Durham Research Online Deposited in DRO: 29 October 2012 Version of attached le: Published Version Peer-review status of attached le: Peer-reviewed Citation for published item: Close, Helen and Mason, James M. and Wilson, Douglas and Hungin, A. P. S. (2012) 'Hormone replacement therapy is associated with gastro-oesophageal reux disease : a retrospective cohort study.', BMC gastroenterology., 12 . p. 56. Further information on publisher's website: http://dx.doi.org/10.1186/1471-230X-12-56 Publisher's copyright statement: c 2012 Close et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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BMC Gastroenterology 2012, 12:56 http://www.biomedcentral.com/1471-230X/12/56 RESEARCH ARTICLE Open Access Hormone replacement therapy is associated with gastro-oesophageal reflux disease: a retrospective cohort study Helen Close1*, James M Mason1, Douglas Wilson1 and A Pali S Hungin2 Abstract Background: Oestrogen and progestogen have the potential to influence gastro-intestinal motility; both are key components of hormone replacement therapy (HRT). Results of observational studies in women taking HRT rely on self-reporting of gastro-oesophageal symptoms and the aetiology of gastro-oesophageal reflux disease (GORD) remains unclear. This study investigated the association between HRT and GORD in menopausal women using validated general practice records. Methods: 51,182 menopausal women were identified using the UK General Practice Research Database between 1995–2004. Of these, 8,831 were matched with and without hormone use. Odds ratios (ORs) were calculated for GORD and proton-pump inhibitor (PPI) use in hormone and non-hormone users, adjusting for age, co-morbidities, and co-pharmacy. Results: In unadjusted analysis, all forms of hormone use (oestrogen-only, tibolone, combined HRT and progestogen) were statistically significantly associated with GORD. In adjusted models, this association remained statistically significant for oestrogen-only treatment (OR 1.49; 1.18–1.89). Unadjusted analysis showed a statistically significant association between PPI use and oestrogen-only and combined HRT treatment. When adjusted for covariates, oestrogen-only treatment was significant (OR 1.34; 95% CI 1.03–1.74). Findings from the adjusted model demonstrated the greater use of PPI by progestogen users (OR 1.50; 1.01–2.22). Conclusions: This first large cohort study of the association between GORD and HRT found a statistically significant association between oestrogen-only hormone and GORD and PPI use. This should be further investigated using prospective follow-up to validate the strength of association and describe its clinical significance. Keywords: Gastro-oesophageal reflux disease, Hormone replacement therapy, Menopause Background The aetiology of GORD remains unclear, although re- Gastro-oesophageal reflux disease (GORD) is a common search has identified the main risk factors as heredity [9], relapsing disorder largely caused by repeated exposure increased body mass index (BMI) [10] and tobacco in the lower oesophagus to the retrograde flow of gastric smoking [11]. Some studies indicate a stronger associ- contents [1]. Epidemiological studies have shown that ation between GORD and obesity in females than males, reflux is experienced by 3–20% of the population at least suggesting a link with female sex hormones [12]. This hy- weekly [2-4]. It is one of the most prevalent conditions pothesis is supported by in-vitro and clinical data which seen in primary care [5,6] and is costly in terms of suggest an indirect action of sex hormones on GI motil- pharmacological therapy and investigations [5]. Symp- ity [13-16], evidence of reduced upper GI motility during toms of GORD, including heartburn, regurgitation and the menstrual cycle [17] and reduced oesophageal nausea, are associated with a reduced quality of life [7,8]. sphincter pressure during pregnancy [18]. Recent studies suggest that hormone replacement therapy (HRT) may * Correspondence: [email protected] be associated with GORD in post-menopausal women 1Durham Clinical Trials Unit, Queen’s Campus, Wolfson Research Institute, University of Durham, University Boulevard, Stockton-on-Tees TS17 6BH, UK [19]. A recent Swedish cohort study of female twins sug- Full list of author information is available at the end of the article gests that oestrogen-only HRT is an independent risk © 2012 Close et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Close et al. BMC Gastroenterology 2012, 12:56 Page 2 of 9 http://www.biomedcentral.com/1471-230X/12/56 factor for GORD symptoms [20] (OR 1.32; 95% CI 1.18– Diagnosis occurred within the cohort window of 01/01/ 1.47). A large US randomised controlled trial reported a 1995 – 31/12/2004 (largely avoiding the subsequent re- similar association among post-menopausal women with duction in HRT following reports of increased cancer hysterectomy [21], findings mirrored in a US cohort and cardiovascular risk). Patients with less than study of post-menopausal registered nurses [22]. Al- 24 months of continuous GP registration were excluded, though a Norwegian case–control study indicated that as were patients with malignancy or pregnancy recorded obesity increases the influence of oestrogen use upon within the study window. The study window for identify- GORD (OR 2.3; 95%CI 1.1–4.8), it is difficult to draw ing the cohort was defined as two years from menopause firm conclusions given the small numbers [12]. These diagnosis (T0 +/− 24 months). Patients who commenced findings contrast with in-vitro evidence suggesting that HRT more than 2 years before or after the first record of progestogen use may play a greater role than oestrogen menopause were excluded, thus a cohort of N = 51,182 in upper GI motility [23]. Furthermore, these European women with a record of menopause were within the and US studies relied on self-reporting of symptoms and study window. A sub-cohort of hormone users were did not take into account time from onset of menopausal matched, according to calendar year, age at menopause, symptoms. In light of these results, the goal of this study socio-economic status of GP practice, and date closest to was to establish the extent of the association between menopause, with one user for every two non-users. upper GI symptoms and the use of forms of HRT, and In addition to GORD, records were evaluated for hys- the relative importance of oestrogen compared with pro- terectomy, osteoarthritis, non-steroidal anti-inflammatory gestogen in the UK population. drugs (NSAIDs), bisphosphonates and calcium supple- ment use at menopause diagnosis. Limited by variable Methods reporting within the GPRD, smoking and alcohol status A retrospective cohort study was designed and conducted, were crudely categorized by “non-user”, “user” or “ex- accessing records from the General Practice Research user” at menopause. Mean BMI was calculated using all Database (GPRD). The GPRD provides anonymised access BMI readings (kg/m2) within the study window and cate- to electronic primary care medical records and prescrip- gorized as underweight (<18.5), normal (18.5 to 24.9), tion data for a representative 6% of the UK population overweight (25 to 29.9), obese (30 to 39.9), morbidly [24], and has been extensively validated as a reliable obese (≥40). GP practices were allocated a quintile score source of GORD information [25]. Diagnoses were identi- for socioeconomic status based in the Index of Multiple fied using Read codes and prescriptions using Prescription Deprivation (IMD) [26]. Pricing Authority (PPA) codes; all codes for GORD symp- toms, outcomes, medications and covariates are available Drug exposure definitions on request. Data were accessed under the Medical Re- Hormone use incorporated the following proprietary and search Council licence for academic groups (protocol generic classifications: Combined hormone (conjugated reference 07109). oestrogen with progestogen; estradiol with progestogen); oestrogen-only (oestradiol only; oestradiol, oestriol and Disease definitions oestrone; oestriol only; oestropipate only; conjugated Menopausal symptoms were defined using a wide range oestrogens only); tibolone; and progestogen (other than of diagnostic and referral codes indicating menopause or for contraception; dydrogesterone; medroxyprogesterone; menopausal