How does estradiol (estrogen) affect hematocrit levels in men and women?

Effects of Estradiol on Hematocrit Levels in Men and Women

Estradiol has opposing effects on hematocrit levels between sexes, with higher estradiol levels associated with decreased hematocrit in men but potentially increased hematocrit in women through complex mechanisms involving erythropoietin inhibition and hemodilution. 1

Sex-Specific Effects of Estradiol on Hematocrit

Effects in Men

• Estradiol acts as an erythropoietin (EPO) inhibitor, leading to decreased red blood cell production in men 1
• Men with high total and free estradiol levels have been associated with higher hematocrit levels compared to men with normal estradiol levels 2
• Low free testosterone and high sex hormone-binding globulin (SHBG) levels are associated with lower hematocrit in men, highlighting the complex interplay between sex hormones 2

Effects in Women

• Women naturally have lower hematocrit levels than men due to higher estradiol levels 1
• Estradiol can cause hemodilution through increased plasma volume via oncotic pressure mechanisms, resulting in lower erythrocyte counts, hemoglobin, and hematocrit 3
• During the menstrual cycle, the approximately ten-fold change in estradiol levels can alter erythropoietic responses 1

Transgender Hormone Therapy and Hematocrit Changes

Transfeminine Individuals (Assigned Male at Birth)

• Estradiol therapy in transgender women causes a significant decrease in hematocrit levels, with most changes occurring within the first 3 months of treatment 4
• After 3 months of gender-affirming hormone therapy, hematocrit drops by approximately 4.1% in transgender women 4
• Hematocrit levels typically stabilize within the female reference range after 6 months of estradiol therapy 1

Transmasculine Individuals (Assigned Female at Birth)

• Testosterone therapy in transgender men increases hematocrit by approximately 4.9% during the first year of treatment 4
• The most pronounced increase (2.7%) occurs during the first 3 months of testosterone therapy 4
• About 11.5% of transgender men develop hematocrit levels ≥50.0% during testosterone treatment 4
• The type of testosterone formulation affects the magnitude of hematocrit increase, with testosterone esters causing larger increases than testosterone undecanoate 4

Clinical Implications and Monitoring

Thrombotic Risk

• Estradiol therapy, particularly oral formulations, increases risk of venous thromboembolism through multiple prothrombotic mechanisms 5, 6
• Estradiol affects multiple hemostatic pathways in a prothrombotic direction, increasing factor VII activity, D-dimer, and prothrombin F1.2, while decreasing anti-thrombin III and tissue plasminogen activator 6
• Recent research shows estradiol provokes a hypercoagulable phenotype, affecting clot formation time, strength, and fibrinolysis 7

Laboratory Monitoring

• For transgender individuals on hormone therapy for ≥12 months, hematocrit should be interpreted using reference ranges for their affirmed gender 1
• If hormone therapy has been stopped for ≥3 months, interpret hematocrit with reference range for sex assigned at birth 1
• Regular monitoring of hematocrit is recommended for individuals on gender-affirming hormone therapy, particularly during the first year 5

Special Considerations

• Combined estrogen-progestin therapy further increases thrombotic risk by 2-3 fold compared to non-users 6
• Individuals with prothrombotic genetic variants (Factor V Leiden, prothrombin 20210A) have significantly higher thrombosis risk when taking estrogen 1, 6
• Transdermal estradiol formulations have lower thrombotic risk compared to oral formulations due to avoiding first-pass hepatic metabolism 5

Pathophysiological Mechanisms

• Estradiol inhibits erythropoietin production, which is a key hormone in red blood cell production 1
• Testosterone promotes erythropoietin production, explaining the higher baseline hematocrit in men 1
• Estradiol increases plasma volume, leading to hemodilution and consequently lower hematocrit 3
• Estradiol and progesterone may have protective effects against oxidative damage, influencing sex differences in hypoxia tolerance and hematological adaptations 1

Understanding these sex-specific effects of estradiol on hematocrit is crucial for clinical management, particularly in hormone therapy for transgender individuals and when evaluating anemia or polycythemia risk in all patients.