Gut Feelings: The over-looked importance of HRT in colonic disease.

Controversy continues to swirl around the benefits and risks associated with hormone-replacement therapy (HRT). Although experts and guidelines support short-term use of HRT to treat unwanted menopausal symptoms, clinicians and scientists are often confused by how HRT impacts the incidence and severity of various maladies. What is often over-looked is the comparatively consistent data linking HRT effects in colon disease and in the reduced incidence of colon cancer.

HRT, an old ‘wonder drug’?

Historically prescriptions of HRTs (such as Premarin released in the 1980s) centred on their beneficial effects treating postmenopausal osteoporosis. Subsequent observational studies showed additional benefits, particularly with cardiovascular protection and decreased mortality, and resulted in large numbers of postmenopausal women using HRT. Thus, at the turn-of-the-century, HRT was being hailed as a new wonder drug.

This all changed upon publication of initial results from the Women’s Health Initiative (WHI); randomised controlled trials designed to address, in part, how oestrogen and progestin impact morbidity and mortality in postmenopausal women. Early results, which forced the trials to be stopped and were widely publicised, indicated HRT use increased heart disease, stroke, and pulmonary embolism. However, when the data was further interrogated, these risks were less pronounced than originally thought, but what did stand out was a clear protective effect of HRT on colon cancer development.

So, in light of this strong epidemiological evidence what do we know now about HRT, and in particular oestrogen, and colorectal disease? The answer is, very little. However, numerous strands of evidence are now starting to emerge suggesting HRT impacts many colon diseases.

Irritable Bowel Syndrome (IBS)

IBS is a multi-component condition characterised by heightened gut sensitivity, altered intestinal motility and impaired secretory function. It affects more females than males with ratios reported as high as 3:1. Furthermore, women who use HRT have an increased risk of developing IBS. Despite this, few studies have characterised IBS differences between females and males. Of the few studies that have looked at gender differences, results indicate that women diagnosed with IBS report an overall lower quality of life and a greater number of symptoms including nausea, constipation, bloating, as well as various other extracolonic symptoms (e.g. urinary urgency, and muscle stiffness).

So, if IBS is worse in females, what happens when these patients hit the menopause? It has been reported that occurrence rates of IBS among females decreases as age increases. If over 70, the rate of incidence among females is comparable to that of males. In males, however, the occurrence of IBS was relatively constant across all age groups. Thus, the decline in incidence observed in women is related to the lowered oestrogen concentrations characteristic of the menopause. Indeed, women on HRT have double the chance of developing IBS. Unfortunately, the exact mechanisms by which oestrogens induce IBS remain to be determined, and therefore current therapeutic targeting of oestrogen action in these patients remains hypothetical.

Ulcerative Colitis (UC)

As for ulcerative colitis (UC), the largest study to explore a potential link between oestrogens and inflammatory bowel disease shows that postmenopausal women taking HRT have an increased risk of UC. This data supports various observational studies associating oral contraceptive use, which contains oestrogen and progestin, increases the risk of UC in premenopausal women.

Furthermore, UC risk seems to be increased with the duration of oestrogen use. For example, those who take HRT for 1-5 years have a 61% increased risk compared with those who have never taken HRT. In women who have taken hormones for over a decade the risk increases to 80%. But 5 years after stopping treatment, the risk for UC reduces, and is no longer statistically different from those who have never taken hormones.

Again, and like IBS, why HRT increases UC remains unknown. It has been suggested that oestrogen compounds modify colonic barrier function and are thought to be involved in the progression of other Type-2 helper T cell-related diseases, which could explain their effect in UC.

Colorectal Cancer (CRC)

Compared to IBS and UC, HRT's story with colorectal cancer is more complex. Data strongly supports HRT as protective against CRC development, which is of interest, and somewhat counterintuitive, considering the role these hormones have in increasing IBS and UC development – both conditions associated with increased CRC incidence. Indeed, recent evidence suggests that women with naturally higher levels of oestrogens are more than 50% less likely to develop CRC after their menopause than women with low levels.

Of even more interest, there is growing evidence suggesting once CRC is formed women taking HRT present to the clinic with a more aggressive and later stage disease. Thus, it seems possible that whilst HRT initially protects against CRC through oestrogen signalling, an alteration in this signalling negatively impacts patient outcomes. However, significant research remains to be done to further determine the importance of HRT and oestrogens on CRC.

Overall, it seems that HRT, and thus oestrogens, have pronounced effects on the gut and colonic disease. Understanding the underlying molecular mechanisms involved in gut oestrogenic action will most likely reveal new therapeutic avenues to treat these conditions.

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