Estrogen therapy in post-menopausal women appears to increase the risk of kidney stones, researchers reported.

Data from two large placebo-controlled trials — part of the Women’s Health Initiative program — showed that the annual rate of kidney stones in women getting estrogen was 39 per 10,000 women, according to Naim Maalouf, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

On the other hand, among women getting placebo in the two trials, the rate was 34 per 10,000 women per year, Maalouf and colleagues reported in the Oct. 11 issue of the Archives of Internal Medicine.

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Note that kidney stones are more common in men than women under the age of 50, but this discrepancy is much less prominent in older patients. That fact has led to the suggestion that estrogen is protective against the formation of kidney stones, in contrast to the findings in this study.

Note also that the type of kidney stone and the mechanism of stone formation in this study are unknown.

The concomitant use of progestin had no effect, the researchers found.

Kidney stones are common among postmenopausal women, affecting between 5% and 7% of the population in the U.S., the researchers noted. They are less common among pre-menopausal women than among men in the same age group, but the disparity lessens after menopause — an observation that has led to the suggestion that estrogen may play a protective role.

To clarify the issue, Maalouf and colleagues turned to two major trials that examined the impact of hormone therapy on women with and without a hysterectomy.

In one, 10,739 post-menopausal women with a hysterectomy were randomized to receive 0.625 milligrams a day of conjugated equine estrogens or placebo and followed for an average of 7.1 years.

In the other, 16,608 post-menopausal women without hysterectomy were randomly assigned to get placebo or estrogen plus progestin (given as the same dose of conjugated equine estrogens with 2.5 milligrams a day of medroxyprogesterone acetate). Women in that trial were followed for an average of 5.6 years.

Both trials were eventually stopped because the harms outweighed the benefits, the researchers noted.

This post hoc analysis was stratified by a pre-study history of kidney stones, so that 2,727 participants were excluded because that data was missing, leaving a total of 24,620 women.

Maalouf and colleagues found there were 335 incident cases of kidney stones among women getting active treatment and 284 cases among women getting placebo. The corresponding annualized incidence rates yielded a hazard ratio of 1.21, with a 95% confidence interval from 1.03 to 1.44.

The researchers noted that the incidence of kidney stones was measured by self-report and was not confirmed by a review of records. As well, they said, only one dosage of each hormone was studied in the trials, so that the ability to apply the findings to other hormone therapy formulations is limited.

The mechanism behind the increased risk remains unclear, they concluded, but one clinical implication is that the finding should be considered when women and their doctors decide on post-menopausal hormone use.