Is estriol effective as a treatment for multiple sclerosis (MS)?

Estriol as a Treatment for Multiple Sclerosis: Current Evidence and Recommendations

Based on the available evidence, estriol shows promise as a treatment for multiple sclerosis, particularly in women, with demonstrated reductions in relapse rates and markers of neurodegeneration, but it is not yet recommended as a standard treatment pending phase 3 trial results.

Mechanism of Action and Rationale

Estriol is a pregnancy estrogen that has gained interest in MS treatment based on several observations:

• The protective effects of pregnancy in MS patients, when estriol levels naturally increase 1
• Estriol binds to estrogen receptor beta (ERβ), which mediates neuroprotective effects 2
• It has dual mechanisms of action:
  • Immunomodulatory effects that reduce inflammation
  • Direct neuroprotective properties that may address both inflammatory and neurodegenerative components of MS 1

Clinical Evidence for Estriol in MS

Phase 2 Trial Results

The most significant clinical evidence comes from a randomized, double-blind, placebo-controlled phase 2 trial of estriol combined with glatiramer acetate in women with relapsing-remitting MS 3:

• 164 women with relapsing-remitting MS were enrolled
• Treatment: Daily oral estriol (8 mg) plus glatiramer acetate 20 mg vs. placebo plus glatiramer acetate
• Results:
  • Annualized relapse rate: 0.25 in estriol group vs. 0.37 in placebo group (rate ratio 0.63, p=0.077)
  • The treatment met the trial's criteria for reducing relapse rates
  • Treatment was well-tolerated over 24 months

Biomarker Evidence

A subsequent analysis showed that estriol treatment reduced serum neurofilament light chain levels, a biomarker of neurodegeneration in MS 4:

• Oral estriol at 8 mg (inducing mid-pregnancy blood levels) reduced this marker of neuro-axonal injury
• This supports estriol's potential neuroprotective effects in MS

Safety Profile

In the phase 2 trial 3:

• Serious adverse events were similar between estriol and placebo groups (10% vs. 13%)
• Irregular menses were more common with estriol (23% vs. 4%, p=0.0005)
• Vaginal infections were less common with estriol (1% vs. 11%, p=0.0117)
• No differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness

Current Status in Treatment Guidelines

Current guidelines and consensus statements do not yet include estriol as a recommended treatment for MS:

• The ECTRIMS and EBMT consensus statement focuses on autologous hematopoietic stem cell transplantation (AHSCT) for MS treatment, with no mention of estriol 5
• Other guidelines focus on established disease-modifying therapies, rehabilitation approaches, and nutritional aspects of MS management 5
• Modafinil is suggested for treatment of hypersomnia secondary to MS, but this addresses a specific symptom rather than the underlying disease process 5

Limitations and Future Directions

Despite promising results, several limitations exist:

• Phase 3 trials are still needed to confirm efficacy and safety 6
• Current evidence is primarily in women with relapsing-remitting MS
• Long-term safety data beyond 24 months is limited
• Optimal dosing and potential combination therapies need further investigation

Practical Recommendations

Based on the current evidence:

1. For women with relapsing-remitting MS who have inadequate response to first-line therapies:

   • Consider discussing estriol as an experimental add-on therapy
   • Emphasize that it is not yet FDA-approved for MS treatment
   • Ideally, refer to centers conducting clinical trials of estriol

2. For clinicians considering estriol:

   • The dose used in clinical trials was 8 mg daily oral estriol
   • Monitor for menstrual irregularities as the most common side effect
   • Regular gynecological follow-up is advisable

3. For research priorities:

   • Phase 3 trials are urgently needed to confirm efficacy
   • Investigation of estriol as an add-on to other disease-modifying therapies
   • Studies examining long-term safety and efficacy beyond 24 months

Conclusion

While estriol shows promise as a treatment for MS with both immunomodulatory and neuroprotective properties, it remains an investigational therapy pending phase 3 trial results. The available evidence suggests it may be particularly beneficial as an add-on therapy for women with relapsing-remitting MS, with a favorable safety profile and potential to address both inflammatory and neurodegenerative aspects of the disease.