Estradiol and its metabolites and their association with knee osteoarthritis

Osteoarthritis, which usually develops between the ages of 40 and 50, is more prevalent in women. It is thought that sex hormones may play a role in developing the disease, since they can be involved in inflammation of the tissues affected by it.

A study published in the August 2006 issue of Arthritis & Rheumatism examined estradiol, the primary estrogen in premenopausal and early perimenopausal women, along with two of the hormones into which it breaks down, to determine if their levels are associated with an increased risk of developing osteoarthritis (OA) in women.

Led by MaryFran R. Sowers of the University of Michigan in Ann Arbor, MI, the study included 842 premenopausal or perimenopausal women from the Southeast Michigan Arthritis Cohort. The women had annual X-rays of both knees along with analysis of blood levels of estradiol and urine levels of 2-hydroxyestrone and 16a-hydroxyestrone, two estrogen metabolites. Patients were also interviewed regarding pain, health, and lifestyle and were followed for three years. The results showed that the women who developed knee OA during the study period had greater odds of having estradiol concentrations and urinary 2-hydroxyestrone levels in the lowest third of the study population, and a higher ratio of 2-hydroxyestrone to 16a-hydroxyestrone, even after adjusting for other risk factors.

"Selected work with animal models provides support for the increased odds of developing OA with lower estradiol concentrations," the authors note. This is one of the few studies that has actually examined hormone concentrations, particularly in relation to new cases of OA, and the first to examine levels of estrogen metabolites. The authors hypothesize that the role of higher 2-hydroxyestrone concentrations in delaying the development of knee OA may be partially through the metabolism of arachidonic acid, a compound from which cells involved in inflammation (such as leukotrienes) are produced, since estrogen metabolites have been shown to play an important role in this pathway.

Previous studies have shown that altered patterns of estrogen metabolism are present in rheumatoid arthritis and systemic lupus erythematosus, suggesting an association with symptoms, such as pain and inflammation, as opposed to disease onset and progression due to structural changes. The authors note that although the 2-hydroxyestrone levels in those with knee OA were significantly lower than in those without the disease, "more detailed investigation is required to establish if primary pathways are associated with symptoms, duration of symptoms, symptom severity, or with response in cartilage and bone."

Given the strong associations of lower estradiol and 2-hydroxyestrone levels with more knee OA, the authors conclude: "If findings are confirmed, then this helps motivate new areas of investigation for intervention. If the mechanistic explanation of 2-hydroxyestrone levels lies, at least in part, in arachidonic acid metabolism associated with pain and inflammation rather than receptor binding, then considering alternative lifestyle and therapeutic pathways to influence these metabolites becomes increasingly viable."