10 March, 2014

The potential association of postmenopausal hormone use and the occurrence of acute pancreatitis was investigated in a prospective study involving 31,494 postmenopausal women (aged 48–8 years) from the population-based Swedish Mammography Cohort [1]. Participants completed a baseline questionnaire in 1997 assessing their use of hormone replacement therapy (HRT). The cohort was linked to the hospital-based Swedish National Patient Register to determine hospital admissions for acute pancreatitis through 2010. Over a total follow-up of 389,456 person-years, 237 cases of incident acute pancreatitis were identified. The age-standardized incidence rates per 100,000 person-years were 71 cases among women who had ever used HRT and 52 cases among women who had never used such hormones. Among ever-users of HRT, the multivariable-adjusted relative risk (RR) of acute pancreatitis was 1.57 (95% confidence interval (CI) 1.20–2.05) compared with never-users. The risk did not differ by current or past use, but it seemed to be higher among women who used systemic therapy (RR = 1.92, 95% CI 1.38–2.66) and among those with duration of therapy of more than 10 years (RR = 1.87, 95% CI 1.11–3.17).

Comment

So let's be realistic. Should this information change our perceptions on the risk of HRT? Does it have any innovative clinical significance? On the one hand, it is a large-scale study, with a long follow-up period. On the other hand, data on hormone use was self-reported and did not include important information on specific hormonal preparations, dose and route of administration of HRT [1]. By the end of the day, there were 19 additional events of acute pancreatitis among 100,000 person-years, or only about two additional cases among 10,000 women per year of use. This seems to be a tiny risk that may not be accounted for when benefit–risk balance of HRT is discussed. Furthermore, no data were presented for the exact definition and severity of acute pancreatitis, i.e. whether a mild course of abdominal pain with elevation of liver enzymes/amylase serum levels, or a serious disease necessitating surgical procedures, or even a fatal outcome, etc. Nevertheless, the authors concluded that 'Physicians should consider this potential increase in risk when prescribing such therapy.'

Addressing the association of HRT with pancreatitis immediately raises the issue of the well-known increase in the risk for gall stone disease in hormone users [2]. In the present study by Oskarsson and colleagues, history of cholelithiasis was recorded in about 10% of the cohort, but adjustment of the results by baseline gall stones did not change the risk (RR = 1.57, 95% CI 1.20–2.06). Also, of the total number of women with acute pancreatitis (n = 237), there were 43 cases of non-gall-stone-related acute pancreatitis in never-users and 72 cases in ever-users of HRT (RR = 1.96, 95% CI 1.32–2.90). Thus, in about half of the total pancreatitis cases, other mechanisms by which HRT might have induced such acute disease should be sought. Except for a possible link to hypertriglyceridemia, another known adverse effect of some formulations of HRT, there were only a few sporadic case reports that suggested other potential etiologies or mechanisms responsible for the pancreatitis [3]. To note that, since the study was done in Sweden, where estradiol is the main estrogen used, one may assume that the impact of higher triglyceride levels secondary to HRT may practically be very small if at all [4], but such information on the exact hormonal medications was not available. Perhaps the lack of difference between current and past users of HRT in regard to the risk for acute pancreatitis supports an assumption that some permanent, metabolic adverse reactions, such as changes in bile content and formation of tiny gall stones, still non-symptomatic and undiagnosed, are the major pathophysiological process after all.

The main adverse outcome of gall bladder disease is cholecystectomy, which has a substantial personal and health-economy-wise impact. Several large-scale population studies have looked into its association with HRT, all reaching the same range of increased risk, between 1.5 and 2.5 [5,6]. While these were US-based studies, new data from Sweden, by the same investigators of the pancreatitis study, brought cholecystectomy data from the same cohort [7]. The relative risk for cholecystectomy in ever-users of HRT was 1.52 (95% CI 1.33-–1.74) when compared to never-users. This risk was somewhat lower than that found in above-mentioned US studies, perhaps reflecting the common use of conjugated equine estrogen in the States (rather than estradiol in Europe), which has stronger triglyceride-elevating characteristics.

In conclusion, the potential adverse effects of HRT on the biliary-pancreatic system were once again documented, although the scope of this risk is minor, when compared to major hazards, such as breast cancer or thromboembolism. If one would argue that all minor risks of HRT must be discussed with women prior to initiation of therapy, then minor benefits, less known and considered, should be put into the risk–benefit equation as well. A good example would be a recent study which showed that HRT significantly reduced the risk for open angle glaucoma [8]. Each additional month of use of estrogen-only therapy was associated with a 0.4% reduced risk for this type of glaucoma. For each and every medication, the potential good effects and the bad effects always coincide and the duty of the health-care provider is to calculate the overall balance and ascertain that the upside of therapy far outweighs the corresponding downside.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Oskarsson V, Orsini N, Sadr-Azodi O, Wolk A. Postmenopausal hormone replacement therapy and risk of acute pancreatitis: a prospective cohort study. CMAJ 2014 Jan 27. Epub ahead of print
http://www.cmaj.ca/content/early/2014/01/27/cmaj.131064.full.pdf+html

2. Hart AR, Luben R, Welch A, Bingham S, Khaw KT. Hormone replacement therapy and symptomatic gallstones – a prospective population study in the EPIC-Norfolk cohort. Digestion 2008;77:4-9
http://www.ncbi.nlm.nih.gov/pubmed/18212501

3. Blake WE, Pitcher ME. Estrogen-related pancreatitis in the setting of normal plasma lipids: case report. Menopause 2003;10:99-101
http://www.ncbi.nlm.nih.gov/pubmed/12544683

4. Al-Azzawi F, Wahab M, Sami S, Proudler AJ, Thompson J, Stevenson J. Randomized trial of effects of estradiol in combination with either norethisterone acetate or trimegestone on lipids and lipoproteins in postmenopausal women. Climacteric 2004;7:292-300
http://www.ncbi.nlm.nih.gov/pubmed/15669554

5. Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA 2005;293:330-9
http://www.ncbi.nlm.nih.gov/pubmed/15657326

6. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet Gynecol 1994;83:5-11
http://www.ncbi.nlm.nih.gov/pubmed/8272307
7. Nordenvall C, Oskarsson V, Sadr-Azodi O, Orsini N, Wolk A. Postmenopausal hormone replacement therapy and risk of cholecystectomy: a prospective cohort study. Scand J Gastroenterol 2014;49:109-13
http://www.ncbi.nlm.nih.gov/pubmed/24256204

8. Newman-Casey PA, Talwar N, Nan B, Musch DC, Pasquale LR, Stein JD. The potential association between postmenopausal hormone use and primary open-angle glaucoma. JAMA Ophthalmol 2014 Jan 30. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/24481323