Elsevier

European Journal of Cancer

Volume 44, Issue 16, November 2008, Pages 2397-2403
European Journal of Cancer

Review
Oestrogen and the enigmatic male predominance of gastric cancer

https://doi.org/10.1016/j.ejca.2008.07.031Get rights and content

Abstract

Gastric cancer is the second most common cause of cancer death worldwide, and annually it causes over 150,000 deaths in Europe and 700,000 deaths globally. The incidence of gastric cancer shows an enigmatic male dominance with a male-to-female ratio of about 2:1. This sex ratio cannot be entirely attributed to the differences in the prevalence of known risk factors between the sexes. This review focuses on the potential role of oestrogen in explaining the male predominance in gastric cancer. Some data argue in favour of sex hormonal influence. Women with a longer fertility life and those on hormone replacement therapy seem to have a decreased risk of gastric cancer, and men who have been treated with oestrogen for prostate cancer have a decreased risk. Use of tamoxifen in women seems to increase their risk of gastric cancer. Animal studies indicate that oestrogen may offer protection against the development of this cancer as for example ovariectomised mice are at an increased risk, whilst administration of female sex hormones decreases the incidence of gastric cancer. Oestrogen may exert its effect by acting on oestrogen receptors (ERs). Both ERα, ERβ and the latest discovered ERβcx have been identified in gastric tissue. The biological means behind this is not yet clear but various mechanisms have been suggested. There are indications that oestrogen may lead to an increased expression of trefoil factor proteins, which protect mucous epithelia or inhibit the expression of c-erb-2 oncogene.

Section snippets

Occurrence

Gastric cancer has a high death rate (700,000 per year) making it the second most common cause of cancer death, after lung cancer.1 In the year 2000, almost 200,000 cases were diagnosed in Europe and more than 150,000 deaths occurred2 with a steady and persistent fall in mortality rates.3 The survival rate is better in Japan (52%)1 where endoscopic mass screening has been implemented since the 1960s, whilst the survival chance is about 25% in the Western World.1, 4 The incidence of gastric

Histology

As more than 90% of all gastric cancers are adenocarcinomas, the remainder being mainly non-Hodgkin’s lymphomas, or leiomyosarcomas,6 for the purpose of this review ‘gastric cancer’ refers to gastric adenocarcinoma. According to Laurén’s classification, there are two histological types of gastric adenocarcinoma: intestinal and diffuse.7

The intestinal type is characterised by the glandlike appearance of neoplastic cells, whilst in the diffuse type, as the name implies, the cells lack cohesion

Aetiology

The aetiology of gastric cancer is multifactorial (Fig. 1). H. Pylori infection is a well-established risk factor13, 14 and tobacco smoking is a moderate one.15 A diet rich in fruit and vegetables seems to offer protection16 in contrast to intake of salt, which seems to possibly increase the risk17 as obesity does in the risk of cardia gastric cancer.18, 19 A higher socioeconomic status has also been found to be associated with a reduced risk of gastric cancer, and that risk was stronger for

Hypothesis of oestrogen protection

There is a strong and enigmatic male dominance in the incidence of this cancer with a male-to-female ratio of about 2:1. This male predominance has been observed in different populations of the world, and cannot entirely be explained on the basis of sex differences in the prevalence of known risk factors.22 Therefore, endogenous factors that either provide protection in women alone or imply an increased risk only in men should play a role. A potentially protective effect of oestrogen against

Animal studies

Some animal studies suggest that hormonal factors may play a suppressive role in the development of gastric cancer. The carcinogenic N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) added to drinking water induced gastric cancer in male rats but not in female. In the same experiment, castrated or oestrogen-treated male rats had a lower incidence of gastric cancer compared to untreated male rats.25 Another study reported that the incidence of gastric cancer increased in castrated female rats.26

Human studies

A global pattern in the sex distribution, unique of gastric cancer, has given further support to the hypothesis of oestrogen protection. Sipponen and colleagues showed that women develop the intestinal type of gastric cancer 10–15 years later than men and that the incidence increases after menopause.30 This pattern was consistent in all the 18 cancer registries used in the study and in populations with high and low gastric cancer incidence. The hypothesis that oestrogen might prevent gastric

Biological mechanisms

The discovery of oestrogen receptors in gastric tissue in 1983 ignited an enormous interest in the possible implication of this finding for the treatment of gastric cancer.53 The potential role of involvement of hormonal factors was discussed and some suggested evaluation of hormonal therapy with oestrogen54 or anti-oestrogen.49, 50 It is proposed that the possible protective effect of oestrogen against gastric cancer is exerted through ERs. Two types of ERs are known: ER alpha (ERα)55, 56 and

Summary and future research

The male dominance in the incidence of gastric cancer can at least be partly explained by a protective effect of oestrogen in women. This is probably true for the intestinal type of gastric adenocarcinoma. A summary of the available studies seems to support this hypothesis, but more research is warranted before this can be established. Especially large series in which the two histological subtypes are distinguished need to be done. Another area of research would be to investigate whether

Conflict of interest statement

None declared.

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