Hormone Replacement Associated With Increased Pancreatitis Risk

Norra MacReady

January 27, 2014

Use of hormone replacement therapy (HRT) has been associated with an increased risk for acute pancreatitis in a prospective study of more than 30,000 women in Sweden.

Women who had ever used HRT had a 57% increase in the risk for acute pancreatitis compared with women who had never used HRT, lead author Viktor Oskarsson, MD, and colleagues report in the current issue of the Canadian Medical Association Journal, published online January 27.

These findings add to the controversy about the negative of effects of HRT. In the Women's Health Initiative (WHI), a double-blind, placebo-controlled trial of combination HRT (conjugated equine estrogens [CEE] and medroxyprogesterone acetate [MPA]) involving 16,608 women aged 50 to 79 years, the investigators ended the trial early because HRT was associated with an increased risk for breast cancer and an overall unfavorable risk-to-benefit ratio. A second arm of the trial, which studied the effects of just CEE in women who had undergone hysterectomy, was also stopped early, when HRT was associated with an increased risk for stroke.

A postintervention follow-up analysis of the WHI data, published in 2013, confirmed that the risk for coronary heart disease and breast cancer was significantly elevated among women in the CEE plus MPA group. Stroke risk was elevated among women in both the CEE plus MPA and CEE-only groups. On the other hand, women in the HRT groups had lower rates of treated diabetes than women in the placebo group, although that difference did not persist in the postintervention and follow-up phases of the study.

Also feeding the controversy was another analysis published in 2013 suggesting that, among women 50 to 59 years of age who underwent hysterectomy, avoidance of postsurgical estrogen-only supplementation could be linked to as many as 91,610 deaths. Those findings were sharply criticized by many readers, including JoAnn Manson, MD, MPH, one of the WHI investigators. Dr. Manson told Medscape Medical News that the analysis was "a mathematical exercise" based on "findings that are inconclusive."

For the current analysis, Dr. Oskarsson, from the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, and coauthors drew on data from 31,494 women participating in the Swedish Mammography Cohort, a population-based prospective study conducted on all women living in 2 counties in central Sweden and born between 1914 and 1948. The investigators used information provided by the women in a 1997 questionnaire on lifestyle factors such as diet, alcohol intake, and smoking history, as well as medications and medical history.

The authors analyzed data from 13,113 women who were current users of HRT at baseline, 3660 past users, and 14,721 women who had never used HRT. Follow-up for this study went through 2010.

They found that never-users of HRT had an incidence of acute pancreatitis of 52 cases per 100,000 person-years, while ever-users had an incidence of 71 cases per 100,000 person-years.

This translated to a multivariable adjusted risk ratio (RR) of 1.57 for pancreatitis among ever-users of HRT (95% confidence interval [CI], 1.20 - 2.05) compared with never-users. The results did not change significantly after controlling for waist circumference, alcohol consumption, multiple adjustments for age at menarche or parity, use of oral contraceptives, or history of diabetes.

The risk for acute pancreatitis did not differ by current or past use of hormone replacement therapy but seemed to be higher in women who used systemic therapy (RR, 1.92; 95% CI, 1.38 - 2.66) and those with duration of therapy more than 10 years (RR, 1.87; 95% CI, 1.11 - 3.17), the authors report. This association remained after adjustment for gallstone disease, "as well as when we used non-gallstone-related acute pancreatitis as the outcome." The authors suggest that the increased risk for pancreatitis may be related to the increase in triglycerides seen with use of HRT.

Possible study limitations include reliance on self-reported use of HRT and lack of information on the preparation, dose, and route of HRT administration. A third limitation was the authors' reliance on the diagnosis reported to the Swedish National Patient Register, although this has been shown to be highly accurate. Finally, the authors may not have accounted for some confounding factors.

Nevertheless, "[u]se of postmenopausal hormone replacement therapy was associated with increased risk of acute pancreatitis," the authors conclude. "If these findings are confirmed by other studies, the risk of acute pancreatitis should be considered when hormone replacement therapy is prescribed."

This study was funded by research grants from the Swedish Research Council/Committee for Infrastructure, Board of Research at Karolinska Institutet, Board of Postgraduate Education at Karolinska Institutet, Strategic Research Program in Epidemiology at Karolinska Institutet, Swedish Society of Medicine, and Centre for Clinical Research Sörmland. The authors have disclosed no relevant financial relationships.

CMAJ. Published online January 27, 2014. Abstract

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