Gastro-oesophageal reflux disease (GORD) is a common relapsing disorder largely caused by repeated exposure in the lower oesophagus to the retrograde flow of gastric contents [1]. Epidemiological studies have shown that reflux is experienced by 3–20% of the population at least weekly [2–4]. It is one of the most prevalent conditions seen in primary care [5, 6] and is costly in terms of pharmacological therapy and investigations [5]. Symptoms of GORD, including heartburn, regurgitation and nausea, are associated with a reduced quality of life [7, 8].

The aetiology of GORD remains unclear, although research has identified the main risk factors as heredity [9], increased body mass index (BMI) [10] and tobacco smoking [11]. Some studies indicate a stronger association between GORD and obesity in females than males, suggesting a link with female sex hormones [12]. This hypothesis is supported by in-vitro and clinical data which suggest an indirect action of sex hormones on GI motility [13–16], evidence of reduced upper GI motility during the menstrual cycle [17] and reduced oesophageal sphincter pressure during pregnancy [18]. Recent studies suggest that hormone replacement therapy (HRT) may be associated with GORD in post-menopausal women [19]. A recent Swedish cohort study of female twins suggests that oestrogen-only HRT is an independent risk factor for GORD symptoms [20] (OR 1.32; 95% CI 1.18–1.47). A large US randomised controlled trial reported a similar association among post-menopausal women with hysterectomy [21], findings mirrored in a US cohort study of post-menopausal registered nurses [22]. Although a Norwegian case–control study indicated that obesity increases the influence of oestrogen use upon GORD (OR 2.3; 95%CI 1.1–4.8), it is difficult to draw firm conclusions given the small numbers [12]. These findings contrast with in-vitro evidence suggesting that progestogen use may play a greater role than oestrogen in upper GI motility [23]. Furthermore, these European and US studies relied on self-reporting of symptoms and did not take into account time from onset of menopausal symptoms. In light of these results, the goal of this study was to establish the extent of the association between upper GI symptoms and the use of forms of HRT, and the relative importance of oestrogen compared with progestogen in the UK population.

A retrospective cohort study was designed and conducted, accessing records from the General Practice Research Database (GPRD). The GPRD provides anonymised access to electronic primary care medical records and prescription data for a representative 6% of the UK population [24], and has been extensively validated as a reliable source of GORD information [25]. Diagnoses were identified using Read codes and prescriptions using Prescription Pricing Authority (PPA) codes; all codes for GORD symptoms, outcomes, medications and covariates are available on request. Data were accessed under the Medical Research Council licence for academic groups (protocol reference 07109).

A total of 42,724 (84%), women had ever been recorded as having GORD symptoms, with a total of 18.5% of all consultations coded as ‘Dyspepsia’, and 3.3% of consultations coded as ‘Gastro-oesophageal Reflux Disease’. The majority of these occurrences were post-menopause. Prior to the study window (pre-menopause), overall 11881 women (23%) consulted their GP for GORD symptoms; GORD reporting rates were comparable between groups prior to hormone exposure (25% of oestrogen-only and tibolone users reported GORD prior to hormone exposure compared to 22% of combined hormone and 23% of progestogen users and non-hormone users).

A total of 35639 women (34.7%) were ever-users of PPIs with a mean number of 64 PPI prescriptions. Pre-menopause, the use of PPI prescriptions was comparable across hormone and non-hormone groups for approximately 6% of women.

Preliminary unadjusted models including BMI, alcohol and smoking had large numbers of missing data. These variables poorly fitted any model of GORD or PPI use in unadjusted analyses. When adjusted models of GORD were analysed with BMI, alcohol and smoking as independent variables, similarly none fitted at a statistically significant level. In unadjusted analysis, there was a small but unimportant association between BMI and PPI use (OR 1.04, 95% CI 1.01–1.056, p = 0.001). Alcohol use (OR 4.17, 95% CI 1.20–14.52, p = 0.025) was an additional independent factor in a model of PPI use among combined hormone users, this may be a chance finding in a model involving small numbers.

Within the range of models tested, there was a consistent association between GORD or PPI-use and oestrogen-only hormone replacement. Our evaluation represents the first direct controlled comparison of hormone types for a clinically meaningful GORD diagnosis in a UK population, allowing for multiple hypothesis testing. The large sample size enabled extensive model refinement and subgroup analyses in three ways. Firstly, simple analyses allowed us to identify the potential association between different forms of HRT and GORD regardless of other patient characteristics. This was the first step in understanding the differences between forms of HRT and showed that oestrogen-only HRT presented a possible association with GORD. Secondly, adjusted analysis allowed us to confirm that, even when accounting for known risk factors (NSAID use and other medications), there was an association between oestrogen-only HRT and GORD. Thirdly, we matched cases with controls according to year, age, and socio-economic status in order to account for the effect of these variables upon the incidence of GORD. This further supports the possible association between oestrogen-only HRT and GORD. This study is also the first to compare progestogen only with hormone replacement therapy. Although progestogen was independently associated with PPI use, this was not consistent across simple and adjusted analyses or across GORD groups but the reasons for this are unclear. It was previously thought that progestogen may have a relaxing effect on lower oesophageal sphincter tone. More recent work suggests that oestrogen increases nitric oxide synthesis, which results in smooth muscle relaxation in both human [27] and animal models [28] and may, therefore, be involved in the pathogenesis of GORD. Our findings suggest that oestrogen-only hormone has a stronger independent association with GORD than progestogen, refuting earlier in-vitro studies suggesting progestogen was the most important hormone in GORD aetiology.

There is a well established association between NSAIDs and GORD, which our study suggests may be higher in magnitude with tibolone use although our findings are not statistically significant. Tibolone has oestrogenic, progestogenic, and androgenic effects which act to prevent bone loss. It has been associated with decreased levels of fibrinogen, factor VII, plasminogen activator inhibitor 1, homocysteine, and tissue plasminogen activator and with increased levels of C-reactive protein, antithrombin III, and D-dimer [29]. However, it is unclear which of these, if any, may be a contributory factor in the possible interaction between NSAIDs and tibolone. This study did not assess whether the effects of NSAIDs on tibolone users and their risk of GORD were mediated by the type of NSAID drug. Naproxen is thought to be more gastrotoxic than ibuprofen and diclofenac; whether this holds true for the potential interaction with tibolone remains to be established. In this study, the term GORD relates to a range of GORD like symptoms; it is possible to suggest that the association between NSAID and GORD may be related to gastrotoxicity, and not to an increase in ‘true’ GORD.

The use of HRT declined following publicity about its possible association with cancer and cardiovascular disease [30, 31]. However, these data go some way to explain the risk of GORD and PPI use in this group and also provide a possible explanation for those now on HRT who may have GORD symptoms. The GP records used in this study may be a more reliable mechanism for recording GORD symptoms than self-reporting methods used in other studies; this may explain the slightly higher level of risk identified in this study compared to other cohort studies [32]. Our findings are likely to be an underestimate of the extent of the problem as many women who chose not to consult for GORD may simply have stopped taking hormone therapy and would therefore be excluded or miscoded in our analysis. Many women might have also have wanted to avoid polypharmacy. Up to 75% of women choose to stop using HRT in the first six months [33] as a result of reported side effects including weight gain, headache, nausea and perceptions of disease risk. While the design of most studies prevents further analysis of side effects [30], it is possible that at least a proportion of these were attributable to GORD. Our findings, if validated in a prospective study, may have important consequences for the management and resources used by patients with upper GI symptoms as these patients would normally constitute a higher use group for acid suppression therapy.

There is a statistically significant independent association between oestrogen-only hormone and GORD and PPI use. Oestrogen-only hormone has a stronger independent association with GORD than progestogen, refuting earlier in-vitro studies suggesting progestogen was the most important hormone in GORD aetiology. The known association between NSAID and GORD appears higher in magnitude with tibolone use than other hormone use but was not found to be statistically significant. This should be further investigated using prospective follow-up to examine the strength of association and describe its clinical significance.

European Society for Primary Care Gastroenterology.