Does oral or rectal progesterone affect the risk of deep vein thrombosis (DVT) in trans women using intramuscular (IM) estradiol?

Progesterone's Effect on DVT Risk in Trans Women Using IM Estradiol

Both oral and rectal progesterone likely increase the risk of deep vein thrombosis (DVT) in transgender women using intramuscular estradiol, though the evidence specifically addressing this combination is limited. 1

Understanding the Risk Factors

Transgender women using gender-affirming hormone therapy (GAHT) already face an elevated risk of venous thromboembolism (VTE) due to estrogen's prothrombotic effects. The addition of progestins may further compound this risk:

• Estrogen therapy alone increases thrombosis risk in transgender women 1
• When progestins are combined with estrogens, there is an increased risk of cardiovascular risk factors 1
• Research shows that adding progestins to estrogen therapy increases VTE risk compared to estrogen alone 2

Route of Administration Considerations

The route of administration significantly impacts thrombotic risk:

• Intramuscular estradiol: Generally has lower thrombotic risk than oral estrogen formulations 3
• Oral progesterone: Likely increases VTE risk through first-pass hepatic metabolism effects on coagulation factors 1
• Rectal progesterone: While sometimes assumed to bypass first-pass metabolism, evidence suggests that any systemic progesterone absorption may still impact coagulation factors 1, 4

Evidence on Progesterone and Thrombosis

While specific studies on progesterone's DVT risk in transgender women using IM estradiol are lacking, we can extrapolate from related evidence:

• Progestogens combined with estrogens increase cardiovascular risk factors and breast cancer risk 1
• Different progestogens have varying impacts on thrombotic risk:
  • Medroxyprogesterone acetate shows deleterious effects on VTE risk 2
  • Micronized progesterone (which is commonly used orally or rectally) may have a better safety profile but still carries risk 2
• The Endocrine Society does not recommend progestins for transgender women due to thromboembolism risk 1

Clinical Decision Algorithm

For transgender women using IM estradiol who are considering progesterone:

1. Assess baseline VTE risk factors:

   • Age (risk increases with age) 1
   • Smoking status
   • BMI ≥30 kg/m²
   • Personal or family history of VTE
   • Known thrombophilia
   • Immobility or recent surgery

2. Consider route of administration:

   • If progesterone is deemed necessary, transdermal routes of estrogen have shown significantly lower VTE risk (OR 0.9) compared to oral routes (OR 4.2) 1
   • Neither oral nor rectal progesterone can be recommended as completely safe options

3. Monitor for DVT symptoms if progesterone is added:

   • Leg pain or tenderness
   • Swelling
   • Warmth or redness

Important Caveats

• The first year of hormone therapy carries the highest VTE risk 4
• The combination of risk factors (age, obesity, smoking) with hormone therapy exponentially increases thrombosis risk 4
• The benefits of gender-affirming hormone therapy for transgender women must be weighed against potential thrombotic risks 5
• Regular follow-up monitoring is essential when using any hormone therapy 5

While some transgender women seek progesterone for potential feminization and breast development effects, evidence suggests limited benefit, with some patients discontinuing use due to absence of measurable effects or mood changes 1.