madman
Super Moderator
The safety of testosterone therapy (TT) and its potential to cause heart problems have been debated for a long time. The sales of testosterone products increased dramatically, but some studies linking TT to heart risks were later found to be flawed. The US FDA advised caution in prescribing TT, though many experts disagreed due to lack of evidence. Short-term studies showed improvements in heart-related factors with TT, and a large analysis didn't find clear short- to medium-term heart risks. However, overall evidence on TT's safety is conflicting, calling for more quality, long-term studies. Guidelines recommending TT for symptomatic deficiency are mainly based on expert opinion, lacking strong evidence
Key Points:
Long-term studies
*An observational study by Saad et al. observed sustained benefits of testosterone therapy (TT) in 428 men over 11 years. Those receiving TT showed improvements in blood markers, weight, lipid profile, and cardiovascular risk compared to controls, but this study's limitations include its observational design.
*TRAVERSE was a randomized, placebo-controlled trial involving 5246 men with cardiovascular risk. Despite an increased risk profile, TT was non-inferior to placebo in terms of major adverse cardiovascular events (MACE) over 22 months. Unexpectedly, TT led to higher incidences of pulmonary embolism, atrial fibrillation, and acute kidney injury.
* The target range of TT in TRAVERSE (350-750 ng/dL) might have been too low to capture potential benefits or harms, given that normal testosterone levels for men range from 300-1000 ng/dL. Maintaining testosterone levels in the mid-normal range (e.g., 550-750 ng/dL) is recommended for better efficacy.
* Since TT is often needed for lifelong treatment, more research is needed to determine its long-term safety and effectiveness.
*There's uncertainty regarding the connection between TT and increased risks of deep vein thrombosis (DVT)/venous thromboembolism (VTE), as well as TT-induced polycythemia and its link to DVT/VTE.
*Some studies show that men on TT have DVT rates similar to the general population. However, another study suggested that the development of polycythemia while on TT increased the risk of MACE/VTE.
* Practice guidelines vary in their recommendations about the association between TT and thromboembolism risk. Some suggest avoiding TT in patients with documented polycythemia, while others are inconclusive.
*Because polycythemia increases the risk of clotting-related issues, intermittent phlebotomy (blood removal) is a safe and effective method to counteract this adverse effect of TT.
Risk of polycythaemia and venous thromboembolism
*The FDA has required testosterone (T) product labels to mention an increased risk of deep vein thrombosis (DVT), yet research findings have been inconsistent. It's currently unclear whether T therapy (TT) heightens the risk of DVT/venous thromboembolism (VTE). Data also lacks clarity on the link between TT-induced polycythemia (high red blood cell count) and DVT/VTE.
*In a study of 694 men with low testosterone receiving TT, 9 developed DVT. Most of these cases were attributed to factors other than TT. The rates of DVT among TT recipients were similar to the general population, and importantly, none of those who developed DVT were polycythemic at the time.
*Another study compared 5842 men on TT who developed polycythemia to those who didn't. It found that polycythemic individuals had a higher risk of major adverse cardiovascular events (MACE) and VTE. This implies that the development of polycythemia might increase the risk of MACE/VTE in men undergoing TT.
* Current guidelines from the Endocrine Society acknowledge the mixed nature of studies on VTE risk with TT and don't provide conclusive recommendations. The European Academy of Andrology guidelines recommend avoiding TT in patients with documented polycythemia, depending on related conditions.
*Due to polycythemia's association with increased risks like thrombosis, stroke, and heart attack, intermittent phlebotomy (blood removal) is suggested as a simple, safe, and effective method to counteract this potential adverse effect of TT.
Testosterone replacement in transgender men
*Transgender men (TGM) are individuals assigned female at birth but identify as male. They often undergo testosterone therapy (TT) to develop masculine traits. To achieve testosterone levels similar to cisgender men, TGM usually receive high doses, which can increase testosterone levels up to 20 times.
*Studies and case reports from various countries indicate that TGM undergoing TT might face an increased risk of cardiovascular (CV) events, such as endothelial dysfunction, venous thromboembolism (VTE), ischemic stroke, and heart attacks (ST-elevation myocardial infarction). These events can be especially concerning since they often occur in young patients.
*The severity of these adverse CV events in young TGM is a significant concern. These findings emphasize the importance of carefully assessing and monitoring the cardiovascular health of individuals undergoing TT.
*Addressing these risks can be challenging, as discontinuing TT might not be practical due to its importance in maintaining the patient's male identity. Some authors propose anticoagulation for TGM after a CV event to manage the risks associated with TT.
*Given the potential risks and the unique challenges faced by TGM, further research is essential to identify safe and effective ways to manage the cardiovascular health of this at-risk patient population.
Testosterone therapy in women
*Low testosterone (T) in women is linked to poorer health and may indicate an increased risk of cardiovascular (CV) issues. Women also experience a decline in androgen levels with age, but these levels return to normal premenopausal levels by the late 70s. Hyperandrogenism, often due to conditions like polycystic ovarian syndrome (PCOS), has been associated with an unfavorable heart health profile. However, some studies suggest that higher endogenous T levels might actually be protective for women.
*A significant study involving healthy women aged 70-95 found that higher circulating T levels were linked to a notably lower risk of major adverse cardiovascular events (MACE), even independent of traditional CV risk factors.
*The positive findings have led to the creation of clinical practice guidelines for the use of testosterone therapy (TT) in treating hypoactive sexual desire disorder (HSDD) in women, although this is still considered an 'off-label' use. FDA-approved medications for HSDD include bremelanotide and flibanserin. However, evidence for TT in various groups, such as premenopausal women and those with known or high CV risk, is still lacking.
*Testosterone therapy has been shown to enhance functional capacity in both men and women with heart failure, reflected in improvements in tests like the 6-minute walk, muscle strength, and peak oxygen consumption. However, structural improvements in cardiac function have not yet been proven, and studies tend to have small sample sizes and short durations. More research is needed to understand TT's potential benefits for individuals with heart failure.
In the treatment of symptomatic hypogonadism, the use of testosterone therapy (TT) is recommended by consensus panels and guidelines, although these are based on expert opinions and lack strong evidence. TT might be safe and effective in the short term for well-chosen patients, but comprehensive data for both men and women are still lacking. The TRAVERSE trial found TT to be comparable to placebo for major cardiovascular risk (MACE), but trial limitations exist in dosing and duration. TT's off-label use for hypoactive sexual desire disorder (HSDD) in women lacks FDA approval. While some short-term efficacy and safety are known, research is needed to confirm TT's safety and efficacy in women over the short and long term. Careful monitoring is essential for transgender men, who face perplexing strategies to prevent recurrent thrombotic events with TT, including therapeutic anticoagulation.
Key Points:
Long-term studies
*An observational study by Saad et al. observed sustained benefits of testosterone therapy (TT) in 428 men over 11 years. Those receiving TT showed improvements in blood markers, weight, lipid profile, and cardiovascular risk compared to controls, but this study's limitations include its observational design.
*TRAVERSE was a randomized, placebo-controlled trial involving 5246 men with cardiovascular risk. Despite an increased risk profile, TT was non-inferior to placebo in terms of major adverse cardiovascular events (MACE) over 22 months. Unexpectedly, TT led to higher incidences of pulmonary embolism, atrial fibrillation, and acute kidney injury.
* The target range of TT in TRAVERSE (350-750 ng/dL) might have been too low to capture potential benefits or harms, given that normal testosterone levels for men range from 300-1000 ng/dL. Maintaining testosterone levels in the mid-normal range (e.g., 550-750 ng/dL) is recommended for better efficacy.
* Since TT is often needed for lifelong treatment, more research is needed to determine its long-term safety and effectiveness.
*There's uncertainty regarding the connection between TT and increased risks of deep vein thrombosis (DVT)/venous thromboembolism (VTE), as well as TT-induced polycythemia and its link to DVT/VTE.
*Some studies show that men on TT have DVT rates similar to the general population. However, another study suggested that the development of polycythemia while on TT increased the risk of MACE/VTE.
* Practice guidelines vary in their recommendations about the association between TT and thromboembolism risk. Some suggest avoiding TT in patients with documented polycythemia, while others are inconclusive.
*Because polycythemia increases the risk of clotting-related issues, intermittent phlebotomy (blood removal) is a safe and effective method to counteract this adverse effect of TT.
Risk of polycythaemia and venous thromboembolism
*The FDA has required testosterone (T) product labels to mention an increased risk of deep vein thrombosis (DVT), yet research findings have been inconsistent. It's currently unclear whether T therapy (TT) heightens the risk of DVT/venous thromboembolism (VTE). Data also lacks clarity on the link between TT-induced polycythemia (high red blood cell count) and DVT/VTE.
*In a study of 694 men with low testosterone receiving TT, 9 developed DVT. Most of these cases were attributed to factors other than TT. The rates of DVT among TT recipients were similar to the general population, and importantly, none of those who developed DVT were polycythemic at the time.
*Another study compared 5842 men on TT who developed polycythemia to those who didn't. It found that polycythemic individuals had a higher risk of major adverse cardiovascular events (MACE) and VTE. This implies that the development of polycythemia might increase the risk of MACE/VTE in men undergoing TT.
* Current guidelines from the Endocrine Society acknowledge the mixed nature of studies on VTE risk with TT and don't provide conclusive recommendations. The European Academy of Andrology guidelines recommend avoiding TT in patients with documented polycythemia, depending on related conditions.
*Due to polycythemia's association with increased risks like thrombosis, stroke, and heart attack, intermittent phlebotomy (blood removal) is suggested as a simple, safe, and effective method to counteract this potential adverse effect of TT.
Testosterone replacement in transgender men
*Transgender men (TGM) are individuals assigned female at birth but identify as male. They often undergo testosterone therapy (TT) to develop masculine traits. To achieve testosterone levels similar to cisgender men, TGM usually receive high doses, which can increase testosterone levels up to 20 times.
*Studies and case reports from various countries indicate that TGM undergoing TT might face an increased risk of cardiovascular (CV) events, such as endothelial dysfunction, venous thromboembolism (VTE), ischemic stroke, and heart attacks (ST-elevation myocardial infarction). These events can be especially concerning since they often occur in young patients.
*The severity of these adverse CV events in young TGM is a significant concern. These findings emphasize the importance of carefully assessing and monitoring the cardiovascular health of individuals undergoing TT.
*Addressing these risks can be challenging, as discontinuing TT might not be practical due to its importance in maintaining the patient's male identity. Some authors propose anticoagulation for TGM after a CV event to manage the risks associated with TT.
*Given the potential risks and the unique challenges faced by TGM, further research is essential to identify safe and effective ways to manage the cardiovascular health of this at-risk patient population.
Testosterone therapy in women
*Low testosterone (T) in women is linked to poorer health and may indicate an increased risk of cardiovascular (CV) issues. Women also experience a decline in androgen levels with age, but these levels return to normal premenopausal levels by the late 70s. Hyperandrogenism, often due to conditions like polycystic ovarian syndrome (PCOS), has been associated with an unfavorable heart health profile. However, some studies suggest that higher endogenous T levels might actually be protective for women.
*A significant study involving healthy women aged 70-95 found that higher circulating T levels were linked to a notably lower risk of major adverse cardiovascular events (MACE), even independent of traditional CV risk factors.
*The positive findings have led to the creation of clinical practice guidelines for the use of testosterone therapy (TT) in treating hypoactive sexual desire disorder (HSDD) in women, although this is still considered an 'off-label' use. FDA-approved medications for HSDD include bremelanotide and flibanserin. However, evidence for TT in various groups, such as premenopausal women and those with known or high CV risk, is still lacking.
*Testosterone therapy has been shown to enhance functional capacity in both men and women with heart failure, reflected in improvements in tests like the 6-minute walk, muscle strength, and peak oxygen consumption. However, structural improvements in cardiac function have not yet been proven, and studies tend to have small sample sizes and short durations. More research is needed to understand TT's potential benefits for individuals with heart failure.
In the treatment of symptomatic hypogonadism, the use of testosterone therapy (TT) is recommended by consensus panels and guidelines, although these are based on expert opinions and lack strong evidence. TT might be safe and effective in the short term for well-chosen patients, but comprehensive data for both men and women are still lacking. The TRAVERSE trial found TT to be comparable to placebo for major cardiovascular risk (MACE), but trial limitations exist in dosing and duration. TT's off-label use for hypoactive sexual desire disorder (HSDD) in women lacks FDA approval. While some short-term efficacy and safety are known, research is needed to confirm TT's safety and efficacy in women over the short and long term. Careful monitoring is essential for transgender men, who face perplexing strategies to prevent recurrent thrombotic events with TT, including therapeutic anticoagulation.
