Estrogen therapy was associated with risk for nephrolithiasis in healthy postmenopausal women, according to the results of an analysis from the Women's Health Initiative (WHI) published in the October 11 issue of the Archives of Internal Medicine.

"Observational studies examining the role of estrogen in the risk of kidney stone formation have shown conflicting results," write Naim M. Maalouf, MD, from the University of Texas Southwestern Medical Center in Dallas, and colleagues from the WHI Hormone Therapy Trials. "However, randomized trial evidence on nephrolithiasis risk with estrogen therapy in postmenopausal women is lacking.... Because the process of kidney stone formation is influenced by a variety of lifestyle and other health-related factors, the true impact of estrogen therapy on the risk of kidney stone formation is difficult to infer from observational studies."

Using data from the WHI estrogen-alone and estrogen-plus-progestin trials performed at 40 US clinical centers, the investigators analyzed the incidence of kidney stones. Participants included 10,739 postmenopausal women with hysterectomy who were randomly assigned to receive 0.625 mg/day conjugated equine estrogens (CEE) or placebo, and 16,608 postmenopausal women without hysterectomy who were randomly assigned to receive placebo or estrogen plus progestin, given as CEE plus medroxyprogesterone acetate (2.5 mg/day).

Average duration of follow-up for determination of kidney stone risk was 7.1 years for the CEE trial and 5.6 years for the estrogen-plus-progestin trial.

The placebo and treatment groups had similar baseline demographic characteristics and risk factors for nephrolithiasis. Risk for kidney stones was significantly increased with estrogen therapy, from 34 to 39 cases per 10,000 person-years (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03 - 1.44). When data were excluded from women once they discontinued study medication, the HR increased to 1.39 (95% CI, 1.08 - 1.78).

Progestin coadministration did not affect the increased nephrolithiasis risk, nor did prerandomization history of nephrolithiasis.

Limitations of this study include reliance on self-report for determination of the incidence of nephrolithiasis and inability to generalize these findings to women taking other HT formulations.

"These data suggest that estrogen therapy increases the risk of nephrolithiasis in healthy postmenopausal women," the study authors conclude. "These findings should be considered in decision making regarding postmenopausal estrogen use. The mechanisms underlying this higher susceptibility remain to be determined."

The National Heart, Lung, and Blood Institute, National Institutes of Health, and the US Department of Health and Human Services funded the Women's Health Initiative. The study authors have disclosed no relevant financial relationships.

Arch Intern Med. 2010;170:1678-1685.