Scandinavian Journal of Gastroenterology. 2014; 49: 109–113

ORIGINAL ARTICLE

Postmenopausal hormone replacement therapy and risk of cholecystectomy: a prospective cohort study

CAROLINE NORDENVALL1, VIKTOR OSKARSSON2, OMID SADR-AZODI1, NICOLA ORSINI2 & ALICJA WOLK2 1

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

2

Abstract Objective. Our aim of this study was to examine the association between the use of postmenopausal HRT and risk of cholecystectomy in Sweden, where the most common regimen of HRT (oral oestradiol in combination with testosterone-like progestin) has been different from those investigated in previous studies. Material and methods. We performed a prospective study of 27 892 postmenopausal women (aged 48–83 years) from the population-based Swedish Mammography Cohort. Use of HRT was assessed by a self-reported questionnaire at baseline in 1997, and the cohort was followed up through 2011 for procedures of cholecystectomy by linkage to the Swedish Patient Register. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results. During 362 728 person-years of follow-up (median 14 years), 995 cases of cholecystectomy were recorded. After adjustment for potential confounders, the HR of cholecystectomy was 1.52 (95% CI, 1.33–1.74) among ever users of HRT compared with never users. The risk did not differ by current or past use (p = 0.38) or duration of use (p = 0.65), but it did differ by indication of use (p = 0.006). Women who used HRT for systemic symptoms had a higher risk of cholecystectomy than those who used it for local symptoms (HR, 1.62; 95% CI, 1.41–1.87 vs HR, 1.21; 95% CI, 0.97–1.50). Conclusions. This prospective study of postmenopausal women adds to the evidence that use of HRT may increase the risk of cholecystectomy.

Key Words: cholecystectomy, epidemiology, gallstone, hormone replacement therapy

Introduction Symptomatic gallstone disease is a common reason for hospital admission among women in developed countries [1]. Although its aetiology is not fully understood, there is accumulating evidence that use of exogenous oestrogen may increase the risk of symptomatic gallstone disease [2–6]. Postmenopausal hormone replacement therapy (HRT) has been positively associated with risk of cholecystectomy (as a proxy for symptomatic gallstone disease) in studies in the USA [2–4], the UK [5], and France [6]. No study has examined whether such an association is present in Sweden, where the most common regimen of HRT has been oral oestradiol in combination with

testosterone-like progestin [7]. This is in contrast to previous studies where a) conjugated oestrogen was the only [2,3] or most common [4,5] compound and b) transdermal route was more common than oral route [6]. Hence, the aim of this study was to examine whether the reported association between HRT and cholecystectomy could be reproduced in a cohort of postmenopausal women from Sweden. Methods Participants The Swedish Mammography Cohort is a populationbased prospective study that recruited 66 651 women

Correspondence: Caroline Nordenvall, Karolinska Institutet, Department of Molecular Medicine and Surgery, Gastrocentrum kirurgi, P:903, Karolinska Sjukhuset, 171 76 Stockholm, Sweden. Tel: +46 70 6579109. Fax: +46 8 33 15 87. E-mail: [email protected]

(Received 2 September 2013; revised 17 October 2013; accepted 17 October 2013) ISSN 0036-5521 print/ISSN 1502-7708 online  2014 Informa Healthcare DOI: 10.3109/00365521.2013.858180

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(74% of all women aged 40–75 years) from two counties in central Sweden between 1987 and 1990 [8]. At recruitment, the women completed a questionnaire that sought information on diet, anthropometric measures and parity. Updated information on dietary and lifestyle factors, as well as additional information on medical history including medication use, was obtained through a second questionnaire that was sent to 56 030 women who were still alive and living in the study area in 1997. Answers were obtained from 70% (n = 39 227) of the women. Eligible for this study were women who completed both questionnaires, due to lack of information on HRT in the first. Ethical approval was acquired from the Regional Ethical Board at Karolinska Institutet (Stockholm, Sweden), and return of a completed questionnaire was considered to imply informed consent. Assessment of HRT and covariates On the questionnaire in 1997, women reported if they had ever used HRT and, if so, whether these hormones were currently taken, the duration of use, and the indication of use (systemic [hot flushes] or local [vaginal] symptoms). Information on menopausal status and age at menopause was determined from the questionnaire (as previously defined [9]). The questionnaire also acquired information on age at menarche, contraceptive use, parity, education, smoking, alcohol drinking, and body mass index (BMI). History of gynecological surgery (i.e., hysterectomy and bilateral oophorectomy) and diabetes was obtained by linkage to the Swedish Patient Register and the Swedish Diabetes Register, respectively, and complemented with information from the questionnaire. Case ascertainment Since gallstones may be asymptomatic [10], and may dissolve [11], we defined cholecystectomy as the outcome of interest. Surgical procedures of cholecystectomy were identified by linkage to the Swedish Patient Register. This register has had a national coverage of nearly 100% since 1987 [12], and its surgical procedures are classified according to the Swedish versions of Classification of Operations 1985 (revised 1988) and Classification of Surgical Procedures 1997. A code of 535 (International Classification of Diseases [ICD]-9) and JKA20 or JKA21 (ICD-10) represents cholecystectomy. Cholecystectomies that occurred between September 15, 1997 and December 31, 2011 were classified as cases. An underlying diagnosis of cholelithiasis or cholecystitis was ascertained by a diagnosis code of

574 or 575 (ICD-9) and K80 or K81 (ICD-10). Information on cancer and death was obtained by linkage to the Swedish Cancer Registry and the Swedish Cause of Death Register, respectively.

Statistical analysis Of the 39 227 eligible women at baseline (September 15, 1997), we excluded the following from the analyses: 243 who had an incorrect personal identity number, 5851 who had a history of cholecystectomy or cancer (other than non-melanoma skin cancer), 3014 who were premenopausal or perimenopausal, 2024 who had missing information on HRT, and 203 (including 33 cases) who developed cancer in the duodenum, liver, gallbladder, biliary ducts, or pancreas during follow-up. Hence, the analytical cohort consisted of 27 892 postmenopausal women. Follow-up was censored at the date of cholecystectomy, date of death, or study end (December 31, 2011), whichever occurred first. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cholecystectomy in relation to use of HRT were estimated with Cox proportional hazards models that used personyears as the underlying time scale; results calculated with age as the underlying time scale were similar. Women were categorized as never or ever users of HRT. Ever users were further categorized according to current use (no or yes), duration of use (12 years), BMI (

Postmenopausal hormone replacement therapy and risk of cholecystectomy: a prospective cohort study.

Our aim of this study was to examine the association between the use of postmenopausal HRT and risk of cholecystectomy in Sweden, where the most commo...
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