Does estriol (estrogen) or estradiol (estrogen) cream increase the risk of uterine fibroids?

Estrogen Creams and Uterine Fibroid Risk

Topical estrogen creams (estriol or estradiol) likely increase the risk of uterine fibroid growth in susceptible women, as estrogen is a key driver of fibroid development and growth. 1

Hormonal Influence on Fibroid Pathophysiology

Uterine fibroids (leiomyomas) are extremely common benign tumors affecting up to 80% of women by age 50. Their growth and development are strongly influenced by sex hormones, particularly:

• Estrogen: Traditionally considered the primary driver of fibroid growth
• Progesterone: More recently recognized as equally critical for fibroid cellular proliferation 1

Key evidence supporting estrogen's role in fibroid pathophysiology:

• No prepubertal cases of fibroids have been documented in medical literature
• Fibroids typically regress after menopause when estrogen levels decline
• Women using estrogen-only hormone replacement therapy have shown a significantly increased risk of uterine fibroids:
  • 6-fold increased risk of fibroids requiring hospitalization compared to never-users
  • 1.9 times greater risk of surgically confirmed fibroids among ever-users
  • Dose-response relationship observed with 8+ years of use associated with higher risk (RR = 2.3) 1

Mechanism of Action

Estrogen affects fibroid growth through multiple pathways:

1. Genomic pathways - Direct and indirect effects on gene expression
2. Non-genomic pathways - Including Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR signaling cascades 2

Fibroids express elevated levels of both estrogen receptor subtypes (ER-α and ER-β) compared to surrounding normal myometrium, making them particularly sensitive to estrogen exposure 2, 3.

Topical Estrogen Considerations

While most research has focused on systemic hormone therapy, topical estrogen creams (estriol/estradiol) applied to vaginal tissue can be absorbed systemically, though typically in lower concentrations than oral formulations. Research specifically on topical estrogen and fibroids is limited, but:

• A 2018 literature review found variable effects of hormone therapy on asymptomatic fibroids in menopausal women
• Some studies demonstrated increased size of pre-existing fibroids and formation of new fibroids with hormone therapy 4

Risk Assessment Before Prescribing

Before initiating topical estrogen therapy in women with known or suspected fibroids:

• Consider measuring the pulsatility index of uterine arteries as a potential screening tool
• Low resistance index in uterine arteries is associated with increased risk of fibroid growth during hormone therapy 4

Alternative Approaches

For women with symptomatic fibroids needing vaginal estrogen for atrophy:

1. Selective Estrogen Receptor Modulators (SERMs) - May have a more favorable profile for women with fibroids, though evidence for their effectiveness in treating fibroids is inconsistent 4, 5

2. Selective Progesterone Receptor Modulators (SPRMs) - Newer agents like ulipristal acetate have shown promise for fibroid treatment, though some have hepatotoxicity concerns 1

3. GnRH Agonists/Antagonists - Effective at reducing fibroid volume but associated with hypoestrogenic side effects 1

Clinical Implications

• Monitor women with known fibroids who use topical estrogen for potential fibroid growth
• Consider lower doses of topical estrogen when treatment is necessary
• Be particularly cautious with long-term use (>8 years) given the potential dose-response relationship
• Regular ultrasound monitoring may be warranted for women with significant fibroids who require topical estrogen therapy

Conclusion

While direct evidence specifically addressing topical estrogen creams and fibroid growth is limited, the established relationship between estrogen exposure and fibroid growth suggests caution is warranted. The risk-benefit ratio should be carefully evaluated, particularly for long-term use.