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Voiding function improves under long‑term testosterone treatment (TTh) in hypogonadal men, independent of prostate size (2023)
Aksam Yassin, · Mustafa Alwani · Raed M. Al‑Zoubi, · Omar M. Aboumarzouk, · Raidh Talib · Joanne Nettleship · Daniel Kelly, · Bassam Albaba
Abstract
Background
Functional hypogonadism is a condition in which some, but not all, older men have low testosterone levels. Rather than chronological age per se, the causality of hypogonadism includes obesity and impaired general health (e.g., metabolic syndrome). An association between testosterone deficiency and lower urinary tract symptoms (LUTS) has been reported, yet due to prostate safety concerns, men with severe LUTS (IPSS score>19) have invariably been excluded from entering testosterone trials. Irrespective, exogenous testosterone has not been demonstrated to cause de novo or worsen mild to moderate LUTS.
Objective
This study investigated whether long-term testosterone therapy (TTh) could have a protective effect on improving the symptoms of LUTS in hypogonadal men. However, the exact mechanism by which testosterone exerts its beneficial effect remains uncertain.
Patients and methods
In this study, 321 hypogonadal patients with an average age of 58.9±9.52 years received testosterone undecanoate in 12-week intervals for 12 years. One hundred and forty-seven of these males had the testosterone treatment interrupted for a mean of 16.9 months before it was resumed. Total testosterone, International Prostate Symptom Scale (IPSS), post-voiding residual bladder volume, and aging male symptoms (AMS) were measured over the study period. Results Prior to TTh interruption, it was observed that testosterone stimulation improved the men’s IPSS, AMS, and postvoiding residual bladder volume, while their prostate volume significantly increased. During the TTh interruption, there was a significant worsening in these parameters, although the increase in prostate volume continued. When TTh was resumed, these effects were reversed, implying that hypogonadism may require lifelong treatment.
Introduction
Functional hypogonadism is characterized by low serum levels of testosterone and associated symptoms in males, demonstrating a higher prevalence as men age [1]. Low testosterone may lead to, and be exacerbated by, concomitant diseases such as metabolic syndrome (MetS), type 2 diabetes (T2D), and obesity, which tend to develop through age [2]. Low testosterone levels affect approximately 20% of men over the age of 60 years, 30% over 70 years, and 50% over 80 years [3], and the associations between functional hypogonadism and its clinical features (including absence or regression of secondary sex characteristics, insulin resistance or T2D, hypertension, dyslipidemia, anemia, muscle wasting, reduced bone mass or bone mineral density, oligospermia, decreased libido, decreased sexual function and abdominal adiposity) and comorbidities leads to a lower quality of life (QoL) and often increased mortality [4]. Considering this, some studies have shown that testosterone therapy (TTh) has great therapeutic potential due to the favorable effects of testosterone on the comorbidities associated with androgenic deficiency [2]. However, there have been limited studies into the long-term effects of TTh and whether lifelong treatment is required.
Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are significant contributors to age-related QoL in men and are both associated with several features of MetS, including obesity in epidemiological studies [5–7]. LUTS are often regarded as a hallmark of benign prostatic hyperplasia (BPH) with an increased incidence as men age [8]. Some studies have identified a correlation between functional hypogonadism and BPH whereby men may have significantly larger prostate volumes (PV) (>31 mL) [3, 9] compared to men with normal testosterone levels [3]. Furthermore, a study by Schatzl et al. reported that approximately 20% of elderly men with LUTS had hypogonadism [10]. Reducing obesity as part of lifestyle intervention has been shown in some studies to lead to improvements in LUTS [11, 12] but not all [13, 14], and weight loss can result in modest increases in serum testosterone levels [15]. While the mechanisms underlying this potential inter-relationship between testosterone, obesity, and LUTS are not known currently, evidence from some studies indicates that TTh may be a useful therapy for improving metabolic and urinary symptoms as well as comorbidities of late-onset hypogonadism (LOH) [16–18]
One of the concerns regarding TTh in elderly men remains increasing prostate volume and worsening urinary function parameters. Indeed, it is acknowledged that the prostate is an androgen-dependent organ that requires testosterone for growth and development, thus raising concerns about the potential risk of increased PV and therefore worsening of the associated risks (including LUTS and prostate cancer) if men are given TTh [19]. A controlled cross-sectional study conducted by Behre et al. (1994) concluded that TTh in hypogonadal men resulted in a significant increase in PV, comparable to age-matched normal men whereas hypogonadal men without TTh had lower PV [20]. This suggested that TTh resulted in a modest but significant increase in PV, however, still remained within normal limits. In contrast to this, a Chinese study showed after age adjustment, the rate of PV growth in aging patients with low testosterone was significantly greater than the normal testosterone level group, after 4 years [3]. In addition, a longitudinal study found that hypogonadal men who received TTh had a 12% increase in PV size on average [21]. However, another placebo-controlled study of hypogonadal males on TTh found no significant differences in PV between TTh-treated men and those on placebo [22]. Despite a potential testosterone-induced PV increase, current research suggests that TTh does not increase the risk of developing prostate cancer (PCa) [23–25] and can even protect against prostatic carcinoma in castration-resistant prostate cancer patients [26, 27] and men with advanced disease, namely, biochemical recurrence or metastatic PCa [28].
The International Prostate Symptom Score (IPSS) is used to assess the severity of LUTS and its related symptoms (for both irritative and obstructive symptoms) which result in a lower QoL; symptoms can include voiding and obstruction (hesitancy, poor/intermittent stream, straining, feeling of incomplete bladder emptying) as well as storage or irritative symptoms (frequency, incontinence, and nocturia) [29]. In a Japanese population study of men with moderate to severe LUTS, TTh resulted in clinically significant improvements in the total IPSS score and the storage symptom score, but the voiding symptom score was not statistically improved after treatment [30]. In a meta-analysis of 14 clinical trials of TTh for hypogonadal men, the change in IPSS was similar among men receiving testosterone versus placebo, suggesting that TTh treatment does not worsen LUTS among men with hypogonadism [31]. The mean follow-up time for the studies included in this meta-analysis was 34.4 months which may indicate that long-term treatment is required for significant improvements in LUTS. Few studies have directly investigated the role of long-term TTh in hypogonadal males on the symptoms of LUTS. The protective role of testosterone and its improvements in LUTS in hypogonadal males were noted in our 2014 study [16]. The weight, waist circumference, and BMI of the males also improved, further decreasing the risk for LUTS. Indeed, we have demonstrated that TTh interruption, and consequential reduced total testosterone levels, result in worsening of symptoms including obesity parameters, aging male symptoms (AMS), IPSS, residual voiding volume and bladder wall thickness, erectile function, and prostate-specific antigen (PSA), while prostate volume remained unchanged until treatment resumed whereby these effects were reversed [32]. This suggests that hypogonadism may require lifelong TTh. In this retrospective registry study, we aimed to assess the long-term effects of testosterone treatment on the symptoms of LUTS (assessed by IPSS, AMS, post-voiding residual bladder volume, PV) in a cohort of 321 hypogonadal males with an average age of 58.9±9.52 years in a urological setting.
The current research has some limitations. Due to this being an observational study with no placebo-controlled group, the direct effects of treatment versus no treatment could not be evaluated, limiting the interpretation of the data. Additionally, TTh was interrupted in 147 males due to reimbursement issues and/or the diagnosis of prostate cancer. While this may skew the data presented, particularly for years 6–8, we have previously discovered that when TTh is resumed, testosterone levels return to pre-interruption levels [32]. As a result, the interruption is unlikely to have altered the circulation levels of hormones measured during the final 12-year follow-up. Indeed, all parameters measured in this study, except prostate volume, regressed in those patients in whom TTh was temporarily interrupted but started improving again after resuming TTh, suggesting a high degree of reversibility. The worsening after testosterone cessation was also observed in short-term studies [63, 64]. The study by Francomano et al. observed that in severely obese men, metabolic, fat but not lean mass, and blood pressure parameters were maintained for a relatively short duration, whereas cardiac and hormonal parameters returned to baseline post-TTh [33]. It is understood that the maintenance of some of the measures may occur over a short term but may be gradually lost over longer durations. Notably, many of the positive effects of TTh, especially in relation to body composition and weight, can take between 6 and 12 months to manifest [17]. Therefore, the long-term duration of the data collected here is a strength of the present study
In conclusion, this study suggests that long-term TTh can improve voiding function and alleviate symptoms of LUTS seemingly independently of prostate volume. These therapeutic benefits develop in parallel to improvements to QoL, as indicated by AMS. TTh may need to be continued indefinitely to retain the favorable effects, as we have previously observed in this cohort a worsening of parameters when TTh is discontinued and the sustained benefits over 12 years in the present study. While TTh may not increase prostate risk despite increases in PV, there is a need for large, placebo-controlled long-term outcome studies to validate current suggestions with more conclusive evidence.
Aksam Yassin, · Mustafa Alwani · Raed M. Al‑Zoubi, · Omar M. Aboumarzouk, · Raidh Talib · Joanne Nettleship · Daniel Kelly, · Bassam Albaba
Abstract
Background
Functional hypogonadism is a condition in which some, but not all, older men have low testosterone levels. Rather than chronological age per se, the causality of hypogonadism includes obesity and impaired general health (e.g., metabolic syndrome). An association between testosterone deficiency and lower urinary tract symptoms (LUTS) has been reported, yet due to prostate safety concerns, men with severe LUTS (IPSS score>19) have invariably been excluded from entering testosterone trials. Irrespective, exogenous testosterone has not been demonstrated to cause de novo or worsen mild to moderate LUTS.
Objective
This study investigated whether long-term testosterone therapy (TTh) could have a protective effect on improving the symptoms of LUTS in hypogonadal men. However, the exact mechanism by which testosterone exerts its beneficial effect remains uncertain.
Patients and methods
In this study, 321 hypogonadal patients with an average age of 58.9±9.52 years received testosterone undecanoate in 12-week intervals for 12 years. One hundred and forty-seven of these males had the testosterone treatment interrupted for a mean of 16.9 months before it was resumed. Total testosterone, International Prostate Symptom Scale (IPSS), post-voiding residual bladder volume, and aging male symptoms (AMS) were measured over the study period. Results Prior to TTh interruption, it was observed that testosterone stimulation improved the men’s IPSS, AMS, and postvoiding residual bladder volume, while their prostate volume significantly increased. During the TTh interruption, there was a significant worsening in these parameters, although the increase in prostate volume continued. When TTh was resumed, these effects were reversed, implying that hypogonadism may require lifelong treatment.
Introduction
Functional hypogonadism is characterized by low serum levels of testosterone and associated symptoms in males, demonstrating a higher prevalence as men age [1]. Low testosterone may lead to, and be exacerbated by, concomitant diseases such as metabolic syndrome (MetS), type 2 diabetes (T2D), and obesity, which tend to develop through age [2]. Low testosterone levels affect approximately 20% of men over the age of 60 years, 30% over 70 years, and 50% over 80 years [3], and the associations between functional hypogonadism and its clinical features (including absence or regression of secondary sex characteristics, insulin resistance or T2D, hypertension, dyslipidemia, anemia, muscle wasting, reduced bone mass or bone mineral density, oligospermia, decreased libido, decreased sexual function and abdominal adiposity) and comorbidities leads to a lower quality of life (QoL) and often increased mortality [4]. Considering this, some studies have shown that testosterone therapy (TTh) has great therapeutic potential due to the favorable effects of testosterone on the comorbidities associated with androgenic deficiency [2]. However, there have been limited studies into the long-term effects of TTh and whether lifelong treatment is required.
Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are significant contributors to age-related QoL in men and are both associated with several features of MetS, including obesity in epidemiological studies [5–7]. LUTS are often regarded as a hallmark of benign prostatic hyperplasia (BPH) with an increased incidence as men age [8]. Some studies have identified a correlation between functional hypogonadism and BPH whereby men may have significantly larger prostate volumes (PV) (>31 mL) [3, 9] compared to men with normal testosterone levels [3]. Furthermore, a study by Schatzl et al. reported that approximately 20% of elderly men with LUTS had hypogonadism [10]. Reducing obesity as part of lifestyle intervention has been shown in some studies to lead to improvements in LUTS [11, 12] but not all [13, 14], and weight loss can result in modest increases in serum testosterone levels [15]. While the mechanisms underlying this potential inter-relationship between testosterone, obesity, and LUTS are not known currently, evidence from some studies indicates that TTh may be a useful therapy for improving metabolic and urinary symptoms as well as comorbidities of late-onset hypogonadism (LOH) [16–18]
One of the concerns regarding TTh in elderly men remains increasing prostate volume and worsening urinary function parameters. Indeed, it is acknowledged that the prostate is an androgen-dependent organ that requires testosterone for growth and development, thus raising concerns about the potential risk of increased PV and therefore worsening of the associated risks (including LUTS and prostate cancer) if men are given TTh [19]. A controlled cross-sectional study conducted by Behre et al. (1994) concluded that TTh in hypogonadal men resulted in a significant increase in PV, comparable to age-matched normal men whereas hypogonadal men without TTh had lower PV [20]. This suggested that TTh resulted in a modest but significant increase in PV, however, still remained within normal limits. In contrast to this, a Chinese study showed after age adjustment, the rate of PV growth in aging patients with low testosterone was significantly greater than the normal testosterone level group, after 4 years [3]. In addition, a longitudinal study found that hypogonadal men who received TTh had a 12% increase in PV size on average [21]. However, another placebo-controlled study of hypogonadal males on TTh found no significant differences in PV between TTh-treated men and those on placebo [22]. Despite a potential testosterone-induced PV increase, current research suggests that TTh does not increase the risk of developing prostate cancer (PCa) [23–25] and can even protect against prostatic carcinoma in castration-resistant prostate cancer patients [26, 27] and men with advanced disease, namely, biochemical recurrence or metastatic PCa [28].
The International Prostate Symptom Score (IPSS) is used to assess the severity of LUTS and its related symptoms (for both irritative and obstructive symptoms) which result in a lower QoL; symptoms can include voiding and obstruction (hesitancy, poor/intermittent stream, straining, feeling of incomplete bladder emptying) as well as storage or irritative symptoms (frequency, incontinence, and nocturia) [29]. In a Japanese population study of men with moderate to severe LUTS, TTh resulted in clinically significant improvements in the total IPSS score and the storage symptom score, but the voiding symptom score was not statistically improved after treatment [30]. In a meta-analysis of 14 clinical trials of TTh for hypogonadal men, the change in IPSS was similar among men receiving testosterone versus placebo, suggesting that TTh treatment does not worsen LUTS among men with hypogonadism [31]. The mean follow-up time for the studies included in this meta-analysis was 34.4 months which may indicate that long-term treatment is required for significant improvements in LUTS. Few studies have directly investigated the role of long-term TTh in hypogonadal males on the symptoms of LUTS. The protective role of testosterone and its improvements in LUTS in hypogonadal males were noted in our 2014 study [16]. The weight, waist circumference, and BMI of the males also improved, further decreasing the risk for LUTS. Indeed, we have demonstrated that TTh interruption, and consequential reduced total testosterone levels, result in worsening of symptoms including obesity parameters, aging male symptoms (AMS), IPSS, residual voiding volume and bladder wall thickness, erectile function, and prostate-specific antigen (PSA), while prostate volume remained unchanged until treatment resumed whereby these effects were reversed [32]. This suggests that hypogonadism may require lifelong TTh. In this retrospective registry study, we aimed to assess the long-term effects of testosterone treatment on the symptoms of LUTS (assessed by IPSS, AMS, post-voiding residual bladder volume, PV) in a cohort of 321 hypogonadal males with an average age of 58.9±9.52 years in a urological setting.
The current research has some limitations. Due to this being an observational study with no placebo-controlled group, the direct effects of treatment versus no treatment could not be evaluated, limiting the interpretation of the data. Additionally, TTh was interrupted in 147 males due to reimbursement issues and/or the diagnosis of prostate cancer. While this may skew the data presented, particularly for years 6–8, we have previously discovered that when TTh is resumed, testosterone levels return to pre-interruption levels [32]. As a result, the interruption is unlikely to have altered the circulation levels of hormones measured during the final 12-year follow-up. Indeed, all parameters measured in this study, except prostate volume, regressed in those patients in whom TTh was temporarily interrupted but started improving again after resuming TTh, suggesting a high degree of reversibility. The worsening after testosterone cessation was also observed in short-term studies [63, 64]. The study by Francomano et al. observed that in severely obese men, metabolic, fat but not lean mass, and blood pressure parameters were maintained for a relatively short duration, whereas cardiac and hormonal parameters returned to baseline post-TTh [33]. It is understood that the maintenance of some of the measures may occur over a short term but may be gradually lost over longer durations. Notably, many of the positive effects of TTh, especially in relation to body composition and weight, can take between 6 and 12 months to manifest [17]. Therefore, the long-term duration of the data collected here is a strength of the present study
In conclusion, this study suggests that long-term TTh can improve voiding function and alleviate symptoms of LUTS seemingly independently of prostate volume. These therapeutic benefits develop in parallel to improvements to QoL, as indicated by AMS. TTh may need to be continued indefinitely to retain the favorable effects, as we have previously observed in this cohort a worsening of parameters when TTh is discontinued and the sustained benefits over 12 years in the present study. While TTh may not increase prostate risk despite increases in PV, there is a need for large, placebo-controlled long-term outcome studies to validate current suggestions with more conclusive evidence.
