Is menopause replacement therapy with estradiol (E2) patch, oral progesterone (PG), and low-dose topical testosterone (T) correlated with new onset mild retinal hemorrhages?

Menopause Replacement Therapy and Retinal Hemorrhages

There is evidence that hormone replacement therapy (HRT) may be associated with retinal vascular events, including retinal hemorrhages, due to its thrombotic effects. 1

Mechanism and Evidence

The FDA drug label for progesterone explicitly mentions retinal vascular thrombosis as a potential adverse effect of estrogen plus progestin therapy 1. The label states: "Retinal vascular thrombosis has been reported in patients receiving estrogen. Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine."

Recent evidence supports this connection:

• A 2023 case report documented branch retinal vein occlusion in a transgender woman using transdermal estradiol gel 2. The authors concluded that "RVO is a complication that must be taken into account by clinicians" when prescribing HRT.

• The thrombotic risk appears to be related to the route of administration and formulation of HRT:

  • Oral estrogen therapy carries a significantly higher risk of venous thromboembolism compared to transdermal delivery (RR 1.63; 95% CI, 1.40-1.90) 3
  • This increased thrombotic risk may extend to the retinal vasculature

Risk Factors and Considerations

The risk of vascular events with HRT is influenced by several factors:

1. Route of administration: Transdermal estradiol (as in your regimen) has a lower thrombotic risk than oral formulations 4, 3

2. Age and time since menopause: Women ≥60 years or >10 years post-menopause have increased vascular risk with estrogen-containing therapy 4

3. Combined therapy: The addition of progesterone (as in your regimen) may further modify vascular risk 5

4. Dose: Higher doses increase risk, with guidelines recommending the lowest effective dose for the shortest duration 4

Clinical Implications

For a patient presenting with new-onset mild retinal hemorrhages while on HRT with estradiol patch, oral progesterone, and low-dose topical testosterone:

• The retinal hemorrhages may be causally related to the hormone therapy, particularly through thrombotic mechanisms 1, 2

• While transdermal estradiol carries lower thrombotic risk than oral formulations 3, it still poses some risk of vascular events

• The addition of testosterone to estrogen therapy has not been well-studied regarding retinal vascular effects, but may potentially compound thrombotic risk

Management Recommendations

1. Immediate ophthalmologic evaluation is essential to assess the extent and progression of the retinal hemorrhages 1

2. Consider temporary discontinuation of HRT pending ophthalmologic assessment, especially if vision changes occur 1

3. If HRT must be continued for severe menopausal symptoms:

   • Consider reducing the estradiol dose to the minimum effective level 4
   • Maintain the transdermal route rather than switching to oral administration 3
   • Evaluate the necessity of the testosterone component

4. Monitor closely for progression of retinal hemorrhages or development of other vascular complications

Prevention and Monitoring

For patients on HRT:

• Regular eye examinations should be part of routine follow-up
• Patients should be educated about reporting visual symptoms promptly
• Consider additional vascular risk factor modification (smoking cessation, blood pressure control)

While some studies suggest HRT may have beneficial effects on retinal blood flow 6, the evidence for retinal hemorrhage risk from the FDA label 1 and case reports 2 should take precedence when considering safety.