madman
Super Moderator
Our study aimed to examine the effect of testosterone replacement therapy (TRT) on blood pressure in opioid-treated men with relative hypogonadism, and whether the effect of TRT on blood pressure was modified by body composition, red blood cell levels, or carotid intima-media thickness. Men (over 18 years old) receiving opioid treatment and total testosterone less than 12 nmol were randomly assigned to receive either TRT or placebo. Baseline and 6-month measurements included anthropometric measurements, office blood pressure(OBPM), 24-hour ambulatory blood pressure, blood samples, and carotid ultrasound.
The mean systolic OBPM increased by 6.2 mmHg (0.2–12.1) in the TRT group and decreased by 7.0 mmHg (1.0–15.1) in the placebo group, with a mean difference of 13.2 mmHg (3.4–23.1), P = 0.01. In the TRT group, a 10 mmHg increase in systolic OBPM was associated with an increase in hematocrit of 0.3% points (0.1–0.5) (P = 0.01), whereas no association was observed in the placebo group (P = 0.266).
Daytime SBP showed a nonsignificant increase of 5.2 mmHg (-1.7, 12.1) (P = 0.134) in the TRT group compared to that in the placebo group. However, the impact of TRT on the increase in daytime ambulatory blood pressure was significantly accentuated by baseline values of BMI, hematocrit, and hemoglobin.
In conclusion, TRT was associated with higher OBPM compared to placebo, and the increase in blood pressure was linked to higher hematocrit during TRT. Our data suggests that men with opioid-induced androgen deficiency, particularly those with obesity or red blood cell levels in the upper normal range, are more susceptible to increased daytime SBP during TRT.
BACKGROUND
Opioid analgesic consumption for nonmalignant pain management is globally increasing [1]. Secondary hypogonadism is one of the most well-described hormonal side effects of opioid treatment and occurs in men with chronic opioid use due to the suppression of the hypothalamic-pituitary-gonadal axis, known as opioid-induced androgen deficiency (OPIAD) [2]. Biochemically, OPIAD is characterized by low serum levels of testosterone and low levels of luteinizing hormone [3]. The magnitude of androgen deficiency depends on opioid treatment duration and dosage of opioids [4]. Furthermore, the severity of androgen deficiency in OPIAD appears to be accentuated in patients with comorbidities such as obesity, diabetes mellitus, hypertension, and hyperlipidemia [5]. Cardiovascular disease (CVD) and chronic pain often coexist [6,7] and the prevalence of hypertension in patients attending tertiary pain management clinics is up to 10 times higher compared to the general population [8].
Studies on the effects of testosterone replacement therapy (TRT) on blood pressure (BP) have shown contradictory results. TRT is associated with increased lean body mass and decreased abdominal subcutaneous adipose tissue [9–11], which may have a beneficial impact on BP [12], but TRT also reduces adiponectin levels and elevates red blood cell counts, potentially contributing to increased BP [13–17].
The indications for TRT in OPIAD remain a topic of debate. Although observational studies have suggested potential benefits of TRT in terms of reducing all-cause mortality and major adverse cardiovascular events [18], no randomized-controlled trials have specifically examined cardiovascular outcomes associated with TRT in OPIAD. Current clinical guidelines emphasize lifestyle interventions and reduction or withdrawal of opioid treatment in individuals with OPIAD, as discontinuation of opioid medications results in normalization of testosterone levels within a few months[19]. However, discontinuation of opioid treatment is not always feasible, necessitating consideration of TRT to alleviate symptoms of androgen deficiency. Clinical guidelines recommend assessment of cardiovascular risk factors prior to initiating TRT and discontinuation of TRT in individuals with consistently elevated hematocrit (Hct) levels [20]. The potential influence of baseline BMI and red blood cell levels on the effects of TRT on BP remains unclear.
Given the potential associations between TRT, BMI, red blood cell levels, and BP, this study aimed to investigate the effects of TRT on BP in opioid-treated men with relative hypogonadism and evaluate whether baseline clinical and laboratory data, such as BMI, Hct, and hemoglobin (Hgb)levels, modify these effects.
Effect of testosterone replacement therapy on blood pressure
Our study demonstrated a significant TRT-associated increase in OSBP (13.2 mmHg compared to placebo. We found an increase in daytime SBP of 5.2 mmHg compared to placebo; however, this was not significant. In cross-sectional studies, endogenous testosterone levels were inversely related to office BP and 24h ABPM levels in men [26–29]. The largest observational study examining the effect of TRT (IPASS) found after injectable testosterone therapy a beneficial effect on BP with a small reduction of SBP and DBP of 2.1 and 1.1 mmHg, respectively [30]. Although most TRT studies have not reported an increase in BP during testosterone treatment, recent studies examining the effect of oral TRT on 24h ABPM report an increase in SBP in the range of 3–5 mmHg [31–34], which is similar to the findings of our study. A recent large randomized study conducted among men with increased cardiovascular risk and total testosterone levels less than 10.4 nmol/investigated the effects of TRT with a follow-up period of 33 months [35]. Although there was no difference in the occurrence of major adverse cardiovascular events between the groups, the study reported a small yet significantly higher BP in the TRT group than in the placebo group. Furthermore, the occurrence of kidney disease and atrial fibrillation, both of which are strongly associated with hypertension, was higher among the participants in the TRT group. These findings suggest a potential cautionary signal as the effects of TRT may not manifest as major cardiovascular events within a relatively short follow-up period.
Interplay between testosterone, erythrocytosis, and blood pressure
In this study, we found a significant positive interaction between baseline levels of red blood cell measurements and the association between TRT and daytime SBP, and that the degree of increase in both OSBP and daytime SBP was associated with an increase in both Hct and Hgb. In large population studies of healthy individuals, Hgb levels were positively associated with BP levels [16,17]. TRT, especially injectable administration, can lead to erythrocytosis, resulting in increased Hct and Hgb levels [36]. Consistent with our findings, a recent (nonplacebo controlled) study examining the effect of oral TRT on ambulatory BP found that an increase in BP was associated with an increase in Hct levels[31]. They found that men in the top quartile of changes in Hct (range, 6–14%) experienced the largest increase in mean ambulatory SBP of 8.3 mmHg. We found that a 10% change in Hct was associated with an increase in daytime SBP of 7.4 mmHg. This is in line with Poiseuille’s law, which states that an increase in viscosity causes an increase in resistance, subsequently leading to increased BP when cardiac output remains constant. To physiologically compensate for a 10% increase in Hct levels, a 20% increase in BP or 5% vasodilation is necessary to maintain adequate perfusion [37].
Interplay between testosterone, body composition, and blood pressure
Our study indicates that the effect of TRT on 24h ABPM is accentuated by baseline BMI. This finding suggests an interplay between testosterone levels, body composition, and BP. Multiple studies have consistently supported an inverse association between testosterone levels and obesity across different age and ethnic groups [38–41]. Visceral adipose tissue is independently associated with reduced bioavailable and free testosterone [15]. Increased aromatase activity, primarily in visceral adipose tissue, can lead to elevated conversion of testosterone to estradiol, resulting in lowered testosterone levels [42]. A recent large observational study reported an interaction between obesity and testosterone levels and BP [43]. They found that endogenous testosterone levels were inversely associated with BP, and this association was attenuated in individuals with high BMI. The authors suggested that serum testosterone levels may have a protective effect on BP that is counteracted by obesity. However, it is challenging to evaluate and delineate the impact of obesity on the testosterone-BP association in cross-sectional studies. It is possible that the association between obesity and BP is accentuated by low testosterone levels, rather than by low testosterone being a causal contributor to increased BP. From this perspective, TRT may not reduce cardiovascular risk and could potentially be harmful in susceptible individuals [44], which is in line with the findings of our study.
Obesity and testosterone may collectively exert their effects on BP through the renin-angiotensin-aldosterone system (RAAS). In obesity, expanded inflamed visceral and perivascular adipose tissue facilitates overactivation of the RAAS [45–48]. TRT may further activate the RAAS, as seen in rat models wherein male rats exhibit higher plasma renin activity than female rats, and castration of male rats reduces plasma renin activity [49]. Clinical studies have also shown that TRT is associated with sodium and water retention, leading to edema, particularly in older individuals [50]. Consequently, the combination of obesity and TRT may potentially adverse activation of the RAAS, causing fluid retention and an increase in BP.
Discrepancy between the effect of testosterone replacement therapy on office blood pressure and 24-h ambulatory blood pressure
A possible explanation for the larger effect of TRT on OSBP compared to that of 24h ABPM could be that TRT increased the participants’ alert reaction to the physician’s presence during measurements. The neuroadrenergic response to a physician’s presence is characterized by generalized vasoconstriction [51,52] with an increase in SBP by 10–20 mmHg when applying a conventional cuff measurement [53,54]. Testosterone is generally considered a vasodilator of resistance arteries (primarily observed at supraphysiological concentrations) [55,56]. However, TRT may also affect vascular response to other vasoactive compounds. One myographical study found that TRT increased the vasoconstrictor response to noradrenaline and reduced the dilating response to acetylcholine in men with hypogonadism [57]. Similarly, other studies have reported that in hypogonadal men, endothelial function is reduced by TRT [58–60]. This could explain why we observed a greater effect of TRT on routine OSBP than that on 24h ABPM. We propose that the neuroadrenergic response to physicians’ presence may result in a higher OBPM in participants in TRT compared to placebo, which is not reflected to the same extent in the ambulatory setting.
Implications
Although low testosterone levels have been associated with various cardiac risk factors, such as obesity, type 2 diabetes Mellitus, and hypertension in cross-sectional studies, this does not necessarily imply that acquired low testosterone levels per se increase CVD risk, and it has not been proven that TRT changes the risk of CVD [61]. In this interventional and placebo-controlled study, we examined the impact of TRT on BP in men with OPIAD for whom the decision to initiate TRT is difficult. Our study highlights the importance of monitoring Hb, Hct, and BP in patients with OPIAD before and during TRT, particularly in obese individuals with red blood cell measurements in the upper-normal range. In men with a substantial increase in Hgb or Hct levels, BP should be monitored closely, including in ambulatory settings.
Strengths and limitations
This is a strength in that the trial was double-blind and placebo-controlled. However, as the primary study outcome was lean body mass, the study could be underpowered to detect minor changes in secondary study outcomes such as 24h ABPM. We did not include information about smoking, alcohol consumption, or other lifestyle factors, which could have changed during the study intervention and affected our study results. Several study outcomes were addressed; therefore, the issue of multiple testing arose, and some positive associations may have occurred by chance.
CONCLUSION
The effect of TRT on BP was accentuated by the baseline levels of Hgb, Hct, and BMI. The magnitude of the increase in BP was predominantly associated with an increase in Hct levels. BP should be carefully assessed and monitored when initiating TRT in men with OPIAD, especially in subjects with obesity and red blood cell counts in the upper normal range.
The mean systolic OBPM increased by 6.2 mmHg (0.2–12.1) in the TRT group and decreased by 7.0 mmHg (1.0–15.1) in the placebo group, with a mean difference of 13.2 mmHg (3.4–23.1), P = 0.01. In the TRT group, a 10 mmHg increase in systolic OBPM was associated with an increase in hematocrit of 0.3% points (0.1–0.5) (P = 0.01), whereas no association was observed in the placebo group (P = 0.266).
Daytime SBP showed a nonsignificant increase of 5.2 mmHg (-1.7, 12.1) (P = 0.134) in the TRT group compared to that in the placebo group. However, the impact of TRT on the increase in daytime ambulatory blood pressure was significantly accentuated by baseline values of BMI, hematocrit, and hemoglobin.
In conclusion, TRT was associated with higher OBPM compared to placebo, and the increase in blood pressure was linked to higher hematocrit during TRT. Our data suggests that men with opioid-induced androgen deficiency, particularly those with obesity or red blood cell levels in the upper normal range, are more susceptible to increased daytime SBP during TRT.
BACKGROUND
Opioid analgesic consumption for nonmalignant pain management is globally increasing [1]. Secondary hypogonadism is one of the most well-described hormonal side effects of opioid treatment and occurs in men with chronic opioid use due to the suppression of the hypothalamic-pituitary-gonadal axis, known as opioid-induced androgen deficiency (OPIAD) [2]. Biochemically, OPIAD is characterized by low serum levels of testosterone and low levels of luteinizing hormone [3]. The magnitude of androgen deficiency depends on opioid treatment duration and dosage of opioids [4]. Furthermore, the severity of androgen deficiency in OPIAD appears to be accentuated in patients with comorbidities such as obesity, diabetes mellitus, hypertension, and hyperlipidemia [5]. Cardiovascular disease (CVD) and chronic pain often coexist [6,7] and the prevalence of hypertension in patients attending tertiary pain management clinics is up to 10 times higher compared to the general population [8].
Studies on the effects of testosterone replacement therapy (TRT) on blood pressure (BP) have shown contradictory results. TRT is associated with increased lean body mass and decreased abdominal subcutaneous adipose tissue [9–11], which may have a beneficial impact on BP [12], but TRT also reduces adiponectin levels and elevates red blood cell counts, potentially contributing to increased BP [13–17].
The indications for TRT in OPIAD remain a topic of debate. Although observational studies have suggested potential benefits of TRT in terms of reducing all-cause mortality and major adverse cardiovascular events [18], no randomized-controlled trials have specifically examined cardiovascular outcomes associated with TRT in OPIAD. Current clinical guidelines emphasize lifestyle interventions and reduction or withdrawal of opioid treatment in individuals with OPIAD, as discontinuation of opioid medications results in normalization of testosterone levels within a few months[19]. However, discontinuation of opioid treatment is not always feasible, necessitating consideration of TRT to alleviate symptoms of androgen deficiency. Clinical guidelines recommend assessment of cardiovascular risk factors prior to initiating TRT and discontinuation of TRT in individuals with consistently elevated hematocrit (Hct) levels [20]. The potential influence of baseline BMI and red blood cell levels on the effects of TRT on BP remains unclear.
Given the potential associations between TRT, BMI, red blood cell levels, and BP, this study aimed to investigate the effects of TRT on BP in opioid-treated men with relative hypogonadism and evaluate whether baseline clinical and laboratory data, such as BMI, Hct, and hemoglobin (Hgb)levels, modify these effects.
Effect of testosterone replacement therapy on blood pressure
Our study demonstrated a significant TRT-associated increase in OSBP (13.2 mmHg compared to placebo. We found an increase in daytime SBP of 5.2 mmHg compared to placebo; however, this was not significant. In cross-sectional studies, endogenous testosterone levels were inversely related to office BP and 24h ABPM levels in men [26–29]. The largest observational study examining the effect of TRT (IPASS) found after injectable testosterone therapy a beneficial effect on BP with a small reduction of SBP and DBP of 2.1 and 1.1 mmHg, respectively [30]. Although most TRT studies have not reported an increase in BP during testosterone treatment, recent studies examining the effect of oral TRT on 24h ABPM report an increase in SBP in the range of 3–5 mmHg [31–34], which is similar to the findings of our study. A recent large randomized study conducted among men with increased cardiovascular risk and total testosterone levels less than 10.4 nmol/investigated the effects of TRT with a follow-up period of 33 months [35]. Although there was no difference in the occurrence of major adverse cardiovascular events between the groups, the study reported a small yet significantly higher BP in the TRT group than in the placebo group. Furthermore, the occurrence of kidney disease and atrial fibrillation, both of which are strongly associated with hypertension, was higher among the participants in the TRT group. These findings suggest a potential cautionary signal as the effects of TRT may not manifest as major cardiovascular events within a relatively short follow-up period.
Interplay between testosterone, erythrocytosis, and blood pressure
In this study, we found a significant positive interaction between baseline levels of red blood cell measurements and the association between TRT and daytime SBP, and that the degree of increase in both OSBP and daytime SBP was associated with an increase in both Hct and Hgb. In large population studies of healthy individuals, Hgb levels were positively associated with BP levels [16,17]. TRT, especially injectable administration, can lead to erythrocytosis, resulting in increased Hct and Hgb levels [36]. Consistent with our findings, a recent (nonplacebo controlled) study examining the effect of oral TRT on ambulatory BP found that an increase in BP was associated with an increase in Hct levels[31]. They found that men in the top quartile of changes in Hct (range, 6–14%) experienced the largest increase in mean ambulatory SBP of 8.3 mmHg. We found that a 10% change in Hct was associated with an increase in daytime SBP of 7.4 mmHg. This is in line with Poiseuille’s law, which states that an increase in viscosity causes an increase in resistance, subsequently leading to increased BP when cardiac output remains constant. To physiologically compensate for a 10% increase in Hct levels, a 20% increase in BP or 5% vasodilation is necessary to maintain adequate perfusion [37].
Interplay between testosterone, body composition, and blood pressure
Our study indicates that the effect of TRT on 24h ABPM is accentuated by baseline BMI. This finding suggests an interplay between testosterone levels, body composition, and BP. Multiple studies have consistently supported an inverse association between testosterone levels and obesity across different age and ethnic groups [38–41]. Visceral adipose tissue is independently associated with reduced bioavailable and free testosterone [15]. Increased aromatase activity, primarily in visceral adipose tissue, can lead to elevated conversion of testosterone to estradiol, resulting in lowered testosterone levels [42]. A recent large observational study reported an interaction between obesity and testosterone levels and BP [43]. They found that endogenous testosterone levels were inversely associated with BP, and this association was attenuated in individuals with high BMI. The authors suggested that serum testosterone levels may have a protective effect on BP that is counteracted by obesity. However, it is challenging to evaluate and delineate the impact of obesity on the testosterone-BP association in cross-sectional studies. It is possible that the association between obesity and BP is accentuated by low testosterone levels, rather than by low testosterone being a causal contributor to increased BP. From this perspective, TRT may not reduce cardiovascular risk and could potentially be harmful in susceptible individuals [44], which is in line with the findings of our study.
Obesity and testosterone may collectively exert their effects on BP through the renin-angiotensin-aldosterone system (RAAS). In obesity, expanded inflamed visceral and perivascular adipose tissue facilitates overactivation of the RAAS [45–48]. TRT may further activate the RAAS, as seen in rat models wherein male rats exhibit higher plasma renin activity than female rats, and castration of male rats reduces plasma renin activity [49]. Clinical studies have also shown that TRT is associated with sodium and water retention, leading to edema, particularly in older individuals [50]. Consequently, the combination of obesity and TRT may potentially adverse activation of the RAAS, causing fluid retention and an increase in BP.
Discrepancy between the effect of testosterone replacement therapy on office blood pressure and 24-h ambulatory blood pressure
A possible explanation for the larger effect of TRT on OSBP compared to that of 24h ABPM could be that TRT increased the participants’ alert reaction to the physician’s presence during measurements. The neuroadrenergic response to a physician’s presence is characterized by generalized vasoconstriction [51,52] with an increase in SBP by 10–20 mmHg when applying a conventional cuff measurement [53,54]. Testosterone is generally considered a vasodilator of resistance arteries (primarily observed at supraphysiological concentrations) [55,56]. However, TRT may also affect vascular response to other vasoactive compounds. One myographical study found that TRT increased the vasoconstrictor response to noradrenaline and reduced the dilating response to acetylcholine in men with hypogonadism [57]. Similarly, other studies have reported that in hypogonadal men, endothelial function is reduced by TRT [58–60]. This could explain why we observed a greater effect of TRT on routine OSBP than that on 24h ABPM. We propose that the neuroadrenergic response to physicians’ presence may result in a higher OBPM in participants in TRT compared to placebo, which is not reflected to the same extent in the ambulatory setting.
Implications
Although low testosterone levels have been associated with various cardiac risk factors, such as obesity, type 2 diabetes Mellitus, and hypertension in cross-sectional studies, this does not necessarily imply that acquired low testosterone levels per se increase CVD risk, and it has not been proven that TRT changes the risk of CVD [61]. In this interventional and placebo-controlled study, we examined the impact of TRT on BP in men with OPIAD for whom the decision to initiate TRT is difficult. Our study highlights the importance of monitoring Hb, Hct, and BP in patients with OPIAD before and during TRT, particularly in obese individuals with red blood cell measurements in the upper-normal range. In men with a substantial increase in Hgb or Hct levels, BP should be monitored closely, including in ambulatory settings.
Strengths and limitations
This is a strength in that the trial was double-blind and placebo-controlled. However, as the primary study outcome was lean body mass, the study could be underpowered to detect minor changes in secondary study outcomes such as 24h ABPM. We did not include information about smoking, alcohol consumption, or other lifestyle factors, which could have changed during the study intervention and affected our study results. Several study outcomes were addressed; therefore, the issue of multiple testing arose, and some positive associations may have occurred by chance.
CONCLUSION
The effect of TRT on BP was accentuated by the baseline levels of Hgb, Hct, and BMI. The magnitude of the increase in BP was predominantly associated with an increase in Hct levels. BP should be carefully assessed and monitored when initiating TRT in men with OPIAD, especially in subjects with obesity and red blood cell counts in the upper normal range.
