Background: Estrogen and Anterior Cruciate Ligament Tears
Epidemiology of Sex Disparities in ACL Injury
Female athletes sustain ACL injuries at rates two to eight times higher than their male counterparts participating in the same sports, with an estimated 38,000 women suffering ACL tears annually in the United States 1, 2. This striking sex disparity emerges during and following puberty, when male and female neuromuscular patterns begin to diverge 1. The incidence of non-contact ACL injuries peaks in athletes aged 15 to 40 years who participate in pivoting sports such as soccer, handball, volleyball, and alpine skiing, with approximately 3% of amateur athletes and up to 15% of elite athletes sustaining ACL injuries each year 1.
The majority of ACL injuries in female athletes occur through non-contact mechanisms, most commonly during deceleration activities such as landing from a jump or cutting maneuvers 2. This pattern suggests that intrinsic biological factors, rather than external trauma alone, play a critical role in the pathogenesis of ACL rupture in women.
Hormonal Influence on ACL Injury Risk
Menstrual Cycle Phase and Injury Timing
Hormonal fluctuations during the menstrual cycle appear to significantly influence ACL injury risk, with a disproportionately high percentage of injuries occurring during the ovulatory (midcycle) phase when estrogen levels peak 3. In a prospective study of 69 female athletes who sustained acute ACL injuries, hormone assays confirmed that women experienced significantly more ACL tears during the ovulatory phase and fewer injuries during the luteal phase of the menstrual cycle 3. Notably, oral contraceptive use diminished this association between ACL tear distribution and the ovulatory phase, suggesting that stabilizing hormone levels may reduce injury risk 3.
Biomechanical Effects of Estrogen on Ligament Tissue
Estrogen exerts direct effects on ligament mechanical properties through multiple mechanisms. High serum estrogen levels correlate with decreased ultimate tensile stress and linear stiffness of ACL tissue, as demonstrated in controlled animal studies where rabbits with elevated estrogen levels (231 pg/mL) showed significantly reduced ligament mechanical strength compared to those with moderate levels (60 pg/mL) 4. This dose-dependent relationship suggests a threshold effect whereby physiologically high estrogen concentrations compromise ligament integrity.
At the cellular level, estrogen inhibits lysyl oxidase activity, the enzyme responsible for collagen cross-linking, thereby reducing ligament mechanical function without necessarily decreasing total collagen content 5. In engineered ligament models using human ACL fibroblasts, exposure to high estrogen (500 pg/mL) for 48 hours resulted in a 76.9% decrease in lysyl oxidase activity 5. When engineered ligaments were subjected to a simulated menstrual cycle pattern—12 days of low estrogen followed by 2 days of physiologically high estrogen—mechanical stiffness decreased significantly despite unchanged collagen levels 5. This finding suggests that the acute rise in estrogen during the follicular phase may transiently weaken ligament tissue, creating a window of vulnerability for injury.
Gene Expression and Extracellular Matrix Regulation
The combined effects of estrogen and mechanical loading uniquely suppress the expression of critical extracellular matrix components in ACL fibroblasts 6. While cyclic tensile loading alone increases collagen type I expression and estrogen alone increases collagen types I and III expression, the combination of estrogen and mechanical loading—conditions specific to female athletes during sports participation—inhibits messenger RNA expression of collagen types I and III as well as biglycan 6. This paradoxical suppression of matrix biosynthesis under combined hormonal and mechanical stress may explain why female athletes are particularly vulnerable during high-demand athletic activities when estrogen levels are elevated.
Clinical Implications and Long-Term Consequences
ACL injuries carry substantial long-term morbidity beyond the acute injury. Without adequate treatment, ACL-deficient knees face increased risk of persistent instability, additional meniscal injury, progressive cartilage damage, and elevated risk of contralateral ACL tear, as noted by the American Academy of Orthopaedic Surgeons 7. The risk for additional cartilage and meniscus damage begins rising within 3 months of ACL rupture, making timely treatment decisions critical for joint preservation 7. Even with successful surgical reconstruction, patients with ACL tears have an increased long-term risk of developing knee osteoarthritis 8.
Understanding the hormonal contribution to ACL injury risk in female athletes is essential for developing targeted prevention strategies and optimizing the timing of return to sport after injury or reconstruction.