Testosterone Replacement Therapy (TRT) has long been the subject of debate when it comes to cardiovascular risks. The Food and Drug Administration (FDA) has advised that TRT should only be prescribed for men who have low testosterone levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus. However, there is no evidence linking TRT with adverse cardiovascular (CV) events. Instead, research suggests that high or low hematocrit levels due to TRT, and the associated increase in estrogen, may contribute to the risk of heart disease.
One mechanism by which TRT can increase cardiovascular risks is through hematocrit levels. Hematocrit represents the portion of red blood cells in the blood. Elevated hematocrit is the most common adverse event related to TRT, and it is important to monitor hematocrit levels in T-treated subjects regularly to avoid potentially serious adverse events. Low or high hematocrit levels are associated with increased morbidity and mortality, mediated via anemia or thromboembolic events, respectively.
The link between hematocrit levels and cardiovascular risk lies in the fact that hematocrit affects blood viscosity, and thus blood flow. Increased hematocrit leads to increased blood viscosity, which can increase the risk of thromboembolic events, such as heart attacks and strokes. Furthermore, estrogen elevates hematocrit levels, which can lead to increased cardiovascular risk.
The Bohr effect explains that for the oxygen molecule to release from the hemoglobin, it needs a minimum level of carbon dioxide (CO2). When the body generates sufficient CO2, it creates a state called hypercapnia. Hypercapnia allows a greater concentration of oxygen to reach the cells, suppressing the formation of lactic acid . When the body cannot produce enough CO2 from carbohydrate, it instead produces lactic acid. Lactic acid contributes to disseminated intravascular coagulation and consumption coagulopathy, and increases the tendency of red cells to aggregate, forming “blood sludge.” This makes red cells more rigid, increasing the viscosity of blood and impairing circulation in the small vessels.
The link between TRT and cardiovascular risks lies in the fact that TRT can elevate hematocrit levels. High hematocrit levels can lead to increased blood viscosity, which increases the risk of thromboembolic events such as heart attacks and strokes. The increase in estrogen due to TRT can also elevate hematocrit levels, leading to increased cardiovascular risks. Therefore, it is important to monitor hematocrit levels regularly in T-treated subjects to avoid potentially serious adverse events.
The Bohr effect states that hemoglobin, which carry oxygen through your blood, require CO2 in order to effectively cleave off the oxygen for use in metabolism.
Hypercapnia allows a greater concentration of oxygen to reach your cells, and a high degree of oxygenation suppresses the formation of lactic acid, a harmful alternative energy source that damages the circulatory system (Li et al., 2005)
Dr. Raymond Peat argues in favor of the link between carbon dioxide displacement and the clotting effects of lactic acid, where he states that an excess of lactic acid causes rigidity in red blood cells and increases blood coagulation, blood viscosity, prevents normal blood circulation and forms what he calls “blood sludge” (Kobayashi et al., 2001; Martin et al., 2002; Peat, 2009; Schmid-Schönbein, 1981; Yamazaki et al., 2006).
Hematocrit reflects the portion of red blood cells in the blood. TRT often elevates hematocrit levels. Low or high hematocrit levels have an association with anemia and stroke (Paller et al., 2012). We find instances of low hematocrit and high blood viscosity, indicating inefficient oxygen transportation in the blood, among patients with sickle cell anemia, and we also find high levels of lactate dehydrogenase in such patients, which indicates that metabolism has shifted away from a typical, healthy oxidative metabolism and toward a glycolytic, lactic acid-based energy pathway (Connes et al., 2013).
Cancer cells require require less oxygen than healthy cells, and normally, cells exposed to reduced oxygen conditions will eventually self-terminate, but some will develop into cancer cells (Greijer & van der Wall, 2004). Over time, cancer cells become more aggressive and apt to survive in low oxygen conditions the cell becomes cancerous, it adapts to the lack of oxygen and becomes more resilient (Greijer & van der Wall, 2004).
Certain mechanisms that the body uses to survive low oxygen conditions can be hijacked by cancer cells, such as the actions of HIF-1, a protein that expands existing blood vessel networks in an effort to increase oxygenation in dire conditions. HIF-1 provides the vascular support for additional tissue, which may be cancer cells (Greijer & van der Wall, 2004; Lee et al., 2021).
I haven’t even began covering estrogen and its implication in breast cancer and gynecomastia. For that, I will publish a separate article.