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  and animal models  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 . 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 . 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  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 , 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.
The GPRD inconsistently records endoscopy findings; because of the lack of secondary care data to verify the presence of GORD, there is a potential risk of misclassification. The current study explored the relationship between HRT and GORD as presenting to and clinically diagnosed by GPs. This is increasingly the only relevant definition at a time when GPs no longer routinely refer patients without alarm signs for endoscopy because of the perceived balance of risks and benefits to these low-risk patients. Because of well acknowledged difficulties in classifying GORD, this study compared a broad definition of GORD encompassing symptoms such as waterbrash, with a more specific definition of ICD 10 codes (K21) indicative of a GORD diagnosis. Simple regression was conducted using both definitions: the similarity of findings strengthens the conclusions. The GPRD records used in this study may in fact be a more reliable mechanism for recording GORD symptoms than self-reporting methods used in other studies.
Given the weaknesses inherent in GORD recording, we also investigated PPI use in this cohort. Although most of the PPI users had a record of GORD, PPI has many other uses. In addition, many patients with GORD were not prescribed PPIs and it is likely that many women suffering side-effects of HRT would not immediately commence PPIs. We therefore treated GORD sufferers and PPI users as two separate ‘proxy’ groups. The fact that findings were similar across these groups strengthens the association between oestrogen-only HRT and GORD.
When seeking causative associations, weaknesses inherent in all observational design are the problem of unmeasured variables, and the difficulties in teasing out temporal relationships. The similarity of hormone users and non-users at baseline and the consistency of effect with different model formulations offers some protection against this. Selection bias is another common threat to validity although in this study GPRD data was collected from a wide cross-section of general practices from across the UK. It is not possible to rule out some underlying factor selecting patients who do and don’t receive HRT which is GORD-related, although there is no evidence for this.
A further potential weakness of any GPRD study is the incompleteness of BMI, smoking and alcohol data due to the fact that most general practices do not routinely and systematically collect this data. For example, only 41% of women had any BMI record within the study window (erroneous range 0.5 to 896000); after data cleaning, only 21% of BMI records were within acceptable limits. The association between these variables and GORD are well established and so in order to understand their relative effect in combination with HRT use, we conducted sub-group analysis on complete cases. Our findings showed that the strength of association with HRT remained the same as in the wider group but because numbers were small, a prospective study design would be required to confirm these findings.
A further limitation of the study, that might weaken the strength of association, is the lack of a direct measure of adherence to prescribed medication. Since HRT may be used in varying doses over time for symptom control, dose dependency could not be adequately examined using this data. We identified outcomes using diagnostic codes but we were unable to assess the severity of GORD symptoms or to assess whether compliance with HRT was affected by the occurrence of GORD. Similarly it was not possible to explore the association between different hormone replacement therapies and the dose or frequency of PPI use in a meaningful way.