Health & Medical Menopause health

Estrogen Alone and Joint Symptoms

Estrogen Alone and Joint Symptoms


In the present post hoc analyses in a randomized clinical trial setting, statistically significantly fewer women in the estrogen-alone group compared with the placebo group had joint pain after 1 year and 3 years. In adherence-adjusted analyses, stronger favorable associations with estrogen use and reduced joint pain are seen. Thus, in a randomized clinical trial, estrogen-alone use in postmenopausal women results in a modest but sustained and statistically significant reduction in joint pain. In contrast, joint swelling was more common in estrogen-alone group participants, but the findings were attenuated in adherence-adjusted analyses.

The current report expands on prior findings in this trial by including information on joint pain severity, joint swelling, and joint symptom severity, and by adding serial and adherence analyses. The statistically significant reduction in joint pain frequency in intention-to-treat analyses after 1 year on the study in the estrogen-alone group included all participants, whereas prior analyses excluded women with mild joint pain. In our review, no other randomized trial has described the influence of estrogen alone on joint symptoms. Although the reduction in joint pain score with estrogen-alone use was modest, it far exceeded the year-to-year increase in joint pain score seen in placebo group participants.

The apparent opposite effects of estrogen alone on joint pain (decrease) and joint swelling (increase) seem contradictory but may be related to the performance of the self-reported joint symptom measures. Self-reported joint pain has reasonable correlation with clinical and radiographic osteoarthritis measures. However, the relation between self-reported joint swelling and articular change has been questioned. Importantly, adherence-adjusted analyses strengthened the association of estrogen alone with reduced joint pain but attenuated its association with increased joint swelling.

Supportive findings for a favorable influence of estrogen-alone use on joint pain come from other prior analyses in this WHI randomized trial. Women who have had a hysterectomy and were randomized to estrogen alone had fewer cases of rheumatoid arthritis (25/5,076 vs 37/5,195 cases for estrogen alone vs placebo, respectively), but the difference was not statistically significant (hazard ratio, 0.69; 95% CI, 0.41-1.14; P = 0.149). Estrogen-alone users in the trial were also found to have significantly fewer hip and knee joint replacements (222/5,076 vs 269/5,195 cases for estrogen alone vs placebo, respectively; hazard ratio, 0.84; 95% CI, 0.70-1.00; P = 0.05). Given that arthroplasty due to osteoarthritis is generally indicated when pain can no longer be managed with pain medications, the findings support an association between estrogen-alone use and a lower frequency of joint symptoms.

In contrast to the findings in the WHI estrogen-alone trial, in the WHI estrogen plus progestin trial on women with an intact uterus, there was no association between combined hormone therapy use and arthroplasty frequency. This difference between the two WHI hormone trials reinforces the message that current findings are based on one regimen (conjugated equine estrogens 0.625 mg/d) alone in women who have had hysterectomy, and the results cannot be extrapolated to other hormone regimens or treatment durations.

Biological plausibility for an association between estrogen and joint pain is provided by clinical studies of estradiol and its metabolites and osteoarthritis risk. In a study of 842 premenopausal and perimenopausal women, women with radiographically defined osteoarthritis had estradiol concentrations in the lowest tertile (odds ratio, 1.88; 95% CI, 1.07-3.51) compared with women without osteoarthritis. More recently, significantly lower free estradiol levels were seen in both premenopausal and postmenopausal women with osteoarthritis compared with levels in healthy women.

Findings from observational studies examining relationships among joint problems (including arthritis) and menopausal hormone therapy have been mixed, and their heterogeneity with respect to outcome measures and study populations has precluded pooling. In a recent review, although insufficient information supporting strong conclusions was acknowledged, evidence was nonetheless supportive of an effect of endogenous and exogenous estrogen on joint health. Although further study is warranted, the current results, seen in a randomized clinical trial setting, support a moderate effect of exogenous estrogen on mitigating joint pain. Any consideration of estrogen use for this purpose must incorporate available information on the identified risks and benefits of menopausal hormone therapy, including the admonition to use the lowest dose for the shortest duration, consistent with the intended therapeutic goal.

Likely mechanisms mediating estrogen's influence on joint pain include reduction in inflammation markers and reduction in cartilage turnover as potential contributors to arthritis risk in both preclinical and clinical settings. In addition, if future studies could confirm associations among cartilage turnover, joint pain, and estrogen levels, a clinical model for more rapidly identifying potential intervention strategies for joint problems could result. Finally, both preclinical and clinical studies suggest that estrogens may modulate pain processing pathways.

The current findings are of utmost relevance to women with limiting climacteric symptoms near the beginning of menopause who have had hysterectomy and are considering estrogen-alone use. Recent follow-up and subgroup analyses from this WHI randomized trial evaluating estrogen alone indicate a favorable benefit/risk balance for estrogen use for about 5 years. A modest and favorable effect on joint symptoms represents one additional factor for women contemplating estrogen-alone use in this setting.

These findings also inform on aromatase inhibitor–associated joint symptoms. Aromatase inhibitors substantially lower circulatory estrogen levels and increase arthralgias. Exogenous estrogen’s reduction of joint pain frequency supports the concept that such arthralgias, at least in part, may be influenced by circulatory estrogen levels. Given the uncertainty regarding the potential influence of exogenous hormones on breast cancer recurrence, estrogen alone should not be used to treat joint symptoms arising from aromatase inhibitor use in women with resected breast cancer.

Study strengths include the large, well-characterized, ethnically diverse study population and serial joint symptom determination within the context of a randomized clinical trial, using a quantitative instrument that was prospectively applied. However, joint symptoms were not primary study endpoints, and the findings emerged from post hoc analyses. In addition, the joint pain and joint swelling scales used have not been compared with other instruments or formally validated.

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