madman
Super Moderator
* Venesection is not recommended except for clonal erythrocytosis, due to its potential pro-thrombotic effects.
* Repeated venesection can lead to decreased tissue oxygen pressure (pO2) and depletion of iron stores; factors which activate biological pathways that may paradoxically promote the risk of thrombosis (43).
* Therefore, venesection should not be considered as a primary treatment for non-clonal erythrocytosis. Instead, the management of both absolute and relative forms should primarily focuses on lifestyle adjustments: quitting smoking, moderating alcohol and achieving weight loss; treating the associated hypertension relatively aggressively with vasodilator drugs rather than diuretics so as to expand the plasma volume (46), and identifying and treating primary respiratory conditions such as OSA (43). Venesection is thus only considered as a last resort, reserved for only the most severe cases of erythrocytosis and when there are no alternatives, e.g. Hct >0.52 in hereditary or clonal erythrocytosis or >0.56 in COPD (47) .
* Hct is a better indicator of RCM than the haemoglobin (Hb) level, which is slightly more influenced by the state of hydration (26).
* There is also a dose- and serum level-dependent increase in Hct and Hb with testosterone treatment that is observed in both hypogonadal and transgender males (27, 49, 50). Thus, whilst stimulation of erythropoiesis by testosterone can benefit anaemia, it can also become an adverse effect when there is overshoot resulting in erythrocytosis. Although assessing Hct is arguably the most important aspect of therapeutic monitoring, the risk of thrombosis is more significantly impacted by other vascular risk factors, such as family history, smoking, diabetes mellitus, body mass index (BMI), hypertension, dyslipidaemia and fibrinogen levels (26, 42).
* In cases of clinically significant erythrocytosis with no other risk factors to address (smoking, obesity, hypertension, sleep apnoea, etc), it is recommended to reduce the testosterone dose and/or switch to transdermal formulations. However, one study found that transgender men on testosterone undecanoate depot injections had lower erythrocytosis rates that those on gels or intermediate-acting IM testosterone esters (9.2% Hct >50% vs 12.8% and 15.9%, respectively), emphasising the relatively greater importance of the overall area-under-curve dose over the actual mode of delivery (54).
* By properly monitoring treatment, adjusting the dose or dose-interval accordingly, collaboratively addressing other risk factors, it should usually be possible to avoid inducing erythrocytosis in the first place. When erythrocytosis does occur, then this can usually be addressed by following the same paradigm, rather than complete interruption of treatment.
Figure. 1. Regulation of Erythropoiesis. EPO is the main regulator of erythropoiesis, and its transcription depends on tissue O2 levels. In normoxia, HIF2α is hydroxylated, binds to pVHL and is subsequently targeted for proteasomal degradation. In hypoxia, this degradation is decreased, allowing HIF2α to dimerize with HIF2b and promotes EPO gene transcription. EPO is primarily produced by renal peritubular interstitial fibroblast and stimulates red blood cells production in the bone marrow. In addition to regulation EPO, HIF2α also enhances iron absorption by upregulating DCYTB (enzyme that convert Fe3+ in Fe2+) and DMT1 (facilitates Fe2+uptake into cytoplasm). Iron is then exported into the bloodstream through ferroportin. EPO indirectly promotes ferroportin activity by suppressing hepcidin, a key negative regulator of iron efflux. DCYTB: duodenal cytochrome b; DMT1: divalentmetal transporter 1.EPO: erythropoietin; Fe3+: ferric iron Fe2+: ferrous iron; HIF2α: Hypoxia-inducible factor alpha; HIF2β: Hypoxia-inducible factor beta; HRE: hypoxia response element; O2: oxygen molecule; OH: hydroxyl group; PHD: prolylhydroxylase domain pVHL: von Hippel–Lindau tumour suppressor protein.\
Abstract
Testosterone is the cornerstone therapy for men with hypogonadism, and also treats any associated anaemia by promoting erythropoiesis. However, excessive doses cause erythrocytosis (raised red cell mass), especially if other risk factors are present. Erythrocytosis is associated with arterial and venous thrombosis in population studies.Testosterone is now increasingly prescribed to older men with functional hypogonadism and obesity, hypertension or type 2 diabetes; who are anyway at higher risk of both erythrocytosis and thrombosis. Although short–medium term testosterone treatment in these men was not associated with adverse cardiovascular outcomes, there were more cases of pulmonary embolism.
Originally envisaged as purely oral hypoglycaemic drugs, Sodium glucose cotransporter 2 inhibitors (SGLT2i) are now increasingly prescribed in chronic kidney disease, ischaemic heart disease and left ventricular impairment, irrespective of glycaemia, and the likelihood of co-prescription with testosterone is thus increased considerably. Crucially, they also increase haematocrit by promoting haematopoiesis.
This review focuses on the current best evidence for managing erythrocytosis, in the context of more prevalent obesity and prescriptions of testosterone and SGLT2i in this population. It highlights the need to balance the metabolic and therapeutic benefits against the potential risks. Management strategies include re-evaluating the original treatment indication, addressing modifiable risk factors, switching to transdermal testosterone and/or reducing the testosterone dose. Venesection is not recommended except for clonal erythrocytosis, due to its potential pro-thrombotic effects. However,combination therapy with testosterone and SGLT2s in men with anaemia of advanced CKD could augment, or even partly supersede, expensive treatment with conventional erythrocytosis-stimulating agents.
Introduction
This review aims to inform Endocrinologists about the physiology of erythropoiesis and mhow many of the various regulatory pathways are modulated by testosterone, which can lead to challenges managing patients who develop erythrocytosis on testosterone treatment. Although there are few data to directly link testosterone treatment with thrombosis, it is clear from general population studies that a higher haematocrit isassociated with a greater rate of thrombosis, even after adjusting for other risk factors. We particularly focus on older men with metabolic syndrome and related secondary hypogonadism, who are anyway at higher risk of both thrombosis and testosterone induced erythrocytosis. We discuss the expanding role for sodium-glucose cotransporter 2 inhibitor drugs (SGLT2i) in this population; highlighting the increasing likelihood of overlapping treatment with both testosterone and SGLT2i in these patients. We also describe the mechanisms that underpin the actions of testosterone and SGLT2Is in promoting erythropoiesis and, given the increasing likelihood of patients receiving both drugs at the same time, we sign post clinicians to effective strategies for managing medication-induced erythrocytosis based on best evidence.
* Male hypogonadism and its relationship to obesity and metabolic syndrome
* Testosterone treatment of obesity-associated functional hypogonadism
* Sodium-glucose co-transporter 2 inhibitors (SGLT2i)
* Haematopoiesis: physiology and pathology
Regulatory mechanisms underpinning erythropoeisis (see also Fig 1)
Erythropoiesis is the process of red blood cell production, primarily occurring in the bone marrow, which is regulated by erythropoietin (EPO), a glycoprotein hormone synthetized mainly in the kidney by peritubular interstitial fibroblasts and, to a lesser extent, by hepatocytes. EPO secretion is upregulated in response to systemic hypoxia, ensuring adequate oxygen delivery by increasing red cell mass (RCM). Hypoxia inducible factors (HIFs), especially HIF2, play a central role in the regulation of EPO production and are also crucial for intestinal iron absorption and the maturation and proliferation of erythroid progenitor cells.
Under normoxic conditions, HIF action is inhibited by von Hippel–Lindau tumour suppressor protein (pVHL), which targets HIFα subunits for polyubiquitination and proteasomal degradation. A necessary condition for the binding between HIF and pVHL is the hydroxylation of a specific proline residue of HIF, an oxygen-dependent process. Under hypoxic conditions, the activities of hydrolyzation and degradation of HIF2a are reduced, enabling the HIF complex to upregulate transcription of EPO and thus increase RBC production.
The stimulation of erythropoiesis increases iron demand in the bone marrow, and HIF2 plays a central role in iron uptake and its utilization acting directly on divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB). DMT1 normally transports iron into cells cytoplasm, while DCYTB reduces ferric iron (Fe³⁺) into ferrous form (Fe2+) facilitating iron uptake from the gut lumen into intestinal cells via DMT1. Additionally, EPO inhibits synthesis of hepcidin, a hepatocyte-derived negative regulator of iron absorption, allowing increased iron transport through ferroportin, the main extracellular iron transporter (24, 25).
Hct is a better indicator of RCM than the haemoglobin (Hb) level, which is slightly more influenced by the state of hydration (26). Hct was traditionally determined through centrifugation, but is presently estimated by automated analysers through bioimpedance analysis or laser flow cytometry. Different analysers and reagents produce different values for Hct subject to calibration by reference samples from a healthy local normal population. Accordingly, the upper limit of normality for male Hct from an accredited laboratory may range from 0.48 to 0.54, depending on how these factors combine, but will most commonly lie between 0.50 and 0.52
* Physiological roles of testosterone in promoting erythropoiesis (see also Fig 2)
In addition to prolonging RBC lifespan (7), androgens have various other effects on the hematopoietic system, including promoting the differentiation of bone marrow hematopoietic stem cells into EPO-responsive cells (27). However, the major pathway promoting RBC synthesis is enhanced iron utilization. Testosterone increases iron availability by suppressing hepcidin secretion by hepatocytes, which allows ferroport into facilitate intestinal iron absorption. Increased iron utilization for Hb synthesis is indicated by higher serum levels of soluble transferrin receptor (sTR) and lower levels of ferritin. T also enhances the sensitivity of erythroid progenitor cells to EPO and stimulates renal EPO secretion leading to an initial rise in circulating EPO levels. Although EPO concentrations return to baseline within six months of starting testosterone treatment, they nevertheless remain comparatively elevated in relation to the new higher Hb and Hct values, suggesting a recalibration of the EPO set point toa higher level in accordance with the new Hb concentration (28, 29)
Conversely, a decline in T levels leads to reduced erythropoietic activity, with both hypogonadism and androgen deprivation are associated with lower Hct levels, potentially leading to anaemia, especially in older men. The pattern of Hb decline with androgen-deprivation parallels that of serum T, with a rapid decrease at the initiation of suppression. (30, 31). Since oestrogens do not impact on erythropoietic parameters,this action of testosterone is necessarily independent of aromatization (30). Supporting the oestrogen-independent action of testosterone on haematopoiesis are the physiological divergence in male and female Hb values from puberty onwards (7); the absence of anaemia in men with rare genetic aromatase deficiency, and the observation that treatment with an aromatas inhibitors can cause erythrocytosist hrough increased T levels, as a result of reduced oestradiol-mediated negativefeed back on gonadotropin secretion (32).
* SGLT2i and erythropoiesis (see also Fig 3)
* Erythrocytosis: subtypes, mechanisms and risks
* Is venesection a reasonable treatment for non-clonal erythrocytosis?
Regular venesection is a straightforward technique that quickly reduces Hb and Hct to reference levels and, in JAK2-positive or clonal erythrocytosis, there is good evidence for its safety and efficacy in mitigating the risk of thromboembolic disease. However, in respect of non-clonal erythrocytosis, where the risk of thrombosis is anyway much lower and there is also potential for addressing the predisposing factors, a deeper dive into the evidence becomes necessary.
Repeated venesection can lead to decreased tissue oxygen pressure (pO2) and depletion of iron stores; factors which activate biological pathways that may paradoxically promote the risk of thrombosis (43). Indeed, in an observational study of SGLT2i-associated erythrocytosis, thrombosis rates were higher among patients who underwent phlebotomy: 21% (6/29) versus 6% (4/71) (33, 44). A similar pattern was observed in Chuvash erythrocytosis, a congenital disorder where the thrombotic risk i slargely independent of Hct and the rate of thrombosis is increased by venesection (45).
Therefore, venesection should not be considered as a primary treatment for non-clonal erythrocytosis. Instead, the management of both absolute and relative forms should primarily focuses on lifestyle adjustments: quitting smoking, moderating alcohol and achieving weight loss; treating the associated hypertension relatively aggressively with vasodilator drugs rather than diuretics so as to expand the plasma volume (46), and identifying and treating primary respiratory conditions such as OSA (43). Venesection is thus only considered as a last resort, reserved for only the most severe cases oferythrocytosis and when there are no alternatives, e.g. Hct >0.52 in hereditary or clonal erythrocytosis or >0.56 in COPD (47) .
* Testosterone treatment: physiology and clinical implications
Physiological responses to testosterone treatmentI mprovements in sexual interest and energy level and resolution of vasomotor symptoms or mastalgia occur within 3‒6 weeks; increased erythropoiesis develops over 2‒3 months, and positive changes in lean body mass and bone density over 6‒12 months, with the benefits continuing to accumulate for at least another three years (1). However, the time needed for testosterone effects to become evident can vary significantly. For instance, in older individuals with erectile or ejaculatory dysfunctions,sexual improvements may take up to 6 months to appear (48).
There is also a dose- and serum level-dependent increase in Hct and Hb with testosterone treatment that is observed in both hypogonadal and transgender males(27, 49, 50). Thus, whilst stimulation of erythropoiesis by testosterone can benefit anaemia, it can also become an adverse effect when there is overshoot resulting inerythrocytosis. Although assessing Hct is arguably the most important aspect of therapeutic monitoring, the risk of thrombosis is more significantly impacted by other vascular risk factors, such as family history, smoking, diabetes mellitus, body mass index (BMI), hypertension, dyslipidaemia and fibrinogen levels (26, 42). In transmasculine people, in whom physiological increases in Hb and Hct with testosterone may appear pathological when plotted against female laboratory reference values, and it is suggested that haematological parameters should be evaluated on affirmed gender rather than the sex assigned at birth during hormone treatment (50).
Although older men are more prone to anaemia when hypogonadal, they are at the same time at greater risk of developing androgen-induced erythrocytosis (27, 51). Hence, testosterone therapy is not generally recommended if baseline Hct approaches or exceeds 50%; indeed, such high levels should lead one to seriously question the original diagnosis of hypogonadism (1). Conversely, in older patients with functional CH and anaemia, testosterone treatment corrected baseline anaemia in 40‒60% of cases, irrespective of whether another cause of anaemia was identified. These men also experienced improvements in energy and vitality that were not observed in the generality of study patients (49, 52).
In relation to the direct effects of testosterone treatment on blood pressure, oral preparations may cause a very small increase (53), with other formulations not showing any increase at physiological doses.
\
* Testosterone formulations and their relationship to the haematocrit
Long-acting testosterone undecanoate IM injections maintain more stable serum testosterone levels compared to shorter-acting one, avoiding peaks. In contrast, short acting testosterone IM injections cause greater fluctuations in T levels, with rapid supraphysiological peaks shortly after injection, followed by a drop to low levels jus tprior to the next injection. These fluctuations appear to be associated with an increased risk of erythrocytosis. Transdermal formulations achieve more stable levels and, potentially, a lower overall area-under-curve serum T concentration (1, 54). In cases of clinically significant erythrocytosis with no other risk factors to address (smoking, obesity, hypertension, sleep apnoea, etc), it is recommended to reduce the testosterone dose and/or switch to transdermal formulations. However, one study found that transgender men on testosterone undecanoate depot injections had lower erythrocytosis rates that those on gels or intermediate-acting IM testosterone ester s(9.2% Hct >50% vs 12.8% and 15.9%, respectively), emphasising the relatively greater importance of the overall area-under-curve dose over the actual mode of delivery (54).
Conclusion
When testosterone is started for a verified diagnosis of pathological hypogonadism, it is anticipated to be continued lifelong under most circumstances. By properly monitoring treatment, adjusting the dose or dose-interval accordingly, collaboratively addressing other risk factors, it should usually be possible to avoid inducing erythrocytosis in the first place. When erythrocytosis does occur, then this can usually be addressed by following the same paradigm, rather than complete interruption of treatment. On the positive side, testosterone therapy in combination with SGLT2i potentially represents a cheaper and safer alternative to ESAs in men with advanced CKD and PH (which is likely underdiagnosed). Given the significant risks and uncertain benefits of conventional bone-specific drugs in men with advanced CKD, this may be especially important for those men with associated osteoporosis (61).
* Repeated venesection can lead to decreased tissue oxygen pressure (pO2) and depletion of iron stores; factors which activate biological pathways that may paradoxically promote the risk of thrombosis (43).
* Therefore, venesection should not be considered as a primary treatment for non-clonal erythrocytosis. Instead, the management of both absolute and relative forms should primarily focuses on lifestyle adjustments: quitting smoking, moderating alcohol and achieving weight loss; treating the associated hypertension relatively aggressively with vasodilator drugs rather than diuretics so as to expand the plasma volume (46), and identifying and treating primary respiratory conditions such as OSA (43). Venesection is thus only considered as a last resort, reserved for only the most severe cases of erythrocytosis and when there are no alternatives, e.g. Hct >0.52 in hereditary or clonal erythrocytosis or >0.56 in COPD (47) .
* Hct is a better indicator of RCM than the haemoglobin (Hb) level, which is slightly more influenced by the state of hydration (26).
* There is also a dose- and serum level-dependent increase in Hct and Hb with testosterone treatment that is observed in both hypogonadal and transgender males (27, 49, 50). Thus, whilst stimulation of erythropoiesis by testosterone can benefit anaemia, it can also become an adverse effect when there is overshoot resulting in erythrocytosis. Although assessing Hct is arguably the most important aspect of therapeutic monitoring, the risk of thrombosis is more significantly impacted by other vascular risk factors, such as family history, smoking, diabetes mellitus, body mass index (BMI), hypertension, dyslipidaemia and fibrinogen levels (26, 42).
* In cases of clinically significant erythrocytosis with no other risk factors to address (smoking, obesity, hypertension, sleep apnoea, etc), it is recommended to reduce the testosterone dose and/or switch to transdermal formulations. However, one study found that transgender men on testosterone undecanoate depot injections had lower erythrocytosis rates that those on gels or intermediate-acting IM testosterone esters (9.2% Hct >50% vs 12.8% and 15.9%, respectively), emphasising the relatively greater importance of the overall area-under-curve dose over the actual mode of delivery (54).
* By properly monitoring treatment, adjusting the dose or dose-interval accordingly, collaboratively addressing other risk factors, it should usually be possible to avoid inducing erythrocytosis in the first place. When erythrocytosis does occur, then this can usually be addressed by following the same paradigm, rather than complete interruption of treatment.
Figure. 1. Regulation of Erythropoiesis. EPO is the main regulator of erythropoiesis, and its transcription depends on tissue O2 levels. In normoxia, HIF2α is hydroxylated, binds to pVHL and is subsequently targeted for proteasomal degradation. In hypoxia, this degradation is decreased, allowing HIF2α to dimerize with HIF2b and promotes EPO gene transcription. EPO is primarily produced by renal peritubular interstitial fibroblast and stimulates red blood cells production in the bone marrow. In addition to regulation EPO, HIF2α also enhances iron absorption by upregulating DCYTB (enzyme that convert Fe3+ in Fe2+) and DMT1 (facilitates Fe2+uptake into cytoplasm). Iron is then exported into the bloodstream through ferroportin. EPO indirectly promotes ferroportin activity by suppressing hepcidin, a key negative regulator of iron efflux. DCYTB: duodenal cytochrome b; DMT1: divalentmetal transporter 1.EPO: erythropoietin; Fe3+: ferric iron Fe2+: ferrous iron; HIF2α: Hypoxia-inducible factor alpha; HIF2β: Hypoxia-inducible factor beta; HRE: hypoxia response element; O2: oxygen molecule; OH: hydroxyl group; PHD: prolylhydroxylase domain pVHL: von Hippel–Lindau tumour suppressor protein.\
Abstract
Testosterone is the cornerstone therapy for men with hypogonadism, and also treats any associated anaemia by promoting erythropoiesis. However, excessive doses cause erythrocytosis (raised red cell mass), especially if other risk factors are present. Erythrocytosis is associated with arterial and venous thrombosis in population studies.Testosterone is now increasingly prescribed to older men with functional hypogonadism and obesity, hypertension or type 2 diabetes; who are anyway at higher risk of both erythrocytosis and thrombosis. Although short–medium term testosterone treatment in these men was not associated with adverse cardiovascular outcomes, there were more cases of pulmonary embolism.
Originally envisaged as purely oral hypoglycaemic drugs, Sodium glucose cotransporter 2 inhibitors (SGLT2i) are now increasingly prescribed in chronic kidney disease, ischaemic heart disease and left ventricular impairment, irrespective of glycaemia, and the likelihood of co-prescription with testosterone is thus increased considerably. Crucially, they also increase haematocrit by promoting haematopoiesis.
This review focuses on the current best evidence for managing erythrocytosis, in the context of more prevalent obesity and prescriptions of testosterone and SGLT2i in this population. It highlights the need to balance the metabolic and therapeutic benefits against the potential risks. Management strategies include re-evaluating the original treatment indication, addressing modifiable risk factors, switching to transdermal testosterone and/or reducing the testosterone dose. Venesection is not recommended except for clonal erythrocytosis, due to its potential pro-thrombotic effects. However,combination therapy with testosterone and SGLT2s in men with anaemia of advanced CKD could augment, or even partly supersede, expensive treatment with conventional erythrocytosis-stimulating agents.
Introduction
This review aims to inform Endocrinologists about the physiology of erythropoiesis and mhow many of the various regulatory pathways are modulated by testosterone, which can lead to challenges managing patients who develop erythrocytosis on testosterone treatment. Although there are few data to directly link testosterone treatment with thrombosis, it is clear from general population studies that a higher haematocrit isassociated with a greater rate of thrombosis, even after adjusting for other risk factors. We particularly focus on older men with metabolic syndrome and related secondary hypogonadism, who are anyway at higher risk of both thrombosis and testosterone induced erythrocytosis. We discuss the expanding role for sodium-glucose cotransporter 2 inhibitor drugs (SGLT2i) in this population; highlighting the increasing likelihood of overlapping treatment with both testosterone and SGLT2i in these patients. We also describe the mechanisms that underpin the actions of testosterone and SGLT2Is in promoting erythropoiesis and, given the increasing likelihood of patients receiving both drugs at the same time, we sign post clinicians to effective strategies for managing medication-induced erythrocytosis based on best evidence.
* Male hypogonadism and its relationship to obesity and metabolic syndrome
* Testosterone treatment of obesity-associated functional hypogonadism
* Sodium-glucose co-transporter 2 inhibitors (SGLT2i)
* Haematopoiesis: physiology and pathology
Regulatory mechanisms underpinning erythropoeisis (see also Fig 1)
Erythropoiesis is the process of red blood cell production, primarily occurring in the bone marrow, which is regulated by erythropoietin (EPO), a glycoprotein hormone synthetized mainly in the kidney by peritubular interstitial fibroblasts and, to a lesser extent, by hepatocytes. EPO secretion is upregulated in response to systemic hypoxia, ensuring adequate oxygen delivery by increasing red cell mass (RCM). Hypoxia inducible factors (HIFs), especially HIF2, play a central role in the regulation of EPO production and are also crucial for intestinal iron absorption and the maturation and proliferation of erythroid progenitor cells.
Under normoxic conditions, HIF action is inhibited by von Hippel–Lindau tumour suppressor protein (pVHL), which targets HIFα subunits for polyubiquitination and proteasomal degradation. A necessary condition for the binding between HIF and pVHL is the hydroxylation of a specific proline residue of HIF, an oxygen-dependent process. Under hypoxic conditions, the activities of hydrolyzation and degradation of HIF2a are reduced, enabling the HIF complex to upregulate transcription of EPO and thus increase RBC production.
The stimulation of erythropoiesis increases iron demand in the bone marrow, and HIF2 plays a central role in iron uptake and its utilization acting directly on divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB). DMT1 normally transports iron into cells cytoplasm, while DCYTB reduces ferric iron (Fe³⁺) into ferrous form (Fe2+) facilitating iron uptake from the gut lumen into intestinal cells via DMT1. Additionally, EPO inhibits synthesis of hepcidin, a hepatocyte-derived negative regulator of iron absorption, allowing increased iron transport through ferroportin, the main extracellular iron transporter (24, 25).
Hct is a better indicator of RCM than the haemoglobin (Hb) level, which is slightly more influenced by the state of hydration (26). Hct was traditionally determined through centrifugation, but is presently estimated by automated analysers through bioimpedance analysis or laser flow cytometry. Different analysers and reagents produce different values for Hct subject to calibration by reference samples from a healthy local normal population. Accordingly, the upper limit of normality for male Hct from an accredited laboratory may range from 0.48 to 0.54, depending on how these factors combine, but will most commonly lie between 0.50 and 0.52
* Physiological roles of testosterone in promoting erythropoiesis (see also Fig 2)
In addition to prolonging RBC lifespan (7), androgens have various other effects on the hematopoietic system, including promoting the differentiation of bone marrow hematopoietic stem cells into EPO-responsive cells (27). However, the major pathway promoting RBC synthesis is enhanced iron utilization. Testosterone increases iron availability by suppressing hepcidin secretion by hepatocytes, which allows ferroport into facilitate intestinal iron absorption. Increased iron utilization for Hb synthesis is indicated by higher serum levels of soluble transferrin receptor (sTR) and lower levels of ferritin. T also enhances the sensitivity of erythroid progenitor cells to EPO and stimulates renal EPO secretion leading to an initial rise in circulating EPO levels. Although EPO concentrations return to baseline within six months of starting testosterone treatment, they nevertheless remain comparatively elevated in relation to the new higher Hb and Hct values, suggesting a recalibration of the EPO set point toa higher level in accordance with the new Hb concentration (28, 29)
Conversely, a decline in T levels leads to reduced erythropoietic activity, with both hypogonadism and androgen deprivation are associated with lower Hct levels, potentially leading to anaemia, especially in older men. The pattern of Hb decline with androgen-deprivation parallels that of serum T, with a rapid decrease at the initiation of suppression. (30, 31). Since oestrogens do not impact on erythropoietic parameters,this action of testosterone is necessarily independent of aromatization (30). Supporting the oestrogen-independent action of testosterone on haematopoiesis are the physiological divergence in male and female Hb values from puberty onwards (7); the absence of anaemia in men with rare genetic aromatase deficiency, and the observation that treatment with an aromatas inhibitors can cause erythrocytosist hrough increased T levels, as a result of reduced oestradiol-mediated negativefeed back on gonadotropin secretion (32).
* SGLT2i and erythropoiesis (see also Fig 3)
* Erythrocytosis: subtypes, mechanisms and risks
* Is venesection a reasonable treatment for non-clonal erythrocytosis?
Regular venesection is a straightforward technique that quickly reduces Hb and Hct to reference levels and, in JAK2-positive or clonal erythrocytosis, there is good evidence for its safety and efficacy in mitigating the risk of thromboembolic disease. However, in respect of non-clonal erythrocytosis, where the risk of thrombosis is anyway much lower and there is also potential for addressing the predisposing factors, a deeper dive into the evidence becomes necessary.
Repeated venesection can lead to decreased tissue oxygen pressure (pO2) and depletion of iron stores; factors which activate biological pathways that may paradoxically promote the risk of thrombosis (43). Indeed, in an observational study of SGLT2i-associated erythrocytosis, thrombosis rates were higher among patients who underwent phlebotomy: 21% (6/29) versus 6% (4/71) (33, 44). A similar pattern was observed in Chuvash erythrocytosis, a congenital disorder where the thrombotic risk i slargely independent of Hct and the rate of thrombosis is increased by venesection (45).
Therefore, venesection should not be considered as a primary treatment for non-clonal erythrocytosis. Instead, the management of both absolute and relative forms should primarily focuses on lifestyle adjustments: quitting smoking, moderating alcohol and achieving weight loss; treating the associated hypertension relatively aggressively with vasodilator drugs rather than diuretics so as to expand the plasma volume (46), and identifying and treating primary respiratory conditions such as OSA (43). Venesection is thus only considered as a last resort, reserved for only the most severe cases oferythrocytosis and when there are no alternatives, e.g. Hct >0.52 in hereditary or clonal erythrocytosis or >0.56 in COPD (47) .
* Testosterone treatment: physiology and clinical implications
Physiological responses to testosterone treatmentI mprovements in sexual interest and energy level and resolution of vasomotor symptoms or mastalgia occur within 3‒6 weeks; increased erythropoiesis develops over 2‒3 months, and positive changes in lean body mass and bone density over 6‒12 months, with the benefits continuing to accumulate for at least another three years (1). However, the time needed for testosterone effects to become evident can vary significantly. For instance, in older individuals with erectile or ejaculatory dysfunctions,sexual improvements may take up to 6 months to appear (48).
There is also a dose- and serum level-dependent increase in Hct and Hb with testosterone treatment that is observed in both hypogonadal and transgender males(27, 49, 50). Thus, whilst stimulation of erythropoiesis by testosterone can benefit anaemia, it can also become an adverse effect when there is overshoot resulting inerythrocytosis. Although assessing Hct is arguably the most important aspect of therapeutic monitoring, the risk of thrombosis is more significantly impacted by other vascular risk factors, such as family history, smoking, diabetes mellitus, body mass index (BMI), hypertension, dyslipidaemia and fibrinogen levels (26, 42). In transmasculine people, in whom physiological increases in Hb and Hct with testosterone may appear pathological when plotted against female laboratory reference values, and it is suggested that haematological parameters should be evaluated on affirmed gender rather than the sex assigned at birth during hormone treatment (50).
Although older men are more prone to anaemia when hypogonadal, they are at the same time at greater risk of developing androgen-induced erythrocytosis (27, 51). Hence, testosterone therapy is not generally recommended if baseline Hct approaches or exceeds 50%; indeed, such high levels should lead one to seriously question the original diagnosis of hypogonadism (1). Conversely, in older patients with functional CH and anaemia, testosterone treatment corrected baseline anaemia in 40‒60% of cases, irrespective of whether another cause of anaemia was identified. These men also experienced improvements in energy and vitality that were not observed in the generality of study patients (49, 52).
In relation to the direct effects of testosterone treatment on blood pressure, oral preparations may cause a very small increase (53), with other formulations not showing any increase at physiological doses.
\
* Testosterone formulations and their relationship to the haematocrit
Long-acting testosterone undecanoate IM injections maintain more stable serum testosterone levels compared to shorter-acting one, avoiding peaks. In contrast, short acting testosterone IM injections cause greater fluctuations in T levels, with rapid supraphysiological peaks shortly after injection, followed by a drop to low levels jus tprior to the next injection. These fluctuations appear to be associated with an increased risk of erythrocytosis. Transdermal formulations achieve more stable levels and, potentially, a lower overall area-under-curve serum T concentration (1, 54). In cases of clinically significant erythrocytosis with no other risk factors to address (smoking, obesity, hypertension, sleep apnoea, etc), it is recommended to reduce the testosterone dose and/or switch to transdermal formulations. However, one study found that transgender men on testosterone undecanoate depot injections had lower erythrocytosis rates that those on gels or intermediate-acting IM testosterone ester s(9.2% Hct >50% vs 12.8% and 15.9%, respectively), emphasising the relatively greater importance of the overall area-under-curve dose over the actual mode of delivery (54).
Conclusion
When testosterone is started for a verified diagnosis of pathological hypogonadism, it is anticipated to be continued lifelong under most circumstances. By properly monitoring treatment, adjusting the dose or dose-interval accordingly, collaboratively addressing other risk factors, it should usually be possible to avoid inducing erythrocytosis in the first place. When erythrocytosis does occur, then this can usually be addressed by following the same paradigm, rather than complete interruption of treatment. On the positive side, testosterone therapy in combination with SGLT2i potentially represents a cheaper and safer alternative to ESAs in men with advanced CKD and PH (which is likely underdiagnosed). Given the significant risks and uncertain benefits of conventional bone-specific drugs in men with advanced CKD, this may be especially important for those men with associated osteoporosis (61).
