjusted risk: RR 2.53 (1.27-5.03); p < 0.001), after adjusting for potential confounders, thus corroborating the clinical importance of hypogonadism status as a key player in terms of overall men's health [106].
On the contrary, a study from Montopoli et al. demonstrated that men with prostate cancer under androgen deprivation therapy (ADT) were at lower risk of being infected by SARS-CoV-2 and hospitalized because of COVID-19 compared to those without ADT [107]. However, the results of this study were based on 118 men with COVID-19 of whom only 4 were on ADT and 114 were not, and subsequent studies have failed to confirm these findings [108-110]. As such, the question of whether androgens have an impact on COVID-19 severity remains a matter of extensive debate [108-110].
Finally, alarming findings from prospective studies highlighted that circulating total testosterone recovered over time after several months from SARS-CoV-2 infection, but more than 50% of men who eventually recovered from COVID-19 still showed low circulating testosterone levels suggestive of hypogonadism at 7-mo follow-up [111]. Of clinical importance, the higher the burden of comorbid conditions at presentation, the lower the probability of testosterone levels recovery over time.
Conclusions
Male hypogonadism and major comorbidities such as T2DM, obesity, and cardiovascular disease, appear closely connected, fostering a vicious cycle that may lead to further hypogonadism. Hypogonadism has also been associated with an increased risk of mortality. As such, TTh has the potential to oppose this pattern and improve cardiovascular and metabolic health in hypogonadal men. There is instead no evidence of an increased risk of prostate cancer among TTh users. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.
Summary
In this narrative review, we discussed and summarized the main aspects related to hypogonadism and testosterone therapy and associated morbidity and mortality outcomes. Overall, men with hypogonadism are at risk of increased mortality when compared to eugonadal men. This increase in mortality might be due to increased cardiovascular risks, especially when considering major adverse cardiovascular events, and increased incidence of metabolic syndrome/type 2 diabetes mellitus. Testosterone therapy is not just aimed at normalizing testosterone levels, thus improving symptoms related to hypogonadism, but has been found also to likely reduce the risk of major cardiovascular events and improve glycemic control, waist circumference, and lipid profile. Despite quite strong evidence supporting these statements, the literature is still heterogeneous owing to different definitions of hypogonadism, different testosterone therapy modalities and therapeutic schemes, and diverse population characteristic in each study. There is instead no evidence of increased risk of prostate cancer among users of testosterone therapy. Of clinical relevance, hypogonadism has been associated with short- and long-term adverse outcomes also in COVID-19 patients.
